Impact of European legislation on marketed pesticides — A view from the standpoint of health...

Environment International 35 (2009) 1096ndash1107

Contents lists available at ScienceDirect

Environment International

j ourna l homepage wwwe lsev ie rcom locate env int

Review article

Impact of European legislation on marketed pesticides mdash A view from the standpointof health impact assessment studies

AJ Karabelas a KV Plakas a ES Solomou a V Drossou a DA Sarigiannis b

a Chemical Process Engineering Research Institute Centre for Research and Technology-Hellas PO Box 60361 6th km Charilaou-Thermi Road Thermi Thessaloniki GR 570-01 Greeceb European Commission-Joint Research Centre Institute for Health and Consumer Protection via E Fermi 1 21027 Ispra (VA) Italy

Corresponding author Tel +30 2310 498181 faxE-mail address karabajcpericerthgr (AJ Karabela

0160-4120$ ndash see front matter copy 2009 Elsevier Ltd Aldoi101016jenvint200906011

a b s t r a c t

a r t i c l e i n f o

Article historyReceived 13 March 2009Accepted 19 June 2009Available online 25 July 2009

KeywordsPesticidesEU legislationHealth impact assessmentDirective 91414EEC

The very significant impact of European legislation (Directive 91414EEC) on the authorization of plantprotection products is reviewed herein which has resulted inwithdrawal of 704 active substances (AS) out of889 assessed so far The list of currently approved 276 AS includes 194 AS ldquoexistingrdquo in the market before1993 and 82 ldquonewrdquo AS introduced during the last 15 years Results of toxicity characterization of the approvedAS are also summarized utilizing several well-known databases Although significant data gaps exist for arather large part of the approved AS it is found that 84 AS are positive for at least one health effect (afterchronic andor acute exposure) including carcinogenicity reproductive and neuro-developmental disordersas well as endocrine disruption The toxicity characterization results of this study are compared to those ofrecent assessments by other organizations (KemI the Swedish Chemicals Agency and the Pesticide SafetyDirectorate of the UK) where interpretation and use is made of AS ldquocut-offrdquo criteria foreseen in new EUlegislation These studies report a comparatively smaller AS number with positive toxicity characterizationThe possibility of some additional AS withdrawal in the near future combined with the rather small rate ofnew AS introduction (approx 5 per year) suggest that the list of approved AS over the next 10ndash15 years maynot change very drastically Consideration of the above trends is necessary and instructive in evaluatingresults of existing health impact assessment (HIA) studies as well as in planning new ones Due to the verydrastic change in the number and type of marketed AS that took place within the past 8ndash9 years it issuggested that new HIA studies (based on epidemiological data after year 2000) should focus on a rathershort time frame and therefore on appropriate cohort groups eg young children For the same reasonresults of epidemiological studies of the past (involving banned AS) should be carefully interpreted and usedwith caution

copy 2009 Elsevier Ltd All rights reserved

Contents

1 Introduction 10962 Council Directive 91414EEC 1098

21 Evaluation programme on existing AS 109822 New active substances 1100

3 Characterization of regulated AS from the standpoint of health impact assessment studies 11004 Comparison with literature assessments regarding the number of approved active substances 11025 Discussion and conclusions 1103Acknowledgements 1104References 1107

+30 2310 498189s)

l rights reserved

1 Introduction

Health impact assessment (HIA) studies related to major policiesprograms or projects have been recognized in recent years assignificant tools helpful to planners and other decision-makers forevaluating the impact of their decisions on human health (European

1097AJ Karabelas et al Environment International 35 (2009) 1096ndash1107

Centre for Health Policy and World Health Organization RegionalOffice for Europe 1999) Regarding pesticides many HIA studies havebeen carried out in the USA Europe and elsewhere in the past 15ndash20 years In Europe significant studies are also currently in progressin the context of large EU-funded projects1 (ie INTARESE HEIMTSANoMiracle) to assess health effects caused by various categories ofenvironmental pollutants including plant protection products whichare commonly referred to as ldquopesticidesrdquo a term used henceforth inthis paper Of paramount importance in such studies is the largevariety of Active Substances (AS) applied for plant protection andtheir toxicity characteristics

The following overview of pesticides regulatory evolution showsthat regarding available pesticides by action on target species (ieinsecticide fungicide herbicide etc) ndash henceforth to be referred to asldquoactionrdquo for simplicity ndash and number of AS employed in agriculturethe situation in the EUwas relatively stable in the last two decades ofthe 20th century However due to Community legislation thispicture changed drastically during the past 8ndash9 years The scope ofthis study is to review the impact of this legislation on the approvedfor marketing pesticides and to characterize their toxicity thusproviding information necessary for carrying out new HIA studies orappraising the results of existing ones furthermore to discuss thepossible impact of the greatly reduced number and the toxicity ofapproved AS on the type and proper design of HIA studies to becarried out in the near future A brief account is presented first of theevolution of legislation and regulatory measures concerning pesti-cide AS

Pesticides help control hundreds of weed species more than onemillion species of harmful insects and roughly 1500 plant diseases(Ware andWhitacre 2004 NACA 1993) Although they are at the topof the list of dangerous pollutants modern pesticides are fast-actingsome of them may be unique in their action against a specific pestthey can control large infestations they are generally easy to applyand lead to increased crop yield by reducing crop losses Overallpesticides seem to significantly contribute to human welfare (Wareand Whitacre 2004 NACA 1993) although human health risksassociated with the use of pesticides are distributed unequally amongvarious population groups Elemental sulphur still in use today as aninsecticide together with other inorganic chemicals such as arsenicmercury and lead are frequently referred as the ldquofirst generationrdquopesticides which were applied to crops for many centuries until thebeginning of the 20th century (Committee on the Future Role ofPesticides in US Agriculture 2000) The use of the first generationpesticides was largely abandoned because they were either tooineffective or too toxic showing also a great tendency to accumulatein soil to the point of inhibiting plant growth Moreover with thepassage of time pests became resistant and tolerant to thesepesticides Expanding agriculture to meet the needs of the growingpopulation necessitated the application of more effective pesticidesthus the ldquosecond-generationrdquo pesticides as they came to be knownwere developed comprising synthetic organic chemicals whichmadetheir debut in the 1930s (Committee on the Future Role of Pesticidesin US Agriculture 2000 Cochrane1979) Themodern era of pesticidesessentially beganwith the introduction in 1939 of the insecticide DDT(dichlorodiphenyl trichloroethane) The astonishing efficacy of DDT

1 The following are Integrated Projects funded by the European Commission

INTARESE Integrated Assessment of Health Risks of Environmental Stressors inEurope (information available at httpwwwintareseorg)HEIMTSA Health and Environment Integrated Methodology and Toolbox forScenario Assessment (available at httpwwwheimtsaeu)NoMiracle Novel Methods for Integrated Risk Assessment of Cumulative stressorsin Europe (available at httpnomiraclejrceceuropaeudefaultaspx)

led to the development of a variety of chlorinated hydrocarbons suchas gamma-lindane and toxaphene which were quickly adopted in theagricultural practice (Daly et al 1998) In the 1940s manufacturersalso began producing large amounts of other synthetic pesticides likethe organophosphates which despite their greater toxicity tomammals and other non-target species enjoyed considerable popu-larity because of their broad spectrum efficacy and rather low cost(Casida and Quistad 1998)

Pesticide use to date has increased 50-fold since 1950 andcurrently there are thousands of synthetic pesticide products madeup of more than 1000 different chemicals and combinations thereof(Miller 2002) Thus the pesticide market has turned into a multi-billion dollar one specialists in business information estimate that theglobal pesticide market surged in 2008 by 29 over the 2007 level of$407billion ndash to $524billion mdash a record increase that came at a timewhen a global financial crisis was in full swing (Reportlinker 2008)Arguably this trend was also the result of surging agriculturalcommodity prices which means that farmers were likely to spraymore expecting greater pesticide effectiveness and thus crop yield(Fernandez-Cornejo et al 1998) This growth trend seems to contra-dict the commonly expressed opinion that the future of pesticideusage is uncertain (Committee on the Future Role of Pesticides in USAgriculture 2000) This uncertainty is due to the increasing number oflegal actions of authorities mainly in the USA and Europe against thesecond generation of pesticides since these products are generallyconsidered to pose significant risks to human health and theenvironment (Walker et al 2003) Potential health risks identifiedin toxicological and epidemiological studies include cancer geneticmalformations neuro-developmental disorders and damage of theimmune system (Skinner et al 1997 Sanborn et al 2004 McKinlayet al 2008)

The urgent ban to major ldquosecond generationrdquo pesticides (DDT andother organochlorine compounds) for valid reasons (Walker et al2003) apparently created the need for a re-evaluation of pesticideapplicability and for the development of a legal framework regulat-ing their production and use By the end of the 1960s this needculminated in the creation of the Environmental Protection Agency(EPA) in the USA which was the first governmental agency takingactions against pesticide usage at that time The risks posed tohumans and the environment by the increased usage of syntheticpesticides was later recognised by the United Nations (UN) The UNGeneral Assembly in 1972 decided to establish the United NationsEnvironment Programme (UNEP) to ldquoserve as a focal point forenvironmental action and co-ordination within the UN systemrdquoUNEP together with the Food and Agriculture Organization (FAO)and the World Health Organization (WHO) promoted more sustain-able practices in replacing persistent organic pesticides withintegrated pest management (IPM) The latter comprises a numberof control techniques that inhibit the development of pest popula-tions keeping pesticides and other interventions to levels that areeconomically justified as well as safe for human health and theenvironment Following the regulatory initiatives of the US EPA andthe UN regarding pesticide usage and monitoring programmes ofpesticide residues in the ecosystem a number of developed countriesmoved later on in the same direction which resulted in a largenumber of different national regulations To deal with inconsisten-cies in regulations among countries an International Code ofConduct on the Distribution and Use of Pesticides was adopted bythe United Nations Food and Agriculture Organization in 1985 whichcreated voluntary standards of pesticide regulation for differentcountries (Willson 1996) The Code was updated in 1998 and 2002(FAO 2002) There are also other efforts and initiatives to improveregulation of international pesticide trade (Reynolds 1997)

