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EC number: 945-518-6
CAS number: -
The toxic effects on rats of both sexes
after repeated oral dosing with test substance, as well as any effects
of the test item on male and female reproductive performance, such as
gonadal function, mating behaviour, conception, development of
conceptuses, parturition and early lactation of the offspring were
investigated. A 4 week treatment-free
period was allowed in order to assess any delayed toxicity or recovery
from any adverse effects observed during the dosing phase.
The vehicle was softened water. All doses
were administered at a constant volume of 5 ml/kg body weight.
The study design was as follows:
Males of the main groups were treated for
2 weeks prior to pairing and during pairing with females until the day
before necropsy, for a total of 46/47 days. Females were treated for 2
weeks prior to pairing, and thereafter during pairing, post coitum and
post partum periods until Day 13 post partum (for at least 51 days).
The following investigations were
performed in both sexes of all groups: mortality check, clinical signs,
body weight, food consumption, oestrous cycle, mating performance,
litter data, sex ratios, macroscopic observations and organ weights.
Sperm analysis was performed in all control and high dose males.
Histopathological examination was performed in control and high dose
groups, as well as on all abnormalities detected during post mortem
observation. The identification of the stages of the spermatogenic cycle
was also performed in five randomly selected males of the control and
high dose groups. Thyroid hormone determination was performed in all
males. Clinical signs were performed in all pups. Thyroid weight and
thyroid hormone determination of 1/pup/sex/litter (where possible) at
Day 14 post partum were evaluated. All pups found dead in the cage were
examined for external and internal abnormalities. All culled pups
sacrificed at Day 4 post partum were subjected to an external
Sex was determined by internal gonads
inspection. All live pups sacrificed on Day 14 post partum were examined
for external abnormalities and sex confirmation
by gonadal inspection. The anogenital
distance in all pups and the presence of nipples/areolae in male pups
were also verified.
Recovery animals were treated for 4
consecutive weeks and killed after 4 weeks of recovery period. The
following parameters were evaluated in these animals: mortality check,
clinical signs, body weight, food consumption, macroscopic observations
and organ weights. Mortality and fate of females
No mortality occurred throughout the
study. Mating was not detected in one female of the mid-dose group.
However, this female gave birth and was sacrificed with the litter on
Day 14 post partum.
One female in the low dose group and one
female in the high dose group were found not pregnant at necropsy. In
addition, one female in the high dose group had unilateral implantation.
The number of females with live pups on
Day 14 post partum was: 10 in the control, 9 in the low dose, 10 in the
mid-dose and 9 in the high dose group.
Main and recovery groups. No signs of
toxicity were observed throughout the study, both sexes, both for main
and recovery groups.
Body weight and body weight gain
Main and recovery groups. No differences
of toxicological relevance were recorded in body weight and body weight
gain, both for main and recovery groups respect to the control groups.
Main and recovery groups. No effects on
food consumption were observed in either males or females throughout the
study, both for main and recovery groups.
Thyroid hormone determination
No treatment-related differences were
noted in hormones levels in parental males and in pups at Day 14 post
partum, when compared to control group animals.
Oestrous cycle, reproductive parameters,
pairing combination and mating performance Oestrous cycle, pre-coital
intervals, copulatory index and fertility index did not show any
differences that could be related to treatment.
Implantation, pre-birth loss data and
gestation length of females
Corpora lutea, implantations, litter size
and pre-natal loss (percentage) were similar in control and treated
groups. Gestation periods were similar between treated and control
females. All pregnant dams gave birth on Day 22 post coitum (mean
Litter data and sex ratio of pups
Litter data at birth on Days 1, 4 and 13
post partum did not show differences of toxicological relevance between
groups. Sex ratios at birth, on Days 4 and 14 post partum did not show
relevant differences between groups, when calculated as the percentage
Clinical signs of pups
Pre-weaning clinical signs, pups found
dead and missing pups were comparable between treated and control
No relevant differences were seen between
the control and treated pups in anogenital distance.
Necropsy findings in pups
Necropsy findings in deceased pups and in
pups sacrificed on Days 4 and 14 post partum did not reveal any
Pup thyroid weight
No significant differences were noted in
mean thyroid weight of pups in control and treated groups.
Terminal body weight and organ weights
Main and recovery groups
No relevant changes were observed on
terminal body weight, absolute and relative organ weight of treated
animals that completed the treatment or recovery period, when compared
No relevant differences were observed at
sperm analysis including sperm motility and concentration, and cauda
weight between the control and the high dose group at the end of
Main and recovery groups. No remarkable
differences were noted at post mortem examination in treated animals
sacrificed at the end of treatment and recovery periods, when compared
No treatment-related changes were noted in
animals sacrificed at the end of the treatment period. Seminiferous
tubules were evaluated with respect to their stage in the spermatogenic
cycle and to the integrity of the various cell types within the
different stages; regular layering in the germinal epithelium was noted.
Based on the results of the present study,
the NOAEL (No Observed Adverse Effect Level) for general and
reproduction/developmental toxicity was considered to be 1000 mg/kg/day.
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