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EC number: 946-788-8
CAS number: -
The test item was examined for mutagenic
activity by assaying for the induction of 5-trifluorothymidine resistant
mutants in mouse lymphoma L5178Y cells after in vitro treatment, in the
absence and presence of S9 metabolic activation, using a fluctuation
method according to the OECD Guideline 490 (2016).
A preliminary solubility trial indicated
that the maximum practicable concentration of the test item in the final
treatment medium was 3400 μg/mL using Minimal Medium A as solvent. On
the basis of this result, a cytotoxicity assay was performed, both in
the absence and presence of S9 metabolic activation, using 9 dose levels
up to 3460 μg/mL.
Based on the results obtained in the
preliminary trial, the first mutation assay was performed using the
following dose levels:
(−S9, 3 h treatment): 830, 692, 576, 480
and 400 µg/mL;
(+S9, 3 h treatment): 865, 721, 601, 501,
417 and 348 µg/mL.
In the absence of S9 metabolic activation,
severe toxicity, reducing Relative Total Growth (RTG) below 10%, was
observed at all concentrations tested, thus the evaluation of mutagenic
effects could not be performed. In the presence of S9 metabolism, severe
toxicity was noted at the three highest concentrations tested, while
marked to moderate toxicity was observed over the three remaining dose
levels, where dose related increases in mutation frequency were noted.
At the highest analysable concentration (501 μg/mL) the RTG was reduced
to 13 % and the observed increase was higher than the Global Evaluation
Factor (GEF). Based on the results obtained, in order to evaluate a
potential mutagenic effect in a sufficient number of concentrations at
adequate levels of cytotoxicity, a second mutation assay was performed,
both in the absence and presence of S9 metabolism, using the short
treatment time and the following lower range of concentrations:
(−S9, 3 h treatment): 346, 288, 240,
200,167, 139 and 116 µg/mL;
(+S9, 3 h treatment): 498, 415, 346, 288,
240 and 200 µg/mL.
Adequate levels of cytotoxicity, covering
a range from the maximum to slight or no toxicity, were observed in both
treatment series. In the presence of S9 metabolism, the induced mutation
frequency was lower than the Global Evaluation Factor (GEF) at all
concentrations tested. However, a statistically significant dose effect
relationship was observed and mutation frequency at the highest
concentration of 498 μg/mL fell out the distribution of the historical
negative control data (95% control limits). In the absence of S9
metabolism, a linear trend was indicated and at the highest dose level,
the observed increase was higher than the GEF and thus was considered a
clear evidence of positive result.
Appropriate negative and positive control
treatments were included in each mutation experiment. The mutant
frequencies in the solvent control cultures fell within the normal
range. Marked increases were obtained with the positive control
treatments indicating the correct functioning of the assay system.
It is concluded that the test item induces
mutation at the TK locus of L5178Y mouse lymphoma cells in vitro in the
absence or presence of S9 metabolic activation, under the reported
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