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    Pesticide residues in food -- 1999



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



    Toxicological evaluations




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

    Rome, 20-29 September 1999


    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 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) 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 the 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 15 7

    (c)  World Health Organization 2000

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    welcomes such applications.

    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 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.

    TABLE OF CONTENTS

    List of participants
    Abbreviations

    Introduction

    Toxicological evaluations 
         Chlormequat (addendum)
         Chlorpyrifos
         Dimethipin 
         Ethoprophos 
         Glufosinate-ammonium (addendum)
         Permethrin
         2-Phenylphenol and its sodium salt
         Propargite
         Propylene thiourea (addendum)
         Pyrethrum extract (Pyrethrins) (addendum)
         Pyriproxyfen*

    Annex 1.  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 2.  Corrigenda to previous editions of JMPR toxicological 
              and environmental evaluations


    ____________

    * First full evaluation
    

    1999 Joint Meeting of the FAO Panel of Experts on Pesticide Residues
    in Food and the Environment and the WHO Core Assessment Group

    Rome, 20-29 September 1999

    PARTICIPANTS

     Toxicological Core Assessment Group 

    Professor A.R. Boobis, Section on Clinical Pharmacology, Division of
         Medicine, Imperial College School of Medicine, London, United
         Kingdom

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

    Dr P. Fenner-Crisp, Senior Science Advisor to the Director, Office of
         Pesticide Programs, US Environmental Protection Agency,
         Washington DC, United States 

    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

    Dr B.G. Priestly, Scientific Director, Chemicals and Non-prescription
         Medicines Branch, Therapeutic Goods Administration, Commonwealth
         Department of Health and Family Services, Woden, ACT, Australia
          (Rapporteur) 

    Professor S.A. Soliman, Department of Pesticide Chemistry, Faculty of
         Agriculture, Alexandria University, El-Shatby, Alexandria, Egypt

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

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

    Dr E.Dutra Caldas, Pharmaceutical Sciences Department, College of
         Health Sciences, University of Brasilia, Brasilia, Brazil
          (Rapporteur) 

    Dr S. Funk, Health Effects Division, Environmental Protection Agency,
         Washington DC, United States

    Mr D.J. Hamilton, Principal Scientific Officer, Animal and Plant
         Health Service, Department of Primary Industries, Brisbane,
         Queensland, Australia  (Chairman) 

     Secretariat 

    Dr A. Ambrus, Agrochemicals Unit, Joint FAO/IAEA Division of Nuclear
         Techniques in Food and Agriculture, IAEA, Vienna, Austria
          (FAO Consultant) 

    Dr R. Bhula, Chemistry and Residue Evaluation Section, National
         Registration Authority for Agricultural and Veterinary Chemicals,
         Kingston, ACT, Australia  (FAO Consultant) 

    Dr E. Bosshard, Section Crop Protection Products, Federal Office of
         Agriculture, Bern, Switzerland   (WHO Temporary Adviser) 

    Dr S.M.F. Calumpang, National Crop Protection Center, University of
         the Philippines, Los Baños, Laguna, Philippines  (FAO 
          Consultant)

    Dr I.C. Dewhurst, Pesticides Safety Directorate, Ministry of
         Agriculture, Fisheries and Food, York, United Kingdom
          (WHO Temporary Adviser) 

    Dr W.G. Dykstra, Office of Pesticide Programs, Environmental
         Protection Agency, Washington DC, United States  (WHO Temporary 
          Adviser)

    Dr W.H. van Eck, Division of Public Health, Ministry of Health,
         Welfare and Sport, The Hague, Netherlands  (Chairman, Codex 
          Committee on Pesticide Residues) 

    Dr K. Fujimori, Division of Xenobiotics, Metabolism and Disposition,
         National Institute of Health Sciences, Tokyo, Japan  (WHO 
          Temporary Adviser)

    Professor J. Hajslova, Institute of Chemical Technology, Department of
         Food Chemistry and Analysis, Prague, Czech Republic  (WHO 
          Temporary Adviser)

    Mrs C. Harris, Pesticides Safety Directorate, Ministry of Agriculture,
         Fisheries and Food, York, United Kingdom  (FAO Consultant) 

    Dr J.L. Herrman, 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 Editor) 

    Dr M. Hirose, Head, Division of Pathology, National Institute of
         Health Sciences, Tokyo, Japan  (WHO Temporary Adviser) 

    Dr J.-J. Larsen, Head, Department of General Toxicology, Institute of
         Toxicology, Danish Veterinary and Food Administration, Sœborg,
         Denmark  (WHO Temporary Adviser) 