Legislation at the European Community level dates back to 1976when Council Directive 76895EEC specified maximum levels forpesticide residues (MRLs) for 43 active substances in and on selected

1098 AJ Karabelas et al Environment International 35 (2009) 1096ndash1107

fruits and vegetables TheMRLs thatwere set in theDirectivewere basedon the best data available at that time More recently Regulation (EC)No 3962005 envisaged full harmonization for all pesticideMRLs acrossthe EU and replaced the previous legislation Based on this legislationthe European Commission took forward a food standards programmeaimed at achieving the harmonization of approximately 900 pesticidesAS which could potentially be present as residues in food MemberStates established specific national MRLs for approx 240 substances(among these900AS)whichwere still in use either in or outside the EUA comprehensive review on EU legislation (directives and regulations)on food-related issues (safety hygiene packaging technology geneti-cally modified organisms additives radiation labelling) can be foundelsewhere (Arvanitoyannis et al 2005 Arvanitoyannis et al 2006)Regulation (EC) 3962005 was fully applicable as of 2 September 2008As a result since September 2008 national MRLs are no longer in forceand only harmonized European legal limits apply (EFSA 2008a) A list ofall relevant legal actions amending legislation in this area is given in theofficial website of the European Commission and specifically in thesection on Plant Health Legislation (European Commission DG Healthand Consumers)

The substantial increase of pesticide legal actions taken at theEuropean level (regulations directives decisions and recommenda-tions) after 1994 (as shown in Fig 1) is due to the large number of EUdecisions in the framework of the 91414EEC Directive (CouncilDirective 91414EEC 1991) In fact 20 years after the condemnationand exclusion from the pesticide market of the organochlorineinsecticides (DDT HCH toxaphene etc) the European Communityestablished a review programme of all pesticide active substances thatwere in the market at the time that legislation entered into force inJuly 1993 This review of pesticides is a major undertaking involvingthe risk assessment of several hundred chemicals used as plantprotection products

On the occasion of completion of the aforementioned evaluationprogram at the end of 2008 the present study summarizes the pro-visions of Directive 91414EEC and its impact on the current statusand on developing trends regarding available plant protectionproducts in Europe The toxicity of the approved pesticide activesubstances is also characterized herein mainly in relation to healthimpact assessment studies More specifically 276 active substancesare characterized in relation to acute toxicity carcinogenicitydevelopmental reproductive and neurological disorders This over-

Fig1Number of EU legal actions regarding pesticides (regulations directives decisionsand recommendations) from 1976 to 2008 (based on data retrieved from EuropeanCommission DG Health and Consumers web page)

view was based on web databases which are maintained byInternational Organizations and Networks like WHO (World HealthOrganization) IARC (International Agency for Research on Cancer)and PAN (Pesticide Action Network)

When the present study was in its final stage the results of similarassessments by the Swedish Chemical Agency KemI (KemI 2008) andthe UK Pesticide Safety Directorate (PSD 2008) became available Theapproach of this study significantly differs from that taken by the othertwo (rather preliminary) assessments in that the latter took intoaccount for AS characterization only the ldquocut-offrdquo criteria adopted in theCommission proposal and the amendments proposed by the Environ-ment Public Health and Food Safety (ENVI) Committee of the EuropeanParliament For completeness a comparison is made of results obtainedfrom the aforementioned two assessments with those from the presentstudy

2 Council Directive 91414EEC

In July 1991 after great difficulties encountered in the developmentof a harmonised framework for authorisation use and control of plantprotection products the European Council adopted Directive 91414concerning the placing of pesticides on the market This Directive wasone of the first major items of European legislation implementing notonly the principle of subsidiarity but also the precautionary principleFrom the outset it explicitly placed protection of human health and ofthe environment above the needs of agricultural production Accordingto its provisions active substances in pesticides formulations are onlyapproved for use in the EU if they have undergone a peer-reviewedsafety assessment The active substances covered by the reviewprogramme were classified as follows

bull Existing the active substances that were already in the market inJuly 1993 (date of Directive enforcement)

bull New the active substances introduced or in the process of applyingfor marketing since July 1993

An essential provision of Directive 91414 is the evaluation of allexisting active substances and other plant protection products (920 intotal) and the creation of a list (referred to as Annex I) of ActiveSubstances (AS) that are considered acceptable in regard to theirimpact on the environment human and animal health and thereforeauthorised for use in pesticide formulations within the CommunityEvaluation of both existing and new active substances is carried outthrough a tiered approach For each substance an initial draft riskassessment report (DAR) must be produced by a designated MemberState this is followed by a peer review by all Member States whichleads to a legislative decision regarding inclusion of the substance inthe Communitys list (Annex I) (EFSA 2008b) Because of the scale ofthe task the 920 existing AS and other related compounds wereassessed in four consecutive stages the last of which ended on 31December 2008 in accordance with Commission Decision 2003565EC of 25 July 2003 extending the time period provided for in Article 8(2) of Council Directive 91414EEC As subsequently discussed onlythe first three stages are of particular interest to this study includingusual pesticide active substances (ie chemical compounds) Thefourth stage established essentially by default is of lesser environ-mental and public health concern

21 Evaluation programme on existing AS

The first stage of the evaluation programme was established byCommission Regulation (EEC) No 360092 as last amended byCommission Regulation 22662000 laying down the detailed rules forthe implementation of thefirst 90 substances whichwere considered atthat time to be themostwidely used on themarket and of clear concernregarding health effects

Table 1Summary results of the Directive 91414EEC evaluation programme

Priority list No of AS Approved Removed Pending

1 90 55 35 02 148 32 116 03 387 48 319 204 295 59 225 11Total 920 194 695 31


The second and third stages of work were laid down by CommissionRegulation (EC) No 4512000 and Commission Regulation 14902002The second stage included a list of 148 substances established inRegulationNo 4512000which comprised all those organo-phosphatesand carbamates that were not in the first stage as well as othersubstances of concern and substances for which industry had indicatedearly availability of dossiers The third stage was comprised of 387chemical substances also considered ldquopesticidesrdquo (as the term iscommonly understood) but not as widely used as those in the secondstage

The fourth stage was laid down by Commission Regulation No22292004 The list of active substances examined during the fourthstage established by default includes the 295 remaining substancesidentified as being of lesser concern and to which data requirementsother than those for stages 1ndash3 might apply It includes (a) microbialpesticides (b) substances already authorised for foodstuffs (c) plantextracts (d) animal products (e) substances used in organic farming(f) rodenticides (g) storage products and (h) commodity chemicalsWhile these substances are conventionally viewed as being of lesserconcern some find relatively wide use in Europe

Progress in terms of the numbers of evaluations that have beenfinalised has not been as rapid as originally anticipated for the firstseven years ie1993 to 2000 On the other hand the solid foundationthat has been laid in legislation in organisation and collaboration aswell as in learning from experience and in planning has acceleratedthe pace of the evaluation process after year 2000 This is clearlyreflected in the increased number of decisions that entered into forceduring the last nine years when a major increase in decision-makingcould be observed from 5 to 24 decisions per year (Fig 2) Moreovera large number of EU decisions were taken during 2008 the last yearof the evaluation period This is due to the acceleration of thetechnical evaluation process observed during this period of time aswell as to the measures taken to expedite decision making In total120 decisions entered into force since 1993 which shows theincreased interest of the European Authorities in regulating pesti-cides among the organic substances synthesized and applied to theenvironment

Among the 920 active substances considered in the four stages ofthe evaluation programme 889 have been assessed until now(December 2008) while evaluation of the 31 remaining activesubstances is still on-going (pending) Table 1 summarizes the resultsof the decisions taken in all four stages of the evaluation programmeIt is of interest to point out that only 194 AS have been included inAnnex I out of 889 evaluated so far This means that 4 out of 5 existingAS are removed from the market as a result of the peer-reviewed

Fig 2Number of EU decisions per year to retain or withdraw AS from Annex I of CouncilDirective 91414EEC

process required by the Directive 91414EEC However it should benoted that voluntary withdrawal (distribution and sale) of somesubstances under Commission Regulation 10952007 took place bythe manufacturing companies on the provision that more completedossiers for those AS may be resubmitted and assessed for possibleinclusion in Annex I An overall view of the outcome of the ldquoexistingrdquo mdashAS assessment from 1994 to 2008 is provided in Fig 3 on a yearlybasis where the effect of decisions to withdraw approximately 640active substances after year 2001 is clearly shown This implies that avery large number of active substances used in the preceding decade(~1990 to ~2001) have been withdrawn as a result of the aforemen-tioned assessment

The annualvariationofAS retention in andwithdrawal fromAnnex Iis depicted in Fig 4(ab) considering their action The evaluation period1993ndash2000was excluded from these figures since only 10 out of 920 ASwhere regulated during this period by the European Commission Themajority (72) of the 194 AS that were positively assessed and retainedin Annex I during the evaluation programme are herbicides (59 AS)fungicides (48 AS) and insecticides (34 AS) the remaining 28 are usedfor secondary purposes (acaricides rodenticides nematicides and plantgrowth regulators) Roughly the same proportions are also observed inthe case of the AS withdrawn from Annex I where more than 60 of ASbelong in the three aforementioned groups with herbicides (162 AS)and insecticides (154 AS) being the two groups most significantlyreduced It is evident that the large number of withdrawn AS especiallyfrom the latter two important pesticide categories creates problems inplant protection practices

