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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY

    WORLD HEALTH ORGANIZATION



    TOXICOLOGICAL EVALUATION OF CERTAIN
    VETERINARY DRUG RESIDUES IN FOOD



    WHO FOOD ADDITIVES SERIES 17





    Prepared by:
    The 26th meeting of the Joint FAO/WHO Expert
    Committee on Food Additives (JECFA)



    World Health Organization, Geneva 1982


         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 assessment of
    the risk to human health and the environment from exposure to
    chemicals, through international peer-review processes, as a
    prerequisite for the 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 UN Conference on
    Environment and Development to strengthen cooperation and increase
    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.

    WHO Food Additives Series, 1982, No. 17

    TOXICOLOGICAL EVALUATION OF CERTAIN FOOD ADDITIVES

    The evaluations contained in this document
    were prepared by the Joint FAO/WHO
    Expert Committee on Food Additives*
    Rome, 19-28 April 1982

    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY

    IPCS

              

    *    Twenty-sixth report of the Joint FAO/WHO Expert Committee on Food
         Additives, Geneva, Wld Hlth Org. techn. Rep. Ser., 683, 1982.

    INTRODUCTION

         The monographs contained in this document have been prepared by
    the Joint FAO/WHO Expert Committee on Food Additives which was held in
    Rome, 19-28 April 1982.

         The editing and printing of this document have been possible
    through the technical and financial contributions of the Lead
    Institutions of the International Programme on Chemical Safety (IPCS)
    which support the activities of the Joint FAO/WHO Expert Committee on
    Food Additives as far as the participation of WHO to this committee is
    concerned.

         A special acknowledgement is given to the following experts for
    preparing the drafts of the monographs: Dr C. Lintas, Istituto
    Nazionale della Nutrizione, Rome, Italy; Dr J. E. Long, Food
    Directorate, Health Protection Branch, Department of Health and
    Welfare, Ottawa, Ontario, Canada; and Dr S. I. Shibko, Division of
    Toxicology, Bureau of Food, Food and Drug Administration, Washington,
    D.C., United States of America.

         Dr G. Vettorazzi, Toxicologist, International Programme on
    Chemical Safety, edited and reviewed the final manuscript for
    consistency with the toxicological evaluations contained in the WHO
    Technical Report Series, No. 683 (1982).

         Any comments or new information on the biological and
    toxicological data on the compounds reported in this document should
    be addressed to: Joint WHO Secretary of the Joint FAO/WHO Expert
    Committee on Food Additives, International Programme on Chemical
    Safety, World Health Organization, Avenue Appia, 1211 Geneva 27,
    Switzerland.

    IPCS 1982

         For rights of reproduction of this document, in part or in
    toto, application should be made to the International Programme on
    Chemical Safety (IPCS), World Health Organization, Geneva,
    Switzerland.

         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 International Programme on
    Chemical Safety concerning the legal status of any 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
    International Programme on Chemical Safety in preference to others of
    a similar nature that are not mentioned.

    JOINT FAO/WHO EXPERT COMMITTEE ON FOOD ADDITIVES

    Rome, 19-28 April 1982

    Members invited by FAO

    Dr W. H. B. Denner, Head, Food Additives Branch, Food Science
         Division, Ministry of Agriculture, Fisheries and Food, London,
         England

    Mr D. F. Dodgen, Staff Scientist, Keller and Hackman, Washington
         Washington, D.C., United States of America

    Dr S. W. Gunner, Chief, Division of Chemical Evaluation, Bureau of
         Chemical Safety, Food Directorate, Health Protection Branch,
         Department of National Health and Welfare, Ottawa, Canada

    Professor K. Kojima, College of Environmental Health, Asabu
         University, Sagamihara-Shi, Kanagawa, Japan (Chairman)

    Dr W. Kroenert, Head, Food Chemistry Division, Federal Health
         Institute, Berlin (West)

    Professor F. J. Pellerin, Faculty of Pharmacy, University of Paris XI,
         Centre hospitalier Courentin Celton, Issy-les-Moulineaux, France

