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        PESTICIDE RESIDUES IN FOOD - 1995


        Sponsored jointly by FAO and WHO
        with the support of the International Programme
        on Chemical Safety (IPCS)




        EVALUATIONS 1995

        PART II - TOXICOLOGY AND ENVIRONMENTAL



        Joint meeting of the
        FAO Panel of Experts on Pesticide Residues
        in Food and the Environment
        and the
        WHO Expert Group on Pesticide Residues
        Geneva, 18-27 September 1995

    This report contains the collective views of two international groups
    of experts and does not necessarily represent the decisions nor the
    stated policy of the Food and Agriculture Organization of the United
    Nations or the World Health Organization.

    The preparatory work for the toxicological and environmental
    evaluations of pesticides carried out by the WHO Core Assessment Group
    for consideration by the Joint FAO/WHO Meeting on Pesticide Residues
    in Food and the Environment is actively supported by the International
    Programme on Chemical Safety (IPCS) within the framework of the Inter-
    Organization Programme for the Sound Management of Chemicals.

    The International Programme on Chemical Safety (IPCS), established in
    1980, is a joint venture of the United Nations Environment Programme
    (UNEP), the International Labour Organisation (ILO), and the World
    Health Organization (WHO). The overall objectives of the IPCS are to
    establish the scientific basis for assessing the risk to human health
    and the environment from exposure to chemicals, through international
    peer-review processes, as a prerequisite for the promotion of chemical
    safety, and to provide technical assistance in strengthening national
    capacities for the sound management of chemicals.

    The Inter-Organization Programme for the Sound Management of Chemicals
    (IOMC) was established in 1995 by UNEP, ILO, the Food and Agriculture
    Organization of the United Nations, WHO, the United Nations Industrial
    Development Organization, and the Organisation for Economic Co-
    operation and Development (Participating Organizations), following
    recommendations made by the 1992 United Nations Conference on
    Environment and Development to strengthen cooperation and increase
    coordination in the field of chemical safety. The purpose of the IOMC
    is to promote coordination of the policies and activities pursued by
    the Participating Organizations, jointly or separately, to achieve the
    sound management of chemicals in relation to human health and the
    environment.

    IPCS gratefully acknowledges the assistance of Mrs E. Heseltine, St
    Léon-sur-Vézère, France, for editing these monographs.

    ISBN 92 4 1665 11 4

    (c) World Health Organization 1996

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    publication do not imply the expression of any opinion whatsoever on
    the part of the Secretariat of the World Health Organization
    concerning the legal status of any country, territory, city or area or
    of its authorities, nor concerning the delimitation of its frontiers
    or boundaries.

    The mention of specific companies or of certain manufacturers'
    products does not imply that they are endorsed or recommended by the
    World Health Organization in preference to others of a similar nature
    that are not mentioned. Errors and omissions excepted, the names of
    proprietary products are distinguished by initial capital letters.

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    TABLE OF CONTENTS

    List of participants

    Abbreviations

    Introduction

    Toxicological evaluations
         Benomyl
         Captan (addendum)
         Carbendazim
         Fenarimol*
         Fenpyroximate*
         Fenthion
         Flusilazole
         Folpet
         Haloxyfop*
         Iprodione (addendum)
         Monocrotophos (addendum)
         Parathion (addendum)
         Parathion-methyl (addendum)
         Piperonyl butoxide
         Quintozene
         Thiophanate-methyl
         Vinclozolin

    Environmental evaluations
         Carbendazim, benomyl, and thiophanate-methyl
         Fenarimol
         Fenthion

    Annex I.   Reports and other documents resulting from previous Joint
               Meetings of the FAO Panel of Experts on Pesticide Residues
               in Food and the Environment and WHO Expert Groups on
               Pesticide Residues

    Annex II.  Corrigenda to previous JMPR toxicological evaluations

              

    * First full evaluation
    

    1995 Joint Meeting of the FAO Panel of Experts on Pesticide Residues
    in Food and the Environment and the WHO Expert Group on Pesticide
    Residues

    Geneva, 18-27 September 1995

    PARTICIPANTS

     Toxicological Core Assessment Group

    Dr A.L. Black, Medical Services Adviser in Toxicology, Department of
         Human Services and Health, Canberra ACT, Australia

