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EC number: 253-057-0
CAS number: 36483-57-5
The purpose of this study was toassess the influence of FR-513 (a
flame retardant) on embryo-fetal survival and development in the
Sprague-Dawley Rat when administered during the organogenesis and fetal
growth phases of pregnancy.
Two groups of 20 females received FR-513 at doses of 100 or 300
mg/kg/day by oral gavage administration, once daily from Day 6 to 19
after mating at a dose volume of 5 mL/kg.
A third treated group of 20 females commenced treatment with
FR-513 at 1000 mg/kg/day, however, this dose level was subsequently
reduced to 500 mg/kg/day shortly after commencement of treatment due to
the severity of the post dosing signs observed. Due to the spread of
mating dates, three females in this group received the dose of 500
mg/kg/day throughout the entire treatment period. All other females
received at least one dose of 1000 mg/kg/day before the reduced dose
level of 500 mg/kg/day was implemented. Females were dosed once daily
from Day 6 to 19 after mating at a dose volume of 5 mL/kg.
A similarly constituted Control group received the vehicle, corn
oil, at the same volume dose and for the same duration as the treated
Animals were killed on Day 20 after mating for reproductive
assessment and detailed fetal examination.
Clinical observations, body weight and food consumption were
recorded. Adult females were examined macroscopically at necropsy on Day
20 after mating and the gravid uterus weight recorded. All fetuses were
examined macroscopically at necropsy and subsequently by detailed
internal visceral examination or skeletal examination.
Treatment of pregnant female Sprague Dawley rats with FR-513 at
1000 mg/kg/day from Day 6 of gestation was not tolerated, with two
females killed for welfare reasons after showing marked signs including
underactive/unresponsive behaviour, partially closed eyelid(s), unsteady
muscle reaction and prostrate posture following one to three doses.
After lowering this dose to 500 mg/kg/day, and for females
receiving 100 or 300 mg/kg/day, administration of FR-513 during Days 6
to Day 19 after mating was well tolerated by pregnant female rats, with
no further deaths and no toxicity related changes in the clinical
condition of the adult females
Signs of chin rubbing and salivation were observed in animals of
all treated groups, however, this was considered to relate to general
distaste of the formulation rather than any effect of toxicity.
At 1000 / 500 mg/kg/day mean body weight loss during Days 6-7 of
gestation (after the first dose), and low food consumption during Days
6-9 of gestation were observed. Mean gravid uterine weight and body
weight change when adjusted for the contribution of the gravid uterus
were also slightly lower than Controls at this dose level.
At 100 or 300 mg/kg/day body weight change during gestation, body
weight change when adjusted for the gravid uterine weight, and food
consumption were similar to Controls and unaffected by treatment.
There were no treatment related findings at macroscopic
examination of the adult females at any of the dose levels investigated.
Embryo-fetal survival, growth and development were considered to
have been unaffected by treatment at 100, 300 or 1000 / 500 mg/kg/day.
Based on the results of this study in Sprague Dawley rats, it was
concluded that, although the initial maternal response to treatment at
1000 mg/kg/day was severe, subsequent reaction to treatment at 500
mg/kg/day was considered to not adverse and this level can be considered
the No Adverse Effect Level (NOAEL).
Within the context of this study, the NOAEL for embryo-fetal
survival, growth and development was also set at 500 mg/kg/day.
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