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EC number: 308-783-3
CAS number: 98510-75-9
Threshold = number of mutant colonies per
106cells of each solvent control plus 126
was not continued due to exceedingly severe cytotoxic effects
was not continued since a minimum of only four analysable concentrations
The study was performed to investigate
the potential of C8 -18 AAPB to induce mutations at the mouse lymphoma
thymidine kinase locus using the cell line L5178Y.
The assay was performed in two
independent experiments, using two parallel cultures each. The first
main experiment was performed with and without liver microsomal
activation and a treatment period of 4 h. The second experiment was
performed with a treatment period of 24 hours in the absence and 4 hours
in the presence of metabolic activation.
The main experiments were evaluated at
the following concentrations:
without S9 mix:
2.4; 4.9; 9.8; 19.5; and 39.0 µg/mL
with S9 mix: 4.9; 9.8; 19.5; 39.0; and 78.0
mix: 10; 20; 40; 50; and 60 µg/mL
mix: 40; 80; 100; 110; and 120 µg/mL
Relevant cytotoxic effects indicated
by a relative total growth of less than 50 % in both parallel cultures
were observed in the absence of metabolic activation at 39 µg/mL in
experiment I following 4 hour treatment and at 40 µg/mL and above in
experiment II following 24 hours treatment. In the presence of metabolic
activation toxic effects as described above occurred at 100 µg/mL and
above in experiment II. No reproducible cytotoxic effects were noted in
the first experiment with metabolic activation. The recommended toxic
range of approximately 10-20 % RTG was covered in the second experiment
with and without metabolic activation.
The isolated minor reduction of the
relative total growth to 43.5 % in the first culture of experiment I
with metabolic activation was not considered a real toxic effect since
no comparable reduction was observed in the parallel culture under
No substantial and reproducible dose
dependent increase of the mutation frequency was observed with and
without metabolic activation. The mutation frequency did not
reproducibly reach or exceed the threshold of 126 above the mutation
frequency of the corresponding solvent control in any of the
experimental parts. An isolated increase exceeding the threshold was
noted in the first culture of experiment I without metabolic activation
at 19.5 µg/mL. However, this increase was judged as irrelevant
fluctuation since it was not reproduced in the parallel culture under
identical experimental conditions. Furthermore, the increase was not
dose dependent as indicated by the lacking statistical significance. In
experiment II the mutant frequency exceeded the range of the historical
solvent control data at several test points without metabolic activation
(both cultures) and at one test point with metabolic activation (culture
I). However, the threshold described above was not reached at any test
point of the second experiment and no dose dependent increase was
indicated by statistical analysis.
A linear regression analysis (least
squares) was performed to assess a possible dose dependent increase of
mutant frequencies using SYSTATâ11statistics software.
No significant dose dependent trend of the mutation frequency indicated
by a probability value of <0.05 was determined in all experimental
In this study the range of the solvent
controls was from 130 up to 164 mutant colonies per 106cells;
the range of the groups treated with the test item was from 83 up to 275
mutant colonies per 106cells. The
solvent controls remained within the range of the historical data.
Methylmethanesulfonate (19.5 µg/mL in
experiment I and 13.0 µg/mL in experiment II) and cyclophosphamide (3.0
µg/mL and 4.5 µg/mL in both main experiments) were used as positive
controls and showed a distinct increase in induced total mutant colonies
at acceptable levels of toxicity with at at least one of the
concentrations of the controls.
There was no concentration related positive
response of induced mutant colonies over background.
This study is classified as acceptable. This
study satisfies the requirement for Test Guidelines Ninth Addendum
to the OECD Guidelines for the Testing of Chemicals, February 1998,
adopted July 21, 1997, Guideline No. 476 "In vitro Mammalian
Cell Gene Mutation Test“ and Commission Regulation (EC) No. 440/2008
B.17: ”Mutagenicity –In vitro Mammalian Cell Gene
Mutation Test“, dated May 30, 2008 for in vitro
mutagenicity (mammalian forward gene mutation) data.
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