APP203605 – Vayego - EPA NZ

SCIENCE MEMO

APP203605 – Vayego

SEPTEMBER/ 2019

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Science memo for application to import or manufacture Vayego for release (APP203605)

SEPTEMBER/ 2019

Executive Summary

The applicant Bayer New Zealand Limited has submitted an application on 18 April 2018 to import for

release Vayego into New Zealand for use as an insecticide in pome fruit, stone fruit, grapes and kiwifruit. It

was given application number APP203605 and was formally received on 7 June 2018 as a category C

application.

Vayego contains the active ingredient (ai) tetraniliprole at 200 g/L, plus other components.

Tetraniliprole is not currently approved in Australia, Canada, Europe, Japan or the USA. Tetraniliprole is

approved in South Korea.

Tetraniliprole is of relatively low acute toxicity in mammals only requiring 6.1E for acute inhalation toxicity. It

is not a skin or eye irritant but requires 6.5B classification for contact sensitisation. Tetraniliprole was found

not to be genotoxic or carcinogenic and does not cause reproductive or developmental toxicity. Tetraniliprole

also should not be classified for target organ toxicity (6.9B).

Tetraniliprole is very ecotoxic to aquatic organisms (9.1A) and highly toxic to terrestrial invertebrates (9.4A).

There are no proposed mammalian toxicity classifications for Vayego. For ecotoxicity the following

classifications are proposed: very toxic to aquatic organisms (9.1A) and very toxic to terrestrial invertebrates

(9.4A).

Tetraniliprole is considered highly persistent in the aquatic environment according to HSNO criteria. Based

on a weight of evidence approach, the substance is considered persistent in soil, however, because of the

potential high persistence in the field, the accumulation potential of the substance in the soil was still

evaluated.

It is considered that there is potential for significant exposure to people and the environment during the use

phase of the lifecycle of Vayego. As such, quantitative risk assessments have been undertaken to

understand the likely exposures to the substance under the use conditions proposed by the applicant, using

the endpoint data available and the standard risk assessment methodologies used by the EPA (EPA 2018).

It is considered that the risks to human health from the proposed use of Vayego are acceptable even in the

absence of appropriate PPE. There is no need for the application of REI or an additional buffer zone to

protect bystanders.

Overall, with the proposed controls, it is estimated that the risks to the environment resulting from the

application of Vayego following the proposed application pattern will be below the level of concern.

A set of controls have been proposed for Vayego, and are detailed under section 6.

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Table of Contents

APP203605 – Vayego ............................................................................................................................. 1

Executive Summary .............................................................................................................................. 2

Table of Contents .................................................................................................................................. 3

1. Introduction/Background ........................................................................................................... 7

2. Hazardous properties ................................................................................................................. 8

Hazard classification of tetraniliprole ............................................................................................. 8

Hazard classification of Vayego .................................................................................................... 8

Identification of components of concern (CMRs, vPBTs etc) ........................................................ 9

3. Risk assessment context ........................................................................................................... 9

4. Human health risk assessment.................................................................................................. 9

5. Environmental risk assessment .............................................................................................. 10

6. Proposed controls ..................................................................................................................... 12

Appendix A: Identity of the active ingredient, use pattern and mode of action ........................... 14

Identity of the active ingredient and metabolites ......................................................................... 14

Regulatory status ........................................................................................................................ 15

Impurities and or restrictions on purity or composition ................................................................ 15

Use pattern and mode of action .................................................................................................. 15

Use pattern ........................................................................................................................ 15

Mode of action ................................................................................................................... 15

Table 6: List of intended uses for Vayego......................................................................... 16

Appendix B: Physico-chemical properties of Vayego ..................................................................... 17

Appendix C: Mammalian toxicology .................................................................................................. 18

Executive summaries and list of endpoints for Vayego ............................................................... 18

Executive summaries and list of endpoints for tetraniliprole ....................................................... 19

General conclusion about mammalian toxicology of tetraniliprole .............................................. 26

Acute toxicity, irritation and sensitisation .......................................................................... 26

Mutagenicity ...................................................................................................................... 26

Carcinogenicity .................................................................................................................. 27

Reproductive and developmental toxicity ......................................................................... 28

Target organ toxicity .......................................................................................................... 28

Toxicokinetics and dermal absorption ............................................................................... 28

Appendix D: Environmental fate ........................................................................................................ 30

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Executive summaries and list of endpoints ................................................................................. 30

Residues relevant to the environment ......................................................................................... 30

Degradation and fate of tetraniliprole and its metabolites in aquatic environments.................... 32

Degradation and fate of tetraniliprole and its metabolites in soil................................................. 33

General conclusion about environmental fate ............................................................................. 35

Appendix E: Ecotoxicity ..................................................................................................................... 36

Executive summaries and list of endpoints ................................................................................. 36

Aquatic toxicity ............................................................................................................................ 36

Metabolites ........................................................................................................................ 41

Uncertainties and data gaps ............................................................................................. 42

General conclusion about aquatic toxicity......................................................................... 42

Soil toxicity................................................................................................................................... 43

Metabolites ........................................................................................................................ 45


General conclusion about soil toxicity ............................................................................... 46

Terrestrial vertebrate toxicity ....................................................................................................... 47

Summary of toxicity of tetraniliprole, its metabolites and Vayego to birds ........................ 48

Acute and short-term dietary toxicity ................................................................................. 48

Sub-chronic and reproduction toxicity ............................................................................... 48

General conclusion about ecotoxicity to terrestrial vertebrates ........................................ 48

Ecotoxicity to pollinators and other terrestrial invertebrates ....................................................... 49

Pollinators ......................................................................................................................... 49


Non-target arthropods ....................................................................................................... 54

General conclusion in relation to classification for terrestrial invertebrate toxicity 58

Appendix F: Hazard classification of Vayego and tetraniliprole .................................................... 59

Appendix G: Human health risk assessment ................................................................................... 65

Quantitative risk assessment ...................................................................................................... 65

Input values for the human health risk assessment .......................................................... 65

Operator exposure assessment ........................................................................................ 66

Re-entry worker exposure assessment ............................................................................ 67

Quantitative bystander risk assessment ........................................................................... 68

Conclusions of the human health risk assessment ........................................................... 68

Appendix H: Environmental risk assessment .................................................................................. 69

Aquatic risk assessment .............................................................................................................. 69

Calculation of expected environmental concentrations .................................................... 69

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Output from the GENEEC2 model .................................................................................... 70

Calculated risk quotients ................................................................................................... 70

Refinement of the aquatic risk assessment ...................................................................... 72

Conclusions of the aquatic risk assessment ..................................................................... 73

Groundwater risk assessment ..................................................................................................... 75

Conclusions of the groundwater risk assessment ............................................................ 75

Sediment risk assessment .......................................................................................................... 76

Conclusions of the sediment risk assessment .................................................................. 76

Terrestrial risk assessment ......................................................................................................... 77

Soil macro-organisms ....................................................................................................... 77

Soil accumulation potential ............................................................................................... 78

Soil microorganisms .......................................................................................................... 78

Conclusions of the soil organism risk assessment ........................................................... 78

Non-target plant risk assessment ................................................................................................ 80

Conclusion for non-target plant risk assessment .............................................................. 80

Bird risk assessment ................................................................................................................... 81

Screening assessment ...................................................................................................... 81

Calculation of TERs .......................................................................................................... 81

Conclusions of the bird screening risk assessment .......................................................... 82

Secondary poisoning ......................................................................................................... 82

Conclusions for bird risk assessment ............................................................................... 82

Pollinator risk assessment ........................................................................................................... 83

Tier I pollinator risk assessment ....................................................................................... 83

Tier II pollinator risk assessment ...................................................................................... 83

Tier III pollinator risk assessment ..................................................................................... 86

Conclusions of the pollinator risk assessment .................................................................. 87

Non-target arthropod risk assessment ........................................................................................ 87

Tier I non-target arthropod risk assessment ..................................................................... 87

Tier II non-target arthropod risk assessment .................................................................... 89

Tier III non-target arthropod risk assessment ................................................................... 90

Conclusions of the ecological risk assessment ........................................................................... 98

Appendix I: Proposed controls ........................................................................................................ 101

Exposure thresholds .................................................................................................................. 101

Impurity limits............................................................................................................................. 101

Other toxicity controls ................................................................................................................ 102

Application restrictions .................................................................................................... 102

Appendix J: Study summaries ......................................................................................................... 104

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Mammalian toxicity .................................................................................................................... 104

Tetraniliprole ................................................................................................................... 104

Vayego ............................................................................................................................ 188

Tetraniliprole metabolites BCS-CR74541 ....................................................................... 197

Environmental fate .................................................................................................................... 198

Residues .................................................................................................................................... 281

Ecotoxicity ................................................................................................................................. 287

Tetraniliprole ................................................................................................................... 287

Vayego ............................................................................................................................ 389

Tetraniliprole metabolites ................................................................................................ 481

Appendix K: Standard terms and abbreviations ............................................................................ 535

Appendix L: References ................................................................................................................... 540

Appendix M: Confidential Composition .......................................................................................... 541

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1. Introduction/Background

1.1. This application is to import for release Vayego into New Zealand for use as an insecticide in pome

fruit, stone fruit, grapes and kiwifruit.

1.2. Vayego is intended to be used for ground-based applications only.

1.3. Vayego contains the active ingredient tetraniliprole at 200 g/L, plus other components.

1.4. Tetraniliprole has not previously been approved in New Zealand. It has been approved in South

Korea but not in other jurisdictions.

1.5. More details about the use pattern of Vayego and the regulatory status of tetraniliprole can be found

in Appendix A.

1.6. It is considered that there is potential for significant exposure to people and the environment during

the use phase of the lifecycle of Vayego. As such, quantitative risk assessments have been

undertaken to understand the likely exposures to the substance under the use conditions proposed

by the applicant, using the endpoint data available and the standard risk assessment methodologies

used by the EPA. Full context related to the risk assessment of Vayego is given in section 3.

1.7. The applicant has submitted to the EPA a number of studies that have been summarized and

reviewed by the EPA.

1.8. Unless otherwise stated, all endpoint data summarised were fully compliant with the relevant

international test methods. The original study reports have been provided and summarised in

Appendix J.

1.9. Physical and chemical properties of Vayego can be found in Appendix B.

1.10. Mammalian toxicological properties Vayego and tetraniliprole have been reported in Appendix C.

1.11. Environmental Fate properties of tetraniliprole have been reported in Appendix D.

1.12. Ecotoxicological properties of Vayego and tetraniliprole have been reported in Appendix E.

1.13. Hazard properties and classification determination of tetraniliprole and Vayego derived from their

properties can be found in Appendix F

1.14. Mammalian toxicological data have subsequently been used to generate human health risk

assessment and this is detailed in Appendix G.

1.15. Environmental fate, ecotoxicological and other relevant data have subsequently been used to

generate environmental risk assessment and this is detailed in Appendix H.

1.16. Relevant study summaries can be found in Appendix J.

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2. Hazardous properties

Hazard classification of tetraniliprole

2.1. The hazard classifications proposed for tetraniliprole are outlined in Table 1. Full details are provided

in Table 35

Table 1: Proposed classification for tetraniliprole

Hazard endpoint Classification

Acute toxicity (inhalation) 6.1E

Contact sensitisation 6.5B

Aquatic ecotoxicity 9.1A

Terrestrial invertebrate toxicity 9.4A

2.2. Tetraniliprole is of relatively low acute toxicity in mammals only requiring 6.1E for acute inhalation

toxicity. It is not a skin or eye irritant but requires 6.5B classification for contact sensitisation.

Tetraniliprole was found not to be genotoxic or carcinogenic and does not cause reproductive or

developmental toxicity. Tetraniliprole also should not be classified for target organ toxicity (6.9B).

2.3. Tetraniliprole is very ecotoxic to aquatic organisms (9.1A) and highly toxic to terrestrial invertebrates

(9.4A).

Hazard classification of Vayego

2.4. Mammalian toxicity studies conducted on Vayego indicate that the substance is of low overall toxicity

and does not trigger any classifications (Table 2). The hazard classifications of Vayego were

determined based on the information provided by the applicant (including toxicity and ecotoxicity

studies). Ecotoxicity studies conducted on Vayego indicate that the substance is very ecotoxic to

aquatic organisms (9.1A) and highly toxic to terrestrial invertebrates (9.4A).

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2.5. Table 36 in Appendix F shows the method used for classification and indicates the main component

that contributes to each hazard classification).

Table 2: Hazard classification of Vayego

Hazard EPA classification

Aquatic ecotoxicity 9.1A

Terrestrial invertebrate ecotoxicity 9.4A

Identification of components of concern (CMRs, vPBTs etc)

2.6. None identified.

3. Risk assessment context

3.1. It is considered that there is potential for significant exposure to people and the environment during

the use phase of the lifecycle of Vayego. As such, quantitative risk assessments have been

undertaken to understand the likely exposures to the substance under the use conditions proposed

by the applicant, using the endpoint data available and the standard risk assessment methodologies

used by the EPA (EPA 2018).

3.2. During the importation, manufacture, transportation, storage and disposal of this substance, it is

estimated that the proposed controls and other legislative requirements will sufficiently mitigate risks

to a negligible level. This assessment takes into account the existing HSNO requirements around

packaging, identification and disposal of hazardous substances. In addition, the Land Transport Rule

45001, Civil Aviation Act 1990, Maritime Transport Act 1994 and New Zealand’s Health and Safety

at Work (HSW) requirements all have provisions for the safe management of hazardous substances.

4. Human health risk assessment

4.1. To assess the risks posed by the substance to human health, the estimated exposure to the active

ingredient for each application scenario was compared to an Acceptable Operator Exposure Limit

(AOEL) value for that active ingredient and a risk quotient (RQ) is calculated.

4.2. RQ values greater than one (RQ>1) indicate that exposure to the substance could result in

significant adverse effects and are above the Level Of Concern (LOC), and that risk mitigating

controls such as Personal Protective Equipment (PPE) should be considered. RQ values less than

one (RQ<1) indicate that predicted exposure to the substance is less than the AOEL and such

exposure is not expected to result in adverse effects.

4.3. The risks from the use of tetraniliprole on users, operators of the substance, re-entry workers and

bystanders are considered as a proxy for Vayego. Full details can be found in Appendix G.

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4.4. Operator Exposure:

Predicted operator exposures to tetraniliprole are below the AOEL for each use pattern, even without

the use of PPE. Therefore, operator exposures are not expected to result in adverse health effects.

4.5. Worker Re-Entry:

Predicted exposures to tetraniliprole for workers re-entering and working in areas where Vayego has

been applied are below the AOEL even without gloves. No re-entry intervals or use of gloves are

necessary.

4.6. Bystanders:

Estimated bystander exposure from spray drift after application of Vayego to the soil around mature

pome and stone fruit, and kiwifruit and grape vines is below the AOEL. No buffer zone is required to

protect bystanders.

4.7. Impurities:

There are no impurities of toxicological concern.

4.8. Overall human health conclusion:

It is considered that the risks to human health from the proposed use of Vayego are acceptable even

in the absence of appropriate PPE. There is no need for the application of REI or an additional buffer

zone to protect bystanders.

5. Environmental risk assessment

5.1. The risks to a range of environmental receptors from the use of tetraniliprole are considered as a

proxy for the risks from Vayego. Full details can be found in Appendix H.

5.2. Aquatic environment:

EECs of tetraniliprole applied as the formulated product Vayego resulted in calculated RQ above the

LOC for the aquatic environment (threatened crustaceans and insects). To mitigate these risks, it is

proposed to apply controls to reduce spray-drift and runoff into the aquatic environment.

5.3. Groundwater:

For tetraniliprole, the risks for groundwater contamination are below the level that might trigger

concern (0.1 µg/L).

5.4. Sediment:

The RQ of tetraniliprole is above the LOC (LOC ≥1). However, it is considered that the controls

proposed to protect the aquatic environment also protect the sediment-dwelling organisms and

reduce the risks to a negligible level.

5.5. Soil organisms:

Predicted acute exposures to soil organisms of tetraniliprole are below the LOC for an earthworm.

No chronic data of the active ingredient are provided. However, chronic data with the substance for

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earthworm and soil mite are provided. The results of the risk assessment indicate a risk below the

LOC. Furthermore, the potential for soil accumulation following three applications per year (worst-

case scenario) of Vayego was evaluated (over a 20 year period) and no risks to soil organisms were

identified.

5.6. Non-target Plants:

Predicted non-target plant exposures to tetraniliprole, when applied to fruit crops and grapes as the

formulated product Vayego, are below the LOC for both threatened and not threatened species.

5.7. Birds:

The screening risk assessment indicates a risk below the LOC to birds from the use of Vayego

according to the provided GAP table. Tetraniliprole is not bioaccumulative so no risk assessment for

secondary poisoning is necessary for this active ingredient.

5.8. Pollinators:

The Tier I assessment indicates a risk above the LOC. In Tier II, residue information was available to

refine the risk assessment for pome and stone fruit, the risks were determined to be below the LOC.

The risks to grapes were also considered below the LOC as grapes are generally not attractive to

bees and thus exposure is likely limited. No information on the residues in kiwifruit was available,

however, considering the maximum residues found and the minimum residue level required to trigger

an effect, these risks are also considered to be below the LOC.

5.9. Non-target Arthropods:

In-field risks:

Parasitic wasps:

Tier I and Tier II of the risk assessment indicates that the in-field risks and off-field risk to the

Parasitic wasp (Aphidius rhopalosiphi) is above the level of concern for all use patterns. Evaluation

of higher Tier information (semi-field studies) indicated that risks from a single application are likely

to be limited. For two applications (stone-fruit) sufficient information was available for Aphelinus mali

for which the effects seemed slightly more pronounced compared to one application (harmless to

slightly harmful after 14 days instead of harmless). For 3 applications, insufficient data are available

to refine the risks which were identified as being above the level of concern at Tier I and II.

Other Non-Target Arthropods:

For the Predatory mite (Typhlodromus pyri), Green lacewing (Chrysoperla carnea) and Ladybird,

(Coccinella septempunctata), risks were determined to be below the level of concern when Vayego

is applied as a single application (kiwifruit) and applied twice (stone-fruit). The potential risk identified

in-field for three applications of Vayego (pome-fruit) are (partially) due to the test design. Higher Tier

information was provided to refine the risk, however, for 3 applications (pome-fruit), insufficient data

are available to refine the risks above the level of concern identified in Tier I and II.

To inform end-users that effect on non-target arthropods (including those used in IPM) cannot be

excluded the following statement is advised:

“WARNING” the substance might not be not compatible with Integrated Pest Management (IPM)

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when applied three times.

Off-field risks:

It concluded that no downwind buffer zones are required for a single application to kiwifruit and

grapes, minor effects cannot be fully excluded but are considered acceptable. The downwind buffer

zone required to mitigate the effects from two applications on stone-fruit is 20 meters, and for three

applications on pome-fruit is 30 meters. These downwind buffer zones considered not to be

practical. If the downwind buffer zones are not applied it is likely that potentially impacted, and not

recovered populations can be impacted at consecutive populations which might have a “knock-on”

effect and potentially the local population cannot recover within a reasonable time-frame. To

minimise effects to non-target arthropods (off-field) the following label statement is advised:

“The best available application technique, which minimises off-target drift should be used to reduce

effects on non-target insects or other arthropods.”

Overall Ecological risk assessment conclusion:



6. Proposed controls

6.1. More details about proposed controls are available in Appendix I.

Exposure thresholds

6.2. The EPA may provide Acceptable Daily Exposure (ADE) and Potential Daily Exposure (PDE) values

for new active ingredients that may become present in food, drinking water or other environmental

media. This is to allow the EPA or other government departments to set standards or guideline

values for food, drinking water or other media where necessary. For example, the Ministry for

Primary Industries (MPI) can use these values to set Maximum Residue Levels (MRLs) in food.

6.3. The following values are proposed for tetraniliprole:

ADE: 0.88 mg/kg bw/day

PDE(Food): 0.62 mg/kg bw/day

PDE(Drinking Water): = 0.18 mg/kg bw/day

PDE(Other): 0.09 mg/kg bw/day

ARfD: Not required

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Application rate

6.4. Pome fruit maximum 3 applications of 60 g ai/ha.

6.5. Stone fruit maximum 2 applications of 60 g ai/ha

6.6. Kiwifruit and grapes maximum 1 application of 60 g ai/ha.

Application method

6.7. Vayego must not be applied when wind speeds are less than 3 km/hr or more than 20 km/hr as

measured at the application site.

6.8. Vayego can only be applied by ground-based methods.

Buffer zones

6.9. Buffer zones are proposed for Vayego as per the information in Table 3.

Table 3: Proposed buffer zones for Vayego

Application method Sensitive area Required buffer

zone (m)

Ground-based

Pome fruit

Waterbody 25

Waterbody

(downwind) 200

Ground-based

Stone fruit

Waterbody 20

Waterbody

(downwind) 140

Ground-based

Kiwifruit and grapes

Waterbody 20

Waterbody

(downwind) 5

Additional label statements

6.10. To inform end-users that effect on non-target arthropods (including those used in IPM) cannot be




6.11. To minimise effects to non-target arthropods (off-field) the following label statement is advised:



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Appendix A: Identity of the active ingredient, use pattern and mode of action

Identity of the active ingredient and metabolites

As this is the first full application under Part 5 of the Hazardous Substances and New Organisms (HSNO)

Act 1996 considered for tetraniliprole, general data on the identification of the active ingredient derived from

“Schneider K. and Hines, D. (2016). Tetraniliprole: Product Chemistry Evaluation – Identity, Physical and

Chemical Properties, Analytical Methods; (M-579566-01-1)” are provided in Table 4.

Table 4: Identification of tetraniliprole

IUPAC name

1-(3-chloropyridin-2-yl)-N-[4-cyano-2-methyl-6- (methylcarbamoyl) phenyl]-3-{[5-

(trifluoromethyl)-2H-tetrazol-2-

yl]methyl}-1H-pyrazole-5- carboxamide (PIN)

CAS name

1H-pyrazole-5-carboxamide, 1-(3-chloro-2-pyridinyl)-N-[4-cyano-2-

methyl- 6-[(methylamino)carbonyl]phenyl]-3-[[5-(trifluoromethyl)-

2H-tetrazol-2- yl]methyl]-

Molecular formula C22H16ClF3N10O2

CAS Number 1229654-66-3

Molecular weight 544.88 g/mol

Structural formula

Purity 900 g/kg

Significant

impurities/additives

(% concentration)

None identified

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Other international

classification &

labelling

Approved in South Korea

Regulatory status

The regulatory history of tetraniliprole is summarised in Table 5 below.

Table 5: Active ingredient regulatory status

Active ingredient name Regulatory history in

New Zealand

International regulatory history

(Australia, Canada, Europe, Japan, USA)

Tetraniliprole New to New Zealand Not currently approved in Australia, Canada,

Europe, Japan, USA

Approved in South Korea

Tetraniliprole is not currently approved in Australia, Canada, Europe, Japan or the USA. Tetraniliprole is

approved in South Korea.

Impurities and or restrictions on purity or composition

No impurity limits for tetraniliprole have been identified

Use pattern and mode of action

Use pattern

The applicant seeks approval for the use of Vayego as an insecticide for the control of a range of pests in

stone fruit, pome fruit, grapes and kiwifruit.

Vayego is a suspension concentrate which is diluted in water. The applicant seeks to have the substance

approved for ground-based application only.

Application will be at the rate of 300 ml of product per hectare (0.3 L/ha) which is equivalent to 0.06 kg ai/ha,

with a maximum frequency of 3 applications per year a minimum of 14 days apart. More details on the

intended uses for Vayego are given in Table 6.

Mode of action

Tetraniliprole belongs to the diamide ryanodine receptor modulator mode of action (IRAC Group 28).

Chlorantraniliprole, cyantraniliprole, cyclaniliprole and flubendiamide also belong to that group

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Table 6: List of intended uses for Vayego

Crop and/or

situation (a)

Use

pattern

(b)

Pests or

group of

pests

controlled (c)

Mixture Application Application rate per treatment

Remarks (l) Type (d-f)

Conc of

ai (g)

Method

and kind

(h-i)

Growth

stage &

season (j)

Number

Min max

(k)

Interval

between

applications –

days

(minimum)

kg ai/hL

min max

water L/ha

min max

kg ai/ha

max

Pome fruit F

Coddling

moth,

leafrollers, etc.

SC 200 broadcast

Biofix, mid-

Dec, 14

days

before

harvest

1-3 21 days 0.003-

0.006

1000-

2000 0.06

Post-bloom,

first

application

after petal

fall

Grapes F leafrollers etc. SC 200 broadcast 80% capfall 1 NA 0.012-

0.024 250-500 0.06 Post-bloom

Kiwifruit F leafrollers etc. SC 200 broadcast Pre-bloom 1 NA 0.003-

0.006

1000-

2000 0.06 Pre-bloom

Stone fruit F leafrollers etc. SC 200 broadcast Petal fall 1-2 14 days 0.003-

0.006

1000-

2000 0.06 Post-bloom

a Where relevant, the use situation should be described (eg fumigation of soil) b Outdoor or field use (F), glasshouse application (G) or indoor application (I). c eg biting and sucking insects, soil-borne insects, foliar fungi, weeds d eg wettable powder (WP), emulsifiable concentrate (EC), granule (GR) e CropLife international, 2008. Technical Monograph no 2, 6th edition. Catalogue of pesticide formulation types and international coding system f All abbreviations used must be explained g g/kg or g/l or others h Method, eg high volume spraying, low volume spraying, spreading, dusting, drench, aerial, etc i Kind, eg overall, broadcast, aerial spraying, row, individual plant, between the plant - type of equipment used must be indicated. If spraying include droplet size spectrum j growth stage at last treatment (BBCH Monograph, Growth Stages of Plants, 1997, Blackwell (ISBN 3-8263-3152-4), including where relevant, information on season at time of application k Indicate the minimum and maximum number of application possible under practical conditions of use l Remarks may include: Extent of use/economic importance/restrictions

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Appendix B: Physico-chemical properties of Vayego

The physicochemical properties of Vayego are listed in Table 7.

Table 7: Physical and chemical properties of Vayego

Property Value Reference

Colour Light beige Schneider, K. and Hines, D. (2017) Tetraniliprole

SC 200 - Product Chemistry Evaluation - Identity,

Physical and Chemical Properties, Analytical

Methods, Confidential Information; Document

Reference: M-579310-02-1

Physical state Aqueous liquid suspension

Odour Musty

Explosive properties None identified

Oxidising/reducing

properties None identified

Flash point >100 oC

pH 4.3 (undiluted)

4.8 (1% in de-ionised water)

Kinematic viscosity

250 mm2/s at 20°C/20 s-1

85 mm2/s at 20°C/100 s-1

215 mm2/s at 40°C/20 s-1

71 mm2/s at 40°C/100 s-1

Relative density D4

20 = 1.115

D440 = 1.095

Size distribution of

Particles

90 % 2.76 m

50 % 0.96 m

10 % 0.45 m

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Appendix C: Mammalian toxicology

Unless otherwise noted, all studies were conducted according to Good Laboratory Practice (GLP) and were

fully compliant with the requirements of the international test guidelines followed.

Executive summaries and list of endpoints for Vayego

The mammalian toxicology data for Vayego are summarised in Table 8.

Table 8: Summary of mammalian toxicology data for Vayego (LD50: Lethal Dose that causes 50%

mortality, LC50: Lethal Concentration that causes 50% mortality)

Endpoint

(Test Guideline)

Klimisch

score Result

HSNO

Classification Reference

Acute oral toxicity

(OECD TG 425; OPPTS

870.1100; EC No.

440/2008, B.1)

1 LD50 >2000 mg/kg bw No

14/095-001P ;

Table 100 ;

Appendix J

Acute dermal toxicity

(OECD TG 402; OPPTS

870.1200; EC No.

440/2008, B.3)


14/095-002P ;

Table 101 ;

Appendix J

Acute inhalation toxicity

(OECD TG 403; OPPTS

870.1300; EC No.

440/2008, B.2)

1 LC50 >4.49 mg/L No

14/095-004P ;

Table 102 ;

Appendix J

Skin irritation/corrosion

(OECD TG 404; OPPTS

870.2500; EC No.

440/2008, B.4)

1

Non-irritating

Mean score - Erythema: 0.0

Oedema: 0.0

No

14/095-006N ;

Table 103 ;

Appendix J

Eye irritation/corrosion

(OECD TG 405; OPPTS

870.2400; EC No.

440/2008, B.5)

1

Non-irritating

Mean Draize Score -

Cornea

-Opacity: 0.0

Conjunctiva

-Redness: 0.0

-Chemosis: 0.0

Iris: 0.0

No

14/095-005N ;

Table 104 ;

Appendix J

Contact sensitisation 1

Non-sensitiser; (SI <3);

Stimulation Index (SI) values

were 0.6, 1.0 and 0.6 at conc.

No

14/095-037E ;

Table 105 ;

Appendix J

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SEPTEMBER/ 2019

Endpoint

(Test Guideline)

Klimisch

score Result

HSNO


(OECD TG 429; OPPTS

870.2600; EC No.

440/2008, B.42)

of 100% (undiluted), 50 and

25% (w/v)

Executive summaries and list of endpoints for tetraniliprole

All data for tetraniliprole, its metabolites and impurities were supplied by the applicant.

Acute toxicity, skin and eye irritation, contact sensitisation and genotoxicity data for tetraniliprole are

summarised in Table 9.

Table 9: Summary of acute toxicity, irritation, sensitisation and genotoxicity data for tetraniliprole

Endpoint

(Test Guideline)

Klimisch

score Result

HSNO


Acute oral toxicity

(OECD TG 423; OPPTS

870.1100; EC No.

440/2008, B.1)


14/218-001P ; Table

70

13/040-001P ; Table 71

; Appendix J

Acute dermal toxicity

(OECD TG 402; OPPTS

870.1200; EC No.

440/2008, B.3

1 LD50 >2000 mg/kg bw No 13/040-002P ; Table 72

Acute inhalation toxicity

(OECD TG 403; OPPTS

870.1300; EC No.

440/2008, B.2)

1 LC50 >5.01 mg/L 6.1E 13/040-004P ; Table 73

Skin irritation/corrosion

(OECD TG 404; OPPTS

870.2500; EC No.

440/2008, B.4)

1

Non-irritating

Mean score - Erythema: 0.2

Oedema: 0.0

No 13/040-006N ; Table 74

Eye irritation/corrosion

(OECD TG 405; OPPTS

870.2400; EC No.

440/2008, B.5)

1

Non-irritating

Mean Draize Score -

Cornea

Opacity: 0.0

Conjunctiva

Redness: 0.44 Chemosis:

0.11

Iris: 0.0

No 13/040-005N ; Table 75

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SEPTEMBER/ 2019

Endpoint

(Test Guideline)

Klimisch

score Result

HSNO


Contact sensitisation

(OECD TG 429; EC No.

440/2008, B.42)

1

Sensitiser (SI >3); SI values

were 7.1, 5.8 and 3.5 at

concentrations of 50, 25 and

10 % (w/v), respectively.

Based on these data, the

calculated EC3 value is 8.2%

w/v

6.5B 16/223-037E ; Table 76

; Appendix J

Mutagenicity: In Vitro

(OECD TG 471; OPPTS

870.5100; EC No.

440/2008, B.13/B.14)

1 Negative (±S9)

No

1548501 ; Table 78 ;

Appendix J

Mutagenicity: In Vitro

(OECD TG 473; OPPTS

870.5375; EC No.

440/2008, B.10)

1 Negative (±S9)

1548502 ; Table 78 ;

Appendix J

Mutagenicity: In Vivo

(OECD TG 474; OPPTS

870.5395; EC No.

440/2008, B.12)

1 Negative TXFVP066 ; Table 79 ;

Appendix J

Results of the repeated dose toxicity studies with tetraniliprole are summarised in Table 10.

Table 10: Summary of repeated dose studies with tetraniliprole (NOAEL: No Observed Adverse

Effects, LOAEL: Lowest Observable Adverse Effect Level)

Study type NOAEL (mg/kg

bw/day)

LOAEL (mg/kg

bw/day Key effect Reference

90-day oral toxicity: rats

10000 ppm (M: 608

mg/kg bw/day; F:

723 mg/kg bw/day);

highest dose tested

NA

No adverse effects

were noted at the

highest dose

SA 10431; Table 87

90-day oral toxicity:

mice

6000 ppm (M: 973

mg/kg bw/day; F:

1224 mg/kg bw/day)

NA

No adverse effects

were noted at the

highest dose

SA 10431; Table 88

90-day oral toxicity: dog

NOAEL: 3200 ppm

(M: 126 mg/kg

bw/day and F: 138

mg/kg bw/day)

LOAEL: 12800 ppm

(M: 440 mg/kg

bw/day; F: 485

mg/kg bw/day

SA 13013; Table 89

1-year oral toxicity:

dogs

2900 ppm (M: 91.2

mg/kg bw/day and

12800 ppm (M: 440

mg/kg bw/day; F:

408 mg/kg bw/day

Decreased bw effects

and increased SA 13268; Table 90

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SEPTEMBER/ 2019


bw/day)

LOAEL (mg/kg


F: 88.4 mg/kg

bw/day)

alkaline phosphatase

activity

18-month dietary

chronic

toxicity/carcinogenicity

study: mice

6500 ppm (M: 825

mg/kg bw/day and

F: 1073 mg/kg)

No toxicity was

observed at the

highest dose

administered

No adverse effects or

tumours were noted

at the highest dose

SA 12225 ; Table

80

2-year chronic

toxicity/carcinogenicity:

rat

4000 ppm (M: 159

mg/kg bw/day and

F: 221 mg/kg

bw/day

LOAEL: 18000 ppm

(M: 741mg/kg

bw/day and F: 1052

mg/kg bw/day

Increased mortality,

decreased bw, and

uterine changes

(cervix: hyperplasia

and endometrium:

metaplasia)

SA 12199; Table 81

Developmental toxicity:

rats

1000 mg/kg bw/day

for both maternal

and foetal effects

No toxicity was

observed at the

highest dose

administered

No toxicity was

observed at the

highest dose

administered

SA 12221; Table 83

Developmental toxicity:

rabbits

1000 mg/kg bw/day

for both maternal

and foetal effects

No toxicity was

observed at the

highest dose

administered

No toxicity was

observed at the

highest dose

administered

SA 12223; Table 84

2-generation

reproductive toxicity:

rats

Parental Toxicity

2700 ppm (equiv. to

the mean achieved

dose before pairing:

196 mg/kg bw/day

for F0 males;

24mg/kg bw/day for

F0 females; 253

mg/kg bw/day for

F1 males; 266

mg/kg bw/day for

F1 females; 307

mg/kg bw/day for

F2 males; 312

mg/kg bw/day for

F2 females).

Foetal: 12000 ppm

(equiv. to the mean

achieved dose

before pairing: 896

mg/kg bw/day for

F0 males; 1032

mg/kg bw/day for

F0 females; 1138

Parental: 12000

ppm (equiv. to the

mean achieved

dose before pairing:

896 mg/kg bw/day

for F0 males; 1032

mg/kg bw/day for

F0 females; 1138

mg/kg bw/day for

F1 males; 1218

mg/kg bw/day for

F1 females; 1361

mg/kg bw/day for

F2 males; 1392

mg/kg bw/day for

F2 females)

Foetal: No toxicity

was observed at the

highest dose

administered

Decreased body

weight (bw) and food

consumption

parameters

TXFVP044; Table

85

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bw/day)

LOAEL (mg/kg


mg/kg bw/day for

F1 males; 1218

mg/kg bw/day for

F1 females; 1361

mg/kg bw/day for

F2 males; 1392

mg/kg bw/day for

F2 females)

Toxicokinetics and dermal absorption studies with tetraniliprole are summarised in Table 11.

Table 11: Summary of toxicokinetics and dermal absorption studies with tetraniliprole

Study type Results

Study 1 (Table 91 ;

Appendix J):

Toxicokinetic (Whole-

body distribution and

pilot metabolism study

Distribution)

Radiolabelled (pyrazole-carboxamide-14C)-active was administered by gavage (5 mg/kg) to

assess absorption from the GI-tract, distribution to and elimination from blood, organs and

tissues were analysed qualitatively and quantitatively by whole-body

autoradioluminography in one rat of each sex (at 1, 4, 8, 24, 48, 72, 120, and 168 hours

after administration). The amounts of radioactivity in excreta (urine and faeces) and

exhaled carbon dioxide were additionally determined (4 males) at 1, 4, 8, and 24 hours

after administration.

The test compound related radioactivity was cleared from blood very fast (<48 hr) and

distributed to the entire body preferentially towards those organs or tissues that are

responsible for metabolism (liver) and excretion (kidney), some glandular organs (eg

adrenal gland, pancreas), brown fat and ovary and uterus in females. In male rats,

maximum Total Radioactive Residue (TRR)-values were reached in all organs and tissues

1-4 hours after administration, while in females it was 1-8. The tissue/blood-concentration

ratios at tmax were highest for liver (factor ~10) and adrenal gland (factor ~4.5) in both sexes.

At the end of the test on Day 7, no residual radioactivity was measured in nearly all organs

and tissues in either sex except in the liver and kidney, where only trace amounts (˂1.0%)

of radioactivity was detected.

One day after administration, more than 95% of the given dose had been excreted and the

excretion was nearly completed after two days in males and three in females. The major

part of the given dose (more than 98% in males and 92% in females) was excreted with

faeces and the minor part (up to ~2%) with urine. The exhalation of 14C-carbon dioxide was

tested for over a period of 48 hours with only a negligible amount (< 0.01%) of the given

dose detected. This demonstrated that the 14C labelling in the pyrazole-carboxamide moiety

of the molecule was stable with regard to the formation of carbon dioxide.

Study 2 (Table 92 ;

Appendix J):

Toxicokinetics (ADME

and metabolite

identification)

Radiolabelled (pyrazole-carboxamide-14C)-active was administered by gavage (2 mg/kg) to

4/sex at 2, 20, and 200 mg/kg, 4 males at 2 mg/kg that were previously treated for 14 days

with active ingredient, and 3/sex after having their bile ducts cannulated to assess bile

excretion. Rats were sacrificed either 48 hrs (bile duct cannulated) or 72 hours after dosing

and the total radioactivity (parents and labelled metabolites) was determined in plasma

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samples, urine, faeces, organs and tissues. The metabolism was investigated in urines and

faecal extracts.

The absorption of test material started immediately after administration and the maximum

plasma concentration (Cmax) was reached within 1 hour (tmax) after the administration for all

low dose tests (including the test after 14 days of pre-treatment). At 20 mg/kg it was 1 hour

for males and 7 hours for females. However, only a minimal amount of absorption occurred

at 20 mg/kg, and at 200 mg/kg plasma concentrations were too low to calculate.

Female rats showed a higher absorption rate (Cmax) and total Area Under the Curve (AUC)

(~2X) compared to male rats for both administered doses (2 and 20 mg/kg).

Bile-duct cannulated animals (males and females) showed that about 35% of the recovered

dose was detected in the bile for males and 24% in the bile for females, indicating a

distribution via enterohepatic circulation.

Absorption rates were calculated by summation of the recovered radioactivity in urine, bile

and body without Gastrointestinal Tract (GIT), and amounted to 41.2% for males and

29.3% for females.

For all low dose tests, the plasma concentration declined to < 2% of the maximum

concentration within 72 hours post administration.

The calculated AUC0-∞ value of test material in the plasma for the 2 and 20 mg/kg animals

was ~2X lower in males compared to females (1.21 v. 2.36 and 0.06 v. 0.12, respectively).

In addition, the AUC0-∞ for low dose rats of both sexes at 2 mg/kg showed ~20X higher

concentration (eg, males 1.21/0.06) compared to high dose (20 mg/kg) rats that received

10X less, due to the restricted absorption of the test compound at higher dose levels.

Generally, in the low and high dose tests, the excretion was almost completed 72 hours

after administration as more than 99% of the recovered dose had been excreted via urine

and faeces. In all tests, the excretion was mainly faecal and ranged from 92 to 99% of the

recovered radioactivity. Rats with a cannulated bile duct showed approx. 35% for males

and 24% for females of the recovered dose in bile.

For all low dose tests (2 mg/kg) the urinal excretion rate ranged from 4.51% to 6.58 % of

the recovered dose. Negligible urinal excretion rates were measured for the high dose tests

at 20 and 200 mg/kg and ranged from 0.08% to 0.57% of the recovered dose. These low

urinal excretion rates also show that there is a significantly reduced absorption of BCS-

CL73507 at higher dose rates.

Generally, there were very low residues in organs and tissues in all test groups. Female

rats showed higher organ concentrations compared to male rats. The highest equivalent

concentrations were detected in the liver at all doses tested.

The majority of metabolites (about 89.59% to 108.29% of the administered dose) were

identified. Parent compound was the major compound in all tests and amounted between

51.32 - 66.42% of the dose for low dose tests and between 88.84 - 107.98% of dose for

high dose test (20 and 200 mg/kg respectively) for both sexes. Major metabolites were

BCS-CL73507-5-hydroxypyridine and the hydroxy-N-methyl moiety and ranged from 4 to

9% of the dose, respectively. In general, there were no different metabolites found for

males and females; and the quantity of the individual metabolites was not significantly sex-

related.

Study 3 (Table 93 ;

Appendix J):


Radiolabelled (pyridinyl-2-14C)-active was administered by gavage (2 mg/kg) to 4/sex at 2

mg/kg. Rats were sacrificed 72 hours after dosing and the total radioactivity (parents and

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and metabolite

identification)

labelled metabolites) was determined in plasma samples, urine, organs and tissues, and

faeces. The metabolism was investigated in urines and faecal extracts.


plasma concentration (Cmax) was reached within 1 hour (tmax) after the administration.

Female rats showed a higher absorption rate for plasma compared to male (Cmax of 0.108

versus 0.096 mg/L). The calculated AUC value for females was also approximately ~1.2x

higher than males (1.21 versus 1.04 mg/L*h).

The plasma concentration declined to < 4% of the maximum concentration within 72 hours

post administration with more than 99% of the recovered dose excreted via urine and

faeces. In all animals of both sexes, the excretion was mainly faecal (~97%) with minimal

amounts in the urine (~2.5%) for both sexes.

Generally, there were very low residues in organs and tissues. At sacrifice < 0.4% of the

administered dose (mean values) was found in the bodies excluding the GIT. The highest

equivalent concentrations of all tests were detected in the liver (0.0778 mg/kg for males and

0.0730 mg/kg for females).

For the investigation of the metabolism, urine and faeces were sampled at different time

points in the individual tests. There were no sex-specific metabolites detected. Slight

quantitative differences in the metabolites between males and female were observed within

the dose group. By trend, males showed more hydroxylation compared to females. Parent

compound was the major compound in all tests and amounted to 61.9% of dose for males

and 71.4% of dose for females.

Major metabolites were BCS-CL73507-5-hydroxypyridine and the hydroxy-N-methyl moiety

and ranged from 2.8 to 7.7% of the dose, respectively.

Study 4 (

Table 94 ; Appendix J):


and metabolite

identification)

Radiolabelled (phenyl-carbamoyl-14C)-active was administered by gavage (2 mg/kg) to

4/sex at 2 mg/kg. Rats were sacrificed 72 hours after dosing and the total radioactivity

(parents and labelled metabolites) was determined in plasma samples, urine, organs and

tissues, and faeces. The metabolism was investigated in urines and faecal extracts.




versus 0.144 mg/L). The calculated AUC value for females was approximately also ~1.8x


The plasma concentration declined to < 2% of the maximum concentration within 72 hours

post administration with more than 99% of the recovered dose excreted via urine and

faeces. In all animals of both sexes, the excretion was mainly faecal (~96%) with minimal

amounts in the urine (~4%) for both sexes.

Generally, there were very low residues in organs and tissues. Female rats showed higher

organ concentrations compared to male rats. At sacrifice < 0.4% of the administered dose

(mean values) was found in the bodies excluding the GIT. The highest equivalent

concentrations of all tests were detected in the liver and amounted to 0.0705 mg/kg for

males and 0.0923 mg/kg for females.



quantitative differences of the metabolites between males and female were observed within


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Major metabolites were BCS-CL73507-5-hydroxypyridine and the hydroxy-N-methyl moiety

and ranged from 3.6 to 7.3% of the dose, respectively.

Study 5 (Table 95 ;

Appendix J):


and metabolite

identification)

Radiolabelled (tetrazolyl-14C)-active was administered by gavage (2 mg/kg) to 4/sex at 2

mg/kg. Rats were sacrificed 72 hours after dosing and the total radioactivity (parents and

labelled metabolites) was determined in plasma samples, urine, organs and tissues, and

faeces. The metabolism was investigated in urines and faecal extracts.




versus 0.161 mg/L). The calculated AUC value for females was also approximately ~1.5x


The plasma concentration declined to < 2% of the maximum concentration within 72 hr post

administration with more than 99% of the recovered dose excreted via urine and faeces. In

all animals of both sexes, the excretion was mainly faecal (~94%) with minimal amounts in

the urine (~5.5%) for both sexes.

Generally, there were very low residues in organs and tissues. Female rats showed higher

organ concentrations compared to male rats. At sacrifice, < 0.3% of the administered dose

(mean values) was found in the bodies excluding the GIT. The highest equivalent

concentrations of all tests were detected in the liver and amounted to 0.0737 mg/kg for

males and 0.0672 mg/kg for females.



quantitative differences of the metabolites between males and female were observed within




Major metabolites were the hydroxy-N-methyl and dihydroxy moiety and ranged from 4.3 to

10.06% of the dose, respectively.

Dermal Absorption (In

vitro – rat and human

skin) ; Table 96 ;

Appendix J

Split-thickness human skin and rat skin membranes were mounted into flow-through

diffusion cells. Receptor fluid was pumped underneath the skin. The skin surface

temperature was maintained at 32°C ± 1°C throughout the experiment. A tritiated water

barrier integrity test was performed and any human skin sample exhibiting absorption

greater than 0.6% of the applied dose was excluded from subsequent absorption

measurements.

Absorption of [14C]-tetraniliprole was assessed by collecting receptor fluid in hourly fractions

from 0 to 8 h post dose, then 2 hourly fractions from 8 to 24 h post dose. At 24 h post dose,

the underside of the skin was rinsed with receptor fluid. The skin was removed from the

cells and dried with a tissue swab. The cell was dismantled and the donor chamber and

receptor chamber were retained separately for analysis. The stratum corneum was

removed by tape stripping and the skin divided into exposed and unexposed skin. Three

different concentration were assessed that represented essentially the absorption of neat

product (concentrated active: 200 g/L) and various “in-use” dilutions (0.3 and 0.01 g/L). The

percent absorption rate results for the various tests at 24 hours were:

Concentration Human Skin Rat Skin

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200 g/L 0.33 ± 0.32% 3.80 ± 2.26%

0.3 g/L 9.20 ± 5.0% 1.90 ± 2.33%

0.01 g/L 4.18 ± 2.24% 4.23 ± 2.28%

Dermal Absorption (In vivo – rat) ;

Table 97 ; Appendix J

The concentrated test item BCS CL73507 SC 200 and the diluted test items containing 14C-

BCS CL73507 were applied on the skin of clipped male rats (16 rats per group). Three

different groups were assessed that represented the absorption of neat product

(concentrated active: 200 g/L) and various “in-use” dilutions (0.3 and 0.01 g/L).

Radioactivity in blood, urine, faeces, tape strips, skin, washing of the application site

(including the protective device and gauze cover(s), remaining skin, cage wash and

carcass were measured at 8, 24, 72 and 96 hours after initial application. The percent

absorption rate results for the various tests were:

Absorbed Dose

Time of Experiment 8 h 24 h 72 h 96 h

200 g/L - 2.83 ± 1.29 0.54 ± 0.22

0.05 ± 0.10*

0.83 ± 0.32**

0.3 g/L - 4.50 ± 2.24 1.57 ± 0.91

0.24 ± 0.44*

3.27 ± 2.47**

0.01 g/L - 7.73 ± 1.83 6.05 ± 5.33

1.28 ± 2.56*

7.57 ± 4.24**

* OECD Guidance ** EFSA Guidance

General conclusion about mammalian toxicology of tetraniliprole

Acute toxicity, irritation and sensitisation

Tetraniliprole is of low acute toxicity by all exposure routes (oral, dermal, and inhalation) routes. Tetraniliprole

is not a skin or eye irritant and should not be classified for 6.3 or 6.4 hazards. Tetraniliprole was shown to

have contact sensitisation properties based on two positive Local Lymph Node Assay (LLNA) and should be

classified 6.5B.

The results of acute toxicity tests on Vayego by oral, dermal and inhalation routes indicate it is not

classifiable. In addition, results from studies on the formulation showed it was not a skin or eye irritant, and

that it was not likely to be a sensitiser (negative LLNA).

Mutagenicity

Tetraniliprole is not a mutagenic hazard.

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Carcinogenicity

In the rat two-year carcinogenicity study with tetraniliprole, a slight increase in uterine epithelial tumours was

observed at the high dose of 18000 ppm in females at the end of the 24-month treatment period, compared

to the control group. The incidence of each tumour type was slightly outside the in-house Historical Control

Data (HCD), but within the RITA (Registry of Individual Toxicology Animal data) control data. However,

based on clear treatment-related non-neoplastic findings in the uterus at 18000 ppm, where a higher

incidence and severity of diffuse squamous cell hyperplasia in the cervix (p≤0.01) and a higher incidence of

focal squamous cell metaplasia in the endometrium were observed when compared to controls, the increase

in uterine tumours was considered to be treatment-related. No uterine tumours were observed at either the

mid- (4000 ppm) or low-dose (900 ppm) and no pre-neoplastic changes were observed after 12-months of

treatment at any dose level tested. Therefore, the findings in the uterus were a late onset occurrence.

The high dose of 18000 ppm equated to an achieved intake of 1052 mg/kg bw/day over 24-months, which

exceeds the guideline-recommended limit dose of 1000 mg/kg bw/day, and based on a reduction of 15% in

final mean body weight and an overall 24% reduction of the mean cumulative body weight gain compared to

controls, this dose level is considered to have exceeded the Maximum Tolerated Dose (MTD). The

histopathological findings in the uterus, vagina and ovary in high-dose females are consistent with the

findings in the H295R steroidogenesis screening assay. In this in vitro assay, tetraniliprole and its main

mammalian metabolite BCS-CQ63359 were evaluated for effects on progesterone, testosterone, estradiol

and cortisol secretion using the H295R cell line, at concentrations which closely corresponded to plasma

concentrations in the rodent and dog long-term toxicity studies. A clear dose-related increase in estradiol

was observed for tetraniliprole and BCS-CQ63359; in contrast, only marginal changes not considered to be

biologically relevant were observed for progesterone and testosterone. Cortisol levels were also increased in

a dose-related manner for both tetraniliprole and BCS-CQ63359; however, in the absence of adverse

changes in the adrenal gland in any of the higher-tier repeat-dose studies in the rodent and dog, this finding

is of no known consequence. If the Mode Of Action (MOA) by which tetraniliprole causes a slight increase in

uterine tumours in the rat cancer bioassay is an estrogenic effect via steroidogenesis perturbation, this MOA

would be relevant to humans.

The in vivo biological significance of the results of this in vitro assay is questioned by the results of several

studies. In higher-tier in vivo estrogenicity testing, which included a uterotrophic/pubertal assay in immature

female rats to investigate estrogenic or anti-estrogenic activity, tetraniliprole had no effect on uterine weight

or vaginal opening in immature female rats at dose levels up to 800 mg/kg bw/day. In addition, no changes in

uterine or any female reproductive tissues were observed in repeat-dose rat studies following up to 12

months administration of tetraniliprole. In the rat two-generation reproduction study, no effect on reproductive

performance was observed up to the highest dose level of 12000 ppm (1032 mg/kg bw/day) in F0 adult

females (pre-mating). No changes in any female reproductive tissues were observed in repeat dose mouse

studies, including the 18-month carcinogenicity study or in the repeat-dose dog studies up to 1-year duration.

Thus, the slight increase in tumours following lifetime expose to rodents was restricted to one tumour type in

one sex in one species. In addition, the increase in uterine epithelial tumours only occurred at a dose level

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above a limit dose of 1000 mg/kg bw/day and which achieved or exceeded MTD criteria. The increased

incidence of each type of uterine epithelial tumour was only slightly above the concurrent control incidence

and in-house HCD, with no incidences at the mid- or low-dose group level and no tumours or preneoplastic

changes at any dose level at the 12-month interim sacrifice. Therefore, the increase in uterine tumours

observed in the rat are a high-dose phenomenon, occurring at a dose level above a guideline limit dose of

1000 mg/kg bw/day, at an MTD in aged females, where perturbation of the estrogen/progesterone balance in

the aged female could be a contributing factor. Based on the battery of in vitro and in vivo genotoxicity

studies conducted with tetraniliprole, none of which showed a genotoxic potential, a genotoxic mechanism

for the induction of the uterine tumours in the rat can be ruled out. A plausible MOA for the very low

incidence of uterine tumours, together with the non-neoplastic changes in the uterus, vagina and ovary,

observed in high-dose females on the 2-year rat carcinogenicity study, is through increased estrogenic

activity via steroidogenesis interference, which is an MOA relevant to humans. However, the tumours were

confined to a high dose in aged females. Therefore, it can be considered that tetraniliprole presents

negligible carcinogenic hazard potential.

Reproductive and developmental toxicity

No evidence of developmental and reproductive toxicity was observed in rats (developmental toxicity and

two-generation reproductive toxicity) and rabbits (developmental toxicity) in studies that exposed animals to

tetraniliprole at dietary levels that resulted in limit dose levels NOAEL >1000 mg/kg bw/day. These negative

results from in vivo studies negate the functional significance of the positive results noted in the in vitro

steroidogenesis assay that indicated both the active and the BCS-CQ63359 metabolite were capable of

inducing the synthesis of estrogen and cortisol in the H295R cell line. The functional significance of the

H295R in vitro assay is also diminished from the results of the in vivo immature rat uterotrophic assay which

showed no evidence of an estrogenic or anti-estrogenic potential of tetraniliprole. In total, the results from the

two in vivo studies indicate a negligible potential for reproductive toxicity.

Target organ toxicity

Results of several repeated exposure studies lasting from 28 days to lifetime exposure durations failed to

identify an organ specifically targeted by tetraniliprole. The lowest Lowest Observable Adverse Effect Level

(LOAEL) observed was greater than the 100 mg/kg bw/day minimum dose level required to trigger a 6.9

classification. The most common effects observed in these studies were non-specific in nature such as

decreased body weights or changes in clinical chemistries with no histological correlates. The clinical

chemistry changes in dogs (both 13- and 52-week studies) of increased platelet count and alkaline

phosphatase levels are consistent with an elevation in cortisol as noted in the H295R assay. The dog was

deemed the most sensitive species with a NOAEL of 2900 ppm (M: 91.2 mg/kg bw/day and F: 88.4 mg/kg

bw/day) following 52-weeks of exposure.

Toxicokinetics and dermal absorption

Five studies were performed to assess the biokinetic behaviour and metabolism of tetraniliprole in the rat

using tetraniliprole radiolabelled (14C) in 4 different positions on the molecule. Four studies assessed

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Absorption, Distribution, Metabolism and Excretion (ADME) and one study that described the distribution of

the radioactivity in male and female rats by quantitative whole-body autoradiography (QWBA). This latter

study also determined how much 14CO2 was exhaled. The results from all the studies were in good

agreement to each other and significant differences in the biokinetic and metabolic behaviour of tetraniliprole

were not observed.

The absorption from the GIT in rodents was fast (about 1 hour) for all low dose tests (2 mg/kg bw). In high

dose tests with 20 and 200 mg/kg bw, a restricted absorption behaviour was observed. The excretion of

radioactivity was almost completed 72 hours after administration. Faecal excretion was predominantly higher

than the renal excretion and ranged between 93 and 109% of the administered dose. In low dose tests, the

renal excretion was ≤ 6.7% of the administered dose. Clear evidence of a reduced oral absorption in the high

dose tests at 20 and 200 mg/kg bw was given by the low renal excretion rate (≤ 0.53% of the administered

dose). Bile-duct cannulated rats showed about 39% of the dose for males and 25% of the dose for females is

eliminated by this route. Absorption rates from the GIT amounted to 41.2% for males and 29.3% for females

(AOEL calculation to be adjusted by 30%). The results of the quantitative whole-body studies demonstrated

low amounts of radioactivity detected in all organs and tissues.

Parent compound was the main compound in faeces of all doses tested. In high dose tests, the metabolism

of parent compound was negligible compared to the low dose tests, in which approx. 30% to 50% of the

dose was metabolised to a high number of metabolites. The metabolite pattern from the four different

labelling positions was identical in all studies for common metabolites. The most important metabolic reaction

was hydroxylation in the methyl group of the phenyl moiety (leading to BCS-CQ63359). Significant

differences between the metabolites of male and female rats were not observed.

Results of two dermal penetration studies using Vayego concentrate (200 g/L) and diluted either to 0.3 g/L or

0.01 g/L were conducted in vitro using human and rat skin and in vivo using rodents. The results of these

studies indicate Vayego is poorly absorbed through the skin as a concentrate or minimally absorbed when

diluted into two in-use spray dilutions (0.3 and 0.01 g/L). The amount of material absorbed for use in the risk

assessment was determined using the 24 hours in vitro (rat/human) and in vivo (rat) absorption values and

the following formula (EFSA 2017)

in vivo human % absorption = (in vivo rat % absorption / in vitro rat % absorption) x in

vitro human % absorption

The results of this indicate the percent absorption for neat Vayego (200 g/L) is 0.25%, and for the 0.3 and

0.01 g/L dilutions it is 15.87% and 7.6% respectively. A value of 0.5% was used for the concentrated

substance and a value of 16% was used for the dilute solutions in the operator and bystander exposure

model calculations. These values are very comparable to those used by the applicant’s values of 0.7% for

the concentrate and 14% for the dilute solutions (values based only on the in vitro absorption dataset).

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Appendix D: Environmental fate

Executive summaries and list of endpoints

Unless otherwise noted, all studies were conducted according to GLP and were fully compliant with all

requirements of the standard international test methods used. All data for tetraniliprole and its metabolites

were sourced from the studies provided by the applicant.

Residues relevant to the environment

The NZ EPA’s User Guide to Thresholds and Classifications (EPA 2012) defines a “major metabolite” as “All

metabolites that are formed in amounts of equal to or more than 10% of the applied amount of substance at

any time-point evaluated during the degradation studies in the appropriate compartment under consideration

(soil or water).”

In laboratory and field degradation studies in soil and water, major metabolites of tetraniliprole (ie, those

found at ≥ 10% Applied Radioactivity (AR)) were identified. The major metabolites are listed in Table 12.

Table 12: Major metabolites of tetraniliprole

Metabolite

code

Chemical name

(IUPAC)

Molecular

Weight

(g/mol)

Physicochemical properties

BCS-CR74541 BCS-CL73507-carboxylic

acid 563.88

Water solubility (pure water at 20°C):0.86 g/L at

pH 7

pKa: 3.7

Log Kow: -0.75 at pH 7

DT50: 118, 78.2, 104, 63.6, 80.8, 75.9, 66.3,

90.1, 47.8, 54.4 days in soil (geomean 75.2 d)

In soil max 47.8%, anaerobic 44.2%

In water systems not detected.

BCS-CU81055

BCS-CL73507-

desmethyl-amide-

carboxylic acid

549.86

Water solubility (pure water at 20°C): 12.11 g/L

at pH 7

pKa: 3.6

Log Kow: -1.1 at pH 7

DT50: 33.8, 25.7, 6.27, 36.3, 14.5, 6.82, 7.39,

12.5, 372, 263, 359 days in soil (geomean 33.7

d)

In soil max 12.0%


BCS-CT30673

BCS-CL73507-N-methyl-

quinazolinone-carboxylic

acid

545.86

Water solubility (pure water at 20°C): 2.8 g/L at

pH 7

pKa: 4.1

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log Kow: 0.8 pH 7

DT50: 29.5, 96.6, 411, 387, 246 days in soil

(geomean 162 d)

In soil max 10.6%, anaerobic 11.2%


BCS-CQ63359 BCS-CL73507-N-methyl-

quinazolinone 526.86

Water solubility (pure water at 20°C):0.19 mg/L

at pH 7

pKa: not determined

log Kow: 3.5 at pH 7

DT50: 65.0, 44.4, 58.5, 62.8, 137, 77.2, 75.7,

65.6, 63.4, 175 days in soil (geomean 75.7 d)

In soil max 33.4%, anaerobic max. 34.7%

Phytolysis water max 39.2%; DT50 = 0.41 d (1.3

d USA, 1.9 d Greece calculated); under dark

conditions max 99% with DT50 between 0.3 and

0.75 days.

In water/sediment (aerobic total system) max

84.8%, in sediment max. 78.9%

In water/sediment (anaerobic system) max. 6.1%

in water, max. 41.1% in sediment, max. 44.0% in

total system

In surface water max 100%

BCS-CY28900 BCS-CL73507-

deschloro-oxazine -

Log Kow: 2.5 at pH 7

aquatic photolysis max 72.7%

In water/sediment not detected

In soil not detected

BCS-CY28897 BCS-CL73507-

deschloro-pyrazine -

Log Kow: 2.0 at pH 7

DT50: -

aquatic photolysis max 38.8%


BCS-CY28906 BCS-CL73507-pyrazole-

5-carboxylic acid -

Water solubility (pure water at 20°C): 0.1 g/L at

pH 7

log Kow: -1.8 at pH 7

DT50: -

Aquatic photolysis max 18%


Results from a range of ecotoxicity studies (aquatic and soil organisms) were submitted by the applicant on

several metabolites. Although metabolites will not be quantitatively assessed because of their

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ecotoxicological properties, the studies provided have been summarised in Appendix J, and the main

findings for the major metabolites have been summarised in Appendix E.

Degradation and fate of tetraniliprole and its metabolites in aquatic

environments

Information on the degradation and fate of tetraniliprole in the aquatic environment is summarised in Table

13. Information on bioaccumulation potential is listed in Table 14.

Table 13: Degradation and fate of tetraniliprole in aquatic environments

Test type Endpoint value Reference

Ready biodegradation Not readily degradable

1% after 28 days

2016/0048/01 ; Table

136 ; Appendix J

Aqueous photolysis half-life (DT50) 0.7 (Tokyo 4.7 calculated, natural

water)

EnSa-13-0321 ; Table

129 ; Appendix J

0.77 (Tokyo 4.9 calculated, natural

water)


130 ; Appendix J

0.4-1.2 days (estimate spring-fall) EnSa-13-0319-01-2;


3.4 (USA 10.5 calculated) EnSa-13-0320 ; Table

128 ; Appendix J

Degradation in aerobic water/sediment (DT50) 11.1 and 122 days total system EnSa-14-0098 ; Table

133 ; Appendix J

Degradation in anaerobic water/sediment

(DT50) days

218 and 104 days total system MEFVP107 ; Table 135

; Appendix J

Water solubility at 20°C [mg/L] Distilled water: 1.2

pH 4: 1.0

pH 7: 1.0

pH 9: 1.3

PA13/078 ;

Hydrolysis half-life (DT50) pH 4: 265

pH 7: 58

pH 9: 1.27


127 ; Appendix J

Mineralisation in surface water DT50 0.9 days EnSa-14-0948 ; Table

134 ; Appendix J

Table 14: Bioaccumulation potential of tetraniliprole and metabolite(s)

Test type Endpoint value for tetraniliprole/ metabolite CQ63359 Reference

Partition coefficient

octanol/water [Log Kow]

Tetraniliprole

pH 4: 2.6

PA13/062

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Test type Endpoint value for tetraniliprole/ metabolite CQ63359 Reference

pH 7: 2.6

pH 9: 1.9

Fish bioconcentration

(whole fish)

Tetraniliprole

BCF lipid normalised steady state 0.419 and 0.23

BCF lipid-normalised growth corrected kinetic 0.452 and 0.255

Low potential for bioaccumulation according to HSNO

EBFVN095 ; Table

147 ; Appendix J

Fish bioconcentration

(whole fish)

Metabolite: BCS-CQ63359

BCF lipid normalised steady state 124 and 183

BCF lipid-normalised growth corrected kinetic 146 and 203


EBFVN155 ; Table

230 ; Appendix J

Degradation and fate of tetraniliprole and its metabolites in soil

Information on the degradation and fate of tetraniliprole and its metabolite(s) in the soil environment is


Table 15: Degradation and fate of tetraniliprole and its metabolite(s) in soil

Test type Endpoint value for tetraniliprole/metabolite Reference

Aerobic half-life in soil

(DT50lab) days1

Tetraniliprole

127, 29.1, 171, 46.7

(normalised)

EnSa-13-0244 ; Table 107 ;

Appendix J


(DT50lab) days1

Tetraniliprole

101, 72.3, 91.9, 149, 111, 56 (normalised)

M 557172-01-1; EnSa-16-0845 ;


Anaerobic degradation

in soil (DT50lab) days

Tetraniliprole

124, 116, 79

EnSa-12-0694; Table 112 ;

Appendix J


(DT50field) days

(field dissipation)

Tetraniliprole

28.2, 31.5, 29.9, 68.4, 33.0, 39.6 (bare soil)

42.4 (turf soil)

M-569279-01-1

MEFVP115

MEFVN027

MEFVN026

MEFVN013

MEFVN015 ; Table 114 ;

Appendix J


(DT50field) days

(field dissipation)

Tetraniliprole

13.9, 30.1, 41.2, 66.3, 92.9, 205

MEFVP117 ; Table 115 ;

Appendix J

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Test type Endpoint value for tetraniliprole/metabolite Reference


(DT50field) days

(field dissipation)

Tetraniliprole

139

MEFVN016 ; Table 116 ;

Appendix J

Soil photolysis half-life

(DT50) days

Tetraniliprole

82.4 (USA), 127.7 (Greece)

M-493228-01-1 ; Table 113 ;

Appendix J

Sorption to soil ( Koc) Tetraniliprole

195.3 (silt loam), 200.4 (loam), 211.0 (loamy sand),

252.3 (silt loam)

M-427580-01-1 ; Table 119 ;

Appendix J

Sorption to soil ( Koc)2 Tetraniliprole

411 (silt loam), 133 (sandy loam), 1920 (silt clay

loam) in sediment

M-557175-01-1 ; Table 118 ;

Appendix J

Sorption to soil ( Koc) CR74541

17.8 (loamy sand), 18.6 (silt loam), 25.6 (loam), 11.6

(loam)

EnSa- 12-0473,;

Metabolites


Sorption to soil ( Koc) CU81055

23.5 (loamy sand), 29.9 (silt loam), 50.4 (loam), 19.5

(loam)

EnSa- 13-0037; Table 121 ;

Appendix J

Sorption to soil ( Koc) CQ63359

4875 (loamy sand), 13416 (silt loam), 9049 (loam),

6464 (loam)

EnSa- 12-0596, Table 122 ;

Appendix J

Sorption to soil ( Koc) CT30673

543 (loamy sand), 568 (silt loam), 718 (loam), 326

(loam)

EnSa- 13-0036 ;


Column leaching BCS-CL 73705 (tetraniliprole) is slightly to moderately

mobile according to JA Guth classification in Brazilian

soils

M-52348 ; Table 126 ; Appendix

J

1: Upper 80% of all DT50 values

2: Lowest value non-sandy soil used for risk assessment

Table 16: Degradation and fate of tetraniliprole in air

Test type Endpoint value for

tetraniliprole/ metabolite

Reference

Half-life in air in days Tetraniliprole

0.404

Report no EnSa-15-1014, M-544693-01-2; Table 137 ;

Appendix J

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General conclusion about environmental fate

Tetraniliprole and metabolites

Degradation and fate in the aquatic environment

Tetraniliprole is considered highly persistent in the aquatic environment according to HSNO criteria (DT50

(whole system) > 2 months). Photolysis is expected to be rapid.

In the aquatic environment, major metabolites were formed: BCS-CQ63359, BCS-CY28900, BCS-CY28897

and BCS-CY28906. Photolysis of BCS-CQ63359 is rapid. The minor metabolite (< 10% of AR) BSC-

CR60014 was identified. No data of DT50 values in water/sediment systems of these metabolites are

available.

The potential for bioaccumulation of the active ingredient and metabolite BCS-CQ63359 is considered to be

low according to HSNO based on bioaccumulation studies. The log Kow for the other metabolites is <3 and

therefore the bioaccumulation potential is also considered low.

Degradation and fate in the soil environment

In aerobic soils laboratory studies, the DT50 values for tetraniliprole ranged from 29.1 to 171 days (best-fit

models). The geometric mean of the DT50 in soil in the laboratory is 131.4 days, indicating that the substance

is persistent (DT50 > 30 days). However, half-lives from field studies are available and the lowest value is

13.9 days, the next value is 28.2 days and the highest value is 205 days. Based on the field studies the

active ingredient is considered to be potentially highly persistent under some circumstances in the field (DT50

> 6 months). .Based on a weight of evidence approach, the substance is considered persistent in soil,

however, because of the potential high persistence in the field, the accumulation potential of the substance

in the soil was still evaluated.

In soil, major metabolites were formed: BCS-CR74541, BCS-CU81055, BCS-CU81056, BCS-CT30673 and

BCS-CQ63359. The minor metabolites (<10% of AR) BCS-CT30672 and BSC-CY28894 were identified. The

degradation of these metabolites is comparable or slower than the parent compound.

Tetraniliprole is highly mobile in soil according to the McCall classification system (McCall P.J., Laskowski

D.A. et al. 1981); in a column leaching study in Brazilian soils, the active ingredient was considered to be

slightly to moderately mobile, however it is unclear how comparable these soils are to New Zealand soils.

Therefore, the active ingredient is considered highly mobile. The soil metabolites are considered to be

immobile till very highly mobile according to McCall classification system.

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Appendix E: Ecotoxicity

Unless otherwise noted, all studies were conducted according to GLP and were fully compliant with all

requirements of the standard international test methods used.

Executive summaries and list of endpoints

Aquatic toxicity

Table 17 contains the acute and chronic aquatic toxicity test results for the active ingredient tetraniliprole,

and Table 18 contains the acute and chronic aquatic toxicity test results for the formulated product Vayego.

Values in bold are those used for the risk assessment. Underlined values are those used to determine the

classification.

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Table 17: Summary of aquatic toxicity data for tetraniliprole (NOEC: No Observed Effect Concentration)

Test species Test type and duration Endpoint value Reference

Fish Acute

Rainbow trout. Oncorhynchus mykiss 96 hours LC50 >10.0 mg ai/L Kuhl K. (2014), Table 141 ;

Appendix J

Common carp, Cyprinus carpio 96 hours LC50 >8.5 mg ai/ L Matlock D., Fannin-Hughes I.J.

(2015), Table 144 ; Appendix J

Fathead minnow, Pimephales promelas 96 hours LC50 >10.0 mg ai/L Kuhl K. (2014), Table 142 ;

Appendix J

Sheepshead minnow, Cyprinodon variegates 96 hours LC50 >9.09 mg ai/L Matlock D., Moore S. (2014),


Fish Chronic

Rainbow trout, Oncorhynchus mykiss 60-day ELS flow-through ND

Sheepshead minnow, Cyprinodon variegatus 35-day, ELS, flow through

NOEC >4.21 mg ai/ L

Matlock D., Moore S. (2016),


Fathead minnow, Pimephales promelas 33-day, ELS, Flow-through

NOEC 2.5 mg ai/ L

Faber D (2016), Table 145 ;

Appendix J

Invertebrates Acute

Water flea, Daphnia magna 48 hours EC50 0.247 mg ai/L Kuhl K., 2015; Table 149

Water flea, Daphnia magna 48 hours EC50 0.173 mg ai/L Kuhl K., 2016; Table 150

Shrimp, Mysidopsis bahia (syn. Americamysis

bahia) 96 hours LC50 7.6 mg ai/ L

Brougher D.S., Zhang L., Martin

K.H., Krueger H. O. (2014) Table

153 ; Appendix J

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Midge, Chironomus riparius 48 hours EC50

spiked water

0.230 mg ai/L Silke G. (2016); Table 167;

Appendix J

Other species Acute

Eastern oyster, Crassostrea virginica 96 hours EC50 2.2 mg ai/ L

Brougher D.S., Zhang L., Martin

K.H., Krueger H. O. (2015); Table

152; .Appendix J

Frog, Xenopus laevis 48 hours LC50 >8.6 mg ai/ L

Banman C.S., Shephard D.W,

Moore S. (2014) Table 148 ;

Appendix J

Invertebrates Chronic

Water flea, Daphnia magna 21-day reproduction, NOEC 0.013 mg ai/L Kuhl K., 2016 Table 151 ;

Appendix J

Shrimp, Mysidopsis bahia (syn. Americamysis

bahia) 30-day, NOEC 0.15 mg ai/L

Claude M.B., Zhang L., Gallagher

S.P., Krueger H. O. (2014) ; Table

154; Appendix J

Amphipod, Hyalella Azteca 10-day, NOEC 0.391 mg ai/kg sediment

Thomas S.T., Zhang L., Martin

K.H. Gallagher S.P., Krueger H.

O. (2015); Table 160; Appendix J

Amphipod, Hyalella Azteca 28-day, spiked sediment, NOEC 0.992 mg ai/kg sediment


K.H. Gallagher S.P. (2016); Table

164; Appendix J

Amphipod, Leptocheirus plumulosus 10-day, NOEC 0.728 mg ai/kg sediment



O. (2015); Table 161 ; Appendix J

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Amphipod, Leptocheirus plumulosus 28-day, spiked sediment, NOEC 12 mg ai/kg sediment Bradley M.J. (2017) ; Table 165;

Appendix J

Midge, Chironomus dilutes 10 day, spiked sediment, NOEC 0.011 mg ai/ kg sediment



O. (2016); Table 162; Appendix J

Midge, Chironomus dilutes 57 day, spiked sediment, NOEC 0.033 mg ai/ kg sediment


K.H. Gallagher S.P. (2016) Table

166 ; Appendix J

Midge, Chironomus riparius 28-day, spiked sediment, NOEC 0.00676 mg ai/kg sediment Silke G. (2015); Table 163;

Appendix J

Midge, Chironomus riparius 28-day, spiked water, NOEC 0.0008 mg ai/L Silke G. (2015); Table 168;

Appendix J

Algae and aquatic macrophytes, Acute

Green alga, Pseudokirchneriella subcapitata 72 hours ErC50 1.97 mg ai/L Kuhl K. (2016); Table 155;

Appendix J

Cyanobacterium, Anabaena flos-aquae 72 hours ErC50 >5.93 mg ai/L

Banman C.S., Shepherd D.W.,

Moore S. (2015); Table 156;

Appendix J

Freshwater diatom, Navicula pelliculosa 72 hours ErC50 >3.19 mg ai/L Matlock D., Moore S. (2015);

Table 157; Appendix J

Marine diatom, Skeletonema costatum 72 hours ErC50 1.49 mg ai/ L Matlock D., Jordan J., Moore S.

(2015); Table 158; Appendix J

Duckweed, Lemna gibba 7-day ErC50 >6.64 mg ai/ L Kuhl K. (2015); Table 159 ;

Appendix J

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Table 18: Summary of aquatic toxicity data for Vayego


Fish Acute

Rainbow trout. Oncorhynchus mykiss 96 hours LC50 (acute) >541 mg substance/L Kuhl K. (2014), Table 187;

Appendix J

Common carp, Cyprinus carpio 96 hours LC50 (acute) >538 mg substance/ L Matlock D., Moore S. (2016),


Rainbow trout. Oncorhynchus mykiss 60-day ELS flow-through (chronic) ND

Fathead minnow, Pimephales promelas 33-day, ELS, Flow-through (chronic) ND

Invertebrates Acute

Water flea, Daphnia magna 48 hours EC50 0.382 mg substance/L Riebschlaeger T., (2014);



Spiked water 4.68 mg substance/L

Silke G. (2016); Table 191;

Appendix J

Invertebrates Chronic

Water flea, Daphnia magna 21-day reproduction ND

Algae and aquatic macrophytes

Green alga, Pseudokirchneriella subcapitata 72 hours ErC50 >5.41 mg substance/L Kuhl K. (2016); Table 190 ;

Appendix J

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Metabolites

Major metabolites in the aquatic environment are BCS-CQ63359, BCS-CY28900, BCS-CY28897, and BCS-

CY28906. Results from a range of ecotoxicity studies (see Table 19) show that the metabolites are less toxic

than the parent compound based on tests with spiked water, the toxicity of BCS-CQ63359 is in the same

order of magnitude. The results of a test with BCS-CQ63359 and spiked sediment indicate that the toxicity of

this metabolite is less than the parent compound. No information is available regarding the persistence of the

metabolites.

Photolysis of the parent compound is rapid as is the photolysis of BCS-CQ63359.

Based on this assessment, the metabolites of tetraniliprole have not been further assessed, the controls

managing the risks from the parent substance are considered to manage the risks from these metabolites.

Table 19: Summary of aquatic toxicity data for metabolites of tetraniliprole

Test species Test type and

duration Endpoint value Reference

Fish Acute

Rainbow trout. Oncorhynchus

mykiss 96 hr LC50 ND

NA

Fish Chronic

Rainbow trout. Oncorhynchus

mykiss 60-day ELS flow-through ND

NA

Invertebrates Acute


Spiked water 0.88 mg CQ63359/L

Silke G. (2016);

Table 240;

Appendix J


Spiked water >0.117 mg CY28900/L

Silke G. (2016);

Table 244;

Appendix J


Spiked water >10 mg CY28897/L

Silke G. (2016);

Table 245;

Appendix J


Spiked water >2.5 mg CY28906/ L

Silke G. (2016)

Table 246;

Appendix J

Midge, Chironomus dilutes 10-day, spiked sediment

NOEC

4.451 mg CQ63359/kg

sediment

Thomas S.T.,

Zhang L., Martin

K.H. Gallagher S.P.,

Krueger H. O.

(2016); Table 236;

Appendix J

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Uncertainties and data gaps

No data gaps identified.

General conclusion about aquatic toxicity

Tetraniliprole and the substance Vayego trigger 9.1A HSNO classification based on their toxicity to

crustacean which is the most sensitive endpoint.

The tested metabolites of tetraniliprole have similar toxicity or are less toxic compared to the parent. The risk

profile of the metabolites is considered similar or lower than that of the parent. Therefore, the risk

assessment for the parent compound will also cover the risks for the metabolites.

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Soil toxicity

Table 20 contains the acute and chronic soil toxicity test results for the active ingredient tetraniliprole. Table

21 contains the acute and chronic soil toxicity test results for the formulated product Vayego. Values in bold

are those used for the risk assessment. Underlined values are those used to determine the classification.

Table 20: Summary of soil toxicity data for tetraniliprole


Soil organisms

Earthworm, Eisenia fetida Acute, 14-day LC50 >1000 mg ai/ kg soil Friedrich S. (2013),

Table 169;

Appendix J

Earthworm, Eisenia fetida Reproduction, 56- day, NOEC ND NA

Soil mite, Hypoaspis aculeifer Reproduction, 14-day, NOEC ND NA

Soil microbial function

Soil microflora Nitrogen mineralisation, 28-

day

No adverse effects on nitrogen

transformation up to 1.116 kg

test item/ ha

Schulz L. (2013),

Table 170;

Appendix J

Soil microflora Nitrogen mineralisation, 28-

day

No adverse effects on nitrogen

transformation up to 1.116 kg

test item/ha (=1.0 kg ai/ha)

Schulz L. (2016),

Table 171;

Appendix J

Soil microflora Carbon mineralisation, 28 -day Active ingredient did not cause

adverse effects on carbon

transformation up to a rate of

1.116 kg test item/ha (=1.0 kg

ai/ha).

Schulz L. (2013),

Table 172;

Appendix J

Soil microflora Carbon mineralisation, 28- day Active ingredient did not cause



1.116 kg test item/ha (=1.0 kg

ai/ha).

Schulz L. (2016),

Table 173;

Appendix J

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Table 21: Summary of soil toxicity data for Vayego


Soil organisms

Earthworm, Eisenia

fetida

Acute, 14-day LC50 > 1000 mg substance/kg soil Friedrich S. (2014),


Earthworm, Eisenia

fetida

Reproduction, 56-day NOEC >1000 mg substance/kg soil Kratz M.A. (2014),


Soil mite, Hypoaspis

aculeifer

Reproduction,14-day NOEC >1000 mg substance/kg soil Kratz M.A. (2014),


Terrestrial plants

Six dicotyledon and

four monocotyledon

crop species

Vegetative vigour, 21 days

Foliar application to seedling

plants

ER25 and ER50 >200 g ai/ha

(>1 L substance/ha)

Some adverse effects were

observed in tomato but these

effects were max.10% and

biological not relevant.

Noeding S. (2016),


Six dicotyledon and

four monocotyledon

crop species

Seedling emergence, 21 days

Application to soil surface


(>1 L substance/ha)

NOER = 200 g ai/ha

Noeding S. (2016),


Solanum

lycopersicum

Vegetative vigour, 21 days

Foliar application to seedling

plants


(>1 L substance/ha)

NOER = 200 g ai/ha

Noeding S. (2016),


Brassica napus Seedling emergence, 21 days

Application to soil surface


(>1 L substance/ha)

NOER = 200 g ai/ha

Noeding S. (2016),



Soil microflora Nitrogen mineralisation, 28 days Substance did not cause

adverse effects on nitrogen


10 L substance/ ha (= 2.0 kg

ai/ha)

Schulz L. (2015), Table

195; Appendix J

Soil microflora Carbon mineralisation, 28 days Substance did not cause



10 L substance /ha (= 2.0 kg

ai/ha)

Schulz L. (2015), Table

196; Appendix J

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2019

Metabolites

In soil, major metabolites were formed: BCS-CR74541, BCS-CU81055, BCS-CT30672, BCS-

CR60014, BCS-CT30673 and BCS-CQ63359. The degradation of these metabolites is comparable or

slower than the parent, thus metabolites show a higher persistency to the parent. The metabolites are

not more toxic compared with the parent (tetraniliprole). Results have been summarized in Table 22.

Based on the maximum concentrations of the metabolites in soil and the lower toxicity compared to

the parent, the metabolites of tetraniliprole have not been further assessed, the controls managing the

risks from the parent substance are considered to manage the risks from these metabolites.

Table 22: Summary of soil toxicity data for the metabolites of tetraniliprole



Soil organisms

Earthworm, Eisenia fetida Acute, 14-day LC50 ND

Earthworm, Eisenia fetida Reproduction, 56-

day, NOEC

CR74541

>100 mg substance / kg soil

Friedrich S. (2015),

Table 247;

Appendix J

Earthworm, Eisenia fetida Reproduction, 56-

day, NOEC

CQ63359



Table 248;

Appendix J

Springtail, Folsomia candida Reproduction 28-

day, NOEC

CR74541



Table 251;

Appendix J

Springtail, Folsomia candida Reproduction 28-

day, NOEC

CQ63359

>562 mg substance/ kg soil


Table 252;

Appendix J

Soil mite, Hypoaspis aculeifer Reproduction, 14-

day, NOEC

CR74541


Schulz L. (2015),

Table 249;

Appendix J

Soil mite, Hypoaspis aculeifer Reproduction, 14-

day, NOEC

CQ63359


Schulz L. (2015),

Table 250;

Appendix J

Terrestrial plants

Six dicotyledon and four

monocotyledon crop species

Vegetative vigour,

21- day

Foliar application to

seedling plants

ND

Six dicotyledon and four

monocotyledon crop species

Seedling

emergence, 21- day

ND

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Application to soil

surface


Soil microflora Nitrogen

mineralisation, 28 -

day

CR74541

Test item did not cause



2.22 kg test item /ha

Schulz L. (2015),

Table 253;

Appendix J

Soil microflora Nitrogen

mineralisation, 28 -

day

CQ63359

Test item did not cause



1.98 kg test item/ha

Schulz L. (2015),

Table 254;

Appendix J

Soil microflora Carbon

mineralisation, 28-

day

ND


No data gaps identified.

General conclusion about soil toxicity

Neither tetraniliprole nor Vayego trigger the HSNO thresholds for toxicity to the soil environment

based on the toxicity to earthworms.

The tested metabolites of tetraniliprole have similar toxicity or are less toxic compared to the parent.

Based on the maximum concentrations of the metabolites in soil and the lower toxicity compared to

the parent, the metabolites of tetraniliprole have not been further assessed, the controls managing the

risks from the parent substance are considered to manage the risks from these metabolites.

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Terrestrial vertebrate toxicity

For effects on terrestrial vertebrates other than birds, refer to the mammalian toxicity section in

Appendix C.

Table 23 contains the acute and chronic avian toxicity test results for the active ingredient

tetraniliprole. Table 24 contains the acute and chronic avian toxicity test Vayego. Values in bold are

those used for the risk assessment. Underlined values are those used to determine the classification.

Table 23: Summary of terrestrial vertebrate toxicity data for tetraniliprole



Bobwhite quail, Colinus

virginianus Acute oral LD50 >2000 mg ai/kg bw

Loveall J.L., Christ M.T.

(2014), Table 174;

Appendix J


virginianus 8-day dietary LC50 >772 mg ai/kg bw/d

Christ M.T., Moore S.M.

(2015), Table 177;

Appendix J


virginianus

Reproductive 1

generation, 23 weeks

NOEL

78 mg ai/kg bw/d

Shepherd J., Christ M.T.,

Moore S.M. (2016), Table

179; Appendix J

Mallard duck, Anas

platyrhynchos Acute oral LD50 ND

Mallard duck, Anas

platyrhynchos 8-day dietary LC50 >1450 mg ai/kg bw/d

Shephard J., Christ M.T.,

Moore S.M. (2014), Table

178; Appendix J

Mallard duck, Anas

platyrhynchos

Reproductive 1

generation, 23 weeks

NOEL

42.9 mg ai/kg bw/d

Bryden M., Temple D.,

Danos L., Martin K

(2016), Table 180;

Appendix J

Canary, Serinus canaria Acute oral LD50 >2000 mg ai/kg bw

Loveall J.L., Christ M.T.

(2015), Table 175;

Appendix J

Chicken, Gallus gallus

domesticus

Acute oral LD50

>2000 mg ai/ kg bw

Hahne J., Breuer -Rehm

M. (2015), Table 176;

Appendix J

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Table 24: Summary of terrestrial vertebrate toxicity data for Vayego




virginianus Acute oral LD50 >2000 mg substance/ kg bw

Hahne J., Breuer -Rehm M.

(2015), Table 202; Appendix J

Chicken, Gallus gallus

domesticus Acute oral LD50 >2000 mg substance/ kg bw

Hahne J., Breuer -Rehm M.

(2015), Table 201; Appendix J

Summary of toxicity of tetraniliprole, its metabolites and Vayego to birds

Acute and short-term dietary toxicity

Vayego

Vayego was tested on its acute toxicity to birds and the results indicate that the substance is not

acutely toxic to birds.

Tetraniliprole

The results of the acute and short term dietary tests indicate that the active ingredient is not acutely

toxic to birds.

Metabolites of tetraniliprole

The toxicity of metabolites of tetraniliprole was not tested to birds.

Sub-chronic and reproduction toxicity

Vayego

Not tested.

Tetraniliprole

The results of the reproduction tests indicate adverse effects of tetraniliprole.

Metabolites of tetraniliprole

The toxicity of metabolites of tetraniliprole was not tested to birds.

General conclusion about ecotoxicity to terrestrial vertebrates

Neither tetraniliprole nor Vayego trigger the HSNO thresholds for toxicity to terrestrial vertebrates

based on the data available.

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Ecotoxicity to pollinators and other terrestrial invertebrates

Pollinators

Acute toxicity

Table 25 contains the toxicity test results for the active ingredient tetraniliprole on honey bees and

bumblebees. Table 26 contains the toxicity test results for Vayego on honey bees and bumblebees.

Table 27 contains the toxicity test results for tetraniliprole metabolite BCS-CQ63359 on honeybees.

Table 25: Summary of pollinators acute toxicity data for tetraniliprole



Honey bee, Apis

mellifera

Adult

Acute oral, 72 hr LD50 = 0.010 µg ai/bee

NOED = 0.0067 µg ai/bee Schmitzer S. 2012 ; Table

181. ; Appendix J

Acute contact, 96 hr LD50 = 0.410 µg ai/bee

NOED = 0.140 µg ai/bee

Honey bee, Apis

mellifera

Larva

Acute oral, 5 d

LD50 = 0.0128 µg ai/ larva

NOED = 0.0033 µg ai/ larva

Rottenberger A, Przygoda

D, Theis M, Gladbach D.

2014. ; Table 182 ;

Appendix J

Bumblebee,

Bombus terrestris Acute oral, 72 hr

LD50 = 0.050 µg ai/bee

NOED = 0.013 µg ai/ bee

Tänzler V. 2016. Table 185

; Appendix J

Bumblebee,

Bombus terrestris Acute contact, 96 hr

LD50 = 21.860 µg ai/bee


Kling A, 2014. ; Table 186 ;

Appendix J

The results of the acute toxicity tests on honey bees and bumblebees indicate that the active

ingredient is highly toxic via the oral and contact route to honey bees, and harmful via the contact

route to bumblebees.

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Table 26: Summary of pollinators acute toxicity data for Vayego



Honeybee, Apis

mellifera


NOED = 0.014 µg ai/bee Schmitzer S. 2012. ; Table

218 ; Appendix J

Acute contact, 96 hr LD50 = 0.440 µg ai/bee


Bumblebee,

Bombus terrestris


NOED = 0.016 µg ai/bee Tänzler V. 2016. ;Table

228 ; Appendix J

Acute contact, 96 hr

LD50 = 93.52 µg ai/bee

NOED = 25 µg ai/bee (96 hours)

The results of the acute toxicity tests on honey bees and bumblebees indicate that Vayego is highly

toxic via the oral route, very toxic via the dermal route to honey bees, and slightly toxic via the dermal

route to bumblebees

Table 27: Summary of pollinators acute toxicity data for tetraniliprole metabolite BCS-CQ63359



Honeybee, Apis

mellifera

Acute oral, 48 hours

LD50 LD50 > 53.3 µg metabolite/bee

Schmitzer S., 2015 ; Table

255 ; Appendix J

Acute contact LD50 LD50 > 100 µg metabolite/bee

The results of the acute toxicity test on honey bees indicates that tetraniliprole metabolite BCS-

CQ63359 is not toxic to bees via the oral and dermal routes.

Chronic toxicity

Table 28 contains the chronic toxicity test results for the active ingredient tetraniliprole on honey bees

larva. Table 29 contains the chronic toxicity test results for Vayego on honey bees.

Table 28: Summary of pollinators chronic toxicity data for tetraniliprole



Honey bee, Apis

mellifera

Larva

Chronic oral, 17 days

LD50 = 0.01209 µg ai/ larva

(cumulative dose)

NOED = 0.010 µg ai/ larva

(cumulative dose)

Przygoda D. 2016. ; Table

183 ; Appendix J

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The results of the chronic toxicity test on honey bee larvae indicates that tetraniliprole is highly toxic to

larvae.

Table 29: Summary of pollinators chronic toxicity data for Vayego



Honeybee, Apis

mellifera Chronic oral, 10 days

LD50 = 0.0137 µg ai/bee/day

NOEDD = 0.00723 µg ai/bee/day

Goßmann A. 2016. ;


The results of the chronic toxicity test on honey bee adults indicates that Vayego is highly toxic to

adult bees.

Semi field and field studies

Table 30 contains the semi-field and field test results for Vayego on honey bees and bumblebees.

Table 30: Summary of pollinators semi-field and field studies

Test

species

Application

rate/ exposure

method

Application

method Conclusions Reference

Key study

Honey bee,

Apis mellifera

60 g ai/ha

(applied as

formulated

product in 300L of

water per ha)

Tunnel test

Foliar spray 5

days before

bees start

foraging on

Phacelia

No major effect was observed

on behaviour, mortality, flight

intensity and colony strength but

a treatment-related transient

effect on brood development

is apparent.

Rexer HU. 2016. ;

Table 226 ;

Appendix J

Supportive studies not performed under the proposed use pattern, same application rate but different

application method

Honey bee,

Apis mellifera

60 g ai/ha

(applied as

formulated

product)

Tunnel test

Soil drench

on Phacelia

No major adverse effects on

colony strength, mortality and

foraging activity were observed

after soil drench application in

the absence of foraging bees. A

small and transient effect on

brood development was

observed.

The active ingredient was

detected in pollen samples.

Tänzler V. 2016.

Table 221 ;

Appendix J

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Test

species

Application

rate/ exposure

method

Application


Honey bee,

Apis mellifera

60 g ai/ha

(applied as

formulated

product) in

20,000L of water

per ha

Tunnel test

Drip irrigation

5 days before

bees start

foraging on

Phacelia

No major adverse effects were

observed after drip application;

however, there might be a

small effect on development

(high termination rate). Low

levels of tetraniliprole can be

detected in flowers (above

LOD of 0.3 µg/kg but below

LOQ 1.0 µg/kg)

Wucherer M.

2016. Table 225 ;

Appendix J.

Supportive studies not performed under the proposed use pattern: lower application rate

Honey bee,

Apis mellifera

20 g ai/ha

(applied as

formulated

product in 300L of

water per ha)

Tunnel test

Foliar spray 13

days before

bees start

foraging on

Phacelia

No major effect was observed


intensity and colony strength but

a small (but not significant)

effect on brood development

is apparent. Residues can be

detected in pollen but are

below the LOD in nectar.

Rexer HU. 2016. ;

Table 226 ;

Appendix J

Honey bee,

Apis mellifera

2.5 and 5 g ai/ha

(applied as

formulated

product) in 400

L/ha

Tunnel test

Foliar spray

while bees are

foraging on

Phacelia


observed after foliar application

at a low application rate in

presence of foraging bees.

NOER for brood development

is 5 g ai/ha.

Klockner A,

Hecht-Rost A,

Staffel J. 2016.

Table 222 ;

Appendix J

Honey bee,

Apis mellifera

2.5, 5 and 10 g

ai/ha (applied as

formulated

product), 200L of

water per ha

Tunnel test

Foliar

application

while bees are

foraging on

Phacelia



at 2.5, 5 or 10 g/ha; however,

there was a transient increase

of mortality of foragers treated

with 10 g/ha, a dose-dependent

increase in behavioural

abnormalities and there might

be a small transient effect on

brood.

Kriszan M. 2014.

Table 223 ;

Appendix J.

Honey bee,

Apis mellifera

2.5, 5 and 10 g

ai/ha (applied as

formulated

product), 200L of

water per ha

Tunnel test

Foliar

application

while bees are

foraging on

Phacelia



at 2.5, 5 or 10 g/ha; however,

there was a transient increase

of mortality of foragers treated

with 10 g/ha and a dose-

dependent increase in

behavioural abnormalities.

Kriszan M. 2014.

Table 224 ;

Appendix J

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Test

species

Application

rate/ exposure

method

Application


Honey bee,

Apis mellifera

81, 158, 318, 624

and 1720 μg of

pure technical ai

/kg of feeding diet

Spiked diet Chronic dietary exposure of

colonies to 1720 μg/kg

tetraniliprole resulted in

reductions in colony

performance and increased

colony loss.

NOAEL: Effects on brood

were observed at 318 μg/kg

and above

Louque J. 2016. ;

Table 184 ;

Appendix J

Bumblebee,

Bombus

terrestris L.

2x 8g ai /ha

(applied as

formulated

product in 300L of

water per ha)

Or furrow

application at 200

g/ha)

Tunnel test

Foliar spray 14

and 8 days

before bees

start foraging

And 1 furrow

application 47

days before

bees start

foraging on

potato

No relevant effect was observed


intensity and colony strength.

No assessment of reproduction

was possible because the hives

were destroyed because the

number of individuals was too

low to proceed to the

reproduction test.

Klein O. 2016.;

Table 229 ;

Appendix J

Most of the higher tier studies summarised in Table 33, although performed according to accepted

guidelines, had insufficient numbers of replicates to detect moderate effects (as shown by Candolfi et

al 2018, the minimum detectable differences relative to the control ranged from 10-15% for endpoints

like foraging, number of brood cells and colony strength to 50% for termination rate with the sample

size used in the studies provided). Some of the effects reported above were below the threshold for

significance, however, given their consistency across studies, they are considered treatment-related

and biologically relevant.

Clear dose-dependent effects of the active ingredient on brood development are observed across the

semi-field studies provided. These effects were of a small magnitude and transient, and not all studies

showed effects reaching significance likely because of the small number of replicates (see Appendix

J). The effect is more pronounced in the study (Rexer HU. 2016. ;Table 226) ;which is closer to the

actual use pattern of the substance (correct application rate, frequency and method, however

spraying is applied 5 days before bees start being exposed and thus potentially decreasing

exposure), smaller effects on brood are also observed at lower application rate or with application

methods that reduce exposure (drip or soil drench). This effect is consistent with the effects observed

with the similar active ingredient cyantraniliprole on the target species (EC 2013).

One semi-field study (Klein O. 2016.;Table 229) was performed on bumblebees with two foliar

applications at 8 g ai/ha. No major effects were detected but all colonies were in poor conditions and

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therefore the study had to be terminated before the assessment of the reproduction ability could be

performed.


Bumblebees are essential for the pollination of kiwifruit, but the semi-field study provided had to be

terminated early due to quality issues with the colonies. The study was performed at a lower

application rate, therefore there is uncertainty regarding the safety of the product for bumblebees.

Non-target arthropods

Tier I - Laboratory studies

Table 31 contains the laboratory toxicity test results for Vayego on the two representative species of

non-target arthropods.

Table 31: Tier I – laboratory studies on non-target arthropods


Parasitic wasp,

Aphidius rhopalosiphi

48 hours LR50

laboratory glass plate 0.627 g ai/ha

Mueller U. 2014,

Table 203 ;

Appendix J

Predatory mite,

Typhlodromus pyri

7-day LR50

laboratory glass plate >44 g ai/ha

Mueller U. 2014,

Table 204 ;

Appendix J

The studies performed in Tier I indicate that parasitic wasps are highly sensitive to Vayego.

For the predatory mite, the tested dose was not high enough to determine the LR50. The highest effect

observed was 4.9% corrected mortality at 44 g ai/ha which was not significant. The maximum tested

dose for predatory mites is below the requested application rate of Vayego.

Tier II - extended laboratory studies

Table 32 contains the extended laboratory toxicity test results for Vayego on three representative

species of non-target arthropods.

Table 32: Tier II – extended laboratory studies on non-target arthropods


Parasitic wasp,

Aphidius

rhopalosiphi

48 hours LR50

Extended laboratory test with fresh,

dry and aged residue on apple

Could not be determined and

is less than 25 g ai/ha

Jans D. 2016,

Table 205 ;

Appendix J

Parasitic wasp,

Aphidius

rhopalosiphi

48 hours LR50

Extended laboratory test with dry

residue on barley

0.7 g ai/ha

Waibel J. 2015,

Table 206 ;

Appendix J

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Green lacewing,

Chrysoperla

carnea

19-day LR50


residue on bean leaves, LR50

>44 g ai/ha

Waibel J. 2015,

Table 208 ;

Appendix J

Ladybird,

Coccinella

septempunctata

19-day LR50


residue on bean leaves, LR50

>44 g ai/ha

Roehlig U.,

2015, Table 207

; Appendix J

The higher tier studies showed that the parasitic wasp is the most sensitive species tested.

