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Genetic toxicity in vitro

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In this in vitro assessment of the mutagenic potential of FRET 11-0539, histidine-dependent auxotrophic mutants ofSalmonella typhimurium, strains TA1535, TA1537, TA98 and TA100, and a tryptophan-dependent mutant ofEscherichia coli, strain WP2 uvrA (pKM101), were exposed to FRET 11-0539 diluted in dimethyl sulphoxide (DMSO). DMSO was also used as a vehicle control.

Three independent mutation tests were performed in the presence and absence of liver preparations (S9 mix) from rats treated with phenobarbital and 5,6-benzoflavone. The first test was a standard plate incorporation assay; the second included a pre-incubation stage. A third mutation test using strain TA100 in the absence of S9 mix only was also performed, this test also included a pre-incubation stage.

Concentrations of FRET 11-0539 up to 5000 µg/plate were tested. This is the standard limit concentration recommended in the regulatory guidelines that this assay follows. Other concentrations used were a series ofcahalf-log10dilutions of the highest concentration.

No signs of toxicity towards the tester strains were observed in the first mutation test following exposure to FRET 11-0539. Toxicity (observed as a reduction in revertant colony numbers) was seen in strains TA98, TA100, and TA1537 in the absence of S9 mix and in strain TA1535 in the presence of S9 mix following exposure to FRET 11-0539 at concentrations up to 5000 µg/plate in the second test. Toxicity (observed as a thinning of the background lawn of non-revertant colonies and a reduction in revertant colony numbers) was seen in strain TA100 in the absence of S9 mix in the third test.

No evidence of mutagenic activity was seen at any concentration of FRET 11-0539 in any mutation test.

The concurrent positive controls verified the sensitivity of the assay and the metabolising activity of the liver preparations. The mean revertant colony counts for the vehicle controls were within or close to the current historical control range for the laboratory.

It was concluded that FRET 11-0539 showed no evidence of mutagenic activity in this bacterial system under the test conditions employed.

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

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