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EC number: 263-471-3 | CAS number: 62256-00-2
The purpose of this study was to assess the general systemic toxicity potential in rats, including a screen for reproductive/developmental effects and assessment of endocrine disruptor relevant endpoints, with administration of 2-ethylhexyl 7-oxabicyclo[4.1.0]heptane-3-carboxylate by oral gavage administration for at least 5 weeks.
Four groups of ten male and ten female rats received 2-ethylhexyl 7-oxabicyclo[4.1.0]heptane-3-carboxylate at doses of 30, 100 or 350 mg/kg/day by oral gavage administration. Males were treated daily for two weeks before pairing, up to necropsy after a minimum of five consecutive weeks. Females were treated daily for two weeks before pairing, throughout pairing, gestation and until Day 13 of lactation. Females were allowed to litter, rear their offspring and were killed on Day 14 of lactation. The F1 generation received no direct administration of the test item; any exposure was in utero or via the milk. A similarly constituted Control group received the vehicle, corn oil, at the same volume dose as treated groups.
During the study, clinical condition, detailed physical examination and arena observations, sensory reactivity, grip strength, motor activity, body weight, food consumption, hematology (peripheral blood), blood chemistry, thyroid hormone analysis, estrous cycles, pre-coital interval, mating performance, fertility, gestation length, organ weight and macroscopic pathology and histopathology investigations were undertaken.
The clinical condition, litter size and survival, sex ratio, body weight, ano-genital distance, nipple counts (male only) and macropathology for all offspring were also assessed.
Four females given 100 mg/kg/day and two females given 350 mg/kg/day died or were sacrificed due to poor clinical condition including decreased activity, unresponsiveness, prostate posture, uncoordinated gait, circling behaviour or hunched posture between lactation Days 9 and 13. There were no pathological findings that elucidated the cause of demise.
There were no clinical signs seen during the weekly detailed physical examinations that were considered to be test item related and no clinical signs were recorded in association with dose administration. Sensory reactivity, grip strength and motor activity were unaffected by treatment.
Body weight gain of males given 350 mg/kg/day was statistically significantly lower than controls (0.76x) and food consumption of females given 100 or 350 mg/kg/day was lower (up to 0.88x) than controls, occasionally attaining statistical significance.
Estrous cyclicity, pre-coital interval, gestation length, mating performance and fertility were unaffected by treatment.
Haematology and blood chemistry investigations revealed no effect of treatment and there was no effect upon circulating levels of thyroxine (T4) in adult males.
After five weeks of treatment for males and on Day 14 of lactation for females, liver weights were higher in males and females given 100 and 350 mg/kg/day and kidney weights were higher in males and females given 350 mg/kg/day. There were no test item related macropathological or micropathological findings in the full list of tissues examined.
Body weight gain of male and female offspring from the 100 and 350 mg/kg/day groups were statistically significantly lower (0.75X to 0.82x) than the Controls.
The clinical condition, litter size, sex ratio and survival indices of offspring were unaffected by parental treatment.
There was no effect of parental treatment upon circulating levels of thyroxine (T4) in offspring on Day 13 of age.
The ano-genital distances of offspring were unaffected by paternal treatment and no nipples were seen on any male offspring on Day 13 of age.
No macroscopic findings in the offspring were considered to be related to paternal treatment.
It was concluded that the oral administration of 2-ethylhexyl 7-oxabicyclo[4.1.0]heptane-3-carboxylate to parental Sprague Dawley male rats at dose levels of 30, 100 or 350 mg/kg/day for two weeks before pairing, during pairing and then up to termination after five weeks of treatment was associated with statistically significantly lower bodyweight gain (0.76x). Oral administration of the same dose levels to female rats for two weeks before pairing, during pairing and during gestation and lactation up to termination on Day 14 of lactation was associated with 4 decedent females during lactation at 100 mg/kg/day and 2 decedent females during lactation at 350 mg/kg/day. There were no pathological changes noted and the cause of the demise was not established. Food consumption was slightly and occasionally statistically significantly reduced in females given 100 (up to 0.88x, gestation and lactation only) or 350 mg/kg/day (up to 0.89x) and considered non adverse.
Growth of offspring from parental doses of 100 or 350 mg/kg/day was slightly and statistically significantly lower (up to0.75x), but considered non adverse. There were no other effects on reproductive performance, fertility, litter size or offspring survival.
In the context of this study,2-ethylhexyl 7-oxabicyclo[4.1.0]heptane-3-carboxylateshowed no evidence of being an endocrine disruptor, as assessed by measurement of thyroxine (T4) in adult males and offspring, organ weights, ano-genital distance and external examination of offspring, and nipple counts in male offspring,
The no-observed-adverse-effect level (NOAEL) of2-ethylhexyl 7-oxabicyclo[4.1.0]heptane-3-carboxylatefor systemic toxicity of males was considered to be 350 mg/kg/day.
The no-observed-adverse-effect level (NOAEL) of2-ethylhexyl 7-oxabicyclo[4.1.0]heptane-3-carboxylatefor systemic toxicity of females was considered to be 30 mg/kg/day, based on mortaliy.
The no-observed-adverse-effect level (NOAEL) of2-ethylhexyl 7-oxabicyclo[4.1.0]heptane-3-carboxylatefor reproductive/developmental toxicity was considered to be 350 mg/kg/day.
There were no unique toxicities identified to a system, so no classification for a STOT is needed.
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