For the green lacewing and ladybird, the tested dose was not high enough to determine the LR50. The

observed mortality (corrected mortality maximum 9.1% for the ladybird and 5.7% for the lacewing)

was not statistically significant. The maximum tested dose for the species is below the requested

application rate of Vayego.

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Tier III - higher tier studies

Semi-field studies

Table 33Table 32 contains the semi-field test results for Vayego on six representative species of non-

target arthropods.

Table 33: Summary of semi-field studies conducted on non-target arthropods

Test species

Application

rate/

exposure

method

Application

method Conclusions

(classification according

to IOBC)

Reference

Key study

Parasitoid wasp,

Aphidius

colemani

1 x 60 g ai/ha

Semi-field

Vegetables

4 studies

Foliar

1 slightly harmful

1 slightly harmful till day 14

thereafter harmless

2 harmless

Ernst G., Kroder S.

2016, Table 212 ;

Appendix J

Parasitoid wasp,

Encarsia

formosa

1 x 60 g ai/ha

Semi-field

Tomatoes

3 studies

Foliar

2 slightly harmful

1 moderately harmful till day

5 thereafter harmless

Ernst G., Kroder S.

2016, Table 211 ;

Appendix J

Parasitoid wasp,

Aphelinus mali

1 x 60 g ai/ha*

(1 study)

2 x 60 g ai/ha*

(3 studies)

2 x 30 g ai/ha*

(1 study)

Apples

5 studies

Foliar

1 slightly harmful till day 14

thereafter harmless

1 harmless, 1 slightly

harmful, 1 slightly harmful till

day 0 thereafter harmless

1 harmless

Ernst G., Kroder S.

2016, Table 210 ;

Appendix J

Supportive studies not performed under the proposed use pattern: lower application rate

Parasitoid wasp,

Eretmocerus

eremicus

2 x 20 g ai/ha

Aubergines

1 study

Foliar harmless

Ernst G., Kroder S.

2016,. Table 209 ;

Appendix J

Predatory mite,

Typhlodromus

pyri

2 x 45 g ai/ha*

Apples Airblast harmless to slightly harmful

Project nr:

IR12BELPFD0422

Table 215;

Appendix J

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Test species

Application

rate/

exposure

method

Application

method Conclusions

(classification according

to IOBC)

Reference

2 x 36 g/ha*

Apples harmless

Project nr:

IR11BELPFS0434

Table 216;

Appendix J

Predatory bug,

Anthocoris

nemoralis

15 g ai/ha/m

CH

(corresponds

to 45 g ai/ha)

Pears

Airblast harmless to slightly harmful

Project

nr:IR12BELPFF0425

Table 217;

Appendix J

Several species of parasitoid wasps were tested in semi-field studies up to an application rate of 60 g

ai/ha, with one or two applications. No data have been provided for an application frequency of three

applications.

Information regarding the effect of a single application to three species is available. The maximum

effects observed in the studies varied between harmless to moderately harmful. In three studies,

effects decreased to harmless within 14 days. In five studies, the effects at the end of the studies

were described as harmless, in three studies the effects at the end of the study were slightly harmful.

Three studies were performed with an application frequency of two, these studies covered a single

species. One study showed that Vayego was harmless, one study indicated that Vayego was slightly

harmful without recovery during the test duration and one study only observed a slightly harmful effect

at the application day meaning that by the end of the study Vayego could be described as harmless.

Studies provided by the applicant indicate that the substance was harmless to slightly harmful to the

predatory mites when exposed to two applications of 45 g ai/ha. The effect after the second

application was more pronounced compared to the first application. The study performed at 45 g ai/ha

indicates a more pronounced effect at the second application (overal study IOBC 1-2) making it likely

that applications at a higher rate and frequency will have more pronounced effects. An application of

36 g ai/ha only showed a slightly harmful effect (IOBC score 1). It should have been noted, however,

that the studies have been performed at lower application rates and fewer frequencies than the

requested use pattern.

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Field studies

Table 34Table 32 contains the field test results for Vayego on non-target arthropods.

Table 34: Summary of field studies conducted on non-target arthropods

Test

species

Application

rate/ exposure

method

Application


Key study

Non-target

arthropods

4 g ai/ha

Field study

off-crop habitats

Foliar

NOER community and

NOEAER population 4 g

ai/ha, highest rate tested

Bakker F., Aldershof

S.A. 2016, Table 213;

Appendix J

NOER community and

NOEAER population 4 g

ai/ha, highest rate tested

Bakker F., Aldershof

S.A. 2016, Table 214;

Appendix J

The No Observed Ecologically Adverse Effect Rate (NOEAER) population for field insects was

determined below the expected off-field exposure of Vayego (applied at 4 g ai/ha). The NOEAER of

the study as a result is below the estimated drift (between 4.8-7.3 g ai/ha per application). It should

however be noted that the NOEAER is the highest concentration tested and in theory could be higher

if a higher application rate was tested.

Statistically significant effects were observed during the studies but recovery of the respective

populations occurred within 2 months after treatment (NOER population 0.4 and 1.6 g a.i./ha).

General conclusion in relation to classification for terrestrial invertebrate

toxicity

Tetraniliprole triggers a 9.4A HSNO classification based on the acute oral toxicity study on bees. The

major soil and aquatic tetraniliprole metabolite BCS-CQ63359 is less toxic than tetraniliprole.

Vayego triggers the 9.4A HSNO classification based on the acute oral toxicity study on bees.

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Appendix F: Hazard classification of Vayego and tetraniliprole

The hazard classifications of tetraniliprole and Vayego are listed in Table 35 and Table 36

respectively.

Table 35: Staff classifications of the active ingredient tetraniliprole

Hazard Class/Subclass

Active

ingredient

classification

– EPA Staff

Method of

classification

Remarks

Test

resu

lts

Read

acro

ss

Class 1 Explosiveness No

Class 2, 3 & 4 Flammability NA

Class 5 Oxidisers/Organic

Peroxides No

Subclass 8.1 Metallic corrosiveness ND

There was no corrosion from

substance stored in HDPE and

PP for 2 years at 30oC

Subclass 6.1 Acute toxicity (oral) No LD50 >2000 mg/kg bw

Subclass 6.1Acute toxicity (dermal) No LD50 >2000 mg/kg bw

Subclass 6.1 Acute toxicity

(inhalation) 6.1E

LC50 >5.01 mg/L (one animal

died at this concentration)

Subclass 6.1 Aspiration hazard NA Active ingredient is a solid

Subclass 6.3/8.2 Skin

irritancy/corrosion No

Mean Draize score below

threshold for classification

Subclass 6.4/8.3 Eye

irritancy/corrosion No

Mean Draize score below

threshold for classification

Subclass 6.5A Respiratory

sensitisation ND

Subclass 6.5B Contact sensitisation 6.5B EC3 value is 8.2%

Subclass 6.6 Mutagenicity No In vivo and in vitro tests are

negative

Subclass 6.7 Carcinogenicity No

There was no significant

evidence to indicate the

material is carcinogenic.

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Subclass 6.8 Reproductive/

developmental toxicity No

No evidence of toxicity was

observed in offspring in the

developmental or the 2-

generation reproductive toxicity

studies


developmental toxicity (via

lactation)

No

No evidence of toxicity was

observed in offspring in the 2-

generation reproductive study

Subclass 6.9 Target organ systemic

toxicity (oral) No

The LOAEL from all the

repeated dose oral toxicity

studies on the ai exceeded the

100 mg/kg bw/day cut-off value

for 6.9B classification


toxicity (dermal) No

Active is poorly absorbed

through the skin and is not

classified by the oral route


toxicity (inhalation) ND

Subclass 9.1 Aquatic ecotoxicity 9.1A EC50 =0. 173 mg ai/L Daphnia.

magna

Subclass 9.2 Soil ecotoxicity No

Subclass 9.3 Terrestrial vertebrate

ecotoxicity No

Subclass 9.4 Terrestrial

invertebrate ecotoxicity 9.4A Oral LD50 = 0.010 µg ai/bee

NA: Not Applicable.

ND: No Data or poor quality data [according to Klimisch criteria (Klimisch, Andreae et al. 1997)]. There is a lack

of data for one or more components.

No: Not classified based on actual relevant data available for the substance. The data are conclusive and

indicate the threshold for classification is not triggered.

The EPA proposes to classify the active ingredient as 9.1A and 9.4A based on test results with this

active ingredient. The applicant did not provide a classification for the active ingredient.

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Table 36: Applicant and EPA Staff classifications of Vayego1


Mixture

classification by:

Method of

classification

Remarks

Applicant EPA

Staff

Mix

ture

data

Read

acro

ss

Mix

ture

ru

les

Class 1 Explosiveness No No

Class 2, 3 & 4 Flammability No No

Class 5 Oxidisers/Organic

Peroxides No No

Subclass 8.1 Metallic

corrosiveness No ND

Substance was not

corrosive to the HDPE

plastic storage container

during stability tests


(oral) No No

LD50 >2000 mg/kg

bw/day

Subclass 6.1Acute toxicity

(dermal) No No

LD50 >2000 mg/kg

bw/day


(inhalation) No No

LC50 >4.49 mg/L

Subclass 6.1 Aspiration

hazard No No

The substance is

aqueous-based and its

kinematic viscosity

exceeds the cut-off value

for classification.

Subclass 6.3/8.2 Skin

irritancy/corrosion No No

Non-irritating

Mean score - Erythema:

0.0 Oedema: 0.0

Subclass 6.4/8.3 Eye

irritancy/corrosion No No

Non-irritating;

Mean Draize Score -

Cornea Opacity: 0.0

Conjunctiva:

-Redness: 0.0

-Chemosis: 0.0

Iris: 0.0

1 Use of mixture rules may not adequately take into account interactions between different components in some circumstances and must be considered of lower reliability than substance (formulation) data.

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Mixture

classification by:

Method of

classification

Remarks

Applicant EPA

Staff

Mix

ture

data

Read

acro

ss

Mix

ture

ru

les

Subclass 6.5A Respiratory

sensitisation No ND

Absence of dermal

sensitisation potential

significantly minimizes

the likelihood it is a

respiratory sensitiser.

Subclass 6.5B Contact

sensitisation No No Non-sensitiser; (SI <3)

Subclass 6.6 Mutagenicity No ND

ND is due to data

missing from several very

minor non-active

components. The

significance of this data

absence is believed to be

minimal as most are

present at <1%, the

amount needed for

mixture classification.

Subclass 6.7 Carcinogenicity No ND

ND is due to data


minor non-active

components. The



minimal.


developmental toxicity No ND

ND is due to data


minor non-active

components. The



minimal.


developmental toxicity (via

lactation)

No ND

ND is due to data


minor non-active

components. The



minimal.

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Mixture

classification by:

Method of

classification

Remarks

Applicant EPA

Staff

Mix

ture

data

Read

acro

ss

Mix

ture

ru

les

Subclass 6.9 Target organ

systemic toxicity (oral) 6.9B No

The LOAEL from all the

repeated dose oral

toxicity studies on the ai

exceeded the 100 mg/kg

bw/day cut-off value for

6.9B classification.

Although data are

missing on some minor

components they are

present below the 1%

cut-off level.


systemic toxicity (dermal) No No

Oral exposure represents

the worst-case scenario

and does not trigger

classification.


systemic toxicity (inhalation) No ND

Subclass 9.1 Aquatic

ecotoxicity 9.1A 9.1A

EC50 = 0.382 mg

substance/L Daphnia

magna

Subclass 9.2 Soil ecotoxicity No No


vertebrate ecotoxicity No No


invertebrate ecotoxicity 9.4A 9.4A

Oral LD50 =0.048 µg

substance/bee

NA: Not Applicable. For instance testing for a specific endpoint may be omitted if it is technically not possible to

conduct the study as a consequence of the properties of the substance: eg very volatile, highly reactive or

unstable substances cannot be used, mixing of the substance with water may cause danger of fire or explosion

or the radio-labelling of the substance required in certain studies may not be possible.

ND: No Data or poor quality data [according to Klimisch criteria (Klimisch, Andreae et al. 1997)]. There is a lack

of data for one or more components.

No: Not classified based on actual relevant data available for the substance or all of its components. The data

are conclusive and indicate the threshold for classification is not triggered.

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There are no proposed mammalian toxicity classifications for Vayego. For ecotoxicity the following

classifications are proposed: very toxic to aquatic organisms (9.1A) and very toxic to terrestrial

invertebrates (9.4A). The EPA classification of Vayego differed from that of the applicant in regard to

target organ systemic toxicity (6.9B). The most likely explanation is that the applicant did not

recognize that this classification is only triggered when the LOAEL in a repeated dose systemic

toxicity is less than 100 mg/kg bw/day, not the NOAEL. The LOAEL from all repeated dose systemic

toxicity studies exceeded 100 mg/kg bw/day.

The ecotoxicity classification of the EPA is the same as the proposed classification of the applicant for

Vayego (9.1A and 9.4A). These classifications are based on test result with the formulated substance.

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Appendix G: Human health risk assessment

Quantitative risk assessment

The operator exposure assessment is based on a modification of the approach used by European

regulators, taking into account New Zealand specific factors. The model is based on the results of

actual measurements carried out in the field and has an established history of providing reliable and

reproducible results.

The re-entry worker exposure assessment is based on a modification of the approach used by

European regulators and the US EPA. The parameters for the modelling are based on empirical data

relating to measurements of dermal exposure of workers from contact with residues on foliage for

various activities and the number of foliar residues that are dislodgeable.

The bystander exposure assessment is based on a modification of the approaches used by European

regulators and the US EPA. Spray drift deposition from ground-based application is estimated using

the AgDrift model using the curves produced by the Australian Pesticides and Veterinary Medicines

Authority (APVMA 2010). The parameters are based on empirical data. Spray drift deposition from

aerial application is estimated using the AGDISP model along with appropriate New Zealand input

parameters.

Full details of the methodology can be found in the risk assessment methodology document (EPA

2018).

To assess risks, the predicted systemic exposures to the active ingredient(s) are compared with an

acceptable operator exposure limit (AOEL) for the active ingredient and a RQ is calculated. RQ

values greater than one indicate that predicted exposures are greater than the AOEL and potentially

of concern. RQ values below one indicate that predicted exposures are less than the AOEL and are

not expected to result in adverse effects.

Input values for the human health risk assessment

No reference doses for tetraniliprole established by internationally reputable regulatory authorities

exist.

The relevant toxicity study that was utilised to derive an AOEL for tetraniliprole is summarised in

Table 37.

Table 37: Summary of studies relevant for establishing an AOEL

Key systemic

effect

NOAEL

mg/kg bw/day

Uncertainty

factors

Absorption

factor

AOEL

mg/kg

bw/day

Justification

Chronic toxicity

(52 weeks) in

dogs: Decreased

2900 ppm (M:

91.2 mg/kg

bw/day and F:

100 100% 0.88 The dog was the

most sensitive

species (lowest

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Key systemic

effect

NOAEL

mg/kg bw/day

Uncertainty

factors

Absorption

factor

AOEL

mg/kg

bw/day

Justification

bw effects and

increased alkaline

phosphatase

activity

88.4 mg/kg

bw/day)

NOAEL). In light of

the data that

indicated oral

absorption in the rat

was very low (30%)

and that there was

no oral absorption

data on the

sensitive species

(dog), the EPA used

the results from the

52 week dog study

as opposed to the

results from the 90

day dog study

(NOAEL 126 mg/kg

bw/day)

Dermal absorption data (human and rat in vitro, and rat in vivo) were provided for Vayego so default

values were not needed. Other input values for the exposure assessment are summarised in Table

38.

Table 38: Input values for human exposure modelling

Active

ingredient

Physical

form

Concentration

of each ai

(%)

Maximum

application rate

(for each ai, for

each method of

application)

(g ai/ha)

Dermal absorption

(%)

AOEL

(mg/kg

bw/day)

Concentrate Spray

Tetraniliprole Liquid 20% 60 0.5 16 0.27

Operator exposure assessment

The results of the operator exposure assessment are shown in Table 39.

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Table 39: Output of operator mixing, loading and application exposure assessment for tetraniliprole

Exposure Scenario: pome fruit, grapes, kiwi,

stone fruit

Estimated operator

exposure (mg/kg bw/day) RQ

Airblast

No PPE during mixing, loading and application 0.0160 0.018

Gloves only during mixing and loading 0.0159 0.018

Gloves only during application 0.0152 0.017

Full PPE during mixing, loading and application (excluding

respirator)

0.0010 0.001

Full PPE during mixing, loading and application (including

FP1, P1 and similar respirator achieving 75 % inhalation

exposure reduction)

0.0009 0.001

Full PPE during mixing, loading and application (including

FP2, P2 and similar respirator achieving 90 % inhalation

exposure reduction)

0.0008 0.001

Predicted operator exposures to tetraniliprole are below the AOEL for each use pattern, even without

the use of PPE. Therefore, operator exposures are not expected to result in adverse health effects.

Re-entry worker exposure assessment

The results of the re-entry worker exposure assessment are summarised in Table 40.

Table 40: Output of the re-entry worker exposure assessment for tetraniliprole

Active

ingredient

Crop/

activity

Internal (absorbed)

dose available for

systemic distribution

(mg/kg bw/8 hours)

AOEL

(mg/kg

bw/day)

RQ immediately

after

application (w/o

gloves)

REI

without

gloves

Tetraniliprole

Pome fruits/

Fruits (from

trees) search,

reach, pick

0.02 0.88 0.02 0.0

Grapes/

reach, pick

0.01 0.01 0.0

Kiwi/ reach,

pick

0.01 0.01 0.0

Stone fruits/

Fruits (from

trees) search,

reach, pick

0.02 0.03 0.0

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Predicted exposures to tetraniliprole for workers re-entering and working in areas where Vayego has

been applied are below the AOEL even without gloves. No re-entry intervals or use of gloves are

necessary.

Quantitative bystander risk assessment

It is considered that the main potential source of exposure to the general public for substances of this

type (other than via food residues which will be considered as part of the registration of this substance

under the Agricultural Compounds and Veterinary Medicines (ACVM) Act 1997) is via spray drift. In

terms of bystander exposure, toddlers are regarded as the most sensitive sub-population and are

regarded as having the greatest exposures. For these reasons, the risk of bystander exposure is

assessed in this sub-population. The AOEL calculated for the operator and re-entry worker exposure

assessments has been used for the bystander assessment, as the use of an oral Chronic Reference

Dose (CRfD) is usually likely to be over precautionary.

The results of the bystander exposure assessment are summarised in Table 41.

Table 41: Output of the bystander exposure assessment for tetraniliprole

Exposure Scenario Estimated exposure of 15 kg

toddler exposed through contact

to surfaces 8 m from an

application area

(µg/kg bw/day)

RQ Buffer zone

needed to

reduce toddler

exposure to the

AOEL

Airblast sparse orchard

(pome/stone fruits)

0.82 / 0.96 0.0009 / 0.0011 0

Airblast dense orchard

(pome/stone fruits)

0.27 / 0.32 0.0003 / 0.0004 0

Airblast vineyard

(grapes and kiwi fruit)

0.03 0.0000 0

Estimated bystander exposure from spray drift after application of Vayego to the soil around mature

pome and stone fruit, and kiwifruit and grape vines is below the AOEL. No buffer zone is required to

protect bystanders.

Conclusions of the human health risk assessment

It is considered that the risks to human health from the proposed use of Vayego are acceptable even

in the absence of appropriate PPE. There is no need for the application of REI or an additional buffer

zone to protect bystanders.

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Appendix H: Environmental risk assessment

Aquatic risk assessment

The basis for the aquatic risk assessment is a comparison of the Expected Environmental

Concentrations (EEC) with toxicity endpoints to which safety factors have been applied. The EEC is

divided by the toxicity endpoint to calculate a RQ value. The methodology for the aquatic risk

assessment, including the LOC ascribed to specific RQ values, is described in detail in the risk

assessment methodology document (EPA 2018).

Calculation of expected environmental concentrations

The parameters used in GENEEC2 modelling are listed in Table 42. Output from the model is given in

Table 43.

Table 42: Input parameters for GENEEC2 analysis for tetraniliprole

Parameters Pome fruit Stone fruit Grapes Kiwifruit

Application rate (kg/ha) 0.06 0.06 0.06 0.06

Application frequency 3 2 1 1

Application interval (days) 21 14 - -

Koc 1331

Aerobic soil DT50 (days) 131.42

Pesticide wetted in? no

Methods of application airblast

‘No spray’ zone 0

Water solubility (ppm) 1.0

Hydrolysis (DT50 in days) 58

Aerobic aquatic DT50 whole system(days) 122

Aqueous photolysis DT50 (days) 10.5

1: Lowest value non-sandy soil used for risk assessment

2: Upper 80% of all DT50 values

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Output from the GENEEC2 model

Table 43: Output values from the GENEEC2 analysis for tetraniliprole

Pome fruit Stone fruit Grapes Kiwifruit

PEAK µg/L 7.22 5.15 2.43 2.43

4 day µg/L 7.18 5.12 2.41 2.41

21 day µg/L 6.95 4.96 2.33 2.33

60 day µg/L 6.44 4.60 2.16 2.16

90 day µg/L 6.09 4.34 2.04 2.04

The maximum Estimated Environmental Concentrations (EEC) for tetraniliprole, when used in Vayego

as estimated by GENEEC2, is 7.22 μg/L (pome fruit scenario).

Calculated risk quotients

The calculated acute risk quotients for each trophic level considering the above EEC and lowest

relevant toxicity figures are presented in Table 44. The calculated chronic risk quotients are presented

in Table 45.

For the acute risks of algae/diatoms the toxicity of a marine species was used as this is the worst

case scenario (Lowest EC50).

Table 44: Acute risk quotients derived from the GENEEC2 model and toxicity data

Species Peak EEC from

GENEEC2 (mg/L)

LC50 or EC50

(mg/L) Acute RQ Conclusion

Pome fruit, worst-case scenario

Fish, Cyprinus carpio

0.0072

>8.5 <0.0008 Below LOC for

threatened/non-threatened

species

Crustacea, Daphnia

magna 0.173 0.04

Below LOC for


species

Marine diatom,

Skeletonema

costatum

1.49 0.005

Below LOC (no threatened

species identified in New

Zealand)

Aquatic plants, Lemna

gibba >6.64 <0.001

Below LOC for


species

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Table 45: Chronic risk quotients derived from the GENEEC2 model and toxicity data

Species

Relevant EEC

from GENEEC2

(mg /L)*

NOEC

(mg/L)

Chronic

RQ Conclusion

Pome fruit, worst-case scenario

Fish, Pimephales

promelas (33 day) 0.00695 2.5 0.003

Below LOC for


species

Crustacea, Daphnia

magna (21 day) 0.00695 0.013 0.525

Above LOC for

threatened species,

below LOC for non-

threatened species

Midge, Chironomus

riparius (28 day) 0.00695 0.0008 8.7

Above LOC for

threatened/non-

threatened species

Stone fruit

Fish, Pimephales

promelas (33 day) 0.00496 2.5 0.002

Below LOC for


species

Crustacea, Daphnia

magna (21 day) 0.00496 0.013 0.382

Above LOC for

threatened species,

below LOC for non-

threatened species

Midge, Chironomus

riparius (28 day) 0.00496 0.0008 6.2

Above LOC for

threatened/non-

threatened species

Grapes, kiwifruit

Fish, Pimephales

promelas (33 day) 0.00233 2.5 0.001

Below LOC for


species

Crustacea, Daphnia

magna (21 day) 0.00233 0.013 0.179

Above LOC for

threatened species,

below LOC for non-

threatened species

Midge, Chironomus

riparius (28 day) 0.00233 0.0008 2.9

Above LOC for

threatened/non-

threatened species

* EEC selected must be as close as possible to the exposure duration of the study selected for risk assessment purposes.

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Refinement of the aquatic risk assessment

No acute risks are identified. The scenario modelled is a worst-case, using the maximum application

rate at the shortest interval and maximum frequency of applications. Therefore, it is considered that

the risks of the other scenarios are also below the LOC.

Predicted chronic exposures were above the LOC for midges for all scenarios, including a single

application. Predicted chronic exposures were above the LOC for threatened crustaceans for all

scenarios, including a single application. Because risks were identified, further modelling was

performed to consider whether buffer zones may be able to mitigate risks from spray drift and runoff.

Spray drift

Following the methodology described in the EPA risk assessment methodology, the required

downwind buffer zone to protect the aquatic environment from adverse effects of the substance due

to spray drift were calculated.

Exact buffer zones are impractical and too precise to be applied in the real world. Therefore, the

buffer zone distances are rounded so they can be visualized and remembered by end-users.

Table 46: Input parameters and calculation of spray drift buffer zone for the refined risk assessment of tetraniliprole

Application scenario

Input

parameters

Pome fruit Stone fruit Grapes/kiwifruit

Application rate (kg/ha) 0.06 0.06 0.06

Application frequency 3 2 1

Application interval (days) 21 14 -

Scenario Dense orchard Vineyard

Koc 133

DT50 soil 131.4

DT50 water/sed 122

Averaging time 28 days

Toxicity endpoint (mg/L) 0.0008 (chronic)

Assessment factor 10

Buffer zone (m) model 204 142 4

Buffer zone (m) control 200 140 5

The EPA proposes a downwind buffer zone of 200, 140 and 5 meters for pome fruit, stone fruit and

kiwifruit/grapes, respectively.

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Runoff

The REXTOX model was also used to calculate the required buffer zone to protect the aquatic

environment from adverse effects of the substance due to runoff (see Table 47). The crop interception

values for each crop are provided in Table 40.

Table 47: Input parameters and calculation of runoff buffer zones for the refined risk assessment


Input parameters

Pome fruit Stone fruit Kiwifruit, grapes

Application rate (kg/ha) 0.06 0.06 0.06

Koc 133

DT50 soil 131.4

Crop interception 65 65 60

Slope 12.7 12.7 12.7

Toxicity endpoint 0.0008 (chronic)


Buffer zone (m) model 23 21 19

Buffer zone (m) control 25 20 20

The EPA proposes buffer zones to protect the aquatic environment from adverse effects due to runoff.

Conclusions of the aquatic risk assessment

Predicted exposures concentrations of tetraniliprole, applied as the formulated product Vayego

resulted in calculated RQ above the LOC for the aquatic environment (chronic exposure to threatened

crustaceans). To manage these risks, it is proposed to apply controls to reduce spray drift and runoff

into the aquatic environment.

The following controls are proposed to reduce exposures below the LOC:

- When applied using ground-based equipment on pome fruit (max 3 applications of 60 g ai/ha

per year), the substance should not be applied within 25 m of any waterbody.

- When applied using ground-based equipment on stone fruit (max 2 applications of 60 g ai/ha


- When applied using ground-based equipment on kiwifruit and grapes (max 1 application of 60

g ai/ha per year), the substance should not be applied within 20 m of any waterbody.


per year), there should be a downwind buffer zone of 200 m for waterbodies.

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- When applied using ground-based equipment on kiwi fruit and grapes (max 1 application of

60 g ai/ha per year), there should be a downwind buffer zone of 5 m for waterbodies.

Together with prescribed controls, additional controls including proposed buffer zones will reduce the

risks to below the LOC.

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Groundwater risk assessment

The predicted concentration of tetraniliprole in groundwater, calculated using the Sci-Grow model, is

shown in Table 48. The concentration is initially compared to the EU limit for the maximum

permissible concentration of pesticide active ingredients and their relevant metabolites of 0.1 µg/L.

Table 48: Input parameters for Sci-Grow analysis and resulting PEC values


Input parameters

Pome fruit Stone fruit Kiwifruit

Application rate (kg ai/ha) 0.06 0.06 0.06

Application rate (lb ai/acre)1 0.054 0.054 0.054

Crop interception (%) 65 65 60

Number of applications 3 2 1

Koc2 133

Aerobic soil DT50 (days) 131.4

PECgw (µg/L) 0.079 0.053 0.03

1 The application rate is a conversion from kg ai/ha to lb/acre (the units required to be entered into the model) by multiplying it by 0.892

2 Lowest Koc from a non-sandy soil (normalised values for the OC, temp and pH)

The predicted levels are below the LOC for the active ingredient tetraniliprole when applied multiple

times.

The active ingredient is highly mobile (McCall P.J., Laskowski D.A. et al. 1981) and its metabolites are

very highly to immobile in soil. The risk assessment considers the highly mobile active ingredient and

the mobility of the metabolites is considered not much higher, therefore the risk assessment is

considered to also cover the metabolites.

Conclusions of the groundwater risk assessment

For tetraniliprole the risks for groundwater contamination are below the level that might trigger


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Sediment risk assessment

The sediment risk assessment for tetraniliprole is performed following the method outlined in the risk

assessment methodology document (EPA 2018).

The input parameters used in the risk assessment are summarised in Table 49.

Table 49: Input values and calculations for sediment risk assessment

Input parameters Value

PEC local water 0.0072

Toxicity value 0.0068


PEC local sediment 0.0276

RQ 38.9

Conclusions of the sediment risk assessment

The RQ for sediment-dwelling organisms was above the LOC. The proposed controls to mitigate risks

to other aquatic organisms are considered to also protect sediment-dwelling organisms as it is based

on the aquatic exposure of sediment dwelling organisms (Chironomids).

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Terrestrial risk assessment

The terrestrial risk assessment considers the risks to soil organisms, terrestrial plants, birds, bees and

non-target arthropods.

The methodology for the terrestrial risk assessment is described in the risk assessment methodology

document (EPA 2018).

Soil macro-organisms

The soil organism risk assessment is based on a comparison of the PEC with toxicity values for the

substance. The toxicity value is divided by the PEC to give a Toxicity Exposure Ratio (TER). The

different levels of concern assigned to specific TER values are listed in the risk assessment

methodology document (EPA 2018).

The results of the acute risk assessment for soil organisms are summarised in Table 50. Results for

the chronic risk assessment for soils organisms are summarised in Table 51.

Table 50: Acute TER values for soil organisms

Species LC50

(mg/kg soil)

Drift

(%)

PEC (mg/kg

soil) TER acute Conclusion

Scenario – 3 times 60 g/ha – “in-field”

Earthworm >1000 NA 0.22 >4636 Below LOC for threatened/non-

threatened species

Scenario – 3 times 60 g/ha – “off-field”

Earthworm >1000 11.01 0.024 >42105 Below LOC for threatened/non-

threatened species

Table 51: Chronic TER values for soil organisms (using converted formulation data)

Species

NOEC

(mg ai/kg

soil)

Drift

(%)

PEC (mg/kg

soil) TER Conclusion

Scenario – 3 times 60 g/ha – “in-field”

Earthworm /

soil mite >200 NA 0.22 >927

Below LOC for threatened/non-

threatened species

Scenario – 3 times 60 g/ha – “off-field”

Earthworm /

soil mite >200 11.01 0.024 >8421

Below LOC for threatened/non-

threatened species

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Soil accumulation potential

According to Annex D (Information Requirements and screening criteria) of the HSNO Act, a

substance is considered persistent “if the half-life of the chemical in water is greater than two months,

or that its half-life in soil is greater than six months or if its half-life in sediment is greater than six

months”.

Given that the active ingredient tetraniliprole meets the above criteria for soil in the study and is

considered persistent using a weight of evidence approach, the potential for soil accumulation

following application of Vayego has been evaluated using the UK Health and Safety Executive’s PEC

Soil Calculator (Version 1.0).

Results of the acute and chronic risk assessment using the calculated peak PECsoil (20 years) are


Table 52: TER values for soil organisms following application of Vayego for 20 years

Species Endpoint

(mg/kg soil)1

Peak

PECsoil, 20

years

(mg/kg soil)

TER Conclusion

Scenario – 60 g/ha, 3 applications per year – “in-field”, acute

Earthworm >1000 0.281 >3559 Risk below LOC

Scenario – 60 g/ha, 3 applications per year – “in-field”, chronic

Earthworm

/ soil mite >200 0.281 >712 Risk below LOC

Given that the peak PECsoil accumulation value without crop interception with the highest application

rate per year is worst-case and no risks were identified, the long-term risk to soil organisms is

considered below the LOC.

Soil microorganisms

No adverse effects on nitrogen and carbon transformation were observed up to a rate of 10 L

substance per ha (2.0 kg ai/ha). As this is much higher than the proposed application rate of 0.06 kg

ai/ha, therefore no adverse effects are expected to soil microflora.

Conclusions of the soil organism risk assessment

Risks resulting from predicted acute exposures of soil organisms to tetraniliprole are below the LOC

for earthworms and soil micro-organisms.

No chronic data on the active ingredient are provided. However, this is not considered a data gap

because chronic data with the substance for earthworms and soil mites are provided. The results of

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these studies, as well as the risk assessment, indicate there are no chronic risks for both species

(NOEC >200 mg ai/kg soil).

The potential for soil accumulation following three applications per year (worst-case scenario) of

Vayego was evaluated (over a 20 year period) and no risks to soil organisms were identified.

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Non-target plant risk assessment

The non-target plant risk assessment is based on a comparison of the PEC with toxicity values for the

substance. Depending on the type of data provided, for non-threatened plants, a TER or an RQ is

calculated (a TER is used when an EC50 is available, an RQ is used when an EC25 is available). For

threatened non-target plants, an RQ is calculated by comparing the PEC with a No Observed Effect

Concentration (NOEC). The different levels of concern assigned to specific TER/RQ values are listed

described in the risk assessment methodology document (EPA 2018).

RQ/TER values for non-threatened non-target plants are shown in Table 53. TER values for

threatened non-target plants are shown in Table 54.

Table 53: RQ/TER value for non-target plant – edge of field

Scenario

Exposure

(g ai/ha) *

drift factor

EC25

(g ai/ha) RQ Conclusion

Fruit crops 3 times

60 g/ha

15 >200

(seedling emergence and

vegetative vigour)

<0.076 Below LOC for


species

Table 54: TER value for threatened non-target plant

Scenarios

Exposure

(g ai/ha) *

drift factor

NOEC

(g ai/ha) RQ Conclusion

Fruit crops 3 times

60 g/ha

15 200

(seedling emergence and

vegetative vigour)

0.076 Below LOC for


species

Conclusion for non-target plant risk assessment

Only the worst-case situation is assessed: the highest application rate and frequency without crop

interception. The predicted RQ to non-target plants calculated for tetraniliprole when applied to fruit

crops is below the LOC for both threatened and non-threatened species. Consequently, the other

uses and the effect of crop interception are not assessed as risks will be lower and therefore below

the LOC.

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Bird risk assessment

The bird risk assessment is based on a comparison of the PEC with toxicity values for the substance.

The toxicity value is divided by the PEC to give a Toxicity Exposure Ratio (TER). The different levels

of concern assigned to specific TER values are listed in the risk assessment methodology document

(EPA 2018).

Screening assessment

Predicted exposure to tetraniliprole under the bird acute dietary and reproduction screening

assessments is shown in Table 54.

Table 55: Exposure of birds for acute and reproduction screening assessments

Screening

type1

Indicator

species2

Applica

tion

rate

(kg/ha)

Short-cut

value

(90th%)3

Time

Weighted

Average4

(TWA)

Multiple

Application

Factor

(MAF)

(90th %)5

Number

of

applicati

ons

Daily

Dietary

Dose

(DDD)

Fruit crops- 3 times 60 g ai/ha, 21-day interval as worst-case scenario

Acute Small

insectivorou

s bird

0.06 46.8 NA 1.2 3 3.37

Reproduction 0.06 18.2 0.53 1.3 3 0.75

Grapes- once 60 g ai/ha

Acute Small

omnivorous

bird

0.06 95.3 NA 1 1 5.72

Reproduction 0.06 38.9 0.53 1 1 2.33

1 EFSA (EFSA 2009), Table 5 p27 2 EFSA (EFSA 2009), Table 6 p28 3 90th %ile short-cut value used for the acute assessment, mean value used for the reproduction assessment. EFSA

(EFSA 2009), Table 6 p28 4 The exposure assessment of the reproduction assessment uses time-weighted average (TWA) exposure estimates

over 1, 2, 3 or 21 days for different phases of the assessment. 1 day = 1.0; 2 days = 0.93; 3 days = 0.9; 21 days = 0.53. EFSA (EFSA 2009), Table 11 p34.

5 90th %ile MAF value used for the acute assessment, mean value used for the reproduction assessment. EFSA (EFSA 2009), Table 7 p29

Calculation of TERs

TER calculations for the acute dietary risk assessment are detailed in Table 56 and calculations for

the reproductive risk assessment are shown in Table 57.

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Table 56: TER values for acute dietary risk assessment (MAF = 1.2 or 1.0)

Crops Generic focal

species1 DDD

Toxicity

endpoint value

(mg/kg bw/d)*

TER

ratio Conclusion

Fruit crops, pome

fruit (worst-case

scenario)

Small

insectivorous

bird

3.37 2000 594

Below LOC for

threatened/non-

threatened species

Grapes Small

omnivorous bird 5.72 2000 350

Below LOC for

threatened/non-

threatened species

Table 57: TER values for reproductive risk assessment (TWA = 0.53; MAF = 1.3 or 1.0)

Crops & BBCH

class

Generic focal

species1 DDD

Toxicity

endpoint value

(mg/kg bw/d)*

TER

ratio Conclusion

Fruit crops, pome

fruit (worst-case

scenario)

Small

insectivorous

bird

0.75 42.9 57

Below LOC for

threatened/non-

threatened species

Grapes Small

omnivorous bird 2.33 42.9 35

Below LOC for

threatened/non-

threatened species

* Normally the NOAEL has to be converted from units of ppm (mg/kg diet) to mg/kg bw/day. In the first instance, a factor of 0.1 is used for such conversion. If specific information is available from the test reports, this is preferable. When reported as ppm in the studies, daily dose (mg/kg/day) = [Concentration in food (mg/kg) * Daily food consumption (g/bird/day)] / body weight (g) (over the entire exposure period).

The worst-case scenario for fruit crops results in risk below LOC. Consequently, the risks of the other

use will be below LOC as well. The risk for the grape scenario is below the level of concern

Conclusions of the bird screening risk assessment

The acute screening risk assessment indicates an acute risk below the LOC to birds from

tetraniliprole from the use of Vayego. In the reproductive screening assessment, the TER values also

indicate a chronic risk below the LOC to birds. As no risks were above the LOC, a Tier 1 risk

assessment was not performed.

Secondary poisoning

Given the criteria under the HSNO Act, tetraniliprole is not considered to be bioaccumulative

(BCF < 500). Therefore, no risk assessment via secondary poisoning is performed.

Conclusions for bird risk assessment

TER values for birds calculated for tetraniliprole when applied to fruit crops as the formulated product

Vayego are below the LOC and any risks are negligible.

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Pollinator risk assessment

The basis for the pollinator risk assessment is a comparison of the Environmental Exposure

Concentration (EEC) with toxicity endpoints to which safety factors have been applied. The EEC is

divided by the toxicity endpoint to calculate a RQ value. The methodology for the pollinator risk

assessment, including the LOC ascribed to specific RQ values, is described in detail in the risk

assessment methodology (EPA 2018).

Vayego is intended to be applied as a broadcast foliar spray at 60 g ai/ha. Up to 3 applications are

intended on pome fruits (post bloom), 2 on stone fruit (post bloom). Only one application per year is

intended on grapes and kiwifruit, but the application on kiwifruit is before bloom.

Tier I pollinator risk assessment

The results of the first tier of the bee risk assessment are shown in Table 58.

Table 58: Bee exposure estimates and RQ values

Use scenario Application

rate (kg ai/ha)

EEC (µg

ai/bee)

Toxicity endpoint

value (µg ai/bee) RQ Conclusion

Acute / Adult bees – contact

Foliar spray 0.060 0.144 0.41 0.35 Below the LOC

Acute / Adult bees – oral

Foliar spray 0.060 1.72 0.01 171.72 Above the LOC

Chronic / Adult bees – dietary


Acute / Larvae – oral


Chronic / Larvae – dietary


The first tier analysis shows risks above the LOC for adults and larvae for oral acute and oral chronic

exposure. Risks from dermal exposure were below the LOC. Because risks to bees were identified, a

higher tier assessment was performed.

Tier II pollinator risk assessment

The applicant provided three studies on residues (the active ingredient is a systemic insecticide). The

results of these studies are summarized in Table 59. Two studies measured tetraniliprole content in

bee relevant matrices collected 6 to 10 months after three post-bloom applications in the previous

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growing season and considered relevant scenarios for pome and stone fruit (pollen cherry 10.8 µg/kg,

apple 0.9 µg/kg; no residues in nectar).

Table 59: Residues in pollen and nectar

Crop

species

Application details Residue level Reference

Cherry trees

3 foliar spray applications

at 60 g ai/ha post

flowering.

Nectar: 0

Pollen: 10.8 µg/kg (measured 10

months post applications)

Boscksch S. 2016. Table

138; Appendix J

Phacelia 1 foliar application at 60 g

ai/ha 16 days before the

onset of flowering

Nectar: 3.2 µg/kg

Pollen (comb): 4.8 µg/kg

Pollen (foragers): 4.3 µg/kg

Kanz C. 2016.; Table

139; Appendix J

Apple 3 foliar spray applications

at 60 g ai/ha post

flowering

Nectar: 0

Pollen: 0.9 µg/kg (measured 6

months post applications)

Fischer DR. and Jerkins

E. 2016.; Table 140 ;

Appendix J.

It is noted that no residue data were available for royal jelly; residue concentration higher than 8 µg/kg

would induce risks above the LOC according to BeeRex model (acute adult RQ=0.42, chronic

RQ=0.58, below LOC for larvae).The residues in apple pollen have been used to refine the risk

assessment for pome fruits (Table 60).

Table 60: Refined bee exposure estimates and RQ values for use on pome fruits

Use

scenario

Application

rate (kg

ai/ha)

Residue

concentration

(µg/kg)

EEC (µg

ai/bee)

Toxicity

endpoint value

(µg ai/bee)

RQ Conclusion


Foliar spray

on pome tree

post bloom

0.060 0.9 0.0000086 0.01 0.00 Below the LOC


Foliar spray

on pome tree

post bloom

0.060 0.9 0.0000086 0.00723 0.00 Below the LOC


Foliar spray

on pome tree

post bloom

0.060 0.9 0.0000032 0.0128 0.00 Below the LOC


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Use

scenario

Application

rate (kg

ai/ha)

Residue

concentration

(µg/kg)

EEC (µg

ai/bee)

Toxicity

endpoint value

(µg ai/bee)

RQ Conclusion

Foliar spray

on pome tree

post bloom

0.060 0.9 0.0000032 0.0033 0.00 Below the LOC

Risks to bees from the use of Vayego on pome fruits were below the LOC at the second tier of

analysis, when using pollen residue data from apple trees.

The residues in cherry pollen have been used to refine the risk assessment for stone fruits (Table 61).

Table 61: Refined bee exposure estimates and RQ values for use on stone fruits

Use

scenario

Application

rate (kg

ai/ha)

Residue

concentration

(µg/kg)

EEC

(µg

ai/bee)

Toxicity

endpoint value

(µg ai/bee)

RQ Conclusion


Foliar spray on

pome tree

post bloom

0.060 11 0.0001 0.01 0.01 Below the LOC


Foliar spray on

pome tree

post bloom

0.060 11 0.0001 0.00723 0.01 Below the LOC


Foliar spray on

pome tree

post bloom

0.060 11 0.00004 0.0128 0.00 Below the LOC


Foliar spray on

pome tree

post bloom

0.060 11 0.00004 0.0033 0.01 Below the LOC

Risks to bees from the use of Vayego on stone fruits were below the LOC at the second tier of

analysis, when using pollen residue data from cherry trees.

No residue analysis was provided for kiwifruit, despite the intended use pattern including pre-bloom

application on this crop which would result in potentially a high exposure of the bees. The applicant

proposes to use residue from a different crop, Phacelia (see Kanz C. 2016.; Table 139as a surrogate

for kiwifruit. The maximum residue level in Phacelia pollen collected from combs (4.8 µg/kg) was

measured 25 days after one application at the target application rate of 60 g ai/ha. Residues from

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pollen collected on foragers were still above the level of detection 16 days after the application. The

applicant proposes a 7-day pre-flowering interval on kiwifruit to protect bees.

The applicant provided a summary of the available information of their product that indicated the

availability of a number of studies on residues, however, these studies were not made available to the

EPA. Given the inter-species variation between residues (apple 0.9 µg/kg versus cherry 11 µg/kg and

variation in other studies provided in the summary), there is uncertainty on whether the residues on

Phacelia are suitable to use as a surrogate for kiwifruit. It was therefore determined that the residues

of Phacelia cannot be used to refine the risk assessment. Residue concentration in kiwifruit pollen

higher than 750 µg/kg would induce risks above the LOC according to BeeRex model (chronic adult

RQ=1.00, chronic larva RQ=0.82). Given that the residue level in kiwifruit pollen would need to be

significantly higher than the maximum level detected in other crops (750 µg/kg vs 140 µg/kg), the risks

to bees from the application on kiwifruit is considered unlikely to be above the LOC.

The applicant has proposed a 7-day pre-flowering interval for kiwifruit. As the risks to pollinators

without this control have been assessed as likely to be low and since there is no information available

to determine if application of a 7-day pre-flowering would result in a substantial decrease in residue

levels, the EPA does not recommend applying a pre-flowering interval for kiwifruit.

No residue analysis was performed on grapes, but given the low attractiveness of flowering grapes to

bees, the risks were considered negligible.

Tier III pollinator risk assessment

Beside residue studies, higher tier studies were provided. These studies were considered to refine the

risk assessment for the use of Vayego on kiwifruit.

One of the studies provided assessed the effect of foliar spray at the intended application rate and

application method (foliar spray at 60 g ai/ha, single application). This semi-field study (Rexer 2016,

Table 227) was performed with one foliar application 5 days before bees start foraging on Phacelia at

full bloom at the intended application rate (60 g ai/ha). This study showed no major effect on

behaviour, mortality, flight intensity and colony strength but a treatment-related transient effect on

brood development was apparent. Since adverse effects were measured in this study and given the

variability in residue levels between plant species highlighted in the tier II analysis, it is considered

that this study cannot be used to refine the risk assessment for use on kiwifruit, however, the

evaluation of the maximum residue levels from other species indicate that the risk is likely low.

One semi-field study was performed on bumblebees (Klein 2016; Table 229) with two foliar

applications at 8 g ai/ha. No major effects were detected but all colonies were in poor conditions and

therefore the study had to be terminated before the assessment of the reproduction ability could be

performed. The results of the study are considered of limited value. No risk assessment is available

for bumblebees but results can be extrapolated from the risk assessment on honey bees for pome

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fruits and stone fruit because the acute oral LD50 value for bumblebees is very similar to that of honey

bees (taking into account the weight difference between the two species).

It is noted that kiwifruit is mainly pollinated by bumblebees, in the absence of residue data, the risk to

bumblebees is considered to be similar to that calculated at tier II for honey bees, therefore unlikely to

be above the LOC.

Conclusions of the pollinator risk assessment

The first tier analysis shows risks above the LOC for adults and larvae for oral acute and oral chronic

exposure. Risks to bees from the use of Vayego on stone fruits and pome fruits were below the LOC

at the second tier of analysis, when using pollen residue data from cherry and apple trees. These

conclusions can be extrapolated to bumble bees.

Even though no residue analysis was provided for grapes, given the application post-bloom and low

attractiveness of this crop, effects are expected to be below the LOC.

The first tier risk assessment indicated a high risk to bees when the substance is applied to kiwifruit in

accordance with the GAP table (Table 6). With the available information, the assessment of the risks

cannot be fully refined, however risks above the LOC are considered to be unlikely based on the

expected residue levels.

Non-target arthropod risk assessment

The non-target arthropod risk assessment is a comparison of the predicted environmental

concentration (PEC) with toxicity endpoints to which safety factors have been applied. The PEC is

divided by the toxicity endpoint to calculate a Hazard Quotient (HQ) value. The methodology for the

non-target arthropods risk assessment, including the LOC ascribed to specific HQ values, is

described in detail in the EPA risk assessment methodology document (EPA 2018).

Tier I non-target arthropod risk assessment

Results of the Tier I in-field and off-field non-target arthropod risk assessment are shown in Table 62

and Table 63, respectively.

Table 62: In-field HQ values for non-target arthropods: Tier I

Species LR50

(g ai/ha)

Application rate

(g ai/ha) MAF HQ Conclusion

Three applications (pome fruit)

Parasitic wasp,

Aphidius rhopalosiphi 0.627 60 2.3 220 Above the LOC

Predatory mite,

Typhlodromus pyri >44 60 2.3 <3

Potentially above

the LOC

Two applications (stone fruit)

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Species LR50

(g ai/ha)

Application rate


Parasitic wasp,


Predatory mite,

Typhlodromus pyri >44 60 1.7 <2.3

Likely below the

LOC

One application (grapes and kiwi fruit)

Parasitic wasp,


Predatory mite,

Typhlodromus pyri >44 60 1.0 <1.4 Below the LOC

Table 63: Off-field HQ values for non-target arthropods: Tier I

Species LR50

(g ai/ha)

Application rate


Three applications (11.01% drift – Pome fruit1)

Parasitic wasp,


Predatory mite,

Typhlodromus pyri >44 60 2.3 <0.35 Below the LOC

Two applications (12.13% drift – stone fruit2)

Parasitic wasp,


One application (8.02% – grapes and kiwifruit3)

Parasitic wasp,


1 “Fruit crops” used as representative crop for pome fruit (maximum three applications)

2 “Fruit crops” used as representative crop for applications to stone fruit (maximum two applications)

3 “Grapevine” used as representative crop for applications to grapes and kiwifruit (one application only)

Tier I conclusion

Risks to predatory wasps are considered to be above the level of concern for all use patterns, in-field

as well as off-field.

For the predatory mite in-field risks is potentially above the level of concern for two and three

applications. The actual risk could not be determined because the LR50 could not be determined in the

studies (highest tested concentration did not cause >50% mortality). The HQ associated with two

applications is very close to the trigger value and therefore risks are likely below the level of concern.

The in-field risks for three applications cannot be fully excluded.For the predatory mite Typhlodromus

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pyri, off-field risks are considered negligible since risks were below the level of concern for the worst-

case application pattern (three applications).

Because risks to parasitic wasps were identified as well as potential risks to predatory mites a higher

tier assessment was performed.

Tier II non-target arthropod risk assessment

Risks were identified as above the level of concern both in-field and off-field from use of Vayego at

Tier I. As such, risks to non-target arthropods have been assessed at Tier II, using the higher tier

extended laboratory studies for the parasitic wasp Aphidius rhopalosiphi, as well as the two additional

species green lacewing Chrysoperla carnea and ladybird beetle Coccinella septempunctata following

the recommendations by the ESCORT2 guidance (Workshop, Candolfi et al.) as shown in Table 64.

In the Tier I assessment potential risks were identified for the predatory mite Typhlodromus pyri when

Vayego is applied three times at 60 g ai/ha. A further evaluation and refinement of this potential risk

would have been appropriate. However, extended laboratory studies with predatory mites were not

available.

Table 64: HQ values for non-target arthropods in-field: Tier II

Species LR50

(g ai/ha)

Application rate


Three applications (pome fruit)

Parasitic wasp,


Green lacewing,

Chrysoperla carnea >44 60 2.3 <3

Potentially above

the LOC

Ladybird,

Coccinella septempunctata >44 60 2.3 <3

Potentially above

the LOC

Two applications (stone fruit)

Parasitic wasp,


Green lacewing,

Chrysoperla carnea >44 60 1.7 <2.3

Likely below the

LOC

Ladybird,

Coccinella septempunctata >44 60 1.7 <2.3

Likely below the

LOC

One application (grapes and kiwi fruit)

Parasitic wasp,


Green lacewing,

Chrysoperla carnea >44 60 1.0 <1.4 Below the LOC

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Species LR50

(g ai/ha)

Application rate


Ladybird,

Coccinella septempunctata >44 60 1.0 <1.4 Below the LOC

Table 65: HQ values for non-target arthropods off-field: Tier II

Species LR50

(g ai/ha)

Application rate


Three applications (11.01% drift – pome fruit)

Parasitic wasp,


Green lacewing,

Chrysoperla carnea >44 60 2.3 <0.4 Below the LOC

Ladybird,

Coccinella septempunctata >44 60 2.3 <0.4 Below the LOC

Two applications (12.13% drift – stone fruit)

Parasitic wasp,


One application (8.02% drift – grapes and kiwi fruit)

Parasitic wasp,


Tier II conclusion

Risks to non-target arthropods have been identified at Tier II. Using the extended laboratory tests,

risks to the parasitic wasp Aphidius rhopalosiphi were identified for all use patterns in-field as well as

off-field.

For the green lacewing and the ladybird, in-field risks are potentially above the level of concern for

two and three applications. The actual risk could not be determined because the LR50 could not be

determined in the studies (highest tested concentration did not cause >50% mortality). The HQ

associated with two applications is very close to the trigger value and therefore risks are likely below

the level of concern. The in-field risks for three applications, however, cannot be fully excluded. For

the green lacewing and the ladybird, off-field risks are considered negligible for all use patterns since

risks were below the level of concern for the worst-case use (three applications).

As risks could not be fully excluded at the Tier II level, a higher tier assessment was performed.

Tier III non-target arthropod risk assessment

Four semi-field studies for parasitoid wasps were submitted (see Table 33).

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In-field

Based on the Tier I and Tier II risk assessments, the highest concern was identified for parasitic

wasps. For the predatory mite, green lacewing and ladybirds the LR50 could not be determined. By

using the worst-case estimate, it was considered that the risks for one and two applications are below

the level of concern. The risks associated with three applications could not be fully excluded based on

the available data in Tier I and Tier II.

The parasitoid wasp has been identified as the most sensitive species in the lower tier assessments

and several semi-field tests have been performed. For a single application of 60 g ai/ha, several

studies with several species in several crops were performed. After considering a reasonable

recovery time of 14 days, Vayego was considered to be harmless to slightly harmful to parasitic

wasps. Using a weight of evidence approach also using the Tier I and Tier II information it is

considered that the effects on parasitic wasps are acceptable when Vayego is applied as a single

application.

One study evaluating the effects of two applications was provided (Ernst G., Kroder S. 2016, Table 210)

this study indicated that when Vayego is applied twice at a rate of 60 g ai/ha, effects vary between

harmless and slightly harmful. In one of the two cases, slightly harmful effects were observed but

these disappeared after one day. In the other case, the effects were still observed after 14 days.

Using a weight of evidence approach also using the Tier I and Tier II information, it is considered that

the effects on parasitic wasps are likely acceptable for one and two applications.

The provided semi-field studies provide insufficient information to evaluate the risks from three

applications of Vayego at a rate of 60 g.ai/ha. Therefore, risks from three applications cannot be

excluded.

The applicant has provided an evaluation regarding the compatibility of other organisms associated

with Integrated Pest Management (ie predatory bugs, earwigs, lady birds) at lower application rates

and/or lower application frequencies. Based on the assessment and associated provided studies, it is

concluded that the risks from a single application at 60 g ai/ha are considered likely below the level of

concern for predatory bugs (eg. Orius spp), earwigs (Forficula sp) and ladybirds (Coccinellidae)2. The

EPA considers that the presented studies do no provide sufficient information to draw conclusions

regarding the additional applications requested in the application (pome and stone fruit). For

predatory mites (Anthocoris nemoralis), Vayego was considered harmless to slightly harmful after two

applications of 45 g ai/ha (Project nr:IR12BELPFF0425; Table 217), a more pronounced effect was

observed after the second application. It is possible that an even more pronounced effect will be

observed with a third application. Insufficient information is also available regarding the potential

effects of three applications to the predatory mite, green lacewing and ladybirds.

2 This study is referred to as 11ZAphidpredAlnusVegiOri-49, a spreadsheet and presentation was

provided. No full study report has been provided and therefore there is no summary in appendix J.

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In conclusion, based on a weight of evidence approach, it is considered highly unlikely that a single

application will have unacceptable adverse effect on the non-target arthropods (at this frequency the

substance is potentially slightly harmful). For two applications, less information is available however

the data suggest that the maximum observed effect likely will be that the substance is slightly harmful.

The EPA considers this acceptable. However, insufficient information is provided to exclude risks from

three applications.



“WARNING” the substance might not be not compatible with Integrated Pest

Management (IPM) when applied three times.

Off-field

In two tests on grassland/meadow as a representative off-crop habitat (Bakker F., Aldershof S.A.

2016, Table 213 and Table 214), the no-observed-effect-rate (NOER) community and no-observed-

ecologically-adverse-effect-rate (NOEAER) population were 4 g ai/ha (one application, maximum rate

tested).

The study assessed the effects after one treatment rather than the two and three applications

requested in the application. In the study statistically significant effects were observed on the

populations of several species (NOER population was 0.4 and 1.6 g ai/ha), however these recovered

after one and two months respectively. The interval between the applications is shorter than the

indicated recovery times. As a result already impacted, and not recovered populations can be

impacted again which might have a “knock-on” effect and potentially the local population cannot

recover.

The NOEAER population (4 g ai/ha) is considered the acceptable maximum allowable off-field

exposure for a single application.

Using the NOEC to determine the required buffer zones for a single application would be too

conservative as both field studies have demonstated recovery prior to the next planned application.

The BBA drift tables from the previous Tier assessments have been used to calculate the downwind

buffer zones. The required downwind buffer zone to mitigate the off-field effects from a single

application on kiwifruit and grapes is 5 m (3.6% drift). It should be noted that this buffer zone is small

and conservative as the NOEAER population is the highest application rate tested. If a higher rate

had been tested, it is possible that a higher NOEAER would be determined and thus a smaller

downwind buffer zone would have been required.

Combining the small size and the conservatism of the assessment, the EPA recommends not to apply

a downwind buffer zone. The risks for off-field effects on non target arthropod populations from a

single application on kiwifruit and grapes is considered low.

The NOEAER population (4 g ai/ha) has a recovery time of 1 and 2 months “incorporatedin its

determination. The application interval for Vayego is shorter than this recovery period, therefore, the

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average NOER population (1.00 g ai/ha average of 0.4 and 1.6 g ai/ha) is used to determine the

downwind buffer zone required to protect off-field non-target arthropods when multiple applictions of

Vayego are envisaged. The same MAF and BBA drift tables from the previous Tier assessments have

been used. The downwind buffer zone required to mitigate the effects from two applications on stone-

fruit is 20 meters, and for three applications on pome-fruit is 30 meters.

The assessment concluded that no downwind bufferzones are required for a single application to

kiwifruit and grapes, minor effects cannot be fully excluded but are considered acceptable. The

downwind buffer zone required to mitigate the effects from two applications on stone-fruit is 20

meters, and for three applications on pome-fruit is 30 meters. However, these downwind buffer zones

are not expected to be practical.

As the downwind buffer zones are considered not to be practical and therefore not recommended. To

minimise effects to non-target arthropods (off-field) the following label statement is advised:

“The best available application technique, which minimises off-target drift should be used to

reduce effects on non-target insects or other arthropods.”

Conclusion for non-target arthropod risk assessments

The results of the non-target risk assessment are summarized in Table 66.

In-field risks:

Parasitic wasps:

Tier I and Tier II of the risk assessment indicates that the in-field risks and off-field risk to the parasitic

wasp (Aphidius rhopalosiphi) is above the level of concern for all use patterns. The evaluation of Tier

III studies in semi-field situations evaluating three different species of parasitic wasps (Aphidius

colemani, Encarsia Formosa and Aphelinus mali) indicate that Vayego is harmless to slightly harmful

after 14 days when applied as a single application (as proposed for application on kiwifruit and grape).

For two applications (stone fruit) sufficient information was available for Aphelinus mali for which the

effects seemed slightly more pronounced compared to one application (harmless to slightly harmful

after 14 days instead of harmless). For the other two species, which showed a slightly more

pronounced effect in the single application study compared with Aphelinus mali, no data was

presented for two applications. No information was available to determine the effect of three

application and a “dose-response” was observed. As such, the effect at three applications is likely to

be more pronounced, however, the degree of severity cannot be determined.

In conclusion the EPA determined that effects from a single application will be limited, for two

applications, effects are likely to be slightly more pronounced but still acceptable (harmless-slightly

harmful), for three applications, insufficient data are available to refine the risks above the level of

concern identified in Tier I and II.

Other non-target arthropods:


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(Coccinella septempunctata) risks were determined to be below the level of concern when Vayego is

applied as a single application (kiwifruit) and applied twice (stone-fruit). The potential risk identified in-

field for three applications of Vayego (pome-fruit) are (partially) due to the test design. The application

rate was too low to determine the 50% effect concentration, and thus the endpoint was expressed as

bigger than. The EPA acknowledges the fact that the actual risk is lower than the identified risk,

however, how much lower is unknown. Additional Tier III data and an evaluation by the applicant

showed sufficient evidence that a single application is indeed unlikely to impact several beneficial

organisms. Some information was provided for two applications indicating that Vayego most likely is

harmless-slightly harmful. For 3 applications (pome-fruit), insufficient data are available to refine the

risks above the level of concern identified in TIER I and II.

Off-field risks:




applications on pome-fruit is 30 meters. However, these downwind buffer zones are not expected to

be practical.

As the downwind buffer zones are considered not to be practical and therefore not recommended.

The interval between the applications is shorter than the indicated recovery times. As a result, already

impacted, and not recovered populations can be impacted again which might have a “knock-on” effect

and potentially the local population cannot recover. To minimise effects to non-target arthropods (off-

field) the following label statement is advised:



Overall conclusion:

Based on a weight of evidence approach, it is considered highly unlikely that a single application of

Vayego will have highly adverse effect on the non-target arthropods (at this frequency the substance

is potentially slightly harmful). For two applications of Vayego, less information is available however

the data suggest that the observed effect likely will be that the substance is slightly harmful to

beneficial insects.

Insufficient information is provided to exclude risks from three applications. If three applications are

being approved, the EPA suggests to include a label statement warning end-users of the potential

negative effects to beneficial insects of three applications. To inform end-users that effect on non-

target arthropods (including those used in IPM) cannot be excluded the following statement is

advised:

“WARNING” the substance might not be not compatible with Integrated Pest

Management (IPM) when applied three times.

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Risk for off-field effects were identified and downwind buffer zones were calculated and considered

necessary for two and three applications. These downwind buffer zones are considered not to be

practical. To minimise effects to non-target arthropods (off-field) the following label statement is

advised:



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Table 66: Summary of the non-target arthropod risk assessment

Species Pome fruit Stone fruit Kiwifruit and grape

3x 60 g a.i/ha 2x 60 g a.i/ha 1x 60 g a.i/ha

In-field Off-field In-field Off-field In-field Off-field

TIER I

Parasitic wasp, Aphidius

rhopalosiphi Above the LOC Above the LOC Above the LOC Above the LOC Above the LOC Above the LOC

Predatory mite, Typhlodromus pyri Potentially above the LOC Below the LOC Likely below the LOC Below the LOC Below the LOC Below the LOC

TIER II

Parasitic wasp, Aphidius

rhopalosiphi Above the LOC Above the LOC Above the LOC Above the LOC Above the LOC Above the LOC

Green lacewing, Chrysoperla carnea Potentially above the LOC Below the LOC Likely below the LOC Below the LOC Below the LOC Below the LOC

Ladybird, Coccinella

septempunctata Potentially above the LOC Below the LOC Likely below the LOC Below the LOC Below the LOC Below the LOC

TIER III

In-field1

Parasitic wasp, Aphidius colemani

(after 14 days) Insufficient data Insufficient data

Harmless-

slightly harmful

Parasitic wasp, Encarsia Formosa

(after 14 days) Insufficient data Insufficient data

Harmless-

slightly harmful

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Species Pome fruit Stone fruit Kiwifruit and grape

Parasitic wasp, Aphelinus mali

(after 14 days) Insufficient data

Harmless-slightly

harmful Harmless

Off-field

Field studies (2x)

Likely that off-field

population effects will be

observed

Likely that off-field

population effects

will be observed

Potential (likely

limited) off-

field population

effects will be

observed

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Conclusions of the ecological risk assessment

The EPA assessed the potential risk to be triggered by the use of Vayego following the instructions

captured in the proposed label and GAP table.

Aquatic organisms:

EECs of tetraniliprole applied as the formulated product Vayego resulted in calculated RQ above the

LOC for the aquatic environment (threatened crustaceans and insects). To mitigate these risks, it is

proposed to apply controls to reduce spray-drift and runoff into the aquatic environment.

The following controls are proposed to reduce exposures below the LOC and thus mitigate the risks:






g ai/ha per year), the substance should not be applied within 20 m of any waterbody.






g ai/ha per year), there should be a downwind buffer zone of 5 m for waterbodies.

- The substance must not be applied when wind speeds are less than 3 km/hr or more than 20

km/hr as measured at the application site.

Groundwater:

For tetraniliprole, the risks for groundwater contamination are below the level that might trigger


Sediment-dwelling organisms:

The RQ of tetraniliprole is above the LOC (LOC ≥1). However, it is considered that the controls

proposed to protect the aquatic environment also protect the sediment-dwelling organisms and

reduce the risks to a negligible level.

Soil organisms:

Predicted acute exposures to soil organisms of tetraniliprole are below the LOC for an earthworm. No

chronic data of the active ingredient are provided. However, chronic data with the substance for

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earthworm and soil mite are provided. The results of the risk assessment indicate a risk below the

LOC. Furthermore, the potential for soil accumulation following three applications per year (worst-

case scenario) of Vayego was evaluated (over a 20 year period) and no risks to soil organisms were

identified.

Non-target plants:

Predicted non-target plant exposures to tetraniliprole, when applied to fruit crops and grapes as the

formulated product Vayego, are below the LOC for both threatened and not threatened species.

Birds:

The screening risk assessment indicates a risk below the LOC to birds from the use of Vayego

according to the provided GAP table. Tetraniliprole is not bioaccumulative so no risk assessment for

secondary poisoning is necessary for this active ingredient.

Pollinators:

The Tier I assessment indicates a risk above the LOC. In Tier II, residue information was available to

refine the risk assessment for pome and stone fruit, the risks were determined to be below the LOC.

The risks to grapes were also considered below the LOC as grapes are generally not attractive to

bees and thus exposure is likely limited. No information on the residues in kiwifruit was available,

however, considering the maximum residues found and the minimum residue level required to trigger

an effect, these risks are also considered to be below the LOC.

Non-target arthropods:

In-field risks:

Parasitic wasps:

Tier I and Tier II of the risk assessment indicates that the in-field risks and off-field risk to the Parasitic

wasp (Aphidius rhopalosiphi) is above the level of concern for all use patterns. Evaluation of higher

Tier information (semi-field studies) indicated that risks from a single application are likely to be

limited. For two applications (stone-fruit) sufficient information was available for Aphelinus mali for

which the effects seemed slightly more pronounced compared to one application (harmless to slightly

harmful after 14 days instead of harmless). For 3 applications, insufficient data are available to refine

the risks which were identified as being above the level of concern at Tier I and II.

Other Non-Target Arthropods:


(Coccinella septempunctata), risks were determined to be below the level of concern when Vayego is

applied as a single application (kiwifruit) and applied twice (stone-fruit). The potential risk identified in-

field for three applications of Vayego (pome-fruit) are (partially) due to the test design. Higher Tier

information was provided to refine the risk, however, for 3 applications (pome-fruit), insufficient data

are available to refine the risks above the level of concern identified in Tier I and II.



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Off-field risks:




applications on pome-fruit is 30 meters. These downwind buffer zones considered not to be practical.

If the downwind buffer zones are not applied it is likely that potentially impacted, and not recovered

populations can be impacted at consecutive populations which might have a “knock-on” effect and

potentially the local population cannot recover within a reasonable time-frame. To minimise effects to

non-target arthropods (off-field) the following label statement is advised:



Conclusion:



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Appendix I: Proposed controls

Exposure thresholds

Exposure thresholds proposed for tetraniliprole are shown in Table 67. ADE and PDE values are not

controls as such but are health-based exposure guidance values which can be used to inform risk

assessments as well as the setting of controls, such as MRLs under the ACVM Act.

Table 67: Derivation of appropriate health-based exposure guidance value for tetraniliprole

Available

international

toxicological

thresholds

Key

Systemic

effect

NOAEL

(mg/kg bw/day)

Uncertainty

factors

Value

(mg/kg

bw/day)

Modificat

ions Remarks

None

Decreased

bw effects

and

increased

alkaline

phosphata

se activity

88.4 100 0.88 None

As no

international

value was

established the

EPA set a value

based on the

results of a 1-

year study in

dogs. (Appendix

J)

Based on the assessment of the available data, the following ADE, PDE and Acute Reference Dose

(ARfD) values have been provided (Table 68).

Table 68: Active ingredient exposure thresholds

Active Ingredient ADE PDE ARfD TEL

Tetraniliprole 0.88 mg/kg

bw/d (source)

PDE (Food) = 0.62

mg/kg bw/d

PDE (Drinking water)

= 0.18 mg/kg

bw/d

PDE (Other) = 0.09

mg/kg bw/day

The low acute toxicity of the

active ingredient means no

ARfD is required.

Not set at this

time

No Tolerable Exposure Limit (TEL) value has been set for this substance. This is because it is

considered that exposure is not likely to result in an appreciable toxic effect based on the quantitative

risk assessment done here.

Impurity limits

No impurity limits are set at this time.

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Other toxicity controls

None identified.

Ecotoxicity controls

Application restrictions

When applied on kiwifruit and grape, the maximum application rate of this substance is 60 g

tetraniliprole/ha (equivalent to 0.3 L/ha), with a maximum of one application per calendar year.

When applied on stone fruit, the maximum application rate of this substance is 60 g tetraniliprole/ha

(equivalent to 0.3 L/ha), with a maximum of two applications per calendar year with a minimum of 14

days between applications.

When applied on stone fruit, the maximum application rate of this substance is 60 g tetraniliprole/ha

(equivalent to 0.3 L/ha), with a maximum of three applications per calendar year with a minimum of 21

days between applications.

Additional and varied controls

It is considered that the prescribed controls will manage most of the risks to humans and the

environment. However, additional controls are recommended to be set and default controls varied to

mitigate the non-negligible risks to the environment. It should be noted that some uncertainties were

identified during the risk assessment and maybe not all risks are managed.

Application restrictions

Significant environmental risks may occur from the use of this substance, due to the hazards posed

by tetraniliprole, the active ingredient in Vayego. Therefore, it is considered necessary to set a

maximum application rate, number of applications and frequency.

Application method

Vayego must only be applied by ground-based methods.

Vayego must not be applied when wind speeds are less than 3 km/hr or more than 20 km/hr as

measured at the application site.

Buffer zone distances

The person in charge of the application of this substance and any person applying this substance

must ensure that the substance is not applied within a specified distance of a waterbody or off-field

non-target arthropod habitat.

For this substance the following buffer zones apply (see Table 69), according to the relevant

application method and scenario:

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Table 69: Proposed buffer zones for Vayego

Application method Sensitive area Required buffer

zone (m)

Ground-based

Pome fruit

Waterbody 25

Waterbody

(downwind) 200

Ground-based

Stone fruit

Waterbody 20

Waterbody

(downwind) 140

Ground-based

Kiwifruit and grapes

Waterbody 20

Waterbody

(downwind) 5

Label Statements

The following label statements are advised:



“WARNING” the substance might not be not compatible with Integrated Pest Management

(IPM) when applied three times.

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Appendix J: Study summaries

Manufacturer code name for tetraniliprole is BCS-CL73507 technical.

Manufacturer code name for Vayego is BCS-CL73507 SC 200 G.

Mammalian toxicity

Mammalian toxicity studies on tetraniliprole/Vayego have been reviewed. These studies are used to

describe potential risks to human health. The effects on mammals in these studies are used as

proxies for the impact on humans. Data from the studies have been used for classifying the active

ingredient and the formulated substance and for the derivation of appropriate health-based criteria

which are used in risk assessment. The summary of the studies is provided in Table 70 to Table 106.

Tetraniliprole

Acute toxicity [6.1]

Table 70: Acute Oral Toxicity [6.1 (oral)] – Study 1

Type of study Acute oral toxicity in male rats (Acute toxic class)

Flag Key study

Test Substance

BCS-CL73507 technical; Batch/Lot Number: 2012-005440; Specification

No.: 102000026788; Purity: 89.6% w/w; Expiry Date: 09 May, 2015;

Vehicle: Polyethylene glycol 400

Endpoint Mortality (LD50)

Value >2000 mg/kg bw

Reference

Matting, E.; 2014. BCS-CL73507 technical - Acute Oral Toxicity Study in

Male Rats; CiToxLAB Hungary Ltd., H-8200 Veszprem,

Szabadsagpuszta, Hungary; Activity ID: TXFVP158; Study Number:

14/218-001P; Edition No.: M-496837-01-2

Klimisch Score 1

Amendments/Deviations None of significance

GLP Yes

Test Guideline/s

OECD Guidelines for Testing of Chemicals No. 423

Commission Regulation (EC) No. 440/2008, B.1.

EPA Health Effects Test Guidelines (OPPTS 870.1100)

Species Rat

Strain CRL:(WI)

No/Sex/Group 6M, 3 animals/group

Dose Levels 2000 mg/kg bw

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Exposure Type Oral by gavage

Study Summary

Test article did not cause any mortality or any clinical signs during the 14

day observation period. Animals gained weight normally and there were

no abnormal observations at necropsy.

Additional Comments No additional comments

Conclusion The LD50 >2000 mg/kg bw and the test article is not classifiable as no

evidence of toxicity was observed.

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Table 71: Acute Oral Toxicity [6.1 (oral)] – Study 2

Type of study Acute oral toxicity in female rats (Acute toxic class)

Flag Key study

Test Substance



Vehicle: Polyethylene glycol 400



Reference

Matting, E.; 2013. BCS-CL73507 technical - Acute Oral Toxicity Study in

Rats; CiToxLAB Hungary Ltd., H-8200 Veszprem, Szabadsagpuszta,

Hungary; Activity ID: TXFVP054; Study Number: 13/040-001P; Edition

No.: M-462506-01-2

Klimisch Score 1


GLP Yes

Test Guideline/s


Commission Regulation (EC) No. 440/2008, B.1.


Species Rat

Strain CRL:(WI)

No/Sex/Group 6F, 3 animals/group



Study Summary



no abnormal observations at necropsy.




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Table 72: Acute Dermal Toxicity [6.1 (dermal)]

Type of study Acute dermal toxicity in rats

Flag Key study

Test Substance

BCS-CL73507 technical; Batch/Lot No.: 2012-005440; Specification No.:

102000026788; Purity: 89.6% w/w; Expiry Date: 28 May, 2013; Vehicle:

water to dampen



Reference

Matting, E.; 2013. BCS-CL73507 Technical - Acute Dermal Toxicity

Study in Rats; CiToxLAB Hungary Ltd., H-8200 Veszprem,

Szabadsagpuszta, Hungary; Laboratory project ID: 13/040-002P; Edition

No.: M-462507-01-1

Klimisch Score 1


GLP Yes

Test Guideline/s



Commission Regulation (EC) No. 440/2008, B.3

Species Rat

Strain Crl:WI Wistar

No/Sex/Group 5M, 5F


Exposure Type Dermal, applied neat (dampened with water) under a gauze and semi-

occlusive wrap for 24 hours

Study Summary

Test article did not cause any mortality. There were no treatment-related

clinical signs during the 14 day observation period nor did it affect weight

gains. There were no abnormal observations at necropsy.


Conclusion The LD50 is >2000 mg/kg bw and the test article is not classifiable as no


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Table 73: Acute Inhalation Toxicity [6.1 (inhalation)]

Type of study Acute inhalation (nose-only) toxicity in rats

Flag Key study

Test Substance



None

Endpoint Mortality (LC50)

Value > 5.01 mg/L

Reference

Nagy, K.; 2013. Acute Inhalation Toxicity Study (Nose-only) in the Rat

with BCS-CL73507 Technical. CiToxLAB Hungary Ltd., H-8200

Veszprem, Szabadsagpuszta, Hungary; Activity ID: TXFVP063; Report

Number: 13/040-004P; Edition No.: M-461520-01-1

Klimisch Score 1


GLP Yes

Test Guideline/s




Species Rat

Strain Crl:WI

No/Sex/Group 1M, 1F: Sighting study (Group 0.1)

5M, 5F: Main study (Group 1)

Dose Levels

4.83 ± 0.80 mg/L (Group 0.1), 5.01 ± 0.15 mg/L (Group 1)

MMAD: 3.72 µm (Group 0.1), 3.64 µm (Group 1)

GSD: 2.47 (Group 0.1), 2.40 (Group 1)

Exposure Type Nose only, 4 hours

Study summary

One male was found dead shortly after the exposure in Group 1.

Clinical observations: Wet fur and fur staining were commonly recorded

on the day of exposure and several days after exposure. These

observations were considered to be related to the restraint and exposure

procedures and, were considered not to be test-item related.

Slight laboured respiration was recorded in exposed animals on the day

of exposure and one day after exposure. In addition, sneezing, noisy

respiration, decreased activity and hunched posture were recorded; in

animals several days after exposure; however all clinical signs ceased

and no clinical signs were noted from Day 3, with the exception of one

female where fur loss around the eyes was recorded until Day 11.

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Following exposure, body weight loss was observed in the majority of

animals, which is due to the restrained procedure during the exposure.

Normal body weight gain was noted for all animals from Day 1 of the

observation period. The mean body weight and body weight gain of the

animals at termination of the study was in the normal range, compared

to untreated animals of the same age and strain.

In surviving animals, no macroscopic changes were noted in either study

group, however dark/red discolouration of the non-collapsed lungs was

macroscopically found in the dead animal from Group 1.


Conclusion The LC50 was considered to be > 5.01 mg/L and the test article should

be classified as 6.1E due to the one observed mortality.

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Eye irritation [6.3/8.2]

Table 74: Skin Irritation [6.3/8.2]

Type of study Acute dermal irritation in rabbits

Flag Key study

Test Substance



None

Endpoint Irritation; Draize score average from 24, 48, and 72-hour recordings

Value Mean score (24, 48,and 72 hr); Erythema: 0.2 and Oedema: 0.0

Reference

Matting, E.; 2013. BCS-CL73507 Technical - Acute Skin Irritation Study

in Rabbits; CiToxLAB Hungary Ltd., H-8200 Veszprem,

Szabadsagpuszta, Hungary; Activity ID: TXFVP061; Report Number:

13/040-006N; Edition No.: M-462513-01-1

Klimisch Score 1


GLP Yes

Test Guideline/s




Species Rabbit

Strain New Zealand White

No/Sex/Group 3M

Dose Levels 0.5 ml

Exposure Type Dermal, applied neat under a gauze and semi-occlusive wrap for 4

hours

Study Summary

The treated skin surface was examined at 1, 24, 48 and 72 hours after

patch removal.

Very slight erythema (score 1) was noted in all animals at 1 hour after

patch removal and very slight erythema (score 1) was noted in two

rabbits 24 hours after patch removal.

At the observation time points, 48 and 72 hours after patch removal,

there were no local signs on the skin of the treated animals and the

study was terminated after the 72-hour observation.

No clinical signs of systemic toxicity were observed in the animals during

the study and no mortality occurred. The body weights of all rabbits were

considered to be within the normal range of variability.


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Conclusion Minimal evidence of irritation was observed and the test article is not

classifiable.

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Table 75: Eye Irritation [6.4/8.3]

Type of study Acute eye irritation in rabbits

Flag Key study

Test Substance



None


Value

Mean Draize Score (24/48/72h)

Cornea Opacity 0.0

Conjunctiva

Redness 0.44

Chemosis 0.11

Iris 0.0

Reference

Matting, E.; 2013. BCS-CL73507 Technical - Acute Eye Irritation Study



13/040-005N; Edition No.: M-462510-01-1

Klimisch Score 1


GLP Yes

Test Guideline/s




Species Rabbit


No/Sex/Group 3M

Dose Levels 0.1 g

Exposure Type Ocular instillation into the conjunctival sac

Study Summary

The eyes were examined at 1, 24, 48 and 72 hours after application.

Fluorescein staining was performed 24 hours before administration and

24, 48 and 72 hours after application. Initial Pain Reaction (IPR) or any

Pain Reaction (PR) was not observed during the experimental period.

One hour after the application, conjunctival redness (score 2), chemosis

(score 2 or 1), discharge (score 2) was noted in all rabbits.

At 24 hours after treatment, conjunctival redness (score 1) was noted in

all animals and chemosis (score 1) was noted in one rabbit.

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At 48 hours after treatment, conjunctival redness (score 1) was noted in

one animal.

At 72 hours after treatment, no clinical signs, and no conjunctival or

corneal effects were observed.

Fluorescein staining was negative in all animals during the observation

period.

As no clinical signs were observed, the study was terminated 72 hours

after treatment of the third animal. There were no notable body weight

changes during the study.


Conclusion

Test material induced a mild amount of irritation up to 48 hours

observation and no evidence of irritation was observed at the 72-hour

observation and beyond. The test substance is not classifiable.

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Contact sensitisation [6.5]

Table 76: Contact Sensitisation [6.5] – study 1

Type of study Local lymph node assay

Flag Key study

Test Substance

Tetraniliprole technical (BCS-CL73507 technical); Batch No.: BECE 47-

140-8; Specification No.: 102000029576; Purity: 89.0% w/w; Expiry

Date: 22 April, 2017; Vehicle: dimethyl sulfoxide (DMSO)

Endpoint Sensitisation based on a Stimulation Index (SI; cellular proliferation in

response to a sensitisation effect)

Value

Sensitiser (SI >3); The observed stimulation index values were 7.1, 5.8

and 3.5 at concentrations of 50, 25 and 10 % (w/v), respectively. Based

on these data, the calculated EC3 value is 8.2% (w/v).

Reference

Varga-Kanizsai, B. 2016. Tetraniliprole Technical - Local Lymph Node

Assay in the Mouse; CiToxLAB Hungary Ltd., H-8200 Veszprem,

Szabadsagpuszta, Hungary; Activity ID: TXFVN260; Laboratory Project

ID: Study No.: 16/223-037E; Edition No.: M-570902-01-2

Klimisch Score 1


GLP Yes

Test Guideline/s




Species Mouse

Strain CBA/CaOlaHsd

No/Sex/Group 7F/3 test substance groups, 5F/positive and negative control group

Dose Levels 50, 25, and 10% (w/v) in DMSO

Exposure Type Topical application on the ear dorsum (25 µl)

Study Summary

Following a preliminary irritation/toxicity test it was determined to assess

test item concentrations of 50, 25, and 10% (w/v) in DMSO. In addition,

there was a negative control group (DMSO) and a positive control group

that received 25% (w/v) α-Hexylcinnamaldehyde (HCA) in DMSO.

No mortality or signs of systemic toxicity was observed during the main

test. Test item precipitate or minimal amount of test item precipitate was

observed for all animals of the 50% (w/v) dose group and for five

animals of the 25% (w/v) dose groups on Days 1-6 and for two animals

of the 25% (w/v) on Days 1-5 and for all animals of the 10% (w/v) dose

groups on Days 1-5. Alopecia around the ears was observed in several

animals of the 50% and 25% (w/v) dose groups at various times. The

ear thickness data showed a mean increase of >25% at the 50 and 25%

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(w/v) dose levels indicating a potential of irritation. The 10% (w/v) was a

non-irritating dose.

The SI values for the high to low test concentrations were 7.1, 5.8 and

3.5, respectively. The EC3 value was calculated as 8.2% (w/v). Based

on the ear thickness data, the two highest dose levels of 50% (w/v), 25%

(w/v) tested in the main experiment had some evidence that the SI

results could have been influenced by irritation. However, at the low

dose of 10% (w/v) which was not an irritant concentration, had an SI

value of 3.5 which is greater than the SI trigger value of 3. Hence the

overall conclusion was that the test item was positive for this test item.

Additional Comments These data confirm the results of the previous study conducted by

Hargitai, J. (2013) summarized below.

Conclusion

Under the conditions of the present assay, tetraniliprole was shown to

have the potential to have contact sensitization potential (SI>3; EC3

8.2% w/v) and is classified as 6.5B.

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Table 77: Contact Sensitisation [6.5] – study 2


Flag Supporting study

Test Substance



DMSO

Endpoint

Sensitisation based on a SI (SI; cellular proliferation in response to a

sensitisation effect)

Value

Sensitiser (SI >3); The observed stimulation index values were 5.6, 3.4

and 1.6 at concentrations of 50, 25 and 10 % (w/v), respectively. Based

on these data, the calculated EC3 value is 21.7%.

Reference

Hargitai, J.; 2013. BCS-CL73507 Technical - Local Lymph Node Assay

in the Mouse; CiToxLAB Hungary Ltd., H-8200 Veszprem,


13/040-037E; Edition No.: M-462501-01-1

Klimisch Score 1


GLP Yes

Test Guideline/s OECD Guidelines for Testing of Chemicals No. 429


Species Mouse

Strain CBA/J Rj

No/Sex/Group 4F/dose/5 groups (3 test substance groups, positive and negative

control group)

Dose Levels 50, 25, and 10% (w/v) in DMSO


Study Summary

No mortality or systemic toxicity was observed during the study. No

treatment-related effects were observed on animal body weights in any

treated groups. There were no indications of any irritancy at the site of

application. Alopecia was observed in the 50% (w/v) dose group on

Days 2-6 and in the 25% (w/v) dose group on Days 3-6. Test item

precipitate was observed on the ears for the animals in all treated group

on Days 1-6. Rigid ears were observed in the 50% (w/v) dose group on

Days 2-6.

The observed stimulation index values were 5.6, 3.4 and 1.6 at

concentrations of 50, 25 and 10 % (w/v), respectively. Based on these

data, the calculated EC3 value is 21.7%.

Additional Comments Although it classifies as a sensitizer (ie, SI>3) it would be considered to

be a weak sensitizer based on the SI of 5.6 and 3.4 at 50 and 25%

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concentration. This study was repeated, see above Varga-Kanizsai, B.

2016 (Edition No.: M-570902-01-2.

Conclusion

Under the conditions of the present assay, BCS-CL73507 was shown to

have the potential to have contact sensitization potential and is classified

as 6.5B

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Genotoxicity [6.6]

Table 78: In Vitro Studies [6.6]

Study type/Test Guideline Result Reference

Salmonella typhimurium reverse

mutation assay (Strains TA1535,

TA1537, T98, TA100 and

TA102)

OECD Guidelines for Testing of

Chemicals No. 471

EPA Health Effects Test

Guidelines (OPPTS 870.5100)

Commission Regulation (EC)

No. 440/2008, B.13/B.14

Negative with and without s9

metabolic activation

Sokolowski, A.; 2013. BCS-

CL73507: Salmonella typhimurium

reverse mutation assay. Harlan

Cytotest Cell Research GmbH

(Harlan CCR) In Den

Leppsteinsweisen 19, 64380

Rossdof, Germany. Harlan Study

Number: 1548501, Sponsor

Reference: TXFVPO57; Edition

No.: M-461517-01-1

Chromosomal aberration test in

Chinese hamster V79 cells


Chemicals No. 473




No. 440/2008, B.10

Negative: No clastogenicity

was observed either with or

without S9 metabolic

activation, and no relevant

increase in the frequencies

of polyploid metaphases was

found compared to the

frequencies of the controls.

Bhonenberger, S.; 2014. BCS-

CL73507: In vitro Chromosome

Aberration Test in Chinese

Hamster V79 Cells. Harlan Cytotest

Cell Research GmbH (Harlan CCR)

In den Leppsteinsweisen 19, 64380

Rossdof, Germany. Harlan Study

Number: 1548502; Sponsor

Reference: TXFVPO64; Edition

No.: M-465032-01-2

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Table 79: In Vivo Studies [6.6]

Study type Micronucleus assay in the bone marrow cells of the mouse

Flag Key study

Test Substance BCS-CL73507 technical; Batch/Lot Number: 2012-005440; Specification

No.: 102000026788; Purity: 89.6% w/w; Expiry Date: 02 November, 2013

Endpoint A biologically significant increase in micronuclei (%) in Polychromatic

Erythrocytes (PCE).

Value Negative

Reference

Dony, E; 2013. BCS-CL73507 Technical - Micronucleus Assay in Bone

Marrow Cells of the Mouse. Harlan Cytotest Cell Research GmbH

(Harlan CCR) In den Leppsteinsweisen 19, 64380 Rossdof, Germany.

Harlan Study Number: 1576300, Bayer CropScience Activity ID:

TXFVP066; Edition No.: M-473874-01-3

Klimisch Score 1


GLP Yes

Test Guideline/s




Species Mice

Strain NMRI

No/Sex/Group

2M / 2F per group (preliminary test)

6M / 6F per group (control, high dose 24 hour and 48 hour, and positive

control) for main study, 48 total

Dose Levels Preliminary test: 2000 mg/kg bw

Main study: 1 dose of 2000 mg/kg bw


Study Summary

The preliminary test indicated a dose level of 2000 mg/kg bw was non-

toxic and deemed suitable.

In comparison to the corresponding vehicle controls, there was no

biologically relevant or statistically significant enhancement in the

frequency of the detected micronuclei at either the 24-hour or 48-hour

preparation interval after administration of the test item with any gender

used. The positive control which showed a substantial increase of

induced micronucleus frequency.

Additional Comments

Staff consider that the toxicokinetic data indicate that the test system

was suitable and that bone marrow exposure to the test substance can

be assumed although this study did not demonstrate it.

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Conclusion

It can be stated that under the experimental conditions reported, the test

item BCS-CL73507 technical did not induce micronuclei and is

considered to be non-mutagenic in this micronucleus assay.

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Carcinogenicity [6.7]

Table 80: Carcinogenicity [6.7]

Study type Chronic toxicity (12 month) and carcinogenicity (18 month) in the mouse

Flag Key study

Test Substance


No.: 102000026788; Purity: 89.6% w/w; Expiry Date: Test material stability

was confirmed through out the study; Vehicle: None

Endpoints

52-week LOAEL: No toxicity was observed at the highest

dose administered

NOAEL: 6500 ppm in both sexes (equiv. to

952 mg/kg bw/day in males and 1225

mg/kg bw/day in females).

78-week

Non-Neoplastic Effects: LOAEL: No toxicity was observed at the highest

dose administered

NOAEL: 6500 ppm in both sexes (equiv. to 825

mg/kg bw/day in males and 1073 mg/kg

bw/day in females)

Neoplastic Effects: LOAEL: No toxicity was observed at the highest

dose administered

NOAEL: 6500 ppm in both sexes (equiv. to 825


bw/day in females)

Tumours

There was no evidence of an effect of the test item on neoplastic findings.

The tumours observed were consistent with the range of neoplastic findings

usually encountered in mice of this age and strain kept under laboratory

conditions and were of similar incidence in control and treated animals. (See

Table 10c pg 515 of main report)

Malignant/Benign Not applicable as there was no effect on tumour findings

Background Incidence Not applicable as there was no effect on tumour findings

Time of Onset

(malignant) Not applicable as there was no effect on tumour findings

Survival (18 months)

6500 ppm: 74% for males, 82% for females



Controls: 86% for males, 86% for females

Reference

Kennel, P.; 2016. BCS-CL73507 Carcinogenicity Study in the C57BL/6J

Mouse by Dietary Administration. Bayer S.A.S. 355, rue Dostoievski, CS

90153 Valbonne, 06906 SOPHIA ANTIPOLIS Cedex, France; Study ID: SA

12225; Activity ID: TXFVP047; Edition No.: M-552413-01-3

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Klimisch Score 1


GLP Yes

Test Guideline

OECD Guidelines for Testing of Chemicals 451

EEC Directive 88/302EEC, Method B.32

US-EPA, OCSPP Guideline No. 870.4200

JMAFF, notification 12 Nousan No. 8147

Species Mouse

Strain C57BL/6J

No/Sex/Group 60 / M and F / group (10/sex were terminated after 52 weeks)

Dose Levels

0, 260, 1300, 6500 ppm

The mean achieved dose levels received by the animals over the 52 week

period were approximately 37.7, 190, 952 mg/kg bw/day in males and 49.5,

248, 1225 mg/kg bw/day in females.

The mean achieved dose levels received by the animals over the 78 week

period were approximately 32.9, 166 and 825 mg/kg bw/day in males and

43.1, 215 and 1073 mg/kg bw/day in females

Exposure Type Oral by the diet for either 52 or 78 weeks

Study Summary

Groups of 60 male and 60 female C57BL/6J mice were fed diet containing

0, 260, 1300 or 6500 ppm of BCS-CL73507. After 52 weeks, 10 males and

10 females from each group allocated to the chronic phase of the study

were necropsied at the scheduled interim sacrifice. The remaining 50

animals/sex/group, allocated to the carcinogenicity phase of the study,

continued treatment until the scheduled final sacrifice of the study after at

least 78 weeks of treatment. Mortality and clinical signs were checked daily.

Additionally, detailed physical examinations including palpation for masses

were performed weekly throughout treatment. Body weight and food

consumption were measured weekly for the first 13 weeks of the study, then

approximately monthly thereafter. Haematology determinations were

performed at Months 13 and 19 from designated animals. A blood sample

was also collected on selected animals for bioanalytical examination at

Months 4, 12 and at the end of the study. Where possible, blood smears

were prepared from moribund animals just before sacrifice. All animals were

subjected to necropsy, with selected organs weighed at scheduled interim

and final sacrifice. Designated tissues were fixed and those allocated to the

carcinogenicity phase were examined microscopically.

Up to the highest dose level tested of 6500 ppm, there were no treatment-

related effects on mean body weight parameters, mean food consumption

and haematology assessments throughout the study, or on an earlier

development or increased incidence of tumours in either sex.

The bioanalytical examination showed a dose-related increase in BCS-

CL73507 and BCS-CQ63359 (metabolite) mean plasma concentrations,

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with similar levels observed throughout the study and slightly higher mean

values in females compared to males.

Exposure

level

Sex 4 months 12 months 18 months

Active Metab. Active Metab. Active Metab.

260 ppm F 0.56 0.041 0.60 0.035 0.61 0.076

M 0.45 0.051 0.42 0.043 0.35 0.050

1300

ppm

F 0.98 0.12 0.95 0.13 1.2 0.17

M 0.60 0.12 0.58 0.11 0.54 0.11

6500

ppm

F 1.2 0.50 1.2 0.60 1.5 0.95

M 0.7 0.35 0.76 0.40 0.68 0.37

High dose groups - 6500 ppm (equating to 825 and 1073 mg/kg bw/day in

males and females, respectively):

There was a marginal increase in the mortality incidence in both sexes

compared to controls (not statistically significant).

At the weekly physical examinations, an increased incidence of ocular

discharge was noted during the second year of the study in females

(p≤0.05), compared to controls. As the incidence of this sign was increased

in one sex and during the second year only and as it was observed in

isolation, it was not considered to be an adverse effect of the treatment.

At the 12-month interim sacrifice, mean terminal body weight and organ

weights were unaffected by treatment in either sex. At the macroscopic

observation, no treatment-related changes were noted in either sex.

Histopathology was not performed for the chronic phase animals.

At the 18-month terminal sacrifice of the carcinogenicity phase animals,

mean terminal body weight and organ weights were unaffected by treatment

in either sex, except for a slight increase in mean absolute and relative liver

weights in males (+8 to 9% compared to controls, p≤0.01 or p≤0.001). As

the magnitude of this change was minor and as the change was not

associated with higher incidences of macroscopic or microscopic findings in

the liver, it was considered not to be an adverse effect of the treatment. At

the macroscopic observation and microscopic examination, no treatment-

related changes were noted in either sex.

Mid dose groups - 1300 ppm (equating to 166 and 215 mg/kg bw/day in


No treatment-related effects were observed at this dose level

Low dose groups - 260 ppm (equating to 32.9 and 43.1 mg/kg bw/day in


No treatment-related effects were observed at this dose level.


Conclusion No test item-related non-neoplastic or neoplastic findings were noted at the

end of the 18-month treatment period.

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The No Observed Adverse Effect Level (NOAEL) over the 52 week period of

dietary administration was 6500 ppm in both sexes (equiv. to 952 mg/kg

bw/day in males and 1225 mg/kg bw/day in females).

The No Observed Adverse Effect Level (NOAEL) over the 78 week period of



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Table 81: Carcinogenicity [6.7]

Study type Chronic toxicity (12 month) and carcinogenicity (24 month) in the rat

Flag Key study

Test Substance


No.: 102000026788; Purity: 89.6% w/w; Expiry Date: Test material stability

was confirmed throughout the study; Vehicle: None

Endpoints

12-month LOAEL: No toxicity was observed at the highest

dose administered

NOAEL: 18000 ppm in both sexes (equivalent to

854 mg/kg bw/day in males and 1147

mg/kg bw/day in females).

24-month

Non-Neoplastic Effects: LOAEL: 18000 ppm (both sexes; equiv. to 741


bw/day in females)

NOAEL: 4000 ppm (both sexes; equiv. to 159


bw/day in females

Neoplastic Effects: LOAEL: 18000 ppm females (equiv. to 1052

mg/kg bw/day)

NOAEL:18000 ppm for males (equiv. to 741

mg/kg bw/day) and the mid dose of 4000 ppm

for females (equiv. to 221 mg/kg

bw/day)

Tumours The only organ with evidence of tumours was the uterus

Malignant/Benign

Malignant: The only tumours deemed of significance are noted in the table

below.

Incidence of Neoplastic Findings in the Uterus

Dose (ppm) 0 900 4000 18000

No. of Animals 59 60 60 60

glandular polyp (benign) 2

(3.4%)

0 0 3

(5.0%)

endometrial adenocarcinoma 1

(1.7%)

0 0 2

(3.3%)

adenosquamous carcinoma 0 0 0 1

(1.7%)

Total Incidence of epithelial

tumours

3

(5.1%)

0 0 6 (10%)

Background Incidence HCD

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In-house HCD Registry of Individual

Toxicology Animal Data

(RITA - HCD)

Min

(%)

Max

(%)

Mean

(%)

Min

(%)

Max

(%)

Mean

(%)

glandular polyp 0.0 1.7 0.4 0.0 8.2 0.7

endometrial

adenocarcinoma

0.0 2.0 0.7 0.0 28.0 4.8

adenosquamous

carcinoma

0.0 0.0 0.0 0.0 2.0 0.1

Time of Onset

(malignant)

endometrial adenocarcinoma (3): Control (1): Day 716; High dose (2): 1 at

termination (Day 743) and 1 at Day 691,

adenosquamous carcinoma (1): Day 688

Survival

18000 ppm: 50.0% for males, 40.0% for females



Controls: 69.5% for males, 65.0% for females

Reference

Odine, M.; 2016. BCS-CL73507 Chronic Toxicity and Carcinogenicity Study

in the Wistar Rat by Dietary Administration. Bayer S.A.S. 355, rue

Dostoievski, CS 90153 Valbonne, 06906 SOPHIA ANTIPOLIS Cedex,

France; Study ID: SA 12199; Activity ID: TXFVP048; Edition No.: M-568723-

03-1

Klimisch Score 1


GLP Yes

Test Guideline


EEC Directive 88/302EEC, Method B.33



Species Rat

Strain Wistar Rj:WI (IOPS HAN)

No/Sex/Group 70 / M and F / group (10/sex were terminated after 12 months)

Dose Levels

0, 900, 4000, 18000 ppm

The mean achieved dose levels received by the animals over the 12-month



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The mean achieved dose levels received by the animals over the 24-month



Exposure Type Oral by the diet for either 12 or 24 months

Study Summary

Groups of 70 male and 70 female rats were fed diet containing 0, 900, 4000,

and 18000 ppm BCS-CL73507. Ten males and 10 females from each group

were allocated to the chronic (12-month) phase and were necropsied after

52 weeks of treatment. The remaining 60 animals/sex/group were allocated

to the carcinogenicity (24-month) phase of the study and continued

treatment until final sacrifice after at least 105 weeks of treatment.

