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Table 1: Thyroid hormone levels, total bilirubin, urea and creatinine
concentrations (day 92 relative to start day)
Anova & Dunnett: * = p <= 0.05
Anova & Dunnett: ** = p <= 0.01
# Historical Control Range TSH hormone Wistar Han rats (2019-2020)
Males (mU/L): mean = 0.1840; P5-P95 = 0.0352 – 0.5412
Females (mU/L): mean = 0.0887; P5-P95 = 0.0100 –
A decreased concentration of T4 hormone was measured for males treated
at 1000 mg/kg bw/day (0.76x of control).
A decreased concentration of TSH hormone (not statistically significant)
was measured for males and females of all treatment groups.
In absence of a dose-response relationship and as mean values remained
within the historical control range, these changes were considered not
No test item-related changes were noted for T3 hormone levels up to 1000
Table 2: Test Item-Related Microscopic Findings in the liver – Scheduled
Euthanasia Animals (Day 92)
A subchronic oral gavage toxicity study in rats following OECD TG 408
was performed with the substance. Based on a low toxicity profile
observed in available studies the dose levels were selected with 0, 100,
300 and 1000 mg/kg bw/day. Formulation analyses confirmed that the test
item formulations in polyethylene glycol 400 were stable, accurate and
A lower food consumption (up to -13.3% compared to controls) was noted
for females treated at 1000 mg/kg/day during the study period. As there
was no test item-related effect on body weight (gain) in these animals
during the study period, the effect on food consumption was considered
Furthermore, a marked decrease in T4 hormone concentration was noted for
males at 1000 mg/kg/day only (minus 24%). There was no histopathological
correlate in the thyroid gland. No other effects on thyroid hormones
At necropsy, prominent lobular architecture of the liver of one male at
1000 mg/kg/day was noted, which was consistent with the hepatocellular
cytoplasmic alteration observed microscopically in 5/10 males at this
dose level (3 minimal, 2 mild). Other microscopic changes in the liver
noted for the 5 affected males were vacuolation at minimal degree and
single cell necrosis in the centrilobular area at minimal degree. This
combination of alterations is interpreted to represent degenerative
findings and is therefore considered to be adverse. Microscopic
examination of the livers of the 100 and 300 mg/kg bw/day treated males
as well as the 1000 mg/kg bw/day treated females revealed no such
No toxicologically significant changes were noted in any of the
remaining parameters investigated in this study (i.e. mortality,
clinical appearance, body weight, functional observations,
ophthalmology, hematology, clinical chemistry, coagulation and organ
In conclusion, administration of the test item by once daily oral gavage
was well tolerated in rats at levels up to 1000 mg/kg/day. Adverse
morphologic alterations were present in the liver of males treated at
1000 mg/kg/day and consisted of centrilobular cytoplasmic alteration,
hepatocellular vacuolation and single cell necrosis. Based on these
results, the no-observed-adverse-effect level (NOAEL) was considered to
be 300 mg/kg/day for male rats and 1000 mg/kg bw for female rats.
In this study, a marked reduction of total T4 was observed in males
treated at 1000 mg/kg/day which was considered to be test item-related.
However, under the conditions of this study no adverse effect was
observed that could be linked to the reduction of total T4 and therefore
this reduction was not taken into account when determining the parental
In a subchronic repeated dose toxicity study (OECD TG 408) on rats with doses of up to and including the limit dose of 1000 mg/kg bw/day, no effects were observed on weight or histopathology of reproductive glands/tissues/organs. The oestrous cycle was also not affected by the treatment.
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