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    CHINOMETHIONAT

    EXPLANATION

         Chinomethionat was evaluated by the JMPR in 1968 (as
    oxythioquinox), 1974, 1977, and 1981 (Annex 1, FAO/WHO 1969a, 1975a,
    1978a, and 1982a). At the 1974 and 1977 JMPR the following
    investigations were requested:

         1.   Studies on the identity and relative toxicity of
              metabolites.

         2.   An additional carcinogenicity study in another species, in
              view of hepatic toxicity observed in rodents.

         In 1981 new studies regarding mutagenicity, teratogenicity and
    eye and dermal irritation were received. The mutagenicity and
    teratogenicity studies are included and evaluated in the present
    monograph addendum.

         The 1984 JMPR decided to withdraw the temporary ADI (established
    at the meeting of 1977) of 0.003 mg/kg bw because requested studies
    had not been submitted.

         The outstanding study requirements and some additional studies
    have become available now and are summarized and discusses in this
    monograph addendum.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOLOGICAL DATA

    Toxicological Studies

    Special studies on carcinogenicity

         See under long-term studies.

    Special studies on teratogenicity

    Rats

         Groups of 25 female Wistar rats received 0, 10, 25, or 62.5 mg
    chinomethionat (purity, 95.1%)/kg bw by gavage from days 6-15 of
    gestation. The fetuses where delivered by caesarian section on day 20
    of pregnancy. The dams were observed daily ofr mortality and body
    weight. The number of implantations, live and dead fetuses, early and
    late resorptions and placenta weight were recorded. The fetuses were
    counted, sexed and weighed and studied for visceral and skeletal
    malformations.

         There were no effects observed on the dams and offspring except
    for a significantly decreased body weight gain in high dosed dams and
    a decrease in fetal and placental weight at all dose levels (not
    clearly and not significant at the highest dose (Renhof, 1986).

    Rabbits

         Groups of 15 rabbits (Himalayan strain) received 13 daily oral
    doses of either 0, 10, 30 and 100 mg chinomethionat (Purity, 91.5%)/kg
    bw from day 6-18 of gestation. The fetuses were delivered by caesarian
    section on day 29 of pregnancy. Maternal toxicity was observed in high
    dosed dams (e.g. diarrhoea, reduced feed intake, loss of weight) and
    in the same dose group a significant decrease in both the number and
    size of fetuses was found.

         Examination of the offspring by standard methods and the
    evaluation of the results gave no indication of teratogenicity
    (Schlülter, 1981).

    Special studies on mutagenicity

         Chinomethionat gave no mutagenic response in test with  Bacillus
     subtilis, Escherichia coli and  Salmonella typhimurium and the
    CHO/HGPRT cell mutation assay as well as in the micronucleus test with
    mice (see table 1.).


        Table 1.  Special studies on the mutagenicity of chinomethionat
                                                                                                                 

    Type of test          Test object       Concentration of      Purity     Results     References
                                            chinomethionat
                                                                                                                 

    In vitro

    Ames test (with       Salmonella        1 µg up to            91%        negative    Shirasu et al., 1979
    and without           typhimurium       5000 µg/plate
    metabolic             TA98, TA100
    activation)           TA1535, TA
                          1537 & 1538

    Reverse mutation      Escherichia       1 µg up to            91%        negative    Shirasu et al., 1979
    assay (with and       coli              5000 g/plate
    without metabolic     WP2 hcr
    activation)

    Recombination         Bacillus          20 µg up to           91%        negative    Shirasu et al., 1979
    assay                 subtilis          2000 µg/plate
                          M45 & H17

    CHO/HGPRT             Chinese           Non activated:        94.4%      negative    Yang, 1986
    mutation assay        hamster ovary     0.1, 0.5, 1.0,                   (1)
    (with and without     cells             1.5 and 2.0/µg/ml
    metabolic             (CHO-K1-BH4)      Activated: 0.1,                  negative
    activation)                             0.5, 1.0, 3.0                    (1)
                                            and 5.0 µg/ml
                                            dissolved in
                                            acetone
                                                                                                                 

