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EC number: 701-122-3
CAS number: 106185-75-5
Body weight change in Main Phase males:
Blood chemistry in Toxicity Subgroup
BIAC: Bile Acids; Bili: Total Bilirubin.
Blood chemistry in toxicity subgroup
females - Recovery Week 2:
Liver weight in males:
Terminal body weight
Liver weight in females:
In a GLP study conducted according to OECD
guideline 422, three groups, each comprising of ten male and ten female
rats for the Main (reproductive) phase and five female rats for the
Toxicity phase received the test item at doses of 100, 300 or 1000
mg/kg/day at a dose volume of 5 mL/kg/day. Main phase males and Toxicity
phase females were dosed daily for a minimum of five consecutive weeks.
An additional five males and five females were dosed with the vehicle or
at 1000 mg/kg/day for five weeks and then given two weeks of recovery
before termination. Main phase females were dosed daily for two weeks
before pairing, throughout mating, gestation and until Day 6 of
lactation. A similarly constituted Control group received the vehicle,
corn oil, at the same volume-dose.
During the study, data was recorded on
clinical condition, performance under detailed physical and arena
examination, sensory reactivity, grip strength, motor activity,
bodyweight, food consumption, water consumption (visual), haematology,
blood chemistry, oestrous cycles, mating performance and fertility and
gestation length. Organ weight, macroscopic and microscopic pathology
investigations were undertaken in the adults. The clinical condition of
offspring, litter size and survival, sex ratio and offspring bodyweight
were assessed and macroscopic pathology investigations were undertaken.
In the 1000 mg/kg/day dose group, four
females allocated to the littering phase of this study were killed prior
to scheduled termination. Two females were killed in late gestation
following deterioration in clinical condition. The females showed signs
including irregular breathing, reduced activity, hunched posture and
dull/pale/partially closed eyes. Both females were pregnant with a live
and normal litter. A further female was killed during parturition with
similar signs, plus limited use of limbs and reduced body tone: most
pups had died and the three that remained were killed at the same time
as the dam. The fourth female was killed on Day 1 of lactation due to
high levels of pup mortality on Day 1 of lactation. The condition of the
litter was poor with small, cold pups that did not appear to be feeding.
The macroscopic findings at necropsy were unremarkable for all four
No significant findings were recorded for
clinical signs, detailed physical examination and arena observations.
Underactive behaviour in males and females and unsteady posture in
females were observed briefly during Week 1 in animals at 1000 mg/kg/day
and dose related increases in post dosing salivation and chin rubbing
were seen. Behavioural testing during Week 5 of dosing, including
sensory reactivity findings, grip strength values and motor activity
scores showed no differences considered to be associated with test
During late gestation females receiving 1000
mg/kg/day showed significantly lower weight gain than Controls but
bodyweight and bodyweight gain were unaffected during lactation.Females
receiving 1000 mg/kg/day showed lower food consumption during late
gestation (Days 14-19) corresponding with the period of lower bodyweight
gain. Food consumption during lactation was not significantly affected.
There was no effect on oestrous cycles,
precoital interval, mating performance or fertility. All females mated
and were pregnant but at 1000 mg/kg/day there was evidence of increased
sensitivity in late gestation: two females had to be terminated before
giving birth and one female was terminated during parturition, leading
to a reduction in the gestation index. Gestation length was within
normal range but there was a slight increase in the numbers of animals
having longer (23 day) gestation periods. All animals in the Control,
100 and 300 mg/kg/day groups gave birth to a live litter. There was no
effect of test material on the number of implantations but at 1000
mg/kg/day post implantation survival index, live birth index and
viability index were all lower than Control so that live litter size was
smaller. Lactation index assessed on Day 7 of lactation was unaffected.
There was no effect at dose levels of 300 mg/kg/day or below. Male and
female offspring bodyweights were not adversely
Among the Toxicity subgroup animals, males
receiving 1000 mg/kg/day showed lower overall weight gain (Week 0-5)
compared with Control. Bodyweight during the recovery phase was similar
to controls. Liver weights were higher in males and females receiving
300 or 1000 mg/kg/day and kidney weights were higher than Control in
females at 1000 mg/kg/day. Organ weight measurement two weeks after the
end of the dosing period showed that the effects had been reversed and
organs were normal size. Biochemical changes in females at 1000
mg/kg/day, such as increased alanine aminophosphatase, alanine
aminotransferase, cholesterol and bilirubin levels also suggest that the
metabolic function of the liver may have been altered by administration
of the test item. All the above discussed parameters showed complete
recovery after 2 weeks.
No-Observed-Adverse-Effect-Level (NOAEL) for males was 300 mg/kg/day,
the NOAEL for maternal toxicity was 300 mg/kg/day and the NOAEL for
reproduction/developmental toxicity was at least 300 mg/kg/day. The
NOAEL for unmated females was 1000 mg/kg/day.
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