The rate at which crop protection products are being removed fromthe market has recently provoked the reaction of a number ofindependent and government scientists who have voiced their concernregarding the negative effects of the pesticide legislation on potentialagricultural production Indeed a number of scientists believe thatfewer active ingredients would inevitably lead to problems regardingprotection against some pests that may develop resistance to pesticidesif inappropriate or irregular treatment is applied (Clarke 2008)Moreover they fear that the scientific community and industry will

Fig 3 Yearly variation of existing active substances (AS) assessed from 1994 to 2008

Fig 4 Number and type of existing active substances a) retained in Annex I andb) withdrawn from Annex I of 91414 EU Directive

Fig 5 New active substances (AS) assessed from 1998 to 2008


not be able to replace the substances banned at the rate thatpolicymakersmayexpect Indeed available data show that the pesticideindustry is only capable of launching approximately five new activeingredients per year (Clarke 2008) Furthermore it seems thatEuropean fruit and vegetable growers are already facing pest resistanceproblems as a result of the limited portfolio of crop protection productsavailable to themBasedalsoon recentestimates specialist cropgrowerscould be left with less than 100 AS available since many products areexpected to be withdrawn from the market in the near future(Horticulture Week 2007) This will be the result of the provisions setby the regulations which will soon replace Directive 91414EEC(SANCO 2001)

The re-assessment after 2008 of all active substances alreadyincluded in Annex I is part of the provisions set by the proposed newlegislation which is going to replace Directive 91414 (ldquoProposal fora Regulation of the European Parliament and of the Councilconcerning the placing of plant protection products on the marketrdquoCOM(2006) 388 final Brussels 1272006) Furthermore the provi-sions of other related directives already in effect significantlyaffect the contents of Annex I For example the active ingredientschlorpyriphos and isoproturon retained in Annex I are classified asldquoPotentially Priority Hazardousrdquo in Annex V of the Water FrameworkDirective ie they are subject to re-evaluation with a high likelihoodto be withdrawn

22 New active substances

The ldquonewrdquo active substances are all compounds introduced in thepesticides market since July 1993 Unlike the priority-list approach

for existing active substances the evaluation process of a new activesubstance can be triggered at any time by an application fromindustry to a Rapporteur EU Member State of its choice A dossier ofscientific information regarding mostly physical and chemicalproperties toxic hazard and exposure potential based on laboratoryexperiments and to a lesser extent on epidemiological evidence aswell as other documents in support of each application is submittedto the Rapporteur State A well-defined evaluation procedurefollows starting with a completeness check of the dossier and asubsequent draft assessment report from the Rapporteur StateDetails on this procedure can be found in the working documentSANCO26922001 of the European Commission Services (SANCO2001)

Since 1993 applicants have concentrated on a limited number ofRapporteur Member States with over half of all applications beingsubmitted in France and Germany ie EU Member States with a largepotential market for such industrial products and home-countriesof prominent chemical factories Although there was a peak of 16applications during 1997 currently approx eight new applications arereceived annually (SANCO 2001) In total the Commission has 146 newactive substances at various stages of examinationwith decisions takenon 91 The annual progress of AS inclusion in orwithdrawal from AnnexI of the 91414EEC directive is depicted in Fig 5 Among the 91 activesubstances regulated since 1998 82 were included in Annex I while 9were rejected The majority of these new AS were herbicides followedby fungicides and insecticides

For new active substances the number of uses (applied for) is farfewer than for existing active substances and this greatly simplifiesevaluation Therefore in general assessment of new active substanceshas been easier and less time consuming than for existing substancesSome new active substances have however presented the Commis-sion and theMember Stateswith regulatoryand scientific challengesmdashoften because these compounds involve new chemistry to achievetheir modes of action (SANCO 2001) Other issues regarding new ASsuch as possible leaching of metabolites into groundwater have alsogenerated concern and extensive debate (Britt et al 1992 Worrallet al 2000)

3 Characterization of regulated AS from the standpoint of healthimpact assessment studies

A toxicity characterization of the 194 (ldquoexistingrdquo) AS retained inAnnex I of Directive 91414EEC and of the 82 ldquonewrdquo AS introducedin the market during the last 15 years is reported in this sectionThe total of 276 AS are characterized in relation to acute toxicitycarcinogenicity developmental reproductive and neurological dis-orders Toxicity data are obtained from online searchable databases

Table 2Summary of results of toxicity characterization of 276 legally marketed AS

Action CarcinogenicAS (US EPA)

CarcinogenicAS (IARC)

Endocrine DisruptorAS (PAN)

AS presenting reproductive anddevelopmental toxicity (PAN)

AS presenting acutetoxicity (WHO)

Total AS corresponding to anyof the five toxic categories

Total ASexamined

Fungicides 24 1 10 11 4 32 78Herbicides 14 7 5 8 7 25 87Insecticides 13 0 9 2 17 24 66Plant growth regulators 1 0 0 1 0 2 16Various 0 0 0 1 1 1 8Unknown ndash ndash ndash ndash ndash ndash 5Not found ndash ndash ndash ndash ndash ndash 16Total 52 8 24 23 29 84 276

Active substances classified according to their action


such as databases of the World Health Organization (WHO 2005)the International Agency for Research on Cancer (IARC 2008) andthe Pesticide Action Network (PAN 2008) as well as the UnitedStates Environmental Protection Agency (US EPA) database (US EPA2008)

PAN a network of over 600 participatingnongovernmental organiza-tions institutions and individuals has created a pesticide database thatsummarizes toxicity and regulatory information for pesticides whileIARC an international organization that is part of WHO evaluateschemicals (not all of which are pesticides) for carcinogenicity Lack oftoxicity data for specific AS in the above databases does not necessarilyimply that they are not toxic This may mean either that they have notbeen evaluated yet or that relevant data are not available to theseorganizations Moreover there are cases where toxicological propertiesof pesticide active ingredients differ among the aforementioneddatabases In order to handle such discrepancies it was decided tocharacterize a substance as toxic if such a characterization appears in atleast one database Finally it should be pointed out that there are ASwhich are not included in any of the aforementioned databaseshowever this is mainly the case for AS examined in the fourth stage oftheevaluationprogramme generally consideredof reduced toxicologicalconcern

Table 2 summarizes the results of toxicity characterization of the276 legally marketed AS classified according to their action It is notedthat 32 out of the 78 fungicides 25 out of the 87 herbicides and 24 outof the 66 insecticides are related to at least one health effect It shouldbe pointed out that there are AS reported to be related to more thanone health effect for example 24-dichlorophenoxyacetic acid (24-D) a herbicide that was widely used in the early 40s because of itsselectivity for broadleaf weeds is suspected of causing cancers andendocrine disorders (Committee on the Future Role of Pesticides in USAgriculture 2000) Details on the toxicity characterization of the 84AS that are identified as having at least one health effect classified bytheir action and chemical class are summarized in Appendix A of thispaper

Table 3Carcinogenicity characterization toxic non toxic and not listed ldquoexistingrdquo activesubstances classified according to their action (US EPA 2008)

Action Toxic Non toxic Not listed a Not found Total

Fungicides 20 6 23 0 49Herbicides 10 14 32 0 56Insecticides 10 13 26 0 49Plant growth regulators 1 1 11 0 13Various 0 0 9 0 9Unknown 0 0 2 0 2Not found ndash ndash ndash 16 16Total 41 34 103 16 194

a Not listed denotes that no assessment has taken place yet by the US EPA

Outof the 194AS included in Annex I of the 91414EECDirective 72AS (37 ) have adverse health effects acute and chronic judged by thetoxicity criteria employed in the databases It is worth noting theunexpectedly high percentage of substances characterized in thiswayasldquotoxicrdquo which are included in Annex I of the 91414EEC Directivedespite the evaluation they have undergone The list of the 72 toxicactive substances includes some of the most widely used AS in Europesuch as chlorothalonil mancozeb maneb and captan which arecharacterized regarding their carcinogenic potency as ldquoprobablerdquo (B2)by US EPA (US EPA 2008) Similarly three other substances (cyperme-thrin dimethoate and pendimethalin) are characterized as ldquopossiblerdquo(C) carcinogens In total the substances with carcinogenic health effectare 47 (based on both US EPA and IARC databases) which amounts toapprox 25 of approved pesticides There are also 29 AS that areidentified by WHO as having an acute toxic effect Furthermore 12 ofthe approved AS are characterized as endocrine disruptors and another12 are identified as responsible for reproductive and developmentaldisorders It is noted here that in a recent literature review by McKinlayet al (2008) 127 AS have been listed as endocrine disruptors It isnoteworthy that 35ASoutof these127AShavebeen included inAnnex IMoreover 14 AS out of the 35 AS are characterized by both McKinlayet al (2008) and the databases searched for thepurposes of this studyasendocrine disruptors Among the 194 AS of Annex I 49 substances(~25) have not been apparently evaluated by any of the aboveorganizations whereas 13 AS are not included in the respectivedatabases

Regarding carcinogenicity potential (according to the US EPA)the toxic non-toxic and not listed ldquoexistingrdquo active substances aresummarized in Table 3 This table shows that 41 of the ldquoexistingrdquofungicides are toxic while 18 and 21 of herbicides and insecticidesrespectively are assessed as carcinogenic (US Environmental Protec-tion Agency US EPA (2008) Thus a large part of fungicides mightsoon be withdrawn according to the criteria used here

