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    PESTICIDE RESIDUES IN FOOD - 1983


    Sponsored jointly by FAO and WHO






    EVALUATIONS 1983





    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, 5 - 14 December 1983

    Food and Agriculture Organization of the United Nations
    Rome 1985

    DAMINOZIDE

    TOXICOLOGY

    Explanation

           The 1977 JMPR was unable to establish an acceptable daily intake
    (ADI) for daminozide owing to a lack of an adequate long-term rat
    study and of information on the bio-transformation in animals. The
    teratogenicity study reviewed by that Meeting was conducted by
    Industrial Bio-Test Laboratories (IBT) and has been found invalid
    (FAO/WHO 1978).1

    TOXICOLOGICAL STUDIES

    Special Study on Teratogenicity

           Daminozide (99 percent pure) was administered daily by gavage at
    doses of 0, 300, 600 and 1 000 mg/kg to female Wistar rats from day 6
    to 15 of gestation. On day 22 the dams were sacrificed and uterine
    contents were removed and examined before necropsy. No signs of
    toxicity were observed. Pregnancy rates, numbers of corpora lutea,
    implantation and resorption rates, foetal deaths, sex ratio, foetal
    weights and number of live foetuses were not significantly different
    from control values. Neither the number of foetal anomalies nor the
    incidence of gross skeletal malformations was found to be
    significantly increased. Unfortunately, individual animal data were
    not reported (Khera et al. 1979).

    Special Studies on Carcinogenicity

    Mice

           Daminozide was administered from six weeks of age over the life
    span of Swiss albino mice as a 2 percent solution in the drinking
    water. Daily intake averaged 134 mg for males and 170 mg for females,
    equivalent to 6.7 g/kg/day and 8.5 g/kg/day, respectively. Groups of
    100 mice of either sex served as controls. The treatment significantly
    shortened survival times compared with untreated controls. Significant
    increases in the incidences of vascular, pulmonary and renal tumours
    were reported. The incidence of vascular neoplasms, principally
    hepatic angiosarcomas and angiomas, was reportedly increased from 8
    percent (controls) to 72 percent in treated females and from 5 percent
    to 74 percent in treated males. Similar increases in lung tumours,
    adenomas and adenosarcomas occurred in treated females (74 percent)


              

    1    See Annex 2 for FAO and WHO documentation.

    and treated males (72 percent) compared to untreated controls (15
    percent and 22 percent, respectively). In addition, 10 percent of
    treated males developed benign renal adenomas; none were reported in
    the controls. Further evaluation of this study was not possible as
    individual animal data was not reported (Toth et al. 1977).

           Groups of 50 male and 50 female Charles River B6C3F1 mice
    received daminozide for 104 weeks at 5 000 and 10 000 ppm in the diet,
    equivalent to 750 and 1 500 mg/kg/day. Twenty animals of either sex
    were used as controls. The animals were observed for a further week
    before sacrifice. The mean body weights of high-dose female mice were
    lower than those of the controls throughout the bioassay. However,
    mouse mortality was unaffected by daminozide treatment. Male mice
    exhibited a dose-related increase in hepatocellular carcinomas, which
    were significantly higher than controls at 10 000 ppm. However, the
    high incidence of these tumours in historical controls obscures the
    possible association of hepatocellular carcinomas with daminozide
    treatment. Furthermore, this trend was not observed in female mice.
    The incidence of alveolar or bronchiolar adenomas and carcinomas in
    treated males was not significantly higher than for the matched
    controls (NCI 1978).

    Rats

           Groups of 50 male and 50 female Fischer 344 rats were
    administered daminozide for 104 weeks at 5 000 and 10 000 ppm in the
    diet, equivalent to 250 and 500 mg/kg/day.

           Twenty rats of either sex served as controls. The animals were
    observed for a further week before sacrifice. Towards the end of the
    study, the mean body weight of the higher-dosed rats was slightly
    depressed. However, overall rat survival was not adversely affected by
    treatment, although male rats had a higher mortality from week 66 to
    the end of the study. Treated male rats exhibited a higher incidence
    of interstitial testicular cell tumours than controls. These tumours
    occur spontaneously at a high incidence in historical controls.
    Treated female rats had small numbers of endometrial adenocarcinomas
    and uterine leiomyosarcomas. Although these tumours were not present
    in the relatively smaller number of controls, the incidence was too
    low to be statistically significant. Nevertheless, the incidences of
    these tumours were higher than expected from historical control data
    (NCI 1978).

    COMMENTS

           Daminozide was reviewed by the 1977 Meeting but an ADI was not
    estimated. The rat teratogenicity study reviewed at that time was
    carried out by IBT and is invalid. A study subsequently published is
    inadequate for the evaluation of teratogenicity. Consequently, the
    Meeting deferred further consideration of this compound.

    FURTHER WORK OR INFORMATION

    Required (before an ADI can be estimated)

    1.     Adequate data to assess the carcinogenicity of daminozide.

    2.     An adequate teratogenicity study.

    3.     Information on biotransformation in animals.

    REFERENCES - TOXICOLOGY

    Khera, K.S., Whalen, C., Trivett, G. & Anyers, G. Teratologic
    1979          assessment of maleic hydrazide and daminozide, and
                  formulations of ethoxyquin, thiabendazole and naled in rats.
                  J. Environ. Sci. Health, B14(6): 1563-77.

    NCI. Bioassay of daminozide for possible carcinogenicity. CAS No.
    1978          1596-84-5. US National Cancer Institute, Bethesda, Md. PB-
                  285-073.

    Toth, B., Wallcave, L., Patil, L., Schmeltz, I. & Hoffman, D.
    1977          Induction of tumours in mice with the herbicide succinic
                  acid 2,2-dimethylhydrazide. Cancer Res., 37: 3497-3500.


    See Also:
       Toxicological Abbreviations
       Daminozide (Pesticide residues in food: 1977 evaluations)
       Daminozide (Pesticide residues in food: 1989 evaluations Part II Toxicology)
       Daminozide (Pesticide residues in food: 1991 evaluations Part II Toxicology)