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EC number: 449-400-0
CAS number: 25822-43-9
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 0.5 % methylcellulose. The treatment volume was 5
A 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 in 0.5 % methylcellulose was stable at room for 3 days in a
refrigerator (5 +/- 3 oC) at the concentrations of 1 and 200 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 91 and 112 % 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
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 21 evaluated litters each in the control and 300 mg/kg bw/day
group, and 19 and 20 in the 100 and 1000 mg/kg bw/day group.
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 on food consumption and body weight indicated.
The test item did not influence the
number of implantations, intrauterine mortality and sex distribution of
There were no test item related
differences in the fetal- and placental weight, body weight retardation
and other external, visceral and skeletal variations. Agnathy observed
at external and proved at skeletal examination (as a markedly
hypoplastic and fused mandible) and other two different skeletal
malformations (one pair of bifurcate ribs, a rudimentary 13thrib and a
misshapen thoracic arch in one fetus, split and fused sternebra and bent
humerus in another fetus) in the 1000 mg/kg bw/day dose group as well as
a displaced- and a supernumerary hemicentric thoracic centrum in one
fetus in the 100 mg/kg bw/day group were judged to be unrelated from the
treatment with the test item considering the historical control database
and the experience with this strain at the lab. This
is also in line with historical control data of another strain of rats,
i.e. CrL:CD(R) BR rats ( Lang,
P.L. (1993) Historical control data for developmental and reproductive
toxicity studies using the Crl:CD®BR rat, compiled by MARTA (Middle
Atlantic Reproduction and Teratology Association), Charles River
Laboratories, September 1993).
Based on these observations the No
Observed Adverse Effect Level (NOAEL) was determined as follows:
NOAEL (maternal toxicity): 1000 mg/kg
NOAEL (developmental toxicity
including teratogenicity): 1000 mg/kg bw/day
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