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    PESTICIDE RESIDUES IN FOOD - 1992


    JOINT FAO/WHO MEETING ON PESTICIDE RESIDUES






    EVALUATIONS 1992

    PART II - TOXICOLOGY



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

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

    Rome, 21-30 September 1992




 

    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.



    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY

    The preparatory work for the toxicological evaluations of pesticide
    residues carried out by the WHO Expert Group on Pesticide Residues
    for consideration by the FAO/WHO Joint Meeting on pesticide Residues
    in Food and the Environment is actively supported by the International
    Programme on Chemical Safety (IPCS).

    The International Programme on Chemical Safety (IPCS) is a joint
    venture of the United Nations Environment Programme, the International
    Labour Organisation, and the World Health Organization.  One of the
    main objectives of the IPCS is to carry out and disseminate
    evaluations of the effects of chemicals on human health and the
    quality of the environment.

    IPCS gratefully acknowledges the assistance of Mr. D. Clegg, Carp.
    Ontario, Canada, for editing these monographs.

    ISBN 92 4 166508 4

    (c) World Health Organization 1993

          Publications of the World Health Organization enjoy copyright
    protection in accordance with the provisions of Protocol 2 of the
    Universal Copyright Convention.  For rights of reproduction or
    translation of WHO publications, in part or  in toto, application
    should be made to the Office of Publications, World Health
    Organization, Geneva, Switzerland.  The World Health Organization
    welcomes such applications.

          The designations employed and the presentation of the material in
    this publication do not imply the impression of any opinion whatsoever
    on the part of the Secretariat of the World Health Organization
    concerning the legal status of every country, territory, city, or area
    or of its authorities, or 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.



    TABLE OF CONTENTS

         List of those attending the Meeting
         Abbreviations
         Introduction

    The Monographs

         *    Abamectin
              Aldicarb
         *    Bifenthrin
              Chlorothalonil
              Chlorpyrifos-methyl
         *    Cycloxydim
              Dicofol
         *    Dithianon
              Fenbutatin oxide
              Iprodione
              Methidathion
         *    Myclobutanil
         *    Penconazole
              Piperonyl butoxide
              Pirimiphos-methyl
         *    Propham
              Pyrazophos
              Thiram

    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


                 
    * First full evaluation
    

    1992 JOINT MEETING OF THE FAO PANEL OF EXPERTS ON PESTICIDE RESIDUES
    IN FOOD AND THE ENVIRONMENT AND THE WHO EXPERT GROUP ON PESTICIDE
    RESIDUES

    Rome, 21-30 September 1992

    PARTICIPANTS

    WHO Expert Group on Pesticide Residues

    Prof. U.G. Ahlborg, Head, Unit of Toxicology, Karolinska Institutet,
       Institute of Environmental Medicine, Stockholm, Sweden

    Dr Vaclav Benes, Head, National Reference Centre for Pesticides,
       National Institute of Public Health, Prague, Czechoslovakia

    Dr A.L. Black, Medical Services Adviser in Toxicology, Department of
       Health, Housing and Community Services, Canberra, Australia
       ( Rapporteur)

    Prof. J.F. Borzelleca, Professor, Pharmacology, Toxicology, Medical
       College of Virginia, Virginia Commonwealth University, Richmond,
       Virginia, USA ( Vice-Chairman)

    Dr P. Fenner-Crisp, Director, Health Effects Division, Office of
       Pesticide Programs, US Environmental Protection Agency,
       Washington, DC, USA

    Prof. A. Rico, Head, Chemical and Metabolic Toxicology Laboratory,
       Ecole Nationale Vétérinaire, Toulouse, France

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

    FAO Panel of Experts on Pesticide Residues in Food and the Environment

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

    Dr R. Greenhalgh, Ottawa, Ontario, Canada

    Dr D. Hamilton, Senior Principal Scientist, Agricultural Chemistry,
       Department of Primary Industries, Queensland Government,
       Brisbane, Queensland, Australia ( Chairman)

    Mr N.F. Ives, Health Effects Division, US Environmental Protection
       Agency, Washington, DC, USA

    Dr J.-R. Lundehn, Federal Biological Research Centre for Agriculture
       and Forestry, Braunschweig, Germany

    Dr K. Voldum-Clausen, National Food Agency, Ministry of Health,
       Soborg, Denmark

