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    PESTICIDE RESIDUES IN FOOD - 1981


    Sponsored jointly by FAO and WHO






    EVALUATIONS 1981







    Food and Agriculture Organization of the United Nations
    Rome

    FAO PLANT PRODUCTION AND PROTECTION PAPER 42

    pesticide residues in food:
    1981 evaluations

     the monographs

    data and recommendations
    of the 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, 23 November-2 December 1981

    FOOD AND AGRICULTURE ORGANIZATION OF THE UNITED NATIONS
    Rome 1982

    CYHEXATIN

    Explanation

         This acaricide was evaluated by the FAO/WHO Joint Meeting in 1970
    and 1978.*  The estimate of the temporary acceptable daily intake for
    man, set in 1970, was extended in 1973 and 1978.

         In 1978 clarification of the no-effect level in the rat in order
    to elucidate the significance of focal bile duct hyperplasia at low
    dose levels was required by 1980. A study to elucidate the possible
    effect on the immune system was desirable.

         A further evaluation of the focal bile duct hyperplasia findings
    is presented herewith. In addition, a report of life-time feeding
    studies of cyhexatin to mice was available. Additional reports of
    toxicological studies of dogs were submitted.

    DATA FOR THE ESTIMATION OF ACCEPTABLE DAILY INTAKE

    TOXICOLOGICAL STUDIES

    Focal bile duct hyperplasia - rats

         All of the liver slides prepared for microscopic examination from
    rats of the dietary study with cyhexatin reported by S.D. Warner
     et al (1977) were re-evaluated by Dr. van der Heijden, pathologist.
    He clearly states that focal bile duct hyperplasia is a common finding
    in livers of ageing rats of various strains and is of little
    pathological significance. However, it appears likely that some
    environmental factor, e.g. contaminants of food or deficiency, is
    responsible for the frequently found high incidence. The occurrence
    of focal bile duct hyperplasia in control and treated rats is
    considered "spontaneous" and generally not associated with a
    particular condition or treatment. There is no association between
    focal bile duct hyperplasia and tumours of the liver or bile ducts and
    no evidence to relate focal bile duct hyperplasia to any preneoplastic
    condition (Van der Heijden 1980).

              

    *    See Annex II for FAO and WHO documentation.

    Short-term studies

    Mice

         Groups of male and female B6C3F1 mice (10/sex/group) received
    diets containing cyhexatin for 13 weeks in concentrations of about 0,
    3, 6 or 10 mg/kg bw/day. Slight, not dose-related, decreases in food
    consumption occurred during some periods in all treated groups of
    females.

         Cyhexatin did not induce dose-related effects on body weight,
    organ weights including the heart, or gross and microscopic pathology.
    At the end of the experiment, PCB-values were significantly increased
    in the male animals of the highest dose level. The no-effect level in
    this study is about 6 mg/kg bw (McCollister  et al 1980).

    Dog

         Groups of 8 male beagle dogs were given oral doses of 0, 0.75,
    1.50 or 6 mg cyhexatin/kg for 6 months. Treatment-related clinical
    signs included intermittent loose stools, inappetence, increased
    physical activity and rough hair. Loose stools were observed in all
    treatment levels in a dose-response manner. After the test compound
    was removed from the basal ration and given separately admixed in
    canned food, food intake was increased, especially at the highest dose
    level. Increased physical activity was first observed at the 6.0 mg/kg
    bw dose level, and thereafter also at the 0.75 and 1.50 mg/kg levels.
    Terminal physical examination did not indicate the presence of any
    abnormality. In the highest dose groups, body weight and body
    temperature were decreased. Cyhexatin did not have clear dose-related
    effects on heart rate, blood pressure, ECG-recording, urinalysis or
    clinical chemistry. At the end of the study, haematological values
    (RBC, Hb and PCV) were decreased in the 6 mg/kg group. In all
    experimental groups, the weight of the heart was not dose-relatedly
    increased. No gross or microscopic alterations were observed that
    could be related to the treatment (Gerbig and Warner 1975).

         In order to study the increased physical activity as found in the
    previous experiment, 3 groups of male beagle dogs received in their
    diets 0, 0.4 to 0.75, and 0.4 to 1.5 mg cyhexatin/kg bw during 13
    weeks. The daily activity of each dog was recorded by means of
    actometers. The activity of dogs fed 1.5 mg/kg bw was clearly
    depressed. No noticeable differences in physical activity occurred
    between the 0.75 mg/kg group and the controls. The absolute heart
    weight was not affected, whereas the relative weight was significantly
    increased (Reuzel 1977).

