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Additional information

The mutagenic potential of BAY 43-9006 (sorafenib base) was initially screened (similar to OECD TG 471) with one plate per dose using the Salmonella/microsome test with the S. typhimurium strains TA 98, TA 100, TA 102, TA 1535 and TA 1537 in the presence and absence of S9 mix (Herbold, 1998). Evidence of mutagenic activity was not seen up to assessable doses of up to 16 µg per plate. No biologically relevant increase in the mutant count, in comparison with the negative controls, was observed. All tested doses caused bacteriotoxic effects. Therefore, the used dose range could only be used to a limited extent up to and including 16 µg per plate for assessment purposes. Substance precipitation occurred at the dose 1600 µg per plate and above (Herbold, 1998). Based on this test, BAY 43-9006 was considered to be non-mutagenic without and with S9 mix in the plate incorporation as well as in the preincubation modification of the Salmonella/microsome test.

In a second trial the mutagenic potential of BAY 54-9085 (tosylate salt of sorafenib) was investigated using the Salmonella/microsome test with the S. typhimurium strains TA 98, TA 100, TA 102, TA 1535 and TA 1537 in the presence and absence of S9 mix according to OECD TG 471 (Herbold, 2000a). Evidence of mutagenic activity was not seen up to assessable doses of up to 64 µg per plate. No biologically relevant increase in the mutant count, in comparison with the negative controls, was observed. Doses up to and including 8 µg per plate did not cause any bacteriotoxic effects. At higher doses, the substance had a strong, strain-specific bacteriotoxic effect, so that this range could only be used to a limited extent up to and including 64 µg per plate for assessment purposes. Substance precipitation occurred at the dose 5000 µg per plate. Based on this test, BAY 54-9085 was considered to be non-mutagenic without and with S9 mix in the plate incorporation as well as in the preincubation modification of the Salmonella/microsome test.

 

The clastogenic potential of BAY 54-9085 (tosylate salt of sorafenib)was evaluated in a chromosome aberration test on Chinese hamster V79 cells in the presence and absence of S9 mix according to OECD TG 473 (Herbold, 2000b). Without S9 mix cytotoxic effects were observed at 10 µg/ml and above. With S9 mix cytotoxic effects were observed at 20 µg/ml and above. Precipitation of BAY 54-9085 in the medium was not observed.In the presence of S9 mix cultures treated with 40 µg/ml BAY 54-9085 showed biologically relevant and statistically significant increased numbers of aberrant metaphases. No clastogenic effects were observed without S9 mix. Based on the results of this test, BAY 54-9085 is considered to be clastogenic for mammalian cells in vitro.

 

In addition, a possible clastogenic potential of BAY 54-9085 (tosylate salt of sorafenib) was examined in the mouse micronucleus assay according to OECD TG 474 (Herbold, 2000c). In this test male NMRI mice received two intraperitoneal administrations of 125, 250 and 500 mg BAY 54-9085/kg bw, respectively, separated by 24 hours. Males of the positive control received a single intraperitoneal treatment with 20 mg/kg cyclophosphamide. The femoral marrow of all groups was prepared, 24 hours after the last administration. Males treated twice with BAY 54-9085 in doses up to 500 mg/kg showed symptoms of toxicity after administration, starting at 125 mg/kg. However, all males survived until the end of the test. There was no altered ratio between polychromatic and normochromatic erythrocytes. After two intraperitoneal treatments of males with doses up to and including 500 mg/kg no indications of a clastogenic effect of BAY 54-9085 were found. Thus, BAY 54-9085 was concluded to be negative in the mouse micronucleus assay.

In summary, genetic toxicology testing revealed no potential for mutagenicity of BAY 43-9006 (sorafenib base) in the Ames test. The micronucleus test for clastogenicity in NMRI mice with intraperitoneal BAY 54-9085 (tosylate salt of sorafenib) doses of 0, 125, 250 or 500 mg/kg bw (sorafenib dose up to 365 mg/kg bw) was negative giving evidence that the test item does not exhibit a significant clastogenic potential in vivo.


Justification for selection of genetic toxicity endpoint
No study was selected, since all relevant key studies (Ames tests and mouse micronucleus test) were negative.

Short description of key information:
Salmonella/microsome test (Ames test; strains TA 98, TA 100, TA 102, TA 1535 and TA 1537 ): negative (+/- S9 mix)
Mouse micronucleus test: negative
Data waiver is claimed for gene mutation test in mammalian cells.

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

Based on the study results a classification according to Regulation (EC) No.1272/2008 (CLP) is not required.