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In vitro studies

Several studies were carried out according to EU Method B.13/14 and OECD Guideline 471 (Bacterial Reverse Mutation Assay). Tested strains include Salmonella typhimurium TA 1535, TA 1537, TA 1538, TA 98, TA 100 and TA102 at concentrations up to 10000 ug per plate, without and with metabolic activation (S9-mix). The test item was not mutagenic in all tests and bacterial strains. The test material did not induce point mutations by base-pair changes or frame shifts in genomes and no significant increases in the frequency of revertant colonies.

Clastogenic potential was assessed using Chinese hamster ovary (CHO) cells in vitro according to EU Method B.10 and OECD Guideline 473 (In vitro Mammalian Chromosome Aberration Test). The tests were performed up to limit concentrations 5000 ug/mL, both in the presence and absence of metabolic activation. The test item was devoid of clastogenic potential and did not induce aberrations.

Mutagenic activity was tested according to EU Method B.17 and OECD Guideline 476 (In vitro Mammalian Cell Gene Mutation Test) up to limit concentrations (5000 mg/mL), both the presence and absence of metabolic activation. No evidence of mutagenic activity was obtained.

Potential to induce mitotic recombination in the yeast Saccharomyces cerevisiae was assessed according to EU Method B.15 and OECD Guideline 481 (Genetic Toxicology: Saccharomyces cerevisiae, Mitotic Recombination Assay). Yeast cells were exposed to the test substance up to the maximum attainable concentrations (limit of its solubility)in the absence and presence of metabolic activation. The test did not induce mitotic recombination in Saccharomyces cerevisiae.

The ability to induce micronuclei was assessed in Chinese hamster ovary cells, following methods described in methods published in the literature. In the absence and presence of metabolic activation cells were treated up to cytotoxic concentrations. No statistically significant increase in the incidence of micronucleated cells over control values was observed. It was concluded that the test item does not induce micronuclei in Chinese hamster ovary cells.

A study was carried out according to OECD Guideline 476 (In vitro Mammalian Cell Gene Mutation Test) assessing the test item for mutagenic activity in mouse lymphoma in the absence and presence metabolic activation. A maximum dose-level of 2000 ug/mL was chosen based on cytotoxicity. The test item did not induce mutations.

In vivo studies

A key study was carried out according to EU Method B.11 and OECD Guideline 375 (Mutagenicity - In Vivo Mammalian Bone-Marrow Chromosome Aberration Test) testing for cytogenetic effects in young adult male and female CD rats. Based on toxicity data concentrations of 200, 640 and 2000 mg/kg bw/day were selected and groups of 5 male and female rats were dosed for 5 consecutive days. No significant differences in the chromosomal aberration frequencies between the vehicle control and test compound treated animals were observed and it was concluded that the test item was not capable of inducing structural or numerical aberrations in bone marrow cells of male and female rats.

In addition a supporting study was carried according to EU Method B.12 and OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test) with the analog substance Nicotinamide. No statistically significant test material-related increase in the number of micronucleated polychromatic erythrocytes was present in either male or female mice at the 24-hour sampling time, in females at the 48-hour sampling time, in males at the 72-hour sampling time, and when analyzed both sexes combined at the 24- and 72-hour sampling times. The statistically significant positive response in males of the 48-hour sampling time and in females of the 72-hour sampling time of the main test could not be verified during the repetition test using two additional dose levels. Therefore, according to the criteria of assessment, Nicotinamide is non-mutagenic in the reported in vivo mouse micronucleus test.


Short description of key information:
A number of in vitro studies on genotoxicity were carried out, including several Ames tests, a chromosome aberration assay, a gene mutation assay, a mitotic recombination assay, a micronucleus test, and a mouse lymphoma assay. Further, the test item was assessed in an in vivo chromosome aberration assay. Additionally, a read-across in vivo micronucleus study testing the analog substance Nicotinamide was available. None of the in vitro or in vivo studies performed revealed evidence for mutagenic or genotoxic potential. Therefore, the substance is considered non-genotoxic.

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

Based on the data available the substance is not classified and labeled according to Regulation 1272/2008/EEC (CLP) and Directive 67/548/EEC (DSD).