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EC number: 200-854-6
CAS number: 75-25-2
The effect of the test substance on
reproduction and fertility in Swiss CD-1 mice was assessed using a
United States National Toxicology Program Reproductive Assessment by
Continuous Breeding Protocol (RACB).
Male and female Swiss CD-1 mice were used
for the study.
The RACB protocol is divided into four
tasks. Task 1 is 14-day toxicity range-finder, Task 2 is a continuous
breading phase, Task 3 is a 1-week mating trial and task 4 is an
assessment of offspring. As the test substance had no
effect on fertility Task 3 was not conducted as part of this study.
Following dose range-finder study (Task 1)
the dose levels selected for Task 2 were 50, 100 and 200 mg/kg bw/day. For
task 2 there were 20 male and female breeding pairs per treatment group
and 40 male and female breeding pairs for control animals). Animals
were dosed daily by gavage using corn oil as the vehicle for a 7-day
pre-cohabitation and a 98-day cohabitation period. The
last litter born during the holding period following the continuous
breeding phase is reared by the dam until weaning, after which treatment
is initiated by the same route and at the same concentration as during
Task 2. These animals are used for assessment of
second generation fertility (Task 4).
Endpoints assessed were clinical signs,
parental body weight and average consumption of drinking water during
representative weeks, fertility (number producing a litter/number of
breeding pairs), litters per pair, live pups per
litter, proportion of pups born alive, sex of live pups and the pup body
weights immediately after birth. For Task 4 the last and generally the
fifth litter was reared and weaned from the control and 200 mg/kg and
kept to sexual maturity (74 ± 10 days) while housed by sex two per cage
(maximum) and receiving the same treatment as their parents. At sexual
maturity a male and female from different litters within the same
treatment group are cohabited for 7 days and then housed singly until
delivery. The endpoints assessed for this mating trial are the same as
Task 2 with the addition of checking for the presence of a copulatory
Six mice died or were sacrificed during this
task. For two mice the cause of death could not be
determined. The deaths of the other four mice were not
considered related to treatment.
Fertility index was 100% for control and
test substance groups (breeding pair was designated fertile if they
produced at least one live or dead pup. The control and bromoform groups
did not significantly differ in number of litters per pair, litter size,
proportion of live pups and proportion of male pups, female pup weight
or combined pup weight at birth. Male absolute pup weights in the 200
mg/kg test substance group were significantly less than control values
but this difference was not significant after pup weights were adjusted
for litter size. The cumulative days to litter were
essentially identical across groups.
Body weights at delivery of dams receiving
200 mg/kg of test substance were consistently less than control values;
these reduced body weights were statistically significant after
delivering the first, second, fourth and fifth litters. During the Task
2 holding period, body weights of lactating dams did not differ among
control and treatment groups.
Male and female adults were weighed on
representative weeks during Task 2 and simultaneously, the water
consumption per cage, or per pair, was monitored. Test substance
treatment had no significant effect on body weight of males or females.
The average daily consumption of drinking water was significantly
increased in males and females treated with 50 mg/kg of test substance
during weeks 2 and 10. In the 100 mg/kg dose group, male and female
consumption was significantly increased during week 10. Consumption was
also significantly increased in the 200 mg/kg dose group for males and
females during weeks 2, 10, and 14.
Eleven F1 mice died during this task. The
cause of death for four mice was not determined. The
remaining deaths were not considered treatment related.
The postnatal survival among F1 pups in the
200 mg/kg bw/day test substance group was significantly lower compared
to the control group. This decline was primarily attributed to three
dams, which lost all their pups by postnatal day 4. One dam in the
control group also lost her litter by postnatal day 4. Although these
incidences are too low to evaluate statistically, they are consistent
with a treatment effect on early maternal behaviour, early lactational
failure, or postnatal developmental processes.
Test substance treatment had no apparent
effect on fertility and reproduction in F1 mice. Some symptoms of
general toxicity were noted in treated F1 mice. This included decreased
male terminal body weights, increased adjusted liver weights in both
sexes with accompanying hepatocellular cell degeneration and decreased
adjusted kidney weights in both sexes. Epididymal ductal epithelium
degeneration was noted in both control and bromoform-treated F1 males,
and was not considered treatment-related.
Treatment with the test substance at up to
200 mg/kg bw/day had no effect reproduction or fertility in either the
parental or F1generation. Treatment
with test substance at 200 mg/kg treatment caused minimal to moderate
histopathologic changes in the liver of second generation CD-1 mice.
The No Observed Effect Level (NOEL) for the
study is considered to be 100 mg/kg bw/day.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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