    Mr Wu Ji Zhuang, Associate Professor, Head of the Department of
       Research Chemicals, China Import and Export Commodity Inspection
       Institute, Beijing, China

    Secretariat

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

    Dr J.R.P. Cabral, Scientist, International Agency for Research on
       Cancer, Lyon, France

    Mrs M. Caris, Toxicological Evaluation Division, Bureau of Chemical
       Safety, Health and Welfare Canada, Ottawa, Ontario, Canada ( WHO
        Temporary Adviser)

    Dr S. Caroldi, Universitŕ di Padova, Istituto di Medicina del
       Lavoro, Padova, Italy ( WHO Temporary Adviser)

    Dr E. Casadei, Joint FAO/WHO Food Standards Programme, Food and
       Agriculture Organization, Rome, Italy

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

    Dr M.A. Clevenger, Senior Toxicologist, Toxicology Branch I, Health
       Effects Division, Office of Pesticide Programs, US Environmental
       Protection Agency, Washington, DC, USA ( WHO Temporary Adviser)

    Mr W.H. van Eck, Food and Product Safety Division, Ministry of
       Welfare, Health and Cultural Affairs, Rijswijk, The Netherlands
       ( Chairman CCPR)

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

    Dr Jens-Jorgen Larsen, Head, Department of General Toxicology,
       Institute of Toxicology, National Food Agency, Ministry of
       Health, Soborg, Denmark ( WHO Temporary Adviser)

    Mr A.F. Machin, London, UK ( FAO Consultant)

    Dr T.C. Marrs, Medical Toxicology and Environmental Health,
       Department of Health, London, UK ( WHO Temporary Adviser)

    Mr W.J. Murray, Pesticide Residues Specialist Plant Protection
       Service, Food and Agriculture Organization of the United Nations,
       Rome, Italy ( FAO Joint Secretary)

    Dr A. Takanaka, Head, Division of Pharmacology, Biological Safety
       Research Center, National Institute of Hygienic Sciences, Tokyo,
       Japan ( WHO Temporary Adviser)

    Dr E.M. den Tonkelaar, Toxicologist, Toxicology Advisory Centre,
       National Institute of Public Health and Environmental Protection,
       Bilthoven, Netherlands ( WHO Temporary Adviser)

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

    Mr M. Watson, Head, Risk Evaluation Branch, Pesticide Safety
       Division, Ministry of Agriculture, Fisheries and Food, Harpenden,
       Herts, UK ( WHO Temporary Adviser)

    ABBREVIATIONS USED IN THESE MONOGRAPHS

    ACH       acetylcholine
    AChE      acetylcholinesterase
    ACTH      adenocorticotropic hormone
    ADI       acceptable daily intake
    ADP       adenosine diphosphate
    A/G       albumin/globulin ratio
    a.i.      active ingredient
    ALAT      alanine aminotransferase
    ALP       alkaline phosphatase
    ALT       alanine transaminase
    ASAT      aspartate aminotransferase
    AST       aspartate transaminase
    ATP       adenosine triphosphate
    AUC       area under the curve

    BUN       blood urea nitrogen
    bw        body weight

    cf        confer, compare to
    ChE       cholinesterase
    Ci        curie
    CHO       Chinese hamster ovary
    CMC       carboxymethylcellulose
    CNS       central nervous system

    DMSO      dimethylsulfoxide
    DNA       deoxyribonucleic acid

    ECG       electrocardiogram
    EEG       electroencephalogram
    ELP       exploratory locomotion pattern
    ESR       erythrocyte sedimentation rate

    F         female
    F0        parental generation
    F1        filial generation, first
    F2        filial generation, second

    dGC       gas chromatography
    GGT       gamma-glutamyltransferase
    G.I.      gastrointestinal
    GIT       gastrointestinal tract
    GM        Geiger meter

    GOT       glutamate-oxoloacetate transaminase
    GPT       glutamate-pyruvate transaminase
    GSH       reduced glutathione
    GSSG      oxidized glutathione

    GST       glutathione-S-transferase
    GTP       alpha-glutamyltranspeptidase

    H         hour
    Ha        hectare
    Hb        haemoglobin
    HCT       haematocrit
    HGRPT     hypoxanthine-guanine phosphoribosyl transferase
    HPLC      high pressure liquid chromatography
    Ht        haematocrit