    Members invited by WHO

    Professor E. A. Bababunmi, Department of Biochemistry, University
         of Ibadan, Ibadan, Nigeria

    Dr H. Blumenthal, Director, Division of Toxicology, Bureau of Food,
         Food and Drug Administration, Washington, D.C., United States of
         America (Vice-Chairman)

    Dr G. Nazario, Department of Food Standards, National Health Council,
         Rio de Janeiro, Brazil

    Dr E. Poulsen, Director, Institute of Toxicology, National Food
         Institute, Soborg, Denmark

    Professor M. J. Rand, Chairman, Department of Pharmacology, University
         of Melbourne, Victoria, Australia (Rapporteur)

    Dr A. Zaitsev, Head, Laboratory for the Hygienic Examination of Food
         Additives, Institute of Nutrition, Academy of Medical Sciences,
         Moscow, USSR

    Observer invited by FAO

    Mr A. Feberwee, Chairman, Codex Committee on Food Additives, c/o
         Ministry of Agriculture and Fisheries, The Hague, Netherlands

    Secretariat

    Dr J. R. P. Cabral, Division of Chemical and Biological
         Carcinogenesis, International Agency for Research on Cancer,
         Lyons, France (WHO Temporary Adviser)

    Mr R. Haigh, Principal Administrator, Commission of the European
         Communities, Brussels, Belgium (WHO Temporary Adviser)

    Dr Y. Hayashi, Division of Pathology, Biological Safety Research
         Centre, National Institute of Hygienic Sciences, Tokyo, Japan
         (WHO Temporary Adviser)

    Dr V. L. Kossila, Animal Production Officer, Feed Resources, Animal
         Production and Health Division, FAO, Rome, Italy

    Dr G. D. Kouthon, Nutrition Officer, Food Policy and Nutrition
         Division, FAO, Rome, Italy (Joint Secretary)

    Dr L. G. Ladomery, Food Standard Officer, Food Quality and Standard
         Service, FAO/WHO Food Standards Programme, Food Policy and
         Nutrition Division, FAO, Rome, Italy

    Dr C. Lintas, Istituto Nazionale della Nutrizione, Via Ardeatina 545,
         Rome, Italy (WHO Temporary Adviser)

    Dr R. K. Malik, Senior Officer, Food Quality and Standards Service,
         Food Policy and Nutrition Division, FAO, Rome, Italy

    Dr J. E. Long, Chief, Toxicological Evaluation Division, Food
         Directorate, Health Protection Branch, Department of National
         Health and Welfare, Ottawa, Ontario, Canada (WHO Temporary
         Adviser)

    Dr F. J. C. Roe, Institute of Cancer Research, University of London,
         London, England (WHO Temporary Adviser)

    Professor A. G. Rico, Laboratory of Radioelements and Metabolic
         Studies (I.N.R.A.), National Veterinary School, Toulouse, France
         (WHO Temporary Adviser)

    Dr S. I. Shibko, Chief, Contaminants and Natural Toxicants Evaluation
         Branch, Division of Toxicology, Bureau of Food, Food and Drug
         Administration, Washington, D.C., United States of America (WHO
         Temporary Adviser)

    Dr P. Shubik, Resident Fellow, Green College College, University of
         Oxford, England (WHO Temporary Adviser)

    Professor R. C. Truhaut, Director, Toxicological Research Centre,
         RenÚ Descartes University, Paris, France (WHO Temporary
         Adviser)

    Dr G. Vettorazzi, Toxicologist, International Programme on Chemical
         Safety, Division of Environmental Health, WHO, Geneva,
         Switzerland (Joint Secretary)

    Dr E. Weisenberg, Director, Institute for the Standardisation and
         Control of Pharmaceuticals, Ministry of Health, Jerusalem, Israel
         (WHO Temporary Adviser)

    Mr A. Yamamoto, Office of Health Studies, Department of Environmental
         Health, Environment Agency, Tokyo, Japan (WHO Temporary
         Adviser)

    ACCEPTABLE DAILY INTAKES AND INFORMATION ON SPECIFICATIONS

                              Specifications1   ADI for man (mg/kg of
                                                body weight) [and other
                                                toxicological decisions]

