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EC number: 201-304-8
CAS number: 80-73-9
The reproductive toxicity of the substance was investigated in a study
which was conducted under GLP conditions and in accordance with the
standardised guideline OECD 422.
During the study the test material was administered at 0 (treated with
the solvent, water for injection, only), 4, 20 or 100 mg/kg/day by
gavage to rats from 14 days prior to mating to the end of the 14-day
mating period. Males were further dosed for 14 days from the end of the
mating period. Daily dosing of the parental females continued
throughout pregnancy and up to day 4 of lactation period. Five males
from the main groups and an additional 5 females (satellite groups) were
used for the observation of reversibility for 14 days post treatment.
In any dose group, there were no effects of the test substance on
the estrus cycle, copulation index and fertility index. At each end of
the dosing and recovery periods, histopathological eaxamination revealed
the marked decrease of spermatogenesis. However, it is considered that
the 2-week dosing of test substance before mating did not affect the
male fertility, because no histological changes of the male reproductive
organs had been found in the 2-week repeated dose preliminary study.
The dosing of test substance did not affect the gestation length,
numbers of corpora lutea and implantation sites, implantation index and
delivery index of dams. At the observation of delivery, 2 dams of 100
mg/kg group showed all dead pups on day 0 of lactation and 1 of these 2
dams showed abnormal nesting. Moreover, each 1 dam of 100 mg/kg group
showed all dead pups on day 2 and 3 of lactation. These results indicate
that treatment of the test substance could affect the lactating behavior
of dams. Atrophy of the thymus was found in the 3 of 4 dams which showed
all dead pups. However, this atrophy is considered not to be due to the
dosing of test substance, because no histopathological changes were
found in these organs.
For the offsprings, no effect(s) of the test substance was
observed on the total numbers of live offspring delivered and sex
ratios. However, 23 offspring of 100 mg/kg group died on day 0 of
lactation, and delivery index, number of live offspring (day 0) and live
birth index (day 0) tended to be lower in the same dose group. One of
the reasons for these findings, the test substance had inhibited the
fetal growth and it induced the immaturity of offspring indicated as the
lower body weights of male and female live offsprings (day 0). Also, the
lower body weights of male and female live offsprings were found in the
same dose group on day 4 of lactation and the body weights did not
increase so much from the day 0. It is considered that the decreases of
number of live offspring and of live birth index on day 4 of lactation
were caused by the growth inhibition effect of test substance after
birth. The external examination and necropsy of newborns on day 4 of
lactation revealed no abnormalities caused by the dosing of the test
On the basis of above results, the No Observed Effect Level (NOEL)
and No Observed Adverse Effect Level (NOAEL) of the test substance for
the males were judged to be 20 mg/kg/day each in the conditions of this
study because of the effects on the testis and epididymis of 100 mg/kg
group. For dams, the NOEL and NOAEL of the test substance were judged to
be 20 mg/kg/day each because of the lower body weight gains of 100 mg/kg
group from the initiation of dosing during the pregnant and lactation
periods and the lower mean daily food consumption of the same group
during the lactation period. For the F1 animals, the NOEL and NOAEL of
the test substance were judged to be 20 mg/kg/day each because of the
fetal growth inhibition and lower viability index on day 4 of lactation
of 100 mg/kg group.
Based on effects seen in this study it is considered appropriate
to classify this substance as Category 2 reproductive toxicant under the
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