Mortality and clinical signs were checked daily. Detailed physical

examinations including palpation for masses were performed at least weekly

throughout the study. Body weight was recorded weekly for the first 13

weeks, then approximately every 4 weeks thereafter. Food consumption

was recorded twice weekly for the first 6 weeks of the study, then

approximately weekly up to Week 13, then every 4 weeks thereafter.

Ophthalmological examinations were performed on all animals during

acclimatization and after approximately one year and on all surviving

animals at two years. On Study Weeks 12, 53 and 104 (Study Days 82, 366

and 723), a blood sample was collected from the sublingual vein of the first

five suitable animals from each treated group for test item analysis.

Haematology and clinical chemistry determinations and urinalysis were

performed during months 3-4, 6, 12, 18-19 and 24-25 on selected animals.

At the scheduled chronic and carcinogenicity phase sacrifice, selected

organs were weighed and designated tissues sampled and examined

microscopically.

During the first 12-months of treatment, no treatment-related clinical signs

were observed and the mortality rate was low across all groups. There were

no treatment-related effects on the following parameters, at any dose-level

tested; food consumption throughout the study, ophthalmic changes at the

12 and 24-month examination, haematology, clinical chemistry or urinalysis

parameters after approximately 3, 6, 12, 18 or 24 months of treatment. In

addition, no treatment-related organ weight changes were observed at

either the 12-month interim or 24-month terminal sacrifice. No macroscopic

or microscopic changes were observed in animals allocated to the 12-month

interim sacrifice phase and no macroscopic changes were observed the 24-

month terminal sacrifice, which could be attributable to treatment.

The bioanalytical examination showed a dose-related increase in BCS-

CL73507 and BCS-CQ63359 (metabolite) mean plasma concentrations,

with similar levels observed throughout the study. At the low and mid-dose,

the concentration of parent compound was higher than the main metabolite

BCS-CQ63359. At the high dose level, the concentration of BCS-CQ63359

was higher than parent compound. Higher concentration levels (mg/L) of

BCS-CL73507 and BCS-CQ63359 were observed in females compared to

males, at the corresponding dose levels, for each of the three sampling

times.

Sex 3 months 12 months 23 months

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Exposure

level

Active Metab. Active Metab. Active Metab.

900 ppm F 0.63 0.34 0.70 0.36 1.1 0.39

M 0.33 0.09 0.30 0.10 0.38 0.12

4000

ppm

F 0.68 0.71 1.2 0.88 1.5 1.1

M 0.37 0.26 0.41 0.31 0.65 0.40

18000

ppm

F 0.96 3.49 2.3 3.5 1.7 3.9

M 0.54 0.78 0.90 1.1 0.75 1.0

High dose group - 18000 ppm:

Over the 2-year duration of the study, the mortality rate of both sexes was

markedly lower than in the corresponding control groups (50.0 % versus

69.5% for males, and 40.0% versus 65.0% for females, adjusting for

censored animals, ie animals which died as a result of accidental trauma or

during anaesthesia for blood sampling)

No treatment-related clinical signs were observed in males throughout the

study or in females during the first year of treatment. During the second year

of treatment, 4/58 females had a prolapsed vagina compared to 1/58

females in the control group.

Mean body weight in males was up to 3% lower than the corresponding

control group from Study Day 8 up to the end of the first year of treatment,

the effect being statistically significant on a number of occasions (p≤0.01 or

p≤0.05). A similar pattern was observed during the second year of

treatment, with a final mean body weight 7% lower than the controls, on

Study Day 729. Mean cumulative body weight gain was lower than the

control group throughout the study, by between 3 to 8% during the first year

of treatment and 4 to 10% during year 2, the effect attaining statistical

significance on a number of occasions (p≤0.05 or p≤0.01). Overall mean

cumulative body weight gain was 10% lower than the controls at the end of

the study on Study Day 729. No effect on terminal body weight was

observed in males.

In females, effects on mean body weight first became apparent at the end of

the first year of treatment, where mean body weight was 5% lower (not

statistically significant) and mean cumulative body weight gain was 8%

lower (p≤0.05) than the controls on Study Day 372. During the second year

of treatment, mean body weight was progressively lower than the controls,

resulting in a 15% reduction in final mean body weight on Study Day 729,

compared to the controls, the effect being statistically significant on most

occasions (p≤0.05, p≤0.01 or p≤0.001). Mean cumulative body weight gain

was reduced by between 8 and 24% during the second year of treatment,

compared to the controls, the effect being statistically significant on most

occasions (p≤0.05, p≤0.01 or p≤0.001). The magnitude of the response was

more pronounced during the latter phase of the study. Overall mean

cumulative body weight gain was 24% lower than the controls at the end of

the study on Study Day 729. At both the 12-month interim sacrifice and the

24-month terminal sacrifice, a lower mean terminal body weight was

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observed in females when compared to controls (-7%, not statistically

significant, -14%, p≤0.05, respectively).

In females at the 24-month terminal sacrifice, a slightly higher incidence of

epithelial uterine tumours was observed compared to the controls, the

incidence being slightly outside the in-house HCD, but within the RITA HCD

(Registry of Industrial Toxicology Animal Data).

The significance of the neoplastic lesions is heightened by the non-

neoplastic findings observed in the uterus, vagina, and ovary. In the uterus,

a higher incidence and severity of diffuse squamous cell hyperplasia in the

cervix (p≤0.01) and a higher incidence of focal squamous cell metaplasia in

the endometrium were observed when compared to controls. In the vagina,

a higher incidence of diffuse squamous cell hyperplasia (p≤0.05) was

observed. In the ovary, a tendency towards a higher severity of corpora

lutea depletion was observed when compared to controls.

Mid dose group - 4000 ppm

Apart from a lower mortality rate in females over the 2-year duration of the

study, compared to the controls (51.4% versus 65.0%, adjusted for

censored animals), there were no treatment-related effects in either sex.

Low dose group - 900 ppm

Apart from a lower mortality rate in females over the 2-year duration of the

study, compared to the controls (48.4% versus 65.0%, adjusted for

censored animals), there were no treatment-related effects in either sex.

Additional Comments

Although the tumour incidence rate exceeded control, the magnitude was

not statistically significant and was within the maximal percentage observed

by the RITA HCD. The study report authors also tempered the significance

of the increase by pointing out that the high dose level exceeded the 1000

mg/kg bw/day MTD and that there was excessive body weight loss (>10%).

The EPA deemed the significance of these latter two observations as being

minimal in regard to the observed increase in tumours. The observed

increase was not deemed of great significance by EPA in light of its lack of

statistical significance, as well as its magnitude relative to the RITA HCD

and incidence rate of tumours in the controls of this study. The control group

in this study was also elevated relative to the in-house HCD relative to

glandular polyps. The increased incidence of uterine and vaginal

hyperplasia in the high dose group is also consistent with the results of the

steroidogenesis assay that showed the active and the metabolite could

induce estrogen synthesis.

Conclusion

In conclusion, adverse treatment-related effects were limited to the high

dose of 18000 ppm in both sexes. In males, these effects were limited to an

effect on body weight parameters whereas, in females, these effects also

included non-neoplastic changes in the uterus, ovary and vagina and a

slight increase in epithelial uterine tumours after two years of treatment.

The No Observed Adverse Effect Level (NOAEL) over a 12-month period of



The No Observed Adverse Effect Level (NOAEL) in terms of carcinogenic

potential was the high dose of 18000 ppm for males (equiv. to 741 mg/kg

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bw/day) and the mid dose of 4000 ppm for females (equiv. to 221 mg/kg

bw/day), based on the slight increase in epithelial uterine tumours observed

in females at 18000 ppm (equiv. to 1052 mg/kg bw/day) following a 24-

month period of dietary administration with BCS-CL73507.

The No Observed Adverse Effect Level (NOAEL) over a 24-month period of

dietary administration rat was 4000 ppm in both sexes (equiv. to 159 mg/kg


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Developmental Toxicity [6.8]

Table 82: Reproductive and Developmental Toxicity (Non-Guideline, Dose Range Finding Studies) [6.8]

Study type Summary Reference

Preliminary study of

reproductive

performance in the rat by

dietary administration

The objective of the study was to assess the influence

of BCS-CL73507 technical on reproductive

performance when continuously administrated via the

diet to Han Wistar rats and to establish suitable

treatment levels for a two-generation reproductive

performance study.

For the F0 generation, three groups of eight male and

eight female rats received BCS-CL73507 technical

orally, via the diet, at concentrations of 1500, 9000 or

15000 ppm for four weeks before pairing, throughout

pairing and gestation. During the lactation phase, the

dietary concentrations were lowered by 50% to 750,

4500 or 7500 ppm. A similarly constituted control group

received untreated basal diet for the same duration.

The F1 generation, comprising of 12 male and 12

female progeny from each group, received treatment

as for the main study phase at 1500, 9000 or 15000

ppm from weaning up to termination (following

completion of sexual maturation).

During the study, data was recorded on clinical

condition, body weight, food consumption, oestrous

cycles, mating performance and fertility, gestation

length, parturition and reproductive performance.

Organ weight and macroscopic pathology

investigations were undertaken on the adult

generation. The clinical condition of offspring, body

weight, litter size, offspring survival and sex ratio were

recorded up to weaning on Day 21 of age, thereafter

sexual maturation, body weight and food consumption

were recorded for selected F1 animals.

Macropathology investigations were undertaken for

unselected offspring at weaning and selected F1

animals following completion of sexual maturation.

Dietary administration of BCS-CL73507 to rats at main

phase concentrations of 1500, 9000 or 15000 ppm and

lactation phase concentrations of 750, 4500 or 7500

ppm was generally well-tolerated. There were no signs

of overt systemic toxicity among the F0 males and

females and their mating performance and fertility were

unaffected by treatment. The survival and clinical

condition of the F1 offspring were unaffected by

treatment. Treatment of the F0 females and litters

during lactation at 4500 ppm or 7500 ppm and

subsequent treatment of selected F1 animals at 1500,

9000 or 15000 ppm was associated with slightly low

Patten, R..;

2016. BCS-

CL73507

technical:

Preliminary

Study of

Reproductive

Performance

in the Han

Wistar Rat by

Dietary

Administration;

Envigo CRS

Limited, Eye,

Suffolk, IP23

7PX: Project

identity:

DNM0059;

Sponsor

reference No.:

TXFVP008;

Edition No.: M-

569906-01-1

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body weight gain of the F1 offspring from Day 14 of

age, resulting in slightly low absolute body weights of

selected F1 animals and a delay in the completion of

vaginal opening among selected F1 females at all dose

levels. Treated F1 males at all dose levels also showed

a significant delay in sexual maturation; however, the

correlation with body weight evolution was not as clear

as in females, as such, the delay may reflect a direct

effect of treatment or may be secondary to a delay in

physical development. Based on the delay in balano-

preputial separation observed at all dose levels a clear

no-observed-adverse-effect level was not established

on this study.

Based on the limited toxicity observed at 15000 (7500)

ppm, which equates to 1250 mg/kg bw/day in F0 males

and 1242 mg/kg bw/day in F0 females, a dietary

concentration which approximates to a limit dose of

1000 mg/kg bw/day in the adult animals during the pre-

mating phase, is expected to be well tolerated in the

main two-generation study in this strain of rat.

Range finding study for

developmental toxicity in

the rabbit by gavage

Groups of 8 time-mated New Zealand White KBL

rabbits were exposed to BCS-CL73507 by oral gavage

from Gestation Day (GD) 6 to 28. The doses given

were 0, 100, 300 and 900 mg/kg bw/day.

Clinical observations were recorded daily. Maternal

body weights were recorded on GD 3, 6, 8, 10, 12, 14,

16, 18, 20, 22, 24, 26 and 29. Food consumption was

measured during the intervals GD 3-4, 4-5, 5-6, 6-8, 8-

10, 10-12, 12-14, 14-16, 16-18, 18-20, 20-22, 22-24,

24-26, 26-28 and 28-29. At scheduled sacrifice, on GD

29, a macroscopic examination of visceral organs was

performed, the gravid uterine weight was recorded and

the dams were evaluated for number of corpora lutea,

number and status of implantations (resorptions, dead

and live foetuses). In addition, the liver weight was

recorded for all pregnant females. Live foetuses were

removed from the uterus, counted, weighed, killed and

examined externally.

Pregnancy rate was unaffected by treatment. The

pregnancy rate was 100% at 900 mg/kg/day and in the

control group and 88% at 100 and 300 mg/kg bw/day.

Up to the dose of 900 mg/kg bw/day, there was no

treatment-related clinical signs and no effect on body

weight parameters or food consumption. The mean

liver weight was unaffected by treatment. No treatment-

related changes were noted on litter parameters,

including the number of live foetuses, the number of

implant sites per dam, the percentages of pre- and

post-implantation losses, the number of early and late

Blanck, M.;

2014. BCS-

CL73507

(formerly BCS-

CO80363) –

Range Finding

Study for

Developmental

Toxicity in the

Rabbit by

Gavage. Bayer

S.A.S. Bayer

CropScience,

Sophia

Antipolis,

France; Study

ID: SA 10426;

Activity ID:

TXRXP067;

Edition No.: M-

425262-01-2

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resorptions, the foetal death status, and the foetal body

weight. There were no treatment-related changes

observed in the external observations.

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Table 83: Developmental Toxicity [6.8]

Study type Developmental toxicity study in the rat

Flag Key study

Test Substance



(study was completed prior to expiry); Vehicle 0.05% aqueous

methylcellulose 400

Endpoint Developmental effects on foetuses and maternal systemic toxicity

Value

Parental Toxicity LOAEL: No toxicity was observed at the highest dose

administered

NOAEL: 1000 mg/kg bw/day

Foetal Toxicity LOEL: 1000 mg/kg bw/day

NOAEL: 1000 mg/kg bw/day; NOEL 250 mg/kg bw/day

Reference

Kennel, P.; 2014. BCS-CL73507 Developmental Toxicity Study in the

Rat by Gavage. Bayer S.A.S. 355, rue Dostoievski, CS 90153 Valbonne,

06906 SOPHIA ANTIPOLIS Cedex, France; Study ID: SA 12221; Activity

ID No.: TXFVP051; Edition No.: M-503758-01-2

Klimisch Score 1


GLP Yes

Test Guideline

OECD guideline 414

EEC Directive 2004/73/EC, Method B.31

US EPA OCSPP Guideline number 870.3700

MAFF IN Japan notification 12 Nousan No. 8147

Species Rat

Strain Crl:CD (SD) Sprague-Dawley

No/Sex/Group 23F/dose

Dose Levels 0, 62.5, 250, 1000 mg/kg bw/day


Study Summary

Clinical observations were recorded daily. Maternal body weights were

recorded for all females on GD 0, 6, 8, 10, 12, 14, 16, 18 and 21. Food

consumption was also measured for all the females during the intervals

GD 1-6, 6-8, 8-10, 10-12, 12-14, 14-16, 16-18 and 18-21. At scheduled

sacrifice, on GD 21, a macroscopic examination of the visceral organs

was performed, the gravid uterine weight was recorded and the dams

were evaluated for number of corpora lutea, number and status of

implantations (resorptions, dead and live foetuses). In addition, the liver

was weighed at scheduled sacrifice for all pregnant females. Live

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foetuses were removed from the uterus, counted, weighed, sexed and

examined externally. Approximately half of the live foetuses from each

litter were fixed in Bouin’s solution and subsequently dissected for

internal examination. The remaining half were eviscerated, skinned, fixed

in absolute ethanol and stained accordingly for skeletal examination of

bone and cartilage.

Pregnancy rate was unaffected by treatment. There were no treatment-

related mortalities, clinical signs or changes in mean maternal body

weight parameters or in mean food consumption throughout the study in

dams. At necropsy, there were no treatment-related macroscopic

findings in dams and mean liver weight was unaffected by treatment.

At caesarean section, the following litter parameters were unaffected by

treatment: the number of live foetuses, number of implant sites per dam,

percentages of pre- and post-implantation losses, number of early and

late resorptions, foetal death status and percentage of male foetuses

were unaffected by treatment at any dose level tested.

There were no treatment-related malformations at the external, visceral

and skeletal foetal examination.

At 1000 mg/kg bw/day:

At caesarean section, the only treatment-related change consisted of a

4% lower mean foetal body weight (combined and per sex) compared to

controls (p≤0.05 for combined sexes and females). Since the mean

values remained within the range of in-house HCD or were only

marginally outside (5.15 g for females compared to 5.16-5.48 g for

corresponding HCD), the change in foetal body weights was considered

not to be an adverse effect of the treatment.

At the external and visceral foetal examinations, there were no

treatment-related variations. At the skeletal foetal examination,

treatment-related changes consisted of an increased incidence of 2

spontaneous variations; “5th and 6th sternebrae: incomplete ossification”

at the foetal level and “5th and/or 6th sternebrae: unossified” at the foetal

and litter levels. As these findings were limited to a delay in ossification

in the 5th and 6th sternebrae, which are commonly seen spontaneous

variations that correlated with slightly lower mean foetal body weights,

they were considered to represent only a slight and transient delay in

foetal development with no adverse long term consequences.

At 250 and 62.5 mg/kg bw/day:

There was no treatment-related effect on any of the parameters assayed.

Additional Comments

Despite the maternal No Observed Effect Level (NOEL) being greater

than the foetal NOEL the observed changes in the treated offspring are

not of sufficient magnitude in both their severity or in their incidence to

warrant classification.

Conclusion

A dose level of 1000 mg/kg bw/day was considered to be a NOEL in

terms of maternal toxicity and a No Observed Adverse Effect Level

(NOAEL) in terms of foetal toxicity. A dose level of 250 mg/kg bw/day

was considered to be a NOEL in terms of foetal toxicity.

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Table 84: Developmental Toxicity [6.8]

Study type Developmental toxicity study in the rabbit

Flag Key study

Test Substance


No.: 102000026788; Purity: 89.6% w/w; Expiry Date: 30 April, 2014;

(study was completed prior to expiry); Vehicle 0.05% aqueous

methylcellulose 400

Endpoint Developmental effects on foetuses and maternal systemic toxicity

Value

Parental Toxicity LOAEL: No toxicity was observed at the highest dose

administered

NOEL: 1000 mg/kg bw/day

Foetal Toxicity LOEL: No toxicity was observed at the highest dose

administered

NOEL: 1000 mg/kg bw/day

Reference

Kennel, P.; 2015. BCS-CL73507 Developmental Toxicity Study in the

Rabbit by Gavage. Bayer S.A.S. 355, rue Dostoievski, CS 90153

Valbonne, 06906 SOPHIA ANTIPOLIS Cedex, France; Study ID: SA

12223; Activity ID No.: TXFVP052; Edition No.: M-510211-02-3

Klimisch Score 1


GLP Yes

Test Guideline

OECD guideline 414

EEC Directive 2004/73/EC, Method B.31

US EPA OCSPP Guideline number 870.3700

MAFF IN Japan notification 12 Nousan No. 8147

Species Rabbit


No/Sex/Group 23F/dose

Dose Levels 0, 62.5, 250, 1000 mg/kg bw/day


Study Summary

Groups of time-mated pregnant rabbits were exposed to BCS-CL73507

from gestation day (GD) 6 to 28. The sperm-positive day was GD 0.

Clinical observations were recorded daily from GD 3 to GD 29. Maternal

body weights were recorded for all females on GD 3, 6, 8, 10, 12, 14, 16,

18, 20, 22, 24, 26 and 29. Food consumption was also measured for all

the females during the intervals GD 3-4, 4-5, 5-6, 6-8, 8-10, 10-12, 12-

14, 4-16, 16-18, 18-20, 20-22, 22-24, 24-26, 26-28 and 28-29. At

scheduled sacrifice, on GD 29, a blood sample was collected on at least

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5 pregnant animals/group for bioanalytical examination. A macroscopic

examination of the visceral organs was performed on all animals, the

gravid uterine weight was recorded and the dams were evaluated for

number of corpora lutea, number and status of implantations

(resorptions, dead and live foetuses). In addition, the liver was weighed

at scheduled sacrifice for all pregnant females. Live foetuses were

removed from the uterus, counted, weighed, sexed and examined

externally. The heads of the foetuses from approximately half of each

litter were immersed in Davidson fixative then in Bouin’s fluid and the

internal structures examined after fixation. The bodies of all foetuses

were dissected for soft tissues anomalies and sex determination.

Foetuses were eviscerated, skinned and fixed in absolute ethanol before

staining for skeletal abnormalities.

Pregnancy rate was unaffected by treatment, with a pregnancy rate of

91% in the control and mid-dose groups, 87% in the high dose group and

78% in the low dose group. The bioanalytical examination showed a

dose-related increase in the test item BCS-CL73507 and the major

metabolite BCS CQ63359 plasma concentrations.

Up to the highest dose level tested of 1000 mg/kg bw/day, there were no

treatment-related maternal mortalities or clinical signs throughout the

study. Mean maternal body weight parameters and food consumption

were unaffected by treatment. At necropsy of dams, there were no

treatment-related macroscopic findings or changes in mean liver weight.

Litter parameters including the number of live foetuses, number of

implant sites per dam, percentages of pre- and post-implantation losses,

number of early and late resorptions, foetal death status, foetal weight

(combined and per sex) and percentage of male foetuses were

unaffected by treatment. At the external, visceral and skeletal foetal

examinations, there were no treatment-related malformations or

variations.

The mean concentration values of BCS-CL73507 in plasma was 0.240,

0.375, and 0.574 mg/ml at the respective dose levels of 62.5, 250, and

1000 mg/ml. The mean concentration values of BCS-CQ63359 (the main

metabolite) in plasma was 0.099, 0.327, and 0.739 mg/ml at the

respective dose levels of 62.5, 250, and 1000 mg/ml.

Additional Comments

Blood plasma levels increased with dose but not in a directly proportional

manner. The presence of the main metabolite was also not found in a

dose proportional manner relative to dose of test material received or

relative to the plasma concentration of the test material.

Conclusion A dose level of 1000 mg/kg bw/day was considered to be a NOEL in both

dams and foetuses.

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Table 85: Reproductive Toxicity [6.8]

Study type Two generation reproductive performance

Flag Key

Test Substance



Vehicle: None

Endpoint Parental systemic toxicity and reproductive performance

Value

Parental Toxicity LOAEL: 12000 ppm (equiv. to the mean achieved dose

before pairing: 896 mg/kg bw/day for F0

males;1032 mg/kg bw/day for F0 females;

1138 mg/kg bw/day for F1 males; 1218 mg/kg

bw/day for F1 females; 1361 mg/kg bw/day

for F2 males; 1392 mg/kg bw/day for F2

females)

NOAEL: 2700 ppm (equiv. to the mean achieved dose

before pairing: 196 mg/kg bw/day for F0

males; 224 mg/kg bw/day for F0 females; 253

mg/kg bw/day for F1males; 266 mg/kg bw/day

for F1 females; 307 mg/kg bw/day for F2

males; 312 mg/kg bw/day for F2 females)

Foetal Toxicity LOAEL: No toxicity was observed at the highest dose

administered

NOAEL: 12000 ppm (equiv. to the mean achieved

dose before pairing: 896 mg/kg bw/day for F0

males; 1032 mg/kg bw/day for F0 females;

1138 mg/kg bw/day for F1 males; 1218 mg/kg

bw/day for F1 females; 1361 mg/kg bw/day

for F2 males; 1392 mg/kg bw/day for F2

females)

Reference

Patten, R..; 2016. BCS-CL73507 technical: Two Generation

Reproductive Performance Study by Dietary Administration to Hans

Wistar Rats; Envigo CRS Limited, Eye, Suffolk, IP23 7PX: Project

identity: DNM0060; Sponsor reference No.: TXFVP044; Edition No.: M-

569724-02-2

Klimisch Score 1


GLP Yes

Test Guideline

OECD guideline 416

US EPA OPPTS Guideline number 870.3800

JMAFF, 12 Nousan No. 8147

Species Rat

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Strain RccHan:(WIST)

No/Sex/Group 24/ M and F/ dose group

Dose Levels Main phase: 0, 300, 600, 2700, and 12000 ppm

Lactation phase: 0, 150, 300, 1350, 6000 ppm

Exposure Type Oral dietary

Study Summary

For the F0 generation males, four groups of 24 animals received BCS-

CL73507 via the diet at concentrations of 300, 600, 2700 or 12000 ppm

for 10 weeks before pairing until termination.

For the F0 generation females, four groups of rats received BCS-

CL73507 via the diet, at concentrations of 300, 600, 2700 or 12000 ppm

for 10 weeks before pairing, throughout pairing and gestation. During

lactation, the dietary concentrations were reduced 50% to 150, 300,

1350, and 6000 ppm.

The F1 generation comprised of two subsets (A and B) both including 24

male and 24 female progeny from each exposure group, and they

continued to receive the relevant diet, as per the F0 generation,

throughout the study until termination.

The F2 generation received the relevant diet from weaning until

termination on Day 70 of age.

During the study, data was recorded on clinical condition, body weight,

food consumption, oestrous cycles, mating performance and fertility,

gestation length and parturition observations and reproductive

performance. Semen analysis, organ weight, and macroscopic and

microscopic pathology investigations were undertaken on the F0 and

F1A generation. Organ weight and macroscopic pathology investigations

were undertaken on the F1B and F2 generation.

The clinical condition of offspring, litter size and survival, anogenital

distance, sex ratio, sexual maturation (selected F1 and F2 generation

only) and body weight gain was assessed and organ weight and

macroscopic pathology investigations were undertaken on each

generation.

Results

F0 Parental

The mean achieved dose during Weeks 1 to 10 of treatment at 300, 600,

2700 and 12000 ppm was 22, 44, 196 and 896 mg/kg bw/day for males

and 25, 51, 224 and 1032 mg/kg bw/day for females, respectively.

During gestation and lactation the achieved doses were 22, 43, 197 and

875 mg/kg bw/day for females at 300, 600, 2700 and 12000 ppm and 23,

47, 211 and 890 mg/kg bw/day for females at 150, 300, 1350 and 6000

ppm, respectively.

There were no unscheduled deaths and no signs at routine physical

examination that could be attributed to treatment. Overall the bodyweight

performance for males during 18 weeks of treatment and for females for

the 10-week pre-pairing period showed no adverse effects of treatment.

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During the first week of gestation (Days 0-7) females receiving 12000

ppm showed marginally low weight gain, and mean body weight gain for

all exposed groups was slightly lower during the second week of

gestation (Days 7-14). During the second week of gestation females at

all dose levels showed slightly but significantly low food consumption

(p<0.05-0.01)

From Day 1 of lactation at the reduced dietary concentrations the body

weight gain (Day 1-4) was slightly higher then controls. Food

consumption during lactation was unaffected by treatment with BCS-

CL73507.

Oestrous cycles, pre-coital interval, mating performance and fertility were

unaffected by treatment. The majority of animals littered within the

normal range of 22 to 23.5 days, including all females at 12000 ppm.

Gestation index was unaffected by treatment.

Assessment of vaginal cytology prior to termination of F0 females on Day

28 post-partum did not reveal any differences across the groups that

could be associated with treatment.

Sperm analysis revealed no adverse effects on number, motility or

morphology of sperm.

Organ weights for males after 18 weeks of treatment and females on

Day 28 post-partum were unaffected by treatment. Macroscopic

observations and microscopic examinations of various tissues performed

on these terminated males and females revealed no changes considered

to be related to treatment.

F1 offspring

The general condition of the offspring was unaffected by treatment. Litter

size, offspring survival, sex ratio and the anogenital distance on Day 1 of

age was unaffected by treatment.

Offspring bodyweight on Day 1 of age and subsequent gain up to Day 7

of age in either sex showed no adverse effects of maternal treatment.

During Days 7 to 14 of age female offspring in each treated group

showed low weight gain when compared with controls, this persisted up

to weaning for offspring receiving 6000 ppm. Following weaning (Days

21 to 25 of age), the weight gain for treated female offspring was not

significantly different from the controls.

High dose (6000 ppm) male offspring showed low weight gain from Day

7 of age up to weaning on Day 21. Following weaning (Days 21 to 25 of

age) selected male offspring receiving diet at the two higher main study

dietary concentrations (300, 600 ppm) also showed slightly but

significantly low weight gain.

Organ weights for offspring on Day 21 of age were unaffected by

treatment. Macroscopic examination of unselected offspring on Day 21 of

age and offspring dying before scheduled termination did not reveal any

findings that could be attributed to treatment.

F1 Parental

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The mean achieved dose during Weeks 1 to 10 of the F1 generation at

300, 600, 2700 and 12000 ppm was 28, 57, 253 and 1138 mg/kg bw/day

for males and 30, 63, 266, and 1218 mg/kg bw/day for females,

respectively.

During gestation and lactation the achieved doses were 23, 47, 211 and

1000 mg/kg bw/day for females at 300, 600, 2700 and 12000 ppm and

23, 47, 215 and 947 mg/kg bw/day for females at 150, 300, 1350, and

6000 ppm, respectively.

There were no signs at routine physical examination that could be

attributed to treatment.

At the start of the F1 generation (Week 0), the mean absolute body

weights for both males and females receiving BCS-CL73507 were

significantly low when compared with controls. Subsequent weight gain

for the males up to Week 10 of the F1 generation was essentially similar

across the groups, however, treated females showed statistically low

weight gain over the same period.

During gestation and lactation, the absolute body weights continued to

be low when compared with the concurrent controls. However, the

weight gain during these phases was essentially similar across the

groups; with the exception of the high dose group that showed high

weight gain during Days 1 to 4 of lactation and low weight gain during

Days 4-7 of lactation (p<0.05).

When compared with controls food consumption for the 10 week period

before animals were paired for mating was variable, but in general,

animals receiving BCS-CL73507 tended to show low consumption up to

Week 5 of the F1 generation; thereafter consumption was similar to

controls. Food consumption for females during gestation and lactation

was unaffected by treatment.

The efficiency of food utilisation for the period before animals were

paired for mating was unaffected by treatment with BCS-CL73507.

The completion of vaginal opening at 12000 ppm was significantly

delayed when compared with the concurrent controls; however, the

mean body weight on completion was essentially similar across the

groups. The onset of vaginal opening and the onset and completion of

balano-preputial separation were unaffected by treatment. Oestrous

cycles, pre-coital interval, mating performance and fertility were

unaffected by treatment.

As seen in the F0 generation, there was a slight shift in gestation length

with a higher percentage of females at 12000ppm showing a shorter

gestation length, although the gestation length of all females at 12000

ppm was within the normal range of 22 to 23.5 days.

Assessment of vaginal cytology prior to termination of F1A females on

Day 28 post-partum and F1B females on Day 70 of age did not reveal

any differences across the groups that could be associated with

treatment.

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Assessment of ovarian follicle counts for F1 control females and females

that received 6000/12000 ppm on Day 28 post-partum did not reveal any

differences that could be related to treatment.

Sperm analysis revealed no adverse effects on number, motility or

morphology of sperm.

On Day 70 of age, the absolute ovarian weights were significantly low

and the body weight relative weight for the Cowper’s gland were

significantly higher for F1B animals that received 12000 ppm.

Analysis of the F1A organ weights for males after 18 weeks of the F1

generation and for females on Day 28 post-partum did not reveal any

differences that could be attributed to treatment.

The macroscopic examination performed on F1B animals on Day 70 of

age, F1A males killed after 18 weeks of the F1 generation and F1A

females killed on Day 28 post-partum, revealed no changes which were

considered to be related to treatment. There were no histopathological

changes in the F1A tissues presented for examination in males killed

after 18 weeks of the F1 generation and females killed on Day 28 post-

partum which were considered to be related to treatment.

F2 Offspring

The general condition of the offspring, litter size, offspring survival and

sex ratio were unaffected by treatment.

The mean anogenital distance for treated female offspring was larger

than that observed for controls; with statistical significance attained at

dietary concentrations of 600/300 ppm or higher, however, no dose

response was apparent. The anogenital distance for male offspring was

unaffected by treatment.

Offspring body weight on Day 1 of age and subsequent gain up to Day

14 of age showed no adverse effects of maternal treatment. From Day

14 to 21 of age both high dose male and female offspring at 6000 ppm

showed significantly low weight gain, with significantly low absolute

weights for male offspring from Day 7 to 25 of age and for female

offspring from Day 21 to 25 of age. Body weight gain after weaning

(Days 21 to 25 of age) was similar across the groups and showed no

adverse effects of treatment.

Organ weights for offspring on Day 21 of age were unaffected by

treatment.

Macroscopic examination of unselected offspring on Day 21 of age and

offspring dying before scheduled termination did not reveal any findings

that could be attributed to treatment.

F2 generation

The mean achieved dose during Weeks 1 to 5 of the F2 generation at

300, 600, 2700 and 12000 ppm was 34, 69, 307 and 1361 mg/kg/day for

males and 34, 68, 312 and 1392 mg/kg/day for females, respectively.

There were no mortalities and no signs at routine physical examination

that could be attributed to treatment.

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Overall the body weight gain from Weeks 0 to 5 of the F2 generation

showed no adverse effects of treatment. At 12000 ppm the absolute

body weights of male and female animals tended to be slightly low when

compared with the controls; the difference attaining statistical

significance (p<0.05) for males on Weeks 0, 1, 2, 4 and 5 and for

females on Weeks 1, 4 and 5.

For the majority of the F2 generation, there was no evidence for any

adverse effects on food consumption.

The efficiency of food utilisation for the F2 animals from Weeks 0 to 5 of

the F2 generation was unaffected by treatment.

The completion of balano-preputial separation at 12000 ppm was

significantly delayed when compared with the concurrent controls

(p<0.05); however the mean body weight on completion was essentially

similar across the groups. The onset and completion of vaginal opening

and the onset of balano-preputial separation were unaffected by

treatment.

Assessment of vaginal cytology prior to termination of F2 females on Day

70 of age did not reveal any differences across the groups that could be

associated with treatment. On Day 70 of age, both the absolute and body

weight relative ovarian weights were significantly low for females that

received 12000 ppm. Macroscopic examination on Day 70 of age did not

reveal any findings that could be related to treatment.

Discussion

Body weight change and food consumption during the pre-

pairing/maturation phases did not show any adverse effects of treatment

with the efficiency of food utilisation essentially similar across the groups.

During gestation, the F0 females receiving BCS-CL73507 showed low

body weight gain and food consumption. In the successive F1 generation

although the absolute body weights were low, the weight gain and food

consumption were unaffected by treatment.

During the lactation phase females that littered received diet at 50% of

the main study dietary concentration. In each generation females at 6000

ppm (reduced from 12000 ppm) showed weight gain during Days 1 to 4

of lactation that was superior to the concurrent controls. This was

considered to be related to the adjustment of the dose level rather than a

direct effect of treatment. Food consumption during lactation showed no

adverse effects of treatment during either generation.

Oestrous cycles, pre-coital interval, mating performance and fertility were

unaffected by treatment during each generation. However, the F0 and F1

females at the high dose tended to show a shorter gestation length.

Since the gestation length for all females at the high dose was within the

normal range of 22 to 23.5 days for both generations and the body

weight on Day 1 of age, the survival and clinical condition of both the F1

and F2 offspring were unaffected by treatment, this finding was

considered not to be adverse.

Despite the slightly shorter gestation length in the high dose group the

mean body weight for offspring on Day 1 of age was essentially similar

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across the groups. Subsequent weight gain up to Day 7 in the F1

offspring and Day 14 in the F2 offspring was considered to be unaffected

by treatment. However subsequent weight gain up to weaning on Day 21

of age was generally low in the high dose group for both males and

females. F1 female offspring in the lower dose groups also showed low

weight gain during Days 7 to 14 of age. A decline in body weight

performance from approximately mid-lactation is not uncommon as this

coincides with offspring beginning to consume solid food. This effect on

body weight gain may, therefore, be related to either a direct effect of

treatment, or an indirect maternal effect on lactation, or a combination of

both a direct and indirect effect.

Following weaning (Days 21 to 25 of age) animals received the main

study dietary concentrations and the F1 males at all dose levels showed

low weight gain during this period; this effect was not apparent for the F1

females or F2 animals. The subsequent Week 0 bodyweight for selected

animals at the start of the successive generations were low for F1 males

and females at all dietary concentrations and for high dose

(12000/6000ppm) F2 males and females; this may provide some

evidence for adaptation between the generations.

The anogenital distance for F1 offspring and F2 male offspring on Day 1

of age was unaffected by treatment. However, for F2 female offspring,

the anogenital distance was greater in the treated groups, although no

dose-response was apparent. In the absence of an effect on F1

anogenital distance, vaginal opening, oestrous cycles, macropathology

or reproductive organ weights for selected F2 females, this finding is

considered to be incidental and is not considered to represent an

adverse effect of treatment.

F1 selected females at 12000 ppm showed a delay in the completion of

vaginal opening whilst F2 selected male offspring at 12000 ppm showed

a delay in the completion of balano-preputial separation. For both of

these parametres, the mean body weight on completion of sexual

maturation was similar to the controls. Therefore as there is no

consistency between the generations and the body weight on completion

was considered to be unaffected, the delays were considered to be

secondary to a delay in physical development rather than a direct effect

of treatment.

F1 and F2 females at 12000 ppm killed on Day 70 of age both had low

absolute ovarian weight and for F2 females the body weight relative

ovarian weight was also low. In the absence of an effect on oestrous

cycles, ovarian weight or histopathology for F0 or F1 females that littered

and were terminated on Day 28 post-partum, the aetiology of this finding

remains unclear and may be more reflective of a lower terminal body

weight, but is not considered to represent an adverse effect of treatment.

At 12000 ppm the mean body weight relative weight of the Cowper's

glands in F1B males at Day 70 of age was marginally but statistically

significantly higher than in controls. As this was an isolated finding with

no effect of treatment on the weights of the other reproductive organs, no

effect on the mating or reproductive performance of the F1 males, and

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was not replicated in the F2 males at Day 70 of age, no relationship to

treatment was inferred.

Additional Comments These data support the absence of in vivo significance to the results of

the in vitro H295R steroidogenesis assay.

Conclusion

Dietary administration to Han Wistar rats of BCS-CL73507 technical at

concentrations of 300, 600, 2700 and 12000 ppm (adjusted to 150, 300,

1350 and 6000 ppm for females during lactation) was generally well-

tolerated.

It is therefore considered that 2700 ppm (equiv. to the mean achieved

dose before pairing: 196 mg/kg bw/day for F0 males; 224 mg/kg bw/day

for F0 females; 253 mg/kg bw/day for F1 males; 266 mg/kg bw/day for

F1 females; 307 mg/kg bw/day for F2 males; 312 mg/kg bw/day for F2

females) represents the no-observed-adverse-effect level (NOAEL) in

this study for both the F0, F1 and F2 adult animals and the F1 and F2

offspring.

In terms of reproductive effects, no treatment-related findings were

observed at any dose level tested; therefore, the high dose of 12000

ppm (equiv. to the mean achieved dose before pairing: 896 mg/kg

bw/day for F0 males; 1032 mg/kg bw/day for F0 females; 1138 mg/kg

bw/day for F1 males; 1218 mg/kg bw/day for F1 females; 1361 mg/kg

bw/day for F2 males; 1392 mg/kg bw/day for F2 females) is considered

to be the NOAEL for reproductive toxicity.

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Target organ Toxicity [6.9]

Table 86: Repeated Dose Toxicity (Non-Guideline, Dose Range Finding Studies) [6.9]

Study type Summary Reference

14-Day

dermal

dose range

finding

study in

rats

The objective of this study was to select the dose levels to be used

in a definitive 28-day dermal toxicity study in rats (5/sex/group)

and to provide preliminary information on possible health hazards

likely to arise from repeated dermal exposure. The solid test item

was moistened with water to form a film and applied uniformly to

the skin at 100, 300 and 1000 mg/kg bw/day for approximately 6

hours/day.

Animal examinations included mortality, general and local clinical

signs, body weights, food consumption, clinical pathology, gross

pathology and organ weights. No histology was performed.

There were no test item administration related clinical and/or local

signs or unscheduled mortality during the study.

There were no signs of toxicity observed on body weights or body

weight gains during the study. There was no effect of treatment on

food consumption. There were no test item-related findings on the

clinical pathology (haematology and clinical chemistry) parameters

evaluated at the completion of the treatment period. No test item-

related changes were seen during gross necropsy at dose levels

up to and including 1000 mg/kg bw/day. There were no clear

toxicologically significant changes in organ weights.

The NOEL to rats in this study was 1000 mg/kg bw/day.

Torok-Batho, M.;

2015. BCS-

CL73507

technical: 14-Day

Dose Range

Finding Dermal

Study in Wistar

Rats; CiToxLAB

Hungary Ltd., H-

8200 Veszprem,

Szabadsagpuszta,

Hungary; Study

Code: 14/21`8-

102PE; Edition

No.: M-513347-

01-1

Exploratory

28-day

dietary

study in

the rat

The objective of this study was to determine the potential systemic

toxicity of BCS-CO80363 (former name for BCS-CL73507) in

Wistar rats (5/sex/group) following 28-days of continuous dietary

administration to provide information for selection of dose levels

for future toxicity studies in this species. This study was a

preliminary study and was not designed to meet regulatory

requirements.

Text material was fed at concentrations of 500, 2000 and 8000

ppm, corresponding to 38, 148 and 599 mg/kg bw/day in males

and 43, 171 and 700 mg/kg bw/day in females, respectively.

All animals were observed for mortality and clinical signs daily,

body weight and food consumption were measured weekly. A

detailed physical examination was performed weekly throughout

the study. Before scheduled necropsy, a blood sample was

collected for haematology and clinical chemistry determinations.

All animals were necropsied, selected organs weighed and a

range of tissues were taken, fixed and examined microscopically.

The remaining portions of the liver were homogenized for

microsomal preparations in order to determine cytochrome P-450

isoenzyme profile and UDPGT.

BCS-CO80363, up to 8000 ppm, did not induce any mortality or

clinical signs. There was no significant effect on body weight and

Lasserre, D.;

2011. BCS-

CO80363

Exploratory 28-

Day Toxicity

Study in the Rat

by Dietary

Administration.

Bayer S.A.S. 355,

rue Dostoievski,

BP153 06903

Sophia Antipolis

Cedex, France;

Study ID: SA

10263; Sponsor

ID: Lynx-PSI No.

TXRXP063;

Edition No.: M-

408743-01-1

of 541


SEPTEMBER/

2019

body weight changes or in food consumption. Haematology and

biochemistry parameters were not affected. Total cytochrome P-

450 and related activities and UDPGT activity were not affected.

The NOEL obtained in this study was 8000 ppm (equating to 599

and 700 mg/kg bw/day) in males and females, respectively.

Preliminary

28-day

dietary

study in

the mouse

The objective of this study was to determine the potential systemic

toxicity of BCS-CO80363 (former name for BCS-CL73507) in

C57BL/6J mice (5/sex/group) following 28-days of continuous

dietary administration to provide information for selection of dose

levels for future toxicity studies in this species. This study was a

preliminary study and was not designed to meet regulatory

requirements.

Test material was fed at concentrations of 0, 600, 3000 and 6000

ppm (equating approximately to 0, 100, 523 and 1010 mg/kg

bw/day in males and 0, 113, 576 and 1159 mg/kg bw/day in

females). Animals were observed daily for mortality and clinical

signs. A detailed physical examination was performed at least

weekly. Body weight and food consumption were recorded

approximately weekly. Selected clinical chemistry parameters

were determined at the end of the study. All animals were

subjected to necropsy, selected organs weighed and a range of

tissues were fixed and examined microscopically.

Exposure up to the limit dose of 6000 ppm did not cause any

mortalities, treatment-related clinical signs, changes in food

consumption, effects on clinical chemistry parameters, or

alterations in organ weights and histopathological findings. At 6000

ppm in females, changes in body weights were noted compared to

the controls.

The NOEL to C57BL/6J mice in this study was 6000 ppm in males

(equating 1010 mg/kg bw/day) and 3000 ppm in females (equating

576 mg/kg bw/day).

Blanck, M.; 2011.

BCS-CO80363

Preliminary 28-

Day Toxicity

Study in the

Mouse by Dietary

Administration.

Bayer S.A.S. 355,

rue Dostoievski,

BP153 06903

Sophia Antipolis

Cedex, France;

Study ID: SA

10288; Sponsor

ID: Lynx-PSI No.

TXRXP060;

Edition No.: M-

408546-01-1

Preliminary

28-day

dietary

study in

the dog

The objectives of this study were to determine the potential toxic

effects of BCS-CL73507 when administered via the diet to beagle

dogs (2 animals/sex/dose group) and to provide information for

selection of dose levels for further studies in this species.

Animals received BCS-CL73507 at doses of 2000, 6000 or 17000

ppm (equating approximately to 62.2, 190, 555 mg/kg bw/day in

males and 60.5, 222, 597 mg/kg bw/day in females). Each animal

was checked for ill-health, moribundity and mortality twice daily or

once daily on weekends. Food consumption was recorded daily

and body weight was measured weekly and prior to necropsy.

Additionally, a detailed clinical examination was performed

approximately weekly prior to treatment and during the treatment

period. Once during the acclimatization phase and at the end of

treatment, ophthalmological examination, blood analysis

(haematology, clinical chemistry) and urinalysis were performed.

All animals were subjected to a detailed necropsy. Selected

Kennel, P. 2012.

BCS-CL73507

(formerly BCS-

CO80363)

Preliminary 28-

Day Toxicity

Study in Dog by

Dietary

Administration.

Bayer S.A.S. 355,

rue Dostoievski,

BP153 06903

Sophia Antipolis

Cedex, France;

Study ID: SA

10439; Sponsor

ID: Lynx-PSI No.

of 541


SEPTEMBER/

2019

organs were weighed and a range of tissues were taken and

processed for histopathological examination.

Dietary administration of BCS-CL73507 induced no mortalities, no

clinical signs and no changes at the physical and ophthalmological

examinations. Body weight parameters, food consumption and

haematology parameters were also unaffected by the treatment.

Plasma levels at the end of the study showed a similar test item

concentration between all treated animals with a marginal increase

observed 4 to 6 hours after food distribution, which likely reflects a

limitation in the absorption of the test item in blood.

At 17000 ppm

Treatment-related effects were noted at the clinical chemistry

determinations, necropsy and histopathological evaluations.

Clinical chemistry determinations revealed increased total

cholesterol concentrations in the two animals from both sexes

(+28% and +37% in males, +40% and +24% in females), when

compared to their own pre-test results. At necropsy, slight red foci

were observed in the stomach in 1/2 females. This change was

correlated with slight glandular erosion/necrosis in the stomach

observed at the microscopic examination

At 6000 ppm: Treatment-related effects were noted at the clinical

chemistry determinations, necropsy and histopathological

evaluations. Clinical chemistry determinations revealed increased

total cholesterol concentrations in the two animals from both sexes

(+38% and +15% in males, +24% and +30% in the females), when

compared to their own pre-test results. At necropsy, minimal red

foci were observed in the stomach in 1/2 females. This change

was correlated with minimal glandular erosion/necrosis in the

stomach observed at the microscopic examination.

At 2000 ppm: No treatment-related change was noted in either

sex.

The NOEL for BCS-CL73507 is considered to be 2000 ppm (an

average dose of 62.2 and 60.5 mg/kg bw/day in males and

females, respectively).

TXFVP005;

Edition No.: M-

440096-01-1

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Table 87: Repeated Dose Toxicity (90-Days) [6.9]

Type of study Subchronic toxicity in rats

Flag Key

Test Substance BCS-CL73507 (formerly BCS-CO80363); Lot/Batch number: NLL 8217-

48-2; Purity: 92.6%

Endpoint

LOAEL: Not determined as no toxicity was observed at highest dose

NOAEL: 10,000 ppm (equating to 608 and 723 mg/kg bw/day in males

and females, respectively)

Reference

Odine, M.; 2016. BCS-CL73507 (formerly BCS-CO80363) 90-Day

Toxicity Study in the Rat by Dietary Administration. Bayer S.A.S. 355,

rue Dostoievski, CS 90153 Valbonne, 06906 SOPHIA ANTIPOLIS

Cedex, France; Study ID: SA 10431; Sponsor ID No.: Nexus No.

TXFVP007; Edition No.: M-443358-02-3

Klimisch Score 1


GLP Yes

Test Guideline/s


EEC 2001/59/EC, Method B.26



Species Rat

Strain Wistar Rj:WI (IOPS HAN)

No/Sex/Group 10M/10F; 6 Groups [control, low, medium, high, and 4 week recovery

groups (control, high)]; 120 total

Dose Levels

0, 900 (M: 55 mg/kg bw/day; F: 66 mg/kg bw/day) , 3000 (M: 178 mg/kg

bw/day; F: 213 mg/kg bw/day), 10000 ppm (M: 608 mg/kg bw/day; F:

723 mg/kg bw/day)

Exposure Type Oral by the diet

Study Summary

BCS-CL73507 was administered continuously to rats via dietary

administration for 90 days at three different concentrations with an

additional 2 groups (control and high dose) maintained on control diet for

one month following termination of the 3-month exposure to assess

recovery.

Animals were observed for clinical signs daily and body weight was

measured weekly. Food consumption was measured twice weekly

during the first 6 weeks of treatment and weekly thereafter. A detailed

physical examination was performed once during the acclimatization

phase and weekly throughout the study. All surviving animals were

subjected to a neurotoxicity assessment (exploratory locomotor activity,

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open field observations, sensory reactivity and grip strength) during

Weeks 11 to 12 of the study. Ophthalmological examinations were

performed on all animals during the acclimatization phase and on all

animals of the control and high dose groups during Week 12. Urine

samples were collected overnight on the week before scheduled

necropsy from all surviving animals. During week 12, a blood sample

was collected from the first five suitable animals of each group for

compound analysis. Before scheduled necropsy, a blood sample was

collected from the retro-orbital venous plexus of each surviving animal

for haematology and clinical chemistry determinations. All animals were

necropsied, selected organs weighed and a range of tissues were taken,

fixed and examined microscopically. Based on the absence of findings in

the neurological and ophthalmological examinations during the

treatment phase, these parameters were not evaluated during the

recovery phase.

For both sexes, there were no treatment-related clinical signs noted

during the study. The few clinical signs recorded in both sexes were

observed in isolation or evenly distributed between groups. No

treatment-related changes were observed in any of the neurobehavioral

assessments [grip strength, landing foot splay, mean spontaneous

motor activity, Functional Observational Battery (FOB)] evaluated in

either sex in any treatment group compared to controls. The very few

signs observed were distributed among all groups including controls

without any relationship with treatment. No deaths were observed during

the treatment or recovery phase except for one control animal (Day-23

of the recovery phase).

There was no treatment-related effect on mean body weight, mean body

weight gain and mean cumulative body weight gain in either sex at any

dose level. In the recovery phase, the mean body weight in group 4 was

comparable to controls from Day 1 to final sacrifice in both sexes. There

was no effect on the mean food consumption at any dose level in the

males when compared to controls. In females, the mean food

consumption was sporadically increased on a few occasions at all dose

levels, when compared to controls and considered as incidental and

therefore not related to the treatment. The mean food consumption of

group 4 was comparable to controls throughout the recovery period for

both sexes.

No treatment-related change was noted at any dose level, in either sex

in haematology. When compared to the controls a tendency towards

higher inorganic phosphorus concentrations was noted at 10000 ppm in

males only (+6%, p≤0.05). In view of the variation of the individual

values and of its low magnitude, this change was considered not to be

treatment-related or biologically significant. This slight elevation became

a statistically significant slight decrease after recovery and was also

considered to be incidental and not treatment-related or biologically

relevant. No treatment-related change was noted at any dose level, in

either sex in the urinalysis.

At 10000 ppm, mean liver to body weight ratio was statistically

significantly higher in males, when compared to the controls. At 10000

ppm, mean absolute kidney weight was statistically significantly higher in

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females when compared to the controls. At 10000 ppm, mean absolute

and relative thyroid gland weights were higher but not statistically

significant in females, when compared to the controls. Since these

differences were slight, and not accompanied with any relevant

microscopic findings, they were considered to be incidental and not

treatment-related. The few other organ weight changes were considered

to be incidental.

In recovery phase animals mean absolute and relative adrenal gland

weights were statistically significantly higher in females when compared

to the controls. Since no modifications were seen at the final sacrifice, it

was considered to be incidental and not treatment-related.

All gross pathological changes were considered as incidental and not

treatment-related. In the thyroid gland, an abnormal morphology

characterized by thyroid dysplasia was observed in two male animals at

10000 ppm and one female at 900 ppm. This abnormality was

associated with higher mean absolute and relative thyroid gland weights

in group 4. However, it was considered not to be treatment-related but

the result of a genetic disorder as already described by Shimoi et al.

(2001) and Weber et al. (2009). A special staining (Periodic acid Schiff)

of the thyroid gland has confirmed the similarity of the genetic

abnormality described by these authors. All other microscopic findings

were those commonly observed in the rat of this strain and age.


0.315, and 0.406 mg/ml in males and 0.875, 0.778, and 0.915 mg/ml in

females at their respective low to high exposure concentrations.

Additional Comments

It appears as if the test article has a restricted absorption potential as

there is only a minor difference in serum levels between the lowest (900

ppm) and highest concentration (10,000 ppm) that is ~10x more. The

higher levels in females are also greater than what would be expected

based on dose alone (female conc. of 0.875 mg/ml at the lowest

concentration dose of 66 mg/kg bw/day vs males 55 mg/kg bw/day

resulting in a blood level of only 0.266 mg/ml). The more than doubling

of plasma conc. levels in females compared to males indicates that

females may either be able to absorb a higher percentage of the test

article or perhaps are unable to clear it from their blood as fast as males.

Conclusion

An exposure level of 10000 ppm BCS-CL73507 (equating to 608 and

723 mg/kg bw/day in males and females, respectively) was considered

to be a No Observed Adverse Effect Level (NOAEL) in the male and

female Wistar rat following a 90-day treatment by dietary administration.

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Study type Subchronic toxicity in mice

Flag Key study

Test Substance BCS-CL73507 (formerly BCS-CO80363); Lot/Batch number: NLL 8217-

48-2; Purity: 92.6%

Endpoint

LOAEL: Not determined as no toxicity was observed at highest dose

NOAEL: 6000 ppm (equating to 973 and 1224 mg/kg bw/day in males

and females, respectively)

Reference

Odine, M.; 2016. BCS-CL73507 (formerly BCS-CO80363) 90-Day

Toxicity Study in the Mouse by Dietary Administration. Bayer S.A.S. 355,

rue Dostoievski, CS 90153 Valbonne, 06906 SOPHIA ANTIPOLIS

Cedex, France; Study ID: SA 10431; Sponsor ID No.: Lynx-PSI No.

Nexus No. TXFVP004; Edition No.: M-448164-02-2

Klimisch Score 1


GLP Yes

Test Guideline


EEC 2001/59/EC, Method B.26



Species Mouse

Strain C57BL/6J

No/Sex/Group 10M/10F; 4 Groups (control, low, medium, high); 80 total

Dose Levels

0, 900 (M: 145 mg/kg bw/day; F: 179 mg/kg bw/day) , 2700 (M: 426

mg/kg bw/day; F: 544 mg/kg bw/day), 6000 ppm (M: 973 mg/kg bw/day;

F: 1224 mg/kg bw/day)


Study Summary

BCS-CL73507 was administered continuously via dietary administration

to mice at concentrations of 0, 900, 2700, and 6000 ppm (equating

approximately to 145, 426, 973 mg/kg bw/day in males and 179, 544,

1224 mg/kg bw/day in females, respectively).

Animals were observed daily for mortality and clinical signs. Body weight

and food consumption were measured weekly. A detailed physical

examination was performed weekly throughout the study. During Week

12 of the study, a blood sample was collected from 5 animals in each

group sample for assessing plasma concentrations. At study termination,

blood was collected from each surviving animal for selected clinical

chemistry determinations. All animals were necropsied, selected organs

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weighed and a range of tissues were taken, fixed and examined

microscopically.

No treatment-related clinical signs were noted at any dose level in either

sex. The few physical examinations observed were considered not to be

related to BCS-CL73507 administration as they were evenly distributed

across the groups including the controls with no evidence of a dose-

related effect.

There were no treatment-related mortalities during the study. One male

from the 6000 ppm group was found dead on Study Day 8. In isolation

and in the absence of any clear microscopic findings which could be

attributed to the cause of death, the death of this animal was considered

to be incidental. Body weight and body weight gain parameters were

unaffected by treatment. Food consumption was unaffected by treatment

in either sex at any dietary level.

A tendency towards higher total cholesterol concentrations was noted at

6000 and 2700 ppm (+16%, p≤0.01 and +10%, p≤0.05 respectively) in

females only. These differences were of a low magnitude and most of

the individual values were within the range of the HCD and they were

considered not to be relevant.

There was no change in mean terminal body weight in treated animals

when compared to the controls. At 6000 ppm in females, a statistically

significantly higher mean liver to body weight ratio was observed when

compared to controls (+6%, p≤0.05). At 2700 ppm in females, statistically

significantly higher mean relative spleen weights were observed when

compared to controls (13% and 15%, p≤0.05). Since these differences

were slight, not dose-related and not associated with any relevant

microscopic findings, they were considered to be incidental and not

treatment-related. The few other organ weight changes were not

statistically significant and were considered to be incidental. No

treatment-related macroscopic or microscopic findings were observed.


0.412, and 0.570 mg/ml in males and 0.697, 0.774, and 1.01 mg/ml in

females at their respective low to high exposure concentrations.

Additional Comments

Similar to rats, it appears as if the test article has a restricted absorption

potential as there is only a minor difference in serum levels between the

lowest (900 ppm) and highest concentration (6,000 ppm) in each sex.

Also, females appear to be able to absorb a higher percentage or

perhaps are unable to clear it from their blood as fast as males. At the

lowest exposure females had almost a 2x higher plasma concentration of

test article compared to males (0.697 vs 0.364 mg/ml) yet only had a

23% higher exposure dose (179 vs. 145 mg/kg bw/day).

Conclusion

An exposure level of 6000 ppm BCS-CL73507 (equating to 973 and

1224 mg/kg bw/day in males and females, respectively) was considered

to be a No Observed Adverse Effect Level (NOAEL) in the male and

female C57BL/6J mouse following a 90-day treatment by dietary

administration.

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Study type Subchronic toxicity in dogs

Flag Key study

Test Substance BCS-CL73507 technical; Batch/Lot Number: 2012-005440; Specification

No.: 102000026788; Purity: 89.6% w/w; Expiry date: August 1, 2015

Endpoint

LOAEL: 12800 ppm (M: 440 mg/kg bw/day; F: 485 mg/kg bw/day

NOAEL: 3200 ppm (M: 126 mg/kg bw/day and F: 138 mg/kg bw/day)

Reference

Kennel, P.; 2015. BCS-CL73507 90-Day Toxicity Study in the Dog by

Dietary Administration. Bayer S.A.S. 355, rue Dostoievski, CS 90153

Valbonne, 06906 SOPHIA ANTIPOLIS Cedex, France; Study ID: SA

13013; Activity ID No.: TXFVP043; Edition No.: M-495692-02-3

Klimisch Score 1


GLP Yes

Test Guideline


EEC Directive 67/548/EEC, Annex V, Method B.27



Species Dog

Strain Beagle

No/Sex/Group 4M/4F; 4 Groups (control, low, medium, high)

Dose Levels

0, 800 (M: 25.6 mg/kg bw/day; F: 29.9 mg/kg bw/day) , 3200 (M: 126

mg/kg bw/day; F: 138 mg/kg bw/day), 12800 ppm (M: 440 mg/kg bw/day;



Study Summary

Dogs received BCS-CL73507 via the diet for at least 13 weeks. Each

animal was checked for ill-health, morbidity, mortality and observed

clinical signs were recorded daily. A detailed clinical examination was

performed approximately weekly and a detailed physical examination was

carried out monthly. Food consumption was recorded daily throughout the

study and body weight was measured weekly and prior to necropsy.

Ophthalmological examination was performed during the acclimatization

phase and at the end of the study. Blood analysis (haematology, clinical

chemistry) and urinalysis were performed once during the acclimatization

phase, at Week 7 and at the end of the study. A blood sample was also

collected on selected animals for bioanalytical examination at the end of

the study. All animals were subjected to a detailed necropsy. Selected

organs were weighed and a range of tissues were collected and

processed for histopathological examination.

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Up to the highest dose level tested (12800 ppm), BCS-CL73507 induced

no mortalities, no treatment-related changes at the ophthalmological

examination, haematology determinations, urinalysis, gross observation

and microscopic examination. The bioanalytical examination showed a

dose-related increase in the test item BCS-CL73507 and metabolite BCS-

CQ63359 plasma concentrations, with similar results observed between

the two sexes.

High dose groups - 12800 ppm (equating to 440 and 485 mg/kg bw/day in

males and females, respectively)

The only treatment-related clinical signs consisted of increased salivation

noted for two dogs on 4 and 6 occasions, respectively, at the clinical

examination. Mean body weight gain during the first week of treatment

was reduced by 88% in males (not statistically significant) and 91% in

females (p≤0.01), compared to controls. Mean body weight gain/week was

also affected on several occasions throughout the study in both sexes,

which resulted in an overall mean body weight gain of 0.58 kg in males

and 0.63 kg in females, compared 17 of 552 to 1.50 and 1.55 kg in the

corresponding controls (-61% and -59%, respectively, p≤0.01 in females

only). As a consequence, mean body weight was decreased from 5% on

Day 8 to 12% on Day 92 in males and from 4% on Day 8 to 11% on Day

92 in females (not statistically significant), compared to controls. The

weekly mean food consumption was marginally affected in females only.

Overall between Weeks 1-13, mean food consumption was decreased by

11% in females compared to controls. Clinical chemistry determination

revealed higher mean alkaline phosphatase activity at Weeks 7 and 13 in

males (+28% and +58%, respectively, not statistically significant) and

females (+53% and +114%, respectively, p≤0.01) when compared to

controls. At necropsy, mean terminal body weight was lower by 12% in

males and 11% in females, when compared to controls (not statistically

significant), whilst mean organ weight parameters were unaffected by the

treatment.

Mid dose groups - 3200 ppm (equating to 126 and 138 mg/kg body

weight/day in males and females, respectively)

The only treatment-related clinical signs consisted of increased salivation

noted on one or more occasions for 3 male dogs at the weekly clinical

examinations and at 2 occasions for one male dog at the monthly physical

examinations. This finding in isolation was considered not to be adverse.

There were no treatment-related changes in the low dose groups - 800

ppm (equating to 25.6 and 29.9 mg/kg body weight/day in males and

females, respectively).

The bioanalytical examination showed a trend towards a dose-related

increase in the test item BCS-CL73507 and metabolite BCS-CQ63359

plasma concentrations, with females showing slightly higher

concentrations.

Exposure

level

Sex 13-Weeks

Active Metab.

800 ppm F 2.68 0.40

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M 2.01 0.40

3200 ppm F 3.89 1.14

M 2.92 0.77

12800 ppm F 4.94 1.62

M 4.64 1.70

Additional Comments

Similar to the 52-week study, test material induced an increase in both

circulating platelet count and alkaline phosphatase enzyme. Such effects

are consistent with an increase in cortisol which might have been present

as seen in the H295R cell line (steroidogenesis) results.

Conclusion

In conclusion, a dietary level of 3200 ppm (equating to 126 and 138 mg/kg

body weight/day in males and females, respectively) administered to

Beagle dogs for at least 13 weeks was considered to be a No Observed

Adverse Effect Level (NOAEL) in males and a NOEL in females.

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Table 90: Repeated Dose Toxicity (52-Weeks) [6.9]

Study type Chronic toxicity in dogs

Flag Key study

Test Substance


No.: 102000026788; Purity: 89.6% w/w; See comments below regarding

expiration.

Endpoint

LOAEL: 12800 ppm (M: 440 mg/kg bw/day; F: 408 mg/kg bw/day

NOAEL: 2900 ppm (M: 91.2 mg/kg bw/day and F: 88.4 mg/kg bw/day)

Reference

Kennel, P.; 2016/amended 2017. BCS-CL73507 Chronic Toxicity Study in

the Dog by Dietary Administration. Bayer S.A.S. 355, rue Dostoievski, CS

90153 Valbonne, 06906 SOPHIA ANTIPOLIS Cedex, France; Study ID:

SA 13268; Activity ID No.: TXFVP045; Edition No.: M-562764-03-1

Klimisch Score 1


GLP Yes

Test Guideline


EEC Directive 88/302/EEC, Method B.30



Species Dog

Strain Beagle

No/Sex/Group 4M/4F; 4 Groups (control, low, medium, high)

Dose Levels

0, 650 (M: 19.8 mg/kg bw/day; F: 18.3 mg/kg bw/day) , 2900 (M: 91.2

mg/kg bw/day; F: 88.4 mg/kg bw/day), 12800 ppm (M: 440 mg/kg bw/day;



Study Summary

Three groups of 4 males and 4 females received test material for at least

52 weeks. Each animal was examined for ill-health, morbidity and

mortality twice daily or once daily on weekends and public holidays during

the acclimatization phase and throughout the study. Observed clinical

signs were recorded daily. A detailed clinical examination was performed

approximately weekly and a detailed physical examination was carried out

monthly. Food consumption was recorded daily throughout the study and

body weight was measured weekly and prior to necropsy.

Ophthalmological examination was performed during the acclimatization

phase and at the end of the study. Blood analysis (haematology, clinical

chemistry) and urinalysis were performed once during the acclimatization

phase, at Months 3-4, 6-7 and at the end of the study. A blood sample

was also collected on selected animals for bioanalytical examination at

Month 4 and at the end of the study. All animals were subjected to a

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detailed necropsy. Selected organs were weighed and a range of tissues

were taken and processed for histopathological examination.

Up to the highest dose level tested no mortalities and no treatment-related

changes were noted at the ophthalmological examination, food

consumption, urinalysis or gross observation.

The bioanalytical examination showed a trend towards a dose-related

increase in the test item BCS-CL73507 and metabolite BCS-CQ63359

plasma concentrations, with similar results observed between the two

sexes.

Exposure

level

Sex 3 months 12 months

Active Metab. Active Metab.

650 ppm F 1.7 0.38 2.9 0.69

M 2.0 0.38 1.8 0.52

2900 ppm F 2.6 0.73 2.4 1.4

M 2.8 0.82 3.6 1.1

12800 ppm F 5.9 2.0 7.4 3.1

M 4.8 2.5 6.4 2.9

High dose groups - 12800 ppm

The only treatment-related clinical signs consisted in increased salivation

noted for one male dog at 15 occasions and for three female dogs up to a

maximum of 34 occasions throughout the study at the daily cage-side

clinical observation and/or weekly detailed clinical examination. Increased

salivation was also noted for one male dog at 3 occasions and for one

female dog at one occasion throughout the study at the monthly physical

examination.

A mean body weight loss of 0.13 kg in males and 0.03 kg in females was

noted during the first week of the study compared to a gain of 0.20 kg in

the controls (p≤0.05 in males only). After 3 months (Day 92), the overall

mean body weight gain was reduced by 62% in males and 49% in

females, compared to controls (not statistically significant). This effect on

mean body weight parameters persisted throughout the study. At the end

of the study (Day 365), the overall mean body weight gain was reduced by

73% in males and 57% in females, compared to controls (p≤0.05 in

females only) and mean body weight was reduced by 14% in males and

13% in females, compared to controls (not statistically significant).

Haematology determinations revealed a higher mean platelet count in

both sexes throughout the study (+50 to +112%, p≤0.01) when compared

to controls. Clinical chemistry determinations revealed a higher mean

alkaline phosphatase activity in males at Months 6 and 12 (+132% and

+200%, respectively, p≤0.05) when compared to controls.

At necropsy, mean terminal body weight was lower by 14% in males and

12% in females, when compared to controls (not statistically significant),

whilst mean organ weight parameters were unaffected by the treatment.

At the microscopic examination, the only treatment-related change

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consisted of a minimal or slight diffuse vacuolation of the zona

glomerulosa noted in the adrenal gland in both sexes. This adrenal gland

microscopic change, characterized by foamy cytoplasm and loss of central

alignment of nuclei of zona glomerulosa cells, was interpreted to be part of

a continuum of focal/multifocal vacuolation of zona glomerulosa and/or

zona fasciculata as it is frequently observed in untreated beagle dogs

(Sato, J. et al.; 2012), including at the Test Facility. In the present study,

focal zona glomerulosa vacuolation was seen in one control male and one

control female. In view of the diffuse change in treated dogs and clear

inter-group difference, this minor finding was considered to be test item-

related and to represent a minor and non-adverse functional adaptation of

the adrenal zona glomerulosa.

Mid dose groups - 2900 ppm

The only treatment-related clinical sign consisted in increased salivation

noted for one male dog at 6 occasions and for two female dogs up to a

maximum of 31 occasions throughout the study at the daily cage-side

clinical observation and/or weekly detailed clinical examination. Increased

salivation was also noted only for one female dog at 2 occasions

throughout the study at the monthly physical examination. In isolation, this

clinical sign was considered not to be an adverse effect of the treatment.

Mean body weight parameters were unaffected by treatment throughout

the study. Haematology determinations revealed a higher mean platelet

count in males at Month 12 (+55%, p≤0.05) and in females throughout the

study (+45 to +65%, p≤0.01) when compared to controls. These

treatment-related changes were considered not to be adverse in the

absence of related histopathological findings.

At necropsy, mean terminal body weight and organ weight parametres

were unaffected by the treatment. At the microscopic examination, the

only treatment-related change consisted of a minimal or slight diffuse

vacuolation of the zona glomerulosa noted in the adrenal gland in both

sexes, which was considered not to be adverse (see aforementioned

conclusion for the high dose groups).

Low dose groups - 650 ppm

The only treatment-related findings consisted of a slightly higher mean

platelet count in females at Month 12 (+41%, p≤0.05), when compared to

controls. In addition at necropsy, a minimal or slight diffuse vacuolation of

the zona glomerulosa was noted at the microscopic examination in the

adrenal gland in both sexes. These treatment-related changes were

considered not to be adverse.

Additional Comments

The study began dosing on February 17, 2014 and was terminated on Feb

17, 2015. There were two Certificate of Analysis (CoA) in the appendix to

cover stability of the testing material during this time period. However, one

(Certificate No.: MZ00601) indicated the test material expired May 28,

2013, ~9 months prior to study initiation. The other CoA (Certificate No.:

MZ00855) analysed test material on May 9, 2014 indicating stability

(expiration date) until May 9, 2015 (after study termination). Thus, the first

~5 months of the study may have used expired test material.

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Toxicokinetics

Table 91: Toxicokinetics (Preliminary study)

The significance of this is minimized as another CoA (Certificate No.:

MZ00755) from another study (Study ID: SA 12223; Activity ID No.:

TXFVP052; Edition No.: M-510211-02-3) showed test material from the

same batch as being stable from a test period of Oct. 2013 till April 30

2014 which would have covered the first 5 months of exposure. Numerous

other CoA’s from other studies indicate test material from this same origin

batch (2012-005440) as being stable over several years of animal testing.

Conclusion

A dietary level of 2900 ppm (equating to 91.2 and 88.4 mg/kg bw/day in

males and females, respectively) administered to Beagle dogs for one

year was considered to be a No Observed Adverse Effect Level (NOAEL)

in both sexes (based on the body weight effects and increased alkaline

phosphatase activities noted at 12800 ppm).

Study type Whole-body distribution and pilot metabolism study


Test Substance [Pyrazole-carboxamide-14C]BCS-CL73507; Radiochemical purity >98%,

Vehicle: 0.5% aqueous tragacanth

Endpoint

The main objectives were to provide data on the:

absorption of radioactivity from the GI-tract, distribution in and

elimination from blood, organs and tissues using the whole body

autoradiography (WBAL)technique

excretion of radioactivity with urine and faeces

radioactivity in exhaled carbon dioxide

metabolic profiles in excreta (urine and faeces), plasma, liver and

kidney

storage stability of frozen plasma samples.

Value

Tmax (hr) = 1(M) and 4(F)

Cmax (blood)(µg equiv./g) = 0.251 (M, 1 hr) and 0.173 (F, 4 hr)

Blood clearance (hr) = <48 (M/F)

Liver/blood (1 hr) = 10(M/F)

~13 metabolites identified in urine 6 in the faeces

Essentially no 14CO2 was eliminated

parent and metabolites appeared to be stable when frozen

Faeces contained 95.4% of the 0-24h dose and urine 2.57%

Reference

Koester, J.; 2015. [Pyrazole-carboxamide-14C]BCS-CL73507 -

Distribution of the Total Radioactivity in Male and Female Rats Determined

by Quantitative Whole Body Autoradiography, Determination of the

Exhaled 14CO2, and Pilot Metabolism Experiments Bayer CropScience

AG, Development - Environmental Safety – Testing, BCS-D-EnSa-Testing

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Alfred-Nobel-Str. 50, D-40789 Monheim am Rhein, Germany Study ID:

M182209-1, Activity ID: MEFVP004; Edition No.: M-526337-01-1

Klimisch Score 1


GLP Yes

Test Guideline

OECD Guideline for Testing Chemicals, 417

US EPA OCSPP 870.7485

Japan/FAMIC-ACIS Annex 2.3 1 to Notification 12 Nousan 8147

Species Rat

Strain Wistar

No/Sex/Group 4 males/pilot metabolism and 8 males and females whole body distribution

Dose Levels 5 mg/kg bw / test


Study Summary

The absorption of radioactivity from the GI-tract, distribution to and

elimination from blood, organs and tissues were analysed qualitatively and

quantitatively by whole-body autoradioluminography. One rat of each sex

was taken for cryosectioning at 1, 4, 8, 24, 48, 72, 120, and 168 hours

after administration.

The amounts of radioactivity in excreta (urine and faeces) and exhaled

carbon dioxide were additionally determined for selected time periods.

With regard to metabolism one male rat was sacrificed at 1, 4, 8, and 24 hr

after administration. The following samples were collected and afterwards

prepared for the chromatographic evaluation by High Performance Liquid

Chromatography (HPLC) with radiometric detection of the metabolic

profiles: urine, faeces, plasma, liver and kidney.

Additionally, plasma samples from the animals sacrificed at 1, 4, and 8

hours were analysed up to approx. 1 year after collection in order to get

information on the stability after storage at ≤ -18o C.

Toxicokinetic Behaviour of Rats (Test 2 and Test 3)

Distribution of Radioactivity to and Elimination from Organs and

Tissues

In male rats, maximum (TRR)-values [equivalent concentration (CEQmax)

expressed as μg a.s. equiv. /g] were reached in all organs and tissues at

one to four hours after administration, while in females it was one to eight.

During this time period, the organ/blood concentration ratio values for most

organs ranged from ~1 to 10 for both sexes. The radioactivity

concentration in these organs and tissues was higher than the

concentration in blood for which however a comparatively low value (0.251

mg/kg) was measured.

The test compound related radioactivity was cleared from blood very fast

(<48 hr) and distributed to the entire body preferably towards those organs

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or tissues that are responsible for metabolism (liver) and excretion

(kidney), some glandular organs (eg adrenal gland, pancreas), brown fat

and ovary and uterus in females. The tissue/blood-concentration ratios at

tmax (1 hr) were highest for liver (factor ~10) and adrenal gland (factor ~4.5)

in both sexes. The relatively lowest values were calculated for the testis

(0.3), the vitreal body (0.1) and spinal cord (0.03). Either no amount, or a

minimal amount, of radioactivity, was detected in the brain for males and

females, respectively.

Residual Concentrations in Organs and Tissues

At the end of the test on Day 7, no residual radioactivity was measured in

nearly all organs and tissues in either sex except in the liver and kidney,

where trace amounts of radioactivity ˂0.6% and 1.0%, respectively were

detected.

Excretion and Exhalation

One day after administration more than 95% of the given dose had been

excreted and the excretion was nearly completed after two days in males

and three in females. The major part of the given dose (more than 98% in

males and 92% in females) was excreted with faeces and the minor part

(up to ~2%) with urine.

The exhalation of 14C-carbon dioxide was tested with four animals for a

period of 48 hours. Only a negligible amount (< 0.01%) of the given dose

was exhaled during this sampling period. This demonstrated that the 14C

labelling in the pyrazole-carboxamide moiety of the molecule was stable

with regard to formation of carbon dioxide.

Metabolism (Pilot Test 1, males)

Approximately. 2.6% and 95.4% of the given dose were excreted via urine

and faeces, respectively within the 24 hours experimental period. The

values in plasma decreased from approx. 0.06% (1 hr) to <0.01% (24 hr).

A similarly significant reduction was observed for the liver, kidney and

erythrocytes: liver from ~4.4% (1 hr) to 0.2% (24 hr), kidney from ~0.1% (1

hr) to <0.01% (24 hr), and erythrocytes from ~0.03% (1 hr) to <0.001% (24

hr).

Metabolic Profile in Excreta (Urine and Faeces)

In the urine samples, 14 metabolites were detected beside the parent

compound. No component exceeded a value of 1% of the given dose.

The parent compound was the largest substance that was detected in the

urine (0.49%) and faeces extract (77.2%). In the faeces, six metabolites

ranged from ~1 to 4% and another nine ranged from 0.2 to 0.6% of the

given dose.

Metabolic Profile in Plasma

The (TRR)-value increased from 0.214 mg/kg at 1 hour to 0.264 mg/kg at 4

hours after dosing before a decrease was noticed for the 8 h sample

(0.118 mg/kg). The TRR-value for the 24 hours sample was too low for a

detailed analytical investigation (0.017 mg/kg). The by far prominent

component was the parent compound ranging from approx. 89% to 67% of

the TRR for the 1 and 8 hours samples, respectively. For the metabolite

BCS-CL73507-N-methyl-quinazolinone, values from 4.2% to 9.1% of the

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Table 92: Toxicokinetics

TRR were calculated. None of the up to five other unknown metabolites

exceeded 10% of the TRR.

Stability of the Metabolic Profile in Plasma

The stability of the metabolic pattern in plasma following a cold storage (≤ -

18 oC) of up to 1 year after sacrifice showed a small increase of the

metabolite BCS-CL73507-N-methyl-quinazolinone. A similar result was

obtained for the 4 and 8 hours samples of animals 80 and 81 that were

analysed latest after 1-year storage. The parent compound was by far the

most prominent component at any time of the investigation.

Additional Comments The metabolic profiling portion of this study was primarily an investigative

study and was more robustly assessed in other studies.

Conclusion

Tetraniliprole (BCS-CL73507), labelled with 14C in the pyrazole

carboxamide moiety of the molecule, was absorbed very limited from the

gastrointestinal tract of male and female Wistar rats after single oral

administration leading to relatively low residue values in the systemic

compartment blood, in organs and tissues, and in the amount that was

excreted with the urine.

The absorbed test compound related radioactivity was distributed

throughout the animal bodies immediately after dosing with a clear

preference to the liver and kidney. Peak concentrations of radioactivity in

most organs and tissues were reached in the course of eight hours after

dosing. Slight delays were observed for some organs and tissues of

female rats relating to the time to reach the maximum value. The

compound related radioactivity was then almost completely and rapidly

eliminated from the central and peripheral compartments of the animals

until sacrifice.

No significant sex-related differences concerning the maximum equiv.

concentrations in blood and in organs and tissues as well as the excretion

via urine and faeces were observed between male and female rats.

The results of the whole body autoradiography experiments of this study

showed that male and female rats exhibited a very similar absorption,

distribution and excretion behaviour. Any accumulation or significant

retention of [pyrazole-carboxamide-14C]BCS-CL73507 related residues in

organs and tissues of male and female rats can be excluded.

Study type Adsorption, Distribution, Excretion, and Metabolism

Flag Key study

Test Substance [Pyrazole-carboxamide-14C]BCS-CL73507; Radiochemical purity >98%,

Vehicle: 0.5% aqueous tragacanth

Endpoint ADME kinetics and metabolite identification

Value

Tmax(hr) =1 (2 mg/kg M/F and 20 mg/kg M) and 7 (20 mg/kg F)

Cmax(mg/L) 2 mg/kg = 0.199 (F) and 0.131 (M, cannulated)- 0.138(M)

Cmax(mg/L) 20 mg/kg = 0.008(F) and 0.006(M)

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Cmax(mg/L) 200 mg/kg = Not detectable in either sex

t1/2 (hr) 2 mg/kg = 18(F) and 27.9(M)

t1/2 (hr) 20 mg/kg = 4.1(F) and 14.3(M)

AUC0-∞ (mg/L*h) 2 mg/kg = 1.21(M) and 2.36(F)

AUC0-∞ (mg/L*h) 20 mg/kg = 0.06(M) and 0.12(F

Reference

Bongartz, R. and Miebach, D.; 2016. [Pyrazole-carboxamide-14C]BCS-

CL73507 - Absorption, Distribution, Excretion and Metabolism in the Rat.

Bayer CropScience AG, Development - Environmental Safety – Testing,

BCS-D-EnSa-Testing Alfred-Nobel-Str. 50, D-40789 Monheim am Rhein,

Germany Study ID: M1824594-3, Activity ID: MEFVP011; Edition No.: M-

549940-01-1

Klimisch Score 1


GLP Yes

Test Guideline




Species Rat

Strain Wistar Unilever HsdCpb:WU

No/Sex/Group 4/sex/group 1 and 2; and 3/sex/group 3

Dose Levels

Group 1: a single dose of either 2, 20 or 200 mg/kg bw

Group 2: a 14-day pre-treatment of 2 mg/kg (non-labelled BCS-CL73507)

before receiving test C14 labelled test material

Group 3: a single dose of 2 mg/kg bw after bile duct cannulation


Study Summary

Rats received the test compound by oral gavage and were sacrificed three

days (72 hr) after dosing (grp 1 and 2), or 48 hrs after bile duct cannulation

(grp 3). The total radioactivity that included the test compound and the

metabolites was determined in plasma samples, urine, faeces, organs and

tissues at sacrifice. The metabolism was investigated in extracts of urines,

bile, and faeces.

Test material recovery from the various test groups ranged from 94.4% to

110.26% of the administered dose.

Absorption

The absorption of test material started immediately after administration as

shown by the measured concentration of radioactivity in the plasma of the

low dose tests (2 mg/kg) and high dose tests at 20 mg/kg. For all low dose

tests, even the test after 14 days of pre-treatment, the maximum plasma

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concentration (Cmax) was reached within 1 hour (tmax) after the

administration and ranged from 0.131 to 0.199 mg/L.

In the high dose tests with 20 mg/kg bw, the measured maximum of the

plasma concentration was reached at 1 hour for males and delayed to

approx. 7 hours for females. For these tests with 20 mg/kg, the highest

measured equiv. plasma concentration amounted to <0.01 mg/L, due to a

restricted absorption of the test compound, and too low to calculate at 48

hours and 72 hours.

In the high dose tests with 200 mg/kg, radioactivity was too low to calculate

a concentration in all plasma samples.

Female rats showed a higher absorption rate (~2X) for plasma compared

to male rats for both administered doses (2 and 20 mg/kg)

Bile-duct cannulated animals showed that about 35% of the recovered

dose was detected in the bile for males and 24% in the bile for females,

indicating a distribution via enterohepatic circulation.

Absorption rates were calculated by summation of the recovered

radioactivity in urine, bile and body without GIT and amounted to 41.2% for

males and 29.3% for females.

Distribution and Plasma Kinetics

For all low dose tests, the plasma concentration declined to < 2% of the

maximum concentration within 72 hours post administration. This indicates

no retention of compound-related residues in the body of the animals.

Plasma dose normalised concentrations of the low dose tests, as well as

the high dose tests at 20 mg/kg, were calculated with a two-compartment

model by TOPFIT. The weighting of 1/y or 1 were used, due to a very fast

elimination phase after reaching the plasma maximum followed by a

slower elimination phase after approx. 24 hr.

The calculated AUC0-∞ value of test material in the plasma for low and high

dose (2 and 20 mg/kg) was ~2X lower in males compared to females (1.21

v. 2.36 and 0.06 v. 0.12, respectively). In addition, the AUC0-∞ for low dose

rats of both sexes at 2 mg/kg showed ~20X higher concentration (eg,

males 1.21/0.06) compared to high dose (20 mg/kg) rats that received 10X

less, due to the restricted absorption of the test compound at higher dose

levels.

Excretion

Generally, in the low and high dose tests, the excretion was almost

completed 72 hours after administration. At this time more than 99% of the

recovered dose had been excreted via urine and faeces. In all tests, the

excretion was mainly faecal and ranged from 92 to 99% of the recovered

radioactivity. Rats with a cannulated bile duct showed approx. 35% for

males and 24% for females of the recovered dose in bile.

For all low dose tests (2 mg/kg) the urinal excretion rate ranged from

4.51% to 6.58 % of the recovered dose. Negligible urinal excretion rates

were measured for the high dose tests at 20 and 200 mg/kg and ranged

from 0.08% to 0.57% of the recovered dose. These low urinal excretion

rates also show that there is a significantly reduced absorption of BCS-

CL73507 at higher dose rates.

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Radioactive Residues in Tissues and Organs at Sacrifice

Generally, there were very low residues in organs and tissues in all test

groups. Female rats showed higher organ concentrations compared to

male rats. At sacrifice low portions of radioactivity [between 0.012% and

0.396% of the administered dose (mean values)] were found in the bodies

excluding GIT showing that the elimination of the test compound related

radioactivity was nearly completed at sacrifice. The highest equiv.

concentrations were detected in the liver of all low dose tests and high

dose tests. They ranged from 0.0526 mg/kg to 0.4247 mg/kg.

Concentrations in plasma and blood cells were very low and amounted to

≤ 0.0062 mg/kg, only. Noticeable was the amount of radioactivity in peri-

renal fat of low dose females (eg 0.0261 mg/kg) because there was no

radioactivity detected in fat of male rats. The concentrations in the other

organs and tissues ranged from 0.0007 to 0.0115 mg/kg.

Metabolism

The metabolic profiles for urine, bile and faeces extracts were determined

by HPLC analysis. Only, quantitative differences of the metabolites were

observed in the profiles of males compared to females, both from low dose

tests. Profiles of the low dose tests showed more metabolic transformation

compared to the high dose tests. In the high dose tests, parent compound

was nearly completely excreted via faeces. There were no significant

differences between urine and faeces extracts of the current study and the

rat ADME study with the phenyl-carbamoyl[14C] label, the pyridinyl-2

label[14C] and the tetrazolyl[14C] label, except for individual label specific

metabolites.

The majority of metabolites (about 89.59% to 108.29% of the administered

dose) were identified. Parent compound was the major compound in all

tests and amounted between 51.32-66.42% of the dose for low dose tests

and between 88.84-107.98% of dose for high dose test (20 and 200 mg/kg

respectively) for both sexes. Major metabolites were BCS-CL73507-5-

hydroxypyridine and the hydroxy-N-methyl moiety and ranged from 4 to

9% of the dose, respectively. In general, there were no different

metabolites found for males and females; and the quantity of the individual

metabolites was not significantly sex-related.

Additional Comments

All results correspond well with the findings in the ADME studies with the

other studies where the phenylcarbamoyl, the pyridinyl-2-, and the

tetrazolyl moieties were labelled.

Conclusion

The toxicokinetic and metabolic behaviour of [pyrazole-carboxamide-14C]BCS-CL73507 can be characterised by the following facts:

BCS-CL73507 was rapidly absorbed and distributed. For all low dose tests

(M and F) and males at 20 mg/kg bw, the maximum plasma concentration

was reached 1 hour after administration, whiles for females at 20 mg/kg it

was ~7 hr.

A restricted absorption behaviour was detected for rats at high dose levels

as the 20 mg/kg dose showed a 20X lower plasma concentration despite a

10 fold higher dose. No radioactivity was detected in the plasma at 200

mg/kg.

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Females showed a higher absorption rate for plasma compared to males.

Absorbed radioactivity was quickly and efficiently eliminated from the

bodies of the rats within 72 hours after administration.

The excretion was predominantly faecal. Low urinal excretion was

detected in low dose tests. For high dose tests (20 and 200 mg/kg) the

urinal excretion was negligible.

For males ~39% of the dose and for females, 25% of the dose were

distributed via the enterohepatic circulation.

Absorption rates were calculated and amounted to 41.2% for males and

29.3% for females.

Parent compound was the main compound in faeces of low and high dose

(2 and 20 mg/kg) tests. In high dose tests, the metabolism of parent

compound was negligible compared to the low dose tests, in which approx.

50% of the dose was metabolised.

There were no significant differences between the metabolites of either

male or female rats.

No metabolite exceeded 10% of the dose


Flag Key study

Test Substance [Pyridinyl-2-14C]BCS-CL73507; Radiochemical purity 99.8%, Vehicle: 0.5%

aqueous tragacanth


Value

Tmax(hr) = 1(M/F)

t1/2 (hr) = 36.0(M) and 11.3(F)

Cmax(mg/L) = 0.096(M) and 0.108(F)

AUC0-∞ (mg/L*h) = 1.04(M) and 1.21(F)

Reference

Bongartz, R. and Miebach, D.; 2016. [Pyridinyl-2-14C]BCS-CL73507 -

Absorption, Distribution, Excretion and Metabolism in the Rat. Bayer

CropScience AG, Development - Environmental Safety - Testing, BCS-D-

EnSa-Testing Alfred-Nobel-Str. 50, D-40789 Monheim am Rhein, Germany

Study ID: M1824605-6, Activity ID: MEFVN007; Edition No.: M-549948-01-

1

Klimisch Score 1


GLP Yes

Test Guideline




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Species Rat


No/Sex/Group 4 M and 4F



Study Summary

Rats received the test compound by oral gavage and were sacrificed 72

hours after dosing. The total radioactivity that included the test compound

and the metabolites was determined in plasma samples, urine, faeces,

organs and tissues at sacrifice. The metabolism was investigated in

extracts from urines and faeces.

Test material recovery of the administered dose was 105.39% and

104.47% for males and females respectively.

Absorption

The absorption of BCS-CL73507 started immediately after administration

as shown by the concentration of radioactivity in the plasma. Female rats

showed a higher absorption rate for plasma compared to male rats based

on a 1 hour normalised Cmax of 0.108 versus 0.096 mg/L. The calculated

AUC value for females was approximately 1.2x higher than males (1.21

versus 1.04 mg/L*h).


The distribution of the test substance from the central compartment to the

different organs and tissues was observed by measuring the concentration

of the total radioactivity in plasma. After a single oral administration of 2

mg/kg to male and to female rats, the maximum of the plasma

concentration of the radioactivity was measured 1 hour after dosage (tmax).

The maximum dose normalised concentration amounted to 0.096 and

0.108 mg/L for males and females respectively. The plasma concentration

declined to < 4% of the maximum concentration within 72 hours post

administration. This indicates no retention of compound-related residues in

the body of the animals.

Dose normalised plasma concentrations were fitted with a two-

compartment model by TOPFIT due to a very fast elimination phase at the

beginning of the test followed by a slower elimination after approx. 24 hr.

Excretion

Generally, the excretion was almost completed 72 hours after

administration. At this time more than 99% of the recovered dose had been

excreted via urine and faeces. In all animals, the excretion was mainly

faecal and amounted to 96.8% of the recovered radioactivity for males and

97.41% of the recovered radioactivity for females. The urinal excretion rate

amounted to 2.89% of the recovered radioactivity for males and 2.40% of

the recovered radioactivity for females.

Residues in Organs and Tissues at Sacrifice

Generally, there were very low residues in organs and tissues. Female rats

showed higher organ concentrations compared to male rats. At sacrifice <

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0.4% of the administered dose (mean values) was found in the bodies

excluding the GIT. Negligible amounts of radioactivity were detected in the

GITs (0.037% of dose for males and 0.029% of dose for females), showing

that the elimination of the radioactivity was nearly completed at sacrifice.

The highest equiv. concentrations of all tests were detected in the liver and

amounted to 0.0778 mg/kg for males and 0.0730 mg/kg for females.

Concentrations in the other organs and tissues ranged from < 0.0001 to

0.0101 mg/kg. From the renal and faecal excretion and from the

elimination kinetics of total radioactivity from plasma it was concluded that

small amounts of residual radioactivity in organs and tissues are subject

for further elimination.

Metabolism

For the investigation of the metabolism, urine and faeces were sampled at

different time points. Parent compound and metabolites were analysed and

quantified by HPLC with radioactivity detection. For the investigation of the

metabolism, urine and faeces were sampled at different time points in the

individual tests.

The metabolite pattern in the urines and extracts of faeces from the current

study and the ADME studies with the pyrazole-carboxamide label, the

phenyl-carbamoyl label and the tetrazolyl label were very similar, except

for the individual label specific metabolites. There were no sex-specific

metabolites detected. Slight quantitative differences of the metabolites

between males and female were observed within the dose group. By trend,

males showed more hydroxylation compared to females.

Parent compound was the major compound in all tests and amounted to

61.9% of dose for males and 71.4% of dose for females. Conjugation with

glucuronic acid was observed as a follow-up reaction after hydroxylation.

Major metabolites were BCS-CL73507-hydroxy-N-methyl and 5-

hydroxypyridine and ranged from 2.8 to 7.7% of the dose.

Further prominent metabolites were BCS-CL73507- deshydrochloro-

dihydrate, BCSCL73507-dihydroxy (males only), BCS-CL73507-deschloro-

desmethyl-amide-dihydroxy, BCS-CL73507-benzylalcohol (males only),

BCS-CL73507-pyridinyl-pyrazole-5-carboxylic acid (males only) and BCS-

CL73507-N-methyl-quinazolinone (females only). These prominent

metabolites were detected in the range from 2.1 to 3.1% of dose.


Conclusion

Test material is rapidly absorbed from the GIT (tmax 1 hr) and is also rapidly

eliminated (<2%) by 72 hr. This study also showed females to have a

higher absorption rate than males as occurred in the repeated dose

studies as the AUC (mg/L*hr) for males was 1.04 and females was 1.21.

More than half (62-71%) of the absorbed material was eliminated as parent

while the other half was metabolised into several metabolites (maximum

7.73%) of the dose.

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Flag Key study

Test Substance [Phenyl-carbamoyl-14C]BCS-CL73507; Radiochemical purity 99%, Vehicle:

0.5% aqueous tragacanth


Value

Tmax(hr) = 1(M/F)

t1/2 (hr)= 22.9(M) and 25.0(F)

Cmax(mg/L) = 0.144(M) and 0.205(F)

AUC0-∞ (mg/L*h) = 1.29(M) and 2.32(F)

Reference

Bongartz, R. and Miebach, D.; 2016. [Phenyl-carbamoyl-14C]BCS-

CL73507 -Absorption, Distribution, Excretion and Metabolism in the Rat.

Bayer CropScience AG, Development - Environmental Safety - Testing,

BCS-D-EnSa-Testing Alfred-Nobel-Str. 50, D-40789 Monheim am Rhein,

Germany Study ID: M1824595-4, Activity ID: MEFVP010; Edition No.: M-

549947-01-1

Klimisch Score 1


GLP Yes

Test Guideline




Species Rat





Study Summary

Rats received the test compound by oral gavage and were sacrificed 72

hours after dosing. The total radioactivity that included the test compound

and the metabolites was determined in plasma samples, urine, faeces,

organs and tissues at sacrifice. The metabolism was investigated in urines

and extracts of faeces.

Test material recovery of the administered dose was 100.03% and

101.66% for males and females respectively.

Absorption




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AUC value for females was approx. 2-times higher compared to males

after oral administration (2.32 versus 1.29 mg/L).





mg/kg bw to male and to female rats, the maximum of the plasma

concentration of the radioactivity was measured approx. 1 hour after

dosage (tmax). The maximum dose normalised concentration amounted to

0.144 and 0.025 mg/L for males and 0females, respectively. The plasma

concentration declined to < 2% of the maximum concentration within 72

hours post administration. This indicates no retention of compound-related

residues in the body of the animals.

Dose normalised plasma concentrations of the low dose tests with 2 mg/kg

were fitted with a two-compartment model by TOPFIT. The weighting of 1/y

was used, due to a very fast elimination phase at the beginning of the test

followed by a slower elimination after approx. 24 hr.

Excretion



excreted via urine and faeces. The main portion of radioactivity was

excreted latest after 24 hr. In all tests, the excretion was mainly faecal and

amounted to 95.68% of the recovered radioactivity for males and 95.00%

of the recovered radioactivity for females. The urinal excretion rate

amounted to 4.04% of the recovered radioactivity for males and 4.52% of

the recovered radioactivity for females.



showed higher organ concentrations compared to male rats. At sacrifice, <


excluding the GIT. Negligible amount of radioactivity was detected in the

GITs (0.033% of dose for males and 0.106 % of dose for females),

showing that the elimination of the radioactivity was nearly completed at

sacrifice.

The highest equiv. concentrations of all tests were detected in the liver and


Noticeable was the amount of radioactivity in peri-renal fat of females

(0.0197 mg/kg) because there was no radioactivity detected in fat of male

rats. The concentrations in the other organs and tissues ranged from

0.0010 to 0.0091 mg/kg.

Metabolism


different time points in the individual tests. Parent compound and

metabolites were analysed and quantified in the urines and the extracts of

faeces by HPLC with radioactivity detection. The metabolite pattern in the

urines and extracts of faeces from the current study and the ADME studies

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with the pyrazole-carboxamide label, the pyridinyl-2 label and the tetrazolyl

label were very similar, except for the individual label specific metabolites.

There were no sex-specific metabolites detected in the current study.

Slight differences of the metabolite concentrations between males and

females were observed within the dose group.

Tentatively, male rats showed more hydroxylation compared to female

rats. The identification rate of parent compound and metabolites was high

and amounted to 94.9% of the dose for males and 96.3% of the dose for

females.


52.7% of dose for males and 59.5% of dose for females. Conjugation with



Conclusion

Test material is rapidly absorbed from the GIT (tmax ~1hr) and is also

rapidly eliminated (<2%) by 72 hr. This study also showed females to have

a higher absorption rate than males as occurred in the repeated dose


Approximately half the absorbed material was eliminated as parent while

the other half was metabolised into several different metabolites with a

maximum of 7.28% of the dose.

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Flag Key study

Test Substance [Tetrazolyl-14C]BCS-CL73507; Radiochemical purity >99%, Vehicle: 0.5%

aqueous tragacanth


Value

Tmax(hr) = 1(M/F); t1/2 (hr)= 31.6(M) and 25.0(F)

Cmax(mg/L) = 0.161(M) and 0.208(F)

AUC0-∞ (mg/L*h) = 1.27(M) and 2.00(F)

Reference

Bongartz, R. and Miebach, D.; 2016. [Tetrazolyl-14C]BCS-CL73507 -

Absorption, Distribution, Excretion and Metabolism in the Rat. Bayer

CropScience AG, Development - Environmental Safety - Testing, BCS-D-

EnSa-Testing Alfred-Nobel-Str. 50, D-40789 Monheim am Rhein, Germany

Study ID: M1824607-8, Activity ID: MEFVN008; Edition No.: M-549952-01-

1

Klimisch Score 1


GLP Yes

Test Guideline




Species Rat





Study Summary

The rats received the test compound by oral gavage and were sacrificed

72 hours after dosing. The total radioactivity that included the test

compound and the metabolites was determined in plasma samples, urine,

faeces, organs and tissues at sacrifice. The metabolism was investigated

in urines and extracts of faeces.

