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EC number: 801-709-5
CAS number: 53146-45-5
Repeated dose toxicity: Oral
for systemic toxicity in males: 25 mg/kg/day
for systemic toxicity in females: 450 mg/kg/day
The purpose of this study was to assess the systemic toxic potential of
the test item, an industrial chemical, in Sprague-Dawley rats, including
a screen for reproductive/ developmental effects, with administration of
the test item by oral gavage administration for at least five weeks.
Main study males were treated daily for two weeks before pairing,
throughout pairing and up to necropsy after a minimum of five
Main study females were treated daily for two weeks before pairing,
throughout pairing, gestation and until Day 7 of lactation. Females were
allowed to litter and rear their offspring to weaning and were killed on
Day 8 of lactation. The F1 generation were killed on Day 7 of lactation,
but received no direct administration of the test substance; any
exposure was in utero or via the milk.
Toxicity phase females were treated daily for a minimum of five
Recovery phase male and female rats were treated daily for a minimum of
six consecutive weeks and were retained, without treatment for 14 days
(non-treatment period commenced from the first main study Dam necropsy
on Day 8 of lactation), to assess the potential for any
treatment-related change to recover. Recovery phase animals were not
A similarly constituted Control group received the vehicle, propylene
glycol, throughout the same relative treatment period.
During the study, clinical condition, detailed physical and arena
observations, sensory reactivity, grip strength, motor activity, body
weight, food consumption, haematology (peripheral blood), blood
chemistry, urinalysis, oestrous cycles, pre-coital interval, mating
performance and fertility, gestation length, organ weight and
macropathology were undertaken. Full histopathology investigations were
undertaken for the first five Main study
males, Main study and Toxicity phase females from the Control and high
dose groups and for skin only from the first five Main study males from
the low and intermediate dose groups and all recovery phase males.
The clinical condition, litter size and survival, sex ratio, body weight
and macropathology for all offspring were also assessed.
One female with a litter, receiving 105 mg/kg/day, was killed for
welfare reasons due to aspiration of fetal material and female with a
litter, receiving 450 mg/kg/day was killed following the death of her
poorly suckled litter, due to poor mammary secretion. Neither was
considered to be related to treatment.
During the first week of treatment at 450 mg/kg/day, the majority or all
of the animals had underactive behavior, with or without piloerection
and/or partially closed eyelids that persisted in some at the end of the
day. All females also had low body temperature on Day 1.
Overall male body weight gain was low at 105 or 450 mg/kg/day and only
partial recovery was evident during the off-dose period. Body weight
gain in un-mated females and during gestation and lactation were
Food intake of females receiving 450 mg/kg/day was low during the first
week of treatment.
There was evidence of mild anaemia in treated males in Week 5;
haematocrit, haemoglobin concentration and red cell count at 25, 105 or
450 mg/kg/day were marginally low and reticulocyte count was marginally
high at 105 or 450 mg/kg/day; activated partial thromboplastin time was
slightly short in males and in non-mated females and females at Day 8 of
lactation at 450 mg/kg/day. Activated partial thromboplastin time was
in males and non-mated females and females on Day 8 of lactation. All
affected parameters showed full recovery, following two weeks respite
from treatment and there were no microscopic correlates.
Urinary protein, glucose, sodium, potassium and chloride concentrations
were high in males and females treated at 450 mg/kg/day and in males
only at 105 mg/kg/day; recovery was apparent after two weeks respite
from treatment and there were no microscopic correlates.
Estrous cycles, pre-coital interval, mating performance and fertility,
gestation length and gestation index were not affected by treatment.
At 450 mg/kg/day, adjusted liver weight was high in males and non-mated
females and females with a litter and remained high following two weeks
respite from treatment; however, there were no microscopic correlates.
All animals were pregnant. Litter size and sex ratio were unaffected by
Overall body weight gain of offspring (birth to Day 7 of age) was
slightly low at 25, 105 or 450 mg/kg/day; however all remained in good
clinical condition and survival indices were unaffected.
In males only, four at 450 mg/kg/day and one at 105 mg/kg/day had slight
to moderate epidermal ulceration and/or necrosis and dermal inflammation
in the skin and all were associated with one or more inflammatory and/or
degenerative changes, including scabs, subcutaneous inflammation,
epidermal hyperplasia, myofibre degeneration/necrosis of the panniculus
carnosus, and dermal/subcutaneous oedema.
It was concluded that the No-Adverse-Effect-Level (NOAEL) for
reproductive and developmental toxicity was 450 mg/kg/day. The NOAEL for
systemic toxicity in males was set at 25 mg/kg/day, since one male at
105 mg/kg/day and four males at 450 mg/kg/day showed macroscopic and
microscopic changes in the skin of unclear aetiology, but which appeared
to be related to treatment. The NOAEL for systemic toxicity in females
was 450 mg/kg/day.
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