Out of the 82 ldquonewrdquo active substances only 46 AS (56) have beenassessed in this study (Table 4) regarding their carcinogenic healtheffects No information was available for the remaining 36 AS indatabases used (US EPA WHO PAN and IARC) Among the 46 ASexamined 12 AS are reported to have adverse health effects (11 ASrelated to cancers mdash Table 4)

Table 5 indicates the availability of toxicological data regarding the84 AS identified as ldquotoxicrdquo in this assessment for health effectssummarized in Table 2 It is noted that out of the total number of 84 ASidentified as ldquotoxicrdquo there are 64 AS with either a slope factor forcarcinogenicity andor a reference dose provided more specificallyfor 30 AS a slope factor and for 52 AS a reference dose are reportedThe slope factor is defined as ldquoan upper bound approximating a 95confidence limit on the increased cancer risk from lifetime exposureto an agentrdquo (US EPA Glossary 2008) This estimate is usuallyexpressed in units of proportion (of a population) affected per mgkgday Reference dose is an estimate (with uncertainty spanningperhaps an order of magnitude) of a daily oral exposure to the human

Table 5Number of AS with known slope factors and reference doses concerning the 84 ASidentified in this study as ldquotoxicrdquo and 52 AS characterized as ldquocarcinogenicrdquo (IRIS 2008US EPA 2008)

Action AS with slopefactors

AS with referencedoses

CarcinogenicAS

Totaltoxic AS

TotalAS

Fungicides 15 22 24 32 78Herbicides 9 15 14 25 87Insecticides 5 13 13 24 66Plant growthregulators

1 1 1 2 16

Various ndash 1 ndash 1 8Unknown ndash ndash ndash ndash 5Not found ndash ndash ndash ndash 16Total 30 52 52 84 276

Table 6ldquoCut-offrdquo criteria for the approval of active substances (included in the new proposal forEU Regulation concerning placing of plant protection products in the market)(Commission of the European Communities 2006)

Active substances (Annex II 36ndash37) Candidate for substitution (Annex II 4)ab

Classified in accordance with theprovisions of Directive 67548EEC asmutagen category 1 or 2

ADI ARfD or AOEL are significantlylower than those of the majority of theapproved active substances

Classified in accordance with theprovisions of Directive 67548EEC ascarcinogen category 1 or 2 unless theexposure to humans is negligible

Two of the criteria to be considered as aPBT substance

Classified in accordance with theprovisions of Directive 67548EEC astoxic for reproduction category 1 or 2unless the exposure to humans is negligible

Developmental neurotoxic orimmunotoxic effects high potential riskfor groundwater

Considered to have endocrine disruptingproperties unless the exposure to humansis negligible

It contains a significant proportion ofnon-active isomers

Considered to be a persistent organic pollutant(POP)

Classified in accordance with theprovisions of Directive 67548EEC ascarcinogen category 1 or 2

Table 4Carcinogenicity characterization toxic non toxic and not listed ldquonewrdquo active substancesclassified according to their action (US EPA 2008)

Action Non toxic Not listed a Toxic Total

Fungicides 11 14 2 27Herbicides 8 19 4 31Insecticides 8 6 3 17Plant growth regulators 1 2 0 3Various 0 1 0 1Unknown 0 1 2 3Total 28 43 11 82



population (including sensitive subgroups) that is likely to be withoutan appreciable risk of deleterious effects Reference doses derive fromNOAELLOAEL2 values by applying several uncertainty factors Out ofthe remaining 20 AS characterized as ldquotoxicrdquo seven (7) have at leasttwo health effects

4 Comparison with literature assessments regarding the numberof approved active substances

New criteria were adopted by the European Council in August2008 concerning the new Regulation of placing plant protectionproducts on the market which will replace the existing legislation(Council Directive 91414EEC) In light of these criteria the SwedishChemicals Agency (KemI) and the UK Pesticide Safety Directorate(PSD) proceeded with preliminary assessments of the impact ofthese criteria on the number of the approved active substances(KemI 2008 PSD 2008) The establishment of the so called ldquocut-offrdquocriteria which are based on hazard identification rather than riskassessment concern a significant number of approved AS which arenow threatened to be withdrawn from Annex I of the 91414EECDirective It is noted parenthetically that recent studies examinedthe benefits of the above cut-off criteria on human health and theenvironment (Guarinoni et al 2008 Blainey et al 2008)

KemI issued in September 2008 a report regarding a preliminaryinterpretation of the new EU ldquocut-offrdquo criteria for approval of activesubstances in plant protection products The new ldquocut-offrdquo criteriaexamined (points 362 to 364 and 37 of Annex II of newRegulation) as well criteria for AS candidate for substitution(Annex II 4 of the new Regulation) are summarized in Table 6Among the criteria included in the new proposal KemI attemptedalso to interpret criteria related to endocrine disruption which arenot yet precisely defined at the European Community level A totalnumber of 271 AS were considered in the study These are thesubstances included in Annex I of 91414EEC Directive (stages 1 to4) as well as a number of substances with decision pending (stage3) Out of these 271 substances 23 (8 herbicides 11 fungicides 3insecticides and 1 plant growth regulator) meet the ldquocut-offrdquo criteriaof Annex II (36ndash37) and may therefore be removed Out of these 23substances 7 substances have been identified as carcinogenicmutagenic and toxic for reproduction (CMR category 1 or 2) 11have been classified as endocrine disruptors (ED) and 4 substances

2 No-observed-adverse-effect level (NOAEL) The highest exposure level at whichthere are no biologically significant increases in the frequency or severity of adverseeffect between the exposed population and its appropriate control some effects maybe produced at this level but they are not considered adverse or precursors of adverseeffects (US EPA 2008 Glossary) Lowest-observed-adverse-effect level (LOAEL) Thelowest exposure level at which there are biologically significant increases in frequencyor severity of adverse effects between the exposed population and its appropriatecontrol group (US EPA 2008 Glossary)

have been identified as persistent bio-accumulating and toxic orvery persistent and very bio-accumulating (PBTvPvB) or persistentorganic pollutants (POP) (KemI 2008)

Another assessment was made in UK by the Pesticides SafetyDirectorate (PSD) an Agency of the Health and Safety Executivewhich among other tasks aims to harmonise pesticide regulationwithin the European Community The PSD assessment dealt withthe impact of various sets of provisions reflecting various stagesin the EC negotiation process In total 278 substances have beenexamined whereas in a previous assessment (May 2008) 286 ASwere considered (PSD 2008) This reduction is due to the fact that 8substances are not included in Annex I of Directive 91414EEC anymore Substances that are marked as ldquoapproval pendingrdquo and thosefrom stage 4 were excluded from the assessment The 278substances have been examined according to the approval criteria

Considered to be a persistent bioaccumulatingand toxic (PBT) substance

Classified in accordance with theprovisions of Directive 67548EEC astoxic for reproduction category 1 or 2

Considered to be a very persistent verybioaccumulating substance (vPvB)

Endocrine disrupting properties thatmay cause adverse effect in humans

a By way of derogation from Article 5 and Article 14(2) an active substancecomplying with the criteria provided for in Article 4 shall be approved for a period notexceeding seven years where other already approved active substances are significantlyless toxic for consumers or operators or present significantly fewer risks for theenvironment The assessment shall take account of the criteria laid down in point 4 ofAnnex II Such a substance is referred to hereinafter as a lsquocandidate for substitutionrsquo

b ADI acceptable daily intake ARfD acute reference dose AOEL acceptable operatorexposure level

Table 7Summary of active substances (AS) identified as toxic by KemI (2008) PSD (2008) andthe present study grouped according to action

Assessed by Total ASexamined

Number of toxic ASa Total numberof toxic ASH F I Other

KemI 271 8 11 3 1 23PSD 278 14 16 28 2 60Present study 276 25 32 24 3 84

a H F and I designate herbicides fungicides and insecticides respectively


adopted in the Commission proposal as well as in the EuropeanParliaments Environment Public Health and Food Safety (ENVI)Committees second reading report adopted in early November2008 The results of this assessment show that up to 14 of thesubstances assessed should be withdrawn This percentage is similarto the 15 estimated in the Commissions original proposal (PSD2008) Other noteworthy comments made in that report (PSD2008) are as follows i) The amendments proposed by the ENVICommittee on the Council common position would increase thenumber of AS to be withdrawn to approx 23 of the substancesassessed by the UK PSD ii) Based on the proposed changes by theENVI Committee regarding the developmental neurotoxicity andimmuno-toxicity criteria a more detailed assessment would berequired which would have greater negative impact on the list ofapproved insecticides

Unlike the above two assessments the present assessment doesnot take into account the ldquocut-offrdquo criteria adopted in the Commis-sion proposal or the amendments proposed by the ENVI Committeesince the objective of this study was to provide a comprehensive yetrealistic estimate of the likely evolution of the pesticide mix used inthe EU as the basis for exposure characterization in health impactassessment 276 AS have been characterized in relation mainly tocarcinogenicity as well as to acute toxicity developmental repro-ductive and neurological disorders Although Directive 67548EECprovides useful information on pesticides characterization theassessment in this study is based on well-known databases selectedby a thorough literature survey which are regarded as reliable andappropriate for a health impact assessment It should be stressedthat the evaluation presented in this study in contrast to the othertwo includes the ldquoexistingrdquo active substances from the four stages ofthe European evaluation programme as well as the ldquonewrdquo activesubstances introduced since July 1993 This evaluation shows that 72out of 194 (ldquoexistingrdquo AS) and 12 out of 82 AS (ldquonew inrdquo AS) have atleast one adverse health effect characterization indicating that ahigher percentage of AS might be withdrawn compared to thepercentages from the aforementioned studies Indeed a number ofactive substances that are identified as ldquotoxicrdquo in the present study(according to the databases examined) are not included in the toxicsubstances of the other two studies and vice versa This is evident byinspecting Tables A1 and A2 in Appendix A where one observes thatonly 14 and 37 toxic AS are common between the present andthe KemI and PSD studies respectively Moreover only 11 AS arecharacterized as hazardous or toxic in all three studies Finally itshould be mentioned that there are cases in which the characteriza-tion used for these 11 AS (common in the three studies) is not thesame in the respective lists The total number of AS examined andthe results obtained by the three assessments are summarized inTable 7