For males 103.55% and for females 102.26% of the administered dose

was recovered from measurement of the total radioactivity in plasma

samples, urines and faeces, as well as in organs and tissues at sacrifice.

Absorption




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AUC value for females was approx. 50% higher compared to males after

oral administration (2.00 versus 1.27 mg/L).





mg/kg bw to male and to female rats (low dose), the maximum of the

plasma concentration of the radioactivity was measured approx. 1 hour

after dosage (tmax). The maximum dose normalised concentration

amounted to 0.161 for males and 0.208 for females. The plasma

concentration declined to < 2% of the maximum concentration within 72

hours post administration. This indicates no retention of compound-related

residues in the body of the animals.

Dose normalised plasma concentrations of the low dose tests with 2 mg/kg

were fitted with a two-compartment model and a weighting of 1/y by

TOPFIT, due to a very fast elimination phase at the beginning of the test

followed by a slower elimination after approx. 24 h.

Excretion



excreted via urine and faeces. The main portion of radioactivity was

excreted latest after 24 hr. In all tests, the excretion was mainly faecal and

amounted to 97.88% of the administered dose for males and 96.02% for

females. The urinal excretion rate amounted to 5.38% of the recovered

radioactivity for males and 5.94% of the recovered radioactivity for

females.



showed higher organ concentrations compared to male rats. At sacrifice <


excluding the GIT. Negligible amount of radioactivity was recovered in the

GITs (0.043% of dose for males and 0.046% of dose for females), showing

that the elimination of the radioactivity was nearly completed at sacrifice.

The highest equivalent concentrations were detected in the liver and


Concentrations in plasma and blood cells were very low and amounted to

≤ 0.0052 mg/kg. Noticeable was the amount of radioactivity in peri-renal fat

of females (0.0087 mg/kg) because there was no radioactivity detected in

fat of male rats. The concentrations in the other organs and tissues of

males and females were comparable and ranged from 0.0009 to 0.0072

mg/kg.

Metabolism


different time points in the individual tests. Parent compound and

metabolites were analysed and quantified in the urines and the extracts of

faeces by HPLC with radioactivity detection. The metabolite pattern in the

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urines and extracts of faeces from the current study and the ADME studies

with the pyrazole-carboxamide label, the pyridinyl-2 label, and the phenyl-

carbamoyl label were very similar, except for the individual label specific

metabolites. Slight quantitative differences of the metabolites between

males and females were observed within the dose group. There were no

sex-specific metabolites detected.

Tentatively, males showed more hydroxylation compared to females. The

identification rate of parent compound and metabolites was high and

amounted to 99.6% of the dose for males and 99.2% of the dose for

females.


46.7% of dose for males and 56.1% of dose for females.

Major metabolites were BCS-CL73507-hydroxy-N-methyl (both genders)

and BCSCL73507-dihydroxy (males only) and ranged from 4.3 to 10.1% of

the dose. Further prominent metabolites were detected in the range from

2.0 to 3.7% of dose.

The most important metabolic reaction was the hydroxylation in the N-

methyl moiety, the methyl group of phenyl moiety and the pyridinyl moiety

leading to mono- and/or dihydroxy compounds. Conjugation with


Additional Comments

All results correspond well with the findings in the ADME studies with the

other studies where the phenylcarbamoyl, the pyridinyl-2-, and the

pyrazole-carboxamide moieties were labelled.

Conclusion

Test material is rapidly absorbed from the GIT (tmax ~1hr) and is also

rapidly eliminated (<2%) by 72 hr. This study also showed females to have

a higher absorption rate than males as occurred in the repeated dose


Approximately half the absorbed material was eliminated as parent while

the other half was metabolised into several different metabolites with a

maximum of 10.06% of the dose.

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Dermal Absorption

Table 96: Dermal Absorption – In Vitro

Study type In vitro dermal absorption through rat and human skin

Flag Key study

Test Substance

Carbon-14 labelled Tetraniliprole ([pyrazole-carboxamide-14C], batch No.:

KML 9817; Specific activity: 3.92 MBq (105.93 μCi)/mg; Radiochemical

purity: 98%; Non-radiolabelled material Test Item Name: Tetraniliprole;

Alternate Name: BCS-CL73507; Batch Code: BCS-CL73507-01-09;

Original Batch No: GSE 61495-1-2; Chemical Purity: 99.3% (w/w); Vehicle;

Diluted with water

Endpoint Absorption kinetics

Value

Concentration Human Skin Rat Skin

200 g/L 0.33 ± 0.32% 3.80 ± 2.26%

0.3 g/L 9.20 ± 5.0% 1.90 ± 2.33%

0.01 g/L 4.18 ± 2.24% 4.23 ± 2.28%

Reference

Blackstock, C.; 2016. The In Vitro Percutaneous Absorption of

Radiolabelled Tetraniliprole in the Concentrate Tetraniliprole SC 200

Formulation and Two In-Use Spray Dilutions Through Human and Rat

Skin. Charles River Laboratories Edinburgh Ltd., Elphinstone Research

Centre, Tranent, East Lothian, EH33 2NE, United Kingdom; Study ID:

795121; Report No.: 35685; Edition No.: M-554633-01-2

Klimisch Score 1


GLP Yes

Test Guideline

OECD Guideline for Testing of Chemicals, Guideline 428: Skin Absorption:

In Vitro Method

OECD Environmental Health and Safety Publications Series on Testing

and Assessment No. 28. Guidance Document for the Conduct of Skin

Absorption Studies.

European Commission Guidance Document on Dermal Absorption –

Sanco/222/2000/Rev. 7

Scientific Opinion on Dermal Absorption (EFSA Journal, 2012, 10(4):

2665)

EPA OCSPP Guideline No. 870.7600

Species Rat and Human

Strain Crl:CD (SD) Sprague-Dawley

No/Sex/Group 13 human (9 abdominal, 3 breast,1 thigh)

Dose Levels Concentrated active:200 g/L; high “In-use” dilution: 0.3 g/L; and low “In-

use” dilution 0.01 g/L

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Exposure Type In vitro using flow-through diffusion chambers

Study Summary

Split-thickness human skin and rat skin membranes were mounted into

flow-through diffusion cells. Receptor fluid was pumped underneath the

skin. The skin surface temperature was maintained at 32°C ± 1°C

throughout the experiment. A tritiated water barrier integrity test was

performed and any human skin sample exhibiting absorption greater than

0.6% of the applied dose was excluded from subsequent absorption

measurements.

Absorption of [14C]-Tetraniliprole was assessed by collecting receptor fluid

in hourly fractions from 0 to 8 h post dose, then 2 hourly fractions from 8 to

24 h post dose. At 24 h post dose, the underside of the skin was rinsed

with receptor fluid (receptor rinse). The skin was removed from the cells

and dried with a tissue swab. The cell was dismantled and the donor

chamber and receptor chamber were retained separately for analysis. The

stratum corneum was removed by tape stripping and the skin divided into

exposed and unexposed skin.

Human skin (200 g/L): At 8 h post dose, 97.48% of the applied dose was

removed during washing. At 24 h post dose, the total dislodgeable dose

was 98.06% of the applied dose. The stratum corneum retained 0.60% of

the applied dose, with 0.37% being removed with the first two tape strips.

The total unabsorbed dose was 98.67% of the applied dose. The total

absorbed dose and dermal delivery were 0.05% and 0.10% of the applied

dose, respectively.

The potentially absorbable dose was calculated for [14C]-Tetraniliprole

since the absorption was “incomplete” as defined in the EFSA Scientific

Opinion – Guidance on Dermal Absorption 2012; 10(4):2665. Absorption is

defined as incomplete if less than 5% of the absorption occurs within the

first half of the experiment (cumulative absorption into the receptor fluid at

12 h and 24 h post-dose was 0.003% and 0.004% of the applied dose,

respectively, therefore 68.64% of the absorption into the receptor fluid

occurred within the first 12 h). The potentially absorbable dose was 0.33 ±

0.32% of the applied dose.

Rat skin (200 g/L): At 8 h post dose, 95.38% of the applied dose was




The total unabsorbed dose was 97.92% of the applied dose. The absorbed

dose and dermal delivery were 0.10% and 2.57%, respectively.

The potentially absorbable dose was calculated for [14C]-tetraniliprole since

the absorption was “incomplete” as defined in the EFSA Scientific Opinion

– Guidance on Dermal Absorption 2012; 10(4):2665. Cumulative

absorption into the receptor fluid at 12 h and 24 h post-dose was 0.044%

and 0.062% of the applied dose, respectively. Therefore, 70.11% of the

absorption into the receptor fluid occurred within the first 12 h. The

potentially absorbable dose was 3.80 ± 2.26% of the applied dose.

Human skin (0.3 g/L): At 8 h post dose, 83.53% of the applied dose was



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The potentially absorbable dose was calculated for [14C]-tetraniliprole since

the absorption was “incomplete” as defined in the EFSA Scientific Opinion

– Guidance on Dermal Absorption 2012; 10(4):2665. Cumulative



absorption into the receptor fluid occurred within the first 12 h. The

potentially absorbable dose was 9.20 ± 5.0% of the applied dose.

Rat skin (0.3 g/L): At 8 h post dose, 83.73% of the applied dose was





dose and dermal delivery were 1.90 ± 2.33% and 10.35%, respectively.

The potentially absorbable dose was not calculated for [14C]-tetraniliprole

since the absorption was “complete” as defined in the EFSA Scientific

Opinion - Guidance on Dermal Absorption 2012; 10(4):2665. Cumulative



absorption into the receptor fluid occurred within the first 12 h.

Human skin (0.01 g/L): At 8 h post dose, 92.85% of the applied dose was






The potentially absorbable dose was calculated since the absorption was

“incomplete” as defined in the EFSA Scientific Opinion – Guidance on

Dermal Absorption 2012; 10(4):2665. Cumulative absorption into the

receptor fluid at 12 h and 24 h post-dose was 0.66% and 0.93% of the

applied dose, respectively. Therefore, 71.29% of the absorption into the

receptor fluid occurred within the first 12 h. The potentially absorbable

dose was 4.18 ± 2.24% of the applied dose.

Rat skin (0.01 g/L): At 8 h post dose, 83.78% of the applied dose was





dose and dermal delivery were 4.23 ± 2.28% and 9.46%, respectively.

The potentially absorbable dose was not calculated since the absorption

was “complete” as defined in the EFSA Scientific Opinion – Guidance on

Dermal Absorption 2012; 10(4):2665. Cumulative absorption into the

receptor fluid at 12 h and 24 h post-dose was 2.77% and 3.52% of the

applied dose, respectively. Therefore, 78.59% of the absorption into the

receptor fluid occurred within the first 12 h.

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Additional Comments

The potentially absorbable dose was used as the % absorbed for the

human skin samples and the high dose rat as absorption was deemed

incomplete after 24 hours. This creates values that are very conservative

as it includes material in stratum corneum take strips that might not be

absorbed.

Conclusion

The results of these studies indicate Vayego is poorly absorbed through

the skin as a concentrate (200 g/L) or minimally absorbed when diluted

into two in-use spray dilutions (0.3 and 0.01 g/L).

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Table 97: Dermal Absorption – In Vivo

Study type In vivo dermal absorption through rat skin

Flag Key study

Test Substance

Carbon-14 labelled Tetraniliprole ([phenyl-carbamoyl-14C], batch No.: KML

9817; Specific activity: 3.92 MBq (105.93 μCi)/mg; Radiochemical purity:

98%; Non-radiolabelled material Test Item Name: Tetraniliprole (BCS-

CL73507); Batch No: GSE 45467-3-6; Chemical Purity: 99.7% (w/w);

Vehicle; Diluted with blank formulation

Endpoint Absorption kinetics

Value

Absorbed Dose


200 g/L - 2.83 ±

1.29

0.54 ±

0.22

0.83 ±

0.32 *

0.05 ±

0.10 **

0.3 g/L - 4.50 ±

2.24

1.57 ±

0.91

3.27 ±

2.47 *

0.24 ±

0.44 **

0.01 g/L - 7.73 ±

1.83

6.05 ±

5.33

7.57 ±

4.24 *

1.28 ±

2.56**

* EFSA Guidance

** OECD Guidance

Reference

Bernal, J.; 2016. In-Vivo Rat Skin Penetration of 14C-tetraniliprole (BCS-

CL73507) in BCS-CL73507 SC 200 Test Item. Eurofins Agroscience

Services Chem SAS 75, Chemin de Sommieres 30310 Vergeze France.

Study ID: S16-04735; Activity ID: TXFVP071; Edition No.: M-568871-01-2

Klimisch Score 1


GLP Yes

Test Guideline

OECD Guideline for Testing of Chemicals, Guideline 427: Skin Absorption:

In Vivo Method

OECD Environmental Health and Safety Publications Series on Testing

and Assessment No. 28. Guidance Document for the Conduct of Skin

Absorption Studies.

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OECD guidance notes on dermal absorption, OECD series on testing and

assessment n°156; [ENV/JM/MONO(2011)36]

Scientific Opinion on Dermal Absorption (EFSA Journal, 2012, 10(4):

2665)

EPA OCSPP Guideline No. 870.7600 Dermal Penetration

Species Rat

Strain Sprague-Dawley

No/Sex/Group 48; 4M / 4 different harvest times (6,24,72,and 96h) / 3 concentration

levels

Dose Levels Concentrated active:200 g/L; high “In-use” dilution: 0.3 g/L; and low “In-

use” dilution 0.01 g/L

Exposure Type Dermal application for 8 hours contact time

Study Summary

The concentrated test item BCS CL73507 SC 200 and the diluted test

items containing 14C-BCS CL73507 were applied on the skin of clipped

male Sprague-Dawley rats (16 rats per group). Three different groups were

assessed that represented the absorption of neat product (concentrated

active: 200 g/L) and various “in-use” dilutions (0.3 and 0.01 g/L).

A protective device was placed on the skin after which the test items were

applied topically and then protected by a gauze cover. After an 8-hour

exposure period, the treated skin was washed with a suitable cleaning

agent. Following the washing procedure, the animals of the 24, 72 and 96-

hour cohort were refitted with a new gauze cover to prevent contact of the

application site with the external environment and to prevent the rats

licking the application site.

Radioactivity in blood, urine, faeces, tape strips, skin, washing of the

application site (including the protective device and gauze cover(s),

remaining skin, cage wash and carcass were measured at 8, 24, 72 and

96 hours after initial application. The percent absorption rate results for the

various tests were:

Concentrated Test Item (200 g/L)


(A) Not absorbed

(%)

96.38 ±

1.77

92.49 ±

6.10

97.47 ±

1.19

97.00 ±

1.46

(B) Absorbable (%) 4.76 ±

1.29

7.87 ±

4.87

3.06 ±

0.84

3.76 ±

1.08

(C) Absorbed (%) 0.004 ±

0.003

0.04 ±

0.07

0.004 ±

0.004

0.05 ±

0.10

Absorbable dose (B

+ C)

(%)

4.76 ±

1.29

- - -

Absorbed dose

(C + skin) (%) *

- 2.83 ±

1.29

0.54 ±

0.22

0.83 ±

0.32 **

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0.05 ±

0.10 ***

Total recovery (%) 101.14 ±

0.56

100.41 ±

1.29

100.53 ±

0.60

100.81 ±

0.39

Diluted Test Item (0.3 g/L)


(A) Not absorbed

(%)

83.48 ±

8.39

84.86 ±

6.75

94.81 ±

4.95

87.79 ±

5.98


2.12

14.07 ±

3.14

9.29 ±

2.64

10.86 ±

5.38

(C) Absorbed (%) 0.42 ±

0.75

0.01 ±

0.01

0.35 ±

0.66

0.24 ±

0.44

Absorbable dose (B

+ C)

(%)

11.51 ±

1.39

- - -

Absorbed dose

(C + skin) (%) *

- 4.50 ±

2.24

1.57 ±

0.91

3.27 ±

2.47 **

0.24 ±

0.44 ***


8.44

98.94 ±

9.49

104.45 ±

3.25

98.89 ±

1.54

Diluted Test Item (0.01 g/L)


(A) Not absorbed

(%)

87.71 ±

1.91

82.94 ±

2.43

82.33 ±

3.25

81.64 ±

3.36


2.62

12.97 ±

1.77

9.17 ±

1.69

13.56 ±

1.92

(C) Absorbed (%) BLQ BLQ 2.30 ±

4.59

1.28 ±

2.56

Absorbable dose (B

+ C)

(%)

11.51 ±

1.39

- - -

Absorbed dose

(C + skin) (%) *

- 7.73 ±

1.83

6.05 ±

5.33

7.57 ±

4.24 **

1.28 ±

2.56***


1.36

95.91 ±

1.22

93.80 ±

6.66

96.49 ±

2.75

BLQ : Below the Limit of Quantification

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According to OPPTS 870.7600 Dermal Penetration Guideline:

(A) Not absorbed part = quantity in skin wash, on the protective cover and in strips 1 and 2 (considered as desquamation)

(B) Absorbable part = quantity in/on the washed skin and in the stratum corneum (strips after strips1 and 2)

(C) Absorbed part = quantity in the urine, cage wash, faeces, blood and in the remaining carcass According to OECD ENV/JM/MONO(2011)36 and EFSA Journal 2012 Guidance:

* As more than 75% of the total BCS CL73507 absorption was recovered at half of the study duration, all the radioactivity contained in strips were considered as not absorbable.

** EFSA Guidance

*** OECD Guidance

Additional Comments

The difference in the EFSA and OECD guidance is that the OECD

excludes the remaining amount of material in the skin at the 96-hour

harvest as it is believed to not be available for absorption. The basis for

choosing the OECD guidance value was that the study results

demonstrate that the amount of material absorbed did not increase over

time and that, therefore, the likelihood of any of the material remaining at

the dose site becoming available systemically was low. Equally the amount

of absorbed material did not considerably increase between 72 hours and

96 hours (taking standard deviations into consideration) which also

suggests that the absorption profile was complete for this compound.

Conclusion

This was a well-conducted study assessing in vivo dermal absorption that

indicated a very minimal amount of material was absorbed (<5%) after 96

hours. The amount of material absorbed at the 200, 0.3, and 0.01 g/L

concentrations was 0.05 ± 0.10, 0.24 ± 0.44, and 1.28 ± 2.56%,

respectively.

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Endocrine Disruption

Table 98: Endocrine Disruption Screen – In Vivo

Study type Immature rat uterotrophjc assay


Test Substance

BCS-CL73507 (formerly BCS-CO80363) technical; Batch/Lot Number:

NLL8217-6-2; Purity: 96.0% w/w; Expiry Date: 21 July, 2011, Vehicle:

aqueous 0.5% methyl cellulose

Endpoint Uterine weight and first day of vaginal opening (evidence of estrogenic and

anti-estrogenic activity)

Value No difference in weight change or day of vaginal opening between treated

and control

Reference

Blanck, M.; 2011. BCS-CO80363 Evaluation in the Immature Rat

Uterotrophic Assay Coupled with Vaginal Opening. Bayer S.A.S. 355, rue

Dostoievski, BP153 06903 Sophia Antipolis Cedex, France; Study ID: SA

10066; Activity ID: TXRXP032; Edition No.: M-407664-03-2

Klimisch Score 1


GLP Yes

Test Guideline US EPA OCSPP 870.SUPP

Species Rat

Strain Sprague Dawley [Crl:CD(SD)]

No/Sex/Group 6 F / 2 groups

Dose Levels Group 1: 0, 100, 400, or 800 mg/kg bw/day

Group 2: 0, 600 mg/kg bw/day


Study Summary

To identify estrogenic activity, groups of 6 immature female rats (19 days

of age) were dosed daily by oral gavage for three days at 0, 100, 400 or

800 mg/kg bw/day. Vaginal opening was checked and uterine weights

were recorded 24 hours after the end of the dosing period. Estradiol

benzoate was used as a positive control for the induction of an uterotrophic

response.

To identify anti-estrogenic activity, additional groups of 6 animals (19 days

old) were dosed for at least 20 days at 0 or 600 mg/kg bw/day. Animals

were checked for vaginal opening on Day 10 and daily thereafter. The

uterine weight was recorded 24 hours after the end of the dosing period.

Administration to immature female rats had no effect on vaginal opening

and uterine weight up to the dose level of 600 mg/kg bw/day for up to 20

days. In addition, the administration of BCS-CO80363 to immature female

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Table 99: Endocrine Disruption Screen – In Vitro

rats had no effect on vaginal opening and uterine weight at a dose of up to

800 mg/kg bw/day for 3 days.

There were no clinical signs observed or effects on body weight in either

group although all dosed animals body weights were 4-5% lower.


Conclusion No evidence of an estrogenic or anti-estrogenic potential was detected

under those conditions.

Study type In vitro assessment of hormone synthesis


Test Substance BCS-CL73507; Batch/Lot Number: 2012-005440

BCS-CQ63359 Batch/Lot Number: NLL 9030-3-1

Endpoint

Secretion levels of progesterone, testosterone, estradiol, and cortisol using the

H295R cell line

Value See study summary

Reference

Tinwell, H.; 2016. Assessment of BCS-CL73507 and BCS-CQ63359 (main

mammalian metabolite of BCS-CL73507) in the H295R Steroidogenesis Screen.

Bayer S.A.S. 355, rue Dostoievski, BP153 06903 Sophia Antipolis Cedex,

France; Study ID: SA 15286; Sponsor ID: Lynx-PSI No. TXCAL002; Edition No.:

M-569723-01-1

Klimisch Score 1


GLP Yes

Test Guideline US EPA OCSPP 890.1550

Species Human cells

Strain H295R

No/Sex/Group 3 replicates/concentration

Dose Levels BCS-CL73507: 0.1, 0.3, 1, 3, 10, 12, and 15 µM

BCS-CQ63359: 0.1, 0.3, 1, 2, 4, 8, and 12 µM

Exposure Type In vitro

Study Summary

Species/Sex Plasma

sample time

Dose Administered [ppm, (mg/kg bw/day)]

Rat (F) 24 months 900 (51.2) 4000 (221) 18000

(1052)

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Plasma

Conc. (µM)

BCS-

CL73507

2.03 2.78 3.04

BCS-

CQ63359

0.74 2.00 7.43

Mouse (F) 18 months 260 (43.1) 1300 (215) 6500 (1073)

Plasma

Conc. (µM)

BCS-

CL73507

1.11 2.14 2.80

BCS-

CQ63359

0.144 0.325 1.81

Dog (M) 12 months 650 (19.8) 2900 (91.2) 12800 (440)

Plasma

Conc. (µM)

BCS-

CL73507

3.32 6.59 11.65

BCS-

CQ63359

0.98 2.15 5.37

Cells were exposed to the appropriate compound at the appropriate

concentration in triplicate for 48h. Forskolin (1 μM) was included as a reference

control to demonstrate the responsiveness of the cells to stimulation of

steroidogenesis. DMSO at 0.1% was used as the vehicle control of the test

system. No statistical analysis was performed on the data due to the low sample

size (n = 3/concentration).

Compound

Conc. (μM)

Percent Control (0 μM pg/ml value)1

Progesterone Testosterone Estradiol Cortisol

BCS-

CL73507

0 3296 (pg/ml) 6757 411 33376

0.1 104 (% C) 104 96 121

0.3 103 111 97 135

1 109 112 95 133

3 138 132 137 187

10 146 133 197 321

12 139 125 208 336

15 131 119 226 329

BCS-

CQ63359

0 3234 (pg/ml) 7472 359 38913

0.1 95 (%C) 92 100 100

0.3 98 96 114 110

1 116 109 142 151

2 131 122 156 198

4 125 117 204 ND2

8 100 138 217 171

12 82 145 181 120

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Forskolin 1 5210 (155%) 11000

(149%)

6398

(1591%)

152233

(481%)

1.) Any value which is ±20 % of the control value is generally considered

to be within the normal variability

2.) No data (values were off the curve high)

All values were off-curve high

Changes in testosterone and progesterone were only marginally increased in

comparison to control. Clear increases in estradiol and cortisol were observed

for BCS-CL73507 starting from 3 μM. The main mammalian metabolite of BCS-

CL73507, BCS-CQ63359, induced increases in estradiol and cortisol secretion

starting from 1 μM. Whereas, marginal increases in testosterone were observed

for BCSCQ63359 starting from 8 μM.


Conclusion

Overall, BCS-CL73507 and its main metabolite, BCS-CQ63359, increased

estradiol and cortisol secretion at biologically relevant concentrations (ie

concentrations similar to those recorded in plasma samples of rats, dogs and

mice following chronic exposure to the parent compound) when tested in the

H295R screen.

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Vayego

Acute toxicity [6.1]

Table 100: Acute Oral Toxicity [6.1 (oral)]

Type of study Acute oral toxicity in rats (Up and Down procedure)

Flag Key study

Test Substance

BCS-CL73507 SC 200 G; Batch number: 2013-006255; Specification

number: 102000026908; Content: BCS-CL73507 (BCS-CL73507):

18.5% w/w, 206.6 g/L; Expiry date: 11 December 2015; Vehicle: Distilled

water



Reference

Zelenak, V.; 2014. BCS-CL73507 SC 200 G - Acute Oral Toxicity Study

the Rat (Up and Down Procedure); CiToxLAB Hungary Ltd., H-8200



Klimisch Score 1


GLP Yes

Test Guideline/s OECD Guidelines for Testing of Chemicals No. 425


Species Rat

Strain RccHan:(WIST)

No/Sex/Group 5M, 5F



Study Summary



no abnormal observations at necropsy




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Table 101: Acute Dermal Toxicity [6.1 (dermal)]

Type of study Acute dermal toxicity in rats

Flag Key study

Test Substance



18.5% w/w, 206.6 g/L; Expiry date: 11 December 2015; Vehicle: None



Reference

Zelenak, V.; 2014. BCS-CL73507 SC 200 G - Acute Dermal Toxicity

Study in Rats; CiToxLAB Hungary Ltd., H-8200 Veszprem,


14/095-002P; Edition No.: M-488651-01-2

Klimisch Score 1


GLP Yes

Test Guideline/s


EPA Health Effects Test Guidelines (OPPTS 870.1200) EPA 712–C–

98–192


Species Rat

Strain Crl:WI

No/Sex/Group 5M, 5F



hours

Study Summary

Test article did not cause any mortality. There were no treatment-related

clinical signs during the 14 day observation period nor did it affect weight

gains. There were no abnormal observations at necropsy.


Conclusion The LD50 is >2000 mg/kg bw and the test article is not classifiable as no


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Table 102: Acute Inhalation Toxicity [6.1 (inhalation)]

Type of study Acute inhalation (nose-only) toxicity in rats

Flag Key study

Test Substance



18.5% w/w, 206.6 g/L; Expiry date: 11 December 2015; Vehicle: Distilled

water, diluted to 70% w/w

Endpoint Mortality (LC50)

Value >4.49 mg/L

Reference

Matyas, A.; 2014. BCS-CL73507 SC 200 G - Acute Inhalation Toxicity

Study (Nose-only) in the Rat; CiToxLAB Hungary Ltd., H-8200



Klimisch Score 1


GLP Yes

Test Guideline/s



Commission Regulation (EC) No 440/2008, B.2

Species Rat

Strain Wistar Crl:WI

No/Sex/Group 1M, 1F: Sighting study (Group 0.1)

5M, 5F: Main study (Group 1)

Dose Levels

4.93 ± 0.29 mg/L (Group 0.1), 4.49 ± 0.20 mg/L (Group 1); both were

deemed as maximum feasible concentrations

MMAD: 3.61 µm (Group 0.1), 3.71 µm (Group 1)

GSD: 1.95 (Group 0.1), 1.98 (Group 1)

Exposure Type Nose only, 4 hours

Study summary

No mortality was noted in either group. Laboured respiration (slight) was

recorded in all animals of the study on Day 0. Red-brown staining and/or

wet fur were also recorded in all animals of the study on the day of the

exposure. These observations were considered to be related to the

restraint and exposure procedures and were considered not to be

toxicologically significant. Each rat was symptom-free from Day 1. In

Group 0.1, slight bodyweight loss (0.4 %) was observed in the male

animal on Day 1 and returned to the initial body weight by Day 3. In

Group 1, slight bodyweight loss (0.4-2.3 %) was recorded in all males

and one female animal on Day 1 and a late bodyweight loss of 2.0% in a

single female on Day 3. All animals of this group normalised in the

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bodyweight by Day 7. No external or internal findings were recorded at

necropsy in any animal.


Conclusion

The LC50 >4.49 mg/L and the test article is not classifiable as this was a

maximum feasible exposure and no evidence of toxicity was observed in

any other acute toxicity study.

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Skin irritation [6.3/8.2]

Table 103: Skin Irritation [6.3/8.2]

Type of study Acute dermal irritation in rabbits

Flag Key

Test Substance





Value Mean score (24, 48,and 72 hr); Erythema: 0.0 and Oedema: 0.0

Reference

Zelenak, V.; 2014. BCS-CL73507 SC 200 G - Acute Skin Irritation Study



14/095-006N; Edition No.: M-495206-01-2

Klimisch Score 1


GLP Yes

Test Guideline/s




Species Rabbit


No/Sex/Group 3M

Dose Levels 0.5 ml


hours

Study Summary

The treated skin surface was examined at 1, 24, 48 and 72 hours after

patch removal. There were neither clinical signs nor skin irritation effects

observed in the treated animals at any time period.


Conclusion No evidence of irritation was observed.

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Table 104: Eye Irritation [6.4/8.3]

Type of study Acute eye irritation in rabbits

Flag Key

Test Substance





Value

Mean Draize Score (24/48/72h)

Cornea Opacity 0.0

Conjunctiva

Redness 0.0

Chemosis 0.0

Iris 0.0

Reference

Zelenak, V.; 2014. BCS-CL73507 SC 200 G - Acute Eye Irritation Study



14/095-005N; Edition No.: M-494111-01-3

Klimisch Score 1


GLP Yes

Test Guideline/s




Species Rabbit


No/Sex/Group 3M

Dose Levels 0.1 g

Exposure Type Ocular instillation into the conjunctival sac

Study Summary

First animal (No: 01035) clinical observation:

At 1 hour after treatment, Conjunctival redness (score 1), chemosis

(score 1) and discharge (score 1) were found.

At 24, 48, 72 hours after treatment, there were no clinical signs and no

conjunctival effects.

Second animal (No: 01025) clinical observation:

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Third animal (No: 01048) clinical observation:





During the study, the control eye of each animal was symptom-free. The

general state and behaviour of animals were normal throughout the

study period. There were no notable body weight changes during the

study period.


Conclusion

Test material induced a mild amount of irritation at the one-hour

observation and no evidence of irritation was observed at the 24-hour

observation and beyond. The test substance is not classifiable.

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Contact sensitisation [6.5]

Table 105: Contact Sensitisation [6.5]


Flag Key

Test Substance



18.5% w/w, 206.6 g/L; Expiry date: 11 December 2015; Vehicle: 1%

aqueous Pluronic PE9200

Endpoint

Sensitisation based on a SI (SI; cellular proliferation in response to a

sensitisation effect)

Value

Non-sensitiser (SI <3); the calculated stimulation index values were 0.6,

1.0 and 0.6 at concentrations of 100% (undiluted), 50 and 25% (w/v),

respectively.

Reference

Valiczko, E.; 2014. BCS-CL73507 SC 200 G - Local Lymph Node

Assay in the Mouse; CiToxLAB Hungary Ltd., H-8200 Veszprem,


14/095-037E; Edition No.: M-489250-01-2

Klimisch Score 1


GLP Yes

Test Guideline/s




Species Mouse

Strain CBA/J Rj

No/Sex/Group 5F/dose/5 groups (3 test substance, positive and negative control)

Dose Levels 100% (undiluted), 50 % and 25% (w/v) using 1% Pluronic as vehicle


Study Summary

No mortality or systemic toxicity was observed during the study. Minimal

amount of test item precipitate was observed on the ears of the animals

in the 100 % (undiluted) dose group on Days 1-6. There were no

indications of any irritancy at the site of application. No treatment-related

effects were observed on animal body weights. Appearance of the

lymph nodes was normal in the negative control group, in the 50 and 25

% (w/v) dose groups. Normal / smaller than normal lymph nodes were

detected in the 100 % (undiluted) group, larger than normal / slightly

enlarged lymph nodes were observed in the positive control group.


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Conclusion

Under the conditions of the present assay, BCS-CL73507 SC 200 G

was shown to have no sensitization potential (non-sensitiser).

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Tetraniliprole metabolites BCS-CR74541

Table 106: Soil Metabolite (In Vitro): BCS-CR74541

Study type/Test Guideline Result Reference

Gene mutation assay in Chinese

hamster V79 cells in vitro

(V79/HPRT)


Chemicals No. 476




No. 440/2008, B17

Negative with and without s9

metabolic activation

Wollny, H-E.; 2014. Gene

mutation assay in Chinese

hamster V79 cells in vitro

(V79/HPRT) BCS-CR74541

technical. Harlan Cytotest Cell

Research GmbH (Harlan CCR)

In den Leppsteinsweisen 19,

64380 Rossdof, Germany.

Harlan Study Number: 1499303;

Edition No.: M-450761-01-2

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Environmental fate

Several studies on the environmental fate of tetraniliprole have been reviewed. These studies are

used to describe how the active ingredient will move through the environment. Data from the studies

have been used to parameterise the models used to determine exposure in the risk assessment

conducted for Vayego. Data from the studies have been used in relevant areas of the risk

assessment. Summary of these studies is provided in Table 107 to Table 137.

Soil degradation

Aerobic conditions

Table 107: Aerobic degradation in soil –study 1

Study type Aerobic degradation, laboratory

Flag Key study

Test Substance BCS-CL73507

Endpoint DT50

Value 127, 29.1, 171, 46.7 days , recalculated

Reference

Hellpointner E., Junge T. 2015 Amendment no 1 to [Pyrazole-carboxamide-14C] BCS-CL73507: Aerobic soil metabolism and time-dependent sorption in

four European soils. Report no EnSa-13-0244, M-465975-02-1

Sur R., Mikolasch B. Kinetic evaluation of the degradation of tetraniliprole and

its metabolites in soil under aerobic laboratory conditions. Report no EnSa-16-

0845, M-568184-01-1

Klimisch Score 1

Amendments/Deviations None that impacted the study

GLP yes

Test Guideline/s

OECD Test Guideline No 307, 2002, Commission Directive 95/36/EC

amending Council Directive 91/414, 1995, Regulation (EC) No.1107/2009,

2009, US EPA OPPTS Test Guideline No. 835.4100, 2008, OECD Test

Guideline No. 106, 2001 (only in parts)

Dose Levels 0.5 mg ai/ kg soil dw (200 g ai/ha)

Analytical

measurements HPLC, LSC

Study Summary

The degradation and time-dependence of sorption of [pyrazole-carboxamide-14C]BCS-CL73507 was investigated in four soils under aerobic conditions in

the dark in the laboratory for 119 days at 20 ± 2 °C (mean:19.7 °C) and a

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soil moisture of 55 ± 5% (mean: 53.9%) of the maximum water holding

capacity.

The characteristics of the German soils are (pH in 0.01 M CaCl2):

Laacher Hof AXXa Monheim, Loamy Sand, pH 6.2, %OC 1.8, max WHC 53.4

Dollendorf II Blankenheim, Loam, pH 7.3, %OC 5.1, max WHC 82.7

Hanscheiderhof Monheim, Silt Loam, pH 5.3, %OC 2.7, max WHC 61.3

Hoefchen Am Hohenseh 4a Burscheid, Silt Loam, pH 6.4, %OC 2.7, max

WHC 66.7.

The study application rate was 549 μg/ kg soil (dry weight), equal to 0.5 mg

BCS-CL73507/kg soil (dry weight). Duplicate test systems were processed

and analysed 0 (after 30 min and 24h), 2, 6, 9, 16, 22, 29, 62, 91 and 119

Days After Treatment (DAT).

Overall mean material balance was 97.2% of %AR for soil Laacher Hof AXXa,

98.5%AR for soil Dollendorf II, 98.0%AR for soil Hanscheiderhof and

98.0%AR for soil Hoefchen Am Hohenseh.

The following maximum amounts of carbon dioxide were detected at DAT-119

(study end): 1.0%AR in soil Laacher Hof AXXa, 2.5%AR in soil Dollendorf II,

0.6%AR in soil Hanscheiderhof and 2.2%AR in soil Hoefchen Am Hohenseh.

Formation of volatile organic compounds was not significant, values being ≤

0.1%AR at all sampling intervals in all soils.

Total extractable residues decreased from 94.3%AR at DAT-0 to 84.3%AR at

DAT-119 in soil Dollendorf II, from 94.1%AR at DAT-0 to 91.9%AR at DAT-

119 in soil Hanscheiderhof and from 94.1%AR at DAT-0 to 90.6%AR at DAT-

119 in soil Hoefchen Am Hohenseh. In soil Laacher Hof AXXa the extractable

radioactivity remained constant over the period of incubation with 95.0%AR at

DAT-0 and 94.4%AR at DAT-119.

Non-Extractable Residues (NER) increased from 0.2, 0.7, 0.3 and 0.3%AR at

DAT-0 to maximum amounts of 5.2, 13.9, 9.3 and 8.1%AR at DAT-119 in soils

Laacher Hof AXXa, Dollendorf II, Hanscheiderhof and Hoefchen Am

Hohenseh, respectively.

The amount of BCS-CL73507 in the soil extracts decreased from 91.2%AR at

DAT-0 to 41.9%AR at DAT-119 in soil Laacher Hof AXXa, from 87.7%AR at

DAT-0 to 4.9%AR at DAT-119 in soil Dollendorf II, from 92.1%AR at DAT-0 to

55.9%AR at DAT-119 in soil Hanscheiderhof and from 88.8%AR at DAT-0 to

17.1%AR at DAT-119 in soil Hoefchen Am Hohenseh, respectively.

Besides the formation carbon dioxide, six major degradation products were

identified. BCS-CU81056 (BCS-CL73507-quinazolinone-carboxylic acid) was

detected with maximum amounts of 6.5%AR at DAT-119 in soil Dollendorf II,

BCS-CQ63359 (BCS-CL73507-N-methyl-quinazolinone) with 14.6%AR at

DAT-91 in soil Hoefchen Am Hohenseh, BCS-CR60014 (BCS-CL73507-

amide) with 6.9%AR at DAT-62 in soil Hanscheiderhof, BCS-CR74541 (BCS-

CL73507-carboxylic acid) with 47.8%AR at DAT-62 in soil Dollendorf II, BCS-

CU81055 (BCS-CL73507-desmethyl-amidecarboxylic acid) with 12.0%AR at

DAT-119 in soil Hoefchen Am Hohenseh and BCS-CT30673 (BCS-CL73507-

N-methyl-quinazolinone-carboxylic acid) with 10.6%AR at DAT-119 in soil

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Dollendorf II. Furthermore, five minor degradation products were found with no

component exceeding 3.5%AR at any sampling interval.

The experimental data could be well described by a double first order in

parallel kinetic model for loamy sand soil and by a first order multi-

compartment kinetic model for the other soils.

The calculated half-lives of BCS-CL73507 under aerobic conditions were 94.5

days in soil Laacher Hof AXXa (kinetic DFOP), 18.4 days in soil Dollendorf II

(kinetic FOMC), 183 days in soil Hanscheiderhof (kinetic FOMC) and 43.8

days in soil Hoefchen Am Hohenseh (kinetic FOMC).

The sorption of BCS-CL73507 to soil increased in the course of the study. The

calculated RTDS values (Ratio of concentration of test item in soil [μg/g]/

concentration of test item in solution [μg/ml]) were 4.61, 11.69, 6.71 and 8.04

ml/g for soils Laacher Hof AXXa, Dollendorf II, Hanscheiderhof and Hoefchen

Am Hohenseh, respectively, at the beginning of the study (DAT-0). With time

of ageing in soil, values increased to 13.91, 38.62, 19.39, and 28.82 ml/g on

DAT-119 for the four soils.

Addition

In a separate report, a kinetic evaluation of the degradation of tetraniliprole

and its metabolites in soil under aerobic laboratory conditions was performed.

The software tool KinGUI 2.1 was used for this evaluation. The normalised

values at 20oC are 127 d loamy sand, 29.1 d loam, 171 d silt loam and 46.7 d

silt loam [(DFOP best fit).

BCS-CQ63359: DT50 = 65 d loamy sand, 44.4 d loam, 58.5 d silt loam, 62.8 d

silt loam.

BCS-CR60014: DT50 =4.68 d loamy sand, 0.924 d loam, 17.2 d silt loam, 4.33

d silt loam.

BCS-CR74541: DT50 = 118 d loamy sand, 78.2 d loam, 104 d silt loam, 63.6 d

silt loam.

BCS-CU81055: DT50 = 33.8 d loamy sand, 25.7 d loam, 6.27 d silt loam, 36.3 d

silt loam.

BCS-CU81056: DT50 = not calculated loamy sand, 213.7 d loam, not

calculated silt loam, 2.65 d silt loam.

BCS-CT30673: DT50 = 29.5 loamy sand, other soils not calculated/detected

In the report is not clarified why the half-life in some soils is not calculated.

Conclusion

DT50 in days: 127 d loamy sand, 29.1 d loam, 171 d silt loam and 46.7 d silt

loam, recalculated

Major metabolites: BCS-CQ63359 14.6%, BCS-CR74541 47.8%,

BCS-CU81055 12%, BCS-CT30673 10.6%, BCS-CU60014 6.9%

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Table 108: Aerobic degradation in soil – study 2


Flag Key study


Endpoint DT50

Value 101, 72.3, 91.9, 149, 111, 56 days

Reference

Mislankar S., Haddix J. 2016 [Pyrazole-carboxamide-14C] BCS-CL73507:

Aerobic soil metabolism and time-dependent sorption in six US soils. Report

no MEFVP098, Doc no M 557172-01-1


its metabolites in soil under aerobic laboratory conditions. Report np EnSa-16-

0845, M-568184-01-1

Klimisch Score 1

Amendments/Deviation

s None

GLP yes

Test Guideline/s

OECD Test Guideline No 307, 2002, US EPA OPPTS Test Guideline No.

835.4100 and 835 1230, 2008, OECD Test Guideline No. 106, 2001 (only in

parts)


Analytical

measurements HPLC

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Study Summary

The degradation and time-dependence of sorption of [pyrazole-carboxamide-

14C]BCS-CL73507 was investigated in six soils under aerobic conditions in the

dark in the laboratory for 120 days at 20 ± 2 °C (mean:20.6 °C) and a soil

moisture between 2.0 and 2.5 pF.

The characteristics of the US soils are (pH in 0.01 M CaCl2):

Kansas (KS), silt loam, pH 5.8, %OC 1.2, max WHC 39.3%

Nebraska (NE) silt loam, pH 6.5, %OC 1.8, max WHC 64.4%

California (CA), sandy loam, pH 6.2, %OC 0.9, max WHC 27.6%

North Dakota (ND), clay loam, pH 6.4, %OC 6.0, max WHC 55.5%

California (CAH), loamy sand, pH 7.1, %OC 0.39, max WHC 21.9%

North Dakota (HCB), clay loam, pH 7.3, %OC 3.7, max WHC 63.7%

The study application rate was 25 μg/ 50 g soil (dry weight), equal to 0.5 mg

BCS-CL73507/kg soil (dry weight). Duplicate test systems were processed and

analysed 0.5 hours, 24 hours and 2, 7,14, 28, 42, 63, 91 and 120 DAT.

parameter Location

KS NE CA ND CAH HCB

Mean material

balance % of

AR

95.2 93.4 97.1 99.5 95.0 95.8

Max carbon

dioxide of %AR

(120 DAT)

1.3 0.8 1.0 0.7 0.8 2.1

Total

extractable

residues of

%AR

Day 0

99.7 99.7 99.7 99.2 100 99.7

Total

extractable

residues of

%AR

Day 120

81.8 83.7 91.4 84.4 89.1 75.2

Non extractable

residues %AR

day 0

≤0.3 ≤0.3 ≤0.3 0.8 <LOD ≤0.3

Non extractable

residues %AR

day 120

10.4 8.4 3.2 12.3 3.5 18.9

BCS-CL73507

%AR Day 0

98.7 98.8 98.8 98.2 98.1 98.7

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BCS-CL73507

%AR Day 120

42.8 32.2 50.7 42.7 39.8 23.5



Two major degradation products were identified with the following maximum

amounts: BCSCR74541- carboxylic acid with 34.8%AR at DAT-120 in HCB

soil and BCS-CQ63359-N-methylquinazolinone with 33.4%AR at DAT-120 in

CAH soil. Furthermore, three minor degradation products were found with no

component exceeding 4.9%AR at any sampling interval.


parallel kinetic model for all soils.

The calculated half-lives of BCS-CL73507 under aerobic conditions were 91.8,

58.3, 90.1, 117.3, 82.5, and 45.8 days for KS, NE, ND, CA, CAH and HCB

soils, respectively.

The calculated RTDS values (Ratio of concentration of test item in soil [μg/g]/

concentration of test item in solution [μg/ml]) were 4.67, 6.87, 1.45, 14.86,

0.58 and 14.91 ml/g for soils KS, NE, CA, ND, CAH and HCB, respectively, at

the beginning of the study (DAT-0). With time of ageing in soil, these values

increased throughout the study in all soils to 12.11, 15.12, 4.64, 80.53, 1.86

and 51.24 ml/g for soils KS, NE, CA, ND, CAH and HCB, respectively, on

DAT-120. At 120 days, the mean RTDS values increased by a factor of 2.22 to

5.4.

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Addition

In a separate report, a kinetic evaluation of the degradation of tetraniliprole and

its metabolites in soil under aerobic laboratory conditions was performed. The

software tool KinGUI 2.1 was used for this evaluation. The normalised values

at 20oC are 101 (KS), 72.3 (NE), 91.9 (ND), 149 (CA), 111 (CAH) and 56

(HCB).

BCS-CQ63359: DT50 = 137 d silt loam, 77.2 d clay loam, 75.7 d clay loam, 65.6

d sandy loam, 63.4 d silt loam, 175 d loamy sand.

BCS-CR60014: DT50 = 2.9 d silt loam, 2.51 d clay loam, 4.69 d clay loam, 13.2

d sandy loam, 4.9 d silt loam, 13.8 d loamy sand.

BCS-CR74541: DT50 = 80.8 d silt loam, 75.9 d clay loam, 66.3 d clay loam,

90.1 d sandy loam, 47.8 d silt loam, 54.4 d loamy sand.

BCS-CU81055: DT50 = 14.5 d silt loam, 6.82 d clay loam, 7.39 d clay loam, not

determined due to bad quality of fit in sandy loam, 12.5 d silt loam, not

detected loamy sand.

BCS-CU81056: not calculated

BCS-CT30673: DT50= 96.6 silt loam, in clay loam not determined due to bad

quality of fit, other soils not calculated

In the report is not clarified why the half-life in some soils is not calculated.

Conclusion DT50 in days:101, 72.3, 91.9, 149, 111, 56.

Major metabolites: BCS-CQ63359 33.4%, BCS-CR74541 34.8%

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Flag Key study

Test Substance BCS-CU81055 (metabolite of ai)

Endpoint DT50

Value 372 d sandy loam, 263 d silt loam, 359 silt loam

Reference

Beckmann M., Koenig H. 2016 [Phenyl-carbamoyl-14C] BCS-CU81055:

Aerobic degradation in three soils. Report no EnSa-13-0204, M-561277-01-1



0845, M-568184-01-1

Klimisch Score 1

Amendments/Deviations None

GLP yes

Test Guideline/s

OECD Test Guideline No. 307, DRAFT SANCO 11802/2010/rev 1 in

accordance with Regulation (EC) No 1107/2009

US EPA OCSPP Test Guideline No. 835.4100 / 835.4200

Japanese MAFF New Test Guidelines Annex No. 2-5-2

Dose Levels 140 µg test substance/kg soil dw (200 g ai/ha)

Analytical

measurements HPLC-MS/MS, LSC

Study Summary

The degradation of [phenyl-carbamoyl-14C] BCS-CU81055 was investigated in

three soils under aerobic conditions in the dark in the laboratory for 120 days

at 20 ± 2 °C (mean: 20.0 °C) and a soil moisture of 55 ± 5% (mean:

53.5%) of the maximum water holding capacity.


Laacher Hof AXXa Monheim, sandy loam, pH 6.4, %OC 1.6, max WHC 49.3

Hanscheiderhof Burscheid, Silt Loam, pH 5.8, %OC 2.7, max WHC 64.4

Hoefchen Am Hohenseh Burscheid, Silt Loam, pH 6.5, %OC 2.0, max WHC

59.0.

The study application rate was 140 μg/ kg soil (dry weight), equal to 200 g

ai/ha. Duplicate test systems were processed and analysed 0, 3, 8, 14, 30, 45,

59, 91 and 120 DAT.

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parameter Location

Laacher

hof

Hoefchen Am

Hohenseh

Hanscheiderhof

Mean material balance

% of AR

98.6 98.8 98.4

Max carbon dioxide of

%AR

(120 DAT)

4.4 5.7 3.0

Total extractable

residues of %AR

Day 0

97.6 96.0 96.5

Total extractable

residues of %AR

Day 120

86.7 84.0 81.4

Non extractable

residues %AR day 0

0.6 2.2

Max 10.2 at

day 59

1.8

Max 17.1 at

day 59

Non extractable

residues %AR day 120

7.4 9.3 14.2

BCS-CU81055 %AR

Day 0

97.3 95.3 96.1

BCS-CU81055 %AR

Day 120

78.5 72.0 76.5



As degradation product BCS-CL73507-quinazolinone-carboxylic acid (BCS-

CU81056) was observed with amounts of 5.4%, 9.7% and 3.4% in soil

Laacher Hof AXXa, Hoefchen am Hohenseh and Hanscheider Hof,

respectively. The total unidentified residues amounted to a maximum of

1.9%AR.

The experimental data could be well described by a First-Order Multi-

Compartment (FOMC) for soil Laacher Hof AXXa and Double First-Order in

Parallel (DFOP) kinetic model for soils Hoefchen am Hohenseh and

Hanscheider Hof.

The calculated half-lives of [phenyl-carbamoyl-14C] BCS-CU81055 under

aerobic conditions were >1000 days for all soils.

Addition

In a separate report, a kinetic evaluation of the degradation of the metabolite

of tetraniliprole and its metabolites in soil under aerobic laboratory conditions

was performed. The software tool KinGUI 2.1 was used for this evaluation.

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The normalised values at 20oC are 372 d sandy loam, 263 d silt loam, 359 silt

loam.

Conclusion DT50 372 d sandy loam, 263 d silt loam, 359 silt loam

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Flag Key study

Test Substance BCS-CT30673 (metabolite of ai)

Endpoint DT50

Value 411 d sandy loam, 387 d silt loam, 246 d silt loam, 334 days for loam soil

Reference

Beckmann M., Koenig H. 2016 [Dihydroquinazoline-2-14C] BCS-CT30673:

Aerobic degradation in three soils. Report no EnSa-13-0079, M-561290-01-1



0845, M-568184-01-1

Klimisch Score 1


s None

GLP yes

Test Guideline/s

OECD Test Guideline No. 307, DRAFT SANCO 11802/2010/rev 1 in

accordance with Regulation (EC) No 1107/2009

US EPA OCSPP Test Guideline No. 835.4100 / 835.4200

Japanese MAFF New Test Guidelines Annex No. 2-5-2

Dose Levels 128 µg test substance/kg soil dw (200 g ai/ha)

Analytical

measurements HPLC-MS/MS

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Study Summary

The degradation of [Dihydroquinazoline-2-14C] BCS-CT30673 was

investigated in three soils under aerobic conditions in the dark in the laboratory

for 120 days at 20 ± 2 °C (mean:20.0 °C) and a soil moisture of 55 ± 5%

(mean: 54.8%) of the maximum water holding capacity.


Laacher Hof AXXa Monheim, loamy sand, pH 6.0, %OC 2.1, max WHC 52.5

Hanscheiderhof Burscheid, Loam, pH 5.4, %OC 2.3, max WHC 60.7

Hoefchen Am Hohenseh Burscheid, Silt Loam, pH 6.3, %OC 1.9, max WHC

60.4.

The study application rate was 128 μg/ kg soil (dry weight), equal to 200 g

ai/ha. Duplicate test systems were processed and analysed 0, 3, 7, 16, 28, 45,

59, 91 and 120 DAT.

parameter Location

Laacher hof Hoefchen Am

Hohenseh

Hanscheiderhof

Mean material balance

% of AR

101.0 100.9 100.9

Max carbon dioxide of

%AR

(120 DAT)

0.4 0.9 0.4

Total extractable

residues of %AR

Day 0

101.3 99.2 99.1

Total extractable

residues of %AR

Day 120

89.8 88.5 82.7

Non extractable

residues %AR day 0

0.4 1.4

Max 11.8 at

day 91

2.3

Non extractable

residues %AR day 120

9.5 11.3 16.8

BCS-CT30673 %AR

Day 0

101.3 99.2 99.1

BCS-CT30673 %AR

Day 120

82.7 82.6 71.2



No degradation product was observed. The total unidentified residues

amounted to a maximum of 1.9%AR.

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parallel kinetic model for all soils.

The calculated half-lives of [Dihydroquinazoline-2-14C] BCS-CT30673 under

aerobic conditions were >1000 days for loamy sand and silt loam soils, and

334 days for the loam soil.

Addition

In a separate report, a kinetic evaluation of the degradation of this metabolite

of tetraniliprole and its metabolites in soil under aerobic laboratory conditions

was performed. The software tool KinGUI 2.1 was used for this evaluation.

The normalised values at 20oC are 411 d sandy loam, 387 d silt loam, 246 d

silt loam.

Conclusion DT50 = 411 d sandy loam, 387 d silt loam, 246 d silt loam, 334 days for loam

soil.

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special conditions

Table 111: Degradation in soil (paddy)

Study type Degradation, laboratory

Flag Key study

Test Substance [pyrazole-carboxamide-14C]BCS-CL73507

Endpoint DT50

Value 4.4 days in water and 84.5 days in total system

Reference

Heinemann O., Kasel D. 2016 [pyrazole-carboxamide-14C]BCS-CL73507:

Paddy soil metabolism in one soil – final report. Report EnSa -14-1369, Study

no M1282322-0, MEFVP109, M545810-01-1

Klimisch Score 1

Amendments/Deviations None that affected the study results

GLP yes

Test Guideline/s

OECD Test Guideline No. 307,

OCSPP Test Guideline No. 835.4100 / 835.4200

Japanese MAFF New Test Guidelines 12 Nousan 8147 No. 2-5-1

Dose Levels 58.9 µg test substance/100 g soil dw (200 g ai/ha)

Analytical


Study Summary

The route and rate of degradation of [[pyrazole-carboxamide-14C]BCS-

CL73507 were investigated in a paddy sandy loam soil in the dark in the

laboratory for 181 days at 25 ± 2 °C. The Italian soil is a sandy loam soil

with a pH of 5.3 and %OC of 1.0. (pH in 0.01 M CaCl2).

The study application rate was 58.9 μg/ 100 g soil (dry weight), and based on

a 3-fold maximum single field application rate of 200 g ai/ha.

The test was performed in static systems consisting of cylindrical flasks each

containing 100 g soil (dry weight equivalents). The soil was covered with 100

ml of water to result in a water layer of approximately 3.5 cm height and mixed

to achieve paddy conditions. The incubation vessels were equipped with traps

(permeable for oxygen) for the collection of carbon dioxide and volatile organic

compounds.

Duplicate samples were processed and analysed 0, 3, 7, 14, 30, 62, 100, 140

and 181 DAT.

The mean material balance was 102% AR (range from 101 to 109% AR).

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The maximum amount of carbon dioxide formed at the end of the study (DAT-

181) was 0.1% AR only. Formation of Volatile Organic Compounds (VOC) was

insignificant as demonstrated by values of ≤ 0.2% AR at all sampling intervals.

Residues in water decreased from DAT-0 to DAT-181 from 54.9 to 2.6% AR.

Extractable residues in soil increased from 47.4% at DAT-0 to 94.0% AR at

DAT-140 and then decreased to 85.9% AR at DAT-181.

Extractable residues in the total system (water and soil extracts) decreased

from DAT-0 to DAT-181 from 102 to 88.5% AR.

NER increased from DAT-0 to DAT-181 from 0.1 to 12.1% AR.

The amount of BCS-CL73507 in the water decreased from DAT-0 to DAT-181

from 54.3 to 0.9% AR. The amount of BCS-CL73507 in the soil extracts

increased from DAT-0 to DAT-30 from 46.9 to 55.9% AR and decreased then

to 34.4% AR at DAT-181.

The amount of BCS-CL73507 in the total system decreased from DAT-0 to

DAT-181 from 101 to 35.3% AR.

One degradation product was identified as BCS-CL73507-N-methyl-

quinazolinone with a maximum occurrence in the total system of 47.6% AR at

DAT-140. The total unidentified residues in the total system amounted to a

maximum of 6.3% AR and no single component exceeded 3.6% AR at any

sampling interval.

The experimental data could be best described by a DFOP kinetic model. The

DT50 value of BCS-CL73507 under paddy conditions was 4.4 days in the water

and 84.5 days in the total system.

Conclusion DT50 = 4.4 days in water and 84.5 days in total system

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Anaerobic conditions

Table 112: Anaerobic degradation in soil

Study type Anaerobic degradation, laboratory

Flag Key study


Endpoint DT50

Value 124, 116 and 79 days

Reference

Heinermann O., 2016 Amendment no 1 to [Pyrazole-carboxamide-14C] BCS-

CL73507: Anaerobic degradation/metabolism in three soils. Report no EnSa-

12-0694, M-478837-02-1

Klimisch Score 1


s None, that impact the study

GLP yes

Test Guideline/s

OECD Test Guideline No 307, 2002, Commission Directive 283/2013 in

accordance with EC 1107/2009, US EPA OPPTS Test Guideline No. 835.4100

and 835.4200, 2008, Japanese MAFF New Test Guidelines Annex No. 2-5-3

Dose Levels 53.3 µg ai/100 g soil dw (200 g ai/ha)

Analytical


Study Summary

The degradation of [pyrazole-carboxamide-14C] BCS-CL73507 was

investigated in three soils under anaerobic conditions in the dark in the

laboratory for 120 days at 20 ± 2 °C (mean:20.1°C). Aerobic incubation

phase is 15 days for Dollendorf soil and 29 days for the other soils. Soil

moisture of 55 ± 5% of the maximum water holding capacity during the

aerobic phase.


Laacher Hof AXXa Monheim, sandy loam, pH 6.3, %OC 1.6, max WHC 49.5

Dollendorf II Blankenheim, Loam, pH 7.1, %OC 4.9, max WHC 81.6

Hoefchen Am Hohenseh 4a Burscheid, Silt Loam, pH 6.1, %OC 1.8, max

WHC 58.4.

The study application rate was 53.3 μg/ 100 g soil (dry weight), equal to 0.5

mg BCS-CL73507/kg soil (dry weight) and 200 g/ha. During the aerobic phase,

duplicate test systems were processed and analysed on day 0 and day 15 or

29 after treatment. During the anaerobic phase duplicate test systems were

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processed and analysed at day 15, 18,22, 29,45, 73, 105, and 134 after

treatment.

parameter Location

Laacher

hof

Hoefchen Am

Hohenseh

Dollendorf

Mean material

balance % of AR

99.4 99.5 101.6

Max carbon

dioxide of %AR

(15 / 29 DAT)

0.3 0.4 0.3

Total extractable

residues of %AR

Day 0

99.2 102.1 101.3

Total extractable

residues of %AR

Day 15/ 29

96.6 93.2 93.8

Non extractable

residues %AR

day 0

0.2 0.3 0.9

Non extractable

residues %AR

Day 15/ 29

3.2 4.7 5.5

Non extractable

residues %AR

Anaerobic phase

Day 15- 134/ 29-

150

7.8 10.4 7.6

BCS-CL73507

%AR Day 0

99.2 102.1 101.3

BCS-CL73507

%AR Day 15/ 29

61.3 60.6 51.7

BCS-CL73507

%AR anaerobic

phase Day 15-134/

29-150

31.7 29.1 22.6



Three major degradation products were identified during the study: BCS-

CL73507-carboxylic acid (BCS-CR74541; max. aerobic: 31.2%AR at DAT-15;

anaerobic: 44.2%AR at DAT-45); BCSCL73507- N-methyl-quinazolinone

(BCS-CQ63359; max. aerobic: 12.6%AR at DAT-29; anaerobic: 34.7%AR at

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DAT-150) and BCS-CL73507-N-methyl-quinazolinone-carboxylic acid (BCS-

CT30673;max. aerobic: < LOD; anaerobic: 11.2%AR at DAT-134).


parallel kinetic model for all soils tested. The calculated half-lives of BCS-

CL73507 under anaerobic conditions were 124 days in soil Laacher Hof AXXa,

116 days in soil Hoefchen am Hohenseh 4a and 79 days in soil Dollendorf II.

Conclusion DT50 in days: 124 sandy loam, 116 silt loam, 79 loam

Major metabolites: BCS-CQ63359, BCS-CR74541, BCS-CT30673

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Table 113: Soil photolysis

Study type Soil photolysis

Flag Key study


Endpoint DT50

Value 82.4 days (USA), 127.7 days (Greece)

Reference

Koenig H., Beckmann M., 2014 [Pyrazole-carboxamide-14C] BCS-

CL73507: Phototransformation on soil. Report no EnSa-14-0217,

M-493228-01-1

Klimisch Score 1


GLP yes

Test Guideline/s

DRAFT SANCO 11802/2010/rev 7 in accordance with Regulation

(EC) No 1107/2009

OECD Draft Test Guideline, Phototransformation of Chemicals on

Soil Surfaces

US EPA OCSPP Test Guideline No. 835.2410


Study Summary

The photolytic route and rate of degradation of [pyrazole-

carboxamide-14C]BCS-CL73507 was investigated in one soil under

exposure to simulated sunlight and aerobic conditions in the

laboratory for 11 days at 20 ± 2 °C (mean:19.8 °C) and a soil

moisture of 55 ± 5% (mean: 53.4%) of the maximum water holding

capacity. The tested German soil is a silt loam with pH of 6.4, %OC

of 1.8 and maximum WHC of 53.5.

The study application rate was 7.3 mg test substance/ kg soil (dry

weight). Duplicate test systems were processed and analysed 0, 1,

2, 4, 7, 9 and 11 DAT.

Overall mean material balance was 98.7% of %AR for irradiated

samples and 100.0%AR for dark samples.

The maximum amount of carbon dioxide was 0.8 and <0.1%AR at

study end in irradiated and dark samples respectively. Formation of

volatile organic compounds was not significant, values being ≤

0.1%AR at all sampling intervals for both irradiated and dark

samples.

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Extractable residues ranged from 94.7 to 102.1%AR in irradiated

samples and from 96.1 to 102.6%AR in dark samples.

NER increased from <0.1%AR at day 0 to 1.3%AR and 0.4%AR in

irradiated and dark samples respectively.

The amount of BCS-CL73507 decreased from 101.65%AR at DAT-

0 to 77.4%AR at DAT-11 in irradiated samples and from 101.5%AR

to 86.5%AR in dark samples, indicating degradation in irradiated

samples.

BCS-CQ63359 (BCS-CL73507-N-methyl-quinazolinone) was

identified as metabolite in irradiated samples with 7.0%AR at DAT-

11 and in dark samples 5.7%AR day 11. The unidentified residues

amounted to a maximum of 12.9%AR in the irradiated samples with

no single component exceeding 1.9%AR and 7.5%AR in the dark

samples with no single component exceeding 2.9%AR.

The experimental data could be well described by a Single First-

Order Kinetics (SFO). The experimental half-lives for BCS-CL73507

were 27.13 and 44.31 days in the irradiated and dark samples,

respectively. The corresponding net photodegradation rate constant

(difference between irradiated and dark samples) was calculated to

0.0100 days-1, resulting in a net photodegradation DT50 of 69.3

days. Based on the experimental DT50 value of 27.1 days for

irradiated samples, the DT50 of BCS-CL73507 under environmental

conditions is calculated to be eg 82.4 solar summer days at

Phoenix, Arizona, USA, or 127.7 solar summer days at Athens,

Greece.

Conclusion DT50 82.4 days (USA), 127.7 days (Greece),

No major metabolites were identified.

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Field dissipation

Table 114: Field dissipation – study 1

Study type Field dissipation

Flag Key study


Endpoint DT50

Value 28.2, 31.5, 29.9, 68.4, 33.0, 39.6 days on bare soil and 42.4 days on

turf soil.

Reference

Xu T., McConnell L.L., 2016 Terrestrial field dissipation of BCS-

CL73507 in California bare ground soil, 2014, Report no MEFVN014,

Doc no M-569279-01-1


CL73507 in Florida bare ground soil, 2014, Report no MEFVP115, Doc

no M-570061-01-1

Ripperger R., McConnell L.L., 2016 Terrestrial field dissipation of BCS-

CL73507 in Midwest bare ground soil, 2015, Report no MEFVN027,

Doc no M-569284-01-1

Ripperger R., McConnell L.L., 2016 Terrestrial field dissipation of BCS-

CL73507 in New York turf and bare ground soil, 2015, Report no

MEFVN026, Doc no M-570641-01-1

Harbin A., McConnell L.L., 2016 Terrestrial field dissipation of BCS-

CL73507 in Ontario, Canada (bare soil), 2014, Report no MEFVN013,

Doc no M-570253-01-1


CL73507 in Washington bare ground soil, 2014, Report no MEFVN015,

Doc no M-569629-01-1

Klimisch Score 1


GLP yes

Test Guideline/s OCSPP 835.6100, Terrestrial Field Dissipation, US EPA, October 2008

PMRA Data Code No.: 8.3.2

Dose Levels 200 g ai/ ha

Study Summary

Terrestrial field dissipation studies of BCS-CL73507 (SC 200) were

conducted at five sites in the United States and one site in Canada:

California (CA), Florida (FL), Iowa (IA), New York (NY), Ontario (ONT),

and Washington (WA). The objective was to evaluate the dissipation

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and mobility of BCS-CL73507 under a range of actual field use

conditions. All sites utilized bare ground plots except NY where bare

ground and turfed plots were side by side. All sites were located within

the ecoregions where target crops are grown.

Soil characteristics:

parameter Location

CA FL IA NY ONT WA

Soil type Sandy

loam

sand Clay

loam

Sandy

loam

Sandy

loam

sand

CEC (meq/100

g)

11.1 2.7 18.6 8.3/8.31

12.4 8.9

Moisture at 1/3

bar (%)

10.2 5.4 23.4 18.7/

12.11

22.8 7.8

pH (1:1

soil:water)

7.9 6.3 6.8 5.8/5.81

6.9 7.7

pH (0.01M

CaCl2)

7.7 5.8 6.5 5.4/5.51

- 7.1

Organic matter

(%)

0.98 1.1 3.8 3.3/2.51

3.3 1.2

1 the first parameter relates to bare ground and the second to turf soil

The target application rate of 200 g ai /ha was used for field dissipation

studies, equal to the maximum single field application rate.

Supplemental irrigation was supplied as needed to maintain at least

110% of 30-year average rainfall or crop requirement, whichever was

greater for CA (142% of crop requirement fruit), FL (citrus), ONT

(potatoes), WA (apples). For IA (corn) and NY (turf), only the 30-year

average rainfall was used to set moisture targets. The overall percent

of target moisture received from precipitation and irrigation was: CA

(142%), FL (104%), IA (136%), NY (103%), ONT (88%), and WA

(99.8%). For ONT, moisture received was 110% of historical rainfall

and 137% of crop requirement. For WA, moisture received was 116%

of the crop requirement.

The field dissipation studies were conducted for 538, 560, 346, 440,

519, and 540 days at the CA, FL, IA, NY, ONT, and WA, sites,

respectively, with nominal soil sampling times of approximately -6, 0, 1,

3, 7, 14, 28, 60, 90, 120, 180, 270, 365, and 540 DAT. The actual

sampling times varied with each site. Soil cores were collected at a

depth of 0 to approximately120 cm (0 to 48 in) and were divided into

15-cm (6 in) segments except for the NY turf plot where the surface

segment was divided into 0-7.5cm and 7.5-15 cm segments. In FL and

ONT the maximum soil core depth was 105 cm (42 in). BCS-CL73507

and its metabolites were extracted from soil using a validated method.

The Limit Of Quantitation (LOQ) and Method Detection Limit (MDL) for

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BCS-CL73507 and its metabolites was 2.0 ng/g and 0.7 ng/g,

respectively.

The application rate was verified using solvent saturation pad and soil

pan application monitors. Application verification solvent saturation

pads showed an average recovery ranging from 71.1% to 98.7%.

Application verification soil pans had an average recovery from 53.8%

to 83.9%. The maximum concentration of BCS-CL73507 in the 0-15 cm

soil segment ranged from 87.5 ng/g at DAT-1 in CA to 223 ng/g at

DAT-1 in the 0 to 7.5 cm soil segment of NY turf. Concentrations of

BCS-CL73507 declined during the studies. At the last interval of each

study, the concentrations of BCS-CL73507 ranged from <MDL in CA to

15.2 ng/g in the 0 to 7.5 cm soil segment of NY turf.

BCS-CL73507 residues were relatively immobile and were primarily

observed in the top 0-15cm soil segment in all studies. The maximum

depth BCS-CL73507 was detected above the MDL was 15-30 cm. The

maximum concentrations detected in the 15-30 cm soil segment

ranged from 1.49 ng/g in ONT to 7.36 ng/g in FL.

BCS-CQ63359 was observed in all studies, and residues were

relatively immobile, observed primarily in the surface soil segment. The

maximum depth BCS-CQ63359 was detected above the MDL was 15-

30 cm. The maximum concentration detected in the 15-30 cm soil

segment was 2.41 ng/g in CA at DAT-89. The maximum concentration

of BCS-CQ63359 observed in all studies was in NY turf at 40.6 ng/g in

the upper 0-7.5 cm soil segment at DAT-180. In the bare soil plots, the

maximum concentration was 29.5 ng/g in FL at DAT-274.

Concentrations of BCS-CQ63359 declined at the end of all studies with

a maximum concentration in the final interval of 31.6 ng/g in NY turf

(DAT-440), and in bare soil plots, the maximum concentration in the

final interval was 23.6 ng/g in FL (DAT-560).

BCS-CR60014 was observed at low levels in all studies, primarily in

the surface soil segment. The maximum depth BCS-CR60014 was

detected above the MDL was 15-30 cm. The maximum concentration

detected in the 15-30 cm soil segment was 3.43 ng/g in NY turf at DAT-

269. The maximum concentration of BCS-CR60014 observed in all

studies was in NY turf at 7.61 ng/g in the 0- 7.5 cm soil segment at

DAT-180 and declined to 1.55 ng/g at DAT-440. In bare soil plots, the

maximum concentration was 3.32 ng/g in FL at DAT-90, declining to

0.765 ng/g in the 0-15 cm soil segment at DAT-560. In all other studies,

concentrations declined to ≤1.80 ng/g by the end of the studies.

BCS-CR74541 was observed in all studies except WA, primarily in the

0-15 cm and 15-30 cm soil segments. The maximum depth BCS-

CR74541 was detected above the MDL was one observation of 0.796

ng/g in the 60-75 cm soil segment of NY turf at DAT-366. The

maximum concentration of BCS-CR74541 in all studies was in NY turf

at 13.4 ng/g in the 0-7.5 cm soil segment at DAT-90, declining to 5.98

ng/g by DAT-440. In the bare soil plots, the maximum concentration

was 7.26 ng/g in ONT at DAT-368 in the 0-15 cm soil segment,

declining to 3.11 ng/g by DAT-519. In all other studies, concentrations

declined to ≤ 3.79 ng/g by the final interval.

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BCS-CT30673 was observed at low concentrations in at least one

interval in all studies except IA, primarily in the 0-15 cm soil segment.

The maximum depth BCS-CT30673 was detected above the MDL was

1.79 ng/g in the 15-30 cm soil segment of WA at DAT-540. The

maximum concentration of BCS-CT30673 in all studies was 6.49 ng/g

at DAT-538 in CA in the 0-15 cm soil segment.

BCS-CU81055 was observed at low concentrations in at least one

interval in ONT and NY turf. The maximum depth BCS-CU81055 was

observed was 0.717 ng/g in the 45-60 cm soil segment of NY turf at

DAT-269. The maximum concentration of BCS-CU81055 was 4.72

ng/g at DAT-119 in NY turf in the 0-15 cm soil segment.

BCS-CU81056 was observed only in the final interval in the surface soil

segment of NY turf and ONT at a maximum of 1.15 ng/g.

Concentration measurements of BCS-CL73507 were converted to units

of g/ha and then to % of applied nominal rate (%ANR) as a means to

assess the potential for residue carryover. For example, in CA, BCS-

CL73507 decreased from a maximum at DAT-1 of 100%ANR to below

detection limit in the final two intervals. In the other studies, the %ANR

remaining at the final interval ranged from 1.5 %ANR in WA to 14.4

%ANR in NY bare soil. Therefore, the potential for carryover of

BCSCL73507 residues is low.

The DT50, DT90 calculations of BCS-CL73507 under terrestrial field

conditions were carried out using kinetics modelling. The estimated

degradation DT50 and DT90 of BCS-CL73507 are stated below.

parameter Location

CA FL IA NY ONT WA

Soil type Sandy

loam

sand Clay

loam

Sandy

loam

Sandy

loam

sand

pH (0.01M

CaCl2)

7.7 5.8 6.5 5.4/5.51 - 7.1

DT50 days 31.5 68.4 39.6 29.942.41

33.0 28.2

DT90 days 105 >1000 132 719/

5471

411 144

Χ2 14.4 15.1 14.8 10.9/14.

81

12.5 9.34

Best fit model SFO FOMC SFO DFOP DFOP FOMC

1 the first parameter relates to bare ground and the second to turf soil

Results of these six terrestrial field dissipation studies indicate the

pattern of formation and decline was similar to that observed in the

aerobic soil metabolism studies and conforms to the proposed route of

degradation. BCS-CQ63359, BCS-CR60014, BCS-CR74541 were

formed in the first two weeks, increased to their maximum

concentration and then declined. Formation of the secondary and

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tertiary metabolites BCS-CT30673, BCS-CU81055, and BCS-CU81056

were observed in some studies, generally in the later intervals.

The degradation rates measured for BCS-CL73507 in the terrestrial

field dissipation studies were also in the range of DT50 values observed

in the laboratory studies. Residues of BCS-CL73507 and its

metabolites remained primarily in the top 30 cm of the soil column with

only trace quantities of the more polar metabolites moving to deeper

soil layers. None of the metabolites were found to move below 75 cm,

even with significant moisture inputs to the soil.

Conclusion

DT50 = 28.2, 31.5, 29.9, 68.4, 33.0, 39.6 days on bare soil and 42.4

days on turf soil.

Major metabolites: BCS-CQ63359, BCS-CR60014, BCS-CR74541,

BCS-CT30673, BCS-CU81055, and BCS-CU81056



Flag Key study


Endpoint DT50

Value 13.9, 30.1, 41.2, 66.3, 92.9 and 205 days

Reference

Heinemann O., Junge T., 2016 Terrestrial field dissipation with BCS-

CL73507 SC 200 in Germany, United Kingdom, France (North),France

(South), Italy and Spain, 2016, Report no MEFVP117, Study ID 13-2700,

M549513

Klimisch Score 1

Amendments/Deviatio

ns None that affected the study results

GLP yes

Test Guideline/s OPPTS 835.6100, NAFTA DIR2006-01

Dose Levels 0.30 L /ha (corresponding to 60 g ai/ha)

Study Summary Terrestrial field dissipation studies of BCS-CL73507 were conducted under

European conditions at six sites in Germany, United Kingdom, France, Italy

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and Spain. BCS-Cl 73507 SC 200 was applied on bare soil plots. Sites were

located within the ecoregions in Northern and Southern Europe.


parameter Location

Germany UK France

North

France

South

Italy Spain

Soil type

(cm)

Silt loam

(0-75)

Loam

(75-100)

Clay

(0-

100)

Sandy

loam

(0-50)

Loam

(50-75)

Clay

loam

(75-

100)

Silty

clay

loam (0-

50)

Silty

clay (50-

100)

Clay

loam

(0-30)

Silty

clay

loam

(30-

50)

Silty

clay

50-

100)

loam

(0-30)

Sandy

loam

(30-75)

Sandy

clay

loam

(75-

100)

pH (1:1

soil:water)

per soil layer

cm

0-30

6.0 7.1

5.8 8.1 7.5 5.8

30-50 6.2 7.8 6.5 8.0 7.8 5.7

50-75 6.3 7.9 7.2 8.0 7.7 5.9

75-100 6.8 8.0 7.2 8.1 7.7 6.1

pH (0.01M

CaCl2)

per soil layer

0-30

5.5 7.0 5.4 7.8 7.2 5.5

30-50 5.8 7.5 6.1 7.8 7.4 5.3

50-75 5.8 7.5 6.8 7.7 7.5 5.4

75-100 6.7 7.6 6.8 7.7 7.5 5.6

Organic

matter (%)

Per soil layer

0-30

0.9 2.1 0.6 0.8 1.7 0.7

30-50 0.2 0.7 00.3 0.6 1.2 0.2

50-75 0.1 0.8 0.3 0.5 0.8 0.1

75-100 0.1 0.3 0.4 0.5 0.6 0.2

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BCS-CL73507 SC 200 was sprayed once onto 304 to 920 m2 plots at a rate

of 0.30 L/ha, corresponding to nominal 60 g/ha BCS-CL73507. The plots

were irrigated with 10 mm (13-2710, 4 mm only) of water unless rainfall

occurred between DAT-0 and DAT-3.

The control plots were at least 5 m away from the treated plots. Soil samples

were taken from day 0 before application up to 759 days post-application to a

maximum depth of 85 cm, homogenized and analysed for BCS-CL73507 and

its degradation products BCS-CQ63359, BCS-CR60014, BCS-CR74541,

BCS-CU81055, BCS-CT30673 and BCS-CU81056.

The amount of BCS-CL73507 decreased from DAT-0 to study end (DAT-

728) from 60.5 to 8.28 g/ha at Burscheid (Germany), from DAT-0 to DAT-518

onwards from 54.7 g/ha to residues below the LOQ at Cambridge(UK), from

DAT-0 to DAT-700 from 62.7 to 14.0 g/ha at Lignieres de Touraine (France

North), from DAT-0 to DAT-89 from 56.4 g/ha to residues below the LOQ at

St. Etienne du Gres (France south), from DAT-0 to DAT-252 from 48.3 g/ha

to residues below the LOQ at Albaro (Italy) and from DAT-0 to DAT-702 from

50.0 to 3.65 g/ha at Vilobi d’ Onyar (Spain).

Residues of BCS-CL73507 remained mainly in the top 0-20 cm of soil.

Dissipation of BCS-CL73507 from soil was moderately to fast with DT50

values ranging from 13.9 to 205 days for all test sites (details below).

parameter Location

Germany UK France

North

France

South

Italy Spain

Soil type

(cm)

Silt loam

(0-75)

Loam

(75-100)

Clay

(0-100)

Sandy

loam

(0-50)

Loam

(50-75)

Clay

loam

(75-

100)

Silty

clay

loam

(0-50)

Silty

clay

(50-

100)

Clay

loam

(0-30)

Silty

clay

loam

(30-50)

Silty

clay

50-

100)

loam

(0-30)

Sandy

loam

(30-75)

Sandy

clay

loam

(75-

100)

pH (0.01M

CaCl2)

5.5 7.0 5.4 7.8 7.2 5.5

DT50 days 92.9 41.2 205 13.9 30.1 66.3

DT90 days 892 183 >1000 57.3 122 610

Chi error 6.0 10.7 4.2 3.7 5.5 4.5

Best fit

model

DFOP DFOP DFOP DFOP DFOP DFOP

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Dissipation of BCS-CL73507 was accompanied by the formation of its

degradation products BCS-CQ63359, BCS-CR60014, BCS-CR74541, BCS-

CT30673, BCS-CU81055 and BCS-CU61056.

The maximum amounts of BCS-CQ63359 in the entire soil profiles were

detected between DAT-59 and DAT-556 and ranged from 4.87 to 27.5 g/ha.

Residues above the LOQ were detected only in the top 0-10 cm soil layer at

five of the six test sites.

BCS-CR60014 residues were detected between the LOD and LOQ in the

entire soil profiles between DAT-8 and DAT-477.

The maximum amounts of BCS-CR74541 in the entire soil profiles were


The major part of the residues was detected in the top 0-10 cm soil layer.

Residues above the LOQ were found down to a depth of 20 cm.

The maximum amounts of BCS-CT30673 in the entire soil profiles were


Residues above the LOQ were detected in the top 0-10 cm soil layer.

BCS-CU81055 and BCS-CU81056 residues in the entire soil profiles were

below the LOD at all sites and at all sampling intervals. All detected residues

of BCS-CU81055 and BCS-CU81056 within the single soil layers were

between the LOD and LOQ.

Conclusion

DT50 = 13.9, 30.1, 41.2, 66.3, 92.9 and 205 days

Metabolites: BCS-CQ63359, BCS-CR60014, BCS-CR74541, BCS-CT30673,

BCS-CU81055, and BCS-CU81056

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Flag Key study


Endpoint DT50

Value 139 days

Reference Harbin A. 2017 Terrestrial field dissipation of BCS-CL73507 in PEI Canada

(bare soil),2017 Report no MEFVN016, Study ID MEFVN016, M584183

Klimisch Score 1


GLP yes

Test Guideline/s OCSPP 835.6100

Dose Levels 200 g ai/ha

Study Summary

Dissipation of tetraniliprole (BCS-CL73507) and its transformation products

under Canadian field conditions was examined in bare soil at one site in New

Glasgow, Prince Edward Island (PEI). The site was located in Queens County

within the 8.1 Ecoregion of North America (mixed wood plains). The soil is a

sandy loam soil with a pH of 5.6 (0-15 cm).

The study was conducted over a period of 514 days using a nominal

application rate of 200 g ai/ha, the current proposed single application

maximum use rate for potatoes. The control plot was located 15 m from the

treated plot. Rainfall was supplemented with irrigation as needed. Total water

input through the study period was 120% of the historical rainfall and 240% of

the crop requirement through study period. The monthly mean air

temperatures during the study were between -0.6 and 4.0 °C of the historical

average monthly mean temperatures.

The application rate was verified using solvent saturation pad and soil pan

application monitors. An average of 90.1% (n = 8) of the expected active

ingredient was recovered from solvent saturation pad monitor samples. An

average of 67.4% (n=4) of the expected active ingredient was recovered from

the soil pan application monitors.

Soil cores were collected from the treated plots on the day of application (0

DAT, v0 DAT) to a depth of 15 cm, and at all other intervals (-3, 3, 7, 15, 29,

59, 88, 172, 318, 359, 423, and 514 DAT) to a depth of 105 cm.

Residues of tetraniliprole and its six degradation products, BCS-CQ63359,

BCS-CR60014, BCS-CR74541, BCS-CU81055, BCS-CT30673 and BCS-

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CU81056, were extracted and analysed using a validated LC/MS/MS method.

The LOQ for all analytes was 2.0 ng/g and the MDL was 0.7 ng/g.

Average recovery of tetraniliprole and its degradation products ranged from 95

to 111% at the 200 ng/g spike level, 82 to 99% at the 40 ng/g spike level, 84 to

103% at the 10 ng/g spike level, and 74 to 105% at the 2.0 ng/g spike level.

The study was terminated after the target 540-day interval (actual interval 514

days), when the pattern of formation, decline and downward movement of

parent and metabolites was clearly defined. The average 0 DAT concentration

of tetraniliprole was 63.0 ng/g in the 0-15 cm soil segment, increasing to a

maximum concentration of 89.0 ng/g at 3 DAT, then declining to 15.8 ng/g by

514 DAT. Tetraniliprole was detected primarily in the upper 0-15 cm soil

segment, although residues were detected at 15-30 cm in all but the 0 DAT

interval, at average concentrations ranging from 0.88 ng/g (<LOQ) to 4.07

ng/g. Tetraniliprole residues were observed at low concentrations at 15, 318,

423 and 514 DAT in the 30-45 cm soil segment (ranging from 1.30 (<LOQ) to

2.60 ng/g). In the 45-60 cm soil segment, tetraniliprole was observed in the

423 and 514 DAT intervals at 1.36 (<LOQ) and 2.08 ng/g (<LOQ),

respectively. No residues greater than the LOQ were observed in deeper

levels.

Degradation products were observed in primarily the 0-15 cm soil segment.

BCS-CQ63359, detected only in the 0-15 cm segments, was first observed at

29 DAT at 1.15 ng/g (<LOQ), increasing to a maximum of 6.68 ng/g by 423

DAT, and declining slightly to 6.18 ng/g by the end of the study. BCS-

CR60014, also detected only in the 0-15 cm segments, was first observed at

15 DAT at 1.96 ng/g (<LOQ), increasing to a maximum of 4.51 ng/g at 88 DAT

and declining to 2.66 ng/g by the end of the study. BCS-CR74541 was

detected between 59 DAT and 514 DAT in the 0-15 cm soil segment at

concentrations ranging from 2.23 ng/g (<LOQ) to 8.25 ng/g, in the 15-30 cm

segments at concentrations ranging from 1.33 ng/g (<LOQ) to 3.64 ng/g, in the

30-45 cm segments at concentrations ranging from 0.71 to 1.33 ng/g (all

<LOQ), and in the 45-60 DAT segment at 0.79 ng/g (<LOQ). BCS-CU81055

was detected only at concentrations <LOQ, and only in the 0-15 cm segment

at 423 DAT and in the 15-30 cm segment at 514 DAT. BCS-CT30673 and

BCS-CU81056 were not detected in any segments during the study.

Examination of total tetraniliprole and degradation product residues in soil as

percent of applied nominal rate (% ANR) indicates that between 0 DAT and 3

DAT residues ranged from 49.6% to 71.9% ANR. Total tetraniliprole declined

throughout the study to 34.2% at 514 DAT. Considering the total residues from

all soil segments, tetraniliprole alone decreased from a maximum of 71.9%

ANR at 3 DAT to 20.2% ANR at the end of the study.

BCS-CQ63359 reached a maximum of 5.4% ANR at 423 DAT, decreasing to

5.0% ANR by the end of the study.

BCS-CR60014 was observed at a maximum of 3.4% ANR at 88 DAT,

decreasing to 2.0% ANR by 514 DAT. BCS-CR74541 was observed at a

maximum of 9.6% ANR at 423 DAT, declining to 6.1% ANR at 514 DAT. BCS-

CU81055 never reached levels >LOQ, and BCS-CR30673 and BCS-CU81056

were not observed.

Under field conditions at New Glasgow, Prince Edward Island, tetraniliprole

had a dissipation DT50 value of 139 days, and a DT90 value of >1000 days

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(Kinetic modelling (KinGUI), FOMC. At the end of the 514-day period, the total

carryover of residues of tetraniliprole was 20.2% of the target applied amount.

The major routes of dissipation of tetraniliprole under field conditions were

transformation and biodegradation. Results of this study support the

degradation pathway observed in the laboratory aerobic soil metabolism

studies.

Conclusion

DT50 = 139 days

Metabolites: BCS-CQ63359 (max 5.5%), BCS-CR60014 (max 3.4%), BCS-

CR74541 (max 9.6%), BCS-CU81055 (<LOQ)

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Table 117: Adsorption/desorption

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Study type Adsorption/ desorption

Flag Key study


Endpoint Kf oc adsorption

Value 195.3, 200.4, 211.0, 252.3

(high mobility)

Reference

Tinnefeld D. 2012 [Pyrazole-carboxamide-14C] BCS-CL73507:

Adsorption/desorption in four European soils, Report no MEF-11/302, M-

427580-01-1

Klimisch Score 1


GLP yes

Test Guideline/s OECD 106, OCSPP 835.1230, Canada PMRA Environmental Chemistry and

Fate, DACO No. 8.2.4.2

Dose Levels 0.5, 0.15, 0.05, 0.015 and 0.005 mg/L

Analytical

measurements LSC

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Study Summary

The adsorption /desorption behaviour of [Pyrazole-carboxamide-14C] BCS-

CL73507 was studied in four different German soils in the dark in the

laboratory at 20 ±1 oC using the batch equilibrium method. The soil

characteristics are as follows:

parameter Location in Germany

Laacher

hof

Hoefchen

Am

Hohenseh

Hanscheiderhof Dollendorf

II

Soil type Loamy

sand

Silt loam Silt loam loam

pH

(0.01 M

CaCl2)

6.2 6.4 5.3 7.3

%OC 1.8 2.7 2.7 5.1

%OM 3.1 4.7 4.7 8.8

WHC at 0.1

bar (pF 2.0)%

13.3 32.0 36.7 38.5

The adsorption phase of the study was carried out using air-dried soils pre-

equilibrated in aqueous 0.01 M CaCl2 solution with a soil-to-solution ratio of 1/4

(5 g soil (dry weight equivalents)/20 ml solution) for soils Laacher Hof,

Hoefchen Am Hohenseh and Hanscheiderhof and 1/10 (2 g soil (dry weight

equivalents)/20 ml solution) for soil Dollendorf II.

BCS-CL73507 was applied at nominal concentrations of 0.5, 0.15, 0.05, 0.015

and 0.005 mg/L in aqueous 0.01 M CaCl2 solution. The desorption phase was

performed by supplying pre-adsorbed soil samples with fresh aqueous 0.01 M

CaCl2 solution for all test concentrations. For the highest test concentration

(0.5 mg/L) two additional desorption cycles were performed likewise. The

adsorption and desorption steps were carried out each for 24 hours under

continuous agitation. For the highest concentration, two additional desorption

cycles were performed with 24 hours equilibration time each.

BCS-CL73507 was sufficient stable throughout the study. The parental mass

balances were 97.0, 95.6, 97.2 and 93.0% of the %AR for soil Laacher Hof,

Hoefchen Am Hohenseh, Hanscheiderhof and Dollendorf II, respectively.

Mean material balances were 95.7, 95.1, 94.9 and 94.1%AR for soil Laacher

Hof, Hoefchen Am Hohenseh, Hanscheiderhof and Dollendorf II, respectively.

At the end of the adsorption phase, 53.8 – 65.4%AR was adsorbed to soil

Laacher Hof, 66.6 – 75.5%AR was adsorbed to soil Hoefchen Am Hohenseh,

60.2 – 70.0%AR was adsorbed to soil Hanscheiderhof and 54.7 –66.1%AR

was adsorbed to soil Dollendorf II. The adsorption/desorption constants and

correlation coefficients of BCS-CL73507 in soil are presented below. The

desorption constants KF, OC(des) were about two times higher than the KF,

OC(ads) values, indicating a strengthened binding of the test item once

adsorbed to the soil.


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Laacher

hof

Hoefchen

Am

Hohenseh


II

Soil type Loamy

sand

Silt loam Silt loam loam

Adsorption

Kf 3.789 6.813 5.274 10.222

1/n 0.897 0.908 0.913 0.899

R2 0.999 0.9998 0.9995 0.9994

Kf, oc 211.0 252.3 195.3 200.4

Desorption

Kf 8.829 13.54 11.56 20.869

1/n 0.926 0.926 0.942 0.924

R2 0.998 0.999 0.9997 0.999

Kf, oc 490.5 501.4 428.2 409.2

Kf oc are the Kf values normalised to organic carbon content.

According to Briggs3, the mobility of BCS-CL73507 can be classified as low for

adsorption and for desorption in all tested soils.

Conclusion

Kf oc adsorption 195.3, 200.4, 211.0, 252.3

According to McCall classification (McCall P.J., Laskowski D.A. et al. 1981)

BCS-CL73507 is considered highly to moderately mobile.

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Soil adsorption

Tetraniliprole

Table 118: Adsorption/desorption tetraniliprole – study 1


Flag Key study



Value 411, 133 (medium-high mobility)

1920 in sediment (slightly mobile)

Reference Haddix J.K., Arthur E.L. 2016 [14C] BCS-CL73507: Adsorption/desorption on

two US soils and one US sediment, Report no MEFVP112, M-557175-01-1

Klimisch Score 1


GLP yes

Test Guideline/s OECD 106, OCSPP 835.1230

Dose Levels 0.5, 0.15, 0.05, 0.015 and 0.005 mg/L

Analytical

measurements LSC

Study Summary


CL73507 was studied in two US soils and one US sediment in the dark in the



parameter Location in US

Nebraska (NE) California (CA) Kansas (KS)

Soil type Silt loam Sandy loam Silt-clay loam

(sediment)

pH

(0.01 M

CaCl2)

6.5 6.2 7.5

%OC 1.8 0.90 0.34

%OM 3.2 1.5 0.58

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WHC at 0.1

bar (pF 2.0)

%

38.6 23.4 44.1


equilibrated in aqueous 0.01 M CaCl2 solution with a soil (sediment)-to-solution

ratio of 1/4.2 (4.8 g soil (dry weight equivalents)/20 ml solution) for soil NE, 1/2

(10 g soil (dry weight equivalents)/20 ml solution) for soil CA and 1/4.6 (4.5 g

soil (dry weight equivalents)/20 ml solution) for the KS sediment.

BCS-CL73507 was applied at nominal concentrations of 0.5, 0.15, 0.05, 0.015

and 0.005 mg/L in aqueous 0.01 M CaCl2 solution. The desorption phase was


CaCl2 solution for one desorption step. The adsorption and desorption steps

were carried out each for 24 hours under continuous agitation.

BCS-CL73507 was sufficient stable throughout the study. The parental mass

balances were 95.3, 94.2 and 92.2%AR for NE, CA and KS, respectively.

Mean material balances for NE and CA soils, and KS sediment were 92.5%AR

(range 87.8 to 97.3%AR), 97.5%AR (range 86.7 to 104.0%AR), and 94.8%AR

(range 92.8 to 96.7%AR), respectively. The overall mean material balance

was 94.9% (SD = 2.5%).

At the end of the desorption phase, 20.0 – 26.1%, 23.1 – 29.5% and 26.0 –

27.8% of the initially adsorbed amount were desorbed from soil NE, CA and

KS sediment, respectively.

The calculated adsorption constants KF-ads from the Freundlich isotherms

ranged from 1.2 to 7.4 ml/g (mean 5.0 ml/g) for three tested matrices. The

Freundlich exponents 1/n were in the range of 0.9381 to 0.9860 (mean

0.9671), indicating that the concentration of the test substance affected the

adsorption behaviour of the test substance in the examined concentration

range. In general, the organic matter in soil or sediment determined as organic

carbon content is the most important component responsible for binding

organic chemicals. Therefore, the adsorption coefficients KF were correlated

with the organic carbon content of the soil/sediment to compare the adsorption

behaviour in different soils or sediment. For BCS-CL73507, the KF-OC-ads

values ranged from 133 to 1,920 ml/g (mean 821 ml/g).

According to Briggs classification scheme4, BCS-CL73507 can be classified

as having low mobility to immobile.

The calculated desorption constants KF-des of the Freundlich isotherms ranged

from 6.6 to 11.4 ml/g (mean: 9.4 ml/g) for the tested matrices. The Freundlich

exponents 1/n ranged from 0.9346 to 1.037 (mean: 0.9856), indicating that the

concentration of the test substance affected the desorption behaviour of the

test substance in the examined concentration range. The KF-OC-des values for

desorption ranged from 567 to 3,355 ml/g (mean 1,552 ml/g). The KF-OC-des

values were significantly higher (1.4 to 5.5 times higher) than the KF-OC-ads

values, indicating a strengthened binding of the test substance once adsorbed

to the soil/sediment.

The adsorption/desorption constants and correlation coefficients of BCS-

CL73507 in soil are presented below.

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parameter Location in US

Nebraska (NE) California

(CA)

Kansas (KS)

Soil type Silt loam Sandy loam Silt-clay loam

(sediment)

Adsorption

Kf 7.4 1.2 6.5

1/n 0.938 0.986 0.977

R2 0.991 0.994 0.998

Kf, oc 411 133 1920

Desorption

Kf 10.2 6.6 11.4

1/n 0.935 1.037 0.985

R2 0.999 0.995 0.999

Kf, oc 567 732 3355


Conclusion

Kf oc adsorption 411, 133,1920 (sediment)

According to McCall classification, the mobility is considered medium to high.

In sediment the substance mobility of the substance is low.

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Table 119: Adsorption/desorption tetraniliprole – study 2


Flag Key study

Test Substance BCS-CR60014 (metabolite)


Value 130.8,181.5, 154.0, 144.5

(low to medium mobility)

Reference

Tinnefeld D. 2012 [Pyrazole-carboxamide-14C] BCS-CR60014:

Adsorption/desorption in four European soils, Report no EnSa- 12-0385, M-

440103-01-1

Klimisch Score 1

Amendments/Deviatio


GLP yes


Fate

Dose Levels 1.0, 0.3, 0.1, 0.03, 0.01 mg/L

Analytical

measurements LSC

Study Summary


CR60014 was studied in four different German soils in the dark in the laboratory

at 20 ±1 oC using the batch equilibrium method. The soil characteristics are as

follows:


Laacher

hof

Hoefchen

Am

Hohenseh


II

Soil type Loamy

sand

Silt loam loam loam

pH

(0.01 M

CaCl2)

6.0 6.3 5.4 7.2

%OC 2.1 1.9 2.3 5.1

%OM 3.6 3.3 4.0 8.8

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WHC at 0.1

bar (pF 2.0)

%

15.6 26.4 27.7 41.4


equilibrated in aqueous 0.01 M CaCl2 solution with a soil-to-solution ratio of 1/10

(2 g soil (dry weight equivalents)/20 ml solution) for soils Laacher Hof, Hoefchen

Am Hohenseh and Hanscheiderhof and 1/20 (1 g soil (dry weight

equivalents)/20 ml solution) for soil Dollendorf II.

BCS-CR60014 was applied at nominal concentrations of 1.0, 0.3, 0.1, 0.03, 0.01

mg/L in aqueous 0.01 M CaCl2 solution. Mercury(II) chloride was added to the

CaCl2 solution at a concentration of 50 mg/L to inhibit microbial activity. The

desorption phase was performed by supplying pre-adsorbed soil samples with

fresh aqueous 0.01 M CaCl2 containing HgCl2 solution for all test

concentrations.

The adsorption and first desorption steps were carried out each for 24 hours

under continuous agitation for soils Laacher Hof, Hoefchen Am Hohenseh and

Hanscheiderhof. For soil Dollendorf II adsorption and one desorption cycle were

limited to 8 and 16 hours, respectively, due to the insufficient stability of the test

item in this soil. For the highest concentration (1.0 mg/L), two additional

desorption cycles were performed with 24 hours equilibration time each. For soil

Dollendorf II only one desorption step was carried out.

BCS-CR60014 was sufficiently stable throughout the study. The parental mass

balances were 95.5, 95.3, 97.7 and 90.2% of the %AR for soil Laacher Hof,

Hoefchen Am Hohenseh, Hanscheiderhof and Dollendorf II, respectively.

