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EC number: 217-568-2
CAS number: 1889-67-4
The test item was examined for its possible
prenatal developmental toxicity. Groups of 22 sperm-positive female Hsd.
Wistar rats were treated with the test item by oral administration daily
at three dose levels of 3, 10 and 30 mg/kg bw/day from day 5 up to and
including day 19 post coitum. A control group of 22 sperm positive
females was included and the animals were given the vehicle sunflower
oil. The treatment volume was 2 mL/kg bw.
Sufficient stability and homogeneity in the
chosen vehicle were verified over the range of relevant concentrations
at the appropriate frequency of preparation. The test item was proved to
be stable in sunflower oil formulations at ~1 and ~200 mg/mL
concentration levels at least for one day at room temperature and at
least for 3 days in the refrigerator (5 ± 3°C). Analytical control of
dosing solutions was performed on the first and last week of treatment.
Concentrations of the test item in the dosing formulations varied in the
acceptable range between 104 and 106 % of nominal concentrations at both
analytical occasions confirming proper dosing. During the study,
mortality was checked and clinical observations were performed. Body
weight and food consumption of the dams were also recorded. The day,
when sperm was detected in the vaginal smear, was regarded as day 0 of
gestation. Caesarean section and gross pathology were performed on
gestational day 20. The number of implantations, early and late
resorptions, live and dead fetuses in each uterine horn and the number
of corpora lutea were recorded. Each fetus was weighed and examined for
sex and gross external abnormalities. The placentas were weighed and
examined externally. About half of each litter was preserved for
visceral examination and the other half of the litters were preserved
for skeletal evaluation. At visceral examination, the bodies were micro
dissected with a dissecting microscope. The heads were examined by
Wilson's free-hand razor blade method. After cartilage-bone staining the
skeletons were examined with a dissecting microscope. All abnormalities
found during the fetal examinations were recorded.
On gestation day 20, a total of 20, 20, 21
and 21 litters in the control, 3, 10 and 30 mg/kg bw/day groups,
respectively, were evaluated. None of the dams died before scheduled
necropsy. No clinical signs of toxicity or treatment related necropsy
findings were observed. In the 30 mg/kg bw/day group, the body weight
was significantly reduced from gestation day 8 up to the end of the
in-life phase, the body weight gain was clearly decreased between
gestation days 5 to 11and from days 0 to 20. The corrected body
weight/body weight gain were clearly reduced in the high dose group (30
mg/kg bw/day). In the high dose group there was also a clearly
statistically significantly lower food consumption of the dams from
gestational days 5-11 and 14-20. The observed clear reductions in body
weight parameter and food consumption are considered to be a consequence
of the treatment. The mean number of implantations, the intrauterine
mortality and sex distribution of the fetuses was not influenced by the
The body weight of the fetuses was slightly
but statistically significantly lower in the 30 mg/kg bw/day group
versus control. Although the values were within the historical control
range, this reduction was considered to be a consequence of the
treatment, maybe due to the moderate maternal toxicity. The placental
weight was statistically significantly lower in all test item groups
than in the control but stayed within the historical control range or
slightly below. The relative placental weight was statistically
significantly lower in the 10 and 30 mg/kg bw/day groups than in the
control, but within the historical control range. The statistically
significance indicated in the lower placental weight parameters might be
attributed to the relatively higher current control values, which were
slightly above the historical control range.
There were no malformed fetuses found at
external examination. The body weight retardation (below 2.74 g for
males and 2.64 g for females) was evaluated as an external variation.
The incidence of body weight retarded fetuses increased moderately and
statistically significantly in the 30 mg/kg bw/day dose group which was
attributed to the treatment and might be a consequence of the moderate
maternal toxicity. The result of the statistical analysis was not
significant if the number of affected litters was evaluated. Placental
changes were found at a low incidence and unrelated to the treatment.
At visceral examination, malformation in the
form of enlarged perimeningeal space and impressed cerebral hemisphere
were found in two fetuses at 10 mg/kg bw/day and in one fetus at 30
mg/kg bw/day, respectively. In addition, a dilated 3rd brain ventricle
was observed in another fetus in the 30 mg/kg bw/day group. Variations
in the form of slightly dilated lateral ventricles were recorded for one
fetus each in the control and in the 3 mg/kg bw/day group. However,
according to the laboratory historical control data similar or identical
brain alterations in the form of slightly dilated lateral brain
vehicles, slightly dilated 3rd ventricle and enlarged perimeningeal
space occurred also in control fetuses with low incidence. Therefore and
based on the single occurrence the more than slightly dilated 3rd brain
ventricle was finally considered as incidental observation. In addition,
there was no dose-response relationship in the incidence of fetuses with
enlarged perimeningeal spaces and impressed cerebral hemispheres. Hence,
all brain findings were finally judged to be not related to the
treatment. Visceral variations were found in the experimental groups
without any dose-response relationship.
Skeletal malformations were only found in
two control fetuses. There were no significant increases in the
incidence of the skeletal variations in the test item treated groups.
Based on these observations, the No Observed
Adverse Effect Levels (NOAELs) were determined as follows:
NOAEL (maternal toxicity): 10 mg/kg bw/day
NOAEL (developmental toxicity including
teratogenicity): 10 mg/kg bw/day
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