5 Discussion and conclusions

The impact of EU legislation on marketed pesticides which wasenacted in 1993 (with Directive 91414EEC) and lasted effectivelyuntil December 2008 became very significant right at the turn of

the century indeed very drastic changes have occurred in the list oflegally marketed pesticides over the past eight years (2001ndash2008)During this period approximately 704 active substances (AS) werebanned of which 26 were insecticides 23 herbicides and 17 fungicides The total number of legally marketed AS in the EuropeanUnion at present is 276 of which 194 existed before year 1993 and82 are new AS introduced in the market during the past 15 yearsover which the assessment of all AS took place There are alsoanother 31 AS under evaluation at present The list of currentlyauthorized 276 AS includes 24 insecticides 32 herbicides and 28fungicides Toxicity characterization of these substances was carriedout by retrieving relevant information from reliable sources such asthe US EPA WHO PAN and IARC

This analysis suggests that a significant number of activesubstances could indeed be characterized as toxic 84 out of 276 AShave at least one positive effect chronic andor acute Specificallythere are 30 AS with reported linear dosendashresponse relationships andwith the corresponding slope factors defined for carcinogenicity and52 with reference doses out of the remaining 20 AS characterized asldquotoxicrdquo seven (7) have at least two health effects Although most ofthe health impact studies deal with chronic effects that occur fromexposure to small doses of pesticides over an extended period of timetheir acute health effects cannot be ignored (Goel and Aggarwal2007) For example pesticides poisoning is apparently a public healthproblem in the United States where more than 300 thousandexposures to pesticides were reported to poison centers for the 5-year period 1985 to 1990 (Klein-Schwartz and Smith 1997) Never-theless in the USA and the rest of the industrialized world theproblem of acute pesticide poisoning is considered to be under control(Leverton et al 2007) and the main focus of attention is on chroniceffects of pesticides that have a latency period of 10 to 15 years Themajority of active substances that are characterized as toxic arefungicides regarding chronic effects whereas mainly some insecti-cides are responsible for acute health effects Moreover a rather largenumber of active substances have been associated withmore than onehealth effect It should be also pointed out that for a significantnumber of approved pesticides the toxicity data in the open literatureare either inadequate or totally unavailable thus no toxicityassessment has been made for these AS In summary there is seriousconcern especially in relation to ldquonewrdquo AS as well as to those to beapproved in the near future that there may not be enough scientificinformation in the open literature (ie toxicological and otherproperties dosendashresponse functions) that is necessary to carry outmeaningful health impact assessment studies

The mean rate of introduction to the market of new compoundsduring the past 15 years is approximately five (5) AS per year Atthis rate one may expect at most an additional 80 to 90 new AS toenter the market over the next 15 years Furthermore according tothe new legislation (Commission of the European Communities2006) all currently marketed AS will be re-assessed which willprobably lead (depending on the criteria set) to withdrawal of an asyet undetermined number Therefore on the basis of present trendsit appears that the list of available ASwill not be greatly enriched overthe next 10ndash15 years However in parallel there is growing concernon the part of key stakeholders (ie farmers pesticides expertspesticide producers associations etc) that there is likely inadequatepest control with the presently available AS that may lead toincreased resistance by some pests with possibly serious negativeeffects on crop yield and even on human health Along these linessignificant reaction to current pesticide legislation by the aforemen-tioned stakeholders that has already gained momentum (eg Clarke2008) might counterbalance the tendency to further reduce the listof approved AS However other groups of stakeholders holdingopposite views (eg consumers general public) may tend to play anequally significant role in shaping policies associated with pesticidesConsequently it is increasingly important to develop better means of


communicationwith the public regarding these issues including therisk analysis process risk management and related decisions (vanDijk et al 2008)

Regarding approved AS the current situation and trends that areshaped by EU legislation appear to have a significant impact on theconditions as well as on the approach to be taken in performing healthimpact assessment (HIA) studies involving pesticides As noted abovea key characteristic of such studies is the significant latency of healtheffects due to rather long-time human exposure to low concentrationsof pesticides The fact that a very large number (~704) of the mosttoxic AS were withdrawn over the past 9 years implies that the resultsof epidemiological type HIA studies of the past (where the currentlybanned toxic AS unavoidably influenced the outcome) should beinterpreted with extra caution especially for drawing conclusionsabout the present day pesticide health impact Similarly ldquoexposurendashresponserdquo functions extracted from epidemiological studies of thepast should be carefully assessed to ensure that the AS used wererelevant to new or future HIA studies for example that these AS wereof equivalent toxicity or chemical class similar to those presentlyused For this not only do we need to assess the chemical family andstructure of the AS against known quantitative structurendashactivityrelationships (QSARs) and chemical grouping methods but also toconsider the mode and mechanism of action for the determination oftoxicity equivalents AS with different mechanisms of action andvastly different stereo-chemical configuration of the active groupscannot be clustered in the same chemical group or described interms of toxic equivalence especially when complex mechanismssuch as endocrine disruption resulting in adverse health effects areconsidered

The time frame as well as the particular AS to be considered innew HIA studies should be carefully chosen in view of the latency ofpesticide health effects and the drastic AS changes after year 2000Taking into account these factors appears to necessitate a certainprioritization of AS in terms of their properties ie toxicity volatilityreactivity or persistence For instance it may be still of interest toinclude in a newHIA the studyof thoseAS and theirmetaboliteswhich(although banned and withdrawn) are characterized by persistenceand are still detected in environmental compartments renderingthemselves amenable to human exposure

Another quite significant aspect relevant to this discussion is theimpact of the drastic changes of approved AS on the type of future HIAstudies involving pesticides Considering that a major goal of suchstudies is to informdecisionmaking (Briggs 2008) on relevant policies(eg land use subsidies ldquooptimizationrdquo in selecting crop types etc)the following comments may be made

Diagnostic type studies (Briggs 2008) of health impact (inevitablyinfluenced by the already banned toxic AS) may have results oflimited direct applicability for obvious reasons Nevertheless onemight derive some benefits from such studies at the methodologicallevel for instance if emphasis in these studies is put on genericfeatures or properties of AS (eg common biological activity ofseveral AS good correlation of chemical formulaclass withspecific health effect) the results may be useful for prognostic-typeHIA studies

Prognostic-type HIA studies are in general appropriate to assesspolicy scenarios that involve pesticide usage directly or indirectlyThe implications and impact of the aforementioned drastic changesin approved AS on prognostic-type studies are evident Here againthe time frame of such studies for pesticides extended into thefuture should be carefully selected to minimize uncertainty whichappears to be very significant at the outset In this respect studiesof relatively short time frame imposed by the type of cohort groupexamined (eg young children) are more appropriate for acute andmedium-term health effects The respective uncertainty in theestimation of the relevant human exposure pattern is much lowerthan the uncertainty associated with studies on latent effects (eg

estimates of lifelong probability of cancer or of endocrinedisruption) considering also the possible future changes inapproved and applied AS over a long time period For long-termeffects after chronic and repeated exposure to pesticides acombination of toxicologically-derived dosendashresponse relation-ships mechanistic modeling of bio-kinetics based on humanphysiology and carefully selected clinical and epidemiologicaldata would seem more appropriate than the sheer use ofepidemiology

Preparing an appropriate ldquolist of pesticides of the futurerdquo to beemployed in prognostic HIA studies should be of prime concernCareful assessment of the present list as well as of current trendsregarding rate of AS approval (as outlined above) should allowreasonable projections in preparing such a list where the majorclasses of approved AS (eg carbamates pyrethroids organopho-sphates) would comprise the largest part

It is also worth considering whether it is preferable or evenpossible for prognostic HIA studies to be based on epidemiologicalrather than on toxicological exposurendashresponse functions or similardata At present it appears that there is an inherent drawback of thelimited epidemiologically-derived exposurendashresponse data existingin the literature due to the fact that they involve (toxic) AS used inthe past most of which have been already withdrawn Thus unlessconcepts of equivalent toxicity of (past and presently used)pesticides chemical grouping or similar generalizations areemployed for data (re-)interpretation such epidemiological studiesmight be of questionable usefulness For these the criteria outlinedabove should be considered Therefore one may conclude that HIAstudies based on available toxicological data are preferableespecially the ones that lead toward the integrated use of toxi-cological and chemical structure data to reveal and assess themechanism of action Such data may effectively support the quan-titative estimation and even reduction of the uncertainty involved inthe assessment