    A.  Specific food additives

    Antioxidants

    anoxomer                      NT             0-82

    butylated hydroxyanisole
    (BHA)                         R              0-0.52,3

    Emulsifying agents

    sorbitan monolaureate         R              0-254

    sorbitan monoleate            R              0-254

    stearyl monoglyceridyl
    citrate                       R              No ADI allocated

    succinylated monoglycerides   R              No ADI allocated

    Enzymes

    glucose isomerase (isolated
    from Streptomyces
    violaceoniger)                S              ADI not specified2,5

    protease (isolated from
    Streptomyces fradiae)         N              ADI not specified2,5

    Flavouring agents

    ethyl lactate                 R              ADI not specified5

    eugenol                       R              0-2.5

    alpha-ionone                  R              0-0.052

    ▀-ionone                      R              0-0.052

    ACCEPTABLE DAILY INTAKES AND INFORMATION ON SPECIFICATIONS (Con't)

                              Specifications1   ADI for man (mg/kg of
                                                body weight) [and other
                                                toxicological decisions]

    Food colours

    Natural food colours

    annatto extracts          R                 0-0.0656

    anthocyanins              S                 ADI not allocated9

    anthocyanins (grape-skin
    extract)                  N                 0-2.5

    beet red                  RT                ADI withdrawn7

    carmines                  R                 0-5.08

    curcumin                  R                 0-0.12

    turmeric                  R                 0-2.52

    Synthetic food colours

    Amaranth                  R                 0-0.752

    Brown HT (formerly
    Chocolate Brown HT)       S                 0-0.252

    Lithol rubine BK          R                 ADI not allocated9

    Patent Blue V             R                 ADI not allocated9

    Quinoline Yellow          RT                0-0.52

    Sunset Yellow FCF         R                 0-2.510

    Inorganic salts and buffering agents

    phosphates and
    polyphosphates11        R, S, N, NT         [70]12

    sodium aluminium
    phosphate, acidic         NT                0-62

    sodium aluminium
    phosphate, basic          N                 0-62

    ACCEPTABLE DAILY INTAKES AND INFORMATION ON SPECIFICATIONS (Con't)

                              Specifications1   ADI for man (mg/kg of
                                                body weight) [and other
                                                toxicological decisions]

    Inorganic salts and buffering agents

    ammonium carbonate        R                 ADI not specified5

    ammonium hydrogen
    carbonate (formerly
    ammonium bicarbonate)     R                 ADI not specified5

    magnesium silicate        R                 ADI not specified5

    Sweetening agents

    sorbitol                  R                 ADI not specified5

    calcium and sodium
    cyclamates                S                 0-1113

    saccharin, potassium and
    and sodium salts          R                 0-2.52

    Thickening agents

    gum arabic                R                 ADI not specified5

    gum ghatti                ST                ADI not allocated9

    modified starches         O, R, RT, S       ADI not specified5,14

    starch sodium
    octenyl succinate         R                 ADI not specified

    Miscellaneous food additives

    quillaia extracts         O                 ADI not allocated15

    sodium hydrogen DL-malate N                 ADI not specified5,16

    ammonium acetate          O                 ADI not specified5,17

    sucrose acetate isobutyrate
    (SAIB)                    RT                ADI not allocated9

    ethyl cellulose           R                 0-2518

    ACCEPTABLE DAILY INTAKES AND INFORMATION ON SPECIFICATIONS (Con't)

                              Specifications1   ADI for man (mg/kg of
                                                body weight) [and other
                                                toxicological decisions]

    B.  Contaminants

    Metals

    copper                    -                 [0.05-0.5]19,20

    tin (inorganic; including
    stannous chloride)        -                 [2.0]20,21

    zinc                      -                 [0.3-1.0]19,20

    Xenobiotic anabolic agents

    trenbolone acetate        O                 ADI not allocated22

    zeranol                   O                 ADI not allocated22

    Notes

    1.   N, new specifications prepared; O, specifications not prepared;
         R, existing specifications revised; S, specifications exist,
         revision not considered; T, the existing new, or revised
         specifications are tentative and comments are invited.

