Carbendazim

Endpoint summary

Key value for chemical safety assessment

Genetic toxicity in vitro

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (positive)

Genetic toxicity in vivo

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (positive)

Justification for classification or non-classification

The results lead to the conclusion tha Carbendazim should be considered as an aneugen not damaging the DNA directly but interacting with a non-DNA target receptor (tubulin). For aneugenic agents of this kind, a threshold for mutagenic activity does exist.

The experimental data show that for the induction of aneuploidy in vivo actually much higher oral doses are required to obtain effective blood or tissue conc. than one would expect on the basis of a direct extrapolation from the in vitro effective concentrations. A single oral dose of 50 mg/kg bw did not increase the frequency of micronucleated erythrocytes in mouse bone marrow, while the lowest oral dose causing an increase in micronucleus incidence was 100 mg/kg bw (12 ug carbendazim/ml). In contrast, a continuous blood conc. of 8 ug carbendazim/ml was not sufficient to increase the micronucleus frequency.

The lowest single oral NOEL in rat germ cells was also 50 mg/kg bw.

Carbendazim did not induce mutation in S.typhi. G46 by means of the host mediated assay and urine of rats treated with 200 mg/kg carbendazim failed to induce mutations in the Ames test.

Carbendazim and benomyl did not induce structural chromosome aberrations and/or lethal gene mutations in mouse and rat germ cells as investigated in several dominant lethal assays using single or multiple exposure protocols.

It can be stated that carbendazim is devoid of gene mutagenic or clastogenic activities, despite of occasional positive findings in in vitro tests.

Positive findings have been traced to aminophenazine by-product impurities which are reduced in present manufacturing processes to amounts < 3.5 ppm, not inducing gene mutations in S.typhi. strains.

Carbendazim does not cause gene mutation or structural chromosome aberrations in in vivo tests for germ cell effects.

Carbendazim was positive in assays for numerical chromosome aberrations; these effects are related to the mechanicm of action of the fungicide. As a consequence cytokinesis is inhibited and aneuploidy is produced above a threshold concentration required for tubulin binding.

It appears reasonably to rely on the in vivo NOAEL of 50 mg/kg bw for the induction of aneuploidy. Unlike primary mutagens, carbendazim does not interact with DNA and does not cause gene mutations or structural chromosome aberrations.

With regard to the positive results in the above-mentioned assays and the threshold which could be estimated for aneuploidy, a classification of carbendazim as mutagen is supported.