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NOAEL (OECD 407, oral, rat) ≥ 1000 mg/kg bw/day
Table 1 Final Body and Organ Weights
@Historical control data obtained from seven 28-day dietary studies
conducted in this laboratory in 2009 – 2011.
* Statistically different from control mean, males and females analyzed
together, by Dunnett’s test, alpha = 0.05.
a Statistically different from control mean, males analyzed
separately, by Dunnett’s test, alpha = 0.05. Bold type indicates
the effects judged to be treatment related.
The purpose of this study was to evaluate the potential toxicity of the
test substance in rats following dietary administration for at least 28
days. Ten male and ten female F344/DuCrl rats per group were given test
diets formulated to supply 0, 100, 300, or 1000 milligrams/kilogram body
weight/day (mg/kg/day, mkd) for at least 28 days. Parameters evaluated
were daily cage-side clinical observations, weekly detailed clinical
observations, functional tests, ophthalmic examinations, body weights,
body weight gains, feed consumption and gross pathologic observations at
the scheduled necropsy. Hematology, prothrombin time, urinalysis,
clinical chemistry and selected organ weights were evaluated on the
first five males and females per dose-group. An extensive
histopathologic evaluation was conducted on the first five males and
females of the control and high-dose groups. In addition,
histopathologic evaluation of liver tissue from the first five male rats
in the low- and intermediate dose-groups were conducted.
There were no treatment-related effects in clinical signs, functional
tests, body weights/body weight gains, feed consumption, ophthalmic
examinations, hematology, prothrombin time, clinical chemistry, urine
parameters or gross pathological observations of male or female rats at
any dose level as compared to their respective controls.
Treatment-related, statistically-identified higher mean relative liver
weights were noted only in male rats given 300 (17.7 %) or 1000
mg/kg/day (14.3 %), as compared to that of the controls and corresponded
to treatment-related very slight hypertrophy of the centrilobular and
midzonal hepatocytes. The hypertrophied hepatocytes had increased
cytoplasmic eosinophilia when compared to those of the controls. The
microscopic liver effects and the modest liver weight increases noted in
males given 300 or 1000 mkd were interpreted to be non-adverse adaptive
changes since there were no associated treatment-related changes in
clinical chemistry parameters or histopathological evidence of
treatment-related hepatocellular necrosis, proliferation, apoptosis or
any other degenerative changes indicative of liver toxicity.
Under the conditions of this study, based on the liver effects noted in
males given 300 or 1000 mg/kg/day, the No-Observed-Effect Level (NOEL)
in F344/DuCrl rats was the targeted dietary dose of 100 mg/kg/day in
males and 1000 mg/kg/day in females. As the liver effects observed in
males given 300 or 1000 mg/kg/day were non-adverse, the
No-Observed-Adverse-Effect Level (NOAEL) was determined to be 1000
mg/kg/day in male and female rats.
Repeated dose toxicity, oral
A subacute oral toxicity study according to OECD 407 and in compliance
with GLP was performed with the test substance in male and female
Fischer 344/DuCrj rats for a period of 28 days (Dow, 2012). Based on the
results of a preliminary 14-day dose-range-finding, the unchanged test
substance was administered daily via the diet to groups of 10 rats per
sex at dose levels of 100, 300 and 1000 mg/kg bw/day over the entire
study period. No mortalities and no clinical signs were observed, except
for one animal of the 300 mg/kg bw/day dose group, which showed red
periocular soiling from Days 15-22. However, this observation was
considered spurious and not related to treatment due to the isolated
occurrence and lack of a dose-response relationship. No
treatment-related effects were observed during functional tests,
including sensory evaluation and assessment of rectual temperature, grip
performance and motor activity. Body weights and body weight gains, food
consumption as well as haematology, clinical chemistry and urinary
parameters were comparable to those of controls. Ophthalmic examinations
did not reveal any treatment-related effects. Treatment-related,
statistically-identified higher mean relative liver weights were noted
in male rats given 300 (17.7 %) or 1000 mg/kg/day (14.3 %), as compared
to that of the controls, which corresponded to treatment-related very
slight hypertrophy of the centrilobular and midzonal hepatocytes. The
hypertrophied hepatocytes showed increased cytoplasmic eosinophilia when
compared to those of the controls. However, the microscopic lesions
observed in liver and the modest liver weight increases noted in males
given 300 or 1000 mg/kg bw/day were interpreted to be non-adverse
adaptive changes since there were no associated treatment-related
changes in clinical chemistry parameters or histopathological evidence
of treatment-related hepatocellular necrosis, proliferation, apoptosis
or any other degenerative changes indicative of liver toxicity.
Based these results, the NOAEL was determined to be ≥ 1000 mg/kg/day in
male and female rats.
The available data on repeated dose toxicity of the substance do
not meet the criteria for classification according to Regulation (EC)
1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not
sufficient for classification.
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