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EC number: 948-052-1
CAS number: -
The purpose of this study was to
screen the test substance, KOMAD 710, for reproductive/developmental
effects and assessment of endocrine disruptor relevant endpoints,
following repeated oral dosing. The assessment of reproductive effects
was made along with assessment of systemic toxicity as part of a
Combined Repeated Dose Toxicity Study with the Reproduction/
Developmental Toxicity Screening Test which also assessed potential
adverse effects of the test item on reproduction. The study was designed
to be compatible with the requirements of the following guideline:
Three groups of ten male and ten
female rats received test substance at doses of 100, 330 or 750
mg/kg/day by oral gavage administration. Males were treated daily for
two weeks before pairing, up to necropsy after a minimum of four
consecutive weeks. Females were treated daily for two weeks before
pairing, throughout pairing, gestation and until Day 13 of
lactation. Females were allowed to litter, rear their offspring and were
killed on Day 13 of lactation. The F1 generation received no direct
administration of the test item; any exposure was in utero or via the
milk. A similarly constituted Control group received the vehicle,
propylene glycol,throughout the same relative treatment period.
During the study, clinical condition,
estrous cycles, pre-coital interval, mating performance, fertility,
gestation length, organ weight and macroscopic pathology and
histopathology investigations were undertaken.
The clinical condition, litter size
and survival, sex ratio, body weight, ano-genital distance and
macropathology for all offspring were also assessed. Nipple counts were
performed on male offspring on Day 13 of age.
On Day 9 of treatment, one female
receiving 330 mg/kg/day was killed for welfare reasons.
On Day 23 of gestation, a second
female receiving 330 mg/kg/day was killed for welfare reasons.
On Day 8 of lactation, a Group 4
female receiving 750 mg/kg/day was terminated early due to total litter
On Day 9 of lactation, a third female
receiving 330 mg/kg/day was terminated early due to total litter loss.
On Day 25 of gestation, three Group 4
females receiving 750 mg/kg/day were killed due to having surpassed the
designated gestational time.
There were no clinical signs observed
among the offspring which were considered to be related to parental
treatment with the test substance.
There were no clinical signs observed
following dose administration or signs at routine clinical examination
that were considered to be associated with treatment.
Overall body weight gains for males
given 750 mg/kg/day were moderately low and slightly low for males given
100 or 330 mg/kg/day. During the two-week pre-pairing period the females
receiving 750 mg/kg/day body weight gain was higher than Controls.
During the gestation and lactation
periods body weight gains was slightly or moderately low for females
receiving 330 or 750 mg/kg/day. For females receiving 100 mg/kg/day,
body weight gain was slightly low during the lactation period, only.
Mean food consumption during gestation
was low for females receiving 750 mg/kg/day and following parturition
was low for females receiving 330 or 750 mg/kg/day. Mean food
consumption for males receiving 100 or 330 mg/kg/day and for females
receiving 100 or 330 mg/kg/day was generally similar to Controls
throughout the dosing period, with exception of the lactation period for
females at 330 mg/kg/day.
An increase in irregular estrous
cycles and extended pre-coital intervals were observed for females
receiving 750 mg/kg/day, there was no effect on these parameters at 100
or 330 mg/kg/day. A slight shift towards longer gestation lengths was
apparent for females receiving 330 or 750 mg/kg/day in comparison with
the concurrent Control. The gestational length of females receiving
100 mg/kg/day was unaffected. The number of females with live litters
born were lower for females receiving either 330 or 750 mg/kg/day. The
rate of conception and fertility index for females receiving 750
mg/kg/day was low compared to Controls. The number of copulation plugs
observed in the cages of females receiving 100, 330 or 750 mg/kg/day
tended to be low when compared with Controls and indicative of a dose
dependent effect. There was no effect of treatment on sperm count
estimates and at termination all females were in diestrous
F1 litter responses
A reduction in mean number of
implantation sites of females receiving 330 or 750 mg/kg/day resulted in
lower mean litter size at both dose levels when compared with Control;
all values were outside the historical control data. The mean number of
implantation sites and litter size were unaffected at 100 mg/kg/day.
The post implantation survival index
and group mean live birth indices were also low at 330 and
750 mg/kg/day. There was also a suggestion of slightly low lactation
survival indices at 330 or 750 mg/kg/day. Offspring survival to Day 13
of age appear unaffectedby parental treatment at 100 mg/kg/day.
Body weight gain of male and female
offspring receiving test substance at a dose level of 750 mg/kg/day were
consistently lower than that of Control. Mean offspring body weights on
Day 1 of age and subsequent body weight gain up to Day 13 of age was
similar to Controls at 100 or 330 mg/kg/day.
The clinical condition, sex ratio and
ano-genital distances of the F1 offspring were unaffected by parental
treatment and at scheduled termination, there were no findings
associated with treatment.
There was no effect of treatment on
the circulating levels of thyroxine (T4) in adult males or in male and
The reduction in the number of uterine
implantations at 330 and 750 mg/kg/day (and as a consequence litter
size) was associated with reduced survival. These differences, however,
were statistically significant and all parameters were outside of the
Historical Control Data values (representing 11 OECD TG 422
studies). This effect is considered to be related to treatment and it is
likely that the male and/or female reproductive systems have been
affected, but the mechanism is undetermined and potentially adverse. It
was therefore concluded that within the context of this study, the NOAEL
for reproductive/developmental toxicity was 100 mg/kg/day.
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