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

    Dr T.C. Marrs, Joint Food Safety and Standards Group, London, United
         Kingdom  (WHO Temporary Adviser) 

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

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

    Mr N. Nakashima, International Programme on Chemical Safety, World
         Health Organization, Geneva, Switzerland

    Mr K. Ogura, Agricultural Chemicals Inspection Station, Tokyo, Japan
          (FAO Consultant) 

    Dr B.C. Ossendorp, Centre for Substances and Risk Assessment, National
         Institute of Public Health and the Environment, Bilthoven,
         Netherlands  (FAO Consultant) 

    Dr R. Solecki, Pesticides and Biocides Division, Federal Institute for
         Health Protection of Consumers and Veterinary Medicine, Berlin,
         Germany  (WHO Temporary Adviser) 

    Dr A.W. Tejada, Pesticide Management Group, Food and Agriculture
         Organization of the United Nations, Rome, Italy  (FAO Joint 
          Secretary) 

    Dr G. Vaagt, Pesticide Management Group, Food and Agriculture
         Organization of the United Nations, Rome, Italy

    Dr J. van Engelen, Centre for Substances and Risk Assessment, National
         Institute of Public Health and the Environment, Bilthoven,
         Netherlands  (WHO Temporary Adviser) 

    Mr D. Wagner, Chemicals Review and International Harmonisation
         Section, Chemical and Non-prescription Drugs Branch, Commonwealth
         Department of Health and Family Services, Canberra, ACT,
         Australia  (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
    AUC            area under the curve
    BrdU           5-bromo-2'-deoxyuridine
    bw             body weight
    CI             confidence interval
    CYP            cytochrome P450
    DMBA           7,12-dimethylbenz[ a]anthracene
    DMSO           dimethyl sulfoxide
    ED50           median effective dose
    F              female
    F0             parental generation
    F1             first filial generation
    F2             second filial generation
    FIFRA          Federal Insecticide, Fungicide and Rodenticide Act
                   (United States)
    GABA           gamma-aminobutyric acid
    GLP            good laboratory practice
    HPLC           high-performance liquid chromatography
    IARC           International Agency for Research on Cancer
    IC50           median inhibitory concentration
    IPCS           International Programme on Chemical Safety
    IU             international unit
    JMPR           Joint FAO/WHO Meeting on Pesticide Residues
    LC50           median lethal concentration
    LD             limit of detection
    LD50           median lethal dose
    LOAEL          lowest-observed-adverse-effect level
    M              male
    MRL            maximum residue limit
    NA             not analysed
    NBHBA           N-nitrosobutyl- N-(4-hydroxybutyl)amine
    NOAEL          no-observed-adverse-effect level
    NOAEC          no-observed-effect concentration
    NR             not reported
    OECD           Organisation for Economic Co-operation and Develeopment
    PEG            polyethylene glycol
    ppm            parts per million
    QA             quality assurance
    S9             9000 ×  g supernatant fraction of rodent liver
    SD             Sprague-Dawley
    SPF            specific pathogen-free
    TBPC           1-[4-(1,1-dimethylethyl)phenoxy]-2-cyclohexanol
    TCP            3,5,6-trichloro-2-pyridinol
    TLC            thin-layer chromatography
    TMRL           tolerable maximum residue limit
    TPA            12- O-tetradecanoylphorbol 13-acetate
    USEPA          US Environmental Protection Agency
    w/v            weight per volume

    Introduction

         The toxicological 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 Rome,
    Italy, on 20-29 September 1999.

         One of the substances evaluated by the Core Assessment Group at
    this Meeting, pyriproxyfen, was evaluated for the first time. The
    other 10 substances had been evaluated at earlier meetings. For four
    of these, chlormequat, glufosinate ammonium, propylene thiourea, and
    pyrethrum extract, only information received since the previous
    evaluations is summarized, in 'monograph addenda'. The appropriate
    earlier documents should be consulted in order to obtain full
    toxicological profiles of these chemicals. Toxicological monographs
    were prepared on chlorpyrifos, dimethipin, ethoprophos, permethrin,
    2-phenylphenol and its sodium salt, and propargite, summarizing new
    data and, where relevant, incorporating information from previous
    monographs and addenda. Reports and other documents resulting from
    previous Joint Meetings on Pesticide Residues are listed in Annex 1.

         The report of the Joint Meeting has been published by the FAO as
     FAO Plant Production and Protection Paper 153. That report contains
    comments on the compounds considered, acceptable daily intakes
    established by the WHO Core Assessment Group, and maximum residue
    limits 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 1999, 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 1999 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 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