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Additional information

The data set for test substance genetic toxicity is robust and provides a thorough evaluation of in vitro and in vivo gene mutations and clastogenicity/aneugenicity and in vivo clastogenicity/aneugenicity.

Negative results were observed in 3 in vitro studies in bacterial cells (assay).

In the mouse lymphoma assay, one negative and one ambiguous equivocal result were observed. However, in the assay with equivocal results, the increased mutant frequencies (MF) observed in the presence of S9 appeared spurious. The positive MF responses in the first and second trials are in low and intermediate dose levels and not accompanied by a dose-response. The dose-response seen in the third trial can be considered artificial based on the very narrow dose range that was tested; the increment between the dose levels is only 6µg/mL. Therefore, what actually might be a single response point appears in a dose-responsive manner. It can also not be excluded that test substance precipitation interfered with the assay, and that the responses seen can be considered in vitro specific. Additionally, these results were not reproducible, as demonstrated by the second mouse lymphoma study with negative results. The weight of evidence indicates that the test substance is not mutagenic.

Negative results were observed in 2 in vitro chromosome aberration (CA) tests in CHO cells. Positive results were observed in an in vitro chromosome aberration test in human peripheral blood cells. The in vitro CA assay in human blood was positive in the absence of S9. However, the observed responses are marginally exceeding the negative control historical range. The responses in the absence of S9 are 5.5 and 6.0, while the historical control range for this testing condition is 0-5. Also, there is no difference in the magnitude of the response between the 4 and 22 hour treatments. It can also not be excluded that test substance precipitation interfered with the assay, and that the responses seen can be considered in vitro specific.

Negative results were observed in an in vivo micronucleus/chromosome aberration test in mice. Toxicity, as evidenced by the clinical observation of piloerection, decreases in the ratio of polychromatic erythrocytes to erythrocytes, and decreased in the mitotic index, indicates that the test substance was bioavailable and produced cytotoxicity in the bone marrow. The weight of evidence indicates that the test substance is neither clastogenic nor aneugenic.

Therefore, the overall conclusion, based on the results from the robust data set, is that there is no genotoxic concern associated with the test material.


Justification for selection of genetic toxicity endpoint
Multiple OECD guideline, GLP studies have been identified as key for this endpoint. In addition the study selected above, Ames assay, in vitro chromosome aberration assay, mouse lymphoma assay, and an in vivo chromosome aberration assay are pertinent to the hazard conclusion for this endpoint.

Short description of key information:
The test substance is considered negative for genotoxicity.

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

Based on an assessment of the robust genetic toxicity data for this substance, the substance does not need to be classified for mutagenicity according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 (ATP02).