    Professor J.F. Borzelleca, Pharmacology, Toxicology, Medical College
         of Virginia, Virginia Commonwealth University, Richmond, VA,
         United States  (Chairman)

    Dr P. Fenner-Crisp, Acting Deputy Director, Office of Pesticide
         Programs, US Environmental Protection Agency, Washington DC,
         United States  (Rapporteur)

    Dr A. Moretto, Istituto di Medicina del Lavoro, Università di Padova,
         Padova, Italy

    Professor O. Pelkonen, Department of Pharmacology and Toxicology,
         University of Oulu, Oulu, Finland

    Professor A. Rico, Biochemistry-Toxicology, Physiopathology and
         Experimental Toxicology Laboratory, Ecole Nationale Vétérinaire,
         Toulouse, France

    Dr P.-P. Yao, Professor of Toxicology, Institute of Occupational
         Medicine, Ministry of Health, Beijing, China

     Environmental Core Assessment Group

    Professor D. Calamari, III Faculty of Sciences, University of Milan,
         Varese, Italy

    Dr S. Dobson, Institute of Terrestrial Ecology, Monks Wood,
         Huntingdon, Cambridgeshire, United Kingdom  (Vice-Chairman)

    Dr P.E.T. Douben, Her Majesty's Inspectorate of Pollution, London,
         United Kingdom  (Rapporteur)

    Dr J. Herkovits, Programa Seguridad Quimica, Instituto de Ciencias
         Ambientales y Salud, Buenos Aires, Argentina

    Dr L. Samsoe-Petersen, VKI Water Quality Institute, Horsholm, Denmark

    Dr J.H.M. Temmink, Department of Toxicology, Wageningen Agricultural
         University, Wageningen, Netherlands

     FAO Expert Group on Pesticide Residues

    Dr A. Ambrus, Budapest Plant Health and Soil Conservation Station,
         Budapest, Hungary  (Rapporteur)

    Dr U. Banasiak, Federal Biological Research Centre for Agriculture and
         Forestry, Kleinmachnow, Germany

    Mr S. Crossley, Pesticide Safety Division, Kings Pool, York, United
         Kingdom

    Mr D.J. Hamilton, Department of Primary Industries, Indooroopilly,
         Brisbane, Queensland, Australia

    Mr N.F. Ives, Health Effects Division, US Environmental Protection
         Agency, Washington DC, United States  (Vice-Chairman)

    Mrs E. Masoller, Servicios de Laboratorios, Ministerio de Ganaderia,
         Agricultura y Pesca, Montevideo, Uruguay

    Dr D. Murphy, National Registration Authority, Canberra ACT, Australia

    Mr T. Sakamoto, Plant Protection Division, Ministry of Agriculture,
         Forestry and Fisheries, Tokyo, Japan

     Secretariat

    Dr E. Bosshard, Federal Office of Public Health, Food Science
         Division, Schwerzenbach, Switzerland  (WHO Temporary Adviser)

    Dr G. Burin, Technology Sciences Group, Washington DC, United States
          (WHO Temporary Adviser)

    Dr P.J. Campbell, Pesticides Safety Directorate, Ministry of
         Agriculture, Fisheries and Food, Kings Pool, York, United Kingdom
          (WHO Temporary Adviser)

    Mr D.J. Clegg, Carp, Ontario, Canada  (WHO Temporary Adviser)

    Dr W.H. van Eck, Food and Product Safety Division, Ministry of Health,
         Welfare and Sport, Rijswijk, Netherlands  (Chairman, Codex
          Committee on Pesticide Residues)

    Dr K. Fujimori, Division of Pharmacology, Biological Safety Research
         Center, National Institute of Health Sciences, Ministry of Health
         and Welfare, Tokyo, Japan  (WHO Temporary Adviser)

    Dr R. Hailey, Environmental Toxicology Program, National Institute of
         Environmental Health Sciences, Research Triangle Park, North
         Carolina, United States  (WHO Temporary Adviser)