    Table 1. (cont'd).
                                                                                                                 

    Type of test          Test object       Concentration of      Purity     Results     References
                                            chinomethionat
                                                                                                                 

    In vivo

    Micronucleus          NMRI mice         500 and 1000 mg/kg    95.2%      negative    Herbold, 1982
    test                                    (administered                    (1)
                                            orally twice,
                                            24 hr apart)
                                                                                                                  

    (1) Positive control yielded positive results.
    
    Special studies on reproduction

    Rats

         Groups of 10 male and 20 female SPF/Cpb rats were fed diets
    containing 0, 15, 60 and 240 ppm chinomethionat (purity 94.6%) in a
    two generation (two litters/generation) study. Diets were maintained
    during mating, gestation and lactation. Observations were made on
    general condition and behaviour, food consumption and body weight.
    Indices for fertility, gestation, viability, lactation and
    insemination as well as litter-and pupweight and abnormalities were
    recorded. Organ weights (liver, kidneys and gonads) were measured for
    the F1b parents only. All parental rats and pups of the highest dose
    group had yellow coats. Maternal toxicity was observed at 240 ppm and
    sometimes at 60 ppm as indicated by a lower body weight gain. F0
    females, F1b parents and F1b, F2a and F2b pups had decreased body
    weight gain at 240 ppm and F0 females and F2b pups also at 60 ppm. F2a
    mean littersize was significantly reduced in the highest dose group.
    Viability was significantly reduced in F1a, F2a and F2b pups at 240
    ppm. Fib females had increased relative liver and kidney weights at
    240 ppm. No effects were observed at 15 ppm (Eiben, 1984).

    Dogs

         The effect of chinomethionat on semen quality was evaluated in
    groups of beagle dogs (6/group) fed diets containing 0, 25, 75 and
    225 ppm chinomethionat (purity 91.5%). The study was part of the one
    year feeding study in dogs (see under short-term studies).

         Semen samples were obtained at 4 month intervals throughout the
    one-year study. Clinical abnormalities were not observed in the dogs
    before each semen collection. Semen samples were observed for volume,
    motility, status, sperm count, total viable sperm, color, viscosity,
    morphology and cellular debris. Evaluations of the three collections
    gives no evidence of reduced semen quality and quantity (Dahlgren,
    1981; Hayes, 1983).

    Special studies on thyroid function

         Groups of 100 male SPF/Cpb rats were fed diets containing 0, 10,
    25, 60, 150, and 500 ppm chinomethionat (purity 95.2%) for 8 weeks,
    surviving animals were observed for another 4 weeks. Besides growth
    and food intake, clinical chemical examinations, including T3 and T4,
    were measured on day 7, 21, 63, 70 and 84. At the same times
    radioiodine uptake by the thyroid was measured in 10 animals which
    were killed 24 hours after 131I administration.

         The fur of the animals of the 500 ppm group was yellow colored.
    In the highest dose group decreased body weight gain (also at 150 ppm)
    and increased relative liver weight were observed to occur in a
    dose-related manner. Thyroid function tests (T3 and T4, and iodine
    uptake) did not provide any indications of a dose- or time-related
    effect on functioning. No consistent differences were observed in
    these parameters nor in other clinical chemical parameters. No effects
    on weight or histopathology of the thyroid were found (Krötlinger
    et al., 1984).

    Short-term studies

    Rats

         Groups of SPF/Cpb rats (20/sex/group) were orally administered
    0, 10, 25, 60, 150, and 500 ppm chinomethionat (purity 95.2%) in the
    diet for three months. All animals were observed daily for mortality
    and clinical signs while body weight and food consumption were
    observed weekly. Hematology, blood chemistry and urinalysis
    examinations were recorded on 10 rats/group after one month and at
    termination of the study. After three months all animals were killed,
    selected organs weighed and complete gross and histopathological
    examinations were performed.

