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    PESTICIDE RESIDUES IN FOOD - 1993


    JOINT FAO/WHO MEETING ON PESTICIDE RESIDUES






    EVALUATIONS 1993

    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

    Geneva, 20-29 September 1993





 

    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.

    ISBN 92 4 166509 2

    (c) World Health Organization 1994

          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

         Amitrole
         Bromopropylate
         Diazinon
         Dichlorvos
         Diquat
         Ethephon
         Ethylenethiourea (ETU)
         Etofenprox*
         Fenpropathrin*
         Mancozeb
         Maneb
         Metiram*
         Monocrotophos
         Phosalone
         Propineb
         Propylenethiourea (PTU)
         Triazophos
         Zineb

    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
    

    1993 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, 20-29 September 1993

    PARTICIPANTS

    WHO Expert Group on Pesticide Residues

    Professor U.G. Ahlborg, Division of Environmental Toxicology,
         Karolinska Institute, Institute of Environmental Medicine,
         Stockholm, Sweden

    Dr A.L. Black, Medical Services Adviser in Toxicology, Department of
         Health, Housing, Local Government and Community Services,
         Canberra, Australia

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

    Mr D.J. Clegg, Carp, Ontario, Canada

    Dr P.A. Fenner-Crisp, Director, Health Effects Division, Office of
         Pesticide Programs (H7509C), US Environmental Protection Agency,
         Washington, DC, USA  (Rapporteur)

    Dr E.M. den Tonkelaar, Toxicologist, Toxicology Advisory Centre,
         National Institute of Public Health and Environmental Protection,
         Bilthoven, The Netherlands

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

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

    Dr D.C. Abbott, AOAC International, Liaison Representative, Ashtead,
         Surrey, United Kingdom

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

    Dr U. Banasiak, Kleinmachnow, Germany

    Mr D.J. Hamilton, Senior Principal Scientist, Agricultural Chemistry,
         Queensland Department of Primary Industries, Indooroopilly,
         Brisbane, Queensland, Australia

    Mr N.F. Ives, Health Effects Division (H7509C), US Environmental
         Protection Agency, Washington, DC, USA  (Vice-Chairman)

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

    Mr K. Voldum-Clausen, VarlØse, Denmark

    Ms H.F. Yeoh, Residue Section, Pesticides Control Branch, Department
         of Agriculture, Kuala Lumpur, Malaysia

    Secretariat

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

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

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

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

    Dr H. Galal-Gorchev, International Programme on Chemical Safety, World
         Health Organization, Geneva, Switzerland

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

    Dr A. Kocialski, Health Effects Division, Office of Pesticide Programs
         (H7509C), US Environmental Protection Agency, Washington, DC, USA
          (WHO Temporary Adviser)

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

    Professor M. Lotti, University of Padua, Institute of Occupational
         Medicine, Padua, Italy  (WHO Temporary Adviser)

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

    Dr T.C. Marrs, Medical Toxicology and Environmental Health, Department
         of Health, Skipton House, Elephant and Castle, London, United
         Kingdom  (WHO Temporary Adviser)

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

    Dr A. Moretto, University of Padua, Institute of Occupational
         Medicine, Padua, Italy  (WHO Temporary Adviser)

    Dr G. Moy, Food Safety, World Health Organization, Geneva, Switzerland

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

    Dr R. Plestina, International Programme on Chemical Safety, World
         Health Organization, Geneva, Switzerland

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

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

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

    Mr M. Walsh, Principal Administrator EEC, Commission of the European
         Communities, Législation des produits végétaux et de nutrition
         animale, VI/B/II.1, Brussels, Belgium  (WHO Temporary Adviser)

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

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

    ABBREVIATIONS USED IN THE 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

    BChE   butyrylcholinesterase
    BUN    blood urea nitrogen
    bw     body-weight

    CCPR   Codex Committee on Pesticide Residues
    CD     caesarean-derived
    cf     confer, compare to
    ChAT   choline acetyltransferase
    ChE    cholinesterase
    Ci     Curie
    CHO    Chinese hamster ovary
    CMC    carboxymethylcellulose
    CNS    central nervous system

