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EC number: 603-837-5
CAS number: 134605-64-4
Table 1. Group mean net grain count values
Dose / mg/kg
Net nuclear grain count (NG)
Net grain count of cells in repair
Percent of cells in repair (NG >= 2)
0 Negative Control (Vehicle only)
10 DMN Positive Control
Hepatocyte preparations of good quality were obtained
with all animals from all dosage groups. Viability after perfusion was
determined to be between 83 and 95%.
Evaluation of the mean nuclear counts of silver grains in
the vehicle controls and after treatment with test substance revealed no
marked differences (Table 1). In consideration of the silver grain
number over the cytoplasm, the mean net nuclear grain counts were
calculated and there was no marked deviation between the treatment
groups and the vehicle controls. Also the percentage of cells in repair
(net nuclear grain count ~ 2.0) revealed no marked differences in
comparison with the vehicle controls. By contrast, the positive control
DMN (15 mg/kg) yielded a marked increase in the mean nuclear grain
counts and the mean net nuclear grain counts in comparison with the
negative. The percentage of cells in repair was also clearly increased.
The test substance was investigated for DNA-damaging
effects on rat hepatocytes after application in vivo and further
investigation of unscheduled DNA synthesis (UDS) in vitro. The assay is
designed to measure unscheduled DNA synthesis (UDS, DNA-repair
synthesis) in freshly isolated rat liver cells (hepatocytes) as a
consequence of DNA-damage induced after in vivo treatment of the animals
with the test substance. The advantage of this test system is, that not
only metabolites formed in the liver itself, but also those formed in
the various other organ and cell systems may have an effect in the
hepatocytes. Hepatocytes are isolated by perfusion technique, and
unscheduled DNA-synthesis caused by the test substance or its
metabolites is detected by reference to the incorporation of 3H-TdR into
DNA during in vitro culture. DNA-repair is determined by scoring
autoradiographs (counts of silver grains over the nuclei; nuclei with<
120 grains are analysed and counts of silver grains over nuclear-sized
cytoplasmic areas). There is ample evidence that occurrence of
unscheduled DNA-synthesis is closely correlated with mutagenic or
carcinogenic properties of a chemical substance, or both. The substance
was suspended in a mixture of carboxymethylcellulose (0.5% [w/v] in
bidistilled water) and Tween 80 (0.1% [v/v] in bidistilled water and
administered orally at single doses of 1250, 2500 and 5000 mg/kg.
Hepatocytes from animals of the treatmentment groups and negative
control groups were isolated 16 hours after administration of the test
substance. Hepatocytes from animals of the positive control group
(dimethylnitrosamine, 15 mg/kg) were isolated 2 hours after application.
In the UDS assay, comparison of the mean nuclear and the
mean net nuclear counts of silver grains in the vehicle controls and in
the hepatocytes of rats treated with the various doses of the substance
revealed no marked deviations. Also the percentage of cells in repair
after treatment with the test substance was not significantly shifted
when compared with the animals of the vehicle control.
It is concluded that, under the given experimental
conditions, no evidence of induction of DNA damage by the substance or
by its metabolites was obtained that could be interpreted as suggestive
of genotoxic properties of the substance.
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