         There were no effects on appearance, behaviour and mortality
    except for high dosed rats which showed a yellow fur. Reduced body
    weight gain and food intake was observed in rats receiving 150 and
    500 ppm. At the highest dose level Hb, Ht, RBC and MCH were
    significantly decreased in both sexes. At the same dose level, females
    had a lower WBC count and males a higher thrombocyte count. In females
    Hb, Ht, RBC and MCH were also significantly decreased at 150 ppm. At
    60 ppm MCH values were still decreased in females after 3 months.
    Decreased protein levels in the urine were found in males and females
    (only after 3 months) at 500 ppm. Relative brain weight was
    significantly increased at 60 (males only), 150 and 500 ppm in both
    sexes. Relative liver and kidney weight were significantly increased
    in females at 150 and 500 ppm and relative lung and relative testes
    weight in males at the same dose levels. At 60 ppm, equal to 4 (males)
    - 4.6 (females) mg/kg bw, only marginal effects were observed
    (Krötlinger & Kaliner, 1983).

    Dogs

         Beagle dogs (6/sex/group) were orally administered 0, 25, 75, or
    225 ppm chinomethionat (purity 95.8%) in the diet for 52 weeks.

         No compound related effects were observed on clinical signs,
    mortality, urinalysis or ophthalmoscopy. Body weight was decreased in
    males and females at 225 ppm (sometimes significantly). Food
    consumption was significantly reduced in males at 225 ppm from week 36

    onwards. Hb, Ht, and RBC were reduced sometimes significantly in males
    and females at 225 ppm and sometimes also at 75 ppm. Alkaline
    phosphatase and alanine amino transferase values were increased in
    males and females receiving 225 ppm. In males absolute heart weight
    was significantly decreased at all dose levels and absolute liver and
    absolute adrenal weight decreased and relative spleen weight increased
    at 225 ppm. In females relative liver and kidney weight were increased
    at 225 ppm At histopathology, marked hepatopathy with early cirrhosis
    at 225 ppm and an increased severity of centrilobular hepatocellular
    pigmentation at 75 and 225 ppm were observed in both male and female
    dogs. Increased splenic hemosiderosis was noted in dogs fed 225 ppm.
    The NOAEL in this study is 25 ppm in the diet, equivalent to
    0.6 mg/kg bw (Hayes, 1983).

    Long-term studies

         Groups of 70 male and 70 female mice (NMRI) were fed diets
    containing 0, 90, 270 and 800 ppm chinomethionat (purity 95.2%) for 21
    months. Twenty male and 20 female mice per group were used for interim
    kill after 12 months. Observations included clinical signs, mortality,
    body weight, food consumption, hematology and clinical chemistry.
    Surviving mice were sacrificed after 21 months. Organs were weighed
    and comprehensive histopathological examinations were made.

         The mortality of males was significantly lower at 800 and
    270 ppm, whereas females showed a higher mortality at 800 ppm
    throughout the study and, at some examination times, also at 270 ppm.
    At 800 ppm growth rate was significantly reduced throughout the study
    in male mice and from week 75 onwards in female mice. At 800 ppm
    significantly decreased values for Hb, Ht and RBC and number of
    leucocytes (a nonsignificant decrease in Hb and Ht was also observed
    at 270 and 90 ppm) were observed in males after 52 weeks. At the end
    of the study males and females showed a nonsignificant decrease in Hb,
    Ht and RBC and a significant increase in MCH and MCV (males).
    Reticulocyte count was increased in females at both times. No
    consistent effects were found on clinical chemistry parameters with
    the possible exception of significantly increased urea values in
    females at 270 and 800 ppm after 21 months. Relative adrenal weight
    was not increased in a dose-related manner in males after 52 weeks.
    Relative testes and brain weight were significantly increased in males
    at 800 ppm. Relative spleen weight was significantly increased in
    females at all dose levels and in males at 270 and 800 ppm (only after
    52 weeks). Relative kidney weight was significantly increased in males
    and females (only after 52 weeks) at 800 ppm. Relative liver weight
    was increased in females at 270 and 800 ppm after 52 weeks. Relative
    heart weight was significantly increased in females at 800 ppm.