There are finally two other issues related to exposure ofEuropean population to pesticides and their residues The first isoccasionally referred to as ldquothe circle of poisonrdquo (Weir andSchapiro 1981 Galt 2008) whereby pesticide AS banned in theEU may continue to be manufactured there (or in other parts of theworld) and exported to developing countries if such pesticides areused on crops imported back into the EU as is often the case theypose a significant risk to consumers by remaining as residues onfood products It appears that only adequate monitoring wouldensure public protection and offer some relevant data for HIAstudies The second issue relates to pesticides still used in the EUeven though they have been banned This might be ldquolegallyrdquo donewhen companies and stores are allowed to sell these products(available in their shelves) over a certain grace period Additionallyillegal sale of banned AS is also known to take place at least insome parts of Europe (ECPA 2008) At the level of HIA studieslittle can be done to account for such factors (ie AS residues onimported food and illegal marketing) when their geographicalscope is at local national or regional (eg European) levels Healthimpact assessment models taking into account global trade andregional agricultural practices alike might be developed for thispurpose

Acknowledgements

This work is co-funded by the European Commission through theintegrated projects INTARESE (with the participation of CERTH)HEIMTSA and NO MIRACLE (with the participation of the JRC) underthe 6th Framework Programme for Research and TechnologicalDevelopment Nonetheless the opinions expressed in this paper arethe sole responsibility of the authors and they do not reflect theofficial position of the European Commission

Table A1Detailed list of 72 existing active substances in Annex I (Council Directive 91414EEC 1991) with at least one adverse health effect

No Active substance Action a

(PAN)Chemical class(PAN)

Acute toxicity(WHO)

Carcinogenicity(IARC)

Carcinogenicity(US EPA)b

EndocrineDisruption(PAN)

Reproductive anddevelopmentaltoxicity (PAN)

KemIc PSDc

Existing Active substances1 Benfluralin H 26-Dinitroaniline Unclassified Not listed Possible Not listed Not listed2 Fluazinam F 26-Dinitroaniline Not listed Not listed Possible Not listed Not listed3 Pendimethalin F 26-Dinitroaniline III Slightly hazardous Not listed Possible (C) Yes Not listed

4 Propyzamide H Amide Unclassified Not listed Probable (B2) Not listed Not listed5 Difenoconazole-M F Azole III Slightly hazardous Not listed Possible (C) Not listed Not listed6 Imazalil

(aka enilconazole)F Azole II Moderately

hazardousNot listed Probable Not listed Yes

7 Propiconazole F Azole II Moderatelyhazardous

Not listed Possible (C) Not listed Yes

8 Tebuconazole F Azole III Slightly hazardous Not listed Possible (C) Not listed Not listed

9 Triadimenol F Azole III Slightly hazardous Not listed Possible (C) Yes Not listed10 Carbendazim F Benzimidazole Unclassified Not listed Possible (C) Yes Not listed

11 Fuberidazole F Benzimidazole II Moderatelyhazardous

Not listed Not listed Not listed Not listed

12 Thiabendazole F Benzimidazole Unclassified Not listed Probable Not listed Yes13 Thiophanate-methyl F Benzimidazole precursor Unclassified Not listed Probable Not listed Yes14 Oxadiazon H Oxidiazoled Unclassified Not listed Probable Not listed Yes15 Fipronil I Pyrazole II Moderately

hazardousNot listed Possible (C) Yes Not listed

16 Tebufenpyrad A Pyrazole III Slightly hazardous Not listed Possible Not listed Not listed17 Amitrole (aminotriazole) H Triazoled Unclassified Unclassified Probable (B2) Yes Not listed

18 Epoxiconazole F Triazoled Not listed Not listed Probable Not listed Not listed

19 Dicamba H Benzoic acid III Slightly hazardous Not listed Unclassified Not listed Yes20 Abamectin

(aka avermectin)A I Botanical Not listed Not listed Not likely Not listed Yes

21 Pyrethrins I Botanical Not listed Not listed Possible Not listed Not listed22 Imidacloprid I Chloro-nicotinyl II Moderately

hazardousNot listed Not likely Not listed Not listed

23 24-D H Chlorophenoxy acid or ester II Moderatelyhazardous

Possible Unclassified Yes Not listed

24 24-DB H Chlorophenoxy acid or ester III Slightly hazardous Possible Not likely Not listed Yes

25 Dichlorprop-P H PGR Chlorophenoxy acid or ester Not listed Possible Not listed Not listed Not listed

26 MCPA H Chlorophenoxy acid or ester III Slightly hazardous Possible Not likely Not listed Not listed

27 MCPB H Chlorophenoxy acid or ester III Slightly hazardous Possible Not listed Not listed Not listed

28 Mecoprop H Chlorophenoxy acid or ester III Slightly hazardous Possible Not listed Not listed Not listed

29 Mecoprop-P H Chlorophenoxy acid or ester III Slightly hazardous Possible Possible Not listed Not listed

30 Warfarin(aka coumaphene)

Ro Coumarin Ib Highly hazardous Not listed Not listed Not listed Yes

31 Tralkoxydim H Cyclohexenone derivative III Slightly hazardous Not listed Probable Not listed Not listed

32 Iprodione F Dicarboximide Unclassified Not listed Probable Yes Not listed

33 Dinocap F I Dinitrophenol derivative III Slightly hazardous Not listed Not likely Not listed Yes

34 Maneb F Dithiocarbamate Unclassified Unclassified Probable (B2) Yes Yes

35 Thiram F Dithiocarbamate III Slightly hazardous Unclassified Not likely Yes Yes

36 Mancozeb F Dithiocarbamate inorganic-zinc

Unclassified Not listed Probable (B2) Yes Yes

37 Metiram F Dithiocarbamate inorganic-zinc


38 Propineb F Dithiocarbamate inorganic-zinc

Unclassified Not listed Not listed Not listed Yes

39 Ziram F Dithiocarbamate inorganic-zinc

III Slightly hazardous Unclassified Possible Yes Yes

40 Formetanate I N-Methyl carbamate Ib Highly hazardous Not listed Not listed Not listed Not listed

41 Methiocarb(aka mercaptodimethur)

I Mo N-methyl carbamate Ib Highly hazardous Not listed Unclassified Not listed Not listed

42 Oxamyl I N N-methyl carbamate Ib Highly hazardous Not listed Not likely Not listed Not listed

43 Pirimicarb I N-methyl carbamate II Moderatelyhazardous

Not listed Probable Not listed Not listed

44 Molinate H Thiocarbamate II Moderatelyhazardous

Not listed Possible Not listed Yes

45 Prosulfocarb H Thiocarbamate II Moderatelyhazardous


46 Bromoxynil H Hydroxybenzonitrile II Moderatelyhazardous


47 Ioxynil H Hydroxybenzonitrile II Moderatelyhazardous


48 Clomazone H Isoxazolidinoned II Moderatelyhazardous

Not listed Not likely Not listed Not listed

49 Fenpropidin F Morpholined II Moderately Not listed Not listed Not listed Not listed

(continued on next page)

Appendix


Table A1 (continued)



Acute toxicity(WHO)





KemIc PSDc

hazardous50 Chlorpyrifos I N Organophosphorus II Moderately

hazardousNot listed Not likely Yes Not listed

51 Dimethoate I organophosphorus II Moderatelyhazardous


52 Ethoprophos I N Organophosphorus Ia ExtremelyHazardous


53 Fenamiphos(aka phenamiphos)

I N Organophosphorus Ib Highly hazardous Not listed Not likely Not listed Not listed

54 Phosmet I Organophosphorus II Moderatelyhazardous

Not listed Possible Not listed Not listed

55 Ethylene PGR Petroleum derivative Not listed Unclassified Not listed Not listed Yes56 alpha-Cypermethrin

(aka alphamethrin)I Pyrethroid II Moderately

hazardousNot listed Not listed Yes Not listed

57 beta-Cyfluthrin I Pyrethroid II Moderatelyhazardous

Not listed Not listed Yes Not listed

58 Cyfluthrin I Pyrethroid II Moderatelyhazardous

Not listed Not likely Yes Not listed

59 Cypermethrin I Pyrethroid Not listed Not listed Possible (C) Not listed Not listed

60 Deltamethrin I Pyrethroid II Moderatelyhazardous

Unclassified Not likely Yes Not listed

61 Esfenvalerate I Pyrethroid II Moderatelyhazardous


62 lambda-Cyhalothrin I Pyrethroid II Moderatelyhazardous

Not listed Unclassified Yes Not listed

63 Pyrimethanil F Pyrimidine Unclassified Not listed Possible (C) Yes Not listed64 Chlorothalonil F Substituted Benzene Unclassified Possible Probable (B2) Not listed Not listed65 Tolylfluanid F I Sulphamided Unclassified Not listed Probable Not listed Not listed66 Clofentezine A Tetrazine Unclassified Not listed Possible (C) Yes Not listed67 Captan F Thiophthalimide Unclassified Unclassified Probable (B2) Not listed Not listed68 Folpet F Thiophthalimide Unclassified Not listed Probable (B2) Not listed Not listed69 Metribuzin H Triazinone II Moderately

hazardousNot listed Unclassified Yes Yes

70 Daminozide PGR Unclassifiedd Unclassified Not listed Probable (B2) Not listed Not listed71 Diuron H Urea Unclassified Not listed Known Not listed Yes72 Linuron H Urea Unclassified Not listed Possible (C) Yes Yes

Comparison with the KemI and PSD study results (KemI 2008 PSD 2008)a H Herbicide I Insecticide F Fungicide PGR Plant Growth Regulator A Acaricide N Nematocide Ro Rodenticide Mo Molluscicideb Probable (B2) Possible (C) based on US EPAs classification of carcinogenicity between 1986 and 1996 (US EPA 2008)c Marks indicate identified adverse health effect caused by pesticides that are common between the present study and those performed by KemI and PSDd Chemical class and action of this AS are taken from FOOTPRINT database (FOOTPRINT 2008)