Mean material balances were 95.9, 95.9, 95.6 and 96.3% AR for soil Laacher


At the end of the adsorption phase, 22.2 – 29.5% AR was adsorbed to soil

Laacher Hof, 26.5 –35.3% AR was adsorbed to soil Hoefchen Am Hohenseh,

26.7 – 33.7% AR was adsorbed to soil Hanscheiderhof and 27.3 –30.0% AR

was adsorbed to soil Dollendorf II. The adsorption constants KF(ads) of BCS-

CR60014 calculated based on the Freundlich isotherms of the four test soils

ranged from 2.746 to 7.367 ml/g (mean: 4.276 ml/g). The Freundlich exponents

1/n were in the range of 0.9130 to 0.9712 (mean: 0.9329), indicating that the

concentration of the test item affects its adsorption behaviour in the examined

concentration range. The corresponding calculated KF, OC(ads) values varied

between 130.8 and 181.5 ml/g (mean: 152.7 ml/g).

After the first desorption phase between 44.0 – 61.5% of the initially adsorbed

radioactivity was desorbed from the respective soils. The desorption constants

KF, OC(des) were about two times higher than the KF, OC(ads) values, indicating a

strengthened binding of the test item once adsorbed to the soil.


CR600014 in soil are presented below.


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Laacher

hof

Hoefchen

Am

Hohenseh


II

Soil type Loamy

sand

Silt loam loam loam

Adsorption

Kf 2.746 3.448 3.541 7.367

1/n 0.919 0.913 0.928 0.971

R2 0.9989 0.9997 0.9995 0.9995

Kf, oc 130.8 181.5 154.0 144.5

Desorption

Kf 5.992 6.952 7.661 12.021

1/n 0.905 0.904 0.925 0.928

R2 0.996 0.999 0.996 0.996

Kf, oc 282.0 365.9 333.1 235.7


According to Briggs, BCS-CR60014 can be classified as low mobile for


Conclusion Kf oc adsorption 130.8, 181.5, 154.0, 144.5

According to McCall classification, the mobility is considered low to medium.

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Metabolites

Table 120: Adsorption/desorption – metabolites - study 1


Flag Key study

Test Substance BCS-CR74541 (metabolite)


Value 17.8, 18.6, 25.6, 11.6 (very high)

Reference

Tinnefeld D. 2012 [Pyrazole-carboxamide-14C] BCS-

CR74541: Adsorption/desorption in four European soils,

Report no EnSa- 12-0473, M-441867-01-1

Klimisch Score 1


GLP yes

Test Guideline/s OECD 106, OCSPP 835.1230, Canada PMRA

Environmental Chemistry and Fate

Dose Levels 1.0, 0.3, 0.1, 0.03, 0.01 mg/L

Analytical measurements LSC

Study Summary

The adsorption /desorption behaviour of [Pyrazole-

carboxamide-14C] BCS-C R74541 (BCS-CL73507-

carboxylic acid) was studied in four different German soils

in the dark in the laboratory at 20 ±1 oC using the batch

equilibrium method. The soil characteristics are as follows:


Laacher

hof

Hoefchen

Am

Hohenseh


II

Soil type Loamy

sand

Silt loam loam loam

pH

(0.01 M

CaCl2)

6.0 6.3 5.4 7.2

%OC 2.1 1.9 2.3 5.1

%OM 3.6 3.3 4.0 8.8

of 541


SEPTEMBER/

2019

WHC at 0.1

bar (pF 2.0)

%

15.6 26.4 27.7 41.4

The adsorption phase of the study was carried out using

air-dried soils pre-equilibrated in aqueous 0.01 M CaCl2

solution with a soil-to-solution ratio of 1/1 (20 g soil (dry

weight equivalents)/20 ml solution) for soils Laacher Hof,

Hoefchen Am Hohenseh and Hanscheiderhof and 1/2 (10 g

soil (dry weight equivalents)/20 ml solution) for soil

Dollendorf II.

BCS-C R74541 was applied at nominal concentrations of

1.0, 0.3, 0.1, 0.03, 0.01 mg/L in aqueous 0.01 M CaCl2

solution. The desorption phase was performed by supplying

pre-adsorbed soil samples with fresh aqueous 0.01 M

CaCl2 solution for all test concentrations. A single

adsorption and desorption cycle was performed. For the

highest concentration (1.0 mg/L), two additional desorption

cycles were performed with 24 hours equilibration time

each. The adsorption and desorption steps were carried out

each for 24 hours under continuous agitation.

BCS-C R74541 was sufficiently stable throughout the study.

The parental mass balances were 97.9, 93.8, 92.8 and

95.4% of the %AR for soil Laacher Hof, Hoefchen Am

Hohenseh, Hanscheiderhof and Dollendorf II, respectively.

Mean material balances were 93.4, 93.4, 102.7 and

98.5%AR for soil Laacher Hof, Hoefchen Am Hohenseh,

Hanscheiderhof and Dollendorf II, respectively.

At the end of the adsorption phase, 26.6 – 35.4 %AR was

adsorbed to soil Laacher Hof, 26.3 –35.0%AR was

adsorbed to soil Hoefchen Am Hohenseh, 37.7 – 45.9%AR

was adsorbed to soil Hanscheiderhof and 23.1 –32.7%AR

was adsorbed to soil Dollendorf II. The adsorption

constants KF(ads) of BCS-CR74541 calculated based on

the Freundlich isotherms of the four test soils ranged from

0.373 to 0.590 ml/g (mean: 0.476 ml/g). The Freundlich

exponents 1/n were in the range of 0.8891 to 0.9281

(mean: 0.9118), indicating that the concentration of the test

item affects its adsorption behaviour in the examined

concentration range. The corresponding, calculated KF,

OC(ads) values varied between 11.6 and 25.6 ml/g (mean:

18.4 ml/g).

After the first desorption phase between 18.7 – 47.5% of

the initially adsorbed radioactivity was desorbed from the

respective soils. The desorption constants KF, OC(des) were

about five times higher than the KF, OC(ads) values, indicating

a strengthened binding of the test item once adsorbed to

the soil.

of 541


SEPTEMBER/

2019

The adsorption/desorption constants and correlation

coefficients of BCS-CR74541 in soil are presented below.


Laacher

hof

Hoefchen

Am

Hohenseh


II

Soil type Loamy

sand

Silt loam loam loam

Adsorption

Kf 0.373 0.354 0.588 0.590

1/n 0.928 0.905 0.925 0.889

R2 0.993 0.996 0.997 0.995

Kf, oc 17.8 18.6 25.6 11.6

Desorption

Kf 2.164 1.897 2.824 2.117

1/n 0.963 0.932 0.939 0.909

R2 0.980 0.991 0.996 0.988

Kf, oc 103.0 99.8 122.8 41.5


According to Briggs, BCS-CR74541 can be classified as

mobile for adsorption and intermediate mobile for

desorption in the tested soils.

Conclusion

Kf oc adsorption 17.8, 18.6, 25.6, 11.6

According to McCall classification, the mobility is

considered very high.

of 541


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2019



Flag Key study

Test Substance BCS-CU81055 (metabolite)


Value 23.5, 29.9, 50.4, 19.5 (very high)

Reference

Beckmann M., Koenig H. 2013 [Phenyl-carbamoyl-14C] BCS- CU81055:

Adsorption/desorption in four European soils, Report no EnSa- 13-0037,

M-456812-01-1

Klimisch Score 1


GLP yes

Test Guideline/s OECD 106, OCSPP 835.1230, Canada PMRA Environmental Chemistry

and Fate

Dose Levels 1.0, 0.3, 0.1, 0.03, 0.01 mg/L


Study Summary

The adsorption /desorption behaviour of [Phenyl-carbamoyl -14C] BCS-

CU81055 (BCS-CL73507-desmethyl-amide-carboxylic acid) was studied

in four different German soils in the dark in the laboratory at 20 ±1 oC

using the batch equilibrium method. The soil characteristics are as

follows:


Laacher

hof

Hoefchen

Am

Hohenseh


II

Soil type Loamy

sand

Silt loam loam loam

pH

(0.01 M

CaCl2)

6.0 6.3 5.4 7.2

%OC 2.1 1.9 2.3 5.1

%OM 3.6 3.3 4.0 8.8

of 541


SEPTEMBER/

2019

WHC at 0.1

bar (pF 2.0)

%

15.6 26.4 27.7 41.4

The adsorption phase of the study was carried out using air-dried soils

pre-equilibrated in aqueous 0.01 M CaCl2 solution with a soil-to-solution

ratio of 1/1 (20 g soil (dry weight equivalents)/20 ml solution) for soils

Laacher Hof, Hoefchen Am Hohenseh and Hanscheiderhof and 1/2 (10 g

soil (dry weight equivalents)/20 ml solution) for soil Dollendorf II.

BCS- CU81055 was applied at nominal concentrations of 1.0, 0.3, 0.1,

0.03, 0.01 mg/L in aqueous 0.01 M CaCl2 solution. The desorption phase

was performed by supplying pre-adsorbed soil samples with fresh

aqueous 0.01 M CaCl2 solution for all test concentrations. For the highest

concentration (1.0 mg/L), two additional desorption cycles were

performed with 24 hours equilibration time each. The adsorption and

desorption steps were carried out each for 24 hours under continuous

agitation.

BCS- CU81055 was sufficiently stable throughout the study. The

parental mass balances were 96.6, 95.0, 94.1 and 95.4% of the %AR for

soil Laacher Hof, Hoefchen Am Hohenseh, Hanscheiderhof and

Dollendorf II, respectively.

Mean material balances were 94.7, 92.7, 95.5 and 96.6%AR for soil

Laacher Hof, Hoefchen Am Hohenseh, Hanscheiderhof and Dollendorf II,

respectively.

At the end of the adsorption phase, 32.8 – 43.7%AR was adsorbed to

soil Laacher Hof, 36.3-46.6%AR was adsorbed to soil Hoefchen Am

Hohenseh, 37.4 – 46.9%AR was adsorbed to soil Hanscheiderhof and

34.3-46.8%AR was adsorbed to soil Dollendorf II. The adsorption

constants KF(ads) of BCS- CU81055 calculated based on the Freundlich

isotherms of the four test soils ranged from 0.494 to 1.159 ml/g (mean:

0.805 ml/g). The Freundlich exponents 1/n were in the range of 0.8947 to

0.9267 (mean: 0.9110), indicating that the concentration of the test item

affects its adsorption behaviour in the examined concentration range.

The corresponding, calculated KF, OC(ads) values varied between 19.5 and

50.4 ml/g (mean: 30.9 ml/g).

After the first desorption phase between 19.5 – 32.7% of the initially

adsorbed radioactivity was desorbed from the respective soils. The

desorption constants KF, OC(des) were about four times higher than the KF,

OC(ads) values, indicating that the test item once adsorbed to the soil is not

readily desorbed.


CU81055 in soil are presented below.


Laacher

hof

Hoefchen

Am

Hohenseh


II

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SEPTEMBER/

2019

Soil type Loamy

sand

Silt loam loam loam

Adsorption

Kf 0.494 0.569 1.159 0.996

1/n 0.910 0.913 0.927 0.895

R2 0.999 0.999 0.999 1.000

Kf, oc 23.5 29.9 50.4 19.5

Desorption

Kf 2.291 2.741 3.625 3.606

1/n 0.931 0.944 0.936 0.938

R2 0.999 0.999 0.997 0.997

Kf, oc 109.1 144.3 157.6 70.7


According to Briggs, BCS- CU81055 can be classified as mobile for

adsorption and low mobile for desorption in the tested soils.

Conclusion Kf oc adsorption 23.5, 29.9, 50.4, 19.5

According to McCall classification, the mobility is considered very high.

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2019

Table 122: Adsorption/desorption – metabolites – study 3


Flag Key study

Test Substance BCS-CQ63359 (metabolite)


Value 4875, 13416, 9049, 6464 (slightly - immobile)

Reference

Tinnefeld D., 2012 [Dihydroquinazoline-4-14C] BCS- CQ63359:

Adsorption/desorption in four European soils, Report no EnSa- 12-0596,

M-441845-01-1

Klimisch Score 1

Amendments/Deviations

Due to abiotic degradation, only one desorption step was carried out

instead of three desorption steps as required by the Canadian PMRA

Guidelines

This does not affect the study results

GLP yes

Test Guideline/s OECD 106, OCSPP 835.1230, Canada PMRA Environmental Chemistry

and Fate

Dose Levels 1.0, 0.3, 0.1, 0.03, 0.01 mg/L


Study Summary

The adsorption /desorption behaviour of [Dihydroquinazoline-4-14C] BCS-

CQ63359 (BCS-CL73507-N- methyl-quinazolinone) was studied in four

different German soils in the dark in the laboratory at 20 ±1 oC using the

batch equilibrium method. The soil characteristics are as follows:


Laacher

hof

Hoefchen

Am

Hohenseh


II

Soil type Loamy

sand

Silt loam loam loam

pH

(0.01 M

CaCl2)

6.0 6.3 5.4 7.2

%OC 2.1 1.9 2.3 5.1

%OM 3.6 3.3 4.0 8.8

of 541


SEPTEMBER/

2019

WHC at 0.1

bar (pF 2.0)

%

15.6 26.4 27.7 41.4

The adsorption phase of the study was carried out using air-dried soils

pre-equilibrated in aqueous 0.01 M CaCl2 solution with a soil-to-solution

ratio of 1/40 (0.5 g soil (dry weight equivalents)/20 ml solution) for all

soils.

BCS- CQ63359 was applied at nominal concentrations of 1.0, 0.3, 0.1,

0.03, 0.01 mg/L in aqueous 0.01 M CaCl2 solution. The desorption phase

was performed by supplying pre-adsorbed soil samples with fresh

aqueous 0.01 M CaCl2 solution for all test concentrations. The adsorption

and desorption step was24 hours under continuous agitation.

BCS- CQ63359 was sufficiently stable throughout the study in control

samples without soil. The parental mass balances were 91.0, 92.3, 93.4

and 92.2% of the %AR for soil Laacher Hof, Hoefchen Am Hohenseh,

Hanscheiderhof and Dollendorf II, respectively.

Mean material balances were 95.9, 95.9, 96.0 and 98.4%AR for soil


respectively.

At the end of the adsorption phase, 74.2-83.7%AR was adsorbed to soil

Laacher Hof, 86.7-87.7%AR was adsorbed to soil Hoefchen Am

Hohenseh, 84.0-89.0%AR was adsorbed to soil Hanscheiderhof and

91.2-93.9%AR was adsorbed to soil Dollendorf II. The adsorption

constants KF(ads) of BCS- CQ63359 calculated based on the Freundlich

isotherms of the four test soils ranged from 102.4 to 329.7 ml/g (mean:

223.8 ml/g). The Freundlich exponents 1/n were in the range of 0.8859 to

0.9831 (mean: 0.9297), indicating that the concentration of the test item

affects its adsorption behaviour in the examined concentration range.

The corresponding calculated KF, OC(ads) values varied between 4875 and

13416 ml/g (mean: 8451 ml/g).

After the first desorption phase between 4.8-20.8% of the initially

adsorbed radioactivity was desorbed from the respective soils. The

desorption constants KF, OC(des) were about 10% higher than the KF, OC(ads)

values, indicating that the test item once adsorbed to the soil is not

readily desorbed.


CQ63359 in soil are presented below.


Laacher

hof

Hoefchen

Am

Hohenseh


II

Soil type Loamy

sand

Silt loam loam loam

Adsorption

Kf 102.366 254.896 208.127 329.652

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SEPTEMBER/

2019

1/n 0.886 0.983 0.933 0.917

R2 0.997 0.996 0.994 0.997

Kf, oc 4875 13416 9049 6464

Desorption

Kf 127.497 259.815 247.676 332.719

1/n 0.873 0.956 0.942 0.889

R2 0.995 0.998 0.996 0.998

Kf, oc 6071 16375 10769 6524


According to Briggs, BCS- CQ63359 can be classified as mobile for

adsorption and desorption in the tested soils.

Conclusion

Kf oc adsorption 4875, 13415, 9049, 6464

According to McCall classification, the mobility is considered slightly to

immobile.

of 541


SEPTEMBER/

2019



Flag Key study

Test Substance BCS-CT30673 (metabolite)


Value 543, 568,718, 326 (low - medium)

Reference

Beckmann M., Koenig H., 2013 [Dihydroquinazoline-2-14C] BCS- CT30673:


467319-01-1

Klimisch Score 1


GLP yes


Fate

Dose Levels 1.0, 0.3, 0.1, 0.03, 0.01 mg/L

Analytical

measurements LSC

Study Summary


CT30673 (BCS-CL73507-desmethyl-amide-carboxylic acid) was studied in

four different German soils in the dark in the laboratory at 20 ±1 oC using the



Laacher

hof

Hoefchen

Am

Hohenseh


II

Soil type Loamy

sand

Silt loam loam loam

pH

(0.01 M

CaCl2)

6.0 6.3 5.4 7.2

%OC 2.1 1.9 2.3 5.1

%OM 3.6 3.3 4.0 8.8

of 541


SEPTEMBER/

2019

WHC at 0.1

bar (pF 2.0)

%

15.6 26.4 27.7 41.4


equilibrated in aqueous 0.01 M CaCl2 solution with a soil-to-solution ratio of

1/10 (2 g soil (dry weight equivalents)/20 ml solution) for all soils.

BCS- CT30673 was applied at nominal concentrations of 1.0, 0.3, 0.1, 0.03,

0.01 mg/L in aqueous 0.01 M CaCl2 solution. The desorption phase was


CaCl2 solution for all test concentrations. For the highest concentration (1.0

mg/L), two additional desorption cycles were performed with 24 hours

equilibration time each. The adsorption and desorption steps were carries out

each for 24 hours under continuous agitation.

BCS- CT30673 was sufficiently stable throughout the study. The parental

mass balances were 102.3, 109.2, 103.1 and 106.5% of the %AR for soil


respectively.



At the end of the adsorption phase, 52.9-67.2%AR was adsorbed to soil

Laacher Hof, 53.8-70.7%AR was adsorbed to soil Hoefchen Am Hohenseh,

64.2-78.4%AR was adsorbed to soil Hanscheiderhof and 65.3-79.9%AR was

adsorbed to soil Dollendorf II. The adsorption constants KF(ads) of BCS-

CT30673 calculated based on the Freundlich isotherms of the four test soils

ranged from 0.782 to 16.602 ml/g (mean: 13.825 ml/g). The Freundlich

exponents 1/n were in the range of 0.8503 to 0.8849 (mean: 0.8618),

indicating that the concentration of the test item affects its adsorption

behaviour in the examined concentration range. The corresponding,

calculated KF, OC(ads) values varied between 325.5 and 718.0 ml/g (mean:

538.5 ml/g).

After the first desorption phase between 13.7-37.0% of the initially adsorbed

radioactivity was desorbed from the respective soils. The desorption constants

KF, OC(des) were about 30% higher than the KF, OC(ads) values, indicating a

strengthened binding of the test item once adsorbed to the soil.


CT30673 in soil are presented below.


Laacher

hof

Hoefchen

Am

Hohenseh


II

Soil type Loamy

sand

Silt loam loam loam

Adsorption

Kf 11.40 10.78 16.51 16.60

of 541


SEPTEMBER/

2019

1/n 0.885 0.850 0.861 0.851

R2 0.996 0.998 0.998 0.999

Kf, oc 543 568 718 326

Desorption

Kf 16.01 14.45 22.56 22.43

1/n 0.867 0.828 0.843 0.840

R2 0.991 0.996 0.994 0.998

Kf, oc 762 760 981 440


According to Briggs, BCS- CT30673 can be classified as mobile for adsorption

and desorption in the tested soils.

Conclusion Kf oc adsorption 543, 568,718, 326

According to McCall classification, the mobility is considered low to medium.

of 541


SEPTEMBER/

2019



Flag Key study

Test Substance BCS-CU81056 (metabolite)


Value 1081, 1104, 1204, 668 (low)

Reference

Beckmann M., Koenig H., 2013 [Dihydroquinazoline-4-14C] BCS- CU81056:


467313-01-1

Klimisch Score 1


GLP yes


Fate

Dose Levels 0.5, 0.15, 0.05, 0.015, 0.005 mg/L


Study Summary


CU81056 (BCS-CL73507-quinazolinone- carboxylic acid) was studied in four

different German soils in the dark in the laboratory at 20 ±1 oC using the



Laacher

hof

Hoefchen

Am

Hohenseh


II

Soil type Loamy

sand

Silt loam loam loam

pH

(0.01 M

CaCl2)

6.0 6.3 5.4 7.2

%OC 2.1 1.9 2.3 5.1

%OM 3.6 3.3 4.0 8.8

WHC at 0.1

bar (pF 2.0)

%

15.6 26.4 27.7 41.4

of 541


SEPTEMBER/

2019


equilibrated in aqueous 0.01 M CaCl2 solution containing HgCl2 with a soil-to-

solution ratio of 1/20 (1 g soil (dry weight equivalents)/20 ml solution) for all

soils.

BCS- CU81056 was applied at nominal concentrations of 0.5, 0.15, 0.05,

0.015 and 0.005 mg/L in aqueous 0.01 M CaCl2 solution. The desorption

phase was performed by supplying pre-adsorbed soil samples with fresh

aqueous 0.01 M CaCl2 containing HgCl2 for one desorption cycle. For the

highest concentration (0.5 mg/L), two additional desorption cycles were

performed with 24 hours equilibration time each. The adsorption and

desorption steps were carries out each for 24 hours under continuous

agitation.

BCS- CU81056 was sufficiently stable throughout the study. The parental

mass balances were 90.9, 93.0, 91.7 and 94.2% of the %AR for soil Laacher

Hof, Hoefchen Am Hohenseh, Hanscheiderhof and Dollendorf II,

respectively.


Hof, Hoefchen Am Hohenseh, Hanscheiderhof and Dollendorf II,

respectively.

At the end of the adsorption phase, 59.7- 73.1%AR was adsorbed to soil

Laacher Hof, 57.3- 71.9%AR was adsorbed to soil Hoefchen Am Hohenseh,

63.9- 77.5%AR was adsorbed to soil Hanscheiderhof and 67.4-75.9%AR

was adsorbed to soil Dollendorf II. The adsorption constants KF(ads) of BCS-

CU81056 calculated based on the Freundlich isotherms of the four test soils

ranged from 20.98 to 34.09 ml/g (mean: 26.36 ml/g). The Freundlich

exponents 1/n were in the range of 0.851 to 0.9045 (mean: 0.870), indicating

that the concentration of the test item affects its adsorption behaviour in the

examined concentration range. The corresponding calculated KF, OC(ads)

values varied between 668 and 1204 ml/g (mean: 1014 ml/g).

After the first desorption phase between 13.5-26.9% of the initially adsorbed

radioactivity was desorbed from the respective soils. The desorption

constants KF, OC(des) were about 70% higher than the KF, OC(ads) values,

indicating a strengthened binding of the test item once adsorbed to the soil.


CU81056 in soil are presented below.


Laacher

hof

Hoefchen

Am

Hohenseh


II

Soil type Loamy

sand

Silt loam loam loam

Adsorption

Kf 22.70 20.98 27.69 34.09

1/n 0.866 0.859 0.851 0.905

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SEPTEMBER/

2019

R2 0.998 0.998 0.998 0.999

Kf, oc 1081 1104 1204 668

Desorption

Kf 34.61 35.58 52.55 56.57

1/n 0.857 0.849 0.869 0.893

R2 0.993 0.997 0.998 0.999

Kf, oc 1648 1873 2285 1109


According to Briggs, BCS- CU81056 can be classified as immobile for

adsorption and desorption in the tested soils.

Conclusion Kf oc adsorption 1081, 1104, 1204, 668

According to McCall classification, the mobility is considered low.

of 541


SEPTEMBER/

2019



Flag Key study

Test Substance BCS-CT30672 (metabolite)


Value 6386, 12624, 5646, 5460 (immobile)

Reference

Hein W., D’Ambrosio A., 2016 [Dihydroquinazoline-2-14C] BCS- CT30672:

Adsorption/desorption in four European soils, Report no AS 446, M-

553074-01-1

Klimisch Score 1


GLP yes


Dose Levels 1.0, 0.3, 0.1, 0.03, 0.01 and 0.003 mg/L


Study Summary


CT30672 was studied in four different German soils in the dark in the




Laacher

hof

Hoefchen

Am

Hohenseh


II

Soil type Sandy

loam

Silt loam Silt loam Clay loam

pH

(0.01 M

CaCl2)

6.5 6.1 5.4 7.3

%OC 1.5 1.9 2.9 4.8

%OM 2.6 3.3 5.0 8.3

CEC [meq /

100g]

8.2 10.5 10.1 18.8

of 541


SEPTEMBER/

2019


equilibrated in aqueous 0.01 M CaCl2 solution with a soil-to-solution ratio of

1/20 (1 g soil (dry weight equivalents)/20 ml solution) for all soils.

BCS- CT30672 was applied at nominal concentrations of 1.0, 0.3, 0.1,

0.03, 0.01 and 0.003 mg/L in aqueous 0.01 M CaCl2 solution. The

desorption phase was performed by supplying pre-adsorbed soil samples

with fresh aqueous 0.01 M CaCl2 solution for all test concentrations. The

adsorption and desorption steps were carries out each for 24 hours under

continuous agitation.

BCS- CT30672 was sufficiently stable throughout the study. The parental

mass balances were in the range of 93.61% and 97.94%AR.

The material balances with respect to the individual vessel ranged from

91.3% to 118.1% of the AR in the four tested soils. Mean recovery rates

above 110% of applied were only measured for the 0.01 mg/L-batch of soil

Laacher Hof AXXa (exception) and for all test systems of the 0.003 mg/L

batch due to the extremely low concentration.

The adsorption parameters were calculated using the Freundlich

adsorption isotherm. Due to the low water solubility (≤ 0.26 mg/L) of the

test item only the three lowest test concentrations (0.003 mg/L – 0.03

mg/L) were used. Calculations including higher concentrations did not

change the result significantly.

At the end of the adsorption phase, 89.3 - 92.1%, 82.3-87.7%, 94.1-96.5%

and 91.2-94.8%AR was adsorbed in soils Hanscheider Hof, Laacher Hof,

Dollendorf II and Hoefchen am hohenseh, respectively. The calculated

adsorption constants KF(ads) of BCS-CT30672 calculated based on the

Freundlich isotherms of the four test soils ranged from 95.8 to 262.1 ml/g

(mean: 190.4 ml/g). The Freundlich exponents 1/n were in the range of

0.9684 to 1.0169 (mean: 0.9953). The corresponding calculated KF, OC(ads)

values varied between 5460 and 12624 ml/g (mean: 7529 ml/g).

At the end of the desorption phase, 5.7 – 8.1%, 4.1 – 6.6%, 2.7 – 4.8% and

10.0 – 13.5% of the initially adsorbed amount were desorbed from soil

Hanscheider Hof, Hoefchen am Hohenseh, Dollendorf II and Laacher Hof,

respectively. The desorption constants KF(des) ranged from 119.7 to 287.9

ml/g (mean: 206.8 ml/g) and the normalized desorption constants KF,

OC(des) ranged from 6650 to 15155 ml/g (mean: 8627 ml/g).


CT30672 in soil are presented below.


Laacher

hof

Hoefchen

Am

Hohenseh


II

Soil type Sandy

loam

Silt loam Silt loam Clay loam

Adsorption

Kf 95.8 239.9 163.7 262.1

1/n 1.003 1.017 0.993 0.968

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SEPTEMBER/

2019

R2 0.9999 1.000 0.999 1.000

Kf, oc 6386 12624 5646 5460

Desorption

Kf 119.7 287.9 192.9 226.7

1/n 0.993 1.011 0.992 0.927

R2 0.999 1.000 0.999 1.000

Kf, oc 7981 15155 6650 4723


According to Briggs11, BCS-CT30672 can be classified as immobile for


Conclusion Kf oc adsorption 6386, 12624, 5646, 5460

According to McCall classification the substance is considered immobile.

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Soil leaching

Table 126: Column leaching

Study type Column leaching

Flag Key study


Endpoint mobility

Value Slightly to moderately mobile

Reference

de Souza T.J.T. 2015 Mobility of [Pyrazole-carboxamide-14C] BCS-

CL73507 in Brazilian soils - soil columns leaching method. Report BCS-

CL73507, M-52348

Klimisch Score 1


GLP yes

Test Guideline/s OECD Test Guideline No 312


Analytical measurements HPLC

Study Summary

The leaching behaviour of [Pyrazole-carboxamide-14C]-BCS-CL73507

was studied in four Brazilian soils under laboratory conditions. The four

soil types were Argissolo (clay), Latossolo vermelho (clay), Neossolo

(loamy sand) and Gleissolo humico (sandy clay loam). Duplicate glass

columns per soil type were filled with the respective soil to a height of 30

cm. After conditioning with 0.01 M CaCl2 solution, the test substance,

[Pyrazole-carboxamide-14C]-BCS-CL73507, was applied to the top of the

columns at a dosage approximating the maximum application rate of 200

g ai/ ha. A product containing monuron was used as a reference

substance and was applied at a rate of 5 kg ai/ ha in the same column.

After the application of the test and reference substances, each column

was irrigated with 200 mm of artificial rain over a 48-hour period, and the

respective leachate samples were collected. After percolation, the soil

columns were divided into 6 layers of ca. 5 cm each, and the soil

samples were extracted with Acetonitrile: water (80:20 v/v). Layers

containing more than 10% of AR were sequentially extracted until the

last extract represented less than 10% of AR. Extracted radioactivity was

analysed by HPLC with radiometric detection.


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parameter Origin in Brazil

Argissolo

(Piracicab

a)

Latossolo

vermelho

(Nova

Prata)

Neossolo

(Osorio)

Gleissolo

humico

(Viamao)

Soil type

(USDA)

clay clay Loamy sand/

sandy loam

loam

pH

(0.01 M

CaCl2)

4.9 4.8 4.3 3.2

pH (H2O)

6.0 5.6 4.8 4.3

%OC 2.7 1.5 0.8 6.5

%OM 4.7 2.6 1.3 11.2

The average mass balance ranged from 102.0% to 105.0% in the four

tested soils. The AR was completely retained in Argissolo, Latossolo and

Gleissolo soils and percolated to the leachate in Neossolo soil after the

application of the artificial rain. The maximum (mean) depth penetration

of the radioactivity in the soil profiles was ≤ 10 cm for Argissolo soil, ≤ 30

cm for Latossolo, > 30 cm for Neossolo, and ≤ 10 cm for Gleissolo soil.

The maximum (mean) depth penetration of Monuron was ≤ 27.5 cm for

Argissolo soil, > 30 cm for Latossolo, > 30 cm for Neossolo and ≤ 10 cm

for Gleissolo soil.

Due to the very high penetration of monuron, the Relative Mobility Factor

(RMF) does not accurately describe the relationship between differential

percolation of BCS-CL73507 and monuron. This relationship can be

better understood by means of the RMF50, Relative Mobility Factor 50%,

ie, the relation between the distances of penetration of 50% of the

applied doses. The depth accumulating half of the AR was ≤ 5 cm for

Argissolo soil, ≤ 10 cm for Latossolo, ≤ 20 cm for Neossolo, and ≤ 5 cm

for Gleissolo soil, while depth containing half of the applied monuron was

≤ 12.5 cm for Argissolo soil, ≤ 22.5 cm for Latossolo, > 30 cm for

Neossolo and ≤ 5 cm for Gleissolo soil.

Extractable radioactivity ranged for all soils from 88.08% to 100.92%,

and non-extractable radioactivity ranged from 3.34% to 14.65%. The

results of the HPLC analysis did not show degradation of the parent

compound during the timescale of the study.

The RMF, in comparison to monuron, for BCS-CL73507 was 0.37 in

Argissolo soil, 1.0 in Latossolo, 1.0 in Neossolo soil and 1.0 in Gleissolo

soil.

Based on these values, BCS-CL73507 can be classified as little mobile

in Argissolo and moderately mobile in Latossolo, Neossolo and Gleissolo

soils. The RFM50 was 0.42 in Argissolo soil, 0.45 in Latossolo, 0.67 in

Neossolo soil, and 1.0 in Gleissolo soil, what would classify BCS-

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CL73507 as little mobile in Argissolo, Latossolo and Neossolo soils and

moderately mobile in Gleissolo soil.

Mobility classes according to JA Guth are used.

Conclusion BCS-CL 73705 is slightly to moderately mobile according to JA Guth

classification

Aquatic degradation

Hydrolysis

Table 127: Hydrolysis

Study type Hydrolysis in aquatic environment

Flag Key study


Endpoint DT50 at 20oC

Value 265, 58 and 1.27 days at pH 4,7 and 9 respectively

Reference Hein E.M., Kasel D., 2016 [Pyrazole-carboxamide-14C] BCS-CL73507: Hydrolytic

degradation Report no EnSa-14-0308, M-565616-01-1

Klimisch Score 1

Amendments/Deviati

ons None

GLP yes

Test Guideline/s OECD Test Guideline No 111, OPPTS Test Guideline No. 835.2120 and

835.2130, Japanese MAFF no 2-6-1

Dose Levels 0.3 mg ai/ L

Analytical


Study Summary

The abiotic hydrolytic degradation of [pyrazole-carboxamide-14C]BCS-CL73507

was investigated at 20, 25 and 50oC in sterile buffer solutions with pH values of

4,7 or 9 in the dark in the laboratory.

An application rate of 0.3 mg/L was applied considering the low water solubility of

the test item and its degradation products.

Duplicate samples were processed and analysed for at least seven sampling

intervals, distributed over the entire incubation period of 30 days. The preliminary

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test (test 1, 50 °C) for pH 9 was terminated after 2 days, due to fast degradation

of the test item (> 95%AR). In the preliminary test (test 1, 50 °C) mean material

balances at pH 4 were 95.7%AR (range from 92.5 to 100.0%AR), at pH 7

97.4%AR (range from 92.5 to 100.9%AR), and at pH 9 97.8%AR (range from 93.2

to 101.1%AR). In the main test (test 2, 25 °C) mean material balances at pH 4

were 95.7%AR (range from 93.0 to 100.0%AR), at pH 7 95.3%AR (range from

92.2 to 100.0%AR), and at pH 9 100.2%AR (range from 98.7 to 103.1%AR). In

the optional test (test 3, 20 °C) mean material balances at pH 4 were 96.6%AR

(range from 93.7 to 101.8%AR), at pH 7 95.8%AR (range from 93.4 to

100.0%AR), and at pH 9 99.5%AR (range from 97.1 to 103.9%AR).

In the preliminary test (test 1, 50 °C) the amount of BCS-CL73507 in test

solution decreased at pH 4 from 100.0%AR at DAT-0 to 16.3%AR at DAT-30, at

pH 7 from 100.0%AR at DAT-0 to 1.6%AR at DAT-30, and at pH 9 from 97.2%AR

at DAT-0 to 2.9%AR at DAT-2.04. In the main test (test 2, 25 °C), the amount of

BCS-CL73507 in test solution decreased at pH 4 from 100.0%AR at DAT-0 to

89.6%AR at DAT-30, at pH 7 from 100.0%AR at DAT-0 to 56.5%AR at DAT-30,

and at pH 9 from 97.2%AR at DAT-0 to 1.8%AR at DAT-30. In the optional test

(test 3, 20 °C), the amount of BCS-CL73507 in test solution decreased at pH 4

from 100.0%AR at DAT-0 to 91.5%AR at DAT-30, at pH 7 from 100.0%AR at

DAT-0 to 68.1%AR at DAT-30, and at pH 9 from 97.2%AR at DAT-0 to 1.5%AR at

DAT-30.

One degradation product was identified as BCS-CL73507-N-methyl-quinazolinone

with a maximum amount of 99.6%AR at DAT-30 (pH 9, optional test, 20 °C). The

total unidentified residues amounted to a maximum of 3.3%AR and no single

component exceeded 3.3%AR at any sampling interval of all conducted tests.

The experimental data could be well described by an SFO kinetic model. The

hydrolytic degradation of BCS-CL73507 was observed to be pH dependent. At 50

°C, the experimental half-lives of BCS-CL73507 were 10.9, 3.74 and 0.04 days

for pH 4, 7 and 9, respectively. At 25 °C, the experimental half-lives of BCS

CL73507 were 287, 38.8 and 0.75 days for pH 4, 7 and 9, respectively. At 20 °C,

the experimental half-lives of BCS CL73507 were 265, 58.0 and 1.27 days for pH

4, 7 and 9, respectively.

It is concluded that hydrolysis of [pyrazole-carboxamide-14C]BCS-CL73507

contributes to the elimination of this compound from the aqueous environment.

Conclusion DT50 at 20oC: 265, 58 and 1.27 days at pH 4,7 and 9 respectively

Hydrolytic degradation strongly depended on temperature and pH.

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Photolysis

Table 128: Photolysis – study 1

Study type Photolysis in aquatic environment

Flag Key study


Endpoint DT50

Value 3.4 days, calculated for USA 10.5 d

Reference Heinemann O., Kasel D., 2014 [Pyrazole-carboxamide-14C] BCS-CL73507:

Phototransformation in water. Report no EnSa-13-0320, M-484185-01-1

Klimisch Score 1

Amendments/Devi

ations None

GLP yes

Test Guideline/s OECD Test Guideline No 316, US EPA OPPTS Test Guideline No. 835.2240,

Japanese MAFF 2-6-2


Analytical

measurements HPLC

Study Summary

The photolytic route and degradation of [pyrazole-carboxamide-14C]BCS-CL73507

were investigated in sterile acetate buffer solution (pH 4) under exposure to simulated

sunlight in the laboratory for 11 days at 25 ± 2 °C (study temp. 25.0 °C mean

irradiated and 25.1 oC mean dark).

The study application rate of 0.48 mg/L was applied due to the low water solubility of

the test item. 11 days of incubation under exposure to simulated sunlight were

equivalent to 34 days under environmental conditions (Phoenix, Arizona, USA). For

comparison, additional samples were incubated in the dark. Duplicate samples were

processed and analyzed 0, 1, 2, 4, 7, 9, and 11 DAT.

Mean material balances were 98.9 and 102.6%AR for irradiated and dark samples,

respectively. The maximum amount of carbon dioxide was 0.4%AR at study end

(DAT-11) and 0.7%AR at DAT-4 in irradiated and dark samples, respectively.

Formation of VOC was insignificant as demonstrated by values of ≤ 0.1%AR at all

sampling intervals for irradiated samples and ≤ 0.5%AR for dark samples.

The amount of BCS-CL73507 in the test solution decreased from 99.6%AR at DAT-0

to 13.2 and 96.3%AR at DAT-11 in irradiated and dark samples, respectively.

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Degradation of BCS-CL73507 in irradiated samples was accompanied by the

formation of one major degradation product, identified as BCS-CL73507-deschloro-

oxazine with the maximum amount of 72.7%AR at DAT-11. The total unidentified

residues amounted to a maximum of 13.1%AR and no single component exceeded

7.0%AR at any sampling interval.

In the test solutions of the dark test systems, no significant formation of degradation

products was observed.

Comparing both dark and irradiated test systems, degradation of the test item was

only observed under exposure to light.

The experimental data could be well described by an SFO kinetic model. The half-life

of BCS-CL73507 in irradiated samples was 3.4 days. Based on this experimental

DT50 value for [pyrazole-carboxamide-14C]BCS-CL73507 in irradiated samples,

predicted environmental DT50 values are calculated to be eg 10.5 solar summer days

at Phoenix, Arizona, USA. The calculated DT50 value for [pyrazole-carboxamide-14C]BCS-CL73507 under dark conditions was 188.5 days.

It is concluded that photodegradation of [pyrazole-carboxamide-14C]BCS-CL73507 in

water systems is a contributor to the elimination of this compound from the aqueous

environment.

Conclusion DT50 in days: 3.4 d (10.5 d USA calculated)

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Flag Key study


Endpoint DT50

Value 0.7 days, calculated for Tokyo 4.7 d

Reference Heinemann O., Junge T., 2014 [Pyrazole-carboxamide-14C] BCS-CL73507:

Phototransformation in natural water. Report no EnSa-13-0321, M-489424-01-1

Klimisch Score 1

Amendments/Deviatio


GLP yes


Japanese MAFF 2-6-2


Analytical

measurements HPLC

Study Summary

The photolytic route and degradation of [pyrazole-carboxamide-14C]BCS-

CL73507 were investigated in natural water (pH 8) from the river Rhine under

exposure to simulated sunlight in the laboratory for 10 days at 25 ± 2 °C

(study temp. 24.9°C mean irradiated and 24.4o C mean dark).

The study application rate of 0.45 mg/L was applied due to the low water

solubility of the test item. 10 days of incubation under exposure to simulated

sunlight were equivalent to 69.1 days of solar summer days in Japan. Additional

samples were incubated in the dark. Duplicate samples were processed and

analyzed 0, 0.25, 1, 2, 4, 7, and 10 DAT.

Mean material balances were 95.6 and 97.6%AR for irradiated and dark

samples, respectively. The maximum amount of carbon dioxide was 10.9 and

≤0.1%AR in irradiated and dark samples, respectively. Formation of VOC was

insignificant as demonstrated by values of ≤ 0.1%AR at all sampling intervals for

both irradiated and dark samples.

The amount of BCS-CL73507 in the test solution decreased from 97.2%AR at

DAT-0 to 1.2 and 4.1%AR at DAT-10 in irradiated and dark samples,

respectively.

Besides the formation of carbon dioxide four degradation products were

identified in irradiated samples with the following maximum occurrences: BCS-

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CL73507-N-methyl-quinazolinone with 34.5%AR at DAT-0.25, BCS-CL73507-

despyridyl-N-methyl-quinazolinone with 7.2%AR at DAT-2, BCS-CL73507-

deschloro-pyrazine with 37.2%AR at DAT-2 and BCS-CL73507-pyrazole-5-

carboxylic acid with 18.0%AR at DAT-10. The total unidentified residues

amounted to a maximum of 56.3%AR and no single component exceeded

9.4%AR at any sampling interval.

In dark samples, BCS-CL73507 was degraded to BCS-CL73507-N-methyl-

quinazolinone with the maximum occurrence of 95.0%AR at DAT-10.

Comparing both dark and irradiated test systems, degradation of the test item

was less rapid under exposure to light.

The experimental data could be well described by a SFO kinetic model. The

half-life of BCS-CL73507 in irradiated samples was 0.7 days. Based on this

experimental DT50 value for [pyrazole-carboxamide-14C]BCS-CL73507 in

irradiated samples, predicted environmental DT50 values are calculated to be eg

4.7 solar summer days at Tokyo, Japan. Under dark conditions [pyrazole-

carboxamide- 14C]BCS-CL73507 had a DT50 value of 0.3 days.

It is considered that photodegradation of [pyrazole-carboxamide-14C]BCS-

CL73507 in natural water systems is a contributor to the elimination of this

compound from the aqueous environment.

Conclusion

DT50 in days: 0.7 d (4.7 d Tokyo calculated)

Although photodegradation contributes to the overall degradation of BCS-

CL73507, degradation in the dark is faster and forms the major metabolite BCS-

CL73507-N-methyl-quinazolinone (max. 95%AR).



Flag Key study


Endpoint DT50

Value 0.77 days, calculated for Tokyo 4.9 d

Reference Heinemann O., Kasel D., 2016 [Pyridinyl-2-14C] BCS-CL73507:

Phototransformation in natural water. Report no EnSa-16-0158, M-568022-01-1

Klimisch Score 1

Amendments/Deviati

ons None that affected the study results

GLP yes

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Japanese MAFF 2-6-2


Analytical

measurements HPLC

Study Summary

The photolytic route and degradation of [Pyridinyl-2-14C] -14C]BCS-CL73507 were

investigated in natural water (pH 8.5) from the river Rhine under exposure to

simulated sunlight in the laboratory for 11 days at 25 ± 2 °C.

The study application rate of 0.5 mg/L was applied due to the low water solubility

of the test item. 11 days of incubation under exposure to simulated sunlight were

equivalent to 69.6 days of solar summer days in Japan. Additional samples were

incubated in the dark. Duplicate samples were processed and analyzed 0.25, 1,

2, 4, 7 and 11 DAT.

Mean material balances were 101 and 103%AR for irradiated and dark samples,

respectively. The maximum amount of carbon dioxide was 38.9 and ≤0.1%AR in

irradiated and dark samples, respectively. Formation of VOC was insignificant as

demonstrated by values of ≤ 0.2%AR at all sampling intervals for both irradiated

and dark samples.

The amount of BCS-CL73507 in the test solution decreased from 97.7%AR at

DAT-0 to non-detectable amounts and 4.8%AR at DAT-10 in irradiated and dark

samples, respectively.

Besides the formation of carbon dioxide two degradation products were identified

in irradiated samples with the following maximum occurrences: BCS-CL73507-N-

methyl-quinazolinone with 39.2%AR at DAT-1 and BCS-CL73507-deschloro-

pyrazine with 38.8%AR at DAT-2. The total unidentified residues amounted to a

maximum of 62.4%AR and no single component exceeded 7.3%AR at any

sampling interval.

In dark samples, BCS-CL73507 was degraded to BCS-CL73507-N-methyl-

quinazolinone with the maximum occurrence of 99.0%AR at DAT-11.

The experimental data could be well described by an SFO kinetic model. The half-

life of BCS-CL73507 in irradiated samples was 0.77 days. Based on this

experimental DT50 value for [Pyridinyl-2-14C] BCS-CL73507 in irradiated samples,

predicted environmental DT50 values are calculated to be eg 4.9 solar summer

days at Tokyo, Japan. Under dark conditions [Pyridinyl-2-14C] BCS-CL73507 had

a DT50 value of 0.75 days.

It is considered that photodegradation of [Pyridinyl-2-14C] BCS-CL73507 in natural

water systems is a contributor to the elimination of this compound from the

aqueous environment.

Conclusion

DT50 in days: 0.77 d (4.9 d Tokyo calculated)

Although photodegradation contributes to the overall degradation of BCS-

CL73507, degradation in the dark is also fast and forms the major metabolite

BCS-CL73507-N-methyl-quinazolinone (max. 99%AR).

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Flag Key study

Test Substance BCS-CQ63359, metabolite of ai

Endpoint DT50

Value 0.41 d (1.3 d USA, 1.9 d Greece calculated)

Reference Beckmann M., Junge T., 2016, BCS-CQ63359: Phototransformation in water.

Report no EnSa-16-0894, M-571379-01-1

Klimisch Score 1

Amendments/Devia

tions None that affected the study results

GLP yes


Japanese MAFF 2-6-2


Analytical

measurements HPLC

Study Summary

The photolytic rate of degradation of BCS-CQ63359 was investigated in sterile

aqueous buffer solution at pH 7 under exposure to simulated sunlight and aerobic

conditions in the laboratory for 1.25 days at 25 °C. Samples were continuously

exposed to a xenon lamp with a mean irradiance of 1086 watt/m2, equivalent to eg

3.8 and 5.9 solar summer days in USA (Phoenix) and Greece (Athens). Additional

samples were incubated in the dark. Duplicate samples were processed and

analyzed 0, 0.08, 0.17, 0.25, 0.33, 1 and 1.25 DAT.

An actual application rate of 91.3 µg/L was applied due to the low water solubility of

this metabolite.

The amount of BCS-CQ63359 in the test solution decreased from 100%AA at DAT-

0 to 13.4%AA at DAT-1.25 in irradiated samples and remained at 100%AA in dark

samples.

The experimental data could be well described by an SFO kinetic model. The half-

life of BCS-CQ63359 in irradiated samples was 0.41 days and >1000 days in dark

samples. Thus, the net experimental photodegradation rate constant (difference

between irradiated and dark samples) was calculated to be 1.67 day-1, resulting in a

net experimental half-life of 0.41 days. Based on the experimental DT50 value of

0.41 days for irradiated samples, the DT50 of BCS-CL73507-N-methyl-

quinazolinone under environmental conditions is calculated to be eg 1.3 solar

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summer days at Phoenix, Arizona, USA or 1.9 solar summer days at Athens,

Greece.

It is concluded that photolytic degradation may contribute to the overall fate of BCS-

CL73507-N-methyl- quinazolinone under aqueous conditions eg by enhancing its

degradation rate.

Conclusion DT50 in days: 0.41 d (1.3 d USA, 1.9 Greece calculated)


Study type Photodegradation in water

Flag Key study


Endpoint DT50

Value 0.4- 1.2 days

Reference

Heinemann O. 2013 [Pyrazole-carboxamide-14C] BCS-CL73507:

Determination of the quantum yield and assessment of the

environmental half-life of the direct photo-degradation in water.

Report no EnSa-13-0319-01-2, M-467310-01-2

Klimisch Score 1


GLP yes

Test Guideline/s OECD Test Guideline No 101 and 316

US EPA OCSPP Test Guideline No. 830.SUPP


Study Summary

The quantum yield of the direct phototransformation of [pyrazole-

carboxamide-14C]BCS-CL73507 was determined in buffer pH 4 at 25

1 °C using polychromatic light according to the ECETOC method.

The Ultra Violet Visible (UV-VIS) absorption spectrum of BCS-

CL73507 in water/acetonitrile (4/1, v/v) showed one shoulder at about

274 nm (abs 0.2822). The UV-VIS absorption spectra of BCS-

CL73507 in buffered neutral and acidic solutions showed similar

absorption properties, whereas the UV-VIS absorption spectrum in

buffered alkaline solution showed a differed absorption with a shift to

longer wavelengths probably due to faster degradation of the test

item in alkaline solution.

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The molar extinction coefficient ε of BCS-CL73507 in buffer pH

4/acetonitrile (4/1, v/v) at 290 nm was determined to be 6717 L x mol-

1 cm-1 and at 295 nm to be 5207 L x mol-1 cm-1. In general, the

absorption properties indicate a potential for direct photolytic

interactions of BCS-CL73507 with sunlight in aqueous solutions.

Degradation of BCS-CL73507 in aqueous buffer pH 4 in a range of

about 98 to 99% was measured by HPLC-radiodetection after a

maximum irradiation period of 500 min. This indicated almost

complete degradability of BCS-CL73507 via direct

phototransformation in buffered acidic solution. A mean quantum

yield of = 0.001312 was calculated on the basis of Ultra Violet (UV)

absorption data and the degradation kinetics determined from both

experiments.

The estimates based on the two modelling concepts (Zepp & Cline or

Frank & Kloepffer1) were comparable. Both estimates considered the

quantum yield and the absorption in the UV-VIS spectrum being in

the range of wavelengths relevant for the environment.

Environmental half-lives of sunlight exposed top surface water layers

were estimated to about 0.4 to 1.2 days for a direct

phototransformation of BCS-CL73507 during periods of main use in

spring to fall. In the winter period half-lives were estimated of 1.4 to

4.3 days.

Thus, direct phototransformation in water may contribute to the

dissipation of BCS-CL73507 from the environment with a high

probability. This assessment does not consider other potential

mechanisms which may enhance the degradation in natural water, eg

indirect photolytic processes.

Conclusion DT50 in days: 0.4 to 1.2 (estimate spring-fall)

1 Zepp R.G., Cline D.M. Environ.Sci.Technol. 11,359 (1977), Frank R., Kloepffer W. UBA Research report no 10602046 (1985)

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Aerobic conditions

Table 133: Aerobic aquatic degradation

Study type Water/sediment study

Flag Key study


Endpoint DT50

Value 11.1 and 122 days, total system

Reference

Stroech K., Kasel D., 2014 [Pyrazole-carboxamide-14C] BCS-CL73507:

Aerobic aquatic degradation/metabolism. Report no EnSa-14-0098, M-

492584-01-1

Sur R., Mikolasch B. Tetraniliprole (BCS-CL73507) and metabolites:

kinetic evaluation of aerobic aquatic metabolism in water-sediment

systems. Report no EnSa -16-0924, MRFVP126, M-574006-02-1

Klimisch Score 1


GLP yes

Test Guideline/s OECD Test Guideline No 308, US EPA OPPTS Test Guideline No.

835.4300/ 835.4400, Draft Sanco 11802/2010/rev 7

Dose Levels 99.0 µg ai/ L

Analytical measurements HPLC, LSC

Study Summary

The route and degradation of [pyrazole-carboxamide-14C]BCS-CL73507

were investigated in two water/sediment systems under aerobic conditions

in the dark in the laboratory for 101 days at 20.3°C.

The characteristics of the systems are stated below.

parameter Location Germany

Anglersee,

Leverkusen

Wiehtalsperre,

Reichshof

Soil type (USDA) sand Silt loam

Sediment pH

(0.01 M CaCl2)

7.2 5.5

Water pH direct

after sampling

7.8 7.7

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%Total OC

sediment

3.5 110

%Total OC water <2 2

The study application rate was 51.5 µg ai/ test system, corresponding to

99.0 µg ai/ L. This rate is based on a 5-fold single field rate of BCS-CL

73507 of 200 g /ha.

Duplicate test systems were processed and analysed 0, 1, 3, 8, 14, 29, 59

and 101 DAT.

Overall mean material balance was 102.4% of %AR for water/sediment

system Anglersee and 101.1%AR for water/sediment system

Wiehltalsperre.

The maximum amount of carbon dioxide was 0.2%AR at study end (DAT-

101) in both water/sediment systems. Formation of VOC was insignificant

as demonstrated by values of ≤ 0.1%AR at all sampling intervals for both

water/sediment systems.

Residues in water decreased from 93.7 to 7.2%AR in system Anglersee

and from 92.5 to 5.1%AR in system Wiehltalsperre from DAT-0 to DAT-

101. Extractable residues in sediment increased from 7.4 to 87.4%AR in

system Anglersee and from 8.8 to 84.9%AR in system Wiehltalsperre from

DAT-0 to DAT-101. Extractable residues in the total system (water and

sediment extracts) decreased in system Anglersee from 101.1 to 94.6%AR

from DAT-0 to DAT-101. In system Wiehltalsperre, extractable residues in

the total system decreased from 101.3 to 87.9%AR from DAT-0 to DAT-59

and increased then slightly to 90.0%AR at DAT-101.

NER increased in system Anglersee from 0.2 to 7.7%AR from DAT-0 to

DAT-101. In system Wiehltalsperre, NER increased from 0.3 to 12.1%AR

from DAT-0 to DAT-29 and decreased then slightly to 10.3%AR at DAT-

101.

BCS-CL73507 dissipated from the water due to degradation and

translocation into the sediment. The amount of BCS-CL73507 in the water

in system Anglersee was 92.9%AR at DAT-0 and was not detectable at

DAT-101. In system Wiehltalsperre, the amount of BCS-CL73507 in the

water decreased from DAT-0 to DAT-101 from 92.5 to 4.3%AR. The

amount of BCS-CL73507 in the sediment extracts increased in system

Anglersee from DAT-0 to DAT-8 from 7.4 to 22.1%AR and decreased then

to below Limit Of Detection (LOD) at DAT-101. In system Wiehltalsperre,

the amount of BCS-CL73507 in the sediment extracts increased from

8.8%AR at DAT-0 to 64.1%AR at DAT-14 and decreased then to 47.7%AR

at DAT-101.

The amount of BCS CL73507 in the total system decreased from

100.2%AR to < LOD in system Anglersee and from 101.3 to 52.0%AR in

system Wiehltalsperre from DAT-0 to DAT-101.

Two degradation products were identified with the following maximum

occurrences in the total system: BCS-CL73507-N methyl-quinazolinone

with 84.8%AR at DAT-59 (system Anglersee) and BCS-CL73507-N

methyl-quinazolinone-amide with 9.2%AR at DAT-101 (system Anglersee).

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The total unidentified residues for both water/sediment systems amounted

to a maximum of 4.1%AR and no single component exceeded 2.7%AR at

any sampling interval for both water/sediment systems.

The experimental data could be best described by SFO and DFOP kinetic

models. The DT50 values for the dissipation of BCS-CL73507 from the

water were 5.3 and 6.3 days in system Anglersee and Wiehltalsperre,

respectively. The DT50 values for the degradation of BCS-CL73507 in the

total water/sediment system were 11.1 and 122 days in system Anglersee

and Wiehltalsperre, respectively.

It is concluded that BCS-CL73507 and its degradation products will be

degraded in the aquatic environment.

Addition

In a separate report, a kinetic evaluation of the degradation of tetraniliprole

and its metabolites was performed according to the recommendations of

FOCUS (FOCUS 2006).

The DT50 was determined to be 10.7 days of the total system of Anglersee.

For the other system, no reliable value could be determined.

Note: the FOCUS model is not applicable for NZ circumstances and EPA

NZ does not use this model.

The EPA will use the study results for the risk assessment as a worst-case

scenario.

Conclusion DT50 = 11.1 and 122 days, total system

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Table 134: Aerobic aquatic degradation

Study type Degradation in water

Flag Key study


Endpoint DT50

Value 0.9 days

Reference

Heinemann O., Kasel D., 2016 [Pyrazole-carboxamide-14C] BCS-

CL73507: Aerobic mineralisation in surface water-final report. Report no

EnSa-14-0948, M-545815-01-2

Klimisch Score 1


GLP yes

Test Guideline/s OECD Test Guideline No 309, US EPA OPPTS Test Guideline No.

835.SUPP, Commission Regulation (EU) no 283/2013

Dose Levels 10.7 and 53.7 µg ai/ L

Analytical measurements HPLC-MS/MS

Study Summary

The route and degradation of [pyrazole-carboxamide-14C]BCS-CL73507

were investigated at two test concentrations in surface water under

aerobic conditions in the dark in the laboratory at 20±.2°C for 65 days at

maximum.

The natural surface water is from a reservoir for the preparation of

drinking water in Germany (Weihltalsperre, North -Rhine-Westphalia).

The pH of the water is 8.0, oxygen saturation 84 %, total and dissolved

organic carbon <2.0 mg/. The study application rates were 10.7 (low) and

53.7 (high) µg ai/L surface water.

The test was performed in test systems consisting of Erlenmeyer flasks

with baffles each containing 100 ml of the sampled surface water and

equipped with traps (permeable for oxygen) for the collection of carbon

dioxide and volatile organic compounds. The surface water in the test

systems was kept in motion during the entire study period.

Duplicate samples of each test concentration were processed and

analysed 0, 0.08, 0.16, 0.25, 1, 3, 7, 14, 21, 30, 45 and 63 DAT. Sterile

samples of both concentrations were processed and analysed at DAT-

65. The amounts of test item and degradation products in surface water

were determined by Liquid Scintillation Counting (LSC) and by TLC/

radiodetection analysis. The amount of volatiles was determined by LSC.

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Test item and degradation products were identified by HPLC-MS(/MS)

including accurate mass determination and/or by co-chromatography

with reference items.

Mean material balances were 104.5% AR for low concentration test

systems (range from 100.8 to 107.1% AR) and 102.7% AR for high

concentration test systems (range from 99.9 to 104.4% AR).

The maximum amounts of carbon dioxide were ≤ 1.4% AR at all

sampling intervals for both concentrations. The amounts of carbon

dioxide formed in sterile samples after 65 days were 0.3% AR for both

concentrations.

Formation of VOC was insignificant as demonstrated by values of ≤ 2.3%

AR at all sampling intervals for both concentrations in degradation

samples as well as in sterile samples.

The residues in surface water ranged between 100.6 and 107.1% AR in

low concentration test systems and between 99.9 and 104.3% AR in high

concentration test systems for all sampling intervals. In sterile samples,

residues in surface water amounted to 105.5% AR in low concentration

test systems and 103.4% AR in high concentration test systems.

The amount of BCS-CL73507 in surface water decreased from DAT-0 to

DAT-63 from 97.2% AR to < LOD in low concentration test systems and

from 93.5 to 3.7% AR in high concentration test systems. In sterile

samples (DAT-65), the amount of BCS-CL73507 in surface water was

3.6% AR in low concentration test systems and 3.5% AR in high

concentration test systems.

One degradation product was identified with the following maximum

occurrences: BCSCL73507- N-methyl-quinazolinone with 104.2% AR at

DAT-45 in low concentration samples and 100.5% AR at DAT-45 in high

concentration samples.

The total unidentified residues amounted to a maximum of 5.7% AR and

no single component exceeded 4.3% AR at any sampling interval for

both concentrations.

In sterile samples, the amount of BCS-CL73507-N-methyl-quinazolinone

in the surface water at DAT-65 was 96.8% AR for low concentration

samples and 94.6% AR for high concentration samples.

The experimental data could be best described by a FOMC kinetic

model. The DT50 values for BCS-CL73507 in the tested surface water

under aerobic conditions were 0.9 days for both concentrations.

Formation of carbon dioxide was insignificant during the test, indicating

that mineralization plays only a minor role in the fate of BCS-CL73507 in

surface water under the conditions of the test.

Conclusion DT50 = 0.9 days

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Anaerobic conditions

Table 135: Anaerobic aquatic degradation

Study type Water/ sediment study

Flag Key study


Endpoint DT50

Value 218, 104 days, total system

Reference

Gabbert D., Arthur E. 2016 [Phenyl-carbamoyl-14C] BCS-CL73507: Anaerobic

aquatic metabolism in two water/sediment systems. Report no MEFVP107, M-

546847-01-2

Sur R., Mikolasch B. Tetraniliprole (BCS-CL73507) and metabolite: kinetic

evaluation of anaerobic aquatic metabolism in water-sediment systems. Report no

EnSa -16-0931, MEFVP126, M-574034-01-1

Klimisch Score 1

Amendments/Deviati

ons None

GLP yes

Test Guideline/s

OECD Test Guideline No 308, US EPA OPPTS Test Guideline No. 835.4300/

835.4400, Commission Regulation (EU) no 283/2013/ draft SANCO

11802/2010/rev 7

Dose Levels 100 µg ai/ L

Analytical


Study Summary

The route and degradation of [Phenyl-carbamoyl--14C]BCS-CL73507 were

investigated in two water/sediment systems under anaerobic conditions in the

dark in the laboratory for 104 days at 20 ±2 ˚C.

The characteristics of the systems are stated below.

parameter Location USA

Wilson (NC) Hughson (CA)

Soil type (USDA) loam Loamy sand

Sediment pH

(0.01 M CaCl2)

4.6 7.7

Water pH

6.9 9.0

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% OC sediment 1.8 0.33

CEC (meq/100g) 6.5 5.0

The study application rate was 17.6 µg ai/ test system, corresponding to 100 µg

ai/ L. This rate is based on a 5-fold single field rate of BCS-CL 73507 of 200 g /ha.

Duplicate test systems were processed and analysed 0, 6,12, 20, 40, 60, 82 and

104 DAT.

Overall mean material balance was 99.8% of %AR for water/sediment system NC

and 98.2%AR for water/sediment system CA.

Volatile compounds (carbon dioxide and volatile organic compounds) remained

low throughout the study at ≤ 0.4%AR for water/sediment system NC and ≤

0.1%AR for water/sediment system CA.

Residues in water decreased from 91.0%AR at DAT-0 to 12.1%AR at DAT-104 in

water/sediment system NC and from 90.7%AR at DAT-0 to 27.3%AR at DAT-104

in water/sediment system CA.

Extractable residues in sediment increased from 5.2%AR at DAT-0 to 78.1%AR at

DAT-104 in water/sediment system NC and from 6.3%AR at DAT-0 to 61.6% at

DAT-82 and decreased to 61.0%AR at DAT-104 in water/sediment system CA.

NER increased from below the detection limit at DAT-0 to 10.4%AR at DAT-82

and slightly decreased to 9.4%AR at DAT-104 in water/sediment system NC. In

water/sediment system CA NER increased from below the detection limit at DAT-

0 to 4.9%AR at DAT-104.

BCS-CL73507 dissipated from the water due to degradation and translocation into

the sediment. The amount of BCS-CL73507 in the water decreased from DAT-0

to DAT-104 from 91.0 to 12.1%AR in water/sediment system NC and from 87.5 to

24.4%AR in water/sediment system CA.

The amount of BCS-CL73507 in the sediment extracts increased in

water/sediment system NC from DAT-0 to DAT-60 from 5.0 to 67.0%AR and

decreased then to 58.6%AR at DAT-104. In water/sediment system CA the

amount of BCS-CL73507 in the sediment extracts increased from DAT-0 to DAT-

12 from 5.9 to 30.0%AR and decreased then to 19.9%AR at DAT-104.

The amount of BCS-CL73507 in the total system decreased from DAT-0 to DAT-

104 from 96.0 to 70.7%AR in water/sediment system NC and from 93.3 to

44.3%AR in water/sediment system CA.

One major degradation product, N-methyl-quinazolinone, was identified during the

study with the following maximum amounts: max. water: 6.1%AR at DAT-20; max.

sediment: 41.1%AR at DAT- 104; max. entire system: 44.0%AR at DAT-104).

The experimental data could be well described by a DFOP kinetic model. The

DT50 values for the dissipation of BCS-CL73507 from the water were 16.0 and

24.1 days in water/sediment system NC and CA, respectively. The DT50 values

for the degradation of BCSCL73507 in the total water/sediment system were 218

and 104 days in days in water/sediment system NC and CA, respectively.

It is concluded that BCS-CL73507 will be degraded slowly in an anaerobic aquatic

water/sediment environment.

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Addition

In a separate report, a kinetic evaluation of the degradation of tetraniliprole and its

metabolites was performed according to the recommendations of FOCUS

(FOCUS 2006).

The DT50 total system was determined to be 218 and 92.8 days for NC and CA

respectively.

[Report EnSa -16-0931, M-574034-01-1]

Note: the FOCUS model is not applicable for NZ circumstances and EPA NZ does

not use this model.

The EPA will use the study results for the risk assessment as a worst-case

scenario.

Conclusion DT50 = 218 and 104 days, total system

Biodegradability

Table 136: Biodegradation

Study type Biodegradation, 28 days

Flag Key study


Endpoint Degradability

Value Not readily biodegradable

Reference Neuhahn A., 2016, Biodegradation of BCS-CL73507 tetraniliprole. Report no

2016/0048/01, M-571269-01-1

Klimisch Score 1

Amendments/Deviatio

ns None

GLP yes

Test Guideline/s OECD Test Guideline No 301 F

EU method C.4-D

Dose Levels 100 mg ai/ L (50-100 mg Theoretical Oxygen Demand (ThOD) or COD/Litre)

Study Summary

A study was performed to assess the ready biodegradability of BCS-CL73507 -

tetraniliprole.

A suspension of BCS-CL73507 – tetraniliprole of 100 mg/L in a mineral medium,

equalling to 50-100 mg ThOD or COD/Litre as the nominal sole source of

organic carbon, was stirred in a closed flask and inoculated at a constant

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temperature (22 ± 1 °C) for up to 28 days under aerobic conditions in the dark.

Test organisms was a mixed population of aquatic microorganisms (activated

sludge) from a wastewater plant treating predominantly domestic sewage.

During the test, degradation was followed by continuous automated BOD

determinations.

BCS-CL73507 - tetraniliprole showed:

0 % degradation after 7 days




Therefore, BCS-CL73507 - tetraniliprole is considered to be “Not Readily

Biodegradable“.

The reference compound sodium benzoate showed 85 % degradation after 14

days.

The toxicity control showed 54% degradation after 14 days indicating that the

substance is not toxic to the microorganisms.

All validity criteria were met.

Conclusion BCS-Cl73507 is not readily biodegradable, 1% after 28 days

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Degradation in air

Table 137: Degradation in air

Study type Degradation in air, calculation

Flag Key study


Endpoint DT50

Value 0.404 days

Reference Beckmann M. 2016 BCS-CL73507: Calculation of the chemical half-life in the

troposphere. Report no EnSa-15-1014, M-544693-01-2

Klimisch Score 1


GLP yes

Test Guideline/s Commission Regulation (EU) no 283/2013,

US EPA OCSPP Test Guideline No. 830.SUPP

Analytical

measurements NA

Study Summary

The half-life in air of BCS-CL73507 was estimated according to the structure-

activity relationship (SAR) methods developed by Atkinson et al1.

The half-life in air was estimated with 0.404 days (long-term scenario)

assuming the typical OH radical concentration averaged over 24 hours (0.5 x

106 radicals/cm³) and 0.270 days (long-term scenario) assuming the typical

OH radical concentration averaged over 12 hours (1.5 x 106 radicals/cm³).

It is concluded that BCS-CL73507 will be rapidly degraded in air, thereby

excluding a potential for long-range transport in the atmosphere.

Conclusion DT50 = 0.404 days

1 Atkinson et al: Kinetics and mechanism of the gas-phase: Reactions of the hydroxyl radical with organic compounds under atmospheric conditions. Chem. Rev. 85, 69-201 (1985). Estimations of OH radical rate constants from H-atom abstraction from C-H and O-H bonds over the temperature range 250-1000 K. Intern. J. Chem. Kinet. 18: 555-568 (1986). A structure-activity relationship for the estimation of rate constants for the gas-phase reactions of OH radicals with organic compounds. Intern. J. Chem. Kinet. 19: 799-828 (1987). Estimation of gas-phase hydroxyl radical rate constants for organic chemicals. Environ. Toxicol. Chem. 7: 435-442 (1988). Kinetics and mechanisms of the gas-phase reactions of the hydroxyl radical with organic compounds. J. Phys. Chem. Ref. Data Monograph No. 1. NY: Amer. Inst. Physics & Amer. Chem. Soc. (1989). Kinetics of the gas-phase reactions of a series of organosilicon compounds with OH and NO3 radicals and O3 at 297 ± 2K. Environ. Sci. Technol. 25: 863-6 (1991). Biermann, H.W., MacLeod, H., Atkinson, R., Winer, A.M., and Pitts, Jr. J.N.: Kinetics of the gas-phase reactions of the hydroxyl radical with naphthalene, phenanthrene, and anthracene. Environ. Sci. Technol. 19: 244-248 (1985). Kwok, E.S.C., Atkinson, R. and Arey, J.: Gas-phase atmospheric chemistry of selected. thiocarbamates. Environ. Sci. Technol. 26: 1798-1807 (1992).

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Kwok, E.S.C. and Atkinson, R.: Estimation of Hydroxyl Radical Reaction Rate Constants for Gas-Phase Organic Compounds Using a Structure-Reactivity Relationship: An Update. Atmospheric Environment (29: 1685-95) [from Final Report to CMA Contract No. ARC-8.0-OR, Statewide Air Pollution Research Center, Univ. of CA, Riverside, CA 92521] (1995).

Kwok, E.S.C., S.M. Aschmann and Atkinson, R.: Rate constants for the gas-phase reactions of the OH radical with selected

carbamates and lactates. Environ. Sci. Technol. 30: 329-34 (1996).

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Residues

Table 138: Residues in cherry trees

Study type Residue study on cherry trees


Test Substance BCS-CL73507 SC 200 G

Exposure

3 foliar spray applications at 60 g/ha at 6-7 day interval before harvest.

Nectar and pollen from cherry flowers were collected during the following bloom

period (so at least 10 months after spraying) at five sampling events (within a

few days of each other) per treatment group.

Test species Cherry trees

Endpoints Quantification of residues in pollen and nectar

Reference

Boscksch S. 2016. Determination of Residues of F4260 (BCS-CL73507) in

Pollen and Nectar Collected from Cherry

Eurofins Agroscience Services EcoChem GmbH / Eurofins Agroscience Services

Ecotox GmbH, Eutinger Straße 24, 75223 Niefern-Öschelbronn, Germany

Klimisch Score 1


GLP Yes

Test Guideline/s US EPA OCSPP 850.SUPP

No/Group 3 trial locations in Michigan

3 replicates per location

Dose Levels 3 applications at 59.8 g ai/ha in 100 gal/acre (935L/ha) at 6-7 day intervals

before fruit harvest

Analytical


Study Summary

This study was designed to determine residues of BCS-CL73507 in hand

collected nectar and pollen from cherry trees after three subsequent applications

with BCS-CL73507 SC 200 G under field conditions in the USA. Trees were

sprayed 6-7 days before fruit harvest and pollen was collected during the next

flowering season.

BCS-CL73507 applied three times with a spray interval of 6-7 days at a rate of

59.8 g ai./ha during post-bloom of cherry trees resulted in residues in pollen that

ranged from <LOD (0.0003 mg/kg) – 10.8 ppb (10.8 µg/kg).

No residues of BCS- CL73507 were detected above the LOQ (0.0001 mg/kg) in

any treated nectar samples.

No residues of BCS-CQ63359 were detected above the LOQ in any treated

pollen or nectar samples.

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Conclusion

No residue of tetraniliprole was detected in nectar.

No residue of the metabolite was detected in nectar or pollen.

The maximum concentration of residue in pollen 10 months after three foliar

applications was 10.8 µg/kg

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Table 139: Residues in Phacelia

Study type Residue study in Phacelia tanacetifolia



Exposure

1 foliar spray applications at the onset of flowering, 17 days before bees are

exposed.

Nectar and pollen from returning foragers and pollen and wax from combs

were collected during the exposure period (8 days)

Test species Phacelia tanacetifolia

Endpoints Quantification of residues in pollen, nectar and wax

Reference

Kanz C. 2016. Determination of Residues of BCS-CL73507 after application of

BCS-CL73507 SC 200 G just before flowering in a semi-field residue study

with honey bees (Apis mellifera L.) in Phacelia tanacetifolia in 2013.

Eurofins Agroscience Services EcoChem GmbH / Eurofins Agroscience

Services Ecotox GmbH, Eutinger Straße 24, 75223 Niefern-Öschelbronn,

Germany

Klimisch Score 1


GLP Yes

Test Guideline/s Guideline 1607/VI/97 (rev. 2) to Directive 91/414/EEC and Regulations (EU)

283/2013 and 284/2013 implementing Regulation (EC) 1107/2009

No/Group

1 trial location in Niefern-Öschelbronn, federal state of Baden-Württemberg,

Southern Germany

1 replicate for control, 3 replicates for T1 and T2

Dose Levels 1 application at 60 g ai/ha in 300L water/ha before the onset of flowering

(BBCH 58-60)

Analytical


Study Summary

The aim of the study was to determine residues of BCS-CL73507 in Phacelia

nectar, Phacelia pollen and honey bee wax after spray applications of BCS-

CL73507 SC 200 G.

Honeybee wax was sampled from combs after exposure. Phacelia nectar and

Phacelia pollen were prepared/sampled from both, forager bees and combs

after exposure of Apis mellifera L. to flowering Phacelia tanacetifolia, which

was treated once before flowering with BCS-CL73507 SC 200 G at a target

rate of 60 g ai/ha respectively. The study was conducted under confined semi-

field conditions.

This study included three treatment groups: T1 (BCS-CL73507 SC 200 G; for

sampling of forager bees), T2 (BCS-CL73507 SC 200 G; for sampling of

nectar, pollen and bee wax from combs) and an untreated control C. In the test

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substance treatment groups, the crop was sprayed 16 days before setup of the

hives in the tunnel tents, just before the onset of flowering at BBCH 58-60.

Bees were allowed to forage on the treated crop for 8 days.

Samplings of forager bees (in T1 and C), Phacelia nectar, pollen and wax from

combs (in T2) inside the tunnel tents started at 0DAE. Thereafter, forager bee

samplings inside the tunnels were performed daily in T1 up to 8DAE (except on

2DAE) and three times in C (3DAE, 4DAE, 8DAE). Phacelia nectar and pollen

from combs in T2 were sampled once per day from 0DAE to 8DAE inside the

tunnels and on four occasions at the monitoring site (10DAE, 16DAE, 22DAE

and 28DAE). Wax from combs (in T2) was sampled at 0DAE, 2DAE, 4DAE

and 8DAE during the exposure phase and on four occasions at the monitoring

site (10DAE, 16DAE, 22DAE and 28DAE).

Pollen samples (sampled from combs or prepared from forager bees), nectar

samples (sampled from combs or prepared from forager bees) and wax

samples from combs were analysed for residues of BCS-CL73507.

No residues of BCS-CL73507 above the respective LOD (0.3 μg/kg) were

found in any of the untreated samples taken from control (nectar and pollen

prepared from forager bees).

No residues of BCS-CL73507 above the respective LOD were found in any of

the wax from combs samples or in the nectar from combs samples taken from

the treated test substance group T2.

No residues of BCS-CL73507 above the respective LOD were found in the

nectar samples prepared from forager bees taken from the treated test

substance group T1, except for the sample taken on 7DAA (T1a), where

residues of BCS-CL73507 with 3.2 μg/kg were determined.

Residues of BCS-CL73507 were determined between < LOD and 4.3 μg/kg in

the pollen samples prepared from forager bees (T1) and between <LOD and

4.8 µg/kg in pollen samples from combs (T2), respectively. Residues in pollen

from combs were detected from 1DAE to 10DAE, with concentrations ranging

from1.9 to 4.8 μg/kg, residues were below the LOD at the next sampling point,

16DAE, after the bees have been removed from the tunnels. Residues in

pollen from foragers were detected from 1DAE to 8DAE (no sampling after),

with concentrations ranging from <LOD to 4.3 μg/kg.

Additional Comments

The rate of decline of residue in pollen is unknown since sampling stopped

after 8 days and the substance was still measured in pollen at concentrations

similar to 1DAE.

Conclusion

No residue of tetraniliprole was detected in wax.

The maximum concentration of residue in nectar was 3.2 µg/kg.

The maximum concentration of residue in pollen collected from was 4.8 µg/kg.

The maximum concentration of residue in pollen from foragers was 4.3 µg/kg.

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Table 140: Residues in apple blossoms

Study type Residue study in apple blossoms



Exposure

3 foliar spray applications after flowering when fruits were present, at 6-7 day

intervals.

Nectar and pollen from apple flowers the next spring (207 to 230 days later)

Species Apple trees

Endpoints Quantification of residues in pollen and nectar

Reference

Fischer DR. and Jerkins E. 2016. Residues of BCS-CL73507 in bee relevant

matrices collected from pome following three foliar applications of BCS-CL73507

SC 200.

Bayer CropScience, 2 T. W. Alexander Drive, Research Triangle Park, NC

27709

Klimisch Score 1

Amendments/Deviations none

GLP Yes

Test Guideline/s US EPA OCSPP 850.SUPP

No/Group 3 trial locations in New York, Illinois and Oregon

1 replicate plot for control, 1 replicate plot for treatment

Dose Levels 3 applications at 60 g ai/ha in 375-452L water/ha

Analytical

measurements LC-MS/MS

Study Summary

The aim of the study was to determine residues of BCS-CL73507 in apple pollen

and nectar following 3 foliar applications (airblast) of BCS-CL73507 SC 200 G at

60 g ai/ha in the previous growing season (21-7 days before harvesting at BBCH

78-87). Nectar and pollen were collected at BBCH 64-65 which was 207-230

days after the last application.

After their collection, apple flowers were hand-processed in a clean laboratory

setting near the field site to obtain the bee-relevant matrices of apple nectar and

pollen for analysis. The processed flowers were discarded.

Residues of BCS-CL73507 were determined between 0.2 and 0.9 μg/kg in the

pollen samples.

No residue was detected in nectar (<LOD).

No residue of the metabolite was detected in pollen or nectar (<LOD).

Conclusion No residue of tetraniliprole was detected in nectar. No residue of the metabolite

was detected in nectar or pollen.

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The maximum concentration of residue in pollen collected from blossoms more

than 6 months after 3 foliar applications was 0.9 µg/kg.

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Ecotoxicity

Several studies on the toxicity of tetraniliprole/Vayego on environmental receptors have been

reviewed. These studies are used to describe the key impacts of tetraniliprole/Vayego on the

environmental compartment. The data from the studies have been used for classifying the active

ingredient and in relevant areas of the risk assessment. Summary of these studies is provided in

Table 141 to Table 255.

Tetraniliprole

Aquatic environment [9.1]

Fish - acute toxicity

Table 141: Acute toxicity – fish – study 1

Study type Limit test, acute toxicity fish

Flag Key study

Test Substance BCS-CL73507 technical

Exposure 96 h, static conditions

Test species Rainbow trout, Oncorhynchus mykiss

Endpoint LC50

Value >11.2 mg test item (10.0 mg ai/L)

Reference

Kuhl K. (2014), BCS-CL73507 (tech) Acute toxicity to fish (Oncorhynchus

mykiss) under static conditions (limit test), report no EBFVP029, M-486042-

01-1,

Klimisch Score 1


GLP yes

Test Guideline/s

EPA-FIFRA § 72-1/SEP-EPA-540/9-85-006 (1982/1985), OCSPP 850.1075

(Public Draft, 1996) Council Regulation (EC) No 440/2008, C.1 (2008),

OECD No. 203 (rev.1992) JMAFF, 12 Nousan No. 8147 (2000)

Dose Levels 11.2 mg test item /L = 10 mg ai/L, (analytically confirmed nominal)


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Study Summary

The aim of the study was to determine the acute effects of tetraniliprole on

rainbow trout (Oncorhynchus mykiss). The limit test at 11.2 mg test item/L

(corresponding to 10.0 mg ai/L) was performed to demonstrate that no lethal

effects to fish occurred at this test item concentration (functional limit of

solubility).

Rainbow trouts were used for the test with a mean body length of 4.1 cm, a

mean body weight of 0.8 g and a biomass loading 0.60 g fish/L test medium.

Thirty fish were exposed in a limit test for 96 hours under static test

conditions to a nominal concentration of 11.2 (10.0) mg test item (ai) / L

against a water control and a solvent control (DMF, 0.1 ml/L) with further 30

fish each. During the test, fish were examined after four hours and then daily

for mortalities and signs of poisoning. Within the study, the pH-value, the

oxygen saturation level and the temperature were measured with commercial

measurement devices, daily. The analytical determination of tetraniliprole (in

water by HPLC – MS/MS) revealed a mean recovery of 107% - 110% of

nominal over the whole testing period of 96 hours at the limit test

concentration of 11.2 mg test item/L (corresponding to 10.0 mg ai/L). The

results of this study are presented based on nominal concentrations. Survival

(mortality) and sublethal behavioural effects (wet weight, biomass loading,

length) were used to determine the endpoints.

Test conditions met all validity criteria. There was less than 5% mortality

within the 48 hour settling-in period and ≤ 10% mortality in the controls.

Dissolved oxygen saturation was greater or equal to 60% throughout the test

and pH variation was ≤ 1.0 units.

Following 96 hours of exposure, there were no mortalities or sublethal effects

observed at the test concentration or the controls. The limit test showed that

at 11.2 mg test item/L tetraniliprole did not cause any mortality to rainbow

trout.

Therefore, the 96h-LC50 was > 11.2 (10.0) mg test item (ai)/L (practical limit

of solubility). None of the 30 fish at this test level showed any symptom after

96 hours. The 96h-NOEC was 11.2 (10.0) mg test item (ai)/L based on

nominal concentration.

Conclusion LC50 >11.2 mg test item /L (10 mg ai/L)

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Flag Key study



Test species Fathead minnow Pimephales promelas

Endpoint LC50

Value >11.2 mg test item (10.0 mg ai/L)

Reference

Kuhl K. (2014), Acute toxicity of BCS-CL73507 (tech) to fish (Pimephales

promelas) under static conditions (limit test), report no EBFVN060, M-

489576-01-1

Klimisch Score 1


GLP yes

Test Guideline/s

EPA-FIFRA § 72-1/SEP-EPA-540/9-85-006 (1982/1985), OCSPP 850.1075

(Public Draft, 1996) Council Regulation (EC) No 440/2008, C.1 (2008),

OECD No. 203 (rev.1992) JMAFF, 12 Nousan No. 8147 (2000)

Dose Levels 11.2 mg test item /L = 10 mg ai/L (analytically confirmed nominal)


Study Summary

The aim of the study was to determine the acute effects of tetraniliprole to

Fathead minnow (Pimephales promelas). Fathead minnows were used for

the test with a mean body length of 3.5 cm, a mean body weight of 0.4 g and

a biomass loading 0.30 g fish/L test medium. Thirty fish were exposed in a

limit test for 96 hours under static test conditions to a nominal concentration

of 11.2 (10.0) mg test item (ai) / L against a water control and a solvent

control (DMF, 0.1 ml/L) with further 30 fish each. During the test, fish were

examined after four hours and then daily for mortalities and signs of

poisoning. Within the study, the pH-value, the oxygen saturation level and the

temperature were measured with commercial measurement devices, daily.

The analytical determination of tetraniliprole (in water by HPLC – MS/MS)

revealed a mean recovery of 107% - 110% of nominal over the whole testing

period of 96 hours at the limit test concentration of 11.2 mg test item/L

(corresponding to 10.0 mg ai/L). The results of this study are presented

based on nominal concentrations. Survival (mortality) and sublethal

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behavioural effects (wet weight, biomass loading, length) were used to

determine the endpoints.

Test conditions met all validity criteria. There was less than 5% mortality

within the 48 hour settling-in period and ≤ 10% mortality in the controls.


and pH variation was ≤ 1.0 units.


observed at the test concentration or the controls. The limit test showed that

at 11.2 mg test item/L tetraniliprole did not cause any mortality to fathead

minnow.

Therefore, the 96h-LC50 was > 11.2 (10.0) mg test item (ai)/L (practical limit

of solubility). The 96h-NOEC was 11.2 (10.0) mg test item (ai)/L based on

nominal concentration.

Conclusion LC50 >11.2 mg test item /L = 10 mg ai/L

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Study type Full test, acute toxicity fish

Flag Key study


Exposure 96 h, static renewal conditions

Test species Sheepshead minnow Cyprinodon variegatus

Endpoint LC50

Value >9.09 mg ai/L (mean measured concentration)

Reference

Matlock D., Moore S. (2014), Acute toxicity of BCS-CL73507 (tech) to fish

sheepshead minnow (Cyprinodon variegatus) under static renewal

conditions, report no EBFVP030, M-508088-01-1

Klimisch Score 1


GLP yes

Test Guideline/s EU Directive 91/414/EEC Regulation (EC) No. 1107/2009


Dose Levels 5.00 and 10.0 mg ai/L nominal

4.52 and 9.09 mg ai/ L mean measured

Analytical measurements LC-MS/MS

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Study Summary


sheepshead minnow (Cyprinodon variegatus). Cyprinodon variegatus (30 fish

per treatment level) were exposed in a static-renewal system over a period of

96 hours to nominal (mean measured) concentrations of 5.00 (4.52) and 10.0

(9.09) mg ai/L, respectively. Analytical verification was daily in old and new

test solutions. In addition, a water control and solvent control (DMF) were

tested. While precipitants were noted in the 10 mg ai/L test level, all samples

were centrifuged prior to analysis. Measured recoveries ranged from 71 to

119% of nominal concentrations. Therefore, the results are based on mean

measured concentrations. Precipitates were observed in the test level with

10.0 mg ai/L in aged test solutions, no precipitates were observed in the test

level with 5.0 mg ai/L.

Mortality and sub-lethal behavioural effects were used to determine the

endpoints. Based on analytical findings the biological endpoints are reported

as mean measured figures.

Test conditions met all validity criteria. There was no mortality within the 48

hour settling-in period in the controls. Dissolved oxygen saturation was

greater or equal to 60% throughout the test.


observed at any test concentration or the controls. The 96-hour-LC50 was >

10.0 mg ai/L, the 96-hour-NOEC was determined to be 10.0 mg ai/L, the

highest concentration tested.

Conclusion LC50 >9.09 mg ai/L

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Table 144: Acute toxicity – Fish – study 4


Flag Key study



Test species Common carp, Cyprinus carpio

Endpoint LC50

Value >8.5 mg ai/L

Reference

Matlock D., Fannin-Hughes I.J. (2015), Acute toxicity of BCS-CL73507

technical to the common carp (Cyprinus carpio) under static conditions,

report no EBFVN100, M-540496-01-1

Klimisch Score 1


GLP yes

Test Guideline/s EU Directive 91/414/EEC Regulation (EC) No. 1107/2009


Dose Levels 10.0 mg ai/L nominal

8.5 mg ai/L mean measured


Study Summary


common carp (Cyprinus carpio). Common carp (10 fish per treatment level)

were exposed in a static system over a period of 96 hours to the nominal

concentrations of 10.0 mg ai/L (considered the maximum soluble

concentration), respectively. In addition, a water control and solvent control

were tested. Measured recoveries ranged from 79 to 91% of nominal

concentrations. Mean measured concentration is 85% of nominal and thus

8.5 mg ai/L.



as mean measured concentration.

Test conditions met all validity criteria. There was no mortality within the 48

hour settling-in period in the controls. Dissolved oxygen saturation was

greater or equal to 60% throughout the test (87 to 93%).

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observed. Therefore, 96-hour-LC50 is >8.5 mg ai/L, the 96-hour-NOEC is 8.5

mg ai/L, the highest concentration tested.


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Fish - chronic toxicity

Table 145: Chronic toxicity – Fish – study 1

Study type Full test, ELS toxicity fish

Flag Key study


Exposure 33 days (28 days post-hatch), flow through conditions

Test species Fathead minnow Pimephales promelas

Endpoint NOEC (growth total length)

Value 2.5 mg ai/L

Reference Faber D (2016), Early life stage toxicity of BCS-CL73507 (tech) to fish

(Pimephales promelas), report no EBFVP031, M-565378-01-1

Klimisch Score 1

Amendments/Deviations None that impacted the validity of the study

GLP yes

Test Guideline/s EPA-FIFRA § 72-4a/SEP-EPA-560/6-82-002 (1982), ASTM E 1241-92 (1992),

OPPTS 850.1400 (1996), OECD No. 210 (adopted 2013)

Dose Levels 0.313, 0.625, 1.25, 2.50 and 5.00 mg ai/L nominal

0.339, 0.646, 1.33, 2.70 and 5.26 mg ai/L mean measured

Analytical


Study Summary


fathead minnow (Pimephales promelas). Early life stages of fathead minnow

(eggs, larvae) were exposed to five test concentrations, a control and a

solvent control (DMF, 0.1 ml/L) under flow-through conditions. The test

duration was 33 days (28 days post-hatch) and four replicates per treatment

group.

The definitive study was conducted at nominal test concentrations of 0.313,

0.625, 1.25, 2.50 and 5.00 mg ai/L. The mean measured concentrations of

tetraniliprole in the test solutions during the test were 0.339, 0.646, 1.33, 2.70

and 5.26 mg ai/L. The overall mean measured values correspond to

recoveries of 103 to 108% of nominal for all test levels (individual

measurements were also in the range of nominal). The results of this study

are based on nominal concentrations of tetraniliprole.

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During the larval phase observations on mortality were done daily and

abnormal behaviour and abnormal morphological appearance were recorded

at least on working days by visually inspecting each growth chamber. At test

termination total length and wet weight were determined

The test fulfilled the validity criteria of the underlying guideline, with the minor

exception of a short exceeding of the allowed temperature range. This

deviation did not influence the biological outcome of the study, as

demonstrated by the overall control data which met the criteria.

On post-hatch day 0 the mean hatching success (based on the number of

inserted eggs) ranged between 89 and 98 % in all dose levels. No significant

difference in any test level compared to the pooled control data was observed.

100% of all fertilised and living embryos in the pooled controls had hatched on

day 5 post-hatching.

Mean larval survival at test termination ranged from 98 to 100 % in all test

levels including controls.

Data analysis showed a statistically significant decrease in total length in

comparison to the pooled control data at the highest test concentration of 5.00

mg a.s./L. No statistically significances were observed for wet and dry weight

in comparison to the pooled control data.

The 33-day exposure of Pimephales promelas to tetraniliprole resulted in an

overall NOEC of 2.50 mg ai/L (based on total length) and a Lowest

Observable Effect Concentration (LOEC) of 5.0 mg ai/L (based on total

length). The resulting Maximum Acceptable Toxicant Concentration (MATC) is

3.54 mg ai/L.

Comments The deviation in temperature did not affect the results of the study as the

validity criteria were met.

Conclusion NOEC = 2.5 mg ai/L (length)

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Table 146: Chronic toxicity – Fish – study 2

Study type Full test, ELS toxicity fish

Flag Key study


Exposure 35 days (28 days post-hatch), flow through conditions

Test species Sheepshead minnow Cyprinodon variegatus

Endpoint NOEC (growth total length)

Value > 4.21 mg ai/L

Reference

Matlock D., Moore S. (2016), Early life stage toxicity of BCS-CL73507

technical to the sheepshead minnow (Cyprinodon variegatus), report no

EBFVP014, M-547597-01-1

Klimisch Score 1


GLP yes

Test Guideline/s EU directive 91/414/EEC, Regulation (EC) no 1107/2009, OPPTS

850.1400


0.306, 0.531, 1.13, 2.41 and 4.21 mg ai/L measured

Analytical measurements LC-MS/MS

Study Summary

The aim of the study was to determine the acute effects of tetraniliprole

to sheepshead minnow (Cyprinodon variegatus). Eggs and fry of

sheepshead minnow were exposed to five test concentrations, a water

control and a solvent control (DMF, 0.1 ml/L) under flow-through

conditions. The test duration was 35 days (28 days post-hatch) and four

replicates per treatment group.

The study was conducted at nominal test concentrations of 0.313, 0.625,

1.25, 2.50 and 5.00 mg ai/L (maximum soluble concentration in the test

system). The mean measured concentrations of tetraniliprole in the test

solutions during the test were 0.306, 0.531, 1.13, 2.41 and 4.21 mg ai/L.

The overall mean measured values correspond to recoveries of 84 to

98% of nominal for all test levels. The results of this study are based on

mean measured concentrations of tetraniliprole.

Behavioural and morphological observations were recorded daily. At test

termination total length and dry weight were determined

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The test fulfilled the validity criteria. The average hatchability in the

controls was >75%. The post hatch average survival in the control was

>80%. The oxygen saturation was above 60%.

Mean

measured

conc mg

ai/L

Mean %

hatch

day 7

% alevin

survival

Day 7

% fry

survival

Day 35

Mean

total

length

(mm)day

35

Mean dry

weight

(mg) day

35

Control 87.1 87.9 98.8 20.4 27.1

Solvent

control

83.6 85.0 98.8 20.9 29.1

0.306 83.6 85.7 92.5 20.8 29.1

0.531 86.4 86.4 97.5 20.8 29.6

1.13 85.0 85.7 95.0 20.9 30.3

2.41 82.1 82.1 93.8 20.8 30.6

4.21 82.9 82.9 91.3 20.7 29.9

No test substance-related abnormalities were recorded. No significant

differences between the treatments and the controls were determined.

The 35-day exposure of Cyprinodon variegatus to tetraniliprole resulted

in an overall NOEC of >4.21 mg ai/L and a LOEC of >4.21 mg ai/L.

Conclusion NOEC > 4.21 mg ai/L

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Fish - Bioconcentration

Table 147: Bioconcentration in fish – study 1

Study type Full study, bioconcentration

Flag Key study


Test species Lepomis macrochirus

Endpoint

BCF steady state, BCF lipid-normalised growth corrected kinetic, whole

fish

Value BCF ss 0.419 and 0.230

BCF KLG 0.452 and 0.255

Reference Kuhl K. (2016) [pyrazole-carboxamide-14C] BCS-CL73507- Aqueous

exposure bioconcentration fish test and biotransformation in fish

(Lepomis macrochirus) Report no EBFVN095, M-568718-01-1

Klimisch Score 1

Amendments/Deviations None that impacted the results of the study

GLP yes

Test Guideline/s OECD 305, OPPTS 850.1730


range 26.1 -35.3 µg/L and 260-387 µg/L measured

Analytical measurements HPLC, LSC

Study Summary

The objective of this study was to measure uptake, depuration and

metabolism of tetraniliprole (BCS-CL73507) by determining its uptake

rate constant (k1), depuration rate constant (k2) and the

BioConcentration Factor (BCF). Additionally, the biotransformation

(metabolism) in fish was investigated by the qualitative and quantitative

characterization of metabolites (≥ 10% of parent and/or ≥ 50 ppb).

The whole study was performed in a flow-through design with bluegill

sunfish (Lepomis macrochirus) in glass aquaria (4 aquaria in total).

Fish were exposed to concentrations of 0.03 and 0.3 mg tetraniliprole/L

in the bioconcentration part of the test (Aquarium B and C,

respectively) and 0.3 mg tetraniliprole/L in the biotransformation part of

the test (Aquarium D). Additionally, a solvent control was performed in

parallel (Aquarium A).

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The bioconcentration part of the test consisted of two phases: the

exposure (uptake) and post-exposure (depuration) phases. At start of

the uptake phase (day 0) 70 randomly selected fish were transferred

into Aquariums B and C (exposure to 0.03 and 0.3 mg tetraniliprole/L,

respectively) and into Aquarium A (solvent control). Afterwards, they

were transferred to pure test water without the test substance for the

depuration phase. The concentration of tetraniliprole in the fish was

followed through both phases of the test. The duration of the uptake

phase was 28 days, followed by the depuration phase of 14 days.

Water samples were collected during the exposure period of 28 days

for Aquarium C and 14 days for Aquarium D. All water samples taken

after day 28 were not further analysed due to low radioactivity. The

radioactive residues were extracted from water samples by Solid

Phase Extraction (SPE) with RP18. The residues were eluted with

acetonitrile and methanol/ tetrahydrofuran, concentrated and analysed

by HPLC with radiodetection. The radioactive concentrations in the

water ranged from 250.5 to 391.7 μg/L. The parent compound was the

only component in the water samples and was identified by comparison

with the HPLC chromatogram of the stock solution.

For the biotransformation part of the test, parent and the metabolites

were analysed for different tissues of the fish (edible and viscera part)

after 7 and 14 days of exposure. No depuration phase was needed for

this part of the study. The biotransformation part started on day 0 of the

bioconcentration test (begin of uptake phase), with assignment of 30

fish to Aquarium D. The test of biotransformation ended on day 14

when the last remaining fish were sampled. For this purpose, edible

parts and viscera of fish were sampled on day 7 and 14 and were

conventionally extracted with acetonitrile/water mixtures. No further

radioactive residues were extracted by exhaustive extraction methods

using microwave assistance and hydrochloric acid. The radioactivity in

the remaining solids after exhaustive extraction was below LOD. The

TRRs were low and amounted to 0.048 mg/kg (day 7) and 0.059 mg/kg

(day 14) in the edible parts and 0.117 mg/kg (day 7) and 0.124 mg/kg

(day 14) in the viscera. Due to the low radioactivity, the residues in the

conventional extracts of the fish samples were characterized as polar

or non-polar by partition against n-hexane, only. In the edible parts of

fish, the entire radioactivity remained in the aqueous phase. In viscera

of fish, the major amount of radioactivity remained in the aqueous

phase, representing 67.5% of the TRR for day 7 and 72.1% for day 14,

while 32.5% and 27.9% of the TRR were found in the organic phase

from viscera for day 7 and day 14, respectively. Due to the partition

behaviour of the residues in fish, it was concluded that the polar

radioactivity in the aqueous phases represents metabolites of

tetraniliprole. Non-polar radioactivity in the organic phases might be

assigned to parent compound or non-polar metabolites.

Tetraniliprole has no accumulation potential in fish. All calculated BCFs

were below 2. BCFs were calculated for the different fish tissues

(edible part, viscera part and whole fish) and the two different

concentrations. All BCFs based on whole fish evaluations are below 1.

The lipid normalized steady-state (BCFSSL) was 0.419 in the lower and

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0.230 in the higher concentration. The lipid-normalized growth-

corrected kinetic BCF (BCFKLG) was 0.452 in the lower and 0.255 in the

higher concentration.