         At macroscopy an increased incidence of pale kidneys and a rough
    kidney surface was observed in females at 270 and 800 ppm. The
    incidence of progressive nephropathy was increased at 800 ppm.

         No enhanced tumor incidence was observed. At 90 ppm, equal to 16
    (males) - 21 (females) mg/kg bw, only marginal effects on the red
    blood cells were observed (Krötlinger, 1986).

    COMMENTS

         The 1984 JMPR withdrew the temporary ADI of chinomethionat
    because the required data, sufficient to carry out a new toxicological
    evaluation, had not been supplied. The data supplied to this meeting
    included studies on reproduction, teratogenicity, mutagenicity,
    carcinogenicity, a short-term study in rats and a 1-year study in
    dogs.

         In reproduction studies, chinomethionat caused decreased
    litter-size, pup weight and viability at maternally toxic dose levels.
    No adverse effects were found at 15 ppm. In teratogenicity studies
    with rats and rabbits, fetotoxicity and maternal toxicity were
    observed but no teratogenic effects were seen. The semen of dogs was
    not affected by chinomethionat administration.

         Chinomethionat was not mutagenic in a battery of tests.

         In a short-term study in the rat, the main effects were reduced
    body weight gain, reduced food intake, and anaemia. Marginal effects
    on red cells were observed at 60 ppm. In a special study with rats,
    changes in thyroid function were not observed. In a one-year study
    with dogs, growth inhibition, anaemia, an increase in serum alkaline
    phosphatase and in alanine amino transferase, as well as
    histopathological changes in the liver and spleen were found. In this
    study the NOAEL was 25 ppm.

         In a long-term toxicity/carcinogenicity study in mice, the same
    effects were found on body weight and hematological parameters.
    Relative organ weights were increased, especially those of the spleen.
    The kidneys showed histopathological changes (progressive
    nephropathy). With the lowest dose level tested (90 ppm) only marginal
    hematological changes were observed. The tumor incidence was not
    enhanced.

         The meeting considered these data together with the data
    previously evaluated in 1974 (acute toxicity and chronic toxicity in
    rats) and 1977 (biotransformation and acute toxicity of chinomethionat
    and its main metabolite) sufficient to allocate an ADI. The NOAEL for
    the rat was based on the long-term study evaluated at the 1974
    Meeting, showing no adverse effects at 12 ppm, the highest dose level
    tested.

    TOXICOLOGICAL EVALUATION

    LEVEL CAUSING NO TOXICOLOGICAL EFFECT

          Rat:    12 ppm in the diet, equivalent to 0.6 mg/kg bw/day
          Dog:    25 ppm in the diet, equivalent to 0.6 mg/kg bw/day

    ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN

         0-0.006 mg/kg bw.

    STUDIES WHICH WILL PROVIDE INFORMATION VALUABLE IN THE CONTINUED
    EVALUATION OF THE COMPOUND

         1.   Observations in man.
         2.   Ongoing studies to identify metabolites in rats and plants.

    REFERENCES

    Dahlgren, R.R., 1981. Evaluation of the effects of oxythioquinox on
    the semen quality in Canines. Unpublished report no. 222 d.d.
    11-11-1981 from Raltech Scientific Services. Submitted to WHO by Bayer
    AG, Bayerwerk, 5090 Leverkusen, FRG.

    Eiben, R., 1984. SS 2074 (new designation SAS 2074)
    (c.n. chinomethionat). Two generation study with rats. Unpublished
    report no. 12794 d.d July, 6 1984 from Institute of Toxicology, Bayer
    AG. Submitted to WHO by Bayer AG, Bayerwerk, 5090 Leverkusen, FRG.

