Registration Dossier

Administrative data

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

negative in Ames Test with Salmonella strains TA 98, TA 100, TA 1535 and TA 1537 (with and without microsomal activation) and negative in Yeast Test in Saccharomyces cerevisiae MP-1 (with and without microsomal activation).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Genetic toxicity in vivo

Description of key information

negative in Chromosome Aberration Test in Chinese Hamster bone marrow cells, spermatogonia, spermatocytes;

negative in Micronucleus Assay in Chinese Hamster bone marrow cells

negative in SCE-Assay in Chinese Hamster bone marrow cells

negative in Dominant Lethal Study in mice

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Additional information

The substance was evaluated for its mutagenic and genotoxic potential in-vitro and in-vivo. Overall the data do not indicate any mutagenic or genotoxic potential of the substance.

in-vitro-Tests:

No evidence for a mutagenic effect was obtained in Salmonella strains TA 98, TA 100, TA 1535 and TA 1537 treated with up to 81 µg per plate in experiments with and without microsomal activation.

No evidence for a mutagenic effect was obtained in Saccharomyces cerevisiae MP-1 treated with up to 10000 µg per plate in experiments with and without microsomal activation.

in-vivo-Tests:

No evidence for a clastogenic effect in Chinese Hamster bone marrow cells was obtained after treatment for two consecutive days by gavage with up to 2000 mg/kg bw/day.

No induction of SCE's in Chinese Hamster bone marrow cells occurred after treatment by gavage with up to 6000 mg/kg bw. In the first experiment one of four animals of the high dose group (4444 mg/kg) showed a statistically significantly increased frequency of SCE's. A statistical analysis of the trends, including all dosage groups, also yielded a positive result. In the repeat experiment performed with doses of up to 6000 mg/kg, the number of SCE's in all treatment groups showed no significant increase in comparison with the concurrent negative control. A statistical analysis of the trends, likewise yielded a negative result in this second experiment. From the results of both investigations together, it can be concluded that the higher rate of SCE's in one animal in the highdose group in the first experiment was purely fortuitous and not due to the test substance.

No evidence for a clastogenic effect or induced aneuploidy in Chinese Hamster bone marrow cells was obtained after treatment by gavage with 500, 1000 or 2000 mg/kg test substance.

No evidence for a clastogenic effect or induced aneuploidy in male mice spermatogonia and spermatocytes was obtained after treatment by gavage with 1481 and 4444 mg/kg.

No evidence for Dominant Lethal effects or reduced male fertility was obtained in male mice treated by gavage with either 1000 or 3000 mg/kg bw.

The studies were found to be adequate to fulfill the purposes of this endpoint.

Assessment of the need of performing studies on mutagenicity in mammalian cells in vitro with test substance

The test on genotoxicity in mammalian cells in vitro will not give any further useful information on genotoxicity. The main argument is that the substance was found to be non carcinogenic in a carcinogenicity study in rats. The study is adequate in design and quality to assess the endpoint of carcinogenicity.

Mutagenicity is one mode of action for the development of cancer and so a carcinogenicity study may give an indication on in-vivo mutagenicity.

In addition, the following arguments are given:

a) The water solubility of the substance is <0.005mg/l (at 20°C) and therefore, due to the sensitivity of cultivated cells to precipitates, the mutagenicity test with mammalian cells in vitro could only be performed with very low concentrations.

b) The substance does not carry structural alerts as identified by the rules of Zeiger (Zeiger, E.; Anderson, B.; Haworth, S.; Lawlor, T.; Mortelmans, K., (1992). Salmonella mutagenicity tests: V. Results from the testing of 311 chemicals. Environ Mol Mutagen, 19 Suppl 21, 2-141.)

c) The substance does not carry structural alerts as identified in the knowledge base of DEREK (Lhasa Inc.).

d) The substance is not mutagenic in the Ames test.

e) No adverse effects were observed in the dominant lethal study in rats.

f) The substance neither induces sister-chromatide-exchanges nor chromosome-aberrations in-vivo.

Justification for classification or non-classification

There are conclusive but not sufficient data for classification of the test substance with regard to mutagenicity.

The substance is not classified for this endpoint in accordance to the CLP Regulation (EC) No 1272/2008