    DCA    dichloroacetaldehyde
    DEP    diethyl phosphoric acid
    DETP   diethyl thiophosphate
    DHPN   dihydroxypropylnitrosamine
    DMSO   dimethylsulfoxide
    DNA    deoxyribonucleic acid
    DNCB   1-chloro-2,4-dinitrobenzene

    EBDC   ethylene bisdithiocarbamate
    EBIS   ethylene bis(isothiocyanate) sulfide
    ECG    electrocardiogram
    EEG    electroencephalogram
    EM     electron microscopy
    ESR    erythrocyte sedimentation rate
    ETU    ethylenethiourea

    F      female
    F0     parental generation
    F1     filial generation, first
    F2     filial generation, second
    FMO    flavin monooxygenase
    FTI    free thyroxine index 

    GC     gas chromatography
    GGT    gamma-glutamyltranspeptidase
    G.I.   gastrointestinal
    GIT    gastrointestinal tract
    GOT    glutamate-oxalate transaminase
    GPT    glutamate-pyruvate transaminase
    GSH    glutathione-SH
    GSSG   oxidized glutathione
    GST    glutathione-S-transferase
    GTP    (alpha)-glutamyltranspeptidase

    h      hour
    ha     hectare
    Hb     haemoglobin
    HCT    haematocrit
    HPLC   high-performance liquid chromatography
    HPMC   hydroxypropylmethyl cellulose
    Ht     haematocrit

    I50    inhibitory dose, median
    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
    MHEC   methylhydroxyethylcellulose

    min    minute
    ml     milliliter
    MMD    mass median diameter
    MMS    methylmethanesulfonate
    mol    mole
    MTD    maximum tolerated dose

    NADPH  nicotinamide adenine dinucleotide phosphate (reduced)
    NOAEL  no-observed-adverse-effect level
    NOEL   no-observed-effect level 
    NSE    non-specific esterase
    NTE    neurotoxic esterase
    NZW    New Zeeland white (rabbit)

    OP     organophosphate

    2-PAM  (2-pyridine aldoxime methyl) chloride
    PAS    periodic acid Schiff reagent
    PBI    protein-bound iodine
    PCV    haematocrit (packed corpuscular volume)
    PEG    polyethylene glycol
    p.o.   per os (by mouth)
    PI     primary irritation
    ppm    parts per million
    PSP    phenolsulfophthalein
    PT     prothrombin time
    PTT    partial thromboplastin time
    PTU    propylenethiourea
    PVC    polyvinyl chloride

    RBC    red blood cell
    RNA    ribonucleic acid

    SAP    serum alkaline phosphatase
    s.c.   subcutaneous(ly)
    SCE    sister chromatid exchange
    SDH    sorbitol dehydrogenase
    SER    smooth endoplasmic reticulum 
    SGOT   serum glutamic-oxaloacetic transaminase
    SGPT   serum glutamic-pyruvic transaminase
    SPF    specific pathogen free

    T3     triiodothyronine
    T4     thyroxin
    TBG    thyroid binding globulin
    TEPP   tetraethyl-pyrrophosphate
    TLC    thin-layer chromatography
    TOCP   tri- ortho-cresyl phosphate
    TSH    thyroid-stimulating hormone (thyrotropin)

    UDS    unscheduled DNA synthesis
    USEPA  US Environmental Protection Agency

    -ve    negative
    v/v    volume per volume

    WBC    white blood cell
    w/v    weight per volume 
    w/w    weight per 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
    Geneva, Switzerland, from 20 to 29 September 1993.  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.  Monographs that
    summarize the data received since the previous evaluations as well as
    relevant data from the previous monographs were prepared on most of
    these compounds. Monograph addenda that summarize only the data
    received since the previous evaluations were prepared on monocrotophos
    and triazophos.  The appropriate documents, which are referenced in
    Annex 1, should be consulted to obtain a full toxicological profile of
    these pesticides.

         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. XXX.  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 1993, 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 1993 Joint Meeting.  A special
    acknowledgement is given to those who prepared these working papers.

         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