    Dr J.L. Herrman, Assessment of Risk and Methodologies, International
         Programme on Chemical Safety, World Health Organization, Geneva,
         Switzerland  (WHO Joint Secretary)

    Mrs E. Heseltine, Communication in Science, St Léon-sur-Vézère, France
          (WHO Consultant)

    Mrs P.H. van Hoeven-Arentzen, National Institute of Public Health and
         Environmental Protection, Bilthoven, Netherlands  (WHO Temporary
          Adviser)

    Dr F.-W. Kopisch-Obuch, Pesticide Group, Plant Protection Service,
         Food and Agricultural Organization, Rome, Italy  (FAO Joint
          Secretary)

    Dr J.-J. Larsen, Head, Department of General Toxicology, Institute of
         Toxicology, National Food Agency of Denmark, Soborg, Denmark
          (WHO Temporary Adviser)

    Dr J.B.H.J. Linders, National Institute of Public Health and
         Environmental Protection, Bilthoven, Netherlands  (WHO Temporary
          Adviser)

    Dr S. Ma, Health Evaluation Division, Pest Management Regulatory
         Agency, Tunney's Pasture, Ottawa, Ontario, Canada  (WHO
          Temporary Adviser)

    Mr A.F. Machin, London, United Kingdom  (FAO Consultant)

    Dr D. McGregor, Unit of Carcinogen Identification and Evaluation,
         International Agency for Research on Cancer, Lyon, France

    Dr M. Morrow, Health Effects Division, Office of Pesticide Programs,
         Environmental Protection Agency, Washington DC, United States
          (WHO Temporary Adviser)

    Dr G. Moy, Food Safety Unit, Division of Food and Nutrition, World
         Health Organization, Geneva, Switzerland

    Mr R.C. Petrie, Ecological Effects Branch, Environmental Fate and
         Effects Division, Environmental Protection Agency, Washington DC,
         United States  (WHO Temporary Adviser)

    Dr R. Plestina, Poisonings Prevention and Treatment, International
         Programme on Chemical Safety, World Health Organization, Geneva,
         Switzerland

    Dr E.M.B. Smith, Assessment of Risk and Methodologies, International
         Programme on Chemical Safety, World Health Organization, Geneva,
         Switzerland

    Mrs A. Sundén-Byléhn, International Register of Potentially Toxic
         Chemicals, United Nations Environment Programme, Châtelaine,
         Switzerland

    Dr G. Vettorazzi, International Toxicology Information Centre, San
         Sebastian, Spain  (WHO Temporary Adviser)

    Mr M. Watson, Risk Evaluation Branch, Pesticides Safety Directorate,
         Ministry of Agriculture, Fisheries and Food, Kings Pool, York,
         United Kingdom  (WHO Temporary Adviser)

    Dr Y. Yamada, Food Standards Officer, Joint FAO/WHO Food Standards
         Programme, Food and Nutrition Division, Food and Agriculture
         Organization of the United Nations, Rome, Italy

    Abbreviations used

    ADI       acceptable daily intake

    a.i.      active ingredient

    BrDU      5-bromo-2'- deoxyuridine

    bw        body weight

    CCPR      Codex Committee on Pesticide Residues

    CKD       cyclin-dependent kinase

    DMSO      dimethyl sulfoxide

    DT50      dissipation half-life

    EC50      median effective concentration in relation to a 50% change
              in a parameter or to a concentration causing a particular
              effect in 50% of the tested population