    Long-term studies

    Mice

         Groups of 60 male and 60 female B6C3F1 mice were maintained on
    diets formulated to supply 0 (96 males and 96 females), 1, 3 or 6 mg
    cyhexatin/kg bw for up to 2 years. After one year, 10 male and 10
    female mice of each group were killed. In the highest dose level
    mortality was increased in the males and decreased in the females. The
    body weight gain in the males was lowered in comparison to controls,
    whereas in both males and females the food intake was marginally
    affected. No dose-related effects were observed on behaviour,
    haematology, clinical chemistry, organ weights or tumour incidence. At
    the highest dose level of 6 mg/kg bw/day, there were indications that
    the incidence of a few of the normal changes may have been affected by
    the treatment, e.g. a decrease in sinusoidal distension and/or
    increased inflammatory or reticuloendothelial cell activity, a
    decrease of uterine endometrial hyperplasia in the lymph nodes and a
    decrease in adenoma formations in the pituitary. Biliary hyperplasia
    or cyst formation occurred only in a few isolated cases. The no-effect
    level is 3 mg/kg bw (Keyes  et al 1981).

    EVALUATION

    COMMENTS

         A six-month toxicity study in dogs has been received and
    evaluated. A subjective observation of dose-related increased activity
    was reported. A second study, measuring activity with an actometer,
    failed to confirm this observation.

         A statement from an independent pathologist indicated that the
    local bile duct hyperplasia noted in an earlier JMPR evaluation is a
    normal finding in ageing rats and may be considered to be of
    negligible pathological significance. This statement was confirmed by
    the Meeting.

         Two mouse studies, one of 13 weeks and one lifetime study, were
    evaluated. The lifetime study permitted the estimation of a no-effect
    level of 3 mg/kg bw/day in this species.

         The estimated temporary acceptable daily intake for man
    (0.008 mg/kg bw) was based on the no-effect level (0.75 mg/kg) in
    2-year dog feeding studies evaluated in 1970. The receipt of the long-
    term study in rats and the additional studies in dogs justified the
    alteration of the temporary ADI to a full ADI.

    Level causing no toxicological effect

         Mouse: 3 mg/kg bw/day
         Rat: 1 mg/kg bw/day
         Dog: 30 ppm in the diet, adjusted to give 0.75 mg/kg bw/day

    Estimated acceptable daily intake for man

         0 - 0.008 mg/kg bw

    FURTHER WORK OR INFORMATION

    Desirable

    1.   A study to elucidate the possible effect on the immune system.

    2.   A study to determine the possibility of CNS effects.

    REFERENCES

    Gerbig, G.G. and Warner, S.D. Results of a six month oral (dietary)
    1975      toxicity study of tricyclohexyltin hydroxide in male beagle
              dogs (Dow Chemical Company. (Unpublished)

    McCollister, S.B.  et al. Cyhexatin: Results of a 13-week toxicity
    1980      study in the diet of B6C3F1 mice. Dow Chemical Company.
              (Unpublished)

    Keyes, D.G.  et al. Cyhexatin: Results of a two-year dietary toxicity
    1981      and oncogenic study in male and female B6C3F1 mice. Dow
              Chemical Company. (Unpublished)

    Reuzel, P.G.J. Sub-chronic (13-week) activity study with TCHT in
    1977      beagle dogs. Report No. R5464. Central Institute for
              Nutrition and Food Research, The Netherlands. (Unpublished)

    Van der Heijden, C.A. Letter d.d. 7-8-1980, to Dow Chemical Europe
    1980

    Warner, S.D., Ayers, K.M., Gerbig, G.G. and Strebing, R.J. Results of
    1977      a two-year chronic toxicity study of tricyclohexyltin
              hydroxide administered to rats by the dietary route. Report
              by Dow Chemical Company, U.S.A. (Unpublished)


    See Also:
       Toxicological Abbreviations
       Cyhexatin (WHO Pesticide Residues Series 4)
       Cyhexatin (WHO Pesticide Residues Series 5)
       Cyhexatin (Pesticide residues in food: 1978 evaluations)
       Cyhexatin (Pesticide residues in food: 1980 evaluations)
       Cyhexatin (Pesticide residues in food: 1983 evaluations)
       Cyhexatin (Pesticide residues in food: 1989 evaluations Part II Toxicology)
       Cyhexatin (Pesticide residues in food: 1991 evaluations Part II Toxicology)
       Cyhexatin (JMPR Evaluations 2005 Part II Toxicological)