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EC number: 479-930-8
CAS number: 613222-52-9
The test item was examined
for its possible prenatal developmental toxicity. Groups of 22
sperm-positive female Hsd. Han: Wistar rats were treated with the test
item by oral administration daily at three dose levels of 100, 300 and
1000 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
A sufficient stability and homogeneity in
the chosen vehicle were verified over the range of relevant
concentrations at the appropriate frequency of preparation. The item in
sunflower oil was stable at room temperature for four hours and for 3
days if stored in the refrigerator at the concentrations of 25 and 500
mg/mL. 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 92 and 100 %
of nominal concentrations at both analytical occasions confirming proper
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 by means of a dissecting microscope. The
heads were examined by Wilson's free-hand razor blade method.
After cartilage-bone staining the skeletons
were examined by means of a dissecting microscope. All abnormalities
found during the fetal examinations were recorded.
In total, on gestation day 20 there were 22,
20, 17 and 19 evaluated litters each in the control, 100, 300 and 1000
mg/kg bw/day groups respectively. None of the female died before
scheduled necropsy and there were no clinical signs recorded. No
treatment related necropsy findings were observed. There was no
treatment related reduction indicated. Number of implantations,
intrauterine mortality and sex distribution of the fetuses were not
influenced by the treatment. With regard to fetal examinations, there
were no test item related differences in the fetal-and placental weight,
body weight retardation and other external, visceral and skeletal
variations. There were no malformed fetuses found in the experimental
groups besides one control fetus with agnathy during external
examination. There were no malformations found at visceral examination
in the 300 and 1000 mg/kg bw/day groups. Internal hydrocephaly (dilated
lateral ventricles) was found in one control fetus at visceral
examination. Situs inversus totalis in a fetus in the 100 mg/kg bw/day
group was considered to be unrelated from the treatment taking into
accound the low incidence (one single fetus) and that situs inversus
totalis occurs in fetuses with low incidence unrelated from the
treatment according to the historical background data of Toxi-Coop Zrt.
The same control fetus which had agnathy was found with multiple
skeletal malformations (skull including mandible, ribs, and vertebrae).
In the test item treated groups only a split and misshapen (wide)
sternum was recorded for one fetus in the 1000 mg/kg bw/day group.
Considering the low incidence and that split sternum occurs sporadically
according to the historical control data, this malformation was judged
to be unrelated to an effect of the test item.
In conclusion, oral treatment of pregnant
Hsd. Han: WISTAR rats from gestation day 5 up to day 19 (the day before
Caesarean section) with the test item at the dose levels of 100, 300 and
1000 mg/kg bw/day did not cause death, clinical signs and necropsy
findings and did not influence the food intake and body weight
development of the maternal animals. The test item did not reveal any
adverse effect on the pre- and postimplantation loss, number of
implantation, sex distribution, body weight, and placental weight,
external, visceral and skeletal development of the fetuses.
Based on these observations the No Observed
Adverse Effect Level (NOAEL) was determined as follows:
NOAEL (maternal toxicity): 1000 mg/kg bw/day
NOAEL (developmental toxicity including
teratogenicity): 1000 mg/kg bw/day
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