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Diss Factsheets

Administrative data

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

The substance is negative in the Ames test (OECD TG 471).


The substance is negative in the Mouse Lymphoma Assay (OECD TG 490).


The substance is negative in the in vitro Micronucleus Assay (OECD TG 487).

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

Additional information

Ames test


The mutagenic activity of the substance in the bacterial reverse mutation test was evaluated in accordance with OECD guideline 471 and GLP. The test was performed in two independent experiments using Salmonella typhimurium strains TA 1535, TA 1537, TA 98, TA 100 and the Escherichia coli strain WP2uvrA, in the absence and presence of a liver fraction of Aroclor 1254-induced rats. The dose levels were selected based on observed cytotoxicity. Adequate negative and positive controls were included. In both tests, in all strains tested, in both the absence and presence of S9-mix, the test substance did not induce a more than 2-fold and/or dose related increase in the mean number of revertant colonies compared to the background spontaneous reversion rate observed with the negative control. It is concluded that the results obtained in Salmonella typhimurium strains TA 1535, TA 1537, TA 98 and TA 100, and in the Escherichia coli strain WP2 uvrA, in both the absence and presence of the S9-mix, indicate that the test substance is not mutagenic under the conditions employed in this study.


 


MLA test


The mouse lymphoma assay with the substance was conducted according to OECD 490 guideline and GLP principles. In the first experiment, the test item was tested up to and including concentrations of 15 and 40 μg/mL in the absence and presence of S9-mix, respectively. The incubation time was 3 hours. Relative total growth (RTG) was 9 and 12% in the absence and presence of S9-mix, respectively. In the second experiment, the test item was tested up to and including concentrations of 5 μg/mL in the absence of S9 -mix. The incubation time was 24 hours. The RTG was 10%. The mutation frequency found in the solvent control cultures was within the range of the acceptability criteria of this assay and within the 95% control limits of the distribution of the historical concurrent solvent control database, except in the second experiment in which the mutation frequency of one of the solvent control cultures was not within the range of the acceptability criteria. Since the mutation frequency was just below the lower limit of the acceptability criteria range and the mutation frequency of the other solvent control culture was within the acceptability criteria range, this deviation in the mutation frequency had no effect on the validity of the results of the second mutation experiment. Positive control chemicals, methyl methanesulfonate and cyclophosphamide, both produced significant increases in the mutation frequency. In the absence of S9-mix, the substance did not induce a significant increase in the mutation frequency in the first experiment. This result was confirmed in an independent experiment with modification in the duration of treatment. In the presence of S9-mix, the substance did not induce a significant increase in the mutation frequency. It is concluded that the substance is not mutagenic in the mouse lymphoma L5178Y test system.


 


In vitro Micronucleus assay


The test substance was evaluated in a micronucleus assay performed according to OECD 487 and following GLP using human lymphocytes both in the presence and absence of an exogenous metabolic activation system (S9-mix). Duplicate cultures of human lymphocytes, treated with the test item, were evaluated for micronuclei in binucleate cells at three dose levels, together with vehicle and positive controls. Three exposure conditions were used for the study. Experiment 1 used a 4‑hour exposure in the presence and absence of a standard metabolizing system (S9) at a 2% final concentration and Experiment 2 used a 24 -hour exposure in the absence of metabolic activation. At the end of the exposure period, the cell cultures were washed and then incubated for a further 24 hours in the presence of Cytochalasin B. The dose levels used in the main experiment were selected using data from the preliminary toxicity test where the results indicated that the maximum concentration should be limited by toxicity. The dose levels selected for the main experiment were 0, 7.5, 15, 20, 30, 60, and 120 µg/mL (4 -hour exposure without S9) and 0, 7.5, 15, 30, 45, 60, and 120 µg/mL (4 -hour exposure with S9 and 24 -hour exposure without S9). All vehicle (dimethyl sulphoxide (DMSO)) controls had frequencies of cells with micronuclei within the range expected for normal human lymphocytes. The positive control items induced statistically significant increases in the frequency of cells with micronuclei. Thus, the sensitivity of the assay and the efficacy of the S9-mix were validated. The test item was toxic to human lymphocytes but did not induce any toxicologically significant increases in the frequency of cells with micronuclei, using a dose range that included a dose level that induced approximately 50% reduction in CBPI. The test item was considered to be non-clastogenic and non‑aneugenic to human lymphocytes in vitro.

Justification for classification or non-classification

Based on the results of genotoxicity tests, the substance is not mutagenic and therefore it does not have to be classified for mutagenicity in accordance with EU CLP (EC no. 1272/2008 and its amendments).