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EC number: 434-430-9 | CAS number: -
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Introduction. The study was designed to investigate the effects of the test material when administered throughout the reproductive cycle of the rat and complies with the OECD Guidelines for Testing of Chemicals No 415 "One Generation Reproduction Toxicity Study" (Adopted 26 May 1983). The study was also designed to assess subchronic exposure to the test material to the rat and is based on the OECD Guidelines for Testing of Chemicals No 408 "Subchronic Oral Toxicity - Rodent" (Adopted 21 September 1998).
This study was also designed to comply with Commission Regulation (EC) No 440/2008 of 30 May 2008 test methods pursuant to Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH).
Methods. For the Subchronic phase (Subgroup A), the test material was administered by gavage to three groups, each of ten male and ten female Wistar Han™: HsdRccHan™: WIST strain rats, for one hundred and eight consecutive days, at dose levels of 50, 250 and 1000 mg/kg/day. A control group of ten males and ten females was dosed with vehicle alone (Arachis oil BP).
Clinical signs, functional observations, bodyweight development, dietary intake and water consumption were monitored during the study. Haematology, blood chemistry and urinalytical investigations were undertaken for all Subgroup A animals during Week 10. Ophthalmoscopic examination was also performed on Subgroup A control and high dose animals once prior to the start of treatment and during Week 10. During Week 11, sensory reactivity, grip strength and motor activity assessments were performed.
During Week 8, females for the reproductive phase (Subgroup B) were introduced to the study. The test material was administered to gavage to three groups, each of twenty-two female Wistar HanTM: HsdRccHanTM: WIST strain rats,for at least twenty-eight days prior to mating and throughout the mating, gestation and lactation phases of the study at dose levels of 50, 250 and 1000 mg/kg/day. A control group of twenty-two females were dosed with vehicle alone (Arachis oil BP).
Clinical signs, bodyweight development, dietary intake and water consumption were monitored for Subgroup B females. Oestrus cycle assessments were also undertaken from the start of treatment until pairing.
After Week 11 of the study, Subgroup A males were paired with Subgroup B females on a one male: one female basis within each dose group, for a maximum of twenty-one days. Pairing was continued until all twenty-two females from each group had mated with a Subgroup A male from the same dose group. On completion of the mating phase, all Subgroup A animals, were subjected to gross necropsy examination and histopathological evaluation of selected tissues from high dose and control animals was performed.
All pregnant Subgroup B females were allowed to girth birth and maintain their offspring until Day 21 post parium. Offspring development was observed during this time. On Day 21 post parium, females and their offspring were subjected to a gross necropsy examination and histopathological examinations of reproductive tissues from high dose and control females was performed.
Mortality: There were no unscheduled deaths during the study in both Subgroup A or Subgroup B.
Clinical observations: No clinical:y observable signs of toxicity were detected throughout the treatment period for both Subgroup A and Subgroup B.
Behavioural assessments: No treatment-related effects were detected for treated Subgroup A animals when compared to Subgroup A controls.
Functional performance tests: No treatment-related effects were detected for treated Subgroup A animals when compared to Subgroup A controls.
Sensory reactivity assessments: No treatment-related effects were detected for treated Subgroup A animals when compared to Subgroup A controls.
Bodyweight: No adverse effect on bodyweight development was detected for Subgroup A animals throughout the treatment period, or for Subgroup B females prior to mating, or during the gestation and lactation phases of the study.
Food consumption: