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EC number: 203-004-2
CAS number: 102-08-9
The objective of this study was to
evaluate the potential toxicity of the test item following daily oral
administration (gavage) to rats for4 weeks.
This study was performed following the
OECD guideline No. 407 and the principles of Good Laboratory Practices.
Three groups of five male and five
female Sprague-Dawley rats received the test item by daily oral
administration for 28 days at dose-levels of 50, 250 or 1000 mg/kg/day.
The test item was administered as a homogenous suspension in the vehicle
(corn oil) at a constant dosage-volume of 5 mL/kg/day. A control group
of five males and five females received the vehicle alone under the same
Test item concentrations were checked
on formulations used in weeks 1 and 4.
The health status of the animals was
checked and detailed clinical examinations were performed at least once
weekly.In addition, a Functional Observation Battery was evaluated in
each animal once in week 4.
Body weight was recorded once before
the beginning of the treatment period, on the first day of treatment and
then at least once a week during the study.The quantity of food consumed
by the animals in each cage was recorded at the same time as body weight.
Hematology, blood biochemistry and
urinalysis were performed on all animalsat the end of the treatment
period. The levels of the thyroid hormones (T3 and T4) and thyroid
stimulating hormone (TSH) were determined on all animals at the end of
the treatment period.
On completion of the treatment period,
the animals were euthanized and submitted to a full macroscopic post-mortem
examination. Designated organs were weighed and selected tissues
were preserved. A microscopic examination was performed on selected
tissues from the control- and high-dose animals sacrificed at the end of
the treatment period and on all macroscopic lesions from all low- and
intermediate-dose animals.Based upon the microscopic results of the
high-dose group, the liver, thyroids, thymus, spleen, heart, lungs,
adrenals, kidneys, stomach and bone marrowwere examined from the low-
and intermediate-dose animals.
The test item concentrations in the
administered dose formulations analyzed in weeks 1 and 4 were within the
There were no unscheduled deaths that
were related to test item treatment.
At 1000 mg/kg/day, thin appearance was
observed from day 6 to day 11 in 3/5 females, along with a body weight
loss of 12% between days 1 and 8 and hunched posture from day 22 one of
these females. No relevant clinical signs were recorded in animals
treated at 50 or 250 mg/kg/day.
Lower body weight and body weight gain
were observed in high-dose animals from week 1, resulting in a lower
body weight at the end of the treatment period.Body weight of animals
given 50 or 250 mg/kg/day was not affected by the test item treatment.
Food intake was not affected by the
test item treatment. There were no test item-related effects on FOB
assays, including motor activity.
Lower neutrophils, eosinophils and
monocytes counts were observed in high-dose males and lower mean white
blood cell count, due to lower eosinophils and basophils counts, were
noted in high-dose females when compared to control values.
In high-dose animals, decreased in red
blood cell parameters were observed (mostly in females). A trend to a
decrease mean red blood cell parameters were observed in mid-dose
Higher mean total protein
concentration, correlating with higher mean albumin concentration and
higher mean calcium concentration, was noted in high-dose animals (more
marked in females than in males) when compared to control values.In
addition, dose-related higher mean cholesterol level was noted from 50
mg/kg/day in both sexes when compared to control values. These findings
could be correlated withthe changes in the thyroids hormones metabolism.
Urinary parameters were not disturbed
by the administration of the test item.
Dose-related increased mean T3 level
was observed from 250 mg/kg/day in females but not in males.
Dose-related decreased mean T4 level and increased mean TSH level were
noted from 250 mg/kg/day in both sexes when compared to control values,
reaching statistically significance at 1000 mg/kg/day for T4 level and
from 250 mg/kg/day for TSH level. These findings correlated with
hypertrophy at microscopic examination.
The following treatment-related
body/organ weight changes were present:
in body weight in males and females receiving 1000 mg/kg/day,
. increase in weight of liver (males
and females at 250 mg/kg/day and above) and thyroid (males and females
at 1000 mg/kg/day),
in weight of thymus (males and females at 50 mg/kg/day and above),
spleen (males and females at 1000 mg/kg/day) and adrenals (females at
The following treatment-related
necropsy findings were present:
thyroids in males and females at 250 mg/kg/day and above,
size of thymus (males at 1000 mg/kg/day, females at 250 mg/kg/day
size of adrenals (males and females at 1000 mg/kg/day).
The following treatment-related
microscopic findings were present:
hepatocyte hypertrophy (males and females at 250 mg/kg/day and above),
. thyroid follicular hypertrophy
(males at 250 mg/kg and above, females at 50 mg/kg/day and above),
and/or inflammation of brown fat in various organs (males and females at
50 mg/kg/day and above),
atrophy in thymus (males at 50 mg/kg/day and above, females at
250 mg/kg/day and above) and in spleen (males and females at 1000
cortical atrophy (males and females at 1000 mg/kg/day),
erosion (males and females at 1000 mg/kg/day),
. reduced cellularity of bone marrow
(females at 1000 mg/kg/day).
The changes in the liver, thyroids and
brown fat were considered to be due to direct effects of the test
compound. Liver and thyroid effects wereconsistent with liver enzyme
induction and secondary thyroid hypertrophy. Atrophy in thethymus,
spleen, and adrenals, erosion in the stomach, and reduced cellularity of
bone marrow were considered to be secondary to cachexia.
Based on increased mean TSH level,
macroscopic and microscopic findings on liver and thyroid (males and
females) at 250 mg/kg/day, the NOAEL (No Observable Adverse Effect
Level) was considered to be at 50 mg/kg/day.
Based on higher mean cholesterol
level, decreases weight of thymus (males and females), degeneration
and/or inflammation of brown fat (males and females), lymphoid atrophy
(males), and thyroid follicular hypertrophy (females) at 50 mg/kg/day,
the lowest dosage evaluated in this study, a NOEL (No Observable Effect
Level) could not be determined.
The test item
was administered daily for 4 weeks by the oral route to male and female
Sprague-Dawley rats at dose-levels of 50,
250 or 1000 mg/kg/dayincorn
Treatment with the test item resulted
in some systemic toxicity (some clinical signs, reducing in body weight,
low white and red blood cellscountand high total protein, albumin and
calcium concentrations) at 1000 mg/kg/day. A trend to a decrease red
blood cell parameters were observed at 250 mg/kg/day. Dose-related
higher cholesterol level was noted from 50 mg/kg/day. Dose-related
decreased T4 level and increased TSH level were noted from 250 mg/kg/day.
Macroscopic and microscopic changes in
the liver from 250 mg/kg/day and thyroids from 50 mg/kg/day were
considered to be due to direct effects of the test compound, and
wereconsistent with liver enzyme induction and secondary to the thyroid
The No Observed
Adverse Effect Level (NOAEL) was considered to be at 50 mg/kg/day based
on the adverse effects observed on thyroid (enlarged thyroid, thyroid
follicular hypertrophy, statistically significant increased TSH level)
and liver (increase in weight, hepatocyte hypertrophy) observed at 250
mg/kg/day in male and female rats.
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