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EC number: 431-620-3
CAS number: 162537-11-3
Based on the results of this study, the no-observed-adverse-effect-level
(NOAEL) for general toxicity was 500 mg/kg/day in the male and female
rats. The reproductive NOAEL was 500 mg/kg/day as there were no test
article-related changes in estrous cycling in the female and mating and
fertility in the males or females. The NOAEL for viability and growth
in the offspring was also 500 mg/kg/day.
The objective of this study was to test for toxic effects/disturbances
resulting from BMS-214702-01 treatment of Crl:CD(SD) male and female
rats before cohabitation, through mating, implantation, gestation and
lactation. The study design was as follows:
P generation male rats were administered the test and/or control article
for 28 days prior to cohabitation, throughout cohabitation and continued
until the day prior to euthanasia. P generation female rats were
administered the test and/or control article for 15 days prior to
cohabitation and continued through Day 3 postpartum (DL 3; rats that
delivered a litter) or Day 24 of Presumed Gestation (DG 24; rats that
did not deliver a litter). Any dam in the process of parturition was not
given the test and/or control article until the following work day.
Such events were noted in the raw data.
Doses were adjusted based on the most recently recorded body weight and
administered at approximately the same time each day.
F1 generation pups were not directly given the test article but may have
been exposed in utero during gestation or via maternal milk during the
The following parameters and end points were evaluated in this study:
viability, clinical signs, food consumption, body weights, body weight
changes, reproductive capacity, maternal behavior, natural delivery
observations, gross necropsy observations, organ weights, and histology
and pathological evaluations.
During the study, two male rats (one in the control group and one in the
500 mg/kg/day dose group) were found dead prior to scheduled euthanasia.
The death in the control group was related to a technician error. The
single death in the 500 mg/kg/day dose group was not considered related
to the test article as all other rats in this group survived to
scheduled euthanasia, and there were no test article related adverse
observations in this rat prior to it being found dead. One female rat
in the 50 mg/kg/day dose group was found dead prior to scheduled
euthanasia. This death was not considered to be test article related
because it was not dose dependent. All additional male and female rats
survived until scheduled euthanasia.
There were no test article-related clinical signs observed in the male
or female rats during the study. Body weights and food consumption were
unaffected by the test article during the dose period in the males and
during the pre-mating, gestation and lactation periods in the females at
doses up to and including 500 mg/kg/day.
The precohabitation estrous cycling observations [mean estrous stages
per 14 days, rats with six or more consecutive days in diestrus and rats
with six or more consecutive days of estrus] were unaffected by doses of
the test article as high as 500 mg/kg/day. All mating and fertility
parameters in the males and females were unaffected by doses of the test
article as high as 500 mg/kg/day.
There were no test article-related necropsy observations in the male or
female rats. There were no toxicologically relevant differences in the
organ weights collected in the males or females.
Pregnancy occurred in 9, 9, 10 and 10 mated females in the 0 (Control
Article), 50, 150 and 500 mg/kg/day dose groups, respectively, and all
of the respective pregnant dams delivered litters.
No clinical observations in the F1 generation pups were attributable to
maternal doses of the test article as high as 500 mg/kg/day. There were
no test article-related necropsy observations in the F1 generation pups.
on the results of the reproductive/developmental toxicity screening
study, a NOAEL of 500 mg/kg bw/day for viability and growth of the first
generation of offspring (F1) was determined. F1 generation pups were not
directly given the test article, but may have been exposed in utero
during gestation or via maternal milk during the lactation period. No
clinical observations in the F1 generation pups were attributable to
maternal doses of the test article as high as 500 mg/kg bw/day. There
were no test article-related necropsy observations in the F1 generation
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