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EC number: 931-335-9
CAS number: 90622-74-5
study was conducted to evaluate the repeated dose oral toxicity of the
test substance, C18-unsatd. MIPA, 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 bw and in most of the animals at 100 mg/kg bw/day bw
(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 bw 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 bw
was considered to be equivocal but of limited toxicological
significance. In males, mean food consumption at 1000 mg/kg bw/day bw
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
bw and in females were not affected. In females, mean cholesterol level
was higher than in controls at 300 and 1000 mg/kg bw/day bw (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 bw or in males. At
histopathology at 1000 mg/kg bw/day bw, 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 bw/day bw, 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 bw. Under the study
conditions, the NOAEL for parent systemic toxicity was considered to be
1000 mg/kg bw/day (Bentz, 2013).
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