Table A2Detailed list of 12 ldquoNewrdquo active substances in Annex I (Council Directive 91414EEC 1991) with at least one adverse health effect

No Activesubstance

Actiona (PAN) Chemical class(PAN)

Acute toxicity(WHO)





KemIc PSDc

ldquoNew inrdquo active substances1 Boscalid F Anilide Not listed Not listed Possible Not listed Not listed2 Mepanipyrim F Bactericide wood

preservativedAnilinopyrimidined Unclassified Not listed Probable Not listed Not listed

3 Iprovalicarb Fd Carbamated Unclassified Not listed Probable Not listed Not listed4 S-Metholachlor H Chloroacetanilide III Slightly hazardous Not listed Possible (C) Yes Not listed5 Thiacloprid I Chloro-nicotinyl II Moderately

hazardousNot listed Probable Not listed Not listed

6 Isoxaflutole H Isoxazoled Not listed Not listed Probable Not listed Not listed7 Spiroxamin F Morpholined II Moderately


8 Thiamethoxam F I Neonicotinoidd Not listed Not listed Probable Not listed Not listed9 Pyraflufen-

ethylH Pyrazolylphenyl Not listed Not listed Probable Not listed Not listed

10 Kresoxim-methyl

F Strobin Not listed Not listed Probable Not listed Not listed

11 Sulfosulfuron H Sulfonylurea Not listed Not listed Probable Not listed Not listed12 Pymetrozine I Triazine Not listed Not listed Probable Not listed Not listed




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Arvanitoyannis IS Choreftaki S Tserkezou P An update of EU legislation (directives andregulations) on food-related issues (safety hygiene packaging technology GMOsadditives radiation labelling) presentation and comments Inter J Food Sci Technol2005401021ndash112

Arvanitoyannis IS Choreftaki S Tserkezou P Presentation and comments on EU legislationrelated to food industriesndashenvironment interactions sustainable development andprotectionof nature andbiodiversitymdashgeneticallymodifiedorganisms Inter J Food SciTechnol 200641813ndash32

Blainey M Ganzleben C Goldenman G Pratt I The benefits of strict cut-off criteria onhuman health in relation to the proposal for a regulation concerning plantprotection products Impact assessment commissioned by the European Parlia-ments Committee on the Environment Public Health and Food Safety 2008 Ref tocontract IPAENVIFWC2007-057C1SC2

Briggs DJ A framework for integrated environmental health impact assessment ofsystemic risks Environ Health 20087(61)

Britt JK Dwinell SE McDowell TC Matrix decision procedure to assess new pesticidesbased on relative groundwater leaching potential and chronic toxicity EnvironToxicol Chem 199211(5)721ndash8

Casida JE Quistad GB Golden age of insecticide research past present or future AnnRev Entomol 1998431-16

Clarke P EU scientists contest anti-pesticide legislation FWi Newsletters 2008available in httpwwwfwicoukArticles20081208113408eu-scientists-contest-anti-pesticide-legislationhtml

Cochrane WW The development of American agriculture a historical analysisUniversity of Minnesota Press Minneapolis 1979

Commission of the European Communities Proposal for a regulation of the EuropeanParliament and of the council concerning the placing of plant protection productson the market COM 2006 388 final Brussels 1272006 (available in httpeceuropaeufoodplantprotectionevaluationcom2006_0388en01pdf

Committee on the Future Role of Pesticides in US Agriculture Board on Agriculture andNatural Resources Board on Environmental Studies and Toxicology NationalResearch Council The future role of pesticides in US agriculture Washington DCNational Academy Press 2000 available in httpwwwnapeducatalog phprecord_id=9598toc

Council Directive 91414EEC of 15 July 1991 concerning the placing of plant protectionproducts on the market (available in httpwwweur-lexeuropaeu LexUriServLexUriServdouri=CELEX31991L0414ENHTML)

Daly H Doyen JT Purcell III AH In Introduction to insect biology and diversity 2nd EdNew York Oxford University Press 1998 p 279ndash300 Chapter 14

European Centre for Health Policy World Health Organization Regional Office forEurope Gothenburg consensus paper Health impact assessment main conceptsand suggested approach Brussels 1999 available in httpwwweurowhointdocumentPAEGothenburgpaperpdf

European Commission DG Health and Consumers Plant Health Plant Protection-Pesticide Residues-Legislation (available in httpeceuropaeufoodplantprotectionpesticideslegislation_enhtm)

European Crop Protection Association (ECPA Counterfeit pesticides across Europe2008 PP08RB17853 Brussels 27 August 2008 (available in httpwwwecpabefilesecpadocumentslive917853_Counterfeit Pesticides across Europe-Facts-Consequences and Actions neededpdf

European Food Safety Authority (EFSA Maximum residue levels (MRLs 2008aavailable in httpwwwefsaeuropaeuEFSAScientificPanelsPRAPER efsa_lo-cale-1178620753812_MaximumResidueLevelshtm

European Food Safety Authority (EFSA Pesticide risk assessment peer review unit(PRAPeR 2008b available in httpwwwefsaeuropaeuEFSA ScientificPanelsefsa_locale-1178620753812_PRAPERhtm

Fernandez-Cornejo J Jans S Smith M Issues in the economics of pesticide use inagriculture a review of the empirical evidence Rev Agric Econ 199820(2)462ndash88

Food and Agriculture Organization of the United Nations (FAO Programmesinternational code of conduct on the distribution and use of pesticides 2002November (available in httpwwwfaoorgWAICENTFAOINFO AGRICULTAGP AGPPPesticidCodeDownloadcodepdf

FOOTPRINT Creating tools for pesticide risk assessment and management in Europe2008 available in httpwwweu-footprintorgppdbhtml

Galt RE Beyond the circle of poison significant shifts in the global pesticide complex1976ndash2008 Global Environ Change 200818786ndash99

Goel A Aggarwal P Pesticide poisoning Natl Med J India 200720(4)182ndash91Guarinoni M Smith DG Perehudoff SK EUs proposed pesticide legislation promises

better environmental health Outlooks on Pest Management 200819(6)249ndash51Horticulture Week EU review threatens pesticide use Horticulture Week 2007

available in httpwwwhortweekcomnews793104Integrated Risk Information System (IRIS US EPA 2008 available in httpcfpubepa

govnceairisindexcfmInternational Agency for Research on Cancer (IARC) 2008 available in httpwww

iarcfrKemI Interpretation in Sweden of the impact of the ldquocut-offrdquo criteria adopted in the

common position of the council concerning the regulation of placing plantprotection products on the market (document 1111908) Sweden 2008

Klein-Schwartz W Smith GS Agricultural and horticultural chemical poisoningsmortality and morbidity in the United States Ann Emerg Med 199729(2)232ndash8

Leverton K Cox V Battershill J Coggon D Hospital admission for accidental pesticidepoisoning among adults of working age in England 1998ndash2003 Clin Toxicol(Philadelphia Pa 200745(5)594ndash7

McKinlay R Plant JA Bell JNB Voulvoulis N Endocrine disrupting pesticidesImplications for risk assessment Environ Int 200834(2)168ndash83

Miller GT Living in the Environment 12th Ed Belmont WadsworthThomsonLearning 2002

National Agricultural Chemicals Association (NACA From lab to labelmdashthe researchtesting and registration of agricultural chemicals 1993 Washington DC

PAN Pesticides Database Chemicals 2008 available in httpwwwpesticideinfo orgSearch_Chemicalsjsp

Pesticides Safety Directorate (PSD Revised assessment of the impact on crop protectionin the UK of the lsquocut-off criteriarsquo and substitution provisions in the proposedregulation of the European Parliament and of the council concerning the placing ofplant protection products on the market York UK 2008

Reportlinkercom Emerging trends and opportunities in the world pesticides market2008 available in httpwwwreportlinkercomp096695Emerging-Trends-and-Opportunities -in-the-World-Pesticides-Markethtml

Reynolds JD International pesticide trade is there any hope for the effective regulationof controlled substances Florida State University J Land Use amp Environ Law1997131 available in httpwwwlawfsuedujournalslanduse Vol131 REYNHTMl

Sanborn M Cole D Kerr K Vakil C Sanin KH Bassil K Systematic review of pesticidehuman health effects Canada The Ontario College of Family Physicians 2004

SANCO26922001 Working document of the Commission Services technical annex toreport from the Commission to the European Parliament and the council on theevaluation of the active substances of plant protection products 2001 of 25 Julyavailable in httpeceuropaeu foodplantprotectionresourcesppp01_ann_enpdf

Skinner JA Lewis KA Bardon KS Tucker P Catt JA Chambers BJ An overview ofthe environmental impact of agriculture in the UK J Environ Manage 199750(2)111ndash28

US Environmental Protection Agency (US EPA 2008 available in httpwwwepagovpesticides

US EPA Risk assessment portal Glossary 2008 available in httpwwwepagovriskglossaryhtm

vanDijk H Houghton J van Kleef E van derLans I RoweG Frewer L Consumer responsesto communication about food risk management Appetite 200850(2ndash3)340ndash52

Walker KR Ricciardone MD Jensen J Developing an international consensus on DDT abalance of environmental protection and disease control Int J Hyg Environ Heal2003206(4ndash5)423ndash35

Ware G Whitacre D The pesticide book 6th Ed A Meister Publication 2004Weir D Schapiro M Circle of poison pesticides and people in a hungry world San

Francisco CA Institute for Food and Development Policy 1981Willson HR Pesticide regulations Radcliffes IPM world textbook University of

Minnesota 1996 available in httpipmworldumneduchapterswillson htmWorld Health Organization (WHO The WHO recommended classification of pesticides

by hazard and guidelines to classification 2004 2005 available in httpwwwwhointipcspublicationspesticides_hazard_rev_3pdf

