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EC number: 695-748-3
CAS number: 65286-55-7
Discussion of the results
The administration of the test substance to rats at 20, 60 and 100 mg/kg
bw/day resulted in statistically significant reductions in body weight
development throughout the treatment period for both males and females
treated with 60 or 100 mg/kg bw/day compared to controls. A reduction in
food consumption for these animals was also apparent throughout the
treatment period and with no visible effects on water intake. No such
effects were detected in animals of either sex treated with 20 mg/kg
bw/day. There were no clinical observations of true systemic toxicity
and only sporadic instances of noisy respiration from isolated
Statistically significant differences in males and females treated with
60 or 100 mg/kg bw/day were noted in comparison to controls for the
hematological and blood chemical parameters measured. Due to the effects
apparent at histological examination an association with treatment
cannot be discounted for the majority of these differences.
The evaluation of Thyroxine (T4) in adults and male/female offspring
(Day 13 of age) did not identify any treatment-related findings in the
offspring. However, the adults did show a dose related reduction
attaining statistical significance for adult males treated with 60 and
100 mg/kg bw/day. This could be an associated effect due to the
histopathological changes to the thyroid gland.
Mating performance and fertility were unaffected by treatment. However,
offspring from 60 or 100 mg/kg bw/day litters showed a reduction (p<0.05
- p<0.001) in body weight, body weight gain and cumulative gains which
resulted in statistically significantly lower litter weights at 100
mg/kg bw/day (p<0.05 - p<0.01). No such effects were noted for
offspring from 20 mg/kg bw/day litters.
Microscopic examination of tissues revealed extensive and unusual
changes within this study which were considered to be a direct effect of
treatment with the test item. Vacuolation/vacuolated macrophages were
present in numerous tissues. Males treated with 20 mg/kg bw/day and
females treated with 60 and 100 mg/kg bw/day also had
vacuolation/vacuolated macrophages present in the choroid plexus.
Vacuolation is seen as part of a degeneration process, degeneration of
hepatocytes was seen in the liver of males at all dose levels and
females at 60 or 100 mg/kg bw/day. Although the exact cause of the
vacuolation cannot be determined, it may be related to the uptake and/or
clearance of the test item or its metabolite(s) or due to
phospholipidosis although this is not clear. It may also be related to
a change in, or disruption of, the storage process within the cells.
Special staining with Oil-Red-O and PAS did not give any indication of
the identity of the contents of the vacuoles.
There were also reduced amounts of splenic hematopoiesis present in all
groups treated with the test item. There were no notable correlating
changes were apparent in the hematology parameters therefore the
significance is unclear but unlikely to be significant.
Based on these findings, a No Observed Adverse Effect Level (NOAEL) for
systemic toxicity can be established for females only at 20 mg/kg bw/day
within the confines of this study, due to the absence of vacuolation or
any further changes in the tissues. This could not be established for
males. A No Observed Effect Level (NOEL) for reproductive toxicity was
considered to be at least 20 mg/kg bw/day.
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