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EC number: -
CAS number: -
A repeated oral dose gavage toxicity study with a
reproduction/developmental toxicity test was conducted in Crl: CD®(SD)
IGS rats to provide information on male and female toxicity and
reproductive performance, including gonadal function, mating behavior,
conception, development of conceptus’, and parturition and lactation
following administration of Rabitle® FP-100.
Ninety-six healthy rats (48 virgin male and 48 virgin female) were
selected for the test and distributed into four groups (12 males and 12
females/dose level). Dose levels of 50, 250, and 1000 mg/kg/day of
Rabitle® FP-100, as well as an vehicle control (olive oil), were
selected for the test.
Males and females received the test substance while housed separately
for a 14-day pre-mating period, followed by dosing through a 14-day
co-habitation period. Upon determination of pregnancy or following the
prescribed 14-day mating period, females were removed and placed in a
separate cage, where dosing continued through the gestation period of
pregnancy until Day 13 of lactation. Males were sacrificed following the
gestation phase and were evaluated for fertility, including
spermatogenic stage and epididymal effects. The males and females were
evaluated histopathologically following scheduled sacrifice on Study Day
44 (males) and LD14 (females).
Animals were observed daily for clinical signs and mortality. The
animals were observed for viability, signs of gross toxicity, and
behavioral changes at least once daily during the study, and
approximately weekly for a battery of detailed observations. Individual
body weights and food consumption were recorded weekly as prescribed for
both sets of animals. Body weights for females were recorded on GD 0, 7,
14, and 21, and on LD 0, 7, and 14. Food consumption for males and
females was recorded to coincide with body weight collection, with the
exception of the mating period.
The neat test substance was determined to be stable under the conditions
of storage at PSL over the course of this study. The test substance was
considered to be homogenously distributed in the dose solutions at all
study concentrations, within an acceptable margin of variation. There
was no evidence of degradation or test substance loss over the period of
dose preparation and storage of 7 Days. Based on concentration
verification results, the animals are considered to have received at
least the targeted concentrations of 10, 50, and 200 mg/mL of Rabitle®
One Group 2 dam and one Group 3 dam were found dead on their respective
GD22. These animals were observed to have difficulty with delivery.
There were no other parental mortalities during the course of the study.
There were no clinical signs in males or females attributable to the
administration of Rabitle® FP-100. Mean estrus cycle length was
comparable between treated and control groups. There were no changes in
parental male or female body weight, body weight gain, food consumption,
or food efficiency attributable to the administration of Rabitle® FP-100.
Fertility endpoints, including mating, fertility, and fecundity indices,
as well as female mean pre-coital length, were comparable for males and
females administered Rabitle® FP-100, as compared to concurrent control
Rabitle® FP-100 administration produced no significant changes in any of
the gestational or birth parameters evaluated during the course of the
present study including gestational length, gestation index, number of
implantation sites, corpora lutea, average resorption (early and late)
numbers and pre-implantation and post-implantation loss. Earlier stage
of gestation indicators such as total litter size, live birth index, and
number of stillborn pups were comparable between treatment groups and
There were no Rabitle® FP-100-related macroscopic findings in any
terminal sacrifice rats. There were no microscopic effects in
reproductive organs in male or female rats due to Rabitle® FP-100
administration. There were no test-substance-related organ weight
changes in the parental generation.
There were no test-substance-related clinical or necropsy findings
observed in the filial generation. There were no test substance related
differences in the average pup body weight per litter. Surviving pups
from all litters increased in weight during the lactation phase. Litter
weight gain was comparable to control values.
Therefore, under the conditions of this study, the
no-observed-adverse-effect level (NOAEL) for the test substance Rabitle®
FP-100 was 1000 mg/kg/day for male and female Sprague-Dawley rats in
this repeated dose oral toxicity study with reproduction/developmental
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