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Three in vitro genetic toxicity studies, namely a mammalian gene mutation assay, a chromosome aberration test and an Ames test were performed in compliance with GLP with FAT 41030 a structural analogue of FAT 41045. Both substances are very similar in their chemical structure and, as demonstrated, in a number of physicochemical properties. Therefore, the use of these studies for read-across is considered to be appropriate, thus avoiding duplicate tests.

To meet the requirement of Korea registration, in vivo micronucleus test of FAT 41045 was conducted.

The mammalian gene mutation study (OECD 476) was performed to investigate the potential of FAT 41030 to induce gene mutations at the HPRT locus in V79 Chinese hamster cells. The assay comprised two independent experiments. In the first experiment, the cells were exposed to FAT 41030 for 4 hours with and without metabolic activation, in the second experiment the cells were exposed for 24 hours in the absence of metabolic activation. Relevant toxic effects were not evident up to the maximum concentration with and without metabolic activation. No relevant and reproducible increase of the mutation frequency was observed up to the highest investigated concentration in both experiments.

 

The chromosome aberration test (OECD 473) was conducted to assess the potential to induce structural chromosome aberrations in V79 Chinese hamster cells in vitro in two independent experiments. In both experiments, biologically relevant increases in the number of cells carrying structural chromosomal aberrations were not evident after treatment with the test material. Biologically relevant increases in the frequencies of polyploid metaphases were also not evident after treatment with the test item as compared to the frequencies of the controls. Hence, FAT 41030 did not induce structural chromosome aberrations in V79 cells.

 

However, the Ames test (OECD 471) performed to investigate the potential of FAT 41030 to induce gene mutations gave a positive result. In this test, Salmonella typhimurium strains TA 1535, TA 1537, TA 98 and TA 100, and Escheria coli strain WP2 uvrA were used. An additional experiment was performed with strain TA 98 using the plate incorporation method. The assay was performed with and without liver microsomal activation. In strain TA 1537 no bacterial growth was observed in experiment I and an additional experiment was performed. Due to the erratic result obtained in this experiment these data had to be dismissed and a third experiment was performed according to the plate incorporation method. The test item was tested at 33; 100; 333; 1000; 2500 and 5000 µg/plate. No toxic effects, evident as a reduction in the number of revertants, occurred in the test groups with and without metabolic activation. No substantial increase in revertant colony was observed following treatment with FAT 41030 at any dose level, neither in the presence nor absence of metabolic activation (S9 mix), except, for strain TA 98 where an increase in revertant colony numbers was observed with and without metabolic activation in all experiments. In conclusion, under the experimental conditions reported, FAT 41030 did induce gene mutations by frameshifts in the genome of strain TA 98.

 

Results of the gene mutation and chromosome aberration studies were negative although the Ames test indicated positive results only for TA 98, the latter being due to a specific bacterial mechanism of the test substance. However, the mammalian mutagenicity studies gave the negative result and these results are more reliable because with these cells there is more similarity to the human metabolic environment. Thus, it is concluded that there is no indication genetic toxicity of FAT 41030 under the experimental conditions.

The in vivo micronucleuas test (OECD 474) was conducted to evaluated for its clastogenic activity and/or disruption of the mitotic apparatus by detecting micronuclei in polychromatic erythrocyte (PCE) cells in rat bone marrow. And under the conditions of this study, the administration of FAT 41045/A TE at doses up to and including a dose of 2000 mg/kg was concluded to be negative in the Micronucleus assay.

Thus, it is concluded that there is no indication genetic toxicity of FAT 41045 under the experimental conditions.


Justification for selection of genetic toxicity endpoint
Each endpoint is considered similarly important, as they highlight different aspects of genetic toxicity.

Short description of key information:
In conclusion under the experimental conditions reported FAT 41030 did not induce mutagenic effects. The same is concluded for the target substance FAT 41045. Also FAT 41045 showed negative result in in vivo micronucleuas test.

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

Based on the available results, FAT 41030 caused no mutagenic potential. Also, FAT 41045 also showed negative results in a in vivo micronucleus test. Therefore, FAT 41030 and its structural analogue FAT 41045 are not to be classified according to the CLP (Reg. 1272/2008) or DSD (Dir. 67/548/EEC) regulations.