Worrall F Wooff DA Seheult AH Coolen FPA New approaches to assessing the risk ofgroundwater contamination by pesticides J Geol Soc 2000157(4)877ndash84


Centre for Health Policy and World Health Organization RegionalOffice for Europe 1999) Regarding pesticides many HIA studies havebeen carried out in the USA Europe and elsewhere in the past 15ndash20 years In Europe significant studies are also currently in progressin the context of large EU-funded projects1 (ie INTARESE HEIMTSANoMiracle) to assess health effects caused by various categories ofenvironmental pollutants including plant protection products whichare commonly referred to as ldquopesticidesrdquo a term used henceforth inthis paper Of paramount importance in such studies is the largevariety of Active Substances (AS) applied for plant protection andtheir toxicity characteristics

The following overview of pesticides regulatory evolution showsthat regarding available pesticides by action on target species (ieinsecticide fungicide herbicide etc) ndash henceforth to be referred to asldquoactionrdquo for simplicity ndash and number of AS employed in agriculturethe situation in the EUwas relatively stable in the last two decades ofthe 20th century However due to Community legislation thispicture changed drastically during the past 8ndash9 years The scope ofthis study is to review the impact of this legislation on the approvedfor marketing pesticides and to characterize their toxicity thusproviding information necessary for carrying out new HIA studies orappraising the results of existing ones furthermore to discuss thepossible impact of the greatly reduced number and the toxicity ofapproved AS on the type and proper design of HIA studies to becarried out in the near future A brief account is presented first of theevolution of legislation and regulatory measures concerning pesti-cide AS

Pesticides help control hundreds of weed species more than onemillion species of harmful insects and roughly 1500 plant diseases(Ware andWhitacre 2004 NACA 1993) Although they are at the topof the list of dangerous pollutants modern pesticides are fast-actingsome of them may be unique in their action against a specific pestthey can control large infestations they are generally easy to applyand lead to increased crop yield by reducing crop losses Overallpesticides seem to significantly contribute to human welfare (Wareand Whitacre 2004 NACA 1993) although human health risksassociated with the use of pesticides are distributed unequally amongvarious population groups Elemental sulphur still in use today as aninsecticide together with other inorganic chemicals such as arsenicmercury and lead are frequently referred as the ldquofirst generationrdquopesticides which were applied to crops for many centuries until thebeginning of the 20th century (Committee on the Future Role ofPesticides in US Agriculture 2000) The use of the first generationpesticides was largely abandoned because they were either tooineffective or too toxic showing also a great tendency to accumulatein soil to the point of inhibiting plant growth Moreover with thepassage of time pests became resistant and tolerant to thesepesticides Expanding agriculture to meet the needs of the growingpopulation necessitated the application of more effective pesticidesthus the ldquosecond-generationrdquo pesticides as they came to be knownwere developed comprising synthetic organic chemicals whichmadetheir debut in the 1930s (Committee on the Future Role of Pesticidesin US Agriculture 2000 Cochrane1979) Themodern era of pesticidesessentially beganwith the introduction in 1939 of the insecticide DDT(dichlorodiphenyl trichloroethane) The astonishing efficacy of DDT

1 The following are Integrated Projects funded by the European Commission

INTARESE Integrated Assessment of Health Risks of Environmental Stressors inEurope (information available at httpwwwintareseorg)HEIMTSA Health and Environment Integrated Methodology and Toolbox forScenario Assessment (available at httpwwwheimtsaeu)NoMiracle Novel Methods for Integrated Risk Assessment of Cumulative stressorsin Europe (available at httpnomiraclejrceceuropaeudefaultaspx)

led to the development of a variety of chlorinated hydrocarbons suchas gamma-lindane and toxaphene which were quickly adopted in theagricultural practice (Daly et al 1998) In the 1940s manufacturersalso began producing large amounts of other synthetic pesticides likethe organophosphates which despite their greater toxicity tomammals and other non-target species enjoyed considerable popu-larity because of their broad spectrum efficacy and rather low cost(Casida and Quistad 1998)

Pesticide use to date has increased 50-fold since 1950 andcurrently there are thousands of synthetic pesticide products madeup of more than 1000 different chemicals and combinations thereof(Miller 2002) Thus the pesticide market has turned into a multi-billion dollar one specialists in business information estimate that theglobal pesticide market surged in 2008 by 29 over the 2007 level of$407billion ndash to $524billion mdash a record increase that came at a timewhen a global financial crisis was in full swing (Reportlinker 2008)Arguably this trend was also the result of surging agriculturalcommodity prices which means that farmers were likely to spraymore expecting greater pesticide effectiveness and thus crop yield(Fernandez-Cornejo et al 1998) This growth trend seems to contra-dict the commonly expressed opinion that the future of pesticideusage is uncertain (Committee on the Future Role of Pesticides in USAgriculture 2000) This uncertainty is due to the increasing number oflegal actions of authorities mainly in the USA and Europe against thesecond generation of pesticides since these products are generallyconsidered to pose significant risks to human health and theenvironment (Walker et al 2003) Potential health risks identifiedin toxicological and epidemiological studies include cancer geneticmalformations neuro-developmental disorders and damage of theimmune system (Skinner et al 1997 Sanborn et al 2004 McKinlayet al 2008)

The urgent ban to major ldquosecond generationrdquo pesticides (DDT andother organochlorine compounds) for valid reasons (Walker et al2003) apparently created the need for a re-evaluation of pesticideapplicability and for the development of a legal framework regulat-ing their production and use By the end of the 1960s this needculminated in the creation of the Environmental Protection Agency(EPA) in the USA which was the first governmental agency takingactions against pesticide usage at that time The risks posed tohumans and the environment by the increased usage of syntheticpesticides was later recognised by the United Nations (UN) The UNGeneral Assembly in 1972 decided to establish the United NationsEnvironment Programme (UNEP) to ldquoserve as a focal point forenvironmental action and co-ordination within the UN systemrdquoUNEP together with the Food and Agriculture Organization (FAO)and the World Health Organization (WHO) promoted more sustain-able practices in replacing persistent organic pesticides withintegrated pest management (IPM) The latter comprises a numberof control techniques that inhibit the development of pest popula-tions keeping pesticides and other interventions to levels that areeconomically justified as well as safe for human health and theenvironment Following the regulatory initiatives of the US EPA andthe UN regarding pesticide usage and monitoring programmes ofpesticide residues in the ecosystem a number of developed countriesmoved later on in the same direction which resulted in a largenumber of different national regulations To deal with inconsisten-cies in regulations among countries an International Code ofConduct on the Distribution and Use of Pesticides was adopted bythe United Nations Food and Agriculture Organization in 1985 whichcreated voluntary standards of pesticide regulation for differentcountries (Willson 1996) The Code was updated in 1998 and 2002(FAO 2002) There are also other efforts and initiatives to improveregulation of international pesticide trade (Reynolds 1997)

Legislation at the European Community level dates back to 1976when Council Directive 76895EEC specified maximum levels forpesticide residues (MRLs) for 43 active substances in and on selected

















1 90 55 35 02 148 32 116 03 387 48 319 204 295 59 225 11Total 920 194 695 31






























Total ASexamined


















CarcinogenicAS

Totaltoxic AS

TotalAS


1 1 1 2 16
























































Acknowledgements





Acute toxicity(WHO)





KemIc PSDc




























































Appendix





Acute toxicity(WHO)





KemIc PSDc






























No Activesubstance


Acute toxicity(WHO)





KemIc PSDc









10 Kresoxim-methyl






References

































































1 90 55 35 02 148 32 116 03 387 48 319 204 295 59 225 11Total 920 194 695 31






























Total ASexamined


















CarcinogenicAS

Totaltoxic AS

TotalAS


1 1 1 2 16
























































Acknowledgements





Acute toxicity(WHO)





KemIc PSDc




























































Appendix





Acute toxicity(WHO)





KemIc PSDc






























No Activesubstance


Acute toxicity(WHO)





KemIc PSDc









10 Kresoxim-methyl






References




































































Total ASexamined


















CarcinogenicAS

Totaltoxic AS

TotalAS


1 1 1 2 16
























































Acknowledgements





Acute toxicity(WHO)





KemIc PSDc




























































Appendix





Acute toxicity(WHO)





KemIc PSDc






























No Activesubstance


Acute toxicity(WHO)





KemIc PSDc









10 Kresoxim-methyl






References




















































CarcinogenicAS

Totaltoxic AS

TotalAS


1 1 1 2 16
























































Acknowledgements





Acute toxicity(WHO)





KemIc PSDc




























































Appendix





Acute toxicity(WHO)





KemIc PSDc






























No Activesubstance


Acute toxicity(WHO)





KemIc PSDc









10 Kresoxim-methyl






References









































































Acknowledgements





Acute toxicity(WHO)





KemIc PSDc




























































Appendix





Acute toxicity(WHO)





KemIc PSDc






























No Activesubstance


Acute toxicity(WHO)





KemIc PSDc









10 Kresoxim-methyl






References




















































Acute toxicity(WHO)





KemIc PSDc




























































Appendix





Acute toxicity(WHO)





KemIc PSDc






























No Activesubstance


Acute toxicity(WHO)





KemIc PSDc









10 Kresoxim-methyl






References




















































Acute toxicity(WHO)





KemIc PSDc






























No Activesubstance


Acute toxicity(WHO)





KemIc PSDc









10 Kresoxim-methyl






References


















































References

















































Impact of European legislation on marketed pesticides — A view from the standpoint of health...

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