    I50       inhibitory dose, 50%
    IBT       Industrial Bio-Test Laboratories, Inc.
    i.m.      intramuscular
    inh       inhalation
    i.p.      intraperitoneal
    IPCS      International Programme on Chemical Safety
    i.v.      intravenous
    JMPR      Joint FAO/WHO Meeting on Pesticide Residues

    l         litre
    LC50      lethal concentration, median
    LD50      lethal dose, median
    LDH       lactate dehydrogenase
    LOAEL     lowest-observed-adverse-effect-level

    m         metre
    M         male
    MCH       mean corpuscular haemoglobin
    MCHC      mean corpuscular haemoglobin concentration
    MCV       mean corpuscular volume
    MFO       mixed function oxidase(s)
    MHEC      methylhydroxyethylcellulose
    ml        milliliter
    mTD       minimum toxic dose
    MTD       maximum tolerated dose

    NADPH     nicotinamide adenine dinucleotide phosphate (reduced)
    NMR       nuclear magnetic resonance
    NOAEL     no-observed-adverse-effect level
    NOEL      no-observed-effect level
    NSE       non-specific esterase
    NTE       neurotoxic target esterase

    OCT       ornithylcarbamyl transferase

    2-PAM     2-pralidoxime
    PCV       haematocrit (packed corpuscular volume)
    PEG       polyethylene glycol
    p.o.      by mouth
    PI        primary irritation

    ppm       parts per million
    PSP       phenolsulfophthalein
    PrT       prothrombin time
    PT        thromboplastin time
    PTT       partial thromboplastin time

    RBC       red blood cell
    RNA       ribonucleic acid

    SAP       serum alkaline phosphatase
    s.c.      subcutaneous(ly)
    SCE       sister chromatide exchange
    SD        standard deviation
    SDH       sorbitol dehydrogenase
    SER       smooth endoplasmic reticulum
    SGOT      serum GOT
    SGPT      serum GPT
    SPF       specific pathogen free

    T3        tri-iodothyronine
    T4        thyroxine
    TLC       thin layer chromatography
    TOCP      tri-ortho-cresyl phosphate
    TSH       thyrotropine
    TWA       time weighted average

    UDS       unscheduled DNA synthesis

    v/v       volume/volume

    WBC       white blood cell
    W/W       weight to weight

    INTRODUCTION

         The toxicological monographs and monograph addenda contained in
    this volume were prepared by a WHO Expert Group on Pesticide
    Residues 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 Rome, Italy, 21 September to 30 September 1992.
    These monographs summarize the safety data on those pesticide
    residues for which sufficient information was provided to the WHO
    Expert Group for it to make decisions regarding acceptable daily
    intakes.

         Most of the compounds considered by the WHO Expert Group at
    this Meeting had been evaluated at previous meetings. For some
    compounds, only new information is summarized in the relevant
    "monograph addenda". In the case of aldicarb, dicofol, fenbutatin
    oxide, iprodione, methidathion and pirimiphos-methyl, toxicological
    monographs, summarizing the data that were received recently and
    incorporating the previous monographs and monograph addenda on these
    compounds, were prepared. Reference is made to 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 which are listed in Annex 1. For
    monograph addenda, the appropriate documents should be consulted to
    obtain a full toxicological profile of the chemicals under
    consideration.

         The report of the Joint Meeting has been published by the Food
    and Agriculture Organization (FAO) of the United Nations as FAO
    Plant Production and Protection Paper No. 116. The report contains
    brief comments on the compounds under consideration, acceptable
    daily intakes established by the WHO Expert Group, and maximum
    residue limits or guideline levels established by the FAO Panel of
    Experts. Residues monographs prepared by the FAO Panel of Experts
    have been published as a companion volume to this one: Evaluations
    1992, Part I- Residues, in the FAO Plant Production and Protection
    Paper series.

         The toxicological monographs and monograph addenda contained in
    this volume are based upon working papers that were prepared by
    Temporary Advisers in advance of the 1992 Joint Meeting. A special
    acknowledgement is given to those who prepared these working papers.
    The monographs were edited by Mr D.J. Clegg, Carp, Ontario, Canada.

         The preparation and editing of the monographs included in this
    volume have been made possible through the technical and financial
    contributions of the lead institutions of the International
    Programme on Chemical Safety (IPCS), which support the activities of
    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 its
    authorities, or 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 biological or
    toxicological data on the compounds reported in this document should
    be addressed 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