The analysis of stock solutions of the test compound from all

aquariums showed that [pryrazolecarboxamide- 14C] BCS-CL73507

was stable in the stock solutions during the exposure phase. On the

basis of the results of this study, it was concluded that [pyrazole-

carboxamide-14C] BCSCL73507 was metabolized in fish. Due to the

low amount of radioactivity in fish, no metabolites were identified and

therefore no metabolic pathway was proposed.

The pH and body length and weight were slightly outside the

recommended range. The other validity criteria were met.

Comments The deviations of the guideline did not affect the results of the study.

Conclusion

BCF ss 0.419 and 0.230

BCF KLG 0.452 and 0.255


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Frog - acute toxicity

Table 148: Acute toxicity - Frogs

Study type Acute toxicity frog

Flag Key study


Exposure 48 h, Static conditions

Test species African clawed frog (Xenopus laevis)

Endpoint LC50

Value >8.6 mg ai/L

Reference

Banman C.S., Shephard D.W>, Moore S. (2014) Acute toxicity of

BCS-Cl73507 to the African clawed frog (Xenopus laevis) under

static renewal conditions, Report no EBFVP016, M-508262-01-1

Klimisch Score 1

Amendments/Deviations Not specified

GLP yes

Test Guideline/s

No formal English guideline exists for this test protocol.

Methodologies from US EPA, OCSPP Guideline 850.1075, US EPA-

FIFRA, 40 CFR, Part 158, Guideline No. 72-1, and OECD Guideline

203

Dose Levels 5.0 and 10.0 mg ai/L nominal,

4.28 and 8.6 mg ai/L mean measured

Analytical measurements LC/MS/MS

Study Summary

The aim of the study was to determine the effects of tetraniliprole

technical on survival of African clawed frog tadpoles (Xenopus

laevis). Tadpoles were exposed in a static renewal system over a

period of 48 hours to nominal (mean measured) concentrations of 5.0

(4.28) and 10.0 (8.60) mg ai/L, respectively. In addition, a water

control and solvent control (DMF) were tested. Three replicates with

10 tadpoles each were tested. Mortality and sublethal behavioural

effects were determined.

Based on analytical findings the biological endpoints are reported as

mean measured concentrations. The measured recoveries ranged

from 87 to 95% at the start of the test and from 75 to 86% at the end

of the test.

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Quality criteria for this study were met: mortality rate during

domestication period did not exceed 5%; mortality rate of the

reference groups did not exceed 10%; dissolved oxygen content in

the test solution was not less than 5.8 mg/L during the test; the test

solution maintained a constant pH value during the test.

One dead tadpole was observed at the highest dose rate. However,

no sub-lethal effects were observed in the other surviving tadpoles.

So it is considered not treatment-related.

The 48-hour-LC50 was > 8.60 mg ai/L, the highest level tested.

Comments none


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Crustacean – acute toxicity

Table 149: Acute toxicity – Daphnia – study 1

Study type Acute toxicity crustacean

Flag Key study


Exposure 48 h, static renewal

Test species Daphnia magna

Endpoint EC50

Value 247 μg ai/L (95% Cl: 226 – 271 μg ai/L)

Reference

Kuhl K., 2015 amendment 1 -Acute toxicity of BCS-CL73507 (tech) to the

water flea Daphnia magna in a static renewal laboratory system, Report no

EBFVP017, M-502273-02-1

Klimisch Score 1


GLP yes

Test Guideline/s

OECD guideline 202 (2004);

EC Council Regulation No 440/2008, Method C.2 (2008);

U.S. EPA Pesticide Assessment Guidelines, Subdivision E, § 72-2 (1982);

OPPTS Guideline 850.1010 public draft 1996 (modified);

JMAFF 12 Nousan No. 8147 (2000)

Dose Levels 47.9, 81.4, 138, 235 and 400 μg ai/L analytically confirmed nominal

Analytical measurements HPLC-MS/MS and HPLC-UV

Study Summary


(tech.) to Daphnia magna. Daphnia magna (<24-hour old neonates) were

exposed in a static renewal system over a period of 48 hours to nominal

concentrations of 47.9, 81.4, 138, 235 and 400 μg ai/L without feeding. In

addition, a water control and a solvent control (DMF, 0.1 ml/L) were tested.

There were six replicates of five daphnia each in the control, solvent control

and each of the treatment levels.

The content of tetraniliprole in exposure media was measured for verification

of the test item concentrations. The measured amounts of tetraniliprole in

the freshly prepared test solutions at the start of each renewal interval

revealed recoveries between 86% and 116% (mean: 108%) of nominal

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concentrations. The corresponding concentrations of the aged test solutions

at the end of each 24-hour exposure period ranged between 83% and 113%

(mean: 101%) of nominal. No contaminations of tetraniliprole were detected

in samples from untreated water control. As the measured concentrations

were within the recommended range of 80 – 120% of nominal, all reported

results are based on nominal concentrations of tetraniliprole.

Immobility was defined as the inability to swim within 15 seconds after gentle

agitation of the test vessel even if the organisms can still move their

antennae. Sublethal and behavioural effects were also assessed during the

course of the study.

The validity criterion of control mortality less than 10% is fulfilled. The validity

criterion of oxygen saturation above 60% (≥ 3 mg/L) is fulfilled.

No immobility or other effects on behaviour occurred in untreated control,

solvent control or treatment groups, less than or equal to 81.4 μg ai/L within

the 48 hours of exposure. At the concentration 235 μg ai/L almost 37%

immobility was observed and at the highest concentration 100%.

Only one sublethal observation in one test replicate of 138 μg ai/L was

made.

The 24-hour-EC50 was determined to be 300 μg ai/L (95% Cl: 270 – 334 μg

ai/L) and the 48-hour-EC50 was determined to be 247 μg ai/L (95% Cl: 226 –

271 μg ai/L).

Comments none

Conclusion EC50 = 247 μg ai/L (95% Cl: 226 – 271 μg ai/L) nominal

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Table 150: Acute toxicity – Daphnia – study 2


Flag Key study


Exposure 48 h, static


Endpoint EC50

Value 173.3 μg ai/L (95% Cl: 147.2 – 199.9 μg ai/L)

Reference

Kuhl K., 2016 amendment 1 -Acute toxicity of tetraniliprole tech. to the water flea

Daphnia magna in a static laboratory system, Final report, Report no EBFV0012,

M-566522-02-1

Klimisch Score 1


GLP yes

Test Guideline/s




OPPTS Guideline 850.1010 public draft 1996 (modified);

JMAFF 12 Nousan No. 8147 (2000)

Dose Levels 41.9, 71.2, 121, 206 and 350 μg ai/L analytically confirmed nominal

Analytical

measurements HPLC-MS/MS and HPLC-UV

Study Summary

The aim of the study was to determine the acute effects of tetraniliprole (tech.) to

Daphnia magna. Daphnia magna (<24-hour old neonates) were exposed in a

static system over a period of 48 hours to nominal concentrations of 41.9, 71.2,

121, 206 and 350 μg ai/L without feeding. In addition, a water control and a

solvent control (DMF, 0.1 ml/L) were tested. There were six replicates of five

daphnia each in the control, solvent control and each of the treatment levels.

The content of tetraniliprole in exposure media was measured for verification of

the test item concentrations. The measured amounts of tetraniliprole in the

freshly prepared test solutions at test initiation revealed recoveries between 89%

and 96% (mean: 92.8%) of nominal concentrations. The corresponding

concentrations of the aged test solutions at the end of the 48-hour exposure

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period ranged between 84% and 88% (mean: 86.4%) of nominal, demonstrating

stability in the test system. No contaminations of tetraniliprole were detected in

samples from untreated water control. As these measured concentrations

ranged well within the recommended range of 80 – 120% of nominal, all reported

results are based on nominal concentrations of tetraniliprole in the test solutions.


agitation of the test vessel even if the organisms can still move their antennae.

Sublethal and behavioural effects were also assessed during the course of the

study.


criterion of oxygen saturation above 60% (≥ 3 mg/L) is fulfilled.

No immobility or other effects on behaviour were observed in the untreated

control within 48 hours of exposure. In the solvent control, 1 daphnid was

immobile within 24 hours but there were no other effects on behaviour observed

in this group. At a test item concentration of 121 μg ai/L, 6.7% of daphnids (n =

2) were immobile after 24 hours of exposure. After 48 hours of exposure, 6.7%

of daphnids were immobile in the group with test item concentration of 41.9 μg

ai/L, immobility increased with increasing concentration resulting in 100% (n =

30) were immobile at the highest test item concentration of 350 μg ai/L. The 24h-

EC50 was 259.8 μg ai/L (95% CL: 225.8 – 298.3 μg ai/L); the 48h-EC50 was

173.3 μg ai/L (95% CL: 147.2 – 199.9 μg ai/L).

Comments none

Conclusion EC50 = 173.3 μg ai/L (95% Cl: 147.2 – 199.9 μg ai/L) nominal

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Crustacean – chronic toxicity

Table 151: Chronic toxicity – Daphnia – study 1

Study type Chronic toxicity crustacean

Flag Key study


Exposure 21 days, static renewal


Endpoint NOEC

Value 13.3 μg ai/L

Reference

Kuhl K., 2016 amendment 1 -effects of BCS-CL73507 tech. on the

development and reproductive output of the water flea Daphnia magna in a

static renewal laboratory test system, amendment no 1 to final report, Report

no EBFVP018, M-538451-02-1

Klimisch Score 1


GLP yes

Test Guideline/s




OPPTS Guideline 850.1300 public draft 1996;

Dose Levels 13.3, 24.0, 43.2, 77.8 and 140 μg ai/L analytically confirmed nominal

Analytical measurements HPLC-MS/MS and HPLC -UV

Study Summary

The aim of the study was to determine the effects of tetraniliprole (tech.) on

development, reproductive capacity and behaviour to Daphnia magna over

21 days under static renewal conditions. Daphnia magna (<24-hour old

neonates) were exposed in a static renewal system over a period of 21 days

to nominal concentrations of 13.3, 24.0, 43.2, 77.8 and 140 μg ai/L. In

addition, a water control and a solvent control (DMF, 0.1 ml/L) were tested.

There were ten replicates with one daphnid per replicate and separate

replicates with one daphnid per replicate for physical/ chemical water

measurements.

For verification of the actual test item concentrations during exposure, water-

samples from start and end of 3 representative exposure-intervals were

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analysed. The measured amounts of tetraniliprole in the freshly prepared test

solutions at the start of the chosen exposure intervals revealed recoveries

between 99% and 115% (mean: 109%) of the corresponding nominal

concentrations. The corresponding concentrations of the aged test solutions

at the end of the exposure intervals ranged between 83% and 105% (mean:

94%) of nominal. As the measured concentrations were within the

recommended range of 80 – 120% of nominal, all reported results are based

on nominal concentrations of tetraniliprole. No precipitants were observed in

any of the test solutions.

As endpoints, the NOEC/ LOEC was determined for the total living offspring

per parental animal, the parental age at first offspring emergence as well as

the rate of parental survivors and their body-length and dry body mass at the

end of the study.

No differences in parent body length and dry body mass were observed.

Immobility was 10% (13.3 μg ai/L), 20% (24 and 77.8 μg ai/L) and 30% (43.2

and 140 μg ai/L).

Total living offspring per parent (from first brood release until study

termination) was around 93% in the controls. At the lowest dose rate 90.7%,

78% at 24 μg ai/L, 59% at 43.2 μg ai/L, 3.2% at 77.8 μg ai/L and 0% at 140

μg ai/L.

The overall chronic NOEC for 21 days of static renewal exposure of

tetraniliprole to Daphnia magna, expressed as nominal test concentration, is

13.3 μg ai/L. This NOEC is based on total number of living offspring produced

per parent animal and on immobilisation of parent animals. The

corresponding LOEC is 24.0 μg ai/L.

Conclusion NOEC = 13.3 μg ai/ L

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Saltwater species – acute toxicity

Table 152: Acute toxicity - oyster

Study type Acute toxicity oyster

Flag Key study


Exposure 96 h, flow through conditions

Test species Eastern oyster, (Crassostrea virginica)

Endpoint EC50

Value 2.2 mg ai/L

Reference

Brougher D.S., Zhang L., Martin K.H., Krueger H. O. (2015) BCS-Cl73507: a

96-hour shell deposition test with the Eastern oyster (Crassostrea virginica)

Report no EBFVP039, M-507732-01-1

Klimisch Score 1


GLP yes

Test Guideline/s US EPA OCSPP 850.1025


0.31, 0.66, 1.3, 2.6 and 5.1 mg ai/L measured (100-104% of nominal)


Study Summary

The aim of the study was to determine the effects of tetraniliprole technical on

shell deposition of Eastern oyster.

Oysters (mean valve height of 32.9 ± 1.8 mm; range: 30.2 to 36.1 mm; 20 per

treatment level) were exposed in a flow-through system over a period of 96

hours to a geometric series of five nominal (mean measured) concentrations

of 0.31 (0.31), 0.65 (0.66), 1.3 (1.3), 2.5 (2.6) and 5.0 (5.1) mg ai/L. In

addition, a dilution water control and a solvent control (DMF, 0.1 ml/L) were

tested.

Test concentrations were measured in samples of test water collected from

each treatment and control group at the beginning, the approximate mid-point

and the end of the test. Measured concentrations of the samples ranged from

approximately 97 to 113% of nominal. When measured concentrations of the

samples collected during the test were averaged, the mean measured test

concentrations for this study were 0.31, 0.66, 1.3, 2.6 and 5.1 mg ai/L,

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representing 100, 102, 100, 104 and 102% of nominal concentrations,

respectively. The results of the study were based on the mean measured

concentrations.

Shell deposition, mortality and sublethal behavioural effects were made at

several time intervals and used to determine the endpoints. Percent inhibition

of shell growth in each treatment group was calculated relative to the pooled

control data. Based on analytical findings the biological endpoints are

reported as mean measured figures.


criterion of control shell growth > 2mm is fulfilled. The validity criterion of

oxygen saturation above 60% is fulfilled.

There were no mortalities or clinical signs of toxicity observed at any

concentration tested. Shell growth inhibition compared to the pooled control

ranged from -22% (0.31 mg ai/L) to 99% (5.1 mg ai/L). The difference in shell

deposition of the doses 2.6 and 5.1 mg ai/L is significant compared to the

pooled control.

The 96-hour-EC50 for shell deposition was 2.2 mg ai/L (CI 95% 1.9-2.4 mg

ai/L), the 96-hour-NOEC was 1.3 mg ai/L.

Conclusion EC50 =2.2 mg ai/L

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Table 153: Acute toxicity - Shrimp

Study type Acute toxicity mysid

Flag Key study


Exposure 96 h, flow through conditions

Test species Saltwater mysid, (Americamysis bahia)

Endpoint LC50

Value 7.6 mg ai/ L nominal

Reference

Brougher D.S., Zhang L., Martin K.H., Krueger H. O. (2014) BCS-CL73507: a

96-hour flow-through acute toxicity test with the saltwater mysid

(Americamysis bahia) Report no EBFVP036, M-503278-01-1

Klimisch Score 1


GLP yes





Study Summary

The aim of the study was to determine the effects of tetraniliprole on the

saltwater mysid during a 96 hour exposure period under flow-through

conditions. Saltwater mysids (<24 hours old) were exposed to 5 nominal

concentrations of 0.56, 1.1, 2.3, 4.5 and 9.0 mg ai/L. In addition, a water

control and a solvent control (DMF, 0.1 ml/L) were tested. There were 2

replicates of ten mysids in the control, solvent control and each of the

treatment levels. In total 20 mysids per concentration.

The content of tetraniliprole in exposure media was measured for verification

of the test item concentrations. Measured concentrations of the samples

ranged from approximately 89 to 118% of nominal. When measured

concentrations of the samples collected during the test were averaged, the

mean measured test concentrations for this study were 0.55, 1.1, 2.2, 4.9 and

9.8 mg ai/L, representing 98, 100, 96, 109 and 109% of nominal

concentrations, respectively. The results of the study were based on the

mean measured concentrations.

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The test solutions appeared clear and colourless, with no evidence of

precipitation observed during the test, in the negative control, solvent control,

0.56 and 1.1 mg ai/L test chambers. Test solutions in the 2.3, 4.5 and 9.0 mg

ai/L test chambers appeared clear and colourless at test initiation and

termination, with white precipitate on the bottom of the test chambers for the

duration of the test. Due to the presence of a precipitate in the 2.3, 4.5 and

9.0 mg ai/L test chambers, all samples were centrifuged prior to analysis.

All mysids in the negative and solvent control groups and the 0.55, 1.1 and

2.2 mg ai/L treatment groups appeared normal throughout the test, with no

mortalities or overt signs of toxicity observed.

The validity criterion of control mortality less than 10% is fulfilled. The validity criterion of oxygen saturation above 60% is fulfilled.

Percent mortality in the 4.9 and 9.8 mg ai/L treatment groups at test

termination was 5 and 70%, respectively. Signs of toxicity observed among

the mysids in the 4.9 and 9.8 mg ai/L treatment groups at test termination

included surfacing, erratic swimming, and lethargy. Mortality was 5% in the

4.9 mg ai/L group and 70% for the highest dose rate.

The 96-hour LC50 value was 8.3 mg ai/L, with a 95% confidence interval of

7.0 to 10.0 mg ai/L. The slope of the concentration-response curve was 7.2.

The NOEC was 2.2 mg ai/L.

Comments The results can be based on nominal concentrations as the measured

concentrations were within 80-120% range

Conclusion LC50 = 7.6 mg ai/ L nominal

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Saltwater species – chronic toxicity

Table 154: chronic toxicity - shrimp

Study type Life-cycle toxicity mysid

Flag Key study


Exposure 30 d, flow through conditions

Test species Saltwater mysid, (Americamysis bahia)

Endpoint NOEC

Value 0.15 mg ai/L

Reference

Claude M.B., Zhang L., Gallagher S.P., Krueger H. O. (2014) BCS-CL73507:

a flow-through life-cycle toxicity test with the saltwater mysid (Americamysis

bahia) Report no EBFVP038, M-508258-01-1

Klimisch Score 1


GLP yes





Study Summary


survival, reproduction and growth of the saltwater mysid during chronic

exposure (30 days) under flow-through conditions. First generation (G1)

juvenile saltwater mysids (<24 hours old) were exposed to 5 nominal

concentrations of 0.075, 0.15, 0.30, 0.60 and 1.2 mg ai/L. In addition, a water

control and a solvent control (DMF, 0.1 ml/L) were tested. There were 4

replicates of 15 mysids in the control, solvent control and each of the

treatment levels. In total 60 mysids per concentration.

Measured concentrations of the samples ranged from approximately 78.1 to

114% of nominal. When measured concentrations of the samples collected

during the test were averaged, the mean measured test concentrations for

this study were 0.071, 0.15, 0.28, 0.58 and 1.1 mg ai/L, representing 95, 100,

93, 97 and 92% of nominal concentrations, respectively. The results of the

study were based on the mean measured concentrations.

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On Day 13 of the test, after mysids attained sexual maturity, male and female

adults were paired in each treatment and control group, with a maximum of

five reproductive pairs per replicate. Reproduction of the paired mysids was

monitored through termination on Day 30 (2 days later compared with the test

guidance). Observations for G1 mysid mortality and signs of toxicity were

conducted daily throughout the test. At test termination, the total body lengths

and dry weights of all surviving first-generation mysids were measured. The

G2 mysids were observed for mortality daily and observed for abnormal

development and behaviour.

Observations of the effects of BCS-CL 73507 on survival, reproduction and

growth were used to determine the NOEC, the LOEC, and MATC. The 7-, 14-

, 21- and 28-day LC50 values were determined, when possible, based on the

mortality of the G1 mysids.

The validity criteria are met. Control mortality of first-generation mysids is

less than 30%, >75% of females produce young and the average number of

young >3 per day.

Mean

measured

conc mg

ai/L

Juvenile

survival

%

day 7

Juvenile

survival

%

day 13

Mean

number

young per

reproductive

day

Mean

number

young

per

surviving

female

Control 100 98.3 0.331 5.4

Solvent

control

100 98.3 0.441 7.1

Pooled

control

100 98.3 0.386 6.2

0.071 98.3 95.0 0.431 6.9

0.15 90.0* 85.0* 0.518 8.3

0.28 98.3 95.0 0.157* 2.7*

0.58 93.3* 91.7* 0.235 4.1

1.1 93.3* 88.3* 0.087* 1.6*

* significant difference

The mean length of the males ranged from 8.05 to 8.33 mm and of the

females from 8.18 to 8.54 mm in the treatments. In the pooled control the

length of the males was 8.17 and of the females 8.27 mm. No statistically

significant differences were observed.

The mean dry weight of the males ranged from 0.79 to 0.96 mg and of the

females from 0.99 to 1.21 mg in the treatments. In the controls, the weight of

the males was 0.93 and 1.05 mg and of the females 1.22 and 1.29 mg. The

weight of the lowest concentration differed significantly compared to the

controls. This was considered not treatment-related as the results of higher

concentrations did not differ significantly.

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G2 cummulative survival was 37.5% in negative control, 60.0% in solvent

control, 75.0% in 0.071 mg ai/L, 77.5% in 0.15 mg ai/L, 91.7% in 0.28 mg

ai/L, 66.7% in 0.58 mg ai/L, and 0.0% in 1.1 mg ai/L.

The NOEC based on G1 mysid reproduction was 0.15 mg ai/L. The LOEC

and the MATC were 0.28 mg ai/L and 0.20 mg ai/L, respectively.

Additional comments

The guideline recommends to make additional observations on G2 mysids if

offspring is produced (number male-female, body length. Only survival is

recorded in this case.

Conclusion NOEC = 0.15 mg ai/L

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Algae and plants – acute toxicity

Table 155: Acute toxicity – Algae – study 1

Study type Full test, Toxicity alga

Flag Key study



Test species Green alga Pseudokirchneriella subcapitata

Endpoint ErC50

Value >1.97 mg ai/L

Reference Kuhl K. (2016) Pseudokirchneriella subcapitata growth inhibition test with

BCS-CL73507. Report no EBFVP020, M-553842-02-1

Klimisch Score 1


GLP yes

Test Guideline/s

US EPA OCSPP 850.4500 and OPPTS 850.100 for the calculation of mean

measured values.

OECD 201


0.440, 0 851, 1.97, 3.90 and 5.77 mg ai/L mean measured (0-72 h)


Study Summary

The aim of the study was to determine the effects of tetraniliprole on

exponentially growing populations of Pseudokirchneriella subcapitata

expressed as NOEC, LOEC and EC50 for growth rate and further endpoints

of algal biomass (cells per volume).

Cultures of Pseudokirchneriella subcapitata with an initial cell density of

10000 cells/ml were exposed in a static system over a period of 72 hours

with a prolongation to 96 hours to nominal concentrations of 0.625, 1.25,

2.50, 5.00 and 10.0 mg ai/L. Quantitative amounts of tetraniliprole were

measured in all treatment groups and in the controls at test start, after 72

hours and test end (96 hours). Mean measured concentrations (0-72 h) of

0.440, 0 851, 1.97, 3.90 and 5.77 mg ai/L), corresponding to mean

measured concentrations (0-96 h) of 0.390, 0.772, 1.73, 3.39 and 5.35 mg

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ai/L in comparison to controls (water- and solvent control

(dimethylformamide) were determined.

The validity criteria were met. Increase biomass was factor of 73.5

(recommended factor 16 in 72h), coefficient of variation section by section

specific growth rate was 23% (recommended ≤35% in 72 h), coefficient of

variation for average specific growth rate was 3.4% (recommended ≤10% in

72 h).

72 and 96-hour growth rates based on cell density and visual assessment of

potential cell deformations were used as endpoints. Morphological change in

algae was observed in the test concentration of 5.00 and 10.0 mg ai/L,

respectively preventing cell counting at these concentrations.

After 72 h the growth rate inhibition was 5.1%, 1.4% and 1.5% at the rate

0.625, 1.25 and 2.5 mg ai/L respectively. At the higher rates, cell counting

was not possible due to cell clumping.

After 96 h the growth rate inhibition was 1.8%, 1.5% and 2.6% at the rate

0.625, 1.25 and 2.5 mg ai/L respectively. At the higher rates, cell counting

was not possible due to cell clumping.

Based on analytical findings the biological endpoints are reported as

geometric mean measured or mean measured test concentrations of the test

item. The 72-hour-ErC50 was >1.97 mg ai/L, the 96- hour-ErC50 was >1.73

mg ai/L.

The 72h- and 96h-NOErC were determined to be 1.97 and 1.73 mg ai/L,

respectively.

Conclusion ErC50 >1.97 mg ai/L

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Study type Limit test, Toxicity alga

Flag Key study



Test species Cyanobacterium, Anabaena flos-aquae

Endpoint ErC50

Value >5.93 mg ai/L

Reference

Banman C.S., Shepherd D.W., Moore S. (2015) Toxicity of BCS-

CL73507 to the Cyanobacterium Anabaena flos-aquae. Report no

EBFVN062, M-535799-01-1

Klimisch Score 2

Amendments/Deviations pH increases > 1.5 and ranged from 7.6 to 9.2. The biological

validation criteria were met.

GLP yes


OECD 201


3.24 and 5.93 g ai/L mean measured (0-72 h)


Study Summary


cyanobacteria Anabaena flos-aquae. Cultures of Anabaena flos-aquae

with an initial cell density of 1.0 x 104 cells/ml were exposed in a static

system over a period of 96 hours to nominal concentrations of 5.0 and

10.0 mg ai/L (4 replicates per treated level). In addition, a water control

and a solvent control (both <LOQ) were tested (6 replicates per the

controls).

Quantitative amounts of tetraniliprole were measured in all treatment

groups and in the control on days 0, 3 and 4 of the exposure period.

The analytical findings of tetraniliprole found on day 0 ranged from 91%

to 98% of nominal concentrations. Geometric mean measured

concentrations from days 0 and 3 ranged from 59% to 65% (3.24-5.93

mg ai/L) of nominal concentrations. Mean measured concentrations

from days 0, 3 and 4 ranged from 55% to 62% (3.09-5.46 mg ai/L) of

nominal concentrations.

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72 and 96-hour growth rates based on cell density and visual

assessment of potential cell deformations were used as endpoints. No

physical abnormalities were observed in the control and in the

treatment groups during the study.

The validity criteria were met, although the pH ranged from 7.6 to 9.2.

Increase biomass was factor of 55 (recommended factor 16 in 72h),

coefficient of variation for control yield was 2.4% (recommended ≤20%

in 96 h) coefficient of variation section by section specific growth rate

was 25% (recommended ≤35% in 72 h), coefficient of variation for

average specific growth rate was 3.6% 0-72 h (recommended ≤10% in

72 h) and 0.45% 0-96h h (recommended ≤12% in 96 h).

The 72-hour growth rate was calculated based on geometric mean

measured concentrations from days 0 and 3. The 72-hour ErC50 was >

5.93 mg ai/L with LOEC and NOEC values of > 5.93 and ≥ 5.93 mg

ai/L, respectively. The 96-hour growth rate was calculated based on

mean measured concentrations from days 0, 3, and 4. The 96-hour

ErC50 was > 5.46 mg ai/L with LOEC and NOEC values of > 5.46 and ≥

5.46 mg ai/L, respectively.

Comments

The test can be considered as a limit test (only two concentrations

tested), therefore at least 6 replicates should be used. The pH

increased with >1.5 which might have limited the growth in the control.

Therefore, the test is considered to be a klimisch score of 2.


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Flag Key study



Test species Diatom Navicula pelliculosa

Endpoint ErC50

Value > 3.19 mg ai/L

Reference

Matlock D., Moore S. (2015) Toxicity of BCS-CL73507 to the

freshwater diatom Navicula pelliculosa during a 96-hour exposure.

Report no EBFVN063, M-535793-01-1

Klimisch Score 1


GLP yes


OECD 201


0.149, 0.285, 0.661, 1.29, and 3.19 mg ai/L) mean measured (0-72 h)

Analytical measurements HPLC-LC-MS/MS

Study Summary


the growth of freshwater diatom Navicula pelliculosa. Cultures of the

diatom with an initial cell density of 1.0 x 104 cells/ml were exposed in

a static system over a period of 96 hours to nominal concentrations of

0.313, 0.625, 1.25, 2.50 and 5.0 mg ai/L (4 replicates per treatment

level). In addition, a water control and a solvent control (DMF at 100

µL/L) were tested.


groups and in the control on days 0, 3 and 4 of the exposure period.

The analytical findings of tetraniliprole found on day 0 ranged from

88% to 105% of nominal concentrations. Geometric mean measured

concentrations from days 0 and 3 ranged from 46% to 64% (0.149-

3.19 mg ai/L) of nominal concentrations. Mean measured

concentrations from days 0, 3 and 4 ranged from 42% to 52% (0.133-

2.60 mg ai/L) of nominal concentrations.

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72 and 96-hour growth rates based on cell density were used as

endpoints. No physical abnormalities were observed in the control

and in the treatment groups during the study.

The validity criteria were met. Increase biomass was factor of 153

(recommended factor 16 in 72h), coefficient of variation for control

yield was 10.0% (recommended ≤15% in 96 h) coefficient of variation

section by section specific growth rate was 16% (recommended

≤35% in 72 h), coefficient of variation for average specific growth rate

was 1.5% 0-72 h (recommended ≤10% in 72 h) and 1.9% 0-96h h

(recommended ≤15% in 96 h).


measured concentrations from days 0 and 3. The 72-hour ErC50 was

> 3.19 mg ai/L with LOEC and NOEC values of 0.661 and 0.285 mg

ai/L, respectively. The 96-hour growth rate was calculated based on

mean measured concentrations from days 0, 3, and 4. The 96-hour

ErC50 was >2.60 mg ai/L with LOEC and NOEC values of 0.553 and

0.266 mg ai/L, respectively.

Conclusion ErC50 >3.19 mg ai/L (72 h)

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Flag Key study



Test species Diatom Skeletonema costatum

Endpoint ErC50

Value 1.49 mg ai/L

Reference

Matlock D., Jordan J., Moore S. (2015) Toxicity of BCS-CL73507 to the

saltwater diatom Skeletonema costatum during a 96-hour exposure.


Klimisch Score 1


GLP yes


OECD 201

Dose Levels

0.0291, 0.0813, 0.228, 0.638, 1.79 and 5.0 mg ai/L nominal

0.020, 0.0516, 0.157, 0.429, 1.26 and 3.71 mg ai/L) mean measured (0-72

h)

Analytical measurements Yes, HPLC-LC-MS/MS

Study Summary


growth of saltwater diatom Skeletonema costatum. Cultures of the diatom

with an initial cell density of 1.0 x 104 cells/ml were exposed in a static

system over a period of 96 hours to nominal concentrations of 0.0291,

0.0813, 0.228, 0.638, 1.79 and 5.0 mg ai/L (4 replicates per treatment

level). In addition, a water control and a solvent control (DMF at 100 µL/L)

were tested.


groups and in the control on days 0, 3 and 4 of the exposure period. The

analytical findings of tetraniliprole found on day 0 ranged from 90% to 93%

of nominal concentrations. Geometric mean measured concentrations from

days 0 and 3 ranged from 45% to 59% of nominal concentrations. Mean

measured concentrations from days 0, 3 and 4 ranged from 63 to 74% of


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72 and 96-hour growth rates based on cell density were used as

endpoints. No physical abnormalities were observed in the control and in

the treatment groups during the study with the exception of some

elongation and deformation of cells at 1.79 and 5.00 mg ai/L.

The validity criteria were met. Increase biomass was factor of 94

(recommended factor 30 in 96h), coefficient of variation for control yield

was 11.1% (recommended ≤15% in 96 h) coefficient of variation section by

section specific growth rate was 23% (recommended ≤35% in 72 h),

coefficient of variation for average specific growth rate was 8.6% 0-72 h

(recommended ≤10% in 72 h) and 2.4% 0-96h h (recommended ≤15% in

96 h).


measured concentrations from days 0 and 3. The 72-hour ErC50 is 1.49 mg

ai/L with LOEC and NOEC values of 1.26 and 0.429 mg ai/L, respectively.

The 96-hour growth rate was calculated based on mean measured

concentrations from days 0, 3, and 4. The 96-hour ErC50 is 1.36 mg ai/L

with LOEC and NOEC values of 0.398 and 0.154 mg ai/L, respectively.

Conclusion ErC50 =1.49 mg ai/L (72 h)

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Table 159: Acute toxicity – Aquatic plants

Study type Full test, Toxicity aquatic plants

Flag Key study


Exposure 7 days, semi-static conditions

Test species Aquatic plant, Lemna gibba

Endpoint ErC50

Value >6.64 mg ai/L

Reference

Kuhl K. (2015) Amendment no 1 to report- Lemna gibba G3 growth

inhibition test with BCS-CL73507 (tech) under semi-static conditions.


Klimisch Score 1


GLP yes

Test Guideline/s US EPA OCSPP 850.4400, OECD 221

EU directive 91/414/EEC Regulation (EC) Number 1107/2009

Dose Levels 0.0954, 0.305, 0.977, 3.13 and 10 mg ai/L nominal 0.0804, 0.268,

0.778, 2.05 and 6.64 mg ai/L Time Weighted Average


Study Summary


exponentially growing populations of Lemna gibba expressed as

NOEC, LOEC and EC50 for growth rate of the measurement variables,

frond number and total area of plants.

Cultures of Lemna gibba G3 with an initial density of 12 fronds per

vessel (4 replicates per treatment) were exposed in a multi-generation

test for 7 days under semi-static conditions. The following nominal

concentrations of 0.0954, 0.305, 0.977, 3.13 and 10 mg ai/L were

tested. These concentrations correspond to Time-Weighted Average

Concentrations (TWAC) of 0.0804, 0.268, 0.778, 2.05 and 6.64 mg

ai/L, respectively. In addition, a water control and solvent control (100

µL DMF/L) were tested.

Plant frond numbers and total frond area of plants were recorded on

days 0, 2, 5 and 7. Frond numbers and total frond area at each

occasion were used to determine the endpoints.

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The analytical findings of tetraniliprole found in all freshly prepared test

levels on day 0, 2, and 5 ranged between 92 and 140% of nominal

concentrations and in aged test levels on days 2, 5, and 7 between 33

and 80% of nominal, respectively. Therefore, all results based on time-

weighted average values. Up to the nominal concentration 0.977

(0.778 TWAC), mg ai/L no remarkable observations (eg precipitation or

turbidity) were recorded in the aged and freshly prepared test media. At

the nominal concentration 3.31 (2.05 TWAC) mg ai/L on day five and

seven in the aged test levels undissolved test item was observed at the

surface. At the test concentration, 10.0 (6.64 TWAC) mg ai/L

undissolved test item was recorded at water surface and the bottom of

the test vessels in the aged test media on day 5 and 7.

The validity criteria were met. The doubling time of frond number in the

control was 1.7 days, corresponding to a 17.9 fold increase. The

validity criterion of a doubling time less than 2.5 days (60 hours) in the

control is fulfilled. The control coefficient of variation (CV) for yield and

growth is < 20% at test termination.

No sublethal or visual effects on Lemna gibba were observed during

the course of the test.

Growth rate for frond number was 2.4, 0.4, 1.5, 2.2 and 10.1 %

inhibition for the concentrations 0.0804, 0.268, 0.778, 2.05 and 6.64

mg ai/L respectively (day 7). Growth rate for total frond area of plants

was 1.6, 03, 0.0, 0.4 and10.8 % inhibition for the concentrations

0.0804, 0.268, 0.778, 2.05 and 6.64 mg ai/L respectively (day 7). The

difference of the highest concentration is significant compared to the

pooled control for both observations.

The ErC50 was >6.64 mg ai /L for growth rate of frond number and total

frond area of plants. The NOErC was determined to be 2.05 mg ai/L for

both observations.


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Sediment-dwelling organisms

Spiked sediment

Table 160: Toxicity to sediment-dwelling organisms- spiked sediment – study 1

Study type Full test, Toxicity amphipod

Flag Key study


Exposure 10 d, flow through conditions, spiked sediment

Test species Amphipod, Hyalella azteca

Endpoint NOEC

Value 391 μg ai/ kg sediment

Reference

Thomas S.T., Zhang L., Martin K.H. Gallagher S.P., Krueger H. O. (2015)

BCS-CL73507: a 10-day acute toxicity test with the freshwater amphipod

(Hyalella azteca) Report no EBFVN134, M-542829-01-1

Klimisch Score 1


GLP yes


Dose Levels

40, 80, 160, 320 and 640 μg BCS-CL73507 / kg of sediment, nominal

22.2, 52.7, 121, 234, 391 μg BCS- CL73507 / kg of sediment, mean

measured

Analytical measurements Yes, HPLC-MS/MS

Study Summary

The aim of the study was to determine the effects of sediment-incorporated

tetraniliprole (BCS-CL73507) on the amphipod Hyalella azteca during a 10-

day exposure period under flow-through test conditions.

Groups of amphipods (approx.7-8 days old) were exposed to a geometric

series of five test concentrations, a solvent control and a negative control for

10 days under flow-through test conditions. Eight replicate test compartments

were maintained in each treatment and control group, with 10 amphipods in

each test compartment, for a total of 80 individuals per test concentration. An

additional two replicates were added in each treatment and control group for

analytical sampling of sediment, pore water and overlying water. Organisms

were added at test initiation to analytical replicates for the Day 10 analysis.

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The Day 0 analytical replicates did not contain organisms. Each test

compartment contained sediment and overlying water.

Nominal definitive test concentrations were 40, 80, 160, 320 and 640 μg

BCS-CL73507 / kg of sediment based on the dry weight of the sediment.

Mean measured concentrations are 22.2, 52.7, 121, 234, 391 μg BCS-

CL73507 / kg of sediment (53.6- 78.7% of nominal). The results of the study

are based on mean measured test concentrations in the sediment and in

pore water. Sediment, overlying water and pore water samples were

collected on Day 0 and at the end of the test.

Observations of mortality and abnormal behaviour were made daily during

the test. Survival and growth (dry weight) were determined at the end of the

10-day test period. The survival/ mortality of organisms present in the

treatment groups at test termination in comparison to the control groups was

used to determine the 10-day LC50 value.

The validity criteria are met. Control survival ≥ 80% (observed 96 and 100%),

dry weight in the controls was 0.084 and 0.085 mg and at the start of the test

0.0155 mg.

Mean

measured

conc

(μg ai / kg)

Mean

number

of

surviving

amphipod

%

reduction

Mean dry

weight

(mg)

%

reduction

Control 9.6 - 0.085 -

Solvent

control

10 - 0.086 -

Pooled

control

9.8 - 0.085 -

22 9.8 0.64 0.091 6.7

53 9.8 0.64 0.093 -9.2

121 9.9 -0.64 0.079 7.2

234 9.9 -0.64 0.091 -6.6

391 9.8 0.64 0.085 0.91

No effects on growth were observed.

The 10-day-LC50 was >391 μg ai/kg based on mean measured

concentrations in the sediment, the highest concentration tested. The LOEC

and NOEC were >391 and 391 μg ai/kg, respectively, based on mean

measured concentrations in the sediment.

The 10-day-LC50 was >1171 μg ai/L based on mean measured

concentrations in the pore water. The LOEC and NOEC were >1171 and

1171 μg ai/L, respectively, based on mean measured concentrations in the

pore water.

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Conclusion NOEC = 391 μg ai/ kg sediment

LC50> 391 μg ai/ kg sediment

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Study type Full test, Toxicity amphipod

Flag Key study


Exposure 10 d, static conditions, spiked sediment

Test species Amphipod, Leptocheirus plumulosus

Endpoint NOEC

Value 728 μg ai/kg sediment

Reference


BCS-CL73507: a 10 day acute toxicity test with the marine amphipod

(Leptocheirus plumulosus) Report no 149A-252A, M-542852-01-1

Klimisch Score 1


GLP yes


Dose Levels 100, 200, 400, 800 and 1600 μg tetraniliprole/kg of sediment, nominal

45, 103, 199, 356, 728 μg BCS-CL73507 / kg of sediment, mean measured


Study Summary


tetraniliprole (BCS-CL73507) on the marine amphipod Leptocheirus

plumulosus during a 10-day exposure period under static conditions.

Groups of amphipods (size 2-4 mm) were exposed to a geometric series of

five test concentrations, a solvent control and a negative control. Five

replicate test compartments were maintained in each treatment and control

group, with 20 amphipods in each test compartment, for a total of 100

individuals per test concentration. An additional replicate was added in each

treatment and control group for analytical sampling of water and sediment.

Organisms were added at test initiation to analytical replicates for the Day 10

analysis. The Day 0 analytical replicates did not contain organisms. Each test

compartment contained sediment and overlying water.


tetraniliprole/kg of sediment based on the dry weight of the sediment. Mean

measured concentrations are 45, 103, 199, 356, 728 μg BCS-CL73507 / kg

of sediment (44.5-51.5% of nominal). The results of the study are based on

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mean measured test concentrations in the sediment and in pore water.

Sediment, overlying water and pore water samples were collected on Day 0

and at the end of the test.


the test. Survival was determined at the end of the 10-day test period. The

survival/ mortality of organisms present in the treatment groups at test

termination in comparison to the control groups was used to determine the

10-day LC50 value.

The validity criteria are met. Control survival ≥90% (observed 100 and 100%)

and dissolved oxygen remained ≥94%.

Mean percent survival was 100% for the controls and the treatments up to

199 μg BCS-CL73507 / kg of sediment. The two highest concentrations had

99% survival.





The 10-day-LC50 was >553 μg ai/L based on mean measured concentrations

in the pore water. The LOEC and NOEC were >553 and 553 μg ai/L,

respectively, based on mean measured concentrations in the pore water.

Additional comments The guideline recommends to determine growth (dry weight) as well.

Conclusion NOEC = 728 μg ai/kg sediment

LC50> 728 μg ai/kg sediment

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Study type Full test, Toxicity midge

Flag Key study



Test species Midge, Chironomus dilutus

Endpoint NOEC


Reference


BCS-CL73507: a 10-day acute toxicity test with the midge (Chironomus

dilutus) using spiked sediment. Amended final report. Report no EBFVN135,

M-542839-02-1

Klimisch Score 1


GLP yes


Dose Levels 10, 20, 40, 80, 160 and 320 μg ai / kg of sediment nominal

6.6,11, 25, 59, 127, 255 μg ai / kg of sediment mean measured

Analytical


Study Summary


tetraniliprole (BCS-CL73507) on the midge Chironomus dilutus during a 10-

day exposure period under flow-through test conditions.

Groups of midges (2nd, 3rd instars, approx. 10 days old) were exposed to a

geometric series of six test concentrations, a solvent control and a negative

control for 10 days under flow-through test conditions.

Eight replicate test compartments were maintained in each treatment and

control group, with 10 midges in each test compartment, for a total of 80

individuals per test concentration. An additional two replicates were added in

each treatment and control group for analytical sampling of sediment, pore

water and overlying water. Organisms were added at test initiation to

analytical replicates for the Day 10 analysis. The Day 0 analytical replicates

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did not contain organisms. Each test compartment contained sediment and

overlying water.

Nominal definitive test concentrations were 10, 20, 40, 80, 160 and 320 μg ai/

kg of sediment based on the dry weight of the sediment. Mean measured

concentrations are 6.6,11, 25, 59, 127, 255 μg ai / kg of sediment (55- 80% of

nominal). The results of the study are based on mean measured test

concentrations in the sediment and in pore water. Sediment, overlying water

and pore water samples were collected on Day 0 and at the end of the test.

Observations of mortality and abnormal behaviour were made daily during the

test. Survival and growth (AFDW = ash-free dry weight) were determined at

the end of the 10-day test period. The percent reduction in the numbers of

organisms present in the treatment groups at test termination in comparison to

the control groups was used to determine the 10-day LC50 value.

The validity criteria are met. Control survival ≥ 70% (observed 91 and 90%),

average larval weight >0.48 mg (observed 1.95 and 2.01 mg).

Mean measured

conc (μg ai / kg)

Mean number

of surviving

midges

%

reduction

Mean dry

weight

(mg)

%

reduction

Control 9.1 - 1.95 -

Solvent control 9.0 - 2.01 -

Pooled control 9.1 - 1.98 -

6.6 8.9 2.1 1.86 6.1

11 8.9 2.1 1.89 4.8

25 6.1* 32 2.18 -10

59 2.9* 68 1.51 24

127 0.0* 100 0.00 100

255 0.13* 99 0.02 99

* significant different

The 10-day-LC50 was 34 μg ai/kg (95% C.I.: 11 and 59 μg ai/kg) based on

mean measured concentrations in the sediment. The LOEC and NOEC were

25 and 11 μg ai/kg, respectively, based on mean measured concentrations in

the sediment.

The 10-day-LC50 was 6.3 μg ai/L (95% C.I.: 1.7 and 11 μg ai/L) based on

mean measured concentrations in the pore water. The LOEC and NOEC were

4.7 and 1.7 μg ai/L, respectively, based on mean measured concentrations in

the pore water.

Conclusion LC50 = 34 μg ai/kg

NOEC = 11 μg ai/kg

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Study type Full test, Chronic toxicity midge

Flag Key study

Test Substance Tetraniliprole (tech)

Exposure 28 days, static conditions, spiked sediment

Test species Midge, Chironomus riparius

Endpoint NOEC

Value 6.76 μg ai/kg dw sediment

Reference

Silke G. (2015) Chironomus riparius 28-day chronic toxicity test with BCS-

CL73507 (tech) in a water-sediment system using spiked sediment. Report

no EBFVP035, M-509624-01-1

Klimisch Score 1


GLP yes

Test Guideline/s OECD 218

Dose Levels

2.50, 5.0, 10.0, 20.0, 40.0 and 80.0 µg test substance/ kg dw sediment,

nominal

1.98, 3.26, 6.76, 12.73, 26.87, 59.75 µg test substance/ kg dw sediment,

initial measured

Analytical measurements HPLC-MS/MS and HPLC-UV,

Study Summary


emergence and development of Chironomus riparius.

Groups of midges (1st instars, < 2-3 days old) were exposed in a static

system over a period of 28 days to the nominal concentrations of 2.50, 5.0,

10.0, 20.0, 40.0 and 80.0 µg test substance/ kg dw sediment. In addition, a

water control and solvent control (acetone) were tested. Four replicates,

containing 20 animals each, were tested for each test item concentration

and the controls.

During the study, the measured concentrations of tetraniliprole and its

metabolite tetraniliprole-N-methyl- quinazolinone (BCS-CQ63359) were

analysed in the sediment, overlying water and pore water four times, on day

0, 4, 8 and 28 in all test levels and also in the control(s). Additional

measurements of sediment samples were made on day -2 for all test

concentrations and the controls directly after sediment spiking. Chemical

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analyses of the sediment, overlying water and pore water show only a small

partitioning of tetraniliprole from the sediment into the water phase over time

(max. 12.5% were found in the overlying water and max. 1.9% in the pore

water).

Analyses of the sediment over time showed recoveries of tetraniliprole

ranging from 63.7% to 79.2% (mean = 69.6%) of nominal for all test

concentrations on day 0. On day 4, 59.6% to 76.4% (mean = 65.7%), on day

8, 53.3% to 67.6% (mean = 58.8%) and on day 28, 42.7% to 54.4% (mean =

47.4%) of nominal were found, respectively. The measured concentration of

the metabolite CQ63359 was 29, 44, 33, 40, 30 and 45% of initial

concentration, respectively.

Analyses of the overlying water over time showed recoveries of tetraniliprole

of 9.6 % to 11.1% (mean = 10.6%) of nominal applied amount of ai per test

concentration on day 0. On day 4, 10.9% to 12.5% (mean = 11.5%), on day

8, 9.9 % to 11.1% (mean = 10.4%) and on day 28, 0% to 5.4% (mean =

3.3%) of nominal were found, respectively. The measured concentration of

the metabolite CQ63359 was <LOQ, <LOQ, 3.8, 3.7, 4.6 and 4.7 % of initial

concentration, respectively.

Analyses of the pore water over time showed recoveries of tetraniliprole of

1.4% to 1.9% (mean = 1.7%) of nominal concentrations on day 0 for all test

concentrations. On day 4, 1.1% to 1.6% (mean = 1.4 %), on day 8, 1.1% to

1.5% (mean = 1.3%) and on day 28, 0 % to 0.9% (mean = 0.6%) of initial

measured concentrations on day 0 were found, respectively. The measured

concentration of the metabolite CQ63359 was <LOQ for the three lowest

concentrations, 0.09, 0.06, and 0.05% of initial concentration, respectively.

Initially measured test concentrations (day 0) in the sediment (in μg ai/kg dw

sed) were used for reporting and evaluation of the results.

Initial measured

conc (μg ai / kg)

Number of

emerged midges

% of emerged

larvae

Development

rate (pooled

sex)

Pooled controls 148 92.5 0.065

1.98 75 93.7 0.064

3.26 76 95.0 0.061

6.76 67 83.8 0.066

12.73 7* 8.8* 0.047*

26.87 0 - -

59.75 0 - -


Emergence, sex ratio and development rates were determined. A statistically

significant difference in emergence was determined for initial measured test

concentrations from 12.73 to 59.75 μg ai/kg dw sed as compared to the

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pooled controls, resulting in a NOEC of 6.76 μg ai/kg dw sed. The EC10

value for the emergence rate was determined to be 5.96 μg ai/kg dw sed.

For the development rate (pooled sex) a statistically significant difference

was found for initial measured test concentrations of 12.73 μg ai/kg dw sed

as compared to the pooled controls, resulting in a NOEC of 6.76 μg ai/kg dw

sed. The EC10 value for the development rate was determined to be 10.7 μg

ai/kg dw sed. No statistically different distribution between sexes.

All validity criteria were met. The emergence in the control(s) had to reach at

least 70% of introduced larvae at the end of the test. The emergence should

occur between 12 and 23 days after their insertion into the control vessels.

The oxygen content in the Waterbody had to be > 60% of saturation at the

end of the test in all test vessels. The pH of the overlying water had to be

between 6 and 9 in all test vessels. The water temperature had not to differ

by more than ± 1°C over the whole exposure period.

Conclusion NOEC = 6.76 μg ai/kg dw sed.

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Study type Full test, Chronic toxicity amphipod

Flag Key study


Exposure 28 d exposure, 14 d clean water, flow through conditions, spiked sediment

Test species Amphipod, Hyalella azteca

Endpoint NOEC


Reference

Thomas S.T., Zhang L., Martin K.H. Gallagher S.P. (2016) BCS-CL73507: a

life cycle toxicity test with the freshwater amphipod (Hyalella azteca) using

spiked sediment Report no EBFVN166, M-560357-02-1

Klimisch Score 1


GLP yes

Test Guideline/s US EPA OCSPP 850.1770, EPA 600/R-99/064

Dose Levels

80, 160, 320, 640 and 1280 μg BCS-CL73507/kg of sediment, nominal

58, 109, 239, 475 and 992 μg BCS-CL73507/kg of sediment, mean

measured


Study Summary


tetraniliprole (BCS-CL73507) on the amphipod Hyalella azteca during a 42-

day exposure period under flow-through test conditions with intermittent

renewal of overlying water daily.

Groups of amphipods (approx.7-8 days old) were exposed to a geometric

series of five test concentrations, a solvent control and a negative control for

28 days under flow-through test conditions.

Twelve replicate test compartments were maintained in each treatment and

control group, with 10 amphipods in each test compartment, for a total of

120 individuals per test concentration. An additional replicate was added in

each treatment and control group for analytical sampling and water quality

sampling. The Day 0 analytical replicates did not contain organisms.

Organisms were added at test initiation to analytical replicates for the Day 14

and 28.

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BCS-CL73507/kg of sediment based on the dry weight of the sediment.

Mean measured concentrations are 58, 109, 239, 475 and 992 μg BCS-

CL73507/kg of sediment (68- 78% of nominal). The results of the study are

based on mean measured test concentrations in the sediment. Mean

measured concentration of the metabolite CQ63359 in the sediment was 7,

12, 24, 53,120 µg metabolite/kg.


the test. Survival and growth (dry weight, length) were determined at the end

of the 42-day test period. The survival/ mortality of organisms present in the

treatment groups at test termination in comparison to the control groups was

used to determine the 42-day LC50 value.

The validity criteria are met. Control survival ≥ 80% (observed 96 and 99%).

The average length was > 3.2 mm in the controls (5.52 and 5.49 mm) and

dry weight in the controls was 0.90 and 0.91 mg (recommended >0.15 mg).

Reproduction was 26.6 and 23.9 young per female (recommended >2 young

per female).

Results of the observations on day 42 are presented below. The number of

young are enumerated on days 28, 35 and 42.

Mean

measured

conc

(μg ai/kg)

%

survival

Average

body

length

(mm)

Average

dry weight

(mg)

Average

number of

young per

surviving

female

Control 94 6.20 1.40 26.6

Solvent

control 99 5.96 1.28 23.9

Pooled

control 96 - - 25.2

58 95 5.95* 1.22* 20.4*

109 98 6.19 1.42 24.0

239 95 6.15 1.41 21.9

475 95 6.19 1.41 21.4

992 95 6.15 1.33 21.6


The effects of the lowest dose rate are considered not treatment-related as

the higher rates did not show significant adverse effects. Therefore, the

NOEC for survival, growth and reproduction was determined to be 992 µg/L.





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The 42-day-LC50 was >50.0 μg ai/L based on mean measured

concentrations in the pore water. The LOEC and NOEC were >50.0 and

50.0 μg ai/L, respectively, based on mean measured concentrations in the

pore water.

Conclusion NOEC = 992 μg ai/kg sediment

LC50>992 μg ai/kg sediment

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Study type Full test, Chronic toxicity amphipod

Flag Key study


Exposure 28 d, static-renewal conditions, spiked sediment

Test species Amphipod, Leptocheirus plumulosus

Endpoint NOEC

Value 12 mg ai/kg sediment

Reference

Bradley M.J. (2017) 28-day toxicity test exposing estuarine amphipods

(Leptocheirus plumulosus) to BCS-CL737507 applied to sediment under static

renewal conditions following EPA test methods- amended final report. Report no

EBFV0027, M-599964-01-1

Klimisch Score 1

Amendments/Deviati


GLP yes

Test Guideline/s OCSPP draft guideline 850.1735

Dose Levels 1.0, 2.6, 6.4, 16 and 40 mg BCS-CL73507 /kg of sediment, nominal

0.32, 0.88, 1.8, 4.6 and 12 mg BCS-CL73507 / kg of sediment, mean measured

Analytical


Study Summary


tetraniliprole (BCS-CL73507) on the marine amphipod Leptocheirus plumulosus

during a 28-day exposure period under static-renewal conditions.

Groups of amphipods (7-14 days old, 0.425-0.60 mm) were exposed to a

geometric series of five test concentrations, a solvent control and a negative

control. Eleven replicate test compartments were maintained in each treatment

and control group. Six replicates with 20 amphipods in each test compartment, for

a total of 120 individuals per test concentration were used for the evaluation of the

biological effects. Five replicate were used for analytical purposes.

Nominal definitive test concentrations were 1.0, 2.6, 6.4, 16 and 40 mg

tetraniliprole/kg of sediment based on the dry weight of the sediment. Mean

measured concentrations are 0.32, 0.88, 1.8, 4.6 and 12 mg BCS-CL73507 / kg of

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sediment (29-34% of nominal). The results of the study are based on mean

measured test concentrations in the sediment.

Observations of survival, growth and reproduction were made at the end of the

test. Results on day 28 are presented below.

Mean

measured

conc (μg ai /

kg)

%

survival

Mean male

growth rate

(mg/d)

Mean

female

growth rate

(mg/d)

Mean

number of

young per

surviving

female

Control 83 0.094 0.058 22

Solvent

control 88 0.096 0.059 20

Pooled

control 86 0.095 0.058 21

0.32 78 0.097 0.059 20

0.88 75 0.10 0.065 31

1.8 73 0.092 0.056 27

4.6 73 0.091 0.062 34

12 79 0.097 0.063 23

The validity criteria are met. Control survival ≥80% is recommended. Growth and

reproduction are measurable and therefore met the criteria.

No significant differences were observed. Therefore, the overall NOEC is 12 mg

ai/kg sediment.

Conclusion NOEC = 12 mg ai/kg sediment

EC50 and LOEC > 12 mg ai/kg sediment

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Flag Key study


Exposure 57 days, flow-through conditions, spiked sediment


Endpoint NOEC


Reference

Thomas S.T., Zhang L., Martin K.H. Gallagher S.P. (2016) BCS-

CL73507 A life-cycle toxicity test with the midge Chironomus dilutes

using spiked sediment. Report no EBFVP046, M-560359-02-1

Klimisch Score 1


GLP yes


Dose Levels 2.5, 5.0, 10, 20 and 40 μg BCS-CL73507 / kg of sediment, nominal

1.2, 2.8, 5.6, 12, 33 µg BCS-CL73507 /kg sediment, mean measured


Study Summary


survival, growth and reproduction of Chironomus dilutus.

Groups of midges (1st instars, 4 days old) were exposed under a flow-

through conditions over a period of 57 days to the nominal

concentrations of 2.5, 5.0, 10, 20 and 40 μg BCS-CL73507/kg of

sediment based on the dry weight of the sediment. In addition, a water

control and solvent control were tested. Twelve replicates, containing

12 animals each, were tested for each test item concentration and the

controls. Three additional replicates were added in each treatment and

control group for analytical sampling.

During the study, the measured concentrations of tetraniliprole were

analysed in the overlying water of the sediment-water three times, on

day 0, 16 and 57 in all test levels and also in the control(s). Water

temperature, pH and dissolved oxygen were measured regularly.

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Mean measured concentrations are 1.2, 2.8, 5.6, 12 and 33 μg BCS-

CL73507/kg of sediment (48-83% of nominal). The results of the study

are based on mean measured test concentrations in the sediment. The

mean measured concentration of metabolite CQ63359 was below limit

of quantitation (2.32 µg metabolite/kg) for concentrations to 10 µg

metabolite/kg nominal, in 20 µg metabolite/kg max 2.5 µg metabolite/kg

and in 40 µg metabolite/kg max 5.3 µg metabolite/kg was measured.

Mean measured concentrations in the pore water are 0.039, 0.085,

0.151, 0.347 and 0.718 33 μg BCS-CL73507/L. The metabolite

CQ63359 was below the limit of quantitation (0.0 µg metabolite/L) with

the exception of one sample in the 5 µg metabolite/kg group, 0.112 µg

metabolite/L was measured.

The biological findings are presented below.

Mean

measured

conc in sed.

(μg ai / kg)

%

survival

day 16

Average ash-

free dry

weight mg

day 16

Average #

eggs per 1st

egg mass

Average %

hatch of 1st

egg mass

Neg. control 100 2.45 1593 86.7

Solvent

control 96 2.59 1523 77.2

Pooled

control 98 2.52 1556 81.6

1.2 87 2.67 1588 92.9

2.8 100 2.58 1353 81.6

5.6 100 2.33 1597 91.0

12 100 2.47 1735 79.6

33 96 2.47 1751 84.9

No statistical differences were observed.

Mean

measured

conc in sed.

(μg ai / kg)

Number

emerged

total

Mean

emergence

ratio

Mean

development

time (days)

Neg. control 88 0.917 25.9

Solvent control 80 0.833 25.4

Pooled control 168 0.875 25.6

1.2 66 0.688* 28.9

2.8 76 0.792 26.3

5.6 79 0.823 25.7

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12 78 0.813 25.5

33 79 0.823 24.4

* statistically different compared to pooled control

The mean development rate was around 0.04 for all objects. The mean

time to death in days was 3.4 and 4.1 in the neg. and solvent control. In

the treatments, the mean time to death ranged from 3.3 to 3.7 days

and was not statistically different from the controls.

All validity criteria were met. Survival in control group was >70%. The

larval weight was > 0.48 mg in the controls. The mean number of eggs

was >800.

Overall the NOEC was determined to be 33 μg ai / kg sediment and

0.1718 μg ai / L pore water.

Conclusion NOEC = 33 μg ai/ kg sediment

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Spiked water

Table 167: Toxicity to sediment-dwelling organisms- spiked water – study 1

Study type Full test, Acute toxicity midge

Flag Key study


Exposure 48 h, static conditions, spiked water


Endpoint EC50

Value 230 μg ai/L

Reference

Silke G. (2016) Amendment no 1- Acute toxicity of BCS-CL73507 (tech.) to

larvae of Chironomus riparius in a 48 h static laboratory test system. Report

no EBFVN126, M-518365-02-1

Klimisch Score 1


GLP yes


Dose Levels

8.0, 16.0, 32.0, 64.0, 128 and 256 μg ai/L, nominal

8.67, 17.5, 34.2, 66.3, 158, 306 μg ai/L, measured day 0

7.57, 16.0, 30.9, 60.9, 147, 282 μg ai/L, measured day 2


Study Summary

The aim of the study was to determine the effects of tetraniliprole (BCS-

CL73507) on larvae of Chironomus riparius.


system over a period of 48 hours to the nominal concentrations of 8.0, 16.0,

32.0, 64.0, 128 and 256 μg ai / L. In addition, a solvent control and a water

control were tested.

Six replicates, containing 5 animals each, were tested for each test item

concentration and the controls. The analysed ai found in all freshly prepared

test levels on day 0 in reference to nominal concentrations ranged between

104 and 123% (average 112%). In aged test levels on day 2, there were

analytical findings between 95 and 115% (average 102%) of nominal. Due to

the high recoveries at the beginning of the exposure and the analytical

findings after 2 days, all results are based on nominal concentrations.

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Immobilisation of the midge larvae and intoxication symptoms were

assessed. After 48 hours 0% immobility was observed in the controls, 8.0

and 16.0 μg ai / L. 3.3%, 23.3%, 30.0% and 50.0% immobility was observed

in 32.0, 64.0, 128 and 256 μg ai / L treatment groups respectively. The

difference was significant for the three highest concentrations.

All validity criteria were met. The validity criterion of control immobility less

than 10% is fulfilled. The validity criterion of oxygen saturation above 60% is

fulfilled.

The 48h-EC50 was nominally 230 μg ai/L (95% CL: 162 to 414 μg ai/L).

The 48h-NOEC was 32 μg ai/L. All endpoints are based on analytically

confirmed nominal concentrations.

Conclusion EC50 = 230 μg ai/L

NOEC = 32 μg ai/L

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Table 168: Toxicity to sediment-dwelling organisms- spiked water – study 2


Flag Key study


Exposure 28 days, static conditions, spiked water

Test species Midge (Chironomus riparius)

Endpoint NOEC

Value 0.80 μg ai/L

Reference

Silke G. (2015) Chironomus riparius 28-day chronic toxicity test with BCS-

CL73507 (tech) in a water-sediment system using spiked water. Report no

EBFVP127, M-532889-01-1

Klimisch Score 1


GLP yes


Dose Levels 0.20, 0.40, 0.80, 1.60, 3.20, and 6.40 µg test substance/L, nominal

0.22, 0.43, 0.87, 1.76, 3.58, 7.30 µg test substance/L, initial measured


Study Summary


emergence and development of Chironomus riparius.


system over a period of 28 days to the nominal concentrations of 0.20,

0.40, 0.80, 1.60, 3.20, and 6.40 µg test substance/ L of a water-sediment

system. In addition, a water control and solvent control (DMF) were tested.

Four replicates, containing 20 animals each, were tested for each test item

concentration and the controls.

During the study, the measured concentrations of tetraniliprole and its

metabolite tetraniliprole-N-methyl- quinazolinone (BCS-CQ63359) were

analysed in the overlying water of the sediment-water four times, on day 0,

4, 8 and 28 in all test levels and also in the control(s). Water temperature,

pH and dissolved oxygen were measured regularly.

Analyses of the overlying water at the beginning of the exposure period

(nearly one hour after spiking) reflect high recoveries of tetraniliprole with

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108% to 114% (mean 110%) of nominal concentrations in all test levels,

thus all results and reporting are based on nominal initial concentrations of

tetraniliprole in the overlying water, expressed in μg ai/L.

Exposure recoveries of tetraniliprole in the overlying water of all test

concentrations were found after 4 days of 52% to 57% (mean 54%), after 8

days of 22% to 31% (mean 27 %) and after 28 days 0% to 1.8% (mean

1.7%).

Chemical analysis of metabolite BCS-CQ63359 (averages) over time yield

0.5% of nominal on day 0, 16% on day 4, 17% on day 8 and 4.4% on day

28.

Initial measured

conc (μg ai / kg)

Number of

emerged

midges

% of emerged

larvae

Development

rate (pooled

sex)

Pooled controls 150 93.75 0.065

0.22 71 88.75 0.067

0.43 67 83.75 0.064

0.87 73 91.25 0.066

1.76 65 81.25* 0.051*

3.58 48 60.0* 0.042*

7.30 6 7.50* 0.038*


Emergence, sex and development rates were determined. A statistically

significant difference in emergence was determined for initial measured

test concentrations from 1.76 μg ai/L and upwards compared to the pooled

controls, resulting in a NOEC of 0.80 μg ai/L. The EC10 value for the

emergence rate was determined to be 0.71 μg ai/L.

No statistically different distribution between sexes compared to the

assumption of 50% females and 50% males was observed.

For the development rate (pooled sex) a statistically significant difference

was found for initial measured test concentrations of 1.76 μg ai/L and

upwards compared to the pooled controls, resulting in a NOEC of 0.80 μg

ai/L. The EC10 value for the emergence rate was determined to be 1.00 μg

ai/L.

All validity criteria were met. The emergence in the control(s) had to reach

at least 70% of introduced larvae at the end of the test. The emergence

should occur between 12 and 23 days after their insertion into the control

vessels. The oxygen content in the Waterbody had to be > 60% of

saturation at the end of the test in all test vessels. The pH of the overlying

water had to be between 6 and 9 in all test vessels. The water temperature

had not to differ by more than ± 1°C over the whole exposure period.

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Conclusion NOEC = 0.80 μg ai/ L

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Soil organisms [9.2]

Earthworms

Table 169: Acute toxicity - earthworms

Study type Full test, acute toxicity earthworm

Flag Key study


Exposure 14 d

Test species Earthworm, Eisenia fetida

Endpoint LC50

Value >1000 mg test substance /kg soil

Reference Friedrich S. (2013), BCS-CL73507 ai- Acute toxicity to the earthworm

Eisenia fetida in artificial soil. Report no 13 10 48 127 S, M-469589-01-1

Klimisch Score 1


GLP yes

Test Guideline/s OECD 207, ISO 11268-1

Dose Levels 100, 178, 316, 562 and 1000 mg test substance/kg dry weight of soil

Analytical measurements NA

Study Summary


survival and growth of earthworms.

Adult earthworms (about 3 months old, four replicates of 10) were exposed

in an artificial soil system over a period of 14 days to concentrations of 100,

178, 316, 562 and 1000 mg test item / kg dry weight of soil containing 69.5%

quartz sand, 20% kaolin clay, 10% sphagnum peat and 0.5% CaCO3. In

addition, an untreated control was tested. A toxic reference (2-

chloroacetamide) was tested in a separate study.

Temperature ranged from 18 to 22 °C and the photoperiod was continuous

light at 550 lux. Mortality and biomass change were determined after 14

days and were used to determine the endpoints.

The validity criteria were met. Mortality in control ≤ 10% (observed 0%) and

loss of biomass ≤20% (observed 6.8%).

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No mortality was observed in most of the treatments with the exception of

178 mg ai/kg soil which had 2.5% mortality.

Biomass change expressed as wet weight was -6.8% in the control. The

biomass change was -7.2%, -6.6%, -6.9%, -7.0% and -7.1% at the

concentrations 100, 178, 316, 562 and 1000 mg ai/kg respectively.

No significant effects were observed.

The 14-day-LC50 was > 1000 mg test item/kg dry weight soil (the highest

concentration tested), the 14-day-NOEC was determined to be 1000 mg test

item/kg dry weight soil.

Conclusion LC50 >1000 mg test substance /kg soil

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Soil microflora

Nitrogen transformation

Table 170: toxicity to soil microflora – nitrogen transformation - study 1

Study type Toxicity soil microflora, nitrogen transformation

Flag Key study


Exposure 28 d

Test species Soil microflora

Endpoint Effects on nitrogen transformation

Value No adverse effects observed

Reference

Schulz L. (2013), BCS-CL73507 ai Effects on the activity of soil

microflora (Nitrogen transformation test). Report no EBFVP013, M-

460650-01-1

Klimisch Score 1


GLP yes


Dose Levels 0.30 and 1.49 mg test substance / kg dry soil

(equivalent to 0.223 and 1.116 kg test substance / ha)


Study Summary

The aim of the study was to determine the effects of tetraniliprole on soil

microflora activity (nitrogen transformation).

Application rates were equivalent to 0.223 and 1.116 kg test

substance/ha. The nitrogen transformation was determined in soil (sandy

loam, pH 6.5, % C 1.38, WHC 36.61) enriched with lucerne meal

(concentration in soil 0.5 %). NH4-nitrogen, NO3- and NO2- nitrogen

were determined by an Autoanalyzer at different sampling intervals (0, 7,

14 and 28 DAT). Three replicates were used.

In a separate study, the reference substance dinoterb caused a

stimulation of nitrogen transformation of +33.7 % and +42.6 % at 16.00

mg and 27.00 mg dinoterb per kg soil dry weight, respectively,

determined 28 days after application.

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The coefficients of variation in the control (NO3-N) were maximum 1.2 %

and thus fulfilled the demanded range (≤15 %).

BCS-CL73507 caused a temporary inhibition of the daily nitrate rate at

the tested concentrations of 0.30 mg/kg and 1.49 mg/kg dry soil at time

interval 7-14 days after application (-30.2% and -46.7% respectively).

However, no adverse effects of BCS-CL73507 on nitrogen

transformation in soil could be observed at both test concentrations (0.30

mg and 1.49 mg test substance/kg dry soil) at the end of the test, 28

days after application (time interval 14-28). Differences from the control

of +11.3 % (test concentration 0.30 mg/kg dry soil) and +21.3 % (test

concentration 1.49 mg/kg dry soil) were measured at the end of the 28-

day incubation period (time interval 14-28).

BCS-CL73507 caused no adverse effects (difference to control < 25 %)

on the soil nitrogen transformation (measured as NO3-N production) at

the end of the 28-day incubation period.

Conclusion Active ingredient did not cause adverse effects on nitrogen

transformation up to a rate of 1.116 kg test substance/ ha.

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Table 171: toxicity to soil microflora – nitrogen transformation - study 2


Flag Key study


Exposure 28 d




Reference

Schulz L. (2016), BCS-CL73507 ai Effects on the activity of soil microflora

tested in a natural soil (clay loam) (Nitrogen transformation test). Report no

EBFVP139, M-546745-01-1

Klimisch Score 1


GLP yes


Dose Levels 0.3 and 1.49 mg test substance/kg dry soil

(equivalent to 0.223 and 1.116 kg test substance/ha)


Study Summary

The aim of the study was to determine the effects of tetraniliprole on soil

microflora activity (nitrogen transformation).

Application rates were equivalent to 0.223 and 1.116 kg test substance/ha.

The nitrogen transformation was determined in soil (clay loam, pH 7.0, %

C 2.41, WHC 43.63) enriched with lucerne meal (concentration in soil 0.5

%). NH4-nitrogen, NO3- and NO2- nitrogen were determined by an

Autoanalyzer at different sampling intervals (0, 7, 14 and 28 DAT, 3

replicates).

In a separate study, the reference substance dinoterb caused a stimulation

of nitrogen transformation of +109.5 %, +212.8 % and 155.6% at 13.00 mg

and 27.00 mg and 40.0 mg dinoterb per kg soil dry weight, respectively,




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BCS-CL73507 caused a temporary non-significant inhibition of the daily

nitrate rate at the tested concentrations of 1.49 mg/kg dry soil at time

interval 7-14 days after application (up to -42.4%). However, no adverse

effects of BCS-CL73507 on nitrogen transformation in soil could be

observed at both test concentrations (0.30 mg and 1.49 mg test

substance/kg dry soil) at the end of the test, 28 days after application (time

interval 14-28). Differences from the control of +1.8 % (test concentration

0.30 mg/kg dry soil) and +0.9 % (test concentration 1.49 mg/kg dry soil)

were measured at the end of the 28-day incubation period (time interval

14-28).

BCS-CL73507 caused no adverse effects (difference to control < 25 %) on

the soil nitrogen transformation (measured as NO3-N production) at the

end of the 28-day incubation period.

Conclusion Active ingredient did not cause adverse effects on nitrogen transformation

up to a rate of 1.116 kg test substance/ha (1.0 kg ai/ha).

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Carbon transformation

Table 172: toxicity to soil microflora – carbon transformation - study 1

Study type Toxicity soil microflora, carbon transformation

Flag Key study


Exposure 28 d


Endpoint Effects on carbon transformation


Reference


microflora (Carbon transformation test). Report no EBFVP012, M-

460648-01-1

Klimisch Score 1


GLP yes





Study Summary


soil microflora activity (carbon transformation).


substance/ha. The carbon transformation was determined in soil

(sandy loam, pH 6.5, % C 1.38, WHC 36.61). Determination of carbon

transformation in soil was performed after addition of glucose. A

respirometer system was used to determine the O2- consumption over

a period of maximum 12 hours at different sampling intervals (0, 7, 14

and 28 DAT, 3 replicates).

In a separate study, the reference substance dinoterb caused an

inhibition of carbon transformation of -39.3 % and -45.2 % at 16.0 mg

and 27.0 mg dinoterb per kg soil dry weight, respectively, determined

28 days after application.

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The coefficients of variation in the control were maximum 2.0 % and

thus fulfilled the demanded range (≤15 %).

No adverse effects of BCS-CL73507 on carbon transformation in soil

were observed at both test concentrations (0.30 mg/kg dry soil and

1.49 mg/kg dry soil) after 28 days. Differences from control of +0.05 %

(test concentration 0.30 mg/kg dry soil) and -4.04 % (test concentration

1.49 mg/kg dry soil) were measured at the end of the 28-day incubation

period.


on the soil carbon transformation (measured as oxygen consumption)

at the end of the 28-day incubation period.

Conclusion

Active ingredient did not cause adverse effects on carbon

transformation up to a rate of 1.116 kg test substance/ ha (=1.0 kg

ai/ha).

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Table 173: toxicity to soil microflora – carbon transformation - study 2


Flag Key study


Exposure 28 d




Reference


microflora tested in a natural soil (clay loam) (Carbon transformation

test). Report no EBFVN138, M-546743-01-1

Klimisch Score 1


GLP yes





Study Summary


soil microflora activity (carbon transformation).


substance/ha. The carbon transformation was determined in soil (clay

loam, pH 7.0, % C 2.41, WHC 43.63). Determination of carbon

transformation in soil was performed after addition of glucose. A

respirometer system was used to determine the O2- consumption over

a period of maximum 12 hours at different sampling intervals (0, 7, 14

and 28 DAT, 3 replicates).


inhibition of carbon transformation of -33.1 % and -47.6 % and -44.7%

at 13.0 mg and 27.0 mg and 40.0 mg dinoterb per kg soil dry weight,

respectively, determined 28 days after application.

The coefficients of variation in the control were maximum 9.6 % and

thus fulfilled the demanded range (≤15 %).

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No adverse effects of BCS-CL73507 on carbon transformation in soil

were observed at both test concentrations (0.30 mg/kg dry soil and

1.49 mg/kg dry soil) after 28 days. Differences from control of +0.2 %

(test concentration 0.30 mg/kg dry soil) and -6.0 % (test concentration

1.49 mg/kg dry soil) were measured at the end of the 28-day incubation

period.


on the soil carbon transformation (measured as oxygen consumption)

at the end of the 28-day incubation period.

Conclusion

Active ingredient did not cause adverse effects on carbon

transformation up to a rate of 1.116 kg test substance/ ha (=1.0 kg

ai/ha).

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Terrestrial vertebrates [9.3]

Birds

Acute toxicity

Table 174: Acute toxicity – birds – study 1

Study type Limit acute toxicity test to birds

Flag Key study


Exposure oral

Test species Northern bobwhite quail

Endpoint LD50

Value >2000 mg ai/ kg bw

Reference

Loveall J.L., Christ M.T. (2014), Toxicity of BCS-CL73507 technical during

an acute oral LD50 with the Northern bobwhite quail (Colinus virginianus).


Klimisch Score 1


GLP yes


Dose Levels 2000 mg ai/ kg bw


Study Summary


Northern bobwhite quail (Colinus virginianus).

Twenty-six-week old adult Northern bobwhite quail were orally dosed via

gelatine capsules at a limit dose level of 2000 mg ai/kg body weight,

adjusted for purity, in comparison to an untreated control group, and

subsequently monitored for a period of 14 days. Ten birds (5 males and 5

females) were exposed for to the substance and included in the control.

Mortality, signs of intoxication, food consumption, body weight and gross

necropsy results were evaluated to determine the endpoints.

There were no mortalities in the control or the 2000 mg ai/kg b.w.

treatment group. Therefore, the validity criteria were met. There were no

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observed effects in the control or 2000 mg ai/kg b.w. treatment group

during the study.

All birds appeared normal following dosing with no effects of regurgitation

observed.

Body weight and individual food consumption measurements were not

significantly different from the control group.

Post mortem examinations revealed no treatment-related gross lesions or

unusual observations.

The acute oral LD50 for tetraniliprole in Northern Bobwhite quail was >

2000 mg ai/kg body weight. The Lowest Lethal Dose (LLD) was > 2000 mg

ai/kg bw.

Conclusion LD50 > 2000 mg ai/ kg bw

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Study type Limit test, acute toxicity to birds

Flag Key study


Exposure oral

Test species Canary (Serinus canaria)

Endpoint LD50


Reference

Loveall J.L., Christ M.T. (2015), Toxicity of BCS-CL73507 technical

during an acute oral LD50 with the canary (Serinus canaria). Report no

EBFVP008, M-521691-01-1

Klimisch Score 1


GLP yes




Study Summary


to canary (Serinus canarias). Two tests were performed, test 1 with 5

males and 5 females ranging from 8 months to 2.5 years old and test 2

with two males and five females of 9 to 12 months old.

The birds were orally dosed via gelatine capsules at a limit dose level of

2000 mg ai/kg body weight, adjusted for purity, in comparison to an

untreated control group, and subsequently monitored for a period of 14

days. Mortality, signs of intoxication, food consumption, body weight and

gross necropsy results were evaluated to determine the endpoints.

There were no mortalities in the control of both tests. Therefore, the


Test 1: One bird was found dead on Day 1 in the 2000 mg ai/kg body

weight treatment group. Four birds were observed with hyporeactivity to

stimuli and one bird exhibited ataxia in the 2000 mg ai/kg body weight

treatment group during Day 0 of the study. All canaries returned to

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normal behaviour by Day 1. No instances of regurgitation were observed

for any birds following dose administration.

Body weight measurements were not significantly different between

treatment and control groups. Body weight change for the 2000 mg ai/kg

b.w. treatment group was significantly different from the control for the

Day -1 to Day 7 interval. For the other intervals, there were no significant

differences.

Test 2: No mortality was observed. Three birds were observed with hypo-

reactivity to stimuli in the 2000 mg ai/kg body weight treatment group. All

canaries returned to normal behaviour by the end of Day 1. No instances

of regurgitation were observed for any birds following dose

administration.

Body weight measurements and changes in body weight for the 2000 mg

ai/kg treatment group were not significantly different from the control

group for any time interval.

The acute oral LD50 for tetraniliprole in canary was > 2000 mg ai/kg body

weight.


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Study type Limit test, acute toxicity test to birds

Flag Key study


Exposure oral

Test species Chicken (Gallus gallus domesticus)

Endpoint LD50


Reference

Hahne J., Breuer -Rehm M. (2015), Acute oral limit test toxicity of

tetraniliprole to chicken (Gallus gallus domesticus). Report no

EBFVP021, M-529716-01-1

Klimisch Score 1


GLP yes




Study Summary


on chicken (Gallus gallus domesticus). Adult female chickens (4-5

months old) were housed individually and acclimated to laboratory

conditions for 18 days. After this period, they were orally dosed one-

time with gelatine capsules filled with the test substance. The limit dose

group of 5 chickens was dosed with 2000 mg ai per kg body weight.

Additionally, 5 control chickens were dosed with empty capsules. After

dosing, all chickens were continuously observed for a time period of 14

days.

Mortality and signs of intoxication were observed continuously during

the first two hours and hourly on the day of dosing and at least once

daily throughout the 14 days observation period. Body weights were

recorded at day -1 (one day before dosing), on study days 3 and 7, and

on day 14 (termination of the study). Feed consumption was measured

daily until day 3 after dosing and afterwards for the time period of days

7 – 14. On study days 1, 2, 3, 7 and 14 all remaining feed was replaced

by fresh feed after cleaning of the feeding container. At the end of the

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study all surviving chickens were sacrificed by CO2 asphyxiation and

afterwards, gross necropsies were carried out on all the sacrificed

chickens.

No mortality was observed in the control, so the validity criteria were

met.

No mortality was observed. During the whole experimental phase (0-14

days), all chickens showed a good and healthy condition. No

symptoms were visible. The food consumption and body weight

change were similar between control and dosed animals.

No signs of intoxication were found during gross pathology.

The acute oral LD50 for tetraniliprole in chicken was > 2000 mg ai/kg

body weight.


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Chronic toxicity

Table 177: Chronic toxicity to birds – study 1

Study type Full test, Dietary toxicity test to birds

Flag Key study


Exposure Dietary, 5 days exposure + 3 days observation


Endpoint LC50 and NOAEL

Value LC50 > 772 mg ai/ kg bw/ d, NOAEL= 473 mg ai/ kg bw/d

Reference

Christ M.T., Moore S.M. (2015), Toxicity of BCS-CL73507 technical

during a dietary LC50 with the Northern bobwhite quail (Colinus

virginianus). Report no EBFVP022, M-521692-01-1

Klimisch Score 1


GLP yes


Dose Levels 313, 625, 1250, 2500 and 5000 mg ai/ kg feed, nominal

394, 691, 1308, 2579, and 5391 mg ai/ kg feed, mean measured

Analytical measurements HPLC-UV

Study Summary

The aim of the study was to determine the sub-acute dietary toxicity

of tetraniliprole technical to bobwhite quail (Colinus virginianus).

Colinus virginianus hatchlings (10 days old) were exposed to treated

feed during a period of 5 days and observed thereafter for another 3

days while fed with untreated feed. 10 hatchlings per treatment level

were tested. In addition, a control containing 10 hatchlings was

included. Nominal concentrations in feed were 0 (untreated control),

313, 625, 1250, 2500 and 5000 mg ai/ kg feed. The average

measured amounts of tetraniliprole were determined as 0 (<LOQ),

394, 691, 1308, 2579, and 5391 mg ai/ kg feed, respectively. The

recovery amounts of tetraniliprole ranged from 103% to 126% of

nominal.

Mortality, signs of intoxication, food consumption, body weight and

gross necropsy were used to determine the endpoints.

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One mortality occurred during the study in the 5391 mg ai/ kg

treatment level. No clinical signs of toxicity or treatment-related

mortalities were noted at any treatment level. Observations at

necropsy included two birds in the control and five birds in the 5391

mg ai/kg treatment group with skin abrasions (ie cuts) on the feet and

legs due to pen-mate aggression. A number of birds were also

observed with gas-filled intestines as follows: control (3), 394 (1), 691

(2), 1308 (2), 2579 (3), and 5391 (1) mg ai/kg feed. Post-mortem

examinations revealed no gross lesions or unusual observations.

Body weight was significantly reduced from the control group at the

5391 mg ai/kg feed level for all body weight change time-points.

Other concentrations did not cause significant weight changes.

There was an apparent reduction in feed consumption in the

treatment level 5391 mg ai/kg feed during the exposure period based

on empirical analysis. However, there was increasing uncertainty

regarding the effect of the highest treatment level on body weight,

body weight change, and feed consumption since there was a

significant effect on body weight change and a reduction in feed

consumption prior to the introduction of treated feed (pre-exposure

phase) in the 5391 mg ai/kg feed level. Other treatment levels did not

cause significant differences in food consumption.

The dietary LC50 of tetraniliprole technical fed to Northern Bobwhite

quail was >5391 mg ai/kg feed or >772 mg ai/kg body weight/ day.

Based on all parameters measured, the NOAEL was 2579 mg ai/kg

feed (473 mg ai/kg body weight/day) and the LOEC was 5391 mg

ai/kg feed (772 mg ai/kg body weight/day).

No mortality was observed in the control. Measured concentrations of

test substance in the feed were above 80% of nominal. Therefore,

the validity criteria were met.

Conclusion LC50 > 772 mg ai/ kg bw/d, NOAEL = 473 mg ai/ kg bw/d

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Study type Full test, Dietary toxicity test to birds

Flag Key study


Exposure Dietary, 5 days exposure + 3 days observation

Test species Mallard duck

Endpoint LC50 and NOAEL

Value LC50 > 1450 mg ai/ kg bw/ d, NOAEL= 374 mg ai/ kg bw/d

Reference

Shephard J., Christ M.T., Moore S.M. (2014), Toxicity of BCS-

CL73507 technical during a dietary LC50 with the Mallard duck (Anas

platyrhynchos). Report no 07SRLS13C68, M-508260-01-1

Klimisch Score 1


GLP yes


Dose Levels 313, 625, 1250, 2500 and 5000 mg ai/ kg feed, nominal

329, 648, 1294, 2573 and 5121 mg ai/ kg feed, mean measured

Analytical measurements yes

Study Summary

The aim of the study was to determine the sub-acute dietary toxicity

of tetraniliprole technical to mallard duck (Anas platyrhynchos).

Duck hatchlings (5 days old) were exposed to treated feed during a

period of 5 days and observed thereafter for another 3 days while fed

with untreated feed. Nominal concentrations in feed were 0

(untreated control), 313, 625, 1250, 2500 and 5000 mg ai/ kg feed.

The average measured amounts of tetraniliprole were determined as

329, 648, 1294, 2573 and 5121 mg ai/ kg feed which corresponded to

daily uptake doses of 94, 176, 374, 660 and 1450 mg ai/kg body

weight/day, respectively. 10 Ducklings were exposed per

concentration, a control of 10 Ducklings was added.

Mortality, signs of intoxication, food consumption, body weight and

gross necropsy were used to determine the endpoints.

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No clinical signs of toxicity or mortalities were noted at any treatment

level. Post-mortem examinations revealed no gross lesions or

unusual observations.

In 329 and 1294 mg ai/kg feed no statistically significant reduction in

body weight was observed compared to the control. The body weight

and feed consumption for the 648 mg ai/kg feed treatment level was

not considered to be biologically significant as the birds lost weight

prior to the addition of treated feed (Day -3 to -1). In addition, there

were no abnormal clinical observations or necropsy findings noted for

the 648 mg ai/kg feed treatment level. Furthermore, no statistically

significant effects for body weight or body weight change were

observed for the 1294 mg ai/kg feed treatment level.

Also, a statistically significant reduction in body weight changes was

observed at the two highest rates 2573 and 5121 mg ai/kg feed.

Feed consumption was reduced in the 648, 2573, and 5121 mg ai/kg

feed during the exposure and recovery periods (significantly

different).

The dietary LC50 of tetraniliprole technical fed to the mallard duck

was >5121 mg ai/kg feed or >1450 mg ai/kg body weight.


test substance in the feed were above 80% of nominal. Therefore,

the validity criteria were met.

Conclusion LC50 > 1450 mg ai/ kg bw/d, NOAEL = 374 mg ai/ kg bw/d

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Study type Reproduction toxicity test

Flag Key study


Exposure Reproduction, 23 weeks


Endpoint NOEL

Value 78 mg ai/ kg bw/d

Reference

Shepherd J., Christ M.T., Moore S.M. (2016), Toxicity of BCS-CL73507

technical on the reproduction of the Northern bobwhite quail (Colinus

virginianus). Amended final report. Report no 07SRLS14C4, M-

542825-02-1

Klimisch Score 1


GLP yes


Dose Levels 111, 333 and 1000 mg ai/kg feed, nominal

120, 350 and 1078 mg ai/ kg feed, mean measured

Analytical measurements yes

Study Summary

The aim of the study was to determine the dietary toxicity of

tetraniliprole technical to bobwhite quail (Colinus virginianus).

Eighteen pairs of birds per treatment of Colinus virginianus (approx. 23

weeks old) were exposed to treated feed during a period of 23 weeks.

Nominal concentrations in feed were 0 (control), 111, 333 and 1000 mg

ai/kg feed (=ppm), respectively, which corresponded to mean

measured concentrations of 0, 120 (108% of nominal), 350 (105% of

nominal) and 1078 (108% of nominal) ppm, respectively, and achieved

daily doses of 0, 9, 25 and 78 mg ai/kg body weight per day,

respectively.

Birds were observed for mortality, abnormal behaviour and signs of

toxicity; adult body weight and feed consumption were measured;

gross pathology was conducted; reproductive parameters, as well as

hatchling health, growth and survival, were examined.

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Four adult mortalities occurred during the test with two birds in the 111

ppm level, one bird in the 333 ppm level, and one bird in the 1000 ppm

level. No adult mortalities occurred in the control group.

No effects were observed in feed consumption and body weight gain

for males and females.

Reproduction parameters are presented below.

Parameter Control 111 mg

ai/kg feed

333 mg

ai/kg feed

1000 mg

ai/kg feed

# eggs per hen 67.3 64.6 66.5 61.1

#eggs cracked per

hen 0.56 1.06 0.29 0.18

Eggshell thickness

(mm) 0.21 0.20 0.21 0.20

%live embryos of

viable embryos per

hen

99.02 97.60 99.71 99.44

% no hatched eggs

laid per hen 83.96 80.17 85.94 81.63

%survived hatchlings

of eggs set per hen 91.69 85.13 92.42 90.25

There were no statistically significant differences at any treatment level

as compared to the control for the number of eggs laid or cracked and

eggshell thickness.

There were no statistically significant treatment-related differences for

% live embryos, the number hatched and hatchling survival, percent

number hatched of eggs set, percent number hatched of eggs laid,

percent number hatched of live embryos and percent 14-day survivors

of eggs set. The NOEL for these endpoints was determined to be 1000

mg ai /kg food for this study.

Necropsy of the adult birds at study termination showed no apparent

treatment-related effects.

The NOEL for both parental toxicity and reproduction endpoints of

northern bobwhite quail exposed to tetraniliprole technical over a 23-

week period was 1000 ppm (mg ai/kg feed; nominal test level), with a

measured concentration of 1078 mg ai/kg feed or the mean achieved

dose of 78 mg ai/kg bw/day.

The Lowest Observed Effect Level (LOEL) was >1000 ppm (nominal

test level) equivalent to the measured concentration of 1078 ppm or the

achieved dose of 78 mg ai/kg bw/day.


test substance in the feed were above 80% of nominal. The shell

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thickness of eggs from the controls was above the species-specific

threshold. The average number of 14-day-old survivors per hen in the

controls was above the species-specific threshold. Therefore, the


Conclusion NOEL = 78 mg ai/ kg bw/d

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Study type Reproduction toxicity test

Flag Key study


Exposure Reproduction, 23 weeks

Test species Mallard duck

Endpoint NOEL

Value 42.9 mg ai/ kg bw/d

Reference Bryden M., Temple D., Danos L., Martin K (2016), BCS-CL73507: A

reproduction study with the mallard. Report no149B-226, M-570069-02-1

Klimisch Score 1


GLP yes


Dose Levels 111, 333 and 1000 mg ai/kg feed, nominal

109, 325 and 938 mg ai/ kg feed, mean measured


Study Summary

The aim of the study was to determine the reproductive effects upon the

adult mallard (Anas platyrhynchos) of dietary exposure to tetraniliprole

technical.

Eighteen pairs of birds per treatment (approx. 25 weeks old) were

exposed to treated feed during a period of 20 weeks. Nominal

concentrations in feed were 0 (control), 111, 333 and 1000 mg ai/kg feed

(=ppm), respectively, which corresponded to mean measured

concentrations of 0, 109 (98% of nominal), 325 (98% of nominal) and

938 (94% of nominal) ppm, respectively, and achieved daily doses of 0,

14.1, 42.9 and 129.5 mg ai/kg body weight per day, respectively.

Birds were observed for mortality, abnormal behaviour and signs of

toxicity; adult body weight and feed consumption were measured; gross

pathology was conducted; reproductive parameters, as well as hatchling

health, growth and survival, were examined.

A single mortality occurred during the test in the 111 ppm level.

Based upon the necropsy findings this mortality was not considered to

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have been related to treatment. No mortalities occurred in the control group or in the other treatment groups.

No effects were observed in feed consumption and body weight gain.

Reproduction parameters are presented below.

parameter control 111 ppm 333

ppm

1000

ppm

Total eggs

laid/group 846 840 791 727

Eggs laid/hen 47 49 44 40

Egg shell

thickness (mm) 0.383 0.368 0.374 0.375

Eggs cracked 2 2 0 0

Viable embryos 712 704 654 584

Hatchlings 631 636 574 503

14 day old

Survivors 624 628 568 498

14 day old chick

body weight (g) 297 301 288 280*

* significant difference from control

There were no statistically significant differences at any treatment level

as compared to the control for the number of eggs laid or cracked and

eggshell thickness.

The only significant treatment-related difference observed was the body

weight of the 14-day old hatchlings at the dose of 1000 ppm.

Necropsy of the adult birds at study termination showed no apparent

treatment-related effects.

The NOEL for both parental toxicity and reproduction endpoints of

mallard duck exposed to tetraniliprole technical over a 20-week period

was 333 ppm (mg ai/kg feed; nominal test level), corresponding with 42.9

mg ai/kg bw/day.


test substance in the feed were above 80% of nominal. The shell

thickness of eggs from the controls was above the species-specific

threshold. The average number of 14-day-old survivors per hen in the

controls was above the species-specific threshold. Therefore, the validity

criteria were met.

Conclusion NOEL = 42.9 mg ai/ kg bw/d

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Terrestrial invertebrates [9.4]

Pollinators

Honey bees

Acute toxicity

Table 181: Acute oral and contact toxicity of tetraniliprole to adult honey bees

Study type Acute oral and contact toxicity test in adult honey bees

Flag Key study


Exposure 72 hours (oral test), 96 hours (contact test)

Test species Apis mellifera L.

Endpoint LD50, behavioural abnormalities

Value

Oral LD50 = 0.010 µg ai/bee (72 hours)

NOED = 0.0067 µg ai/bee (72 hours)

Contact LD50 = 0.41 µg ai/bee (96 hours)


Reference

Schmitzer S. 2012. Effects of BCS-CL73507 tech. (acute contact and oral) on

honey bees (Apis mellifera L.) in the laboratory

IBACON GmbH, Arheilger Weg 17, 64380 Rossdorf, Germany

Klimisch Score 1


GLP Yes

Test Guideline/s OECD 213 and 214

No/Sex/Group 10 per replicate, all females, 3 replicates per treatment group

Dose Levels Oral: 0.14, 0.069, 0.031, 0.020, 0.012 and 0.0067 μg ai/bee

Contact: 2.0, 1.0, 0.50, 0.25, 0.13 and 0.063 µg ai/bee (5 μLdroplet)


Study Summary

The purpose of the study was to determine the effects of tetraniliprole (purity:

91.8% w/w) on mortality of the honey bee after oral or contact exposure. For

the contact test, a wetting agent was used.

Oral test:

In the sugar solution and acetone control groups of the oral toxicity test, no

mortality occurred during the 72-hour observation period. The 24-hour oral

LD50 value for the reference substance was 0.12 μg dimethoate/bee and

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within the acceptable range. Consequently, validity criteria for both control and

reference substance mortality were met and the test was deemed valid.

In the oral toxicity test, in the group treated with of 0.012 µg ai/bee, mortality

increased by 10% between 24h and 48h, therefore, the test was prolonged to

72 hours.

At the highest tested dose level of 0.14 µg ai/bee, 100% mortality was

observed after 48 hours. At the end of the test, treatment-related mortalities

were observed at 0.069 µg ai/bee (100% mortality), 0.031 µg ai/bee (100%

mortality), 0.020 µg ai/bee (100% mortality), 0.012 µg ai/bee (73.3% mortality)

and 0.0067 µg ai/bee (3.3% mortality). Behavioural abnormalities (apathy)

were observed in the surviving bees up to 24 hours after treatment in all

treatment groups. Thereafter, no effects were observed.

Contact test:

In the water and acetone control groups of the contact toxicity test, 3.3%

mortality occurred during the 96-hour observation period. The 24-hour contact

LD50 value for the reference substance was 0.26 μg dimethoate/bee and

within the acceptable range. Consequently, validity criteria for both control and


In the contact toxicity test, at the highest tested dose level of 2 µg ai/bee,

mortality increased by 60% between 24h and 48h, therefore the test was

prolonged to 96 hours. 96.7% mortality was observed after 96 hours. At the

end of the test, treatment-related mortalities were observed at 1 µg ai/bee

(76.7 % mortality), 0.5 µg ai/bee (66.7% mortality), 0.25 µg ai/bee (46.7%

mortality) and 0.13 µg ai/bee (3.3% mortality). During the whole test

behavioural abnormalities (eg movement coordination problems and/or

apathy) were observed in the surviving bees for groups treated with 0.25 µg

and higher doses, except at 2.0 µg ai/bee at which no effects were observed

at the end of the test. No behavioural abnormalities were found in the 0.13 and

0.063 μg ai/bee dose groups during the exposure period.

Conclusion Oral LD50 = 0.010 μg ai/bee (72 hours)

Contact LD50 = 0.410 μg ai/bee (96 hours)

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Table 182: Acute oral toxicity of tetraniliprole to honey bee larvae

Study type Acute oral toxicity test in honey bee larvae

Flag Key study


Exposure 72 hours (oral test), 96 hours (contact test)

Test species Apis mellifera carnica

Endpoint LD50

Value

Oral LD50 = 0.0172 μg ai/larva (72h)

LOED = 0.010 μg ai/larva (72h)

NOED = 0.0033 μg ai/larva (72h)

Oral LD50 = 0.0128 μg ai/larva (96h)

LOED = 0.010 μg ai/larva (96h)


Reference

Rottenberger A, Przygoda D, Theis M, Gladbach D. 2014. BCS-CL73507 tech.:

Effects of a single exposure to spiked diet on honey bee larvae (Apis mellifera

carnica) in an in vitro laboratory testing design

Bayer CropScience AG, BCS-AG-D-EnSa-Testing, 40789 Monheim, Germany

Klimisch Score 1


GLP Yes

Test Guideline/s

OECD Draft Test Guideline on Honey Bee (Apis mellifera) Larval Toxicity Test,

Single Exposure (Version of 21 February 2013) post–WNT25 Approval Larval

Honey Bee Test (April 2013)

No/Sex/Group 16 larvae per replicate, females, 3 replicates per treatment group

Dose Levels Nominal doses: 0.0011, 0.0033, 0.010, 0.030 and 0.090 μg ai/larva


Study Summary

The purpose of this study was to assess the effects of tetraniliprole on honey

bee larvae, after a single exposure (feeding) event, using spiked diet after four

days of acclimatisation in an in vitro laboratory testing design. Mortality

thereafter was monitored for 72h after which the test was extended for another

24 hours.

Analytical measurements showed that the concentration of the stock solution

was within the nominal concentration (103% of nominal).

