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EC number: 445-790-1
CAS number: 404362-22-7
The test material induced small but statistically significant increases
in the frequency of cells with aberrations in the 48 hour continuous
exposure group and in the 6(18)-hour exposure group. It should be noted
however, that in both cases the responses were within the historical
maxima for that time point, both were in comparison to very low vehicle
control values and were not part of any dose-related response.
Therefore, both increases were considered to be of no toxicological significance.
The test material did not induce any statistically significant increases
in the number of polyploid cells at any dose level in either treatment
This study was conducted according to a method which was designed to
assess the potential chromosomal mutagenicity of a test material on the
metaphase chromosomes of the Chinese Hamster Lung (CHL) cell line
according to OECD TG 473.
Duplicate cultures of Chinese Hamster Lung (CHI+) cells were treated
with the test material at several dose levels, together with vehicle and
positive controls. Five exposure groups were used: Experiment 1 included
a 6(18)-hour exposure, both with and without the addition of an induced
rat liver homogenate metabolising system; Experiment 2 included a
24-hour continuous exposure, a 48-hour continuous exposure and a repeat
of the 6(18)-hour exposure with metabolic activation.
The dose levels evaluated in the main experiments were selected from a
range of dose levels based on the results of a preliminary toxicity test
and were in the range of 3.75 to 120 µg/mL for the 6(18)-hour exposure,
both with and without S9, and 0.25 to 5 µg/mL for the 24 and 48-hour
The vehicle (solvent) controls gave frequencies of cells with
aberrations within the range expected for the CHL cell line. All the
positive control chemicals induced highly significant increases in the
frequency of cells with aberrations indicating the satisfactory
performance of the test and of the activity of the metabolising system.
The test material did not induce any toxicologically significant
increases in the frequency of cells with aberrations in any of the
exposure groups. The test material was shown to be toxic to CHL cells in
vitro and optimal levels of toxicity were achieved.
The test material was shown to be non-clastogenic to CHL cells in vitro.
This GLP study was designed to assess the mutagenic potential of the
test material. The method meets the requirements of the OECD TG 471.
Salmonella typhimurium strains TA1535, TA1537, TA98 and TA100 and
Escherichia coli strain WP2uvrA¯ were treated with the test material
using the Ames plate incorporation method at up to seven dose levels, in
triplicate, both with and without the addition of a rat liver homogenate
metabolising system (10% liver S9 in standard co-factors). The dose
range for the range-finding study was determined in a preliminary
toxicity assay and ranged between 0.5 and 1500 µg/plate depending on
presence or absence of S9-mix. The experiment was repeated on a separate
day using a similar dose range to the range-finding study, fresh
cultures of the bacterial strains and fresh test material formulations.
Additional dose levels were included in both experiments to allow for
the toxicity of the test material, ensuring there were a minimum of four
The vehicle (dimethyl sulphoxide) control plates gave counts of
revertant colonies within the normal range. All of the positive control
chemicals used in the test induced marked increases in the frequency of
revertant colonies, both with and without metabolic activation. Thus,
the sensitivity of the assay and the efficacy of the S9-mix were
validated. The test material caused a visible reduction in the growth of
the bacterial background lawn to all of the bacterial tester strains,
initially at 150 and 500 µg/plate without and with S9, respectively. The
test material was, therefore, tested up to the toxic limit. No test
material precipitate was observed on the plates at any of the doses
tested in either the presence or absence of S9-mix. No significant
increases in the frequency of revertant colonies were recorded for any
of the bacterial strains, with any dose of the test material, either
with or without metabolic activation.
The test material was considered to be non-mutagenic under the
conditions of this test.
The potential chromosomal mutagenicity of a test material on the
metaphase chromosomes of the Chinese Hamster Lung (CHL) cell line was
assessed according to OECD TG 473. Duplicate cultures of Chinese Hamster
Lung (CHI+) cells were treated with the test material at several dose
levels, together with vehicle and positive controls. Five exposure
groups were used: Experiment 1 included a 6(18)-hour exposure, both with
and without the addition of an induced rat liver homogenate metabolising
system; Experiment 2 included a 24-hour continuous exposure, a 48-hour
continuous exposure and a repeat of the 6(18)-hour exposure with
Potential to induce mutations
The study was performed to investigate the potential of Gaskamine 240 to
induce mutations at the mouse lymphoma thymidine kinase locus using the
cell line L5178Y. The study was performed under GLP and followed OECD TG
The study was performed in three independent experiments with and
without liver microsomal activation. The highest concentration (3440
μg/mL) applied in the pre-experiments was chosen with regard to the
molecular weight of the test item corresponding to a molar concentration
of about 10 mM. The concentration range of the main experiments was
limited by cytotoxic effects of the test item. Experiment I was
performed with and without metabolic activation with a treatment time of
4 hours. Experiment II was performed with a treatment time of 24 hours
in the absence and 4 hours in the presence of metabolic activation.
Relevant cytotoxic effects indicated by a relative total growth (RTG) of
less than 50% of survival in both parallel cultures were observed in the
first experiment at 10.0 and 20.0 μg/mL with and at 5.0 μg/mL without
metabolic activation. In the second experiment cytotoxic effects as
described above were noted at 10.0 μg/mL with and at 3.8 and 5.0 μg/mL
without metabolic activation. The recommended cytotoxic range of
approximately 10-20% relative total growth was covered in the second
experiment with and in the first experiment without metabolic
activation. In the first experiment with and the second experiment
without metabolic activation the RTG was in a range from 5.5 to 8.0% at
the maximum analysable concentration. Although the RTG dropped below 10%
the data are acceptable since the exception criteria set by the IWGT
apply. According to those criteria a set of data is acceptable provided
that there is no evidence of mutagenicity in a series of data points
between 100% to 25% and there is also a negative data point between 10%
and 1% RTG.
No substantial and reproducible dose dependent increase of the mutation
frequency was observed up to the maximum concentration with and without
metabolic activation. In the first culture of the first experiment
without metabolic activation the threshold of 126 plus the solvent
control count and the historical range of solvent controls was exceeded
at 2.5 μg/mL. This isolated increase was judged as irrelevant since no
comparable increase was noted in the parallel culture under identical
conditions or at the next higher concentration in both parallel
cultures. Furthermore, the increase was not dose dependent as indicated
by the lacking statistical significance. Another irrelevant increase of
the mutation frequency exceeding the threshold mentioned above occurred
in the second culture of the second experiment with metabolic activation
at 10 μg/mL. This increase, however, is based on the low solvent
control. The absolute value of the mutation frequency remained within
the range of the historical solvent controls.
Appropriate reference mutagens were used as positive controls and showed
a distinct increase in induced mutant colonies, indicating that the
tests were sensitive and valid.
In conclusion it can be stated that during the mutagenicity test
described and under the experimental conditions reported the test item
did not induce mutations in the mouse lymphoma thymidine kinase locus
assay using the cell line L5178Y in the absence and presence of
metabolic activation. Therefore, Gaskamine 240 is considered to be
non-mutagenic in this mouse lymphoma assay.
All the tests on genotoxicity were negative. The test item is therefore
considered to be non-genotoxic.
The test item is considered to be non-genotoxic, no classification
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