CARBENDAZIM     JMPR 1977

    Explanation

    Carbendazim was evaluated by the Joint Meeting in 1973 (FAO/WHO 1974).
    No recommendations for an acceptable daily intake were made. Further
    work and information were required, especially long-term studies for
    the investigation of chronic toxicity and carcinogenicity,
    reproduction and teratogenicity studies, metabolism and distribution
    studies in several animal species, elucidation of the effect on the
    liver in female rats and dogs and information on the nature and level
    of residues in meat, milk and eggs, after feeding animals on crops or
    feedstuffs treated with carbendazim. Some further data on residues and
    methods of analysis were evaluated in 1976 (FAO/WHO, 1977b).
    Additional toxicological data have now become available and are
    summarized in the following monograph addendum.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    TOXICOLOGICAL STUDIES

    Special study on mutagenicity

    Groups of 15 male rats were maintained on a diet containing
    carbendazim at concentrations of 0, 100 and 1000 ppm for 4 months.
    Following the feeding period the male rats were mated with untreated
    females for 10 consecutive weeks. No difference could be seen between
    control and treated animals with respect to the parameters ordinarily
    used in the dominant lethal test.

    Cytogenic analyses of chromosome aberrations in the bone marrow of
    male rats fed with 0, 100 and 1000 ppm carbendazim for 300 days gave
    likewise no indication of a mutagenic effect (Benes and Sram, 1976).

    Special study on carcinogenicity

    Mouse

    Groups of 10 Swiss mice, with a control group of 40 mice, aged 4-6
    weeks, at different stages of pregnancy were treated intragastrically
    with carbendazim (5x500 mg/kg) together with 0.05% sodium nitrite, in
    drinking water. This combination should result in the formation of
    2-methyl-M-nitrosobenzimidazole carbamate. The young were killed
    between week 20 and 43.

    Malignant lymphomas developed in 33.3% of young mice whose mothers
    were treated in the first week of pregnancy, in 53.3% of those whose
    mothers were treated during the second week and 38.8% of those born of
    mothers treated during the third week.

    Treatment during the whole period of pregnancy yielded on an average
    70.0% malignancy in offspring. In most cases the thymus was enlarged,
    infiltrating the thoracic wall. Enlarged tumorous lymph nodes and

    hepatomegaly were also observed. Electron microscopy showed tumour
    cells similar to lymphoblasts. However, administration of carbendazim
    or nitrite alone throughout pregnancy did not produce lymphomas in the
    first generation. In the offspring of the untreated control animals
    0.4% malignant lymphomas were observed Börzsönyl et al., 1976).

    Special study on cytogenicity

    Mouse

    In a micro-nucleus test ICR mice about 8 weeks old were used.
    Application of the test compound was either by intraperitoneal
    injection in DMSO (500 mg/kg) or by gavage in gum arabic solution (50,
    100, 500 and 1000 mg/kg).

    The test compound was given twice 24 hours apart and the animals were
    killed 30 hours after the first treatment. Using this technique
    results were negative. However when the compound was administered by
    the peroral route in acid solution a dose-related increased number of
    micro-nucleated erythrocytes was observed.

    An examination of the mouse-bone-marrow smears after two oral
    treatments with carbendazim at 1000 mg/kg, demonstrates that the
    action of carbendazim is on mitosis, by inhibiting the mitotic
    process, interfering somehow with spindle formation or spindle
    function. Carbendazim did not induce chromosome breakage in chinese
    hamster bone-marrow cells.

    From experiments with several benzimidazole derivates, it was,
    according to the author, evident that the methylcarbamate group plays
    the significant role in the spindle inhibitory action (Seiler, 1976).

    COMMENTS

    Carbendazim is formed during the degradation of benomyl and
    thiophante-methyl, to which an ADI for man was previously allocated.

    Malignant lymphomas were induced after 20-43 weeks in mice whose
    mothers were treated with carbendazim combined with nitrite. Treatment
    with carbendazim alone was ineffective.

    No indication of mutagenic activity was found in a dominant lethal
    test and in cytogene analyses of the bone marrow of rats treated with
    up to 1000 ppm of carbendazim in the diet.

    In a micro-nucleus test however, a dose-related increased number of
    nucleated erythrocytes was observed.

    Since the required toxicological data were not submitted, no
    recommendation for an ADI for humans can be made, the decisions on
    this compound were postponed to a future meeting.

    FURTHER WORK OR INFORMATION

    See Report of 1976 Meeting (FAO/WHO, 1977a, p. 27).

    REFERENCES

    Benes, V. and Sram, R. (1976) Mutagenicity Testing of Carbendazim
    (BCM) in Rats. Unpublished report of the Institute of Hygiene and
    Epidemiology, Prague.

    Börzsönyl, M., Pinter A., Surjan, A. and Farkas, I. (1976)
    Transplacental induction of lymphomas in Swiss mice by carbendazim and
    sodium nitrite. Int. J. Cancer, 17, no. 6, 742-747.

    FAO/WHO (1974) 1973 evaluations of some pesticide residues in food.
    AGP:1973/M/9/1; WHO Pesticide Residues Series No. 3.

    FAO/WHO (1977a) Pesticide residues in food. Report of the 1976 Joint
    Meeting of the FAO Working Party of Experts on Pesticide Residues and
    the WHO Expert Committee on Pesticide Residues. FAO Plant Production
    and Protection Series, No. 8; WHO Technical Report Series No. 612.

    FAO/WHO (1977b) 1976 evaluations of some pesticide residues in food.
    FAO/AGP:1977/M/5.

    Seiler, J.P. (1976) The mutagenicity of benzimidazole and
    benzimidazole derivatives. Cytogenetic effects of benzimidazole
    derivatives in the bone marrow of the mouse and the Chinese hamster.
    Mutation Research 40, 339-348.
    

    See Also:
       Toxicological Abbreviations
       Carbendazim (EHC 149, 1993)
       Carbendazim (HSG 82, 1993)
       Carbendazim (ICSC)
       Carbendazim (WHO Pesticide Residues Series 3)
       Carbendazim (Pesticide residues in food: 1976 evaluations)
       Carbendazim (Pesticide residues in food: 1978 evaluations)
       Carbendazim (Pesticide residues in food: 1983 evaluations)
       Carbendazim (Pesticide residues in food: 1985 evaluations Part II Toxicology)
       Carbendazim (Pesticide residues in food: 1995 evaluations Part II Toxicological & Environmental)
       Carbendazim (Pesticide residues in food: 1995 evaluations Part II Toxicological & Environmental)
       Carbendazim (JMPR Evaluations 2005 Part II Toxicological)