No mortality was recorded in the water control group, 4.2% mortality was

recorded in the acetone control group. 89.6% mortality was recorded in the

group fed with 8.8 μg dimethoate/larva (corresponding to 266.7 mg/kg diet).

The validity criteria were met.

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At the highest tested dose level of 0.090 μg ai/bee, 91.7% mortality was

observed after 72 hours of exposure. Treatment-related mortalities were

observed at 0.030 μg ai/bee (79.2% mortality) and 0.010 μg ai/bee (27.1%

mortality).

Mortality was monitored for an additional day as recommended by the later

version of the guideline [published in 2015 but available as a draft at the time of

study completion]. At the highest tested dose level of 0.090 μg ai/bee, 95.8%

mortality was observed 96 hours after exposure. Treatment-related mortalities

were observed at 0.030 μg ai/bee (87.5% mortality) and 0.010 μg ai/bee

(29.2% mortality).

Conclusion Oral LD50 = 0.0172 μg ai/larva (72h)


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Chronic toxicity

Table 183: Chronic oral toxicity of tetraniliprole to honey bee larvae

Study type Chronic oral toxicity test in honey bee larvae

Flag Key study

Test Substance BCS-CL73507: technical tetraniliprole

Exposure 4 days (spiked diet administered from day 3 until day 6, mortality and

developmental effects monitored until day 22)

Test species Apis mellifera

Endpoint LD50

Value

Oral LD50 = 0.01209 μg ai/larva (cumulative dose over 4 days)

LOED = 0.030 μg ai/larva (19 days after first exposure)

NOED = 0.010 μg ai/larva (19 days after first exposure)

Reference

Przygoda D. 2016. Tetraniliprole tech. (BCS-CL73507): Effects of a repeated

exposure to spiked diet on honey bee larvae (Apis mellifera) in an in vitro

laboratory testing design

Bayer CropScience AG, BCS-AG-D-EnSa-Testing, Alfred-Nobel-Str. 50,

40789 Monheim, Germany

Klimisch Score 1


GLP Yes

Test Guideline/s OECD Draft Guidance Document for Testing Chemicals – Honey Bee (Apis

mellifera) Larval Toxicity Test, Repeated Exposure (April 2015)

No/Sex/Group 16 larvae per replicate (all females), 3 replicates per treatment group

Dose Levels

Nominal doses: 0.0024, 0.0072, 0.0216, 0.0649 and 0.1948 μg ai/g of diet

Cumulative nominal doses: 0.00037, 0.0001, 0.0033, 0.010 and 0.030 μg

ai/larva (cumulative dose after 4 days of feeding)


Study Summary

The purpose of this study was to assess potential adverse effects of

tetraniliprole on the development of honey bee larvae to adulthood in an in

vitro oral toxicity test over 22 days (exposure started 3 days after initiation of

the test) comparing control and treatment. The study was performed as a

dose-response test.

2.1% mortality was recorded in the water control group, no mortality was

recorded in the acetone control group. The adult emergence rate was 85.4%

in the water control group and 89.6% in the acetone control group. 95.7%

mortality was recorded in the group fed with 7.4 μg dimethoate/larva. The


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The actual content of tetraniliprole in the diet was tested and met the target

concentrations (106-112% of nominal concentration).

At the highest tested dose level of 0.030 μg ai/bee, 100% mortality was

observed at day 8. At 0.010 μg ai/larva mortality was 4.2% at day 8, but no

effects on adult emergence were observed. No treatment-related mortalities

or reduction in adult emergence were observed at doses up to 0.0033 μg

ai/larva. The number of larvae not consuming food at day 8 increased with

the concentration of the spiked diet (up to 9/46 for 0.010 μg ai/larva).

Comments

The first two attempts were unsuccessful due to mortality in the control

groups.

No hive treatment for at least 4 weeks prior to experiment.

The emergence weight and any deformities are not reported, this information

is not required but would be valuable.

Conclusion Oral LD50 = 0.01209 μg ai/larva (cumulative dose)

NOED = 0.010 μg ai/larva (cumulative dose)

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Field studies

Table 184: Field study on toxicity of tetraniliprole to honey bee colony

Type of study Field study toxicity to honey bee colony

Flag Key study

Test Substance Tetraniliprole

Exposure Oral exposure through supplementary feeding (2L replaced twice a week) for

6 weeks, observations for 9 months


Endpoints

Number of adult bees, eggs, pupae and larvae

Colony health (food stores, brood status and colony strength) during exposure

and after exposure

Varroa load 1 week before feeding, 1 week after end of feeding and 1 week

after winter by ethanol wash

Nosema: spore counts

Weight of hives: every hour

Residues

Reference

Louque J. 2016. Colony feeding study evaluating the chronic effects of

tetraniliprole-fortified sugar diet on honey bee colony health under free foraging

conditions

Smithers Viscient, Carolina Research Center, 2900 Quakenbush Road, Snow

Camp, NC 27349, USA

Klimisch Score 1

Amendments/Deviations None that are likely to affect the results of the study.

GLP Yes (some parts of the preliminary experiments were not GLP compliant)

Test Guideline/s OECD 2003 (statistics)

No/Group

12 colonies per treatment (reduced to 11 due to suspected poisoning in one

apiary), 24 colonies for controls, 84 hives in total, all colonies are from sister

queens

Hives located in 12 apiary sites (min 1 mile apart), 8 hives per apiary (2 control

hives, 5 treated hives, 1 hive for residues)

Dose Levels

81, 158, 318, 624 and 1720 μg ai/kg of feeding diet (mean measured

concentration in 50% sucrose), 3200 µg formulated product/L (pilot study, data

not shown)

Analytical


Study Summary

Study design:

A colony-feeding study was conducted with honey bees in a field setting with

free-foraging colonies, exposed through sucrose solution dosed with

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tetraniliprole at nominal rates of 100 ppb, 200 ppb, 400 ppb, 800 ppb or 3200

ppb. Mean measured concentrations of test solutions were 81, 158, 318, 624,

and 1720 μg/kg. The purpose of this study was to evaluate the potential of

tetraniliprole exposure to result in adverse effects on the long-term survival and

condition of honey bee colonies.

Treatment solutions were placed inside hives and renewed twice weekly over a

6-week exposure period. Assessments were made to evaluate the overall

colony performance at several time points during and after the exposure

period, as well as in the fall and following spring.

The hives were located in sites that lacked extensive acreages of crops treated

with pesticides and treated sucrose solutions were supplied during a time of

year when there was an expected dearth of available floral nectar.

Pilot study:

Pilot study performed with up to 500 µg ai/L showed no effect. Second pilot

study with concentrations ranging between 3.2 and 15 mg formulated product/L

induced mortality and reduced food intake. The concentrations chosen for the

definitive study were 3200 µg formulated product/L, 800 µg ai/L, and dilutions

1:2.

Stability of the test substance:

The test solutions were tested for their stability in field conditions, the

concentration ranged from 75% to 85% of the initial tetraniliprole concentration

for the diets with pure ai, and 81-94% with the diet with the formulated product.

Metabolite BCS CQ63359 was detected at 1.1 to 2.1% for diets containing

tetraniliprole and 0.11 to 0.21% for diets containing the formulated product.

External factors:

Suspected poisoning occurred in one apiary, all hives were therefore removed

from the analysis. No pesticide residues were found to be the cause of death.

Traces of clothianidin, 5 ppb of esfenvalerate and 108 ppb of cyhalothrin were

detected in pollen collected by foragers at several apiaries, these levels are

unlikely to affect the results of the study. Nectar had thymol due to Apivar

treatment but only during the last sampling.

Colony health:

Colony mortality is presented below.

Treatment Mortality Suspected cause

Control 11/22 Unknown (4), queen problem (5), varroa (2)

1720 μg ai /kg 10/12 Treatment (10), 1 of 2 surviving hives

contained only 242 adult bees and no eggs

624 μg ai /kg 4/11 Treatment (3?), queen (1)

318 μg ai /kg 3/11 Treatment (1?), queen (1)

158 μg ai /kg 2/11 Treatment (1?), varroa (1)

81 μg ai /kg 3/12 Queen (1), poisoning (1), no eggs (1)

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Only colonies treated with 1720 μg ai /kg had higher mortality than controls,

but control mortality (91.6%) was higher than normal. Swarming, absence of

queen and varroa infestation were observed in up to 12 of control hives during

summer, 7 of those hives died. The mortalities of the groups treated with lower

doses (81 to 624 μg ai /kg) were in the historical national averages in the US.

There were no treatment-related mortality before winter, except for the group

fed the highest dose (one hive in the 81 μg ai /kg group died).

All treatment groups except the highest one had similar number of adult bees

across the summer and autumn. Numbers were lowest at the beginning of

Spring for the group exposed to 158 μg ai /kg, but increased rapidly to the

same level as controls.

The overall number of eggs, larva and pupal cells was not affected by

treatment apart for the three highest doses. Lower number of eggs were

detected in the 318 and 624 μg ai /kg groups after winter, with 4/8 and 4/7

hives with no eggs compared to 2/11 for controls (colonies without eggs: 18%

of surviving controls, 22% of 81 μg ai/kg, 22% of 158 μg ai/kg, 50% of 318 μg

ai/kg, 57% of 624 μg ai/kg, 50% of 1720 μg ai /kg (1/2 colonies).

Pollen stores (bee bread) were only significantly lower than the controls at day

19 in the 1720 μg/kg. Nectar/honey stores were not affected by the treatments.

No statistical increases in Varroa mite loads were observed for any treatment

level at any assessment (varroa loads were lower in the 158 and 1720 groups).

There were no statistical increases in Nosema spore loads for any tetraniliprole

treatment.

All treatment groups except the highest one consumed 100% the sugar

solutions readily and consistently over time, consumption in the highest

treatment group declined over time from 100% to 37% of the available solution.

Residues

Residues of tetraniliprole (0.41-6.14 ppb) were detected in uncapped nectar in

up to 3 of the control hives. Residues (0.59-1.9 ppb) were detected in capped

honey in up to 4 of the control hives.

Samples analysed from day 20 showed that tetraniliprole was detected in

uncapped nectar (at ~50% of the concentration in the feeding diet), capped

honey (at ~10-15% of the concentration in the feeding diet) and beebread (at

~10-15% of the concentration in the feeding diet), except for the hives fed the

highest concentration (65-85%). Tetraniliprole was still detected (~1-4%) in

capped honey 290 days after the start of the experiment (following spring).

Comments

The loss of hives in the control group is very high (96%, much higher than the

average 30% loss in the USA in 2017/20183), therefore comparisons of

mortality rates between treatments and control are not relevant.

There is an uncertainty regarding how statistical analysis took into account the

decline of the number of samples over time (due to mortality).

3 https://beeinformed.org/results/honey-bee-colony-losses-2017-2018-preliminary-results/

https://beeinformed.org/results/honey-bee-colony-losses-2017-2018-preliminary-results/

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Chronic dietary exposure of colonies to 1720 μg/kg tetraniliprole resulted in

reductions in colony performance and increased colony loss.

The no observable adverse effect level (NOAEL) at the level of the colony for

this study proposed by the authors is 624 μg/kg tetraniliprole; however, some

treatment-related effects on colony strength in spring (number of colonies with

no eggs) were observed at 318 and 624 μg/kg (these results were significant

despite the low sample size and clear dose-dependent effects were observed).

Conclusion NOAEL = 318 μg/kg of diet

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Bumble bees

Acute toxicity

Table 185: Acute oral toxicity of tetraniliprole to bumble bees

Study type Acute oral toxicity test in bumblebees

Flag Supportive study


Exposure 72 hours oral

Test species Bombus terrestris L.


Value Oral LD50 = 0.05 µg ai/bee (72 hours)


Reference

Tänzler V. 2016. BCS-CL73507 tech.: Effects (Acute Oral) on Bumblebees

(Bombus terrestris L.) in the Laboratory


Klimisch Score 1 (after revision of the LD50)


GLP Yes

Test Guideline/s OECD 213 (with modifications)

Ring test bumblebee acute oral toxicity

No/Sex/Group 30 females per treatment group

Dose Levels Oral nominal dose: 0.24, 0.12, 0.06, 0.03 and 0.015 μg ai/bee

Oral actual dose: 0.19, 0.10, 0.05, 0.03 and 0.013 μg ai/bee

Analytical

measurements NA

Study Summary

The purpose of the study was to determine the acute oral toxicity of tetraniliprole

(purity: 89.6% w/w) to the bumblebee in the laboratory.

In the sugar control group, no mortality occurred during the 72-hour observation.

In the solvent (acetone) control group, 6.7% mortality occurred during the 72-

hour observation.

The reference substance induced 60% mortality at 2.5 μg dimethoate/bee. This

indicates that the LD50 value is likely to be higher than the reference for honey

bees (0.1-0.35 μg/bee), but given the difference in size of the two species, this

was considered acceptable. Consequently, validity criteria for both control and


In the oral toxicity test, at the highest tested dose level of 0.19 µg ai/bee, 76.7%

mortality was observed after 72 hours. Mortalities were observed at 0.10 µg

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ai/bee (93.3% mortality), 0.05 µg ai/bee (60% mortality), 0.03 µg ai/bee (30%

mortality) and 0.013 µg/bee (3.3% mortality).

Behavioural abnormalities were observed in most of the bees (20/30, 26/30,

17/30 for the 0.19, 0.10 and 0.05 dose groups, respectively) up to 48 hours after

treatment with the three higher doses but ceased thereafter in the surviving

bumblebees. Most surviving bees had been exposed to doses lower than the

target.

Even though there was no definite dose-response relation in the two highest

concentrations, an LD50 could be determined. The LD50 value was calculated to

be 0.04 µg/bee

Comments

The test allows measuring the individual dose consumed per bee. In the two

groups fed with the highest doses, bees that survived were bees that had

ingested less than the target dose,

The LD50 was re-calculated without the bees that ingested less than the target

dose, the recalculated LD50 is 0.05 µg/bee

Conclusion Oral LD50 = 0.05 µg ai/bee

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Table 186: Acute contact toxicity of tetraniliprole to bumble bees

Study type Acute contact toxicity test in bumble bees


Test Substance BCS-CL73507: technical tetraniliprole

Exposure Type 96 hours, contact



Value Contact LD50 = 21.86 µg ai./bee (96 hours)


Reference

Kling A, 2014. BCS-CL73507: Acute Contact Toxicity to the Bumblebee,

Bombus terrestris L. (Hymenoptera, Apidae) under Laboratory Conditions

Eurofins Agroscience Services, EcoChem GmbH, Eutinger Straße 24, 75223

Niefern-Öschelbronn, Germany

Klimisch Score 1


GLP Yes

Test Guideline/s

OECD 214 (with modifications)

OEPP/EPPO 170

Van der Steen (2001)

No/Sex/Group 3 x 10 young workers per treatment group, of similar weight

Dose Levels Contact doses: 6.25, 12.5, 25, 50 and 100 μg ai/bee in acetone (2 μL droplet)

Analytical

measurements NA

Study Summary

The purpose of the study was to determine the acute oral toxicity of tetraniliprole

(purity: 89.6% w/w) to the bumblebee in the laboratory.

In the control groups, no mortality occurred during the 96-hour observation. The

reference substance induced 80% mortality at 11 μg dimethoate/bee. This

indicates that the LD50 value is likely to be higher than the reference for honey

bees (0.1-0.30 μg/bee), but given the difference in size of the two species, this

was considered acceptable. Consequently, validity criteria for both control and


In the contact toxicity test, at the highest tested dose level of 100 µg ai/bee

96.7% mortality was observed after 96 hours. Mortalities were observed at 50

µg ai/bee (86.7% mortality), 25 µg ai/bee (56.7% mortality) and 12.5 µg ai/bee

(23.3% mortality).

Behavioural abnormalities were observed in the surviving bees up to 96 hours

after treatment with the four higher doses. The number of impacted bees

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appeared not to be dose-related. No behavioural effects were observed in the

lowest test dose (6.25 µg/bee)

Conclusion Contact LD50 = 21.86 µg ai/bee


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Vayego


Fish - acute toxicity

Table 187: Aquatic toxicity – Fish – Vayego – study 1


Flag Key study

Test Substance BCS-CL73507 SC 200 g


Test species Rainbow trout, Oncorhynchus mykiss

Endpoint LC50

Value >541 mg test item/L

Reference Kuhl K. (2014), BCS-CL73507 SC 200 G- Acute toxicity to fish (Oncorhynchus

mykiss) under static conditions, report no EBFVP118, M-494951-01-1

Klimisch Score 1

Amendments/Deviati

ons None

GLP yes

Test Guideline/s

EU Directive 91/414/EEC Regulation (EC) No. 1107/2009


OECD guideline 203

Dose Levels 23.1, 50.8, 112, 246 and 541 mg prod./L nominal

Analytical


Study Summary

The aim of the study was to determine the acute effects of tetraniliprole SC 200 G

to rainbow trout (Oncorhynchus mykiss). Ten rainbow trout in each dose level

were used for the test with a mean body length of 3.8 cm, a mean body weight of

0.5 g, the loading was 0.13 g fish/L. The fish were exposed for 96 hours under

static test conditions to a nominal concentration of 23.1, 50.8, 112, 246 and 541

mg substance/ L.

During the test, fish were examined after four hours and then daily for mortalities

and signs of poisoning. Within the study, the pH-value, the oxygen saturation level

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and the temperature were measured with commercial measurement devices,

daily. The analytical determination of tetraniliprole (in water by HPLC – MS/MS)

revealed a mean recovery of 105% - 118% of nominal over the whole testing

period of 96 hours. Therefore, the results are based on the nominal

concentrations.

Test conditions met all validity criteria. There was less than 5% mortality within the

48-hour settling-in period and ≤ 10% mortality in the control (0%). Dissolved

oxygen saturation was greater or equal to 60% throughout the test (>93%) and pH

variation was ≤ 1.0 units (6.9-7.1).

Following 96 hours of exposure, there were no mortalities observed at any test

concentration or the controls. Therefore, the 96h-LC50 was > 541 mg substance/

L.

In all test levels of 50.8 mg test item/L and higher behavioural changes were

observed during the entire test period. The fish remained for unusually long

periods on the bottom of the vessel, showed laboured respirations and weaker

colouration, and remained for unusually long periods at the water surface.

Therefore, the NOEC is 23.1 mg test item/L.

Comments

Several test vessels showed turbidity and thus likely that the exposure

concentration was lower. Laboured breathing could also (partially) be due to

mechanical interference.

Conclusion LC50 >541 mg substance/ L

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Table 188: Aquatic toxicity – Fish – Vayego – study 2


Flag Key study



Test species Common carp, Cyprinus carpio

Endpoint LC50

Value >538 mg formulation/L

Reference

Matlock D., Moore S. (2016), Acute toxicity of tetraniliprole SC 200 to the

common carp (Cyprinus carpio) under static conditions, report no EBFVN130,

M-554732-01-1

Klimisch Score 1


GLP yes

Test Guideline/s OECD 203, US EPA OCSPP 850.1075

Dose Levels 23.0, 50.5, 111, 244, 538 mg formulation /L nominal

Analytical

measurements HPLC

Study Summary


common carp (Cyprinus carpio). Common carp (10 fish per treatment level)

were exposed in a static system over a period of 96 hours to the nominal

concentrations of 4.28, 9.39, 20.7, 45.4, 100 mg ai/L. In addition, a water

control was tested. Mean measured recoveries of the active ingredient ranged

from 87 to 107% of nominal concentrations.



as nominal concentration.

Test conditions met all validity criteria. There was no mortality in the control.


(68 to 97%).


observed in the control and most treatment levels. One dead fish was

observed in the lowest treatment level and in the second highest treatment

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level. These are considered not treatment-related as no dose response was

observed. Therefore, 96-hour-LC50 is >538 mg formulation/L, the 96-hour-

NOEC is 538 mg formulation/L, the highest concentration tested.

Comments Big fish were used in the test (50.3 mm), recommended is 3.0 mm ±1 mm.

This could decrease sensitivity to test item.

Conclusion LC50 >538 mg formulation/L

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Crustacean – acute toxicity

Table 189: Acute toxicity - Daphnia


Flag Key study

Test Substance BCS-CL73507 SC 200G

Exposure 48 h, static


Endpoint EC50

Value 382 μg substance/ L

Reference

Riebschlaeger T., 2014 Acute toxicity of BCS-CL73507 SC200G to the water flea

Daphnia magna in a static laboratory system, Report no EBFVP119, M-494976-

01-1

Klimisch Score 1

Amendments/Deviati

ons None

GLP yes

Test Guideline/s OPPTS Guideline 850.1010

Dose Levels 20.0, 34.0, 57.8, 98.3, 167 and 284 μg product/L nominal

Analytical

measurements HPLC-MS/MS, HPLC -UV

Study Summary

The aim of the study was to determine the acute effects of tetraniliprole SC 200G

to Daphnia magna. Daphnia magna (<24-hour old neonates) were exposed in a

static system over a period of 48 hours to nominal concentrations of 20.0, 34.0,

57.8, 98.3, 167 and 284 μg product/ L without feeding. In addition, a water control

was tested. There were six replicates of five daphnia each in the control and each

of the treatment levels.

The content of tetraniliprole in exposure media was measured for verification of

the test item concentrations. The chemical analysis of Tetraniliprole SC 200 G in

the freshly prepared test solutions at test initiation revealed measured contents

between 106% and 120% (mean: 111%) of nominal. The measured

concentrations in the aged test solutions at the end of the 48-hours exposure

period ranged between 93% and 106% (mean: 97%) of nominal.

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No contaminations of tetraniliprole were detected in samples from untreated water

control. As the toxicity has to be attributed to the tested formulation as a whole,

the EC50 values have been calculated based on nominal test concentrations.


agitation of the test vessel even if the organisms can still move their antennae.

Sublethal and behavioural effects were also assessed during the course of the

study.

The validity criterion of control mortality less than 10% is fulfilled. Dissolved

oxygen concentrations ranged from 103.3% oxygen saturation at test start to

102.1% at the end of the test, the pH value was 7.8 and the water temperature

ranged from 20.2°C to 20.7°C in all test vessels over the whole testing period.

No immobility or other effects on behaviour were observed in the untreated

control within 48 hours of exposure. Based on nominal concentrations of

Tetraniliprole SC 200 G, EC50 values for immobilisation of 479 and 382 μg

substance/L after 24 and 48 hours of static exposure, were calculated,

respectively.

Comments none

Conclusion EC50 = 382 μg substance/ L (95% Cl: 173- 843 μg prod./L)

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Table 190: Acute toxicity - Algae


Flag Key study




Endpoint ErC50

Value >541 mg product/L

Reference

Kuhl K. (2016) Amendment no 2- Pseudokirchneriella subcapitata growth

inhibition test with BCS-CL73507 SC 200G. Report no EBFVP120, M-

506044-03-2

Klimisch Score 1


GLP yes


US EPA Pesticide Assessment Guidelines, Subdivision J, §122-2, 123-2

Dose Levels 5.16, 16.5, 52.8, 169 and 541 mg substance./L


Study Summary

The aim of the study was to determine the effects of tetraniliprole SC 200

G on exponentially growing populations of Pseudokirchneriella

subcapitata expressed as NOEC, LOEC and EC50 for growth rate and

further endpoints of algal biomass (cells per volume).


10,000 cells/ml were exposed in a static system over a period of 72

hours with a prolongation to 96 hours to nominal concentrations 5.16,

16.5, 52.8, 169 and 541 mg prod./L in comparison to an untreated

control. Four replicates were tested per test concentration and six

replicates were included for the control.

The analytical findings of tetraniliprole in the treatment levels found on

day 0 were 92.8% to 106% of nominal (average 102%). After 72 hours

analytical findings of 67.2% to 100% of nominal (average 89.3%) were

found and after 96 hours analytical findings of 56.3% to 99.7% of

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nominal (average 85.5%) were found. Although some measured

concentrations in the aged test media were below 80% of nominal, the

toxicity has to be attributed to the test formulation as a whole. Therefore,

all results are based on nominal test concentrations of the formulation.

The validity criteria were met (OECD 201). Increase biomass was factor

of 78.2 (recommended factor 16 in 72h), coefficient of variation section

by section specific growth rate was 19.1% (recommended ≤35% in 72 h),

coefficient of variation for average specific growth rate was 1.8%


Morphological examinations of cells using a microscope were made after

0, 24, 48, 72 and 96 hours. Cell numbers per volume (as a surrogate for

biomass per volume) and possible alterations in algae cells such as

unusual cell size were estimated by direct algae cell counting under a

microscope at a magnification of 400 times.

No morphological change in algae was observed in any test

concentration.

Growth inhibition (0-72 h) was -0.7, 1.7, 3.2, 12.3 and 27.5% for the dose

rates 5.16, 16.5, 52.8, 169 and 541 mg prod/ L respectively.

The 72 and 96 hour-ErC50 was >541 mg product /L. The 72h- and 96h-

NOErC were determined to be 52.8 mg product/L.

Conclusion ErC50 >541 mg product/L

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Spiked water

Table 191: Toxicity to sediment-dwelling organisms- spiked water


Flag Key study

Test Substance Tetraniliprole SC 200G



Endpoint EC50

Value 4.68 mg test substance/L

Reference

Silke G. (2016) Acute toxicity of BCS-CL73507 SC 200 G to

larvae of Chironomus riparius in a 48 h static laboratory test

system. Report no EBFVN169, M-559963-01-1

Klimisch Score 1


GLP yes


Dose Levels

0.54, 1.19, 2.61, 5.75, 12.7 and 27.8 mg test substance/ L,

nominal (corresponding with 0.10, 0.22, 0.49, 1.07, 2.36, 5.17 mg

ai/L)

0.46, 1.02, 2.31, 4.9, 10.6, 22.9 mg test substance/L geometric

mean


Study Summary


SC 200 G on larvae of Chironomus riparius.

Groups of midges (1st instars, < 2-3 days old) were exposed in a

static system over a period of 48 hours to the nominal

concentrations of 0.54, 1.19, 2.61, 5.75, 12.7 and 27.8 mg test

substance/ L. In addition, a water control was tested. Six

replicates, containing 5 animals each, were tested for each test

item concentration and the controls.

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The analysed substance (based on active ingredient) found in all

freshly prepared test levels on day 0 in reference to nominal

concentrations ranged between 89-95% (average 92%, 0.0918,

0.209, 0.450, 1.01, 2.15, 4.58 mg ai / L). In aged test levels on

day 2 there were analytical findings between 77 and 84%

(average 79%, 0.0783, 0.174, 0.411, 0.831, 1.82, 3.96 mg ai/ L)

of nominal. Due to the recoveries < 80% of nominal after two days

of exposure, the results for determination of EC50 values are

based on geometric mean concentrations. As the toxicity has to

be attributed to the test formulation as a whole, the results of the

statistical evaluation endpoints (EC50, NOEC) submitted by this

report are related to calculated geom. mean test concentrations of

the formulated product.

Immobilisation of the midge larvae and intoxication symptoms

were assessed. After 48 hours 0% immobility was observed in the

control. The immobility was 0%, 6.7%, 6.7%, 46.7%, 93.3% and

100% in the treatments 0.46, 1.02, 2.31, 4.95, 10.6, 22.9 mg test

substance/L. The difference was significant at the three highest

concentrations. Larvae were observed to show reduced mobility

at several concentrations at 24 and 48 hours. At 48 hours the

effects do not seem to be dose-related.

All validity criteria were met. The validity criterion of control

mortality less than 15% is fulfilled. The validity criterion of oxygen

saturation >3 mg oxygen/L was fulfilled.

The 48h-EC50 was 4.68 mg test substance/L

The 48h-NOEC was 2.31 mg test substance/L.

Conclusion EC50= 4.68 mg test substance/L. geometric mean

NOEC = 2.31 mg test substance/L. geometric mean

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Earthworms

Table 192: Acute toxicity to earthworms

Study type Full test, acute toxicity earthworm

Flag Key study

Test Substance BCS-CL73507SC 200G

Exposure 14 d


Endpoint LC50

Value >1000 mg test substance /kg soil

Reference Friedrich S. (2014), BCS-CL73507 SC 200 G.- Acute toxicity to the earthworm

Eisenia fetida in artificial soil. Report no 14 10 48 120 S, M-503245-01-2

Klimisch Score 1

Amendments/Deviati

ons None

GLP yes

Test Guideline/s OECD 207, ISO 11268-1, OCSPP 850.supp

Dose Levels 18, 32, 56, 100, 178, 316, 562 and 1000 mg test substance / kg dry weight of soil

Analytical

measurements NA

Study Summary

The aim of the study was to determine the acute effects of tetraniliprole SC 200 G

on survival and growth of earthworms.

Adult earthworms (about 3 months old, four replicates of 10) were exposed in an

artificial soil system over a period of 14 days to concentrations of 18, 32, 56, 100,

178, 316, 562 and 1000 mg test item/kg dry weight of soil containing 69.5%

quartz sand, 20% kaolin clay, 10% sphagnum peat and 0.5% CaCO3. In addition,

an untreated control was tested. A toxic reference (2-chloroacetamide) was tested

in a separate study.

Temperature ranged from 18 to 21 °C and the photoperiod was continuous light at

540 lux. Mortality and biomass change were determined after 14 days and were

used to determine the endpoints.

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The validity criteria were met. Mortality in control ≤ 10% (observed 0%) and loss

of biomass ≤20% (observed 3.2%).

No mortality was observed in the control and 18, 32, 100, 178 and 562 mg

product/kg soil. 2.5% mortality was observed at 56, 316 and 1000 mg product/kg

soil.

Biomass change based on wet weight was -3.2% in the control. The biomass

change was -2.2%, -4.6%, -5.3%, -6.1%, -3.4%, -4.6%, -2.6% and -6.4% at the

concentrations 18, 32, 56, 100, 178, 316, 562 and 1000 mg test substance /kg

respectively.


The 14-day-LC50 was > 1000 mg test substance /kg dry weight soil (the highest

concentration tested), the 14-day-NOEC was determined to be ≥1000 mg test

substance/kg dry weight soil.

Conclusion LC50 >1000 mg test substance /kg soil

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Table 193: Chronic toxicity to earthworms

Study type Full test, chronic toxicity earthworm

Flag Key study

Test Substance BCS-CL73507SC 200G

Exposure 56 d (28 days exposure and another 28 days observations)


Endpoint NOEC

Value >1000 mg test item/kg soil

Reference

Kratz M.A. (2014), BCS-CL73507 SC 200 G.- Effects on survival

growth and reproduction of the earthworm Eisenia fetida tested in

artificial soil. Report no kra/Rg-R-160/14, M-489574-01-2

Klimisch Score 1


GLP yes


Dose Levels 100, 178, 316, 562 and 1000 mg test item / kg dry weight of soil


Study Summary


SC 200 G on survival and growth and reproduction of earthworms.

Adult earthworms (about 4 months old, four replicates of 10 for

treatments, eight replicates of 10 for the control) were exposed in

an artificial soil system with 10% peat content over a period of 28

days to concentrations of 100, 178, 316, 562 and 1000 mg test item

/ kg dry weight of soil. In addition, an untreated control was tested.

After this reproduction (juveniles in soil) was evaluated for another

28 days. A toxic reference (carbendazim) was tested in a separate

study.

Temperature was 20±2 °C and the photoperiod was 16 h light (400-

800 lux) and 8 hours dark. Mortality, growth and reproduction were

determined and were used to determine the endpoints.

The validity criteria were met. Mortality in control ≤ 10% (observed

0%) and rate of reproduction ≥30 (observed ranging from 155 up to

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206) and coefficient of variance of reproduction in the control ≤30%

(observed 10.5%).

No mortality was observed in the control and the treatments after

28 days.

Change of body weight was 31.33% in the control after 28 days.

The change in body weight was 25.35%, 20.76%, 30.09%, 36.38%

and 41.56% at the concentrations 100, 178, 316, 562 and 1000 mg

test item /kg respectively.

Mean number of offspring after 56 days was 181.9 in the control.

The offspring was 175.0, 191.5, 195.3, 173.8 and 171.8 % at the

concentrations 100, 178, 316, 562 and 1000 mg test item/kg

respectively.


The NOEC was determined to be ≥1000 mg test item/kg dry weight

soil for growth and reproduction.

Conclusion NOEC ≥1000 mg test item /kg soil

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Soil mites

Table 194: Toxicity to soil mites

Study type Full test, toxicity soil mite

Flag Key study

Test Substance BCS-CL73507SC SC 200G

Exposure 14 d

Test species Soil mite, Hypoaspis aculeifer

Endpoint NOEC

Value ≥1000 mg test substance/kg soil

Reference

Kratz M.A. (2014), BCS-CL73507 SC 200G Influence on mortality

and reproduction of the soil species Hypoaspis aculeifer tested in

artificial soil. Report no LAR-HR-102/14, M-489573-01-2

Klimisch Score 1


GLP yes

Test Guideline/s US EPA OCSPP 850.supp, EU directive 91/414/EEC regulation

(EC) no 1107/2009

Dose Levels 100, 178, 316, 562 and 1000 mg test substance/kg dry weight of

soil


Study Summary


SC 200G on survival and reproduction of predatory soil mites.

Adult female mites (four replicates of 10) were exposed in an

artificial soil system with 5% peat content over a period of 14 days

to concentration of 100, 178, 316, 562 and 1000 mg test

substance/kg dry weight of soil. In addition, a water control was

tested with 8 replicates. A toxic reference (dimethoate) was tested

in a separate study.

Temperature was 20 ±2°C and the photoperiod was 16 h light

(400-800 lux) and 8 hours dark. Mortality and reproduction were



2.9%) and number of juveniles per replicate ≥50 (observed 285.4)

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and coefficient of variance of reproduction in the control ≤30%

(observed 8.4%).

The EC50 values of the toxic reference was 5.28 mg ai/ kg soil for

reproduction and LC50 was 3.51 mg ai/kg soil for mortality.

Mortality was 2.9% in the control. In the treatment groups, 2.5,

3.3, 2.5, 2.5 and 10.0% mortality occurred for the 100, 178, 316,

562 and 1000 mg prod./kg dw soil treatment groups, respectively.

Mean number of offspring after 14 days was 285.4 in the control.

In the treatment groups 295.0, 280.3, 297.0, 311.8 and 265.0

number of juveniles were observed for the concentrations 100,

178, 316, 562 and 1000 mg prod./kg dw soil, respectively.

No significant effects were observed. It seems that the mortality

was not statistically analysed.

The NOEC was determined to be ≥1000 mg test substance/kg dry

weight soil.

Conclusion NOEC ≥1000 mg test substance /kg soil

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Soil microflora


Table 195: Toxicity to soil flora – nitrogen transformation


Flag Key study


Exposure 28 d




Reference

Schulz L. (2015), Tetraniliprole (BCS-CL73507) SC 200 G: Effects on the

activity of soil microflora (Nitrogen transformation test). Report no

EBFVP130, M-542769-01-1

Klimisch Score 1


GLP yes



(equivalent to 1 L and 10 L test substance / ha)


Study Summary


G to soil microflora activity (nitrogen transformation).

Application rates were 1.49 and 14.92 mg test substance/ kg dry soil ha,

equivalent to 1 and 10 L test substance/ha). The nitrogen transformation

was determined in soil (silty sand, pH 6.2, % C 1.35, WHC 38.40). NH4-

nitrogen, NO3- and NO2-nitrogen were determined by an Autoanalyzer at

different sampling intervals (0, 7, 14 and 28 DAT, 3 replicates).


stimulation of nitrogen transformation of +39.1% and +62.5% and

112.0% at 6.8 mg, 16.0 mg and 27.0 mg dinoterb per kg soil dry weight,

respectively, determined 28 days after application.

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No adverse effects of BCS-CL73507 SC 200 G on nitrogen

transformation in soil were observed at both test concentrations (1.49

mg/kg dry soil and 14.92 mg/kg dry soil) after 28 days. Differences from

control of -5.6% (test concentration 1.49 mg/kg dry soil) and -20.6 % (test


day incubation period.

BCS-CL73507 SC 200 G caused no adverse effects (difference to

control < 25 %) on the soil nitrogen transformation (measured as oxygen

consumption) at the end of the 28-day incubation period.

Conclusion Product did not cause adverse effects on nitrogen transformation up to a

rate of 10 L product/ha (= 2.0 kg ai/ha)

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Carbon transformation

Table 196: Toxicity to soil flora – carbon transformation


Flag Key study


Exposure 28 d




Reference

Schulz L. (2015), Tetraniliprole (BCS-CL73507) SC 200 G: Effects on the

activity of soil microflora (Carbon transformation test). Report no

EBFVP129, M-542771-01-1

Klimisch Score 1


GLP yes



(equivalent to 1 L and 10 L test substance / ha)


Study Summary


G to soil microflora activity (carbon transformation).


equivalent to 1 and 10 L test substance/ha). The carbon transformation

was determined in soil (silty sand, pH 6.2, % C 1.35, WHC 38.40).

Determination of carbon transformation in soil was performed after

addition of glucose. A respirometer system was used to determine the

O2- consumption over a period of maximum 12 hours at different

sampling intervals (0, 7, 14 and 28 DAT, 3 replicates).


inhibition of carbon transformation of -30.1 % and -39.6 % at 16.0 mg

and 27.0 mg dinoterb per kg soil dry weight, respectively, determined 28

days after application.

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The coefficients of variation in the control were maximum 3.3 % and thus

fulfilled the demanded range (≤15 %).

No adverse effects of BCS-CL73507 SC 200 G. on carbon

transformation in soil were observed at both test concentrations (1.49

mg/kg dry soil and 14.92 mg/kg dry soil) after 28 days. Differences from

control of -3.3% (test concentration 1.49 mg/kg dry soil) and -0.4 % (test


day incubation period.

BCS-CL73507 SC 200 G caused no adverse effects (difference to

control < 25 %) on the soil carbon transformation (measured as oxygen


Conclusion Product did not cause adverse effects on carbon transformation up to a

rate of 10 L product/ha (= 2.0 kg ai/ha)

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Non-Target Plants

Seedling emergence

Table 197: Seedling emergence test – study 1

Study type Full test, Toxicity to seedling emergence non-target plants

Flag Key study


Exposure Soil application

Test species Brassica napus

Endpoint ER25, ER50 and NOER

Value >200 g ai/ha,

NOER = 200 g ai/ha

Reference

Noeding S. (2016), Tetraniliprole SC 200 (200 g/L) Effects on the

seedling emergence and growth of one species of non-target terrestrial

plants (tier 2) -final report. Report no SE16/020, M-563418-01-1

Klimisch Score 1

Amendments/Deviations None that affected the results of the study

GLP yes


Dose Levels 7.15, 16.4, 37.8, 86.9, 200 g ai/ha


Study Summary

The aim of the study was to determine the effects of tetraniliprole SC

200G on seedling emergence and growth of Brassica napus following a

pre-emergence application of the product to the soil surface.

The seeds were sown in 15 cm pots on the day of the application of the

test substance to the soil surface. The used soil was a silt loam.

Planting density included 2 seeds per pot, with 20 replicate pots, for a

total of 40 seeds per treatment level. The plant species was treated

with five test substance rates (7.15 / 16.4 / 37.8 / 86.9 / 200 g ai/ha) in

comparison to a water control. Following application, the pots with

seeds (later plants) were maintained under greenhouse conditions.

The control pots of Brassica napus were observed daily for the number

of seedlings emerged until 50% of the control seedlings had emerged

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(= day 0). Assessments were made on this day (= day 0) and 7, 14 and

21 days post-emergence of 50% of the control seedlings. Assessments

were made for emergence, plant survival, visual phytotoxicity,

additionally plant growth stage (BBCH), shoot length and shoot dry

weight were determined at the final assessment.

The germination rate of the seeds used in this study was ≥ 70% and

survival was ≥ 90% in the control. Normal growth occurred in the

control and no visible phytotoxicity was observed. All validity criteria

were met.

The analysis of the tetraniliprole content in the test substance stock

solution revealed measured concentrations of 102.5% of nominal.

No adverse effects on emergence, survival, shoot length, shoot dry

weight, growth stage development or visual phytotoxicity above the

25% effect level were detected. The growth ranged from BBCH 14 to

17 in the control and the treatments. Some light stunting in a small

number of plants was observed (0.5%) in the treatments 16.4, 86.9 and

200 g ai/ha. The Lowest Observed Effect Rate (LOER) was outside

the range tested and the NOER is reported as the highest test

substance rate, 200 g ai/ha. The ER25 and ER50 values for Brassica

napus could not be calculated and are reported as >200 g ai/ha.

Conclusion ER25 and ER50 > 200 g ai/ha, NOER = 200 g ai/ha

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Table 198: Seedling emergence test – study 2

Study type Limit test, toxicity to seedling emergence non-target plants

Flag Key study


Exposure Soil application

Test species 6 dicotyledonae and 4 monocotyledonae


Value >200 g ai/ha,

NOER = 200 g ai/ha

Reference

Noeding S. (2016), Tetraniliprole SC 200 (200 g/L) Effects on the seedling

emergence and growth of ten species of non-target terrestrial plants (tier 1)

-final report. Report no SE15/043, M-559339-01-1

Klimisch Score 1


GLP yes




Study Summary

The aim of the study was to determine the effects of tetraniliprole SC 200G

on seedling emergence and growth of Beta vulgaris, Brassica napus,

Cucumis sativus, Glycine max, Helianthus annuus, Lycopersicon

esculentum, Allium cepa, Avena sativa, Tricum aestivum and Zea mays

following a pre-emergence application of the product to the soil surface.

The seeds were sown in 15 cm pots on the day of the application of the

test substance to the soil surface. The used soil was a silt loam. Planting

density included 2 or 4 seeds per pot, with 20 or 10 replicate pots, for a

total of 40 seeds per treatment level. The test was conducted as a limit test

with a single application rate of 200 g ai/ha in comparison to a water

control. Following application, the pots were maintained under greenhouse

conditions.

The control pots of each species were observed daily for the number of

seedlings emerged until 50% of the control seedlings had emerged (= day

0). Assessments were made on this day (= day 0) and 7, 14 and 21 days

post-emergence of 50% of the control seedlings. Final assessments were

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made for emergence, plant survival, visual phytotoxicity, plant growth

stage (BBCH), shoot length and shoot dry weight.

The germination rate of the seeds used in this study was ≥ 70% and

survival was ≥ 90% in the control. Normal growth occurred in the control

and no visible phytotoxicity was observed. All validity criteria were met.


solution revealed measured concentrations of 100.1-100.5% of nominal.

At the test substance rate of 200 g ai/ha slight phytotoxic symptoms were

observed in a few cases for Brassica napus (2.5%, stunting), Cucumis

sativus (4%, leaf deformation and stunting), Solanum lycopersicum (0.5%,

stunting) and Zea mays (1.5%, stunting). There was no phytotoxic effect

on the other plant species tested.

At the test substance rate of 200 g ai/ha emergence for Beta vulgaris,

Allium cepa, Triticum aestivum and Zea mays increased by 5.7%, 6.3%,

5.3% and 2.6%, respectively, compared to the water treated controls.

There was no effect on Glycine max and Helianthus annuus for

emergence. Emergence was reduced for Brassica napus, Cucumis

sativus, Solanum lycopersicum and Avena sativa by 10.3%, 2.5%, 2.6%

and 2.6%, respectively, compared to the water treated controls.

At the test substance rate of 200 g ai/ha survival for Solanum

lycopersicum, Allium cepa and Triticum aestivum increased by 2.6%,

10.3% and 2.7%, respectively. Survival for Zea mays was reduced by

2.5% compared to the water treated controls. There was no effect on

survival for the other plant species tested.

At the test substance rate of 200 g ai/ha shoot dry weight for Helianthus

annuus, Solanum lycopersicum, Allium cepa, Avena sativa and Zea mays

increased by 5.4%, 13.1%, 37.6%, 1.8% and 1.3%, respectively. Shoot dry

weight for Beta vulgaris, Brassica napus, Cucumis sativus, Glycine max

and Triticum aestivum was reduced by 2.0%, 3.6%, 1.2%, 2.6% and 2.3%,

respectively.

At the test substance rate of 200 g ai/ha shoot length for Beta vulgaris,

Glycine max, Helianthus annuus, Solanum lycopersicum, Allium cepa,

Avena sativa and Triticum aestivum increased by 4.2%, 1.2%, 7.3%, 6.1%,

6.3%, 1.8% and 0.1%, respectively. Shoot length for Brassica napus,

Cucumis sativus, and Zea mays was reduced by 3.9%, 2.1%, and 0.6%,

respectively.

The development stage of the plant (expressed as BBCH) in the

treatments was similar to the control.

No significant effects were observed

No adverse effects on emergence, survival, shoot length, shoot dry weight,

growth stage development or visual phytotoxicity above the 25% effect

level were detected. The LOER was outside the range tested and the

NOER is reported as the highest test substance rate, 200 g ai/ha. The

ER25 and ER50 values could not be calculated and are reported as >200 g

ai/ha.


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Vegetative vigour

Table 199: Vegetative vigour test – study 1

Study type Limit test, toxicity to vegetative vigour non-target plants

Flag Key study


Exposure Foliar application

Test species 6 dicotyledonae and 4 monocotyledonae

Endpoint ER25, ER50

Value >200 g ai/ha

Reference


vegetative vigour of ten species of non-target terrestrial plants (tier 1).

Report no VV15/044, M-552710-01-1

Klimisch Score 1


GLP yes




Study Summary

The aim of the study was to determine the effects of tetraniliprole SC 200G

on vegetative vigour of Beta vulgaris, Brassica napus, Cucumis sativus,

Glycine max, Helianthus annuus, Lycopersicon esculentum, Allium cepa,

Avena sativa, Tricum aestivum and Zea mays following a post-emergence

application of the product onto the foliage of plants at the 2-4 leaf stage.

The plants were grown in 15 cm pots with 2 to 4 plants per pot. The used

soil was a silt loam. Each treatment level contained 16 or 8 replicate pots

giving a total of 32 plants per treatment level. The test was conducted as a

limit test with a single application rate of 200 g ai/ha in comparison to a

water control. Following application, the pots were maintained under

greenhouse conditions.

Assessments (7, 14 and 21 DAT) were made for plant survival, visual

phytotoxicity, plant growth stage (BBCH), shoot length and shoot dry

weight.

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Slight phytotoxic symptoms (chlorosis, necrosis, deformation, stunting)

were observed in a few individuals for Brassica napus, Helianthus annuus,

Lycopersicon esculentum, Triticum aestivum and Zea mays.

There was no effect on survival for all plant species tested in comparison

to the control.

Shoot dry weight for Beta vulgaris, Cucumis sativus, Allium cepa, Avena

sativa and Zea mays increased by 1.8%, 0.4%, 0.2%, 11.3% and 0.3%,

respectively. Shoot dry weight for Brassica napus, Glycine max, Helianthus

annuus, Lycopersicon esculentum, and Triticum aestivum was reduced by

2.8%, 3.3%, 2.4%, 9.8% and 6.1%, respectively. The shoot dry weight

reduction of Lycopersicon esculentum was statistically significant.

Shoot length for Beta vulgaris, Cucumis sativus, Glycine max, Helianthus

annuus and Avena sativa increased by 0.2%, 3.2%, 1.0%, 0.4% and 4.4%,

respectively. There was neither increase nor reduction in shoot length for

Allium cepa compared to the control (0%). Shoot length for Brassica

napus, Lycopersicon esculentum, Triticum aestivum, and Zea mays was

reduced by 2.1%, 4.7%, 1.4%, and 0.6%, respectively. The shoot length

reduction of Lycopersicon esculentum was statistically significant.

No adverse effects on emergence, survival, shoot length, shoot dry weight,

growth stage development or visual phytotoxicity above the 25% effect

level were detected. The ER25 and ER50 values could not be calculated

and are reported as >200 g ai/ha. NOER could not be determined as shoot

length reduction and dry weight reduction of tomato were statistically

significant.

Additional comment

Based on these results another test with tomato has been performed. See

below.

Although the effects on tomato were significant, the effects were max. 10% and therefore not biologically relevant.

Conclusion ER25 and ER50 > 200 g ai/ha

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Table 200: Vegetative vigour test – study 2

Study type Toxicity, vegetative vigour non-target plants

Flag Key study


Exposure Foliar application

Test species Solanum lycopersicum


Value >200 g ai/ha,

NOER = 200 g ai/ha

Reference


vegetative vigour of one species of non-target terrestrial plants (tier 2).

Report no VV16/021, M-563249-01-1

Klimisch Score 1


GLP yes


Dose Levels 7.15, 16.4, 37.8, 86.9, 200 g ai/ha


Study Summary


200G on vegetative vigour of Solanum lycopersicum following a post-

emergence application of the product onto foliage of plants at the 2-4

leaf stage.

Planting density included 2 plants per pot, with 16 replicate pots, for a

total of 32 plants per treatment level. The plant species was treated

with five test substance rates (7.15 / 16.4 / 37.8 / 86.9 / 200 g ai/ha) in

comparison to a water control. Following application, the pots with

plants were maintained under greenhouse conditions.

Assessments were made on day 7, 14 and 21 days after application.

Assessments were made for plant survival, visual phytotoxicity,

additionally plant growth stage (BBCH), shoot length and shoot dry

weight were determined at the final assessment.

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Normal growth occurred in the control and no visible phytotoxicity was

observed. Survival was >90% in the control and seedling emergence

was >70%. All validity criteria were met.


solution revealed measured concentrations of 102.5% of nominal.

No adverse effects on survival, shoot length, shoot dry weight, growth

stage development or visual phytotoxicity above the 25% effect level

were detected. The growth ranged from BBCH 51 to 61 in the control

and the treatments with the exception of one plant in the treatment

group 86.8 and one plant in the treatment group 200 g ai/ha (BBCH 15

and 13 respectively). Some light stunting was observed (1.3-5.0%) in

the treatments 7.15, 37.8, 86.9 and 200 g ai/ha. The effects were not

statistically different from the control.

The LOER was outside the range tested and the NOER is reported as

the highest test substance rate, 200 g ai/ha. The ER25 and ER50 values

for Solanum lycopersicum could not be calculated and are reported as

>200 g ai/ha.


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Terrestrial vertebrates [9.3]

Birds

Acute toxicity


Study type Limit acute toxicity test

Flag Key study


Exposure oral

Test species Chicken (Gallus gallus domesticus)

Endpoint LD50

Value >2000 mg formulation/ kg bw

Reference


tetraniliprole SC 200 (200 g/L) to chicken (Gallus gallus domesticus).


Klimisch Score 1


GLP yes


Dose Levels 2000 mg formulation/ kg bw


Study Summary

The aim of the study was to determine the acute effects of

tetraniliprole SC 200 (200 g/L) to chicken (Gallus gallus domesticus).

Adult female chickens (4-5 months) were housed individually and

acclimated to laboratory conditions for 18 days. After this period, they

were orally dosed one-time with gelatine capsules filled with the test

substance. The limit dose group of 5 chickens was dosed with 2000

mg formulation per kg body weight. Additionally, 5 control chickens

were dosed with empty capsules. After dosing, all chickens were

continuously observed for a time period of 14 days.



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recorded at day -1 (one day before dosing), on study days 3 and 7,

and on day 14 (termination of the study). Feed consumption was

measured daily until day 3 after dosing and afterwards for the time

period of days 7 – 14. On study days 1, 2, 3, 7 and 14 all remaining

feed was replaced by fresh feed after cleaning of the feeding

container. At the end of the study all surviving chickens were

sacrificed by CO2 asphyxiation and afterwards, gross necropsies

were carried out on all the sacrificed chickens.


met.

No mortality was observed. During the whole experimental phase (0-

14 days), all chickens showed a good and healthy condition. No

symptoms were visible. The food consumption and body weight

change were similar between control and dosed animals.


The acute oral LD50 for tetraniliprole in chicken was > 2000 mg

formulation/kg body weight.

Conclusion LD50 > 2000 mg formulation/ kg bw

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Study type Limit test, acute toxicity test to birds

Flag Key study


Exposure oral


Endpoint LD50

Value >2000 mg formulation/ kg bw

Reference


tetraniliprole SC 200 (200 g/L) to bobwhite quail (Colinus virginianus).


Klimisch Score 1


GLP yes


Dose Levels 2000 mg formulation/ kg bw


Study Summary

The aim of the study was to determine the acute effects of

tetraniliprole SC 200 (200 g/L) to bobwhite quail (Colinus virginianus).

Five adults (male and female) bobwhite quails were orally dosed one-

time with gelatine capsules filled with 2000 mg formulation per kg

body weight. Additionally, 5 control quails were dosed with empty

capsules. All birds were dosed by oral gavage After dosing, all birds

were continuously observed for a time period of 14 days.




recorded at day -1 (one day before dosing), on study days 3 and 7,

and on day 14 (termination of the study). Feed consumption was

measured daily until day 3 after dosing and afterwards for the time

period of days 3-7 and 7 – 14. At the end of the study, all surviving

birds were sacrificed by CO2 asphyxiation and afterwards gross

necropsies were carried out on all the sacrificed birds.

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met.

No mortality was observed. During the whole experimental phase (0-

14 days), all quails showed a good and healthy condition. No

symptoms were visible.

The food consumption was lower during the first 24 hours after

dosing (incl. control birds). Overall the food intake of the dosed birds

was lower than that of the control group.

Dosed quails showed a loss of body weight of approx. 4% during the

first 7 days after dosing. Afterwards, they started gaining weight so

that on day 14 the weight loss represented only 1.6%. The control

quails showed also a loss of body weight of approx. 1.1% during the

first 7 days after dosing. With the exception of one control quail, all

others obtained at least their initial weight at the end of the study or

increased it.


The acute oral LD50 for tetraniliprole in bobwhite quail was > 2000 mg

formulation/kg body weight.

Conclusion LD50 > 2000 mg formulation/ kg bw

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Non-target Arthropods

Tier I – laboratory studies

Table 203: Laboratory study on Aphidius rhopalosiphi

Study type Acute Toxicity test – arthropods

Flag Key study

Test Substance BCS-CL73507 SC 200 g/L

Exposure Glass plate, 48 h

Test species Parasitoid wasp, Aphidius rhopalosiphi

Endpoint LR50

Value 0.627 g ai/ ha

Reference

Mueller U. 2014, Toxicity to the parasitoid wasp Aphidius rhopalosiphi (

Hymenoptera Braconidae) using a laboratory test BCS-Cl73507 SC

200 g/L. Report noCW14/014, M-50555-01-2

Klimisch Score 1


GLP yes

Test Guideline/s Mead Briggs et al (2000), Candolfi et al (2001)

Dose Levels 3, 6, 11, 22 and 44 g ai/ha, first run

0.5, 0.9, 1.6, 2.8 and 5.0 g ai/ha, second run


Study Summary

The aim of the study was to determine the toxicity of tetraniliprole SC

200 G on the parasitoid wasp Aphidius rhopalosiphi when exposed on

a treated glass surface.

The test substance was compared with a control using deionised

water. In the first run the test substance rates of 3, 6, 11, 22 and 44 g

ai/ha, respectively, in 200 L deionised water were tested. As in the

lowest rate of 3 g ai/ha of the first run, the corrected mortality was still

above 50%, a second run at rates of 0.5, 0.9, 1.6, 2.8 and 5.0 g ai/ha,

respectively, in 200 L deionised water was conducted. A toxic

reference (ai dimethoate) applied at 0.04 g ai/ha was included in both

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runs to indicate the relative susceptibility of the test organisms and the

test system.

Mortality of 60 adult wasps, Aphidius rhopalosiphi, not older than 48 h

(4 replicates with 15 wasps per test group), was assessed 2, 24 and 48

hours after exposure in both runs.

In the first run, the corrected mortalities were above 50% (55.2-87.9%).

The corrected mortality of the second run was 41.7%, 63.3%, 71.7%,

76.7% and 90.0% for the rates 0.5, 0.9, 1.6, 2.8 and 5.0 g ai/ha,

respectively. The second run was used to calculate the LR50.

No mortality was observed in the control and mortality was 53.3% in

the toxic reference. Therefore, the validity criteria were met.

The LR50 for Tetraniliprole SC 200 G was calculated to be 0.627 g

ai/ha (95% CL: 0.373 – 0.856) in a laboratory test on glass plates on

the parasitoid wasp Aphidius rhopalosiphi.

Conclusion LR50 = 0.627 g ai/ha

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Table 204: Laboratory study on Typhlodromus pyri

Study type Toxicity test – arthropods

Flag Key study


Exposure Glass plate, 14 d

Test species Predatory mite, Typhlodromus pyri

Endpoint LR50

Value >44 g ai/ha mortality and reproduction

Reference

Mueller U. 2014, Toxicity to the predatory mite Typhlodromus pyri (Acari

Phytoseiidae) using a laboratory test BCS-Cl73507 SC 200 g/L. Report no

CW14/013, M-504426-01-2

Klimisch Score 1


GLP yes

Test Guideline/s Bleume et al (2000) and Candolfi et al (2000)

Dose Levels 3, 6, 11, 22 and 44 g ai/ha


Study Summary

The aim of the study was to determine the toxicity of tetraniliprole SC 200 G

on the predatory mite Typhlodromus pyri when exposed on a treated glass

surface.

The test substance was applied at rates of 3, 6, 11, 22 and 44 g ai/ha in 200

L deionised water and compared with a control using deionised water. A toxic

reference (ai dimethoate) applied at 5 g ai/ha was included to indicate the

relative susceptibility of the test organisms and the test system.

Mortality of 100 mites (protonymphs, 5 replicates of 20 mites per test group),

was assessed 1, 4, 7, 9, 11 and 14 days after exposure by counting the

number of living and dead mites. The number of escaped mites was

calculated as the difference from the total number exposed. The reproduction

rate of surviving mites was evaluated from day 7 to day 14 after treatment by

counting the total number of offspring (eggs and larvae) produced.

The corrected mortality was 3.7%, -3.7%, -11%, -7.3% and 4.9% for the rates

3, 6, 11, 22 and 44 g ai/ha, respectively.

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The number of eggs/female was 4.04, 4.81, 4.84, 5.40 and 4.53 for the rates

3, 6, 11, 22 and 44 g ai/ha, respectively.

No significant differences were observed in the mortality and reproduction

compared to the control.

Mortality was 18% in the control (recommended ≤20%) and the corrected

mortality was 90.2% in the toxic reference (recommended ≥50%). Average

number of eggs/female was 5.25 (recommended ≥4). Therefore, the validity

criteria were met.

The LR50 for Tetraniliprole SC 200 G was calculated to be >44 g ai/ha for

mortality in a laboratory test on glass plates on the predatory mite

Typhlodromus pyri. The NOER for mortality and reproduction was ≥ 44 g

ai/ha.

Conclusion LR50 > 44 g ai/ha (mortality)

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Tier II – extended laboratory studies

Table 205: extended laboratory study on Aphidius rhopalosiphi – study 1


Flag Key study


Exposure Extended laboratory test, fresh and aged residue on apple


Endpoint LR50

Value Could not be determined, <25 g ai/ha

Reference

Jans D. 2016, Toxicity to the parasitoid wasp Aphidius rhopalosiphi (

Hymenoptera Braconidae) using an extended laboratory test with aged

residues on apple- Tetraniliprole (BCS-Cl73507) SC 200 g/L. Report no

CW15/023, M-551609-01-2

Klimisch Score 1

Amendments/Deviations

None that affected the results of the study

Use of treated apple seedlings, wasps exposed to freshly applied and under

semi-field conditions aged residues on detached leaves.

GLP yes

Test Guideline/s

Mead-Briggs et al. (2010) Use of treated apple seedlings, wasps exposed to

freshly applied and under semi-field conditions aged residues on detached

leaves.

Candolfi et al (2001)


Analytical

measurements NA

Study Summary


on the parasitoid wasp Aphidius rhopalosiphi when exposed to fresh and aged

residues of the test substance on apple.

The test substance was applied twice with 25 g ai/ha diluted in 400 L

deionised water/ha on potted apple seedlings. The application interval was 14

days. The control was treated with deionised water. A toxic reference (ai

dimethoate) applied at 4 g ai/ha was included on the second application day to

indicate the relative susceptibility of the test organisms and the test system.

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Ageing of the spray deposits of the test substance on the potted apple

seedlings took place under semi-field conditions with UV permeable rain

protection during the first six weeks of the study. Five bioassays were

performed, the first started on the second application day of the test substance

(0DAT2 = 0 DAT 2) and the last one nine weeks later (63DAT2).

Parasitoid wasps (Aphidius rhopalosiphi) were exposed to these residues on

the treated leaf surfaces. Mortality of 30 female wasps, not older than 48 h at

study start (6 replicates with 5 wasps per test group), was assessed 2, 24 and

48 h after exposure in all bioassays.

Repellency of the test substance was assessed during the initial 3 h after the

release of the females. Five separate observations were made at 30-minute

intervals starting 15 - 30 minutes after the introduction of all wasps.

The reproductive performance was assessed only in the bioassay started on

day 14 after the second application of the test substance (14DAT2). For this

15 impartially chosen females from the water control and the test substance

group were each transferred to a cylinder containing untreated barley

seedlings infested with Rhopalosiphum padi for a period of 24 h. The number

of mummies was assessed 12 days later.

Corrected mortality of the test substance after 48h exposure to the residue

ranged from 50% (14DAT2) up to 93.1% (42DAT2). Even aged residue on day

63 after 2nd application caused 83.3% mortality. All results were statistically

different compared to the control.

No repellent effect could be observed.

Due to the corrected mortality above 50% in the first, third, fourth and fifth

bioassay, the effects on reproduction were only assessed in the second

bioassay (14DAT2) which showed 50% mortality. A reduction in reproduction

of 34.8% was observed which was not statistically different compared to

control.

Mortality of the control was maximal 3.3% 42DAT (recommended ≤10%),

corrected mortality of the toxic reference was 86.7 or 100% (recommended

≥50%). The reproduction per female in the control was 49.6 (recommended

≥5%) and the number of wasps in the control producing zero values for

reproduction was 0 (recommend ≤2). Therefore, all validity criteria were met.

Tetraniliprole SC 200 G was tested on the parasitoid wasp Aphidius

rhopalosiphi in an extended laboratory test with aged residues on potted apple

seedlings. In the 5th bioassay started nine weeks after the second application

of the test substance (63DAT2), the corrected mortality was still > 50%.

Conclusion LR50 could not be determined, less than 25 g ai/ha

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Table 206: extended laboratory study on Aphidius rhopalosiphi – study 2

Study type Chronic Toxicity test – arthropods

Flag Key study


Exposure Extended laboratory test, residue on barley


Endpoint LR50

Value 0.7 g ai/ha

Reference

Waibel J. 2015, Toxicity to the parasitoid wasp Aphidius rhopalosiphi

(Hymenoptera Braconidae) using an extended laboratory test on barley -

tetraniliprole (BCS-Cl73507) SC 200 g/L. Report no CW14/035, M-

533156-01-2

Klimisch Score 1


GLP yes

Test Guideline/s Mead-briggs et al. (2010), Candolfi et al. (2001)

Dose Levels 0.3, 0.5, 0.9, 1.7 and 3.0 g ai/ha


Study Summary

The aim of the study was to determine the toxicity of tetraniliprole SC 200

G on the parasitoid wasp Aphidius rhopalosiphi when exposed on a plant

surface.

The test substance was applied on barley seedlings (Hordeum vulgare)

at rates of 0.3, 0.5, 0.9, 1.7 and 3.0 g ai/ha diluted in 400 L deionised

water/ha. The control was treated with deionised water. A toxic reference

(ai dimethoate) applied at 4 g ai/ha was included.

Parasitoid wasps (Aphidius rhopalosiphi) were exposed to residues on

the treated leaf surfaces. Mortality of 30 female wasps, not older than 48

h at study start (6 replicates with 5 wasps per test group), was assessed

2, 24 and 48 h after exposure.

Repellency of the test substance was assessed during the initial 3 h after

the release of the females. Five separate observations were made at 30-

minute intervals starting 15 - 30 minutes after the introduction of all

wasps.

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From the water control and the test substance rates of 0.3 and 0.5 g

ai/ha, 15 impartially chosen females per treatment were each transferred

to untreated barley seedlings infested with Rhopalosiphum padi for a

period of 24 h. The number of mummies was assessed 11 days later.

Corrected mortality of the test substance after 48h exposure to the

residue ranged from 20.0% up to 93.3% at the rates 0.3, 0.5, 0.9, 1.7,

and 3.0 g ai/ha respectively. In all rates the difference was significant.

No repellent effect could be observed.

Reproduction was assessed for the two lowest test substance rates of

0.3 and 0.5 g ai/ha. The mean number of mummies per female in the

control group was 32.7 compared to 22.1 mummies/female in the 0.3 g

ai/ha rate and 15.2 mummies/female in the 0.5 g ai/ha rate of the test

substance. The reduction in reproductive success relative to the control

at the 0.3 and 0.5 g ai/ha rate was 32.4% and 53.6%, respectively and

differed significantly.

No mortality of the control was observed (recommended ≤10%),

corrected mortality of the toxic reference was 63.3% (recommended

≥50%). The reproduction per female in the control was 32.7

(recommended ≥5%) and the number of wasps in the control producing

zero values for reproduction was 0 (recommend ≤2). Therefore, all


The effects of Tetraniliprole SC 200 G residues on the parasitoid wasp

Aphidius rhopalosiphi in an extended laboratory test with treated barley

seedlings can be quantified as LR50 of 0.7 g ai/ha. The NOER for

mortality and reproduction <0.3 g ai/ha.

Conclusion LR50 = 0.7 g ai/ha

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Table 207: extended laboratory study on Coccinella septempunctata

Study type Chronic toxicity test – arthropods

Flag Key study


Exposure Extended laboratory test, residue on bean leaves

Test species Ladybird, Coccinella septempunctata

Endpoint LR50

Value > 44 g ai/ha

Reference

Roehlig U., 2015, Effects of BCS-Cl73507 SC 200 (200 g/L) on the ladybird

Coccinella septempunctata under extended laboratory conditions. Report no

14 10 48 069 A, M-513153-01-2

Klimisch Score 1

Amendments/Deviations modified for the exposure on natural substrate (extended laboratory test) this

does not impact the validity of the study

GLP yes

Test Guideline/s IOBC Schmuck et al 2000

Dose Levels 3, 6, 11, 22, and 44 g ai/ha

Analytical

measurements NA

Study Summary


on the ladybird Coccinella septempunctata when exposed to a treated leaf

surface.

Larvae of Coccinella septempunctata L. (3-4 days old) were exposed in 40

replicates per treatment group and 1 larva per replicate to dried spray residues

of Tetraniliprole SC 200 G, reference substance and control treatments,

respectively. Tetraniliprole SC 200 G was applied onto detached bean leaves

(Phaseolus vulgaris) at rates of 3, 6, 11, 22, and 44 g ai/ha in 200 L deionised

water. The leaves were dried for 1 hour. The control was treated with

deionised water (200 L/ha). Dimethoate EC 400 (12 g ai/ha in 200 L deionised

water) was used as a toxic reference substance.

The number of dead larvae and pupae and hatched beetles, as well as the

number of eggs laid and larvae hatched, were recorded over a period of 48

days. From these data, the endpoint mortality was calculated. Additionally,

effects on reproduction were investigated.

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Corrected mortality of the test substance after 19 days to the dried spray

ranged from -6.1 % and 9.1%. No statistically significant effects on mortality

were determined.

The average number of fertile eggs per female per day of the test substance

ranged from 2.7 and 2.9 in comparison with the control with 2.9 fertile eggs

per female per day.

Mortality of the control was 17.5% (recommended ≤30%), corrected mortality

of the toxic reference was 75.8% (recommended ≥40%). The average number

of fertile eggs per female and day was 2.9 (recommended ≥2). Therefore, all


The effect of Tetraniliprole SC 200 G residues on larvae of the ladybird beetle

Coccinella septempunctata L. exposed on a treated surface of bean leaves

can be quantified as: the LR50 > 44 g ai/ha, the NOER for pre-imaginal

mortality ≥ 44 g ai/ha. The reproductive performance was not affected up to

and including 44 g ai/ha.

Conclusion LR50 >44 g ai/ha

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Table 208: extended laboratory study on Chrysoperla carnea

Study type Chronic Toxicity test – arthropods

Flag Key study


Exposure Extended laboratory test, residue on bean leaves

Test species Lacewing, Chrysoperla carnea

Endpoint LR50

Value > 44 g ai/ha

Reference

Waibel J. 2015, Toxicity to the green lacewing Chrysoperla carnea (Neuroptera

Chrysopidae) using an extended laboratory test on bean BSC-Cl73507 SC 200

g/L. Report no CW14/036, M-511602-01-2

Klimisch Score 1

Amendments/Deviati

ons

Voght et al. (2000) modified for use of natural substrate (bean leaves) instead of

glass plate this does not impact the validity of the study

GLP yes

Test Guideline/s Candolfi et al. (2001), Vogt et al. (2000)

Dose Levels 3, 6, 11, 22, and 44 g ai/ha

Analytical

measurements NA

Study Summary

The aim of the study was to determine the toxicity of tetraniliprole SC 200 G on

the green lacewing Chrysoplera carnea when exposed to a treated bean leaf

surface.

Larvae of Chrysoperla carnea (2 days old) were exposed in 40 replicates per

treatment group and 1 larva per replicate to dried spray residues of Tetraniliprole

SC 200 G, reference substance and control treatments, respectively.

Tetraniliprole SC 200 G was applied onto detached bean leaves (Phaseolus

vulgaris) at rates of 3, 6, 11, 22, and 44 g ai/ha in 200 L deionised water. The

control was treated with deionised water (200 L/ha). Dimethoate EC 400 (36 g

ai/ha in 200 L deionised water) was used as a toxic reference substance.

The pre-imaginal mortality of larvae was assessed over 19 days (till the hatch of

the imagines). The fertility and fecundity of the surviving hatched adults were then

evaluated over the period of one week.

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Corrected mortality of the larvae after 19 days exposure to the residue ranged

from -2.8 % to 5.7%. No statistically significant effects on mortality were

determined.

The average number of eggs per surviving adult female per day of the test

substance ranged from 24.1 to 38.3 in comparison with the control with 30.4 eggs

per female per day. Hatching rate ranged from 74.7% to 82.0%. Hatching rate of

the control was 81.1%.

Mortality of the control was 5.1% (recommended ≤20%), corrected mortality of the

toxic reference was 68.4% (recommended ≥50%). The average number of eggs

per female and day was 30.4 (recommended ≥15%) and hatching rate was 81.1%

(recommended ≥70%). Therefore, all validity criteria were met.

The effect of Tetraniliprole SC 200 G residues on larvae of green lacewing

exposed on a treated surface of bean leaves can be quantified as: the LR50 > 44

g ai/ha, the NOER for pre-imaginal mortality is 44 g ai/ha. The reproductive

performance was not affected up to and including 44 g ai/ha.

Conclusion LR50 >44 g ai/ha

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Tier III – higher tier studies

Semi-field studies

Table 209: Semi-field study – Eretmocerus eremicus

Study type Semi-field Toxicity test – arthropods

Flag Supplemental study


Exposure Semi-field

Test species Parasitoid wasp, Eretmocerus eremicus

Endpoint Adverse effects on parasitation and hatching

Value <25%

Reference

Ernst G., Kroder S. 2016, Side-effects of tetraniliprole (BSC-CL73507) on

parasitoid wasp Eretmocerus eremicus (Hymenoptera Aphelinidae) in

aubergine under semi-field conditions. Report no M-564380-01-1

Klimisch Score 2

Amendments/Deviations NA

GLP No, GEP certified trial site

Test Guideline/s NA

Dose Levels Twice 20 g ai/ha with interval of 7 days


Study Summary


G on the parasitoid wasp Eretmocerus eremicus in a walk- in net tunnel

study.

The test substance was applied on plants 2 times at a single application

rate of 20 g ai/ha and a spray interval of 7 days. Effects (parasitation

rate, hatching rate on the parasitoids were compared to those of an

untreated control and a toxic reference (active ingredient: lambda-

cyhalothrin) applied at 12.5 g ai/ha was included to indicate the relative

susceptibility of the test organisms and the test systems.

The trials were conducted in 3 replicates using randomized complete

block design under semi-field conditions in a walk-in net tunnel in Spain

in 2012.

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Parasitation rates were assessed by counting the number of living and

parasitized hosts on each sampling date starting on the day of

application. Effects on hatching were evaluated by counting number of

hatched and unhatched parasitized whitefly pupae when applicable up to

28 days after the first and 21 days after the second application.

The reduction in parasitation rate was -11.6% 7DAA2, 17.6% 15DAA2

and -2.7% 21DAA2 for the test substance. For the toxic reference

parasitasion rate was -18.1%, 74.8% and 59.0% respectively.

Hatching rate was reduced for 2.3% 15DAA2 and 9.0% 21DAA2 for the

test substance. Due to significantly less parasitation of the reference, the

hatching rate of the reference was -10.5% and -34.8% respectively.

The exposure of Eretmocerus eremicus to tetraniliprole under semi-field

conditions indicates no unacceptable adverse effects on parasitation rate

and reproduction. At the test substance rate of 2 x 20 g tetraniliprole/ha,

effects remain <25% in all samplings during the study period.

The IOBC classification is determined to be 1 (harmless) in post-

application samplings.

Conclusion Effects <25% during the study (twice 20 g ai/ha)

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Table 210: Semi-field study – Aphelinus mali

Study type Field Toxicity test – arthropods


Test Substance BCS-CL73507 SC 200 g/L, in one study another formulation with 25 g

ai/L was used.

Exposure Field conditions

Test species Parasitoid wasp, Aphelinus mali

Endpoint Adverse effects

Value <25% in two studies, 25-50% in three studies

Reference

Ernst G., Kroder S. 2016, Side-effects of tetraniliprole (BSC-CL73507)

on parasitoid wasp Aphelinus mali (Hymenoptera Aphelinidae) in

apples under field conditions. Report no M-564376-01-1

Klimisch Score 2


GLP No, GEP certified trial sites

Test Guideline/s NA

Dose Levels Once or twice 10 or 20 g ai/ha/ m canopy height with interval of 13-14

days


Study Summary


200 G (in one study it was a 25 g ai/L formulation) on the parasitoid

wasp Aphelinus mali in five field studies.

The test substance was applied on plants 1 or 2 times at an application

rate of 10 or 20 g ai/ha and a spray interval of 13-14 days to different

varieties of apples. Effects on the parasitoids were compared to those

of an untreated control and a toxic reference (active ingredient:

clothianidin or lambda-cyhalothrin) was included to indicate the relative


The trials were conducted in 3 replicates using randomized complete

block design under field conditions in orchards in Germany, France,

Italy and Belgium between 2010 and 2014.


parasitized hosts on each sampling date starting on the day of

application in all trials. In one study, effects on hatching were evaluated

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by counting number of hatched and unhatched parasitized aphids

when applicable. Results are percentage reduction relative to control, a

negative value indicates a higher parasitation rate/ hatching rate

compared with the control.

Results of study 1 (1 x 20 g ai/ha):

The parasitation rate was 0% 0DAA, 36.5% 7DAA, 40.0% 14DAA and

3.4% 21DAA for the test substance. For the toxic reference

parasitasion rate was 0, 39.7, 43.0 and 11.8%, respectively.


The parasitation rate was 0.1% 0DALA, 11.0% 7DALA, -0.2% 14DALA,

11.7% 22DALA, and 9.7% 28DALA for the test substance. For the toxic

reference parasitasion rate was 9.3, 12.7, -12.7, 5.8 and 2.1%

respectively.


The parasitation rate was 9.9% 0DALA, 9.1% 7DALA, 35.6% 14DALA

for the test substance. For the toxic reference parasitation rate was

14.8, 13.6 and 20.6%, respectively.


The parasitation rate was 1.0% 0DALA, 1.3% 8DALA, and 0.5%

21DALA for the test substance. For the toxic reference parasitasion

rate was 0, 1.7 and 0.7% respectively.

Hatching rate was 32.3% 0DALA, 20.1% 8DALA for test substance.

For the reference hatching rate was -19.8 and -4.7% respectively


The parasitation rate was -155.3% 0DALA, -8.8% 14DALA, 17%

28DLAA, 17% 42DALA and -5.8% 56DALA for the test substance. For

the toxic reference parasitasion rate was -576, -258, 34.2, 21.8 and -

9.0% respectively.

The exposure of Aphelinus mali to tetraniliprole under field conditions

indicates adverse effects on parasition rates and reproduction and is

considered slightly harmful in three studies according to IOBC

classifications. These effects reduce over time (after 14 days). In the

other studies, the test substance is considered to be harmless.

Conclusion

Effects 25- 50% in three studies (slightly harmful, one study 1x 20 g

(substance 25 g ai/L) and two studies 2 x 20 g ai/ha/m canopy height),

in the other studies effects <25% (1x 10 g ai/ha/m canopy height and 2

x 20 g ai/ha/canopy height)

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Table 211: Semi-field study – Encarsia formosa



Test Substance BCS-CL73507 SC 25 g/L, not proposed formulation

Exposure Semi-field

Test species Parasitoid wasp, Encarsia formosa

Endpoint Adverse effects, parasitation and hatching rate

Value >25%

Reference


parasitoid wasp Encarsia formosa (Hymenoptera Aphelinidae) in tomatoes

under semi-field conditions. Report no M-564379-01-1

Klimisch Score 2


GLP No, GEP certified trial site

Test Guideline/s NA



Study Summary

The aim of the study was to determine the effects of tetraniliprole SC 25 on

the parasitoid wasp Encarsia formosa in three greenhouse studies.

The test substance was applied to tomato plants at an application rate of

60 g ai/ha. Effects on the parasitoids were compared to those of an

untreated control and a toxic reference (active ingredient: lambda-

cyhalothrin) applied at 12.5 g ai/ha was included to indicate the relative


The trials were conducted in 3 replicates using randomized complete block

design under semi-field conditions in greenhouses in Germany and Italy in

2010.


parasitized hosts on each sampling date starting on the day of application.

Effects on hatching were evaluated by counting number of hatched and

unhatched parasitized whitefly pupae when applicable. Results are

percentage reduction relative to control, a negative value indicates a

higher parasitation rate/ hatching rate compared with the control.

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Results of study 1:

The parasitation rate reduction was 12.6% 0DAA, -32.0% 3DAA, -42.8% 6-

7DAA and -50.3% 12DAA for the test substance. For the toxic reference

parasitasion rate was 1.3%, -46.8%, -9.6% and -5.6%. respectively.

Hatching rate reduction was 32.0% 6-7DAA and 27.4 12DAA for the test

substance. For the reference hatching rate was 100% and 88.4%,

respectively.

Results of study 2:

The parasitation rate reduction was 6.7% 0DAA, -19.4% 3DAA, -24.7%

5DAA, -35.6% 9DAA and -25.2% 12DAA for the test substance. For the

toxic reference parasitasion rate was -4.6, 0.6, 3.5, 10.7 and 24.3%

respectively.

Hatching rate reduction was 53.5% 5DAA, 14.1% 9DAA and -5.2% 12DAA

for the test substance. For the reference hatching rate was 91.0, 93.9 and

94.9%, respectively.

Results of study 3:

The parasitation rate reduction was -81.0% 0DAA, -56.3% 3DAA, -50.3%

6-7DAA and -17.3% 16DAA for the test substance. For the toxic reference

parasitasion rate was 2.7%, 11.0%, -1.5% and 14.0% respectively.

Hatching rate reduction was 39.3% 16 DAA for the test substance. For the

reference hatching rate was 76.3%.

The exposure of Encarsia formosa to tetraniliprole under semi-field

conditions indicates adverse effects on parasition rates and reproduction

especially up to 5 DAT and is considered slightly to moderately harmful

according to IOBC classifications.

Additional comments

In study 1 the parasitation rate of the toxic reference is better compared to

the control. This might be caused by sufficient suppression of the whitefly

population.

Conclusion Effects >25% (up to 54%) during the study, considered slightly to

moderately harmful according to IOBC classification

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Table 212: Semi-field study – Aphidius colemani



Test Substance BCS-CL73507 SC 25, not proposed formulation

Exposure Semi-field conditions

Test species Parasitoid wasp, Aphidius colemani

Endpoint Adverse effects

Value <25% in two studies, and >25% in two studies (after 19 days slightly

harmful)

Reference


parasitoid wasp Aphidius colemani (Hymenoptera Braconidae) in vegetables

under semi-field conditions. Report no M-564374-01-1

Klimisch Score 2


GLP No, GEP certified trial sites

Test Guideline/s NA



Study Summary

The aim of the study was to determine the effects of tetraniliprole SC 25 on

the parasitoid wasp Aphidius colemani in four greenhouse studies.

The test substance was applied to plants (Zucchini, savoy cabbage) at an

application rate of 60 g ai/ha. Effects on the parasitoids were compared to

those of an untreated control and a toxic reference (active ingredient:

lambda-cyhalothrin) applied at 12.5 g ai/ha was included to indicate the

relative susceptibility of the test organisms and the test systems.

The trials were conducted in 3 replicates using randomized complete block

design under semi-field conditions in greenhouses in Germany and Italy in

2010.


parasitized hosts on each sampling date starting on the day of application.

Effects on hatching were evaluated by counting number of hatched and

unhatched parasitized aphids when applicable. Results are percentage

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reduction relative to control, a negative value indicates a higher parasitation

rate/ hatching rate compared with the control.

Results of study 1:

The parasitation rate reduction was 51.7% 0DAA, -5.7% 3DAA, 2.9% 7DAA

and 24.7% 17DAA for the test substance. For the toxic reference

parasitasion rate reduction was 10.4, 2.4, -5.3 and 1.8%, respectively.

Hatching rate reduction was -5.8% 17DAA for the test substance. For the

reference hatching rate reduction was -2.8%.

Results of study 2:



toxic reference parasitasion rate reduction was 15.9, -1216, -1369, -1752

and -1979% respectively.

Hatching rate reduction was -362.4% 7DAA, 35.3% 14DAA and 21.9%

19DAA for the test substance. For the reference hatching rate reduction was

100, 45.6 and 34.2%, respectively.

Results of study 3:

The parasitation rate reduction was 3.4% 0DAA, -21.5% 4DAA, -107.1%


toxic reference parasitasion rate reduction was 13.4, -1640, -1685, -1916

and -2219%, respectively.

Hatching rate reduction was 43.6% 7DAA, 26.4% 14DAA and 29.0% 19DAA

for test substance. For the reference hatching rate reduction was 100, 53.3

and 41.7% respectively.

Results of study 4:


7DAA, -101.3% 11DAA, -136.7% 14DAA for the test substance. For the toxic

reference parasitasion rate was -33.2, -882, -927, -939 and -988%

respectively.

Hatching rate reduction was 21.7% 7DAA, 4.8% 11DAA and 5.7% 14DAA

for test substance. For the reference hatching rate was 92.4, 94.6 and

95.6% respectively

The exposure of Aphidius colemani to tetraniliprole under semi-field

conditions indicates adverse effects on parasition rates and reproduction

and is considered slightly to moderately harmful according to IOBC

classifications in two studies. At the end of these studies, the effect reduces

to harmless and slightly harmful. In the other studies, the results indicate that

the test substance is harmless according to IOBC classifications.

Additional comments

The parasitation rate of the tested substance and the reference is higher

than in the control. This is caused by the suppression of the aphid population

by these treatments.

Conclusion Effects 25-50% in two studies (slightly harmful at the end of the studies) and

<25% in the other two studies.

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Field studies

Table 213: Field study on non-target arthropods – study 1


Flag Key study



Test species Non -target arthropods

Endpoint NOER community and NOEAER population

Value 4 g ai/ha, and 4 g ai/ha

Reference

Bakker F., Aldershof S.A. 2016, A field study to assess the effects of

BCS-CL73507 SC 200 (200 g/L) on the non-target, surface- and plant-

dwelling arthropod fauna of a grassland habitat (off-crop) The

Netherlands during spring /summer. Report no B166FFN/ EBFVN053,

M-563750-01-3

Klimisch Score 1


GLP Yes

Test Guideline/s

IOBC (Hassan, 1992), Anonymous (1992), Brown (1998), IOBC, BART

and EPPO Joint Initiative (Candolfi et al., 2000, 2001), De Jong et al.,

2010

Dose Levels 0.2, 0.4, 0.8, 1.6 and 4.0 g ai/ ha


Study Summary

Tetraniliprole SC 200 G is an insecticide with a nominal content of

active substance of 200 g/L. This field study was designed to assess

the potential adverse effects of non-intentional spray drift on non-target

arthropods (NTA) in off-crop habitats that might occur at various

distances from a treated area for current and future use patterns of the

test substance.

The study was performed in a true off-crop habitat, ie a meadow

habitat with low agricultural input in The Netherlands. This approach

has the advantage that the observed response will pertain to a

representative off-crop NTA community, ie a community not previously

under selection in an agricultural regime. For this reason, the study

outcome represents a realistic worst case situation. The study was

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designed as a NOER-type (Bakker and Miles, 2007; De Jong et al,

2010). The choice for a NOER approach makes the results applicable

to any product use pattern. At the same time, the assessment of a

NOEAER/LOEAER avoids the caveats of assessing the acceptability of

certain effect levels at given drift rates (Bakker, 2012; Miles and

Bakker, 2012). The finding that the NOER or NOEAER may be

expected to occur at a certain distance from a treated area will be

unambiguously interpretable.

The study period was set at two months, which permitted the effects to

be classified in accordance with duration of effect, as described in de

Jong et al. (2010). Initial effects followed by recovery within this time

frame were considered ecologically acceptable.

Tetraniliprole SC 200 G was applied once to a grassland meadow at

nominal rates of 0.2, 0.4, 0.8, 1.6 and 4.0 g ai/ha, equivalent to typical

drift values for various use patterns of the test substance. A water

control treatment and a toxic reference treatment (lambda-cyhalothrin

at a rate of 40 g ai/ha) were run in parallel. Nominal application

volumes were 200 L/ha.

The soil-surface- and plant-dwelling arthropod communities were

monitored shortly before application, and three days, one, two, four and

eight weeks after application. A broad spectrum of arthropods was

sampled with a combination of sampling methods, viz. pitfall trapping,

Berlese-Tullgren extraction from weed samples and suction sampling.

The trial had a randomized complete block design with 4

replicates/treatment. Each block had seven treatment plots of 30 x 30

m. Each plot was surrounded by untreated areas of at least 4 m wide.

The effects of Tetraniliprole SC 200 G were expressed in terms of

population and community changes relative to the water control. The

NOER was defined at the community level and at the population level

as the rate at which adverse responses were not significantly different

from the water control at any time point. The NOEAER was defined at

the community level and at the population level as the highest rate at

which statistically significant adverse responses were observed, but

recovery was demonstrated within two months after application. By

analogy, the LOEAER (for community and population responses) was

defined as the lowest test rate at which adverse effects were

statistically significantly different from the water control without

recovery occurring.

The analytical chemistry showed that the water used to prepare

solutions was uncontaminated and that the actual content of the active

ingredient was within 85%-101% of the nominal concentration. Actual

application rates were therefore not adjusted on basis of these results.

More than 4 million specimens from 525 taxa were identified; 89 of

which were included in population analyses. Highly abundant taxa were

springtails, Aphidoidea, some dipteran taxa from the suborder

Nematocera (mosquitoes), the beetle family Hydrophilidae and the

mites of the family Tarsonemidae. Collembola were largely dominating

the arthropod community (85% from all specimens).

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With the exception of most Acari and Collembola, the majority of taxa

were adversely and statistically significantly affected by the toxic

reference substance treatment. The validity criterion for the reference

treatment, at least 50% effect on at least one sample date for at least

10% of the taxa evaluated (De Jong et al., 2010), was evidently met. A

maximum proportion of 65% of taxa reduced by at least 50% compared

to the control was observed one week after treatment. Two months

after application 52% of all taxa evaluated were still reduced by 50% or

more in comparison to the control.

Based on statistical analyses and considerations, effects of

Tetraniliprole SC 200 G applied to an off-crop grassland arthropod

fauna in The Netherlands were classified as follows:

No statistically significant adverse community effects were found at a

rate of 4 g ai/ha or lower in any of the datasets analysed. This rate is

classified as the community NOER. BCS-CL73507 SC 200 G applied

at the rate of 4 g ai/ha is the population NOEAER.

Statistically significant adverse effects were observed for few taxa at

this rate, but recovery of all populations occurred within one month

after treatment. Affected taxa were adult Erigone dentipalips, juvenile

Erigoninae (Linyphiidae, Araneae), the beetles Stenus (Staphylinidae)

Hydrophilidae and Alticinae (Chrysomelidae; Coleoptera),

Lonchopteridae (Aschiza, Diptera) and Braconidae (Ichneumonoidea,

Hymenoptera).

Tetraniliprole SC 200 G applied at the rate of 1.6 g ai/ha is the

population NOER. At this rate, no adverse treatment-related effects

were detected for any of the 89 taxa examined at the population level.

The community LOER and population LOEAER are higher than 4 g

ai/ha, the highest rate tested in this study.

Conclusion NOER community = 4 g ai/ha

NOEAER population = 4 g ai/ha

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Flag Key study



Test species Non -target arthropods

Endpoint NOER community and NOEAER population

Value 4 g ai/ha, and 4 g ai/ha

Reference

Bakker F., Aldershof S.A. 2016, A field study to assess the effects of

BCS-CL73507 SC 200 (200 g/L) on the non-target, surface- and plant-

dwelling arthropod fauna of a grassland habitat (off-crop) in SW France

during spring /summer. Report no EBFVN054, M-563748-01-1

Klimisch Score 1


GLP Yes

Test Guideline/s

IOBC (Hassan, 1992), Anonymous (1992), Brown (1998), IOBC, BART

and EPPO Joint Initiative (Candolfi et al., 2000, 2001), De Jong et al.,

2010

Dose Levels 0.2, 0.4, 0.8, 1.6 and 4.0 g ai/ha

Analytical measurements Yes

Study Summary

Tetraniliprole SC 200 G is an insecticide with a nominal content of

active substance of 200 g/L. This field study was designed to assess

the potential adverse effects of non-intentional spray drift on non-target

arthropods (NTA) in off-crop habitats that might occur at various

distances from a treated area for current and future use patterns of the

test substance.

The study was performed in a true off-crop habitat, ie a meadow

habitat with low agricultural input in South-West France. This approach

has the advantage that the observed response will pertain to a

representative off-crop NTA community, ie a community not previously

under selection in an agricultural regime. For this reason, the study

outcome represents a realistic worst case situation. The study was

designed as a NOER-type (Bakker and Miles, 2007; De Jong et al,

2010). The choice for a NOER approach makes the results applicable

to any product use pattern. At the same time, the assessment of a

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NOEAER/LOEAER avoids the caveats of assessing the acceptability of

certain effect levels at given drift rates (Bakker, 2012; Miles and

Bakker, 2012). The finding that the NOER or NOEAER may be

expected to occur at a certain distance from a treated area will be

unambiguously interpretable.

The study period was set at two months, which permitted the effects to

be classified in accordance with duration of effect, as described in de

Jong et al. (2010). Initial effects followed by recovery within this time

frame were considered ecologically acceptable.

Tetraniliprole SC 200 G was applied once to a grassland meadow at

nominal rates of 0.2, 0.4, 0.8, 1.6 and 4.0 g ai/ha, equivalent to typical

drift values for various use patterns of the test substance. A water

control treatment and a toxic reference treatment (lambda-cyhalothrin

at a rate of 40 g ai/ha) were run in parallel. Nominal application

volumes were 200 L/ha.

The soil-surface- and plant-dwelling arthropod communities were

monitored shortly before application, and three days, one, two, four and

eight weeks after application. A broad spectrum of arthropods was

sampled with a combination of sampling methods, viz. pitfall trapping,

Berlese-Tullgren extraction from weed samples and suction sampling.

The trial had a randomized complete block design with 4

replicates/treatment. Each block had seven treatment plots of 30 x 30

m. Each plot was surrounded by untreated areas of at least 4 m wide.

The effects of Tetraniliprole SC 200 G were expressed in terms of

population and community changes relative to the water control. The

NOER was defined at the community level and at the population level

as the rate at which adverse responses were not significantly different

from the water control at any time point. The NOEAER was defined at

the community level and at the population level as the highest rate at

which statistically significant adverse responses were observed, but

recovery was demonstrated within two months after application. By

analogy, the LOEAER (for community and population responses) was

defined as the lowest test rate at which adverse effects were

statistically significantly different from the water control without

recovery occurring. from 745 taxa were identified; 73 of which were

included in population analyses. Abundant taxa were Cicadellidae,

Thysanoptera and mites of the order Oribatida and of the family

Tarsonemidae. Collembola were encountered relatively few in this

study.

With the exception of most Acari and Collembola, the majority of taxa

were adversely and statistically significantly affected by the toxic

reference substance treatment. The validity criterion for the reference

treatment, at least 50% effect on at least one sample date for at least

10% of the taxa evaluated (De Jong et al., 2010), was evidently met. A

maximum proportion of 66% of taxa reduced by at least 50% compared

to the control was observed one week after treatment. Two months

after application 28% of all taxa evaluated were still reduced by 50% or

more in comparison to the control. Over the full post-application period

67% of all taxa were considered adversely affected at some sample

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date. Statistically significant and persistent adverse effects of the toxic

reference treatment were seen for most spider taxa and hemipteran

taxa, but also for more mobile Hymenoptera and Diptera.

Based on statistical analyses and considerations, effects of

Tetraniliprole SC 200 G applied to an off-crop grassland arthropod

fauna in South-West France were classified as follows:

The community LOER is higher than 4 g ai/ha, the highest rate tested

in this study. No statistically significant adverse community effects were

found in any of the datasets analysed. The 4 g ai/ha rate is classified

as the community NOER.

Tetraniliprole SC 200 G applied at the rate of 4 g ai/ha is the population

NOEAER. Statistically significant adverse effects were observed, but

recovery of all populations occurred within two months after treatment.

Affected taxa were Nelima doriae (harvestmen, Arachnida), Zelotes

(Gnaphosidae, Araneae), Alticinae (Chrysomelidae; Coleoptera),

juvenile Silphidae (Coleoptera) and Acrididae (Orthoptera).


population LOER. At this rate moderate adverse treatment-related

effects of at maximum one month were observed for juvenile Silphidae.


population NOER. At this rate, no adverse treatment-related effects

were detected for any of the 73 taxa examined at the population level.

Conclusion NOER community = 4 g ai/ha

NOEAER population = 4 g ai/ha

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Flag Key study


Exposure Field trial on apple


Endpoint IOBC score

Value 1-2

Reference

unknown. 2013, Determine the selectivity of BCS-CL73507

(SP102000026908) on Typhlodromus pyri.in comparison with

Coragen on apple Project nr: IR12BELPFD0422

Klimisch Score 2


GLP No

Test Guideline/s No guideline reported

Dose Levels Two applications of 15 g ai/ha/m CH (corresponds to 45 g ai/ha)

Analytical measurements Unknown

Study Summary

The trial was conducted in an apple Jonagold orchard with a good an

homogeneous presence of the predatory mite.

A negative (3.75 g lambda-cyhalothrin/ha/m CH), positive (25 g

fenpyroximate/ha/m CH) and reference control were included (15 g

chlorantraniliprole/ha/m CH). BCS-CL73507 was applied at a rate of

15 g ai/ha/m CH.

The trial was performed in 4 replicates with a plot size of 6 trees. The

first application was at BBCH 71 and the second at BBCH 73.

During the second application two solutions were swapped but

results were still considered to be reliable.

The toxic reference (lambda-cyhalothrin) was determined to have an

IOBC score of 4. The positive reference (fenpyroximate) was

determined to have an IOBC score of 2. The reference substance

(chlorantraniliprole) had an IOBC score of 1.

The first application of BCS-CL73507 did not result in a significant

reduction in the number of mites. The second application a more

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pronounced reduction was observed but the population was able to

recover. The overall IOBC was determined to be IOBC 1-2

Comments Not a full study report is provided a summary and raw data has been

provided

Conclusion BSC-CL73507 is considered to be fully compatible with IPM when

applied as tested.

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Flag Key study


Exposure Field trial on apple


Endpoint IOBC score

Value 1-2

Reference

unknown. 2012, Determine the selectivity of BCS-CL73507 200 SC

(SP102000025595) +/- Mero on Typhlodromus pyri.in comparison with

Coragen. Determine the selectivity of MET52 EC11. Project nr:

IR11BELPFS0434

Klimisch Score 2


GLP No


Dose Levels Two applications of 15 g ai/ha/m CH (corresponds to 36 g ai/ha)


Study Summary

The trial was conducted in an apple Jonagold orchard with a good an

homogeneous presence of the predatory mite.

A negative (3.75 g lambda-cyhalothrin/ha/m CH), positive (25 g

fenpyroximate/ha/m CH) and reference control were included (12 g

chlorantraniliprole/ha/m CH). BCS-CL73507 was applied at a rate of 12 g

ai/ha/m CH solo and in combination with 0.1% Stefes Mero. Also the

selectivity of metarhizium Anisopliae was determined (0.417 l/ha/m CH of

a 11% solution).

The trial was performed in 4 replicates with a plot size of 6 trees. The first

application was at BBCH 72 and the second at BBCH 74.


IOBC score of 4. The positive reference (fenpyroximate) was determined

to have an IOBC score of 2. The reference substance

(chlorantraniliprole) had an IOBC score of 1(2).

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The application of BCS-CL73507 did not result in a significant reduction

in the number of mites with and without Stefes Mero. The overall IOBC

was determined to be IOBC 1(2)


provided

Conclusion BSC-CL73507 is considered to be fully compatible with the use of

predatory mites in IPM when applied as tested

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Flag Key study


Exposure Field trial on pear

Test species Predatory bug, Anthocoris nemoralis

Endpoint IOBC score

Value 1-2

Reference

unknown. 2013, Determine the selectivity of BCS-CL73507

(SP102000026908) on beneficial fauna towards Psylla pyri –

Anthocoris nemoralis Project nr: IR12BELPFD0425

Klimisch Score 2


GLP No


Dose Levels One application of 15 g ai/ha/m CH (corresponds to 45 g ai/ha)


Study Summary

The trial was conducted in an pear Conference orchard with a known

high presence of Anthocoris nemoralis. A high number of larvae was

confirmed.

A negative (6.25 g lambda-cyhalothrin/ha/m CH) and positive control

(85 g spirodiclofen/ha/m CH) were included. BCS-CL73507 was

applied at a rate of 15 g ai/ha/m CH.

The trial was performed in 4 replicates with a plot size of 8 trees. The

first application was at BBCH 74 and the second at BBCH 75.


IOBC score of 4. The positive reference (spirodiclofen) was determined

to have an IOBC score of 1.

The first application of BCS-CL73507 did not result in a significant

reduction in the number of adults but had an IOBC score of 1-2 for

larvae. The second application a more pronounced reduction was

observed but the population was able to recover. The overall IOBC was

determined to be IOBC 1-2

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provided

Conclusion BSC-CL73507 is considered to be fully compatible with IPM when

applied as tested.

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Pollinators

Honey bees

Acute toxicity

Table 218: Acute oral and contact toxicity of formulated product to honey bees

Study type Acute oral and contact toxicity test in honey bees

Flag Key study


Exposure 48 hours for oral and 96 hours for contact



Value


Oral NOED = 0.014 µg ai/bee (96 hours)


Contact NOED = 0.13 µg ai/bee (96 hours)

Reference

Schmitzer S. 2012. Effects of BCS-CL73507 SC 200 G (Acute Contact and

Oral) on Honey Bees (Apis mellifera L.) in the Laboratory


Klimisch Score 1

Amendments/Deviations None that impacted the study.