    2.   Temporary acceptance.

    3.   Group ADI. As BHA, BHT, TBHQ singly or in combination.

    4.   Group ADI. As the sum of the sorbitan esters of lauric, oleic,
         palmitic and stearic acid.

    5.   The statement "ADI not specified" means that, on the basis of the
         available data (chemical, biochemical, toxicological, and other),
         the total daily intake of the substance, arising from its use at
         the levels necessary to achieve the desired effect and from its
         acceptable background in food, does not, in the opinion of the
         Committee, represent a hazard to health. For this reason, and for
         the reasons stated in the individual evaluations, the
         establishment of an acceptable daily intake (ADI) is not deemed
         necessary.

    6.   The ADI is in terms of the carotenoid content expressed as bixin.

    7.   The previous temporary ADI "not specified" allocated in the
         eighteenth report of the Committee and extended in the twenty-
         second report has been withdrawn since the additional information
         requested in the earlier evaluations was not available.

    8.   The ADI includes ammonium carmine or the equivalent of calcium,
         potassium or sodium salts.

    9.   No sufficient toxicological data were available.

    10.  The previous ADI of 0-5.0 mg/kg of body weight was revised in the
         light of reconsideration of earlier studies together with newer
         studies.

    11.  Aluminium-containing phosphates are not included.

    12.  This figure represents the maximum tolerable daily intake (MTDI)
         of phosphates. It is not an ADI. The MTDI is expressed as
         phosphorus and it applies to the sum of phosphates naturally
         present in food and the additives listed in Annex 4. It also
         applies to diets that are nutritionally adequate in respect of
         calcium.    However, if the calcium intake were high, the intake
         of phosphate could be proportionately higher, and the reverse
         relationship would also apply.

    13.  Expressed as cyclamic acid.

    14.  Does not include starches modified by the use of the crosslinking
         agent epichlorohydrin.

    15.  No specifications are available on these substances.

    16.  Group ADI. The group ADI "not specified" for DL-malic acid and
         bases now includes sodium and potassium hydrogen DL-malates.

    17.  Group ADI. Included in the group ADI for other ammonium salts and
         acetates.

    18.  Group ADI including ethyl cellulose, hydroxypropyl cellulose,
         hydroxylpropyl methyl cellulose, methyl cellulose, methyl ethyl
         cellulose, and sodium carboxymethyl cellulose.

    19.  Daily dietary requirement/maximum tolerable daily intake.
         Expressed in mg/kg of body weight.

    20.  Provisional.

    21.  Maximum tolerable daily intake.

    22.  Necessary documentation on residue levels was not available for
         full evaluation of this compound.

    CONTENTS

    THE MONOGRAPHS

    Food additives

    Ammonium carbonate and ammonium hydrogen carbonate (formerly
         ammonium bicarbonate)

    Annatto extracts

    anoxomer

    Anthocyanins

    Arabic gum

    Carmines

    Cyclamates, calcium, sodium and cyclohexyalmine

    Ethyl-L-lactate

    Eugenol

    Glucose isomerase (Streptomyces violaceoniger)

    Modified starches:

         acetylated distarch adipate
         acetylated distarch glycerol
         acetylated distarch phosphate
         acid-treated starches
         dextrins
         hydroxypropyl distarch glycerol
         hydroxypropyl starch
         phosphated distarch phosphate
         starch acetate
         starch sodium octenyl succinate

    Phosphoric acid and phosphate salts

    Protease (Streptomyces fradiae)

    Quillaia extracts

    Saccharin

    Sodium aluminium phosphate (acidic and basic)

    Sorbitan monoesters of palmitic, stearic, oleic
    and lauric acids and triesters of stearic acid

    Sucrose acetate isobutyrate (SAIB)

    Sunset Yellow FCF

    Turmeric and curcumin

    Food contaminants

    Copper

    Tin and stannous chloride

    Zinc

    ANNEX I

    ANNEX II
    





















    See Also:
       Toxicological Abbreviations