    F0        parental generation

    F1        first filial generation

    F2        second filial generation

    5-HBC     5-hydroxybenzimidazol-2-ylcarbamate

    hCG       human chorionic gonadotropin

    HPLC      high-performance liquid chromatography

     hprt      hypoxanthine-guanine phosphoribosyl transferase gene

    IIPCS     International Programme on Chemical Safety

    JECFA     Joint FAO/WHO Expert Committee on Food Additives

    JMPR      Joint FAO/WHO Meeting on Pesticide Residues

    LC50      median lethal concentration

    LD50      median lethal dose

    LOAEL     lowest-observed-adverse-effect level

    MATC      maximal acceptable toxicant concentration

    NAD       nicotinamide adenine dinucleotide

    NADH      reduced nicotinamide adenine dinucleotide

    NADP      nicotinamide adenine dinucleotide phosphate

    NADPH     reduced nicotinamide adenine dinucleotide phosphate

    NOAEL     no-observed-adverse-effect level

    NOEC      no-observed-effect concentration

    NR        not reported

    P450      cytochrome P450

    PCNA      proliferating cell nuclear antigen

    PEC       predicted environmental concentration

    ppm       parts per million

    S9        9000 × g supernatant fraction

    SD        standard deviation

    TER       toxicity:exposure ratio

    TLC       thin-layer chromatography

    TOCP      tri- ortho-cresol phosphate

    Tween 80  polyoxyethylenesorbitan monooleate

    v/v       volume per volume

    WP        wettable powder

    w/v       weight per volume

    w/w       weight per weight

    Introduction

         The toxicological and environmental monographs and monograph
    addenda contained in this volume were prepared by a WHO Core
    Assessment Group that met with the FAO Panel of Experts on Pesticide
    Residues in Food and the Environment in a Joint Meeting on Pesticide
    Residues (JMPR) in Geneva, Switzerland, on 18-27 September 1995.

         Fourteen of the compounds considered by the WHO Expert Group at
    this Meeting had been evaluated at earlier meetings. For five of
    these, captan, iprodione, monocrotophos, parathion, and parathion-
    methyl, only information received since the previous evaluation is
    summarized, in 'monograph addenda'. The appropriate earlier documents
    should be consulted in order to obtain a full toxicological profile of
    these chemicals. In the cases of benomyl, carbendazim, fenthion,
    flusilazole, folpet, piperonyl butoxide, quintozene, thiophanate-
    methyl, and vinclozolin, toxicological monographs were prepared,
    summarizing new data and incorporating information from previous
    monographs and addenda. Reports and other documents resulting from
    previous Joint Meetings of the FAO Panel of Experts on Pesticide
    Residues in Food and the Environment and WHO Expert Groups on
    Pesticide Residues are listed in Annex I. Toxicological monographs
    summarizing all of the available information were prepared on the
    pesticides evaluated for the first time (fenarimol, fenpyroximate, and
    haloxyfop).

         For the first time, environmental evaluations were made for
    certain of the pesticides covered in this document. An Environmental
    Core Assessment Group thus met concurrently with the other two groups
    to evaluate the related compounds carbendazim, benomyl, and
    thiophanate-methyl, and also fenarimol and fenthion for environmental
    effects.

         The report of the Joint Meeting has been published by the FAO as
     FAO Plant Production and Protection Paper No. 133.  The report
    contains brief comments on the compounds considered, acceptable daily
    intakes established by the WHO Core Assessment Group, and maximum
    residue limits or guideline levels established by the FAO Panel of
    Experts. Monographs on residues prepared by the FAO Panel of Experts
    are published as a companion volume, as  Evaluations 1995, Part I,
     Residues, in the FAO Plant Production and Protection Paper series.

         The toxicological monographs and addenda contained in this volume
    are based on working papers that were prepared by temporary advisers
    before the 1995 Joint Meeting. A special acknowledgement is made to
    those advisers. The monographs were edited by Mrs E. Heseltine,
    St Léon-sur-Vézère, France.

         The preparation and editing of this volume were made possible by
    the technical and financial contributions of the lead institutions of
    the International Programme on Chemical Safety (IPCS), which supports
    the activities of the JMPR. The designations employed and the
    presentation of the material in this publication do not imply the
    expression of any opinion whatsoever on the part of the Central Unit
    of the IPCS concerning the legal status of any country, territory,
    city or area or of its authorities, nor concerning the delimitation of
    its frontiers or boundaries. The mention of specific companies or of
    certain manufacturers' products does not imply that they are endorsed
    or recommended by the IPCS in preference to others of a similar nature
    that are not mentioned.

         Any comments or new information on the biology or toxicology of
    the compounds included in this volume should be ad dressed to: Joint
    WHO Secretary of the Joint FAO/WHO Meeting on Pesticide Residues,
    International Programme on Chemical Safety, World Health Organization,
    Avenue Appia, 1211 Geneva 27, Switzerland.





















    See Also:
       Toxicological Abbreviations