GLP yes


OECD 214

No/Sex/Group 10 per group, females, 3 replicates per group

Dose Levels Oral actual dose: 0.22, 0.11, 0.053, 0.027, 0.014 and 0.0064 μg ai/bee

Contact dose: 2.0, 1.0, 0.5, 0.25, 0.13 and 0.06 μg ai/bee (5 µL droplet)

Analytical

measurements NA

Study Summary

The purpose of the study was to determine the effects of BCS-CL73507 SC

200 G on the honey bee after acute contact and oral exposure in the

laboratory.

Contact test

In most treated groups, mortality increased by 10% or more between 24h and

48h, therefore, the test was prolonged to 96 hours.

In the solvent (0.5 % Adhäsit) control group, 3.3% mortality occurred during the

96-hour observation. The reference substance induced 83.3% mortality at 0.3

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μg dimethoate/bee and was within the acceptable range. Consequently,

validity criteria for both control and reference substance mortality were met and

the test was deemed valid.


86.7% mortality was observed after 96 hours. Treatment-related mortalities

were observed at 1 µg ai/bee (93.3% mortality), 0.5 µg ai/bee (60% mortality),

0.25 µg ai/bee (33.3% mortality), 0.13 µg ai/bee (6.7% mortality) and 0.06 µg

ai/bee (3.3% mortality).

Behavioural abnormalities (eg movement and coordination problems, apathy)

were observed in the surviving bees exposed to 0.13 µg ai/bee and above. No

behavioural abnormalities were observed at the lowest dose. Abnormalities

decreased with time after 96 hours only effects were observed at the highest

dose level.

Oral test

In most treated groups, mortality increased by 10% or more between 24h and

48h, therefore, the test was prolonged to 96 hours.

In the water (50% sugar) control group, no mortality occurred during the 96-

hour observation. The reference substance induced 96.7% mortality at 0.29 μg

dimethoate/bee and was within the acceptable range. Consequently, validity

criteria for both control and reference substance mortality were met and the

test was deemed valid.

In the oral toxicity test, at the highest tested dose level of 0.22 µg ai/bee,


were observed at 0.11 µg ai/bee (90% mortality), 0.053 µg ai/bee (46.7%

mortality), 0.027 µg ai/bee (23.3% mortality) and 0.014 µg ai/bee (10%

mortality). No mortality was observed at 0.0064 µg ai/bee

Behavioural abnormalities (apathy) were observed in the bees before they died

in the groups exposed to 0.014 µg ai/bee and above. No behavioural

abnormalities were observed at the lowest dose. Abnormalities decreased with

time.

Comments

Conclusion Oral LD50 = 0.048 µg ai/bee

Contact LD50 = 0.44 µg ai/bee

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Chronic toxicity

Table 219: Chronic oral toxicity of formulated product to honey bees

Study type Chronic oral toxicity test in honey bees

Flag Key study


Exposure 10 days, oral

Test Species Apis mellifera L.

Endpoint LC50, LLD50, NOEC NOEDD, behavioural abnormalities

Value

Chronic oral LDD50 = 0.0137 µg ai/bee/day

(equivalent to LC50 = 579 µg ai/kg feeding solution)

NOEDD = 0.00723 µg ai/bee/day

(equivalent to 247 µg ai/kg feeding solution)

Reference

Goßmann A. 2016. Chronic Oral Toxicity Test of BCS-CL73507 SC 200 G on

the Honey Bee (Apis mellifera L.) in the Laboratory


Klimisch Score 1


GLP yes

Test Guideline/s

OECD 213

CEB No. 230 with modifications and current recommendations of the ring test

group (2014)

No/Sex/Group 10 per group, 2-day old workers, 3 replicates per group

Dose Levels mean ingested dose: 0.00122, 0.00311, 0.00726, 0.0141 and 0.0386 µg ai/bee

per day

Analytical

measurements NA

Study Summary

The purpose of this study was to determine the chronic oral toxicity of

tetraniliprole SC 200 G to the honey bee for a period of ten days.

In the water (50% sugar) control group, 3.3% mortality occurred during the 10-

day observation period. The reference substance induced 100% mortality at

28.7 ng dimethoate/bee by day 7. Consequently, validity criteria for both

control and reference substance mortality were met and the test was deemed

valid.

In the highest tested dose level of 38.6 ng ai/bee/day, 100% mortality was

observed after 5 days. Further mortality was observed at 0.0144 µg ai/bee/day

(60% mortality after 10 days) and at 0.00723 µg ai/bee/day. The effects at

0.00723 µg ai/bee/day were considered not to be significant.

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Behavioural abnormalities (apathy and moribund bees) were observed in

surviving bees in the groups exposed to 0.0386 µg ai/bee (from day 1), 0.0144

µg ai/bee (from day 2) and 0.00723 µg ai/bee (from day 2). At 0.00723 µg

ai/bee/day no behavioural abnormalities were observed at day 9 and 10. No

behavioural abnormalities were observed at the two lowest doses.

Comments

Conclusion

Chronic oral LD50 = 0.0137 µg ai/bee/day (equivalent to LC50 = 579 µg ai/kg

feeding solution)

NOEDD = 0.00723 µg ai/bee/day (equivalent to 247 µg ai/kg feeding solution)

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Table 220: foliage residue toxicity study to bees with formulated product

Study type Foliage Residue Toxicity Study

Flag Discarded study

Test Substance BCS-CL73507 200 SC

Exposure 24 hours contact with treated foliage aged for 3, 8 or 24 hours


Endpoint

RT25 (the residual time needed to reduce the activity of the test substance,

resulting in bee mortality of 25%)

mortality, behavioural abnormalities

Value RT25 = 3 hours

Reference

Porch J, Krueger H. 2016. Tetraniliprole: A Foliage Residue Toxicity Study with

the Honeybee.

Wildlife International (now EAG Laboratories), 8598 Commerce Drive Easton,

Maryland 2160, USA

Klimisch Score 2


GLP Yes

Test Guideline/s


Korean Rural Development Administration Ecological Effects Test Guideline

13-1-10


Dose Levels Nominal dose: 0, 30, 60 and 100 g ai/ha

Actual dose: 0, 30, 57, 104 g ai/ha

Analytical


Study Summary

The objective of this study was to evaluate the toxicity to the honey bee of

residues of tetraniliprole (formulated as Tetraniliprole SC 200 G) on plant

foliage after weathering for various periods. Mortality of the bees and sublethal

effects such as changes in behaviour were evaluated. The RT25 (the residual

time needed to reduce the activity of the test substance, resulting in bee

mortality of 25%) of a 24-hour exposure was estimated.

A single application of tetraniliprole was made to alfalfa plants at three different

rates (30, 60 and 100 g ai/ha), plus a water-only control.

Three separate plots for each treatment and control group consisting of at least

2-m2 area. The 60 g ai/ha plots each consisted of approximately 9 m2 of alfalfa.

Applications of the test material were made using a backpack sprayer with a

handheld boom. The control plots received an application of water only, prior to

any applications of the test substance. Foliage within the treatment plots was

observed to be dry at every collection interval. Sprayed alfalfa foliage was

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collected from the treatment plots at approximately 1 (analytical confirmation

only), 3, 8, and 24 hours after the applications of the test material. Foliage was

harvested from each of the three plots per treatment or control group, mixed

within each group, and used to prepare six replicate test chambers for each

treatment and control group, as well as to provide three samples from each

treatment group for chemical residue analysis.

Twenty-five worker honey bees were introduced into each test chamber and

maintained for an exposure period of approximately 24 hours, at which time

they were observed for mortality and any other toxicological responses.

Mortality in the control group exposed to foliage 3 hours after water treatment

was less than 20 %; therefore, the validity criterium was met.

Mortality in the treatment group is presented below:

Group Foliage treated

3 hours before

Foliage treated

8 hours before

Foliage treated

24 hours before

control 9% 9% 1%

30 g/ha 5% 13% 0%

60 g/ha 5% 16% 1%

100 g/ha 9% 16% 1%

Mean residue concentrations measured in the treated foliage are presented

below:

Group

Foliage

collected

directly after

application

Foliage

treated 3

hours before

Foliage

treated 8

hours before

Foliage

treated 24

hours before

30 g/ha 1.17 ppm 0.97 ppm 1.2 ppm 1.1 ppm

60 g/ha 4 ppm 3.3 ppm 4 ppm 3.2 ppm

100 g/ha 5.43 ppm 3.5 ppm 5.2 ppm 3.7 ppm

Comments

Bees are provided with sucrose solution in the exposure chamber, this reduces

the likelihood that they will come in contact with the foliage because bees

prefer to stay on vertical surfaces (compared to having sugar at the bottom of

the cage with the foliage). Actual exposure to bees is therefore unknown

because no measurement of residues in bees is provided.

Conclusion

Honeybees showed no treatment-related effects on 459behaviour or survival

when exposed for 24 hours to alfalfa foliage collected at 3, 8 and 24 hours

after application of Tetraniliprole SC 200 G at the application rates nominally

equivalent to 30, 60 and 100 g a.s./ha. RT25 < 3 hours.

This study is not considered valid because exposure is not demonstrated.

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Semi-field studies

Table 221: Semi-field study on toxicity of formulated product to honey bee brood – study 1

Study type Semi-field study on toxicity of formulated product to honey bee brood



Exposure

Tunnel test, application as soil drench (60 g ai/ha) on Phacelia tanacetifolia 4

days before the bees are introduced in the tunnels. Control and reference

spraying is undertaken 3 days later. Exposure lasts for 11 days.

Test species Apis mellifera carnica L.

Endpoint

Number of eggs, mortality of adult, pupae and larvae, foraging activity

Colony health (food stores, brood status and colony strength)

Reference

Tänzler V. 2016. BCS-CL73507 SC 200 G: Effects on Honey Bee Brood (Apis

mellifera L.) under Semi-Field Conditions - Tunnel Test


Klimisch Score 1


GLP Yes

Test Guideline/s OECD guidance document 75

OEPP/EPPO No. 170 (4)(2010)

No/Group

One colony per tunnel with 5,648 to 7,616 bees per colony.

Four tunnels per treatment: control (tap water), treated (60 g/ha) and reference

(fenoxycarb 300g/ha)

Two additional tunnels to collect pollen and nectar residues on foraging bees

and inside the hive for both control and treated groups.


Analytical

measurements HPLC

Study Summary

The purpose of the study was to determine potential side effects of

Tetraniliprole SC 200 G on the honey bee under semi-field conditions in

Phacelia tanacetifolia in Germany.

No major precipitation happened after the application of BCS-CL73507 SC 200

G, the temperature ranged from 1.37 to 30°C. Application method was tested

for calibration.

Small healthy queen right colonies were used, colonies were related (queen

were sisters). The hives were not treated for 4 weeks prior to the experiment

and were free of obvious diseases. The colonies contained 11 combs with at

least 5 brood combs containing all brood stages and an appropriate amount of

nectar and pollen.

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On day 0, the test substance was applied as a soil drench on two plots of

Phacelia before full bloom (40 m2) with no bees present. The two control plots

and the two reference plots were left untreated. The next day the tunnels were

installed on all plots. On day 4, all hives are transferred in their respective

tunnels, a single hive was used per tunnel. On day 7, the control plots were

treated with tap water and the reference plots with fenoxycarb by hand

spraying while the bees were foraging. The plots were in full bloom at that time.

The treatment, control and reference substance consisted of four replicates

each. In addition, two tunnels were prepared to collect residues from a treated

and control crop.

Mortality was high for all three groups during the first three days of confinement

in the tunnels, with a daily mean number of dead bees > 100, there was no

difference between groups. Authors report the high temperatures during the

experiments might have caused mortality (temperature reached 37.1°C during

the foliar sprays).

After the tunnels were removed, the mean daily mortality was higher in the

treated group compared to the control, whether this is treatment-related is

uncertain. No significant effects were identified. The group treated with the

reference substance did not show increased mortality, but the active ingredient

is a growth inhibitor, therefore mortality of adults is not expected.

No difference in foraging activity was observed, even in the reference

substance group. However, treated bees had a slightly lower foraging activity

than controls at day 4 (8 bees per m2 versus 14). No test substance or

reference substance-related behavioural abnormalities occurred at any time

during the whole assessment period

No difference in mortality of pupae was observed initially. Higher mortality was

observed in the reference substance group only and at a later date (after

removal of the tunnel). A slightly higher termination rate was observed in the

treated brood compared to controls (16.6% versus 11.4%); the termination rate

was clearly higher in the reference brood (55%). The brood compensation

index (terminated brood replaced by fresh eggs) was identical between the

control and treated group (4.6 and 4.4% at day 22) but was significantly lower

in the reference group (2.6%). The brood development was slightly delayed in

the treated group at day 10 and 16 post egg-laying compared to the control but

was not different at day 22. The brood development was significantly reduced

in the reference group from day 5 forward and did not recover. The number of

bees in the control, reference and treated groups increased over the

observation period (day 34), no differences were detected.

The residue analysis conducted by Bayer did not detect tetraniliprole or its

metabolite in any of the sample taken from the control site. No residue was

detected in the nectar taken from the treated site (nectar is from the hive, or

from returning foragers). Pollen sampled from hives placed in the treated plot

had 1.3 to 2.3 µg/ kg of tetraniliprole when collected at day 4-7, one sample

from pollen collected on foraging bees had 6.9 µg/ kg of tetraniliprole when

collected at day 0 but tetraniliprole was not detected thereafter.

Additional Comments The application is as soil drench whereas the intended use is as a foliar spray.

The formulated product is applied 3 days before the experiment starts.

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The applicant provided the following comment regarding drench application:

Although drench application is not intended for Vayego® in New Zealand, this

is the case for some other countries in the world. BCS has therefore also

studied potential effects due to drench application of the product. The study

has been included in the submission as BCS aims to provide a comprehensive

overview of the pollinator toxicity profile of Vayego® and should be regarded

as supportive information.

The exposure to treatment or water or the reference is different between the

groups, it is 11 days for the treated groups and 7 days for the water and

reference groups.

Intended water rate is 50 - 2,000 L/ha

Conclusion

No major adverse effects on colony strength, mortality and foraging activity

were observed after soil drench application in the absence of foraging bees. A

small and transient effect on brood development was observed.

The active ingredient was detected in pollen samples.

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Table 222: Semi-field study on toxicity of formulated product to honey bee brood – study 2

Study type Semi-field study on toxicity of formulated product to honey bee brood


Test Substance BCS-CL73507: formulated tetraniliprole

Exposure Tunnel test, application as foliar spray on Phacelia tanacetifolia in full bloom

while bees are foraging. Bees continue foraging on the treated plot for 7 days.

Test species Apis mellifera carnica L.

Endpoint

Number of eggs, mortality of adult, pupae and larvae, foraging activity

Colony health (food stores, brood status and colony strength) during exposure

and after exposure

Reference

Klockner A, Hecht-Rost A, Staffel J. 2016. Semi-field brood study to evaluate

potential effects of BCS-CL73507 on brood development of honey bees (Apis

mellifera L.)

RIFCON GmbH, Goldbeckstraße, 13 69493, Hirschberg, Germany

Klimisch Score 1


GLP Yes

Test Guideline/s

OECD 13

OECD 6

OECD 75

Pistorius et al. 2012

No/Group

Four tunnels per treatment: control (tap water), treated (2.5 g/ha), treated (5

g/ha), and reference (fenoxycarb 250g/ha)

Colony size: 6,435 bees (control), 6,110 bees (tetraniliprole 2.5 g/ha), 6,679

bees (tetraniliprole 5 g/ha), 6,468 (reference: fenoxycarb 250g/ha)

Dose Levels 2.5 and 5 g ai/ha in 400 L/ha

Analytical

measurements 20.6 % tetraniliprole in the formulated product

Study Summary

The objective of the study was to determine potential effects on colonies of

honey bees following one spray application of Tetraniliprole SC 200 G in two

dose rates during bee flight in P. tanacetifolia under semi-field conditions in

Germany.

No major precipitation happened after the application of BCS-CL73507 SC 200

G, the temperature ranged from 18.1 to 34.5°C. Application method was tested

for calibration.

Small healthy queen right colonies were used, colonies were related (queen

were sisters). The hives were not treated for 4 weeks prior to the experiment

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and were free of obvious diseases. The colonies contained 10 combs with 2 to

6 brood combs and an appropriate amount of nectar and pollen.

The study is considered to be valid since the brood termination-rate and the

pupal mortality of the toxic reference was statistically significantly increased

during the post-exposure phase compared to the control. Additionally, mean

foraging activity shortly before application was above >10 bees/m² in all

treatment groups.

Colonies placed in tunnel 11 days before application, monitoring continues for

26 days after application.

Adult mortality was within expected range for the four groups during the four

days before application, with a daily mean number of dead bees ~19-45; there

was no difference between groups. No increase in mortality was observed in

the treated groups compared to the control during the 7 day observation

period, the daily mean number of dead bees ranged from 25 (5 g ai/ha) to 51

(control). Mortality decreased to 10-15 dead bees/day for all four groups after

the colonies were removed from the tunnels, there was no difference between

groups.

Foraging activity decreased by ~15% after application of the treatments and

the reference compared to controls for up to 3 days. The authors do not assess

this decrease as treatment-related, but the consistency of the decreased

foraging activity over 4 days and its more pronounced effect shortly after the

beginning of exposure suggest treatment-related effects.

No abnormal behaviour was reported in the test substance group.

Mortality of pupae was low (<1) before application and during the 7 day

observation period; no difference was observed, even in the reference

substance group during this time. Mortality of pupae increased at day 14 and

16 after application only for the bees exposed to fenoxycarb. The proportion of

brood increased during the observation period in the control and treated

groups (up to 127% of the initial number at the end of the test) but decreased

in the reference group (74%). The number of eggs and larvae was similar in

the control and treated groups, no effects were observed in the reference

group. The brood termination rate and brood compensation index were not

affected by the treatment compared with control but was significantly

decreased in the reference group.

Additional Comments

The application rates tested are 1/12 and 1/24 of the intended application rate.

The applicant provided the following explanation: Objective of this study is to

determine the actual NOER of the product. This NOER is used for risk

assessment of off-crop exposure situations (eg spray drift to flowering weeds

at the edge of the treated field). The study gives a generic endpoint for the

product and is not related to the intended application rate or crop.

Conclusion

No relevant adverse effects were observed after foliar application at a low

application rate in presence of foraging bees.

NOER for brood development is 5 g ai/ha.

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Table 223: Semi-field study on side effects of formulated product to honey bees – study 1

Study type Semi-field study on side effects of formulated product to honey bees



Exposure

Tunnel test, application with boom sprayer (2, 5 and 10 g ai/ha, 200L of water

per ha) on Phacelia tanacetifolia in full bloom while bees are foraging. Bees

continue foraging on the treated plot for 8 days.

Each tunnel is 80 m2


Endpoints Mortality, flight intensity, behaviour, development of brood, strength of colonies,

food storage

Reference

Kriszan M. 2014. Assessment of side effects of BCS-CL73507 SC 200 G on

honey bee (Apis mellifera L.) in the semi-field after one application on Phacelia

tanacetifolia in Germany 2013.



Germany

Klimisch Score 1


GLP Yes

Test Guideline/s OEPP/EPPO Guideline No. 170(4) (2010)

No/Group

Three tunnels per treatment: control (tap water), treated (2.5, 5 and 10 g/ha

applied as foliar spray) and reference (dimethoate 400g/ha applied as a foliar

spray)

Colony size: 4800 bees (control, 6-8 brood combs), 4,725 bees (tetraniliprole 2.5

g/ha, 7-8 brood combs), 4,931 bees (5 g/ha, 7-9 brood combs) 4,894 (10 g/ha, 8

brood combs) and 4,950 (reference, 6-7 brood combs)

Dose Levels 2, 5 and 10 g ai/ha

Analytical

measurements NA

Study Summary

The purpose of the study was to determine potential side effects of Tetraniliprole

SC 200 G on the honey bee under semi-field conditions in Phacelia tanacetifolia

in Germany.

The weather conditions were good and there was no rainfall during the

confinement period.

Hives were introduced in the tunnels 4 days before the application of the

treatment on Phacelia tanacetifolia in full bloom (BBCH65). The trial consisted of

3 replicates per treatment, 3 replicates for the control and 3 replicates for the

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reference substance. Bees were foraging in the tunnels for 8 days after

application and were monitored for 28 days after application.

Mortality was within expected range for the control and treated groups during the

3 days before application, with a daily mean number of dead bees ~50; there

was no difference between groups.

Mortality increased in all groups over time, a likely effect of the confinement,

from ~50 dead bees per day before application to 92-136 after application.

Mortality was significantly higher the group treated with 10 g/ha on day 1 and 4

after application. When the entire confinement period after application was

considered no significant effects were observed. Mortality was significantly

higher in the reference group.

Mean daily

mortality Control T1 T2 T3 Reference

Before application 52.7 56.8 35.9 48.9 45.7

After application 107 91.9 84.6 135.7 347.7

No difference in flight intensity was observed in treated groups compared to the

control, almost no bees were foraging in the reference group.

No bees were observed with behavioural abnormalities in the control group.

During the first 7 days after application 10 bees were observed to show

abnormal behaviour in the group treated with 2.5 g/ha, 18 bees in the group

treated with 5 g/ha and 20 bees in the group treated with 10 g/ha. The authors

considered that this relatively small number of bees was not related to the test

substance, however, there was clearly a small yet dose-dependent effect. In the

reference group, a high number of bees were observed showing abnormal

behaviour.

There was no effect of exposure to the test substance on the number of bees

per hive during the observation period.

The number of brood cells varied in all groups, showing a decline 7DAA for most

groups. At 15DAA, brood numbers continued to decline slightly in all groups

treated with the substance, but this effect was transient and there were no

differences at 28DAA.

There was no effect of the treatments on food stores.

Additional Comments

The statistical values associated with each test (test value, degrees of freedom

and p values) are not provided, and whether all comparisons are made is

unclear.

Conclusion

No major adverse effects were observed after foliar application at 2.5, 5 or 10

g/ha; however, there was a transient increase of mortality of foragers treated

with 10 g/ha, a dose-dependent increase in behavioural abnormalities and there

might be a small transient effect on brood.

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Exposure

Tunnel test, application with boom sprayer (2, 5 and 10 g ai/ha, 200L of water

per ha) on Phacelia tanacetifolia in full bloom while bees are foraging. Bees

continue foraging on the treated plot for 7 days.




food storage

Reference

Kriszan M. 2014. Assessment of side effects of BCS-CL73507 SC 200 G on

honey bee (Apis mellifera L.) in the semi-field after one application on Phacelia

tanacetifolia in Spain 2013.



Germany

Klimisch Score 1


GLP Yes

Test Guideline/s OEPP/EPPO Guideline No. 170(4) (2010)

No/Group

Three tunnels per treatment: control (tap water), treated (2.5, 5 and 10 g/ha

applied as foliar spray) and reference (dimethoate 400g/ha applied as a foliar

spray)

Colony size: 5,483 bees (control, 3-4 brood combs), 6,256 bees (tetraniliprole

2.5 g/ha, 3-4 brood combs), 7,303 bees (5 g/ha, 3-4 brood combs), 6,484 bees

(10 g/ha, 3-4 brood combs) and 7,485 bees (reference, 3-4 brood combs)

Dose Levels 2, 5 and 10 g ai/ha in 200 L/ha

Analytical

measurements NA

Study Summary

The purpose of the study was to determine potential side effects of Tetraniliprole

SC 200 G on the honey bee under semi-field conditions in Phacelia tanacetifolia

in Spain.

The weather conditions were good, there was rainfall once, 2 hours after the

application (1 mm).

Hives were introduced in the tunnels 3 days before the application of the

treatment on Phacelia tanacetifolia in full bloom (BBCH64-65). The trial

consisted of 3 replicates per treatment, 3 replicates for the control and 3

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replicates for the reference substance. Bees were foraging in the tunnels for 8

days after application and were monitored for 28 days after application.

Mortality was within expected range for the control and treated groups during

the 3 days before application, with a daily mean number of dead bees ~50-100;

there was no difference between groups.

Mortality was similar in control and treated groups across the observation

period, mortality was higher, although not significantly different from the control,

one day after application in the group treated with 10 g/ha, whether this effect is

treatment-related is uncertain (2/3 colonies had higher mortality). Mortality in the

reference group was significantly higher every day of the observation period.

No difference in flight intensity was observed in treated groups compared to the

control, almost no bees were foraging in the reference group.

No bees were observed with behavioural abnormalities in the control group,

over the 7 day observation period; 9 bees showed abnormal behaviour in the

group treated with 2.5 g/ha, 20 bees in the group treated with 5 g/ha and 30+ in

the group treated with 10 g/ha. The authors considered that this relatively small

number of bees was not related to the test substance, however, there was

clearly a small yet dose-dependent effect.

There was no effect of exposure to the test substance on the number of bees

per hive during the observation period. The number of brood cells varied in all

groups, showing a decline 7 days after application for most groups but

increasing after apart for the reference group.

There was no effect of the treatments on food stores.

Additional Comments

The statistical values associated with each test (test value, degrees of freedom

and p values) are not provided, and whether all comparisons are made is

unclear.

A small increase in mortality is observed shortly after application in this study

and in Kriszan 2014 in Germany (Table 229).

Conclusion

No major adverse effects were observed after foliar application at 2.5, 5 or 10

g/ha; however, there was a transient increase of mortality of foragers treated

with 10 g/ha and a dose-dependent increase in behavioural abnormalities.

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Test Substance Tetraniliprole SC200

Exposure

Tunnel test, application in drip irrigation system (60 g ai/ha, 20,000L of water

per ha) 5 days before bees are introduced on Phacelia tanacetifolia in full

bloom. Bees continue foraging on the treated plot for 11 days.




food storage, residues

Reference

Wucherer M. 2016. Assessment of Side Effects of Tetraniliprole SC200 on the

Honey bee (Apis mellifera L.) in the Semi-Field after One Application on

Phacelia tanacetifolia in Germany 2015.



Germany

Klimisch Score 1


GLP Yes

Test Guideline/s

OECD 75


OEPP/EPPO Guideline No. 170(4) (2010)

Regulation (EC) No. 1107/2009

Directive 2003-01 (Canada/PMRA)

US EPA OCSPP 850.SUPP

No/Group

Four tunnels per treatment: control (tap water applied as drip irrigation system),

treated (60 g/ha applied as drip irrigation system) and reference (fenoxycarb

300g/ha applied as a foliar spray)

Colony size: 9,376 bees (control, 4-5 brood combs), 8,840 bees (tetraniliprole

60 g/ha, 3-4 brood combs) and 10,400 (reference: fenoxycarb 250g/ha, 5-6

brood combs)

Dose Levels 60 g ai/ha in 20,000 L/ha

Analytical


Study Summary

The aim of the study was to evaluate potential side effects of a drip application

of Tetraniliprole SC 200 G on the honey bee under confined semi-field

conditions in the crop Phacelia tanacetifolia.

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Hives (single box, 10 combs and with one queen) were introduced in the tunnels

5 days after the application of the treatment on Phacelia tanacetifolia in full

bloom (BBCH65).

Adult mortality was within expected range for the control and treated groups

during the 3 days before application, with a daily mean number of dead bees

~10; there was no difference between groups. Mortality increased in all 3 groups

at the start of the confinement period then decreased.

Increase in mortality in bees (including larvae and pupae) exposed to the

reference treatment during multiple observations was observed. Increased

mortality (including larvae and pupae) was observed, although not significant in

the treated group, 12, 13, 14, 16, 23 and 25 days after exposure.

There was no effect of any treatment on mortality of only larvae and pupae,

which was very low throughout the observation period (<1).

Flight intensity was similar in all 3 groups during the observation period.

In the control group, a maximum of 5 inactive bees was observed but was

higher for the treated (20 bees) and reference group (17 bees) on the day of the

application of the treatment. However, the reference group had not yet be

treated at this point. Authors suggest this is due to the disturbance around the

hives rather than the effect of treatment.

There was no effect of exposure to the test substance on the overall brood

index and compensation index. However, although not significant, the

development was slightly but consistently slower, and the termination rate was 3

times higher. Brood in the reference group had a significantly slower

development and a higher termination rate.

No effect on colony strength, mean amount of brood and food storage is

reported.

Residues:

Detection of tetraniliprole was below the LOQ (1 µg/kg) in flowers and below the

LOD (0.3 µg/kg) for pollen and nectar. Concentrations of metabolite BCS-

CQ63359 was below the LOD in flowers, pollen and nectar.

Comments

The recommended water rate is 50 to 2,000L/ha whereas here it is 20,000L.

Application via a drip irrigation system whereas the intended use is as foliar

spray, the reference substance is applied as a foliar spray (boom sprayer) 3

days after the introduction of the hives in tunnels.

The statistical values, degrees of freedom etc are not provided, and whether all

comparisons are made is unclear.

Conclusion

No major adverse effects were observed after drip application; however, there

might be a small effect on development (high termination rate). Low levels of

tetraniliprole can be detected in flowers (only above the LOD).

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Type of study Semi-field study on side effects of formulated product to honey bees



Exposure

Tunnel test, application by boom sprayer (20 g ai/ha, 300L of water per ha) on

Phacelia tanacetifolia before flowering. Bees continue foraging on the treated

plot for 8 days. Monitoring continues for 28 days




food storage, residues

Reference

Rexer HU. 2016. Assessment of Side Effects of BCS-CL73507 SC 200 G and

Determination of Residues of BCS-CL73507 after One Pre-Flowering

Application in a Semi-Field Study with Honey Bees (Apis mellifera L.) in

Phacelia tanacetifolia in Germany in 2015.



Germany

Klimisch Score 1


GLP Yes

Test Guideline/s

OECD 75



Guideline 1607/VI/97 (rev. 2) to Directive 91/414/EEC and Regulations (EU)

283/2013 and 284/2013 implementing Regulation (EC) 1107/2009

No/Group

4 tunnels for control (tap water applied as foliar spray)

1 tunnel for untreated group (for residue analysis)

10 tunnels for the treatment (20 g/ha applied as foliar spray) including 4 tunnels

for biological assessments, 3 tunnels for sampling of forager bees and 3 tunnels

for residue sampling.

4 tunnels for the reference (fenoxycarb 300g/ha applied as a foliar spray)

Colony size: mean 12,708 bees (control, 6-8 brood combs), mean 12,399 bees

(tetraniliprole 20 g/ha, 6.8 brood combs) and mean 12.366 (reference:

fenoxycarb 300g/ha, 7-8 brood combs)

Dose Levels 20 g ai/ha in 300 L/ha

Analytical

measurements

206.6 g tetraniliprole/L in the formulated product

Residue analysis by HPLC (MS/MS)

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Study Summary

The aim of the study was to evaluate potential side effects of BCSCL73507 SC

200 G on the honey bee (Apis mellifera L.) after one pre-flowering application on

Phacelia tanacetifolia under confined semi-field conditions. Application of the

treatment was performed 13 days before the bees were exposed.


13 days after the application of the treatment on Phacelia tanacetifolia so that

they were in full bloom when bees were introduced (BBCH 64-65).

Mortality of adults was similar for all 3 groups during the 8 days of confinement

in the tunnels and was significantly higher for the reference group after the hives

were moved to the monitoring site (only significant at 22 days after exposure).

Mortality of pupae was similar for all 3 groups during confinement but increased

significantly for the reference group after the hives were moved.

Flight intensity was similar in 3 groups during the confinement period.

No effect on behaviour was observed.

There was no overall effect of exposure to the test substance on brood index

and compensation index, but the development was slightly but consistently

slower and the compensation index was significantly lower on day 6.

Furthermore, the termination rate was twice as high although not significant.

Brood in the reference group had slower development and a higher termination

rate.

No effect on colony strength, mean amount of brood and food storage was

observed.

Residues:

No detection in pollen, nectar or wax from control combs or bees.

Detection was below the LOD (0.3 µg/kg) for nectar from treated bees or combs,

detection was between below the LOD and 6.3 µg/kg in bee wax, between

below the LOD and 28 µg/kg in pollen combs, and between 1.4 to 25 µg/kg for

pollen collected on forager bees .

The concentration of tetraniliprole seem to decline with time in pollen from

combs and collected on foragers, but no statistical analysis was performed.

Additional Comments The statistical values, degrees of freedom etc are not given, and whether all

relevant comparisons are made is unclear.

Conclusion

No major effect was observed on behaviour, mortality, flight intensity and colony

strength but a small effect on brood development is apparent.

Residues can be detected in pollen but are below the LOD in nectar.

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Exposure

Tunnel test, application by boom sprayer (60 g ai/ha, 300L of water per ha) on

Phacelia tanacetifolia before flowering. Bees start foraging on the treated plot in

the tunnels 5 days after application of the treatment and are confined for 8 days.

Monitoring continues until 28 days.




food stores

Reference

Rexer HU. 2016. Assessment of side effects of BCS-CL73507 SC 200 G on the

honey bee (Apis mellifera L.) in the semi-field after one pre-flowering application

on Phacelia tanacetifolia in Spain 2013



Germany

Klimisch Score 1


GLP Yes

Test Guideline/s

OECD 75



No/Group

4 colonies for control (tap water applied as foliar spray, 300 L/ha)

4 colonies for the treatment (60 g/ha applied as foliar spray)

4 colonies for the reference (fenoxycarb 150 g/ha applied as a foliar spray)

Colony size: mean 8,924 bees for control hives (3-4 brood combs), mean 8,702

bees for treatment hives (3-5 brood combs) and mean 7,610 for the reference

hives (3-4 brood combs).

Dose Levels 60 g ai/ha in 300 L/ha

Analytical

measurements NA

Study Summary


200 G on the honey bee (Apis mellifera L.) after one pre-flowering application at

60 g ai/ha on Phacelia tanacetifolia under confined semi-field conditions.

Application of the treatment was carried out 5 days before the bees were

exposed by introduction in the tunnels. Application of tap water or reference was

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carried out the day after the colonies were introduced in the tunnels. Bees were

confined in the tunnels for 8 days.


5 days after the application of the treatment on Phacelia tanacetifolia so that

they were in full bloom when bees were introduced (BBCH65).

Mortality of adults, pupae and larvae was similar for all 3 groups before

introduction in tunnels; it increased for all groups upon confinement. Mortality

was higher in the treatment and reference group after application; it reached

significance only for the treatment group. Mortality was similar in all groups for 7

days, so whether mortality on 00DAA2 was treatment or reference related is

uncertain. In the observation period from 8DAA2 to 28DAA2, significantly

increased mortalities were observed in the reference groups; however, some

increases in the reference or treatment group mortalities are not reported as

significant,). Most of the mortality in treated and reference groups was due to

pupae (mean total daily number per colony across the observation period is

137.8 deaths in treatment, 20.8 in control and 187.5 in the reference group),

however, this mortality was only high in one of the four treated colonies.

Flight intensity was similar in 3 groups during the confinement period, apart from

one day in which the reference group had lower activity.

No major effect on behaviour was observed, treated hives had a slightly higher

number of inactive bees than controls (17 vs 3) and dead bees on flowers (7 vs

3) and 2 treated colonies were aggressive.

There was a strong negative and significant effect of exposure to the test

substance on brood index from day 6 onwards. There was a strong negative

and significant effect of exposure to the test substance on brood compensation

index on day 6 and 10, with some recovery afterwards although the value was

lower the effects were considered not significant. Brood termination rates were

consistently and significantly higher (about 3 times higher) in the treatment

group compared to the control, and similar to the reference group.

No effect on colony strength, mean amount of brood and food storage was

observed. The mean amount of brood declined slightly in the treatment group

(no statistics provided), but this effect was small and transient.

Comments

The statistical values, degrees of freedom etc are not given, and whether all

relevant comparisons are made is unclear.

Even though treatment-related increased mortality was uncertain in this study,

this effect was observed in Kriszan 2014 in Spain and in Germany (Tables 229

and 230).

Conclusion

No major effect was observed on behaviour, mortality, flight intensity and colony

strength but a treatment-related transient effect on brood development is

apparent.

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Bumble bees

Acute toxicity

Table 228: Acute oral and contact toxicity of formulated product to bumble bees

Study type Acute oral and contact toxicity test in bumblebees



Exposure Type 48 hours (oral)

96 hours (contact)



Value


Oral NOED = 0.016 µg ai/bee (48 hours)


Contact NOED > 25 µg ai/bee (96 hours)

Reference

Tänzler V. 2016. BCS-CL73507 SC 200 G: Effects (Acute Oral and Contact) on

Bumblebees (Bombus terrestris L.) in the Laboratory


Klimisch Score 1 (after revision)


GLP Yes

Test Guideline/s



Van der Steen (2001)

Ring test bumblebee acute oral toxicity

No/Sex/Group 30 females per treatment group

Dose Levels

Oral nominal dose: 6.25, 12.5, 25, 50 and 100 µg ai/bee

Oral actual dose (average): 0.016, 0.03, 0.05, 0.12 and 0.23 μg product/bee

Contact dose: 6.25, 12.5, 25, 50 and 100 μg product/bee (5 µL droplet)

Analytical

measurements NA

Study Summary

The purpose of the study was to determine the acute oral toxicity of BCS-

CL73507 SC 200 G to the bumblebee in the laboratory.

Contact test

In the solvent (Triton X-100) control group, 6.7% mortality occurred during the

96-hour observation. The reference substance induced 100% mortality at 12 μg

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dimethoate/bee. This indicates that the LD50 value is likely to be higher than the

reference for honey bees (0.1-0.3 μg/bee), but given the difference in size of the

two species, this was considered acceptable. Consequently, validity criteria for

both control and reference substance mortality were met and the test was

deemed valid.



were observed at 50 µg ai/bee (40% mortality), 25 µg ai/bee (20% mortality),

12.5 µg ai/bee (10% mortality) and 6.25 µg ai/bee (13.3% mortality). Even

though there was no definite dose-response relation in the two lowest

concentrations, an LD50 could be determined.

Behavioural abnormalities were observed in the surviving bees up to 96 hours

after treatment with the two higher doses (5/13 bees and 2/18 bees at the end of

the test for the 100 and 50 µg ai/bee dose groups, respectively) and at 12.5 µg

ai/bee (1/27 bees at the end of the test). Effects were also observed at 25 µg

and 6.25 µg ai/bee but only lasted for 72 hours with 24-26 bees surviving until

the end of the test without any further symptoms.

The LD50 calculated in the study was 93.52 µg ai/bee.

The NOED was 25 µg/bee.

Oral test

In the water (50% sugar) control group, no mortality occurred during the 48-hour

observation. The reference substance induced 60% mortality at 2.5 μg

dimethoate/bee (mean concentration). This indicates that the LD50 value is likely

to be higher than the reference for honey bees (0.1-0.35 μg), but given the

difference in size of the two species, this was considered acceptable.

Consequently, validity criteria for both control and reference substance mortality

were met and the test was deemed valid.

In the oral toxicity test, at the highest tested dose level of 0.23 µg ai/bee, 96.7%

mortality was observed after 48 hours. Treatment-related mortalities were

observed at 0.12 µg ai/bee (90% mortality), 0.05 µg ai/bee (76.7% mortality) and

0.03 µg ai/bee (20% mortality). No mortality was observed at the lowest dose

(0.016 µg ai/bee).

Bees exposed to 0.23 µg ai/bee showed symptoms after 4 hours (21/30) and 24

hours (1/2). The last surviving bee at 48 hours did not show any symptoms. At

0.12 µg ai/bee, surviving bees showed symptoms at 4, 24 and 48 hours of

exposure (2/3 at the end of the test). At 0.05 µg ai/bee, symptoms were

observed throughout the test (3/6 at the end of the test). At 0.03 µg ai/bee,

symptoms were observed up to 24 hours after exposure (18/26 at 24 hours). At

0.016 µg ai/bee, symptoms were observed throughout the test with 1 bee

showing symptoms after 48 hours, all other 29 bees showed normal behaviour.

The LD50 calculated in the study was 0.05 µg ai/bee.

The NOED was 0.016 µg ai/bee.

Comments

The oral test allows measuring the individual dose consumed per bee. In the

two groups fed with the highest doses, bees that survived were bees that had

ingested less than the target dose.

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The LD50 was re-calculated without the bees that ingested less than the target

dose.

Conclusion Oral LD50 = 0.04 µg ai/bee (48 hours)


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Semi-field study

Table 229: Semi-field study on side effects of formulated product to bumble bees

Study type Semi-field study on side effects of formulated product to bumble bees



Exposure

Tunnel test, application by boom sprayer (2 foliar applications at 8 g ai/ha in 80

L/ha, 14 and 8 days before bees start foraging) or furrow application (1 direct

application on furrows at 200 g/ha, 47 days before exposure) on flowering

(BBCH69) potato (Solanum tuberosum L.) crop. Monitoring continues for 4

weeks.

Each tunnel is 60 m2 for biological assessments, 200 m2 for residue analysis


Endpoints Mortality, flight intensity, weight of hives, sugar consumption, behaviour,

development of brood, strength of colonies, residues

Reference

Klein O. 2016. A Semi-Field Study to Evaluate Effects of BCS-CL73507 SC 200

G on the Bumble Bee (Bombus terrestris L; Hymenoptera, Apidae) in Potato in

Germany in 2014.



Germany

Klimisch Score 1

Amendments/Deviations No deviation

GLP Yes

Test Guideline/s SETAC/ESCORT recommendations (Barrett et al. 1994)

OEPP/EPPO Guideline No. 170 (4), 2010

No/Group

5 colonies in 5 tunnels for control

5 colonies in 5 tunnels for the treatment T1 (8 g/ha in 300 L water/ha applied as

2 foliar spray applications, with an interval of 6 days)

5 colonies in 5 tunnels for the treatment T2 (200 g/ha applied as one furrow

application at 80L water/ha)

4 colonies per tunnel for residue analysis: 1 tunnel for control, 1 tunnel for foliar

application and 1 tunnel for furrow application

Colony size: mean 111.4 bees for control hives, mean 109.4 bees for treatment

T1 hives and mean 107.6 bees for treatment T2 hives

Dose Levels

Foliar application: 2 applications at 8 g ai/ha in 300 L/ha, with an interval of 6

days

Furrow application: 1 application at 200 g ai/ha

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Analytical


Study Summary


200 G on bumblebees after two pre-flowering applications at 8 g ai/ha on potato

or one furrow application at 200 g ai/ha under confined semi-field conditions.

The treatment was applied as foliar applications 14 and 8 days before the bees

were exposed by introduction in the tunnels. The in-furrow treatment was

applied at planting, 47 days before exposure. Bees were confined in the tunnels

for 4 weeks. Exposure occurred during flowering (BBCH 62).

The bumblebee colonies developed weakly due to insufficient and restricted

food supply in the tunnels (pollen of potato flowers only) and did not enter the

reproduction phase. Therefore, no assessment of production of queens was

done.

Mortality of adults inside the hive was initially high after introduction in the

tunnels (~30-40 bees, a third of the initial population) and decreased after, it

was similar in all treatments.

Mortality of larvae varied across time, it was relatively high for all 3 groups at

day 6-10. There was significantly more death in the T2 group on day 10, but

overall mortality does not appear to be treatment-related. Mortality in the tunnels

was low and similar for all groups, only 1 dead larva was observed in the tunnel.

Foraging activity and the number of bees leaving the hives varied across the

days (depending on weather conditions/temperature) and was similar for all 3

groups. Regarding the remaining assessments, there were no statistically

significant differences between the control, the first test substance treatment

(T1) and the test substance treatment 2 (T2).

The weight of hives varied slightly on a daily basis, there were no statistical

differences between treatments but treatment hives were consistently lighter.

The consumption of sugar varied slightly on a daily basis, there were two

statistical differences between control and T2 (one higher and one lower),

therefore the effect is unlikely to be treatment-related.

Only 30-40 workers were alive in colonies at the end of the exposure period.

Due to insufficient and restricted food supply in the tunnels, queen mortality in

all 3 treatment groups was observed and colonies developed weakly: 2/5 control

hive had dead queens, 4/5 T1 had dead queens and 1/5 T2 hives. For these

reasons, the experiment did no assess reproductive success.

Residue levels of tetraniliprole in bumblebee forager pollen were 7.7 μg/kg, 4.6

μg/kg and < LOQ for the test substance treatment T1 at 3, 7 and 20 days after

exposure, respectively. For test substance treatment T2, residue levels of

tetraniliprole in bumblebee forager pollen were 1.4 μg/kg, 1.2 μg/kg and < LOQ

at 3, 7 and 20 days after exposure, respectively.

Additional Comments

The statistical values, degrees of freedom etc are not given.

No assessment of reproduction was performed due to the low number of

surviving bees.

Conclusion No major effect was observed on behaviour, mortality, flight intensity and colony

strength.

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No assessment of reproduction was possible because the number of individuals

was too low to proceed to the reproduction test.

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Tetraniliprole metabolites


Fish - Bioconcentration

Table 230: Bioconcentration in Fish - BCS-CQ63359 metabolite

Study type Full study, bioconcentration

Flag Key study

Test Substance BCS-CQ63359 metabolite of tetraniliprole

Exposure Lepomis macrochirus

Test species BCF steady state, BCF lipid-normalised growth corrected kinetic, whole fish

Endpoint

BCF steady state

BCF kinetic

Value

BCF ss 124 and 183 L/kg whole fish (lipid normalised)

BCF k 180 and 240 L/kg whole fish

BCF klg 146 and 203 L/kg whole fish

Reference

Kuhl K. (2016) [dihydroquinazoline-4-14C] BCS-CQ63359- Aqueous exposure

bioconcentration fish test and biotransformation in fish (Lepomis

macrochirus) Report no EBFVN155, M-569144-01-1

Klimisch Score 1


GLP yes

Test Guideline/s OECD 305, OPPTS 850.1730

Dose Levels 0.03 and 0.3 mg test substance/L nominal

27.1 µg/L and 230 µg/L mean measured

Analytical measurements HPLC,. LSC

Study Summary

The objective of this study was to measure uptake, depuration of the test item

BCS-CL73507-N-methyl- quinazolinone (BCS-CQ63359) by determining its

uptake rate constant (k1), depuration rate constant (k2) and the BCF.

The whole study was performed in a flow-through design with bluegill sunfish

(Lepomis macrochirus) in glass aquaria (3 aquaria in total). Fish were

exposed to concentrations of 0.03 and 0.3 mg BCS-CQ63359/L (Aquarium B

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and C, respectively). Additionally, a solvent control was performed in parallel

(Aquarium A).

The study consisted of two phases: an exposure (uptake) and a post-

exposure (depuration) phase. At start of the uptake phase (day 0), 70

randomly selected fish were transferred into each aquarium. Fish were

sacrificed during sampling. After 28 days of exposure, the remaining fish

were transferred to pure test water without the test substance for the

depuration phase of 14 days. The concentration of BCSCQ63359 in the fish

was followed through both phases of the test. Samples of the test medium,

the fish and the stock solutions were taken at different intervals during the

test. Water samples for the radioactivity measurements (to determine

substance concentrations) were taken before addition of the fish and

throughout the uptake and depuration phases (on days -1, 0, 1, 3, 7, 10, 14,

21, 28, 29, 31, 35, 38 and 42; all aquaria). Furthermore, throughout the

uptake and depuration phases, fish were sampled at regular intervals (on

days 1, 3, 7, 10, 14, 21, 28, 29, 31, 35, 38 and 42; all aquaria). The fish were

sacrificed and the length and weight of each fish were recorded. The fish

were also dissected into edible tissues and viscera and processed to

determine the TRR in the respective tissues. On fewer occasions (days 0, 28

and 42; all aquaria), fish were sacrificed to determine the lipid content of the

whole fish. Finally, stock solution samples for the radioactivity measurements

in Aquaria B and C were taken at day – 4 and day 28.

For the nominal metabolite concentration of 0.03 mg/L, the measured mean

value was 27.1 μg/L with a range of 24.5 to 30.2 μg/L in the uptake phase.

For the nominal metabolite concentration of 0.3 mg/L, the measured mean

value was 230 μg/L with a range of 200 to 263 μg/L in the uptake phase.

For the lower concentration of 0.03 mg/L the mean BCFSS for the edible

tissue was 69.2 L/kg and 306 L/kg for the viscera tissue, resulting in a BCFSS

for the whole fish of 163 L/kg. For the higher concentration of 0.3 mg/L,, the

mean BCFSS for the edible tissue was 121 L/kg and 418 L/kg for the viscera

tissue, resulting in a BCFSS for the whole fish of 241 L/kg. Lipid normalised

steady state for the whole fish was 124 and 183 L/kg.

For the lower concentration of 0.03 mg/L,, the mean BCFK for the edible

tissue was 76.1 L/kg and 339 L/kg for the viscera tissue, resulting in a BCFK

for the whole fish of 180 L/kg. For the higher concentration of 0.3 mg/L, the

mean BCFK for the edible tissue was 119 L/kg and 420 L/kg for the viscera

tissue, resulting in a BCFK for the whole fish of 240 L/kg.

Lipid normalised growth corrected kinetic BCF was 146 and 203 L/kg whole

fish.

The analysis of stock solutions of the test compound from all aquariums

showed that BCS-CL73507- N-methyl-quinazolinone (BCS-CQ63359) was

stable in the stock solutions during the exposure phase.

No mortality or other adverse effects were observed.

The validity criteria were met.

Comments none

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Conclusion

BCF ss 163 and 241 whole fish, lipid normalised steady state 124 and 183

L/kg

BCF k 180 and 240 L/kg whole fish

BCF klg 146 and 203 L/kg whole fish

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Table 231: Acute toxicity to algae - BCS-CR74541 metabolite


Flag Key study

Test Substance BCS-CL73507 carboxylic acid (BCS-CR74541 metabolite)



Endpoint ErC50

Value >10.0 mg test substance/L

Reference

Kuhl K. (2016) Pseudokirchneriella subcapitata growth inhibition test with

BCS-CL73507-carboxylic acid (BCS-CR74541) Final report. Report no

EBFVP065, M-560207-01-1

Klimisch Score 1


GLP yes


Dose Levels

0.625, 1.25, 2.50, 5.0 and 10 mg test substance/ L nominal

0.563, 1.12, 2.22, 4.42 and 8.54 mg test substance/L mean measured

(0-72 h)


Study Summary

The aim of the study was to determine the effects of BCS-CR74541 on


expressed as NOEC, LOEC and EC50 for growth rate and further

endpoints of algal biomass (cells per volume).



with a prolongation to 96 hours to nominal concentrations 0.625, 1.25,

2.50, 5.0 and 10 mg test substance in comparison to a water control.

The analytical findings of the metabolite in the treatment level found on

day 0 were 88.2 to 90.4% of nominal. After 72 hours analytical findings of

85.4 to 90.1% of nominal were found and after 96 hours analytical

findings of 86.0 to 91.2% were found. Therefore, the results are based

on nominal concentrations.

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Cell counts were performed after 24, 48, 72 and 96 hours. Cell

abnormalities were conducted as well. No morphological abnormalities

have been observed.

Growth inhibition (0-72 h) was 5.3, 6.2, 6.0, 6.8 and 8.9% at 0.0625,

1.25, 2.5, 5.0 and 10.0 mg test substance/L respectively. Growth

inhibition (0-96 h) was 2.7, 3.2, 3.0, 4.2 and 7.4% at 0.0625, 1.25, 2.5,

5.0 and 10.0 mg test substance/L respectively. The inhibition was

significant for all concentrations.

The 72 and 96 hour-ErC50 was >10 mg test substance /L. The 72 and 96-

hour NOErC was determined to be <0.625 mg test substance/L.

Conclusion ErC50 >10.0 mg test substance/L 72 h

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Table 232: Acute toxicity to algae - BCS-CR60014 metabolite

Study type Limited test, Toxicity alga

Flag Key study

Test Substance BCS-CL73507-amide (BCS-CR60014 metabolite)



Endpoint ErC50


Reference

Kuhl K. (2016) Pseudokirchneriella subcapitata growth inhibition test with BCS-

CL73507-amide (BCS-CR60014) Final report. Report no EBFVP093, M-561144-

01-1

Klimisch Score 1

Amendments/Deviati


GLP yes


Dose Levels 10 mg test substance/ L nominal

8.24 mg test substance/L mean measured (0-72 h)

Analytical


Study Summary

The aim of the study was to determine the effects of BCS-CR60014 on

exponentially growing populations of Pseudokirchneriella subcapitata expressed

as NOEC, LOEC and EC50 for growth rate and further endpoints of algal biomass

(cells per volume).

Cultures of Pseudokirchneriella subcapitata with an initial cell density of 10000

cells/ml were exposed in a static system over a period of 72 hours with a

prolongation to 96 hours to nominal concentration of 10 mg test substance/L in

comparison to a water control.

The analytical findings of tetraniliprole in the treatment level found on day 0 was

85% of nominal. After 72 hours analytical findings of 80% of nominal was found

and after 96 hours analytical findings of 66%) was found. Therefore, the results

are based on mean measured concentrations.

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The validity criteria were met (OECD 201). Increased biomass was factor of 47.4

(recommended factor 16 in 72h), coefficient of variation section by section specific

growth rate was 31.9% (recommended ≤35% in 72 h), coefficient of variation for

average specific growth rate was 5.9% (recommended ≤10% in 72 h).

Morphological examinations of cells using a microscope were made after 0, 24,

48, 72 and 96 hours. Cell numbers per volume (as a surrogate for biomass per

volume) and possible alterations in algae cells such as unusual cell size were

estimated by direct algae cell counting under a microscope at a magnification of

400 times. No morphological changes were observed.

Growth inhibition (0-72 h) was -3.3% and 1.3% over the period 0-96 h.

The 72 hour-ErC50 was >8.24 mg test substance /L and >7.67 mg test

substance/L for 0-96 h period. The 72h NOErC was determined to be ≥ 8.24 mg

test substance/L and 96 h NOErC was determined to be ≥ 7.67 mg test

substance/L.


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Table 233: Acute toxicity to algae - BCS-CU81055 metabolite


Flag Key study

Test Substance BCS-CL73507-desmethyl-amide-carboxylic acid (BCS-CU81055

metabolite)



Endpoint ErC50


Reference


BCS-CL73507-desmethyl-amide-carboxylic acid (BCS-CU81055). Report

no EBFVP051, M-559105-01-1

Klimisch Score 1


GLP yes





Study Summary

The aim of the study was to determine the effects of BCS-CU81055 on






with a prolongation to 96 hours to nominal concentration of 10 mg test

substance in comparison to a water control. Six replicates were tested for

the control and the test concentration.

The analytical findings of tetraniliprole in the treatment level found on day 0

was 91.4% of nominal. After 72 hours analytical findings of 80.9% of

nominal was found and after 96 hours analytical findings of 64.0%) was

found. Therefore, the results are based on mean measured

concentrations.

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The validity criteria were met (OECD 201). Increase biomass was factor of

68.3 (recommended factor 16 in 72h), coefficient of variation section by

section specific growth rate was 17.9% (recommended ≤35% in 72 h),




abnormalities were conducted as well. No morphological changes were

observed

Growth inhibition (0-72 h) was 1.0% (significantly different) and 0.7% over

the period 0-96 h.


substance/L for 0-96 h period. The 72h NOErC was determined to be <8.6

mg test substance/L and 96 h NOErC was determined to be ≥ 7.88 mg test

substance/L.


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Table 234: Acute toxicity to algae - BCS-CT30673 metabolite


Flag Key study

Test Substance BCS-CL73507 -N-methyl-quinazolinone-carboxylic acid (BCS-CT30673

metabolite)



Endpoint ErC50


Reference


BCS-CL73507—M-methyl-quinazolinone-carboxylic acid (BCS-CT30673)


Klimisch Score 1


GLP yes


Dose Levels

0.625, 1.25, 2.50, 5.0 and 10 mg test substance/ L nominal

0.518, 1.02, 2.01,4.07, 8.05 mg test substance/L mean measured (0-72

h)


Study Summary

The aim of the study was to determine the effects of BCS-CT30673 on






with a prolongation to 96 hours to nominal concentrations 0.625, 1.25,

2.50, 5.0 and 10 mg test substance in comparison to a water control.

Four replicates were tested per test concentration and the control.

The analytical findings of the metabolite in the treatment level found on

day 0 were 81 to97% of nominal. After 72 hours analytical findings of 80

to 84% of nominal were found and after 96 hours analytical findings of 78

to 83% were found. Therefore, the results are based on mean measured

concentrations.

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abnormalities were conducted as well. No morphological changes were

observed.

Growth inhibition (0-72 h) was 0.7, 0.0, 1.3, 0.8, 7.9% at 0.0625, 1.25,

2.5, 5.0 and 10.0 mg test substance/L respectively. Inhibition was

significant at the highest concentration. Growth inhibition (0-96 h) was

1.1, 1.1, 2.1, 2.5, 7.3% at 0.0625, 1.25, 2.5, 5.0 and 10.0 mg test

substance/L respectively. The inhibition was significant for the two

highest concentrations.

The 72 hour-ErC50 was >8.05 mg test substance /L and NOErC was

determined to be 4.07 mg test substance/L.

The 96 hour-ErC50 was >7.98 mg test substance /L and NOErC was

determined to be 2.01 mg test substance/L.


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Table 235: Acute toxicity to algae - BCS-CU81056 metabolite


Flag Key study

Test Substance BCS-CL73507-quinazolinone -carboxylic acid (BCS-CU81056 metabolite)



Endpoint ErC50


Reference

Kuhl K. (2016) Amendment no 1- Pseudokirchneriella subcapitata growth

inhibition test with BCS-CL73507-quinazolinone-carboxylic acid (BCS-

CU81056). Report no EBFVP077, M-561164-02-1

Klimisch Score 1


GLP yes





Study Summary

The aim of the study was to determine the effects of BCS-CU81056 on


expressed as NOEC, LOEC and EC50 for growth rate and further endpoints

of algal biomass (cells per volume).



with a prolongation to 96 hours to nominal concentration of 10 mg test

substance in comparison to a water control. Six replicates were tested for

the control and at 10 mg/L.

The analytical findings of tetraniliprole in the treatment level found on day 0

was 76% of nominal. After 72 hours analytical findings of 68% of nominal

was found and after 96 hours analytical findings of 69% was found.

Therefore, the results are based on mean measured concentrations.

The validity criteria were met (OECD 201). Increase biomass was factor of

68.3 (recommended factor 16 in 72h), coefficient of variation section by

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section specific growth rate was 17.9% (recommended ≤35% in 72 h),



Cell counts were performed after 24, 48, 72 and 96 hours. Cell abnormalities

were conducted as well. No abnormalities were observed.

Growth inhibition (0-72 h) was 0.3% and 0.6% over the period 0-96 h.


substance/L for 0-96 h period. The 72h NOErC was determined to be ≥ 7.18

mg test substance/L and 96 h NOErC was determined to be ≥ 7.11 mg test

substance/L.


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Spiked sediment

Table 236: Toxicity to sediment-dwelling organisms- spiked sediment - BCS-CQ63359, metabolite

Study type Full test, Toxicity midge

Flag Key study

Test Substance BCS-CQ63359, metabolite



Endpoint NOEC

Value 4451 μg metabolite/ kg sediment

Reference

Thomas S.T., Zhang L., Martin K.H. Gallagher S.P., Krueger H. O.

(2016) BCS-CQ63359: a 10 day acute toxicity test with the midge

(Chironomus dilutus) Report no 149A-260, M-558812-01-1

Klimisch Score 1


GLP yes


Dose Levels 313, 625, 1250, 2500 and 5000 μg BCS-CQ63359 / kg of sediment

285, 567, 1260, 2437, 4451 μg BCS-CQ63359 / kg of sediment


Study Summary

The aim of the study was to determine the effects of sediment-

incorporated tetraniliprole-N-methyl-quinazolinone (BCS-CQ63359) on

the midge Chironomus dilutus during a 10-day exposure period under

flow-through test conditions.

Groups of midges (3rd instars, approx. 10 days old) were exposed to a

geometric series of five test concentrations, a solvent control and a

negative control for 10 days under flow-through test conditions.

Eight replicate test compartments were maintained in each treatment

and control group, with 10 midges in each test compartment, for a total of

80 individuals per test concentration. An additional two replicates were

added in each treatment and control group for analytical sampling of

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sediment, pore water and overlying water. The sediment/water mixtures

were allowed to acclimate for 21 days prior to the introduction of the test

organisms. Organisms were added at test initiation to analytical

replicates for the Day 10 analysis. The Day 0 analytical replicates did not

contain organisms. Each test compartment contained sediment and

overlying water.

Nominal definitive test concentrations were 313, 625, 1250, 2500 and

5000 μg BCS-CQ63359/kg of sediment based on the dry weight of the

sediment. Mean measured concentrations are 285, 567, 1260, 2437,

4451 μg BCS-CQ63359/kg of sediment (89-101% of nominal). The

results of the study are based on mean measured test concentrations in

the sediment and in pore water. Sediment, overlying water and pore

water samples were collected on Day 0 and at the end of the test.

Observations of mortality and abnormal behaviour were made daily

during the test. Survival and growth, AFDW was determined at the end of

the 10-day test period. The percent reduction in the numbers of

organisms present in the treatment groups at test termination in

comparison to the control groups was used to determine the endpoints.

The validity criteria are met. Control survival ≥ 70% (observed 93 and

95%), average larval weight >0.48 mg (observed 0.99 and 1.02 mg).

Mean

measured

conc. (μg

BCS-CQ63359

/ kg)

Mean

number of

surviving

midges

%

reduction

Mean dry

weight (mg) % reduction

Control 9.3 - 0.99 -

Solvent control 9.5 - 1.02 --

Pooled control 9.4 - 1.00

285 8.4 11 1.13 -12

567 9.0 4.0 1.15 -15

1260 9.1 2.7 1.13 -13

2437 9.5 -1.3 1.08 -7.2

4451 9.6 -2.7 1.05 -4.2

No effects on growth were observed.

The LOEC and NOEC were >4451 and 4451 μg metabolite/kg,

respectively, based on mean measured concentrations in the sediment.

The LOEC and NOEC were >22.9 and 22.9 μg metabolite/L,

respectively, based on mean measured concentrations in the pore water.

Conclusion NOEC = 4451 μg metabolite/ kg sediment

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Spiked water

Table 237: Toxicity to sediment-dwelling organisms- spiked water - BCS-CR60014, metabolite


Flag Key study

Test Substance BCS-CR60014, metabolite



Endpoint EC50

Value >10 mg test substance /L

Reference

Silke G. (2015) Acute toxicity of BCS-CL73507-amide (BCS-CR60014)

to larvae of Chironomus riparius in a 48 h static laboratory test system.


Klimisch Score 1


GLP yes


Dose Levels

0.43, 0.94, 2.08, 4.57, and 10.0 mg test substance/ L., nominal

0.444, 0.962, 2.25, 4.93, 10.1 mg test substance / L, measured day 0

0.449, 0.966, 2.18, 4.76, 9.66 mg test substance / L, measured day 2


Study Summary

The aim of the study was to determine the effects of tetraniliprole-

amide (BCS-CR60014) on larvae of Chironomus riparius.


system over a period of 48 hours to the nominal concentrations of 0.43,

0.94, 2.08, 4.57, and 10.0 mg test substance/L. In addition, a solvent

control and a water control were tested.

Six replicates, containing 5 animals each, were tested for each test

item concentration and the controls. The analysed metabolite found in

all freshly prepared test levels on day 0 in reference to nominal

concentrations ranged between 101 and 108% (average 105%). In

aged test levels on day 2, there were analytical findings between 97

and 105% (average 103%) of nominal. Due to the high recoveries at

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the beginning of the exposure and the analytical findings after 2 days,

all results are based on nominal concentrations.


assessed. After 48 hours 0% immobility was observed in the pooled

control, 0.43 and 0.94 mg test substance/L. At other concentrations

6.7% immobility was observed. The difference was not significant.

All validity criteria were met. The validity criterion of control mortality

less than 15% is fulfilled. The validity criterion of oxygen saturation

above 60% is fulfilled (observed 98.7%).

The 48h-EC50 was nominally > 10 mg test substance/L

The 48h-NOEC was 10 mg test substance/L.

Conclusion EC50 > 10 mg test substance/L.

NOEC = 10 mg test substance/L.

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Table 238: Toxicity to sediment-dwelling organisms- spiked water - BCS-CR74541, metabolite

Study type Limit test, Acute toxicity midge

Flag Key study

Test Substance BCS-CR74541, metabolite



Endpoint EC50


Reference

Silke G. (2015) Acute toxicity of BCS-CL73507-carboxylic acid (BCS-

CR74541) to larvae of Chironomus riparius in a 48 h static laboratory test

system- limit test. Report no EBFVN064, M-542895-01-1

Klimisch Score 1


GLP yes


Dose Levels

10.0 mg test substance/L., nominal

9.01 mg test substance/L, measured day 0



Study Summary


carboxylic-acid (BCS-CR74541) on larvae of Chironomus riparius.


system over a period of 48 hours to the limit concentrations of 10.0 mg

test substance/ L. In addition, a water control was tested. Six replicates,

containing 5 animals each, were tested for the test item and the control.

The analysed metabolite found in all freshly prepared test levels on day 0

in reference to nominal concentrations was 90%. In aged test level on

day 2 was also 90% of nominal. Due to the high recoveries at the

beginning of the exposure and the analytical findings after 2 days, all

results are based on nominal concentrations.


assessed. After 48 hours 0% immobility was observed in the control and

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treatment. 1 larvae was found trapped at the surface in the control and

treatment but this was considered not to be treatment-related.

All validity criteria were met. The validity criterion of control mortality less

than 15% is fulfilled. The validity criterion of oxygen saturation above

60% is fulfilled.

The 48h-EC50 was nominally> 10 mg test substance/ L




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Table 239: Toxicity to sediment-dwelling organisms- spiked water - BCS-CU81055, metabolite


Flag Key study

Test Substance BCS-CU81055, metabolite



Endpoint EC50


Reference

Silke G. (2016) Acute toxicity of BCS-CL73507-desmethyl-amide-

carboxylic acid (BCS-CU81055) to larvae of Chironomus riparius in a 48

h static laboratory test system- limit test. Report no EBFVN052, M-

556353-01-1

Klimisch Score 1


GLP yes


Dose Levels





Study Summary


desmethyl-amide-carboxylic-acid (BCS-CU81055) on larvae of

Chironomus riparius.



test substance/ L. In addition, a water control was tested. Six replicates,




day 2 was 103% of nominal. Due to the high recoveries at the beginning

of the exposure and the analytical findings after 2 days, all results are

based on nominal concentrations.

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assessed. After 48 hours 0% immobility was observed in the treatment.

In the control, 3.3% immobility was observed. Other observations were

made after 48 hours of incubation, one of the exposed larvae of the limit

test concentration got trapped at the water surface, showing no other

signs of stress or disease.



60% is fulfilled.

The 48h-EC50 was nominally> 10 mg test substance/L




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Table 240: Toxicity to sediment-dwelling organisms- spiked water - BCS-CQ63359, metabolite


Flag Key study

Test Substance BCS-CQ63359, metabolite



Endpoint EC50

Value 0.88 mg test substance/ L

Reference

Silke G. (2016) Amendment no 1- Acute toxicity of BCS-CL73507-N-methyl-

quinazolinone (BCS-CQ63359) to larvae of Chironomus riparius in a 48 h static

laboratory test system. Report no EBVFVP086, M-538273

Klimisch Score 1

Amendments/Deviatio


GLP yes


Dose Levels

0.05, 0.11, 0.24, 0.53, 1.17 and 2.58 mg test substance/ L., nominal

0.043, 0.100, 0.226, 0.488, 1.096, 2.028 mg test substance / L mean measured

concentration

Analytical


Study Summary

The aim of the study was to determine the effects of tetraniliprole--N-methyl-

quinazolinone (BCS-CQ63359) on larvae of Chironomus riparius.

Groups of midges (1st instars, < 2-3 days old) were exposed in a static system

over a period of 48 hours to the nominal concentrations of 0.05, 0.11, 0.24,

0.53, 1.17 and 2.58 mg test substance/L. In addition, a solvent control and a

water control were tested.

Six replicates, containing 5 animals each, were tested for each test item

concentration and the controls. The analysed metabolite found in all freshly

prepared test levels on day 0 in reference to nominal concentrations ranged

between 88-102% (average 94%). In aged test levels on day 2, there were

analytical findings between 55 and 94% (average 84%) of nominal. At the

highest test concentration of 2.58 mg pure metabolite (pm)/L, precipitations

were observed on the bottom of the test vessels and the analytical

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measurements found only 55% of nominal after 2 days of incubation. Thus the

further statistical evaluations were done with the mean measured test

concentrations and all results are based on mean measured test concentrations.

Immobilisation of the midge larvae and intoxication symptoms were assessed.

After 48 hours 0% immobility was observed in the solvent control and 3.33% in

the water control. The immobility was 0%, 3.3%, 13.3%, 20.0%, 60.0% and

83.3% in the treatments 0.05, 0.11, 0.24, 0.53, 1.17 and 2.58 mg test

substance/L. The difference was significant at the two highest concentrations.

All validity criteria were met. The validity criterion of control mortality less than

15% is fulfilled. The validity criterion of oxygen saturation above 60% is fulfilled.

The 48h-EC50 was 0.88 mg test substance/L


Conclusion EC50 =0.88 mg test substance/L.

NOEC = 0.49 mg test substance/L.

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Table 241: Toxicity to sediment-dwelling organisms- spiked water - BCS-CT30673, metabolite


Flag Key study

Test Substance BCS-CT30673, metabolite



Endpoint EC50

Value >10 mg ai/L

Reference

Silke G. (2016) Acute toxicity of BCS-CL73507-N-methyl-quinazolinone-

carboxylic acid (BCS-CT30673) to larvae of Chironomus riparius in a 48

h static laboratory test system- limit test. Report no EBFVP069, M-

556371-02-1

Klimisch Score 1


GLP yes


Dose Levels

10.0 mg test substance/ L., nominal

9.19 mg test substance / L, measured day 0



Study Summary

The aim of the study was to determine the effects of BCS-CL73507-N-

methyl-quinazolinone-carboxylic acid (BCS-CT30673) on larvae of

Chironomus riparius.



test substance/ L. In addition, a water control and a solvent control were

tested. Six replicates, containing 5 animals each, were tested for the test

item and the controls.






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assessed. After 48 hours 0% immobility was observed in the control and

treatment. No other sublethal effects were observed.



60% is fulfilled.





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Table 242: Toxicity to sediment-dwelling organisms- spiked water - BCS-CU81056, metabolite


Flag Key study

Test Substance BCS-CU81056, metabolite



Endpoint EC50

Value >10 mg test substance/L

Reference

Silke G. (2015) Acute toxicity of BCS-CL73507-quinazolinone-carboxylic

acid (BCS-CU81056) to larvae of Chironomus riparius in a 48 h static

laboratory test system- limit test. Report no EBFVN078, M-542858-01-1

Klimisch Score 1


GLP yes


Dose Levels





Study Summary

The aim of the study was to determine the effects of BCS-CL73507-

quinazolinone-carboxylic acid (BCS-CU81056) on larvae of Chironomus

riparius.











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assessed. After 48 hours 0% immobility was observed in the controls. In

the treatment, 3.3% immobility was observed. At 48 hours of incubation

was larvae of the control was trapped at the surface but did not show any

other signs of stress.



60% is fulfilled.





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Table 243: Toxicity to sediment-dwelling organisms- spiked water - BCS-CT30672, metabolite


Flag Key study

Test Substance BCS-CT30672, metabolite



Endpoint EC50


Reference

Silke G. (2016) Acute toxicity of BCS-CL73507-N-methyl-quinazolinone-

amide (BCS-CT30672) to larvae of Chironomus riparius in a 48 h static


Klimisch Score 1


GLP yes


Dose Levels

2.50 mg test substance/ L., nominal




Study Summary

The aim of the study was to determine the effects of BCS-CL73507-N-

methyl-quinazolinone-amide (BCS-CT30672) on larvae of Chironomus

riparius.


system over a period of 48 hours to the limit concentrations of 2.50 mg test

substance/ L. In addition, a water control and a solvent control were tested.

Six replicates, containing 5 animals each, were tested for the test item and

the controls.

The analysed metabolite found in all freshly prepared test levels on day 0 in

reference to nominal concentrations was 93%. In aged test level on day 2

was 86% of nominal. Due to the high recoveries at the beginning of the

exposure and the analytical findings after 2 days, all results are based on


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assessed. After 48 hours 0% immobility was observed in the controls and in

the treatment. No other sublethal effects were observed.



fulfilled.

The 48h-EC50 was nominally> 2.50 mg test substance/ L


Conclusion EC50 > 2.50 mg test substance/L.


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Table 244: Toxicity to sediment-dwelling organisms- spiked water - BCS-CY28900, metabolite


Flag Key study

Test Substance BCS-CY28900, metabolite



Endpoint EC50

Value >0.117 mg test substance/L geometric mean

Reference

Silke G. (2016) Acute toxicity of BCS-CL73507-deschloro-oxazine

(BCS-CY28900) to larvae of Chironomus riparius in a 48 h static

laboratory test system- limit test. Report no EBFVN074, M-566032-01-

1

Klimisch Score 1


GLP yes


Dose Levels 2.50 mg test substance/ L., nominal

0.117 mg test substance / L, geometric mean


Study Summary


deschloro-oxazine (BCS-CY28900) on larvae of Chironomus riparius.



test substance/ L. In addition, a water control and a solvent control

were tested. Six replicates, containing 5 animals each, were tested for

the test item and the controls.

The analysed metabolite found in all freshly prepared test levels on day

0 in reference to nominal concentrations was 88%. Due to the very low

stability in aqueous solution, on day 2 no metabolite could be detected

any more. Because recovery was > 80% at test initiation, results are

based on the nominal concentration. Additionally, the geometric mean

concentration was calculated using the measured amount on day 0

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(2.19 mg pm/L) and half the LOQ (0.00625 mg/L). This resulted in a

geometric mean test concentration of 0.117 mg pm/L.


assessed. After 48 hours 0% immobility was observed in the controls

and in the treatment. No sublethal effects were observed.

All validity criteria were met. The validity criterion of control mortality

less than 15% is fulfilled. The validity criterion of oxygen saturation

above 60% is fulfilled.

The 48h-EC50 was > 2.50 (0.117) mg test substance/L (geometric

mean)

The 48h-NOEC was 2.50 (0.117) mg test substance/L. (geometric

mean)



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Flag Key study




Endpoint EC50


Reference

Silke G. (2016) Acute toxicity of BCS-CL73507-deschloro-pyrazine (BCS-

CY28897) to larvae of Chironomus riparius in a 48 h static laboratory test

system- limit test. Report no EBFVN079, M-565370-01-1

Klimisch Score 1


GLP yes


Dose Levels





Study Summary


deschloro-pyrazine (BCS-CY28897) on larvae of Chironomus riparius.


system over a period of 48 hours to the limit concentrations of 10.0 mg test

substance/ L. In addition, a water control was tested. Six replicates,


The analysed metabolite found in all freshly prepared test levels on day 0 in

reference to nominal concentrations was 98%. In aged test level on day 2

was 97% of nominal. Due to the high recoveries at the beginning of the

exposure and the analytical findings after 2 days, all results are based on



assessed. After 48 hours 0% immobility was observed in the control and in

the treatment. No other sublethal effects were observed.

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fulfilled.

The 48h-EC50 was > 10.0 mg test substance/L

The 48h-NOEC was 10.0 mg test substance/L



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Flag Key study




Endpoint EC50


Reference

Silke G. (2016) Acute toxicity of BCS-CL73507-pyrazole-5-carboxylic

acid (BCS-CY28906) to larvae of Chironomus riparius in a 48 h static


Klimisch Score 1


GLP yes


Dose Levels





Study Summary


pyrazole-5-carboxylic acid (BCS-CY28906) on larvae of Chironomus

riparius.











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assessed. After 48 hours 0% immobility was observed in the solvent

control, 3.3% in the water control and 6.6% in the treatment. One larva in

the solvent control was trapped at the surface at 48 hours of incubation



60% is fulfilled.

The 48h-EC50 was > 2.50 mg test substance/ L


Conclusion EC50 >2.50 mg test substance/L.


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Earthworms

Table 247: Chronic toxicity to earthworms - BCS-CR74541, metabolite

Study type Limit test, chronic toxicity earthworm

Flag Key study

Test Substance BCS-CL73507SC carboxylic acid (BCS-CR74541, metabolite)



Endpoint NOEC

Value >100 mg test substance/kg soil

Reference

Friedrich S. (2015), Tetraniliprole-carboxylic acid (BCS-CR74541)

Sublethal toxicity to the earthworm Eisenia fetida in artificial soil.

Report no M53864515 10 48 123S, M-538645-01-2

Klimisch Score 1


GLP yes

Test Guideline/s OECD 222, ISO 11268-2

Dose Levels 100 mg test substance/kg dry weight of soil


Study Summary


carboxylic acid (BCS-CR74541) on survival and growth and

reproduction of earthworms.

Adult earthworms (about 3 months old, eight replicates of 10) were

exposed in an artificial soil system with 10% peat content over a

period of 28 days to concentration of 107.1 mg test substance/kg dry

weight of soil (100 mg pure metabolite/kg soil). After this reproduction

(juveniles in soil) was evaluated for another 28 days. In addition, an

untreated control was tested. A toxic reference (carbendazim) was

tested in a separate study.

Temperature was 20.2 -22.0°C and the photoperiod was 16 h light

(540 lux) and 8 hours dark. Mortality, growth and reproduction were


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1.3%) and number of juveniles per replicate ≥30 (observed ranging

from 139 up to 203) and coefficient of variance of reproduction in the

control ≤30% (observed 18.6%).

Mortality was 1.3% in the control and the treatment after 28 days.

Change of body weight was 26.7% in the control after 28 days. The

change in body weight was 26.0 at the concentration 100 mg test

substance /kg respectively.

Mena The number of offspring after 56 days was 16.2 in the control

and 16.7 in the treatment.



weight soil for growth and reproduction.


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Table 248: Chronic toxicity to earthworms - BCS-CQ63359, metabolite

Study type Limit test, chronic toxicity earthworm

Flag Key study

Test Substance BCS-CL73507SC-N-methyl-quinazolinone (BCS-CQ63359,

metabolite)



Endpoint NOEC

Value >100 mg test substance/kg soil

Reference

Friedrich S. (2015), Tetraniliprole-N-methyl -quinazolinone (BCS-

CQ63359) Sublethal toxicity to the earthworm Eisenia fetida in

artificial soil. Report no 15 10 48 120 S, M-538642-01-2

Klimisch Score 1


GLP yes




Study Summary

The aim of the study was to determine the effects of tetraniliprole- N-

methyl -quinazolinone (BCS-CQ63359) on survival and growth and

reproduction of earthworms.

Adult earthworms (about 3 months old, eight replicates of 10) were

exposed in an artificial soil system with 10% peat content over a

period of 28 days to concentration of 102.4 mg test substance/kg dry

weight of soil (100 mg pure metabolite/kg soil). After this reproduction

(juveniles in soil) was evaluated for another 28 days. In addition, an

untreated control was tested. A toxic reference (carbendazim) was



(540 lux) and 8 hours dark. Mortality, growth and reproduction were



1.3%) and number of juveniles per replicate ≥30 (observed ranging

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from 139 up to 203) and coefficient of variance of reproduction in the

control ≤30% (observed 18.6%).


Change of body weight was 26.7% in the control after 28 days. The

change in body weight was 27.4 at the concentration 100 mg test

substance /kg respectively.

Mena number of offspring after 56 days was 16.2 in the control and

15.2 in the treatment.



weight soil for growth and reproduction.


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Soil mites

Table 249: Chronic toxicity to soil mites - BCS-CR74541

Study type Limit test, toxicity soil mite

Flag Key study


Exposure 14 d


Endpoint NOEC


Reference

Schulz L. (2015), Tetraniliprole-carboxylic acid (BCS-CR74541) Effects

on the reproduction of the predatory mite Hypoaspis aculeifer. Report no

15 10 48 122S, M-538003-01-2

Klimisch Score 1


GLP yes

Test Guideline/s OECD 226, US EPA OCSPP 850.supp



Study Summary


carboxylic acid (BCS-CR74541) on survival and reproduction of

predatory soil mites.

Adult female mites (eight replicates of 10) were exposed in an artificial

soil system with 5% peat content over a period of 14 days to

concentration of 107.1 mg test substance/kg dry weight of soil (100 mg

pure metabolite/kg soil). In addition, quartz sand was tested as a control.

A toxic reference (dimethoate) was tested in a separate study.

Temperature was 19.7 -21.5°C and the photoperiod was 16 h light (518

lux) and 8 hours dark. Mortality and reproduction were determined and

were used to determine the endpoints.

The validity criteria were met. Mortality in control ≤ 20% (observed 2.5%)

and number of juveniles per replicate ≥50 (observed 257.4) and

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coefficient of variance of reproduction in the control ≤30% (observed

8.4%).

The EC50 values of the toxic reference was 6.7 mg ai/ kg soil.

Mortality was 2.5% in the control and 5% the treatment after 14 days.

Mean number of offspring after 14 days was 257.4 in the control and



The NOEC was determined to be ≥100 mg test substance/kg dry weight

soil.

Conclusion NOEC ≥100 mg test substance/kg soil

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Table 250: Chronic toxicity to soil mites - BCS-CQ63359

Study type Limit test, toxicity soil mite

Flag Key study

Test Substance BCS-CL73507SC-N-methyl-quinazolinone (BCS-CQ63359,

metabolite)

Exposure 14 d


Endpoint NOEC


Reference

Schulz L. (2015), Tetraniliprole—N-methyl-quinazolinone (BCS-

CQ63359) Effects on the reproduction of the predatory mite

Hypoaspis aculeifer. Report no 15 10 48 119 S, M-538040-01-2

Klimisch Score 1


GLP yes




Study Summary

The aim of the study was to determine the effects of tetraniliprole-N-

methyl-quinazolinone (BCS-CQ63359) on survival and reproduction

of predatory soil mites.

Adult female mites (eight replicates of 10) were exposed in an

artificial soil system with 5% peat content over a period of 14 days to

concentration of 102.4 mg test substance/kg dry weight of soil (100

mg pure metabolite/kg soil). In addition, quartz sand was tested as a

control. A toxic reference (dimethoate) was tested in a separate

study.


(518 lux) and 8 hours dark. Mortality and reproduction were



6.3%) and number of juveniles per replicate ≥50 (observed 244.1)

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(observed 10.1%).

The EC50 values of the toxic reference was 6.7 mg ai/ kg soil.

Mortality was 6.3% in the control and 0% the treatment after 14 days.

Mean number of offspring after 14 days was 244.1 in the control and




weight soil.

Conclusion NOEC ≥100 mg test substance/kg soil

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Collembolan

Table 251: Chronic toxicity to collembolan- BCS-CR74541

Study type Limit test, toxicity collembolan

Flag Key study


Exposure 28 d

Test species Collembolan Folsomia candida

Endpoint NOEC


Reference

Friedrich S. (2016), Tetraniliprole-carboxylic acid (BCS-CR74541)

Effects on the reproduction of the collembolan Folsomia candida.

Report no M536483, M-536483-02-2

Klimisch Score 1


GLP yes

Test Guideline/s OECD 232, US EPA OCSPP 850.supp, ISO 11267



Study Summary


carboxylic acid (BCS-CR74541) on survival and reproduction of

collembolan.

Ten juvenile collembolans (eight replicates, 9-12 days old) were

exposed in an artificial soil system with 5% peat content over a period

of 28 days to concentration of 107.1 mg test substance/kg dry weight

of soil (100 mg pure metabolite/kg soil). In addition, quartz sand was

tested as a control (eight replicates). A toxic reference (boric acid)

was tested in a separate study.

Temperature was 20.2-22.0°C and the photoperiod was 16 h light

(520 lux) and 8 hours dark. Mortality and reproduction were



2.5%) and number of juveniles per replicate ≥100 (observed 1078)

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(observed 8.0%).

The EC50 values of the toxic reference was 103 mg ai/ kg soil

reproduction and LC50 was 162 mg /kg soil mortality.


Mean number of offspring after 28 days was 1078 in the control and

1094 in the treatment.



weight soil.

Conclusion NOEC ≥100 mg test substance /kg soil reproduction

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Table 252: Chronic toxicity to collembolan - BCS-CQ63359

Study type Full test, toxicity collembolan

Flag Key study

Test Substance BCS-CL73507SC-N-methyl-quinazolinone (BCS-CQ63359, metabolite)

Exposure 28 d

Test species Collembolan Folsomia candida

Endpoint NOEC


Reference

Friedrich S. (2015), Tetraniliprole-N-methyl-quinazolinone (BCS-

CQ63359) Effects on the reproduction of the collembolan Folsomia

candida. Report no 15 10 48 1185, M-538638-01-2

Klimisch Score 1


GLP yes

Test Guideline/s OECD 232, US EPA OCSPP 850.supp, ISO 11267

Dose Levels 10, 18, 32, 56, 100, 178, 316 and 562 mg test substance / kg dry

weight of soil


Study Summary


methyl-quinazolinone (BCS-CQ63359) on survival and reproduction of

collembolan.

Ten juvenile collembolans (four replicates, 9-12 days old) were

exposed in an artificial soil system with 5% peat content over a period

of 28 days to concentration of 10, 18, 32, 56, 100, 178, 316 and 562

mg test substance/kg dry weight of soil. In addition, quartz sand was

tested as a control (4 replicates). A toxic reference (boric acid) was


Temperature was 20.1-21.6°C and the photoperiod was 16 h light (540

lux) and 8 hours dark. Mortality and reproduction were determined and

were used to determine the endpoints.


1.3%) and number of juveniles per replicate ≥50 (observed 1300) and

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coefficient of variance of reproduction in the control ≤30% (observed

8.9%).

The EC50 values of the toxic reference was 103 mg ai/ kg soil

reproduction and LC50 was 162 mg /kg soil mortality.

Mortality was 1.3% in the control and in the treatments, the mortality

ranged from 0-2.5% after 28 days.

Mean number of offspring after 28 days was 1300 in the control. In the

treatments the number of juveniles was 1271, 1308, 1286, 1336, 1304,

1278, 1326 and 1281 for the concentrations 10, 18, 32, 56, 100, 178,

316 and 562 mg test substance / kg dry weight of soil respectively.



weight soil.

Conclusion NOEC ≥ 562 mg test substance /kg soil reproduction

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Soil microflora


Table 253: Toxicity to soil flora – nitrogen transformation - BCS-CR74541, metabolite


Flag Key study

Test Substance BCS-CL73507 -carboxylic acid (BCS-CR74541, metabolite)

Exposure 28 d




Reference

Schulz L. (2015), Tetraniliprole-carboxylic acid (BCS-CR74541): Effects on

the activity of soil microflora (Nitrogen transformation test). Report no

EBFVP061, M-533233-01-1

Klimisch Score 1


GLP yes



(equivalent to 0.222 kg and 2.22 kg test substance / ha)


Study Summary


carboxylic acid on soil microflora activity (nitrogen transformation).


equivalent to 0.222 and 2.22 kg test substance/ha). The nitrogen

transformation was determined in soil (sandy loam, pH 6.1, % C 1.32,

WHC 39.54) enriched with Lucerne meal (concentration in soil 0.5%).

NH4-nitrogen, NO3- and NO2-nitrogen were determined by an


replicates).

In a separate study, the reference substance dinoterb caused a stimulation

of nitrogen transformation of +39.1% and +62.5% and 112.0% at 6.8 mg,

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16.0 mg and 27.0 mg dinoterb per kg soil dry weight, respectively,




No adverse effects of BCS-CR74541 on nitrogen transformation in soil

were observed at both test concentrations (0.30 mg/kg dry soil and 2.96

mg/kg dry soil) after 28 days. Differences from control of -10.2% (test

concentration 0.30 mg/kg dry soil) and +6.0 % (test concentration 2.96

mg/kg dry soil) were measured at the end of the 28-day incubation period.

BCS-CR74541 caused no adverse effects (difference to control < 25 %) on

the soil nitrogen transformation (measured as oxygen consumption) at the

end of the 28-day incubation period.

Conclusion Test substance did not cause adverse effects on nitrogen transformation

up to a rate of 2.22 kg test substance /ha

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Table 254: Toxicity to soil flora – nitrogen transformation - BCS-CQ63359, metabolite


Flag Key study

Test Substance BCS-CL73507 -N-methyl-quinazolinone (BCS-CQ63359, metabolite)

Exposure 28 d




Reference

Schulz L. (2015), Tetraniliprole-N-methyl-quinazolinone (BCS-

CQ63359): Effects on the activity of soil microflora (Nitrogen

transformation test). Report no EBFVP089, M-536950-01-1

Klimisch Score 1


GLP yes



(equivalent to 0.198 kg and 1.98 kg test substance / ha)


Study Summary


methyl-quinazolinone on soil microflora activity (nitrogen

transformation).

Application rates were 0.26 and 2.63 mg test substance/ kg dry soil

ha, equivalent to 0.198 and 1.98 kg test substance/ha). The nitrogen

transformation was determined in soil (sandy loam, pH 6.2, % C 1.35,

WHC 38.40) enriched with Lucerne meal (concentration in soil 0.5%).

NH4-nitrogen, NO3- and NO2-nitrogen were determined by an


replicates).


stimulation of nitrogen transformation of +39.1% and +62.5% and

112.0% at 6.8 mg, 16.0 mg and 27.0 mg dinoterb per kg soil dry

weight, respectively, determined 28 days after application.

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The coefficients of variation in the control (NO3-N) were maximum

3.8 % and thus fulfilled the demanded range (≤15 %).

No adverse effects of BCS-CQ63359 on nitrogen transformation in

soil were observed at both test concentrations (0.26 mg/kg dry soil

and 2.63 mg/kg dry soil) after 28 days. Differences from control of

+23.8% (test concentration 0.26 mg/kg dry soil) and +5.5 % (test

concentration 2.63 mg/kg dry soil) were measured at the end of the

28-day incubation period.

BCS-CQ63359 caused no adverse effects (difference to control < 25

%) on the soil nitrogen transformation (measured as oxygen


Conclusion Test substance did not cause adverse effects on nitrogen

transformation up to a rate of 1.98 kg test substance /ha

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Pollinators

Honey bees

Acute toxicity

Table 255: Acute oral and contact toxicity to honey bees - BCS-CQ63359, metabolite

Type of study Acute oral and contact toxicity test in honey bees

Flag Key study

Test Substance Tetraniliprole-N-methyl-quinazolinone tech. (BCS-CQ63359)

Exposure 48 hours, oral and contact

Species Apis mellifera L.

Endpoint Mortality

Value Oral LD50 > 53.3 µg metabolite/bee (48 hours)

Contact LD50 > 100 µg metabolite/bee (48 hours)

Reference

Schmitzer S. 2015. BCS-CL73507-N-methyl-quinazolinone tech. (BCS-

CQ63359): Effects (acute contact and oral) on honey bees (Apis mellifera L.) in

the laboratory - 2nd final report amendment (amended in 2016 by Przygoda)


Klimisch Score 1


GLP yes


OECD 214


Dose Levels

Oral actual dose: 53.3 μg ai/bee, dissolved in water and sugar (50%) available

for 70 minutes

Contact dose: 100 μg ai/bee (5 µL droplet)


Study Summary

The purpose of the study was to determine the effects of BCS-CL73507-N-

methyl-quinazolinone (BCS-CQ63359) on the honey bee after acute contact and

oral exposure in the laboratory.

Contact test

In the solvent (acetone) control group, 4% mortality occurred and in the water

control (0.5 % Adhäsit) no mortality occurred during the 48 hour observation

period. The reference substance induced 94% mortality at 0.3 μg

dimethoate/bee and within the acceptable range. Consequently, validity criteria

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for both control and reference substance mortality were met and the test was

deemed valid.

In the contact toxicity test at 100 μg metabolite/bee, no mortality nor behavioural

abnormalities were observed during 48 hours.

Oral test

In the water (50% sugar) and solvent control (acetone + Tween) groups, no

mortality occurred during the 48 hour observation period. The reference

substance induced 100% mortality at 0.32 μg dimethoate/bee and within the

acceptable range. Consequently, validity criteria for both control and reference

substance mortality were met and the test was deemed valid.

In the oral toxicity test at 53.3 µg ai/bee, no mortality nor behavioural

abnormalities were observed during 48 hours.

Comments

Conclusion Contact LD50 > 100.0 μg metabolite/bee.

Oral LD50 > 53.3 μg metabolite/bee.

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Appendix K: Standard terms and abbreviations

Abbreviation Definition

a.s active substance

ACVM Agricultural Compounds and Veterinary Medicines

ADE Acceptable Daily Exposure

ADME Absorption, Distribution, Metabolism and Excretion

AFDW Ash-Free Dry Weight

ai active ingredient

AOEL Acceptable Operator Exposure Level

AR Applied Radioactivity

ARfD Acute Reference Dose

AUC Area Under the Curve

BBCH Biologische Bundesanstalt, Bundessortenamt und CHemische Industrie

BCF BioConcentration Factor

BLQ Below the Limit of Quantification

bw body weight

CAS # Chemical Abstract Service Registry Number

cm centimetres

CMR Carcinogenic, Mutagenic & Reprotoxic

CoA Certificate of Analysis

COD Chemical Oxygen Demand

conc. concentration

CRfD Chronic Reference Dose

DAT Days After Treatment

DDD Daily Dietary Dose

DFOP Double First-Order in Parallel

DMF N,N-dimethylformamide

DMSO dimethyl sulfoxide

DT50 Dissipation Time (days) for 50% of the initial residue to be lost

dw dry weight

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EC European Commission

EC25 Effective Concentration at which an observable adverse effect is caused in 25 % of

the test organisms

EC50 Effective Concentration at which an observable adverse effect is caused in 50 % of

the test organisms

EEC Estimated Environmental Concentration

EEL Environmental Exposure Limit

EFSA European Food Safety Authority

equiv. equivalent

ER50 Effective Residue concentration to 50% of test organisms

ErC50 EC50 with respect to a reduction of growth rate (r)

FOB Functional Observational Battery

FOMC First-Order Multi-Compartment

g grams

GAP Good Agricultural Practice

GENEEC Generic Estimated Environmental Concentration

geom. geometric

GIT Gastrointestinal Tract

GLP Good Laboratory Practice

ha hectare

HCA α-Hexylcinnamaldehyde

HCD Historical Control Data

HPC Hazardous Property Controls

HPLC High Performance Liquid Chromatography

HPLC-MS/MS High Performance Liquid Chromatography-Mass Spectrometry/Mass Spectrometry

HQ Hazard Quotient

HS Hazardous Substances

HSW Health and Safety at Work

IPM INTEGRATED Pest Management

Kd partition (distribution) coefficient

kg Kilogram

Koc organic carbon adsorption coefficient

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Kow octanol-water partition coefficient

L litres

Lb pounds

LC50 Lethal Concentration that causes 50% mortality

LC-MS/MS Liquid Chromatography–Mass Spectrometry/Mass Spectometry

LD50 Lethal Dose that causes 50% mortality

LLD Lowest Lethal Dose

LLNA Local Lymph Node Assay

LOAEL Lowest Observable Adverse Effect Level

LOC Level Of Concern

LOD Limit Of Detection

LOEAER Lowest Observed Ecologically Adverse Effect Rate

LOEC Lowest Observable Effect Concentration

LOEL Lowest Observable Effect Level

LOER Lowest Observed Effect Rate

LOQ Limit Of Quantitation

LR50 Lethal Rate that causes 50% mortality

LSC Liquid Scintillation Counting

m metre

MAF Multiple Application Factor

MATC Maximum Acceptable Toxicant Concentration

MDL Method Detection Limit

mg milligram

MOA Mode Of Action

mol mole(s)

MPI Ministry of Primary Industries

MRL Maximum Residue Level

MSDS Material Safety Data Sheet

MTD Maximum Tolerated Dose

NA Not Applicable

NAEL No Adverse Effect Level

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ND No Data

NER Non-Extractable Residues

ng nanogram

No Not Classified

NOAEL No Observed Adverse Effect Level

NOEAER No Observed Ecologically Adverse Effect Rate

NOEC No Observed Effect Concentration

NOEL No Observed Effect Level

NOER No Observed Effect Rate

OECD Organisation for Economic Cooperation and Development

PBT Persistent, Bioaccumulative & Toxic

PCE Polychromatic Erythrocytes

PDE Potential Daily Exposure

pKa Acid dissociation constant (base 10 logarithmic scale)

pm pure metabolite

ppb parts per billion (10-9)

PPE Personal Protective Equipment

ppm parts per million (10-6)

prod. product

REI Restricted Entry Interval

RITA Registry of Individual Toxicology Animal data

RMF Relative Mobility Factor

RPE Respiratory Protective Equipment

RQ Risk Quotient

RTDS Ratio of concentration of test item

SDS Safety Data Sheet

SFO Single First-Order Kinetics

SI Stimulation Index

SPE Solid Phase Extraction

TEL Tolerable Exposure Limit

ThOD Theoretical Oxygen Demand

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TRR Total Radioactive Residue

TWAC Time-Weighted Average Concentrations

UDPGT Uridine diphosphate glucuronosyltransferase

UV Ultra Violet

UV-VIS Ultra Violet Visible

VOC Volatile Organic Compounds

μg microgram

μm micrometre (micron)

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Appendix L: References APVMA (2010). "Standard spray drift risk assessment scenarios."

EC (2013). Cyantraniliprole - Report and Proposed Decision of the United Kingdom (RMS) and

France (Co-RMS) made to the European Commission under Regulation (EC) No. 1107/2009 for first

approval of an active substance. Section B.9: Ecotoxicology: 315.

EFSA (2009). "Risk Assessment for Birds and Mammals." EFSA Journal 7(12): 1438.

EFSA (2017). "Guidance on dermal absorption." EFSA Journal 15(6): e04873.

EPA (2012). Thresholds and Classifications under the Hazardous Substances and New Organisms

Act 1996. HSNO

EPA (2018). Risk Assessment Methodology for Hazardous Substances ; Draft for Consultation.

HSNO

Klimisch, H. J., M. Andreae and U. Tillmann (1997). "A systematic approach for evaluating the quality

of experimental toxicological and ecotoxicological data." Regul Toxicol Pharmacol 25(1): 1-5.

McCall P.J., Laskowski D.A., Swann R.L. and D. H.J. (1981). Measurement of sorption coefficients of

organic chemicals and their use, in environmental fate analysis. Test Protocols for Environmental

Fate and Movement of Toxicants, Proceedings of AOAC Symposium, AOAC. Washington DC.

Workshop, E., M. P. Candolfi, S. Europe and C. Commission of the European Guidance document on

regulatory testing and risk assessment procedures for plant protection products with non-target

arthropods : from the ESCORT 2 Workshop (European Standard Characteristics of Non-Target

Arthropod Regulatory Testing) : a joint BART, EPPO/CoE, OECD, and IOBC workshop organised in

conjunction with SETAC Europe and EC : held at Wageningen International Conference Center,

Wageningen, the Netherlands, 21-23 March 2000, Pensacola, FL, Society of Environment Toxicology

and Chemistry.

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Appendix M: Confidential Composition

The composition of Vayego is listed in confidential.

APP203605 – Vayego - EPA NZ

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