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.