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Key value for chemical safety assessment

Additional information

The following considerations based on the similar substance are also applicable to the target substance. For read across justification see the relevant document in the read across section

Valid experimental data were available to assess the genetic toxicity in vitro and in vivo.

Gene mutation in bacteria

The test substance was mutagenic in a standard plate Ames test with and without metabolic activation according to OECD guideline 471 (tested up to 5000μg/plate with Salmonella typhimurium TA1535, TA 1537, TA 98 and TA 100; A bacteriotoxic effect was not observed but a precipitation of the test substance between 100 and 5000 µg/plate. Precipitation correlated with mutagenic activity. The result indicated that an impurity of the test material could have been responsible for the genotoxic effect.

In a second study the test substance was tested in a standard plate Ames test with and without metabolic activation according to OECD guideline 471 (tested up to 7500μg/plate with Salmonella typhimurium TA 100). A bacteriotoxic effect was observed for the test substance >6000 µg/plate. The test substance was mutagenic w/o metabolic activation in high amounts of >2000 µg/plate.

The test substance was again tested in a standard plate Ames test with and without metabolic activation according to OECD guideline 471 (tested up to 7500μg/plate with Salmonella typhimurium TA1535, TA 1537, TA 1538, TA 98 and TA 100. A bacteriotoxic effect was not observed. The test substance showed a strain-dependent weak to moderate mutagenic effect without metabolic activation from 2500µg/plate onward. In presence of metabolic activation no mutagenic effect was observed for TA1535,TA1538 and TA98 and a weak mutagenic effect for TA100 and TA1537 (>2500 µg/plate).

Bacterial tests indicated a mutagenic potential of the test substance, but not in each set-up and strain and particularly without metabolic activation. Thus, it was indicated that metabolic systems/enzymes from mammalian cells could detoxify the parent substance. Due to the fact that toxicokinetic studies indicated that the test substance could already be metabolized in the intestine, an intrasanguineous mouse host-mediated assay using Salmonella typhimurium TA 1535, TA98 or TA 100 was performed. Here, the indicator bacteria were inoculated into living animals and could subsequently be recovered from the liver and assayed for induced genetic effects. The test substance was administered per os up to 4000 µg/kg bw in Swiss random bred rats and the effect on intravenously injected bacteria that had been re-isolated from rat liver 3 h after inoculation was investigated. Revertant colonies in comparison to solvent controls were determined. The test substance showed no mutagenic activity.

Other tests in bacteria are currently not available.

Under the experimental conditions chosen in those studies, the test substance showed some mutagenic activity in the bacterial reverse mutation test on Salmonella typhimurium in the presence and particularly in the absence of a metabolic activation system. A modified test system where test substance and bacteria were processed in vivo, did not show any mutagenic activity of the test substance.

 

Gene mutation in mammalian cells

The potential of the test substance to induce gene mutations at the HGPRT locus using chinese hamster ovary cells was tested in vitro with and without metabolic activation according to OECD guideline 476 (tested up to 3420μg/ml). Cytotoxicity was observed in an intermediate concentration range around 20 µg/ml of test substance, presumably induced by inhibition of enzymes of the S9-mix. The test substance showed no mutagenic effects on the HGPRT locus of CHO cells.

 

Cytogenicity in mammalian cells

Actually, there is no information available.

 

Other studies

Actually, there is no information available.

 

Cytogenicity in vivo

The potential of the test substance to induce chromosome damage or spindle poisoning was investigated in an OECD guideline 474 conform standard micronucleus test study in male and female NMRI mice. Test substance was given orally in CMC-vehicle in concentrations of 1700,3400 and 6800 mg/kg bw (>limit dose tested in acute oral toxicity study) and bone marrow was isolated after 16,24 and 48 h. No signs of toxicity and no pathological changes of the organs were observed in any dose groups. Microscopic evaluation of bone-marrow derived erythrocytes showed that the test substance did not impair erythropoeisis, did not induce any chromosome-damaging (clastogenic) effects and did not impair chromosome distribution in the course of mitosis.

A second in vivo rat hepatocyte UDS indicator test was done according to OECD guideline 486. The test material was administered in water orally to rats (4000,2000,1000 and 500 mg/kg bw) and 4 h later hepatocytes were isolated, labelled with 3H-thymidine, processed and net nuclear grains were determined via microscopic evaluation. The test substance did not induce nuclear staining differently from vehicle control levels and no dose-related trend was observed, thus, the test material was inactive in the UDS-test in the dose range tested.

Short description of key information:

Gene mutation in bacteria

S. typhimurium TA 1535, TA 1537, TA 98, TA 100 with and without metabolic activation (Ames test, OECD 471): positive (BASF AG, 1993) (standard plate test).

S. typhimurium TA 1535, TA 1537, TA 1538, TA 98, TA 100 with and without metabolic activation (Ames test, OECD 471): weakly positive (BASF AG, 1984) (standard plate test).

S. typhimurium TA 100 with and without metabolic activation (Ames test): positive (BASF AG, 1986) (standard plate test).

S. typhimurium TA 1535, TA 100 with metabolic activation in vivo: negative (Hazleton Laboratories America, 1986).

Gene mutation in mammalian cells

Chinese hamster ovary cells (OECD 476;BASF AG, 1992): negative

Cytogenicity in mammalian cells

No data available

Cytogenicity in vivo

In vivo micronucleus test (OECD 474; BASF AG, 1985): negative

In vivo UDS-test (OECD 486; Hazleton Laboratories America, 1988): negative

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

The following considerations based on the similar substance are also applicable to the target substance. For read across justification see the relevant document in the read across section

The test substance showed genotoxic reactions only in in vitro experiments using bacteria (Ames test). In all other experiments using bacteria in vivo (host mediated assay), mammalian cells in vitro (CHO, hamster; HGPRT test), mammalian cells in a combined in vitro/in vivo study (UDS test) or whole animals (in vivo micronucleus test) the test substance did not exhibit any genetic activity.

Therefore, based on the information currently available, there is no need for classification of the test substance for mutagenic effects.