    Hayes, R.H., 1983. Chronic dietary toxicity of oxythioquinox
    (Morestan) to dogs. Unpublished toxicology report no. 363 d.d.
    March 7, 1983 from Mobay Chemical Corporation, Stilwell, Kansas 66085
    USA. Submitted to WHO by Bayer AG, Bayerwerk, 5090 Leverkusen, FRG.

    Herbold, B., 1982. SS 2074/Chinomethionat (ISO), Oxythioquinox (BSI),
    Morestan active ingredient/Micronucleus test on the mouse to evaluate
    for mutagenic effect. Unpublished report no. 10616 d.d 5-12-1982 from
    Institute of Toxicology, Bayer AG. Submitted to WHO by Bayer AG,
    Bayerwerk, 5090 Leverkusen, FRG.

    Krötlinger, F., 1986. SAS 2074 (Chinomethionat, Morestan active
    ingredient). Chronic toxicology investigation with mice (Feeding study
    over 21 months). Unpublished report no. 14973 d.d August 8, 1986 from
    Institute of Toxicology, Bayer AG. Submitted to WHO by Bayer AG,
    Bayerwerk, 5090 Leverkusen, FRG.

    Krötlinger, F. & Kaliner, G., 1983. SS 2074 (Chinomethionat, Morestan
    active ingredient). Subchronic study of toxicity to rats (feeding
    study over three months). Unpublished report no. 12313 d.d
    December 19, 1983 from Institute of Toxicology, Bayer AG. Submitted to
    WHO by Bayer AG, Bayerwerk, 5090 Leverkusen, FRG.

    Krötlinger, F. Weber, H. & Kaliner, G., 1984. SS 2074 (Chinomethionat,
    Morestan active ingredient). Subchronic toxicological study with rats
    to establish the dose-time-effect relationship for the thyroid.
    Unpublished report no. 12485 d.d February 23, 1984 from Institute of
    Toxicology, Bayer AG. Submitted to WHO by Bayer AG, Bayerwerk,
    5090 Leverkusen, FRG.

    Renhof, M., 1986. SS 2074, common name chinomethionat. Study for
    embryotoxic effects on rats after oral administration. Unpublished
    report no. 14278 d.d 27.1/86 and 14278 d.d. 11.8.86 from Institute of
    Toxicology, Bayer AG. Submitted to WHO by Bayer AG, Bayerwerk,
    5090 Leverkusen, FRG.

    Schluter, G., 1981. SS 2074 (Morestan Active Ingredient) evaluation
    for embryotoxic and teratogenic effects in orally dosed rabbits.
    Unpublished report no. 9784 d.d. February 5, 1981 from Institute of
    Toxicology, Bayer AG. Submitted to WHO by Bayer AG, Bayerwerk, 5090
    Leverkusen, FRG.

    Shirasu, Y., 1979. Chinomethionat (Morestan) mutagenicity test on
    bacterial systems. Institute of Environmental Toxicology, Japan,
    November 16, 1979. Unpublished report, submitted to WHO by Bayer AG,
    Bayerwerk, 5090 Leverkusen, FRG.

    Yang, Li.L., 1986. CHO/HGPRT mutation assay in the presence and
    absence of exogenous metabolic activation microbiological associates.
    Unpublished report no. 772 d.d. 15-7-1986 from Mobay Corporation.
    Submitted to WHO by Bayer AG, Bayerwerk, 5090 Leverkusen, FRG.

    


    See Also:
       Toxicological Abbreviations
       Chinomethionat (WHO Pesticide Residues Series 4)
       Chinomethionat (Pesticide residues in food: 1977 evaluations)
       Chinomethionat (Pesticide residues in food: 1981 evaluations)
       Chinomethionat (Pesticide residues in food: 1983 evaluations)
       Chinomethionat (Pesticide residues in food: 1984 evaluations)