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EC number: 931-338-5
CAS number: 90622-77-8
study was conducted to determine the repeated dose toxicity of the test
substance, C18-unsatd. MIPA, in rats according to OECD Guideline 422, in
compliance with GLP. Groups of ten male and ten female Sprague-Dawley
rats received the read across substance at dose-levels of 0, 100, 300 or
1000 mg/kg bw/day daily by oral (gavage) administration 2 weeks before
mating, during mating, gestation and until up to Day 5 p.p. The
concentration of the dose formulation was checked in study Weeks 1, 3
and 6. The animals were checked at least twice daily during the dosing
period for mortality and morbidity and once daily for clinical signs.
Detailed clinical observations were performed once a week. Body weight
and food consumption were recorded once a week during premating and
mating periods (food consumption not during mating), and during
gestation on Days 0, 7, 14 and 20 p.c. and lactation on Days 1 and 5
p.p. The animals were paired for mating after 2 weeks of treatment and
the females were allowed to litter and rear their progeny until Day
5 p.p. The total litter sizes and the sex of each pup were recorded
after birth. The pups were observed daily for clinical signs, abnormal
behaviour and external abnormalities and weighed on Days 1 and 5 p.p. At
the end of the treatment period, Functional Observation Battery, motor
activity and laboratory investigations (hematology and blood
biochemistry) were carried out on five males and five females. The males
were sacrificed after at least 5 weeks of treatment and the females on
Day 6 p.p. Final body weights and selected organs weights (adrenals,
brain, epididymides, heart, kidneys, liver, spleen, testes and thymus)
were recorded and a complete macroscopic post-mortem examination was
performed, with particular attention paid to the reproductive organs. A
microscopic examination was performed on selected organs from five males
and five females in the control- and high-dose groups, on liver, thymus,
seminal vesicles and bone marrow from five males and/or five females in
the low- and intermediate-dose groups and on all macroscopic lesions.
The pups were sacrificed on Day 5 p.p. and submitted for a macroscopic
post-mortem examination of the principal thoracic and abdominal organs.
The read across substance concentrations checked during the study were
within an acceptable range of variations when compared to the nominal
values (± 15%). There was no read across substance in control
formulations. There were no read across substance-related deaths.
Clinical signs consisted of ptyalism in all animals at 300 and
1000 mg/kg bw/day and in most of the animals at 100 mg/kg bw/day (minor
toxicological significance), as well as hypoactivity, loud breathing,
piloerection and/or round back observed in a few animals at 300 and
1000 mg/kg bw/day for a few days (limited toxicological significance).
There were no relevant effects on mean body weight, mean Functional
Observation Battery (FOB), as well as on mean hematology parameters in
any group and sex. An effect of the read across substance treatment on
mean motor activity data at 300 and/or 1000 mg/kg bw/day was considered
to be equivocal but of limited toxicological significance. In males,
mean food consumption at 1000 mg/kg bw/day was reduced in the first week
of treatment only (23 g/male/day, vs. 27, p<0.001). This effect was
considered to be of limited toxicological significance. Mean food
consumption in males at 100 and 300 mg/kg bw/day and in females were not
affected. In females, mean cholesterol level was higher than in controls
at 300 and 1000 mg/kg bw/day (up to 1.9 mmol/L, vs.1.2, p<0.01) and
considered to be non-adverse in absence of adverse correlates in the
study. There were no relevant blood biochemistry findings in females at
100 mg/kg bw/day or in males. At histopathology at 1000 mg/kg bw/day,
minimal hepatocellular hypertrophy correlating with higher mean liver
weight was seen in the liver of both sexes (about +28% in males and +20%
in females compared to controls, p<0.01 generally). In females, mild
lymphoid atrophy was seen in the thymus of 2/5 females, correlating with
lower mean weight at necropsy (about -22% from controls). At 300
mg/kg/day, only minimal hepatocellular hypertrophy was seen in the liver
of a single male correlating with minor higher mean absolute weight in
this group. All these microscopic findings were considered to be
non-adverse (low number of animals affected and/or minimal to slight
grades). There were no histopathological effects at 100 mg/kg bw/day.
There were no effects on mean mating, fertility and delivery data in any
group. There were no read across substance-related effects on pup
viability, clinical signs, body weight and sex ratio. Dilated ureter and
renal pelvis were recorded with dose-relationship in a few litters at
necropsy at 300 (1 or 2 litters affected out of 10) and 1000 (2/7
litters) mg/kg bw/day, vs. none in the controls. An effect of the read
across substance treatment was considered to be of minor toxicological
significance. Under the study conditions, the NOAEL for parental
toxicity, the NOEL for reproductive performance (mating and fertility)
and the NOAEL for toxic effects on progeny were considered to be
1000 mg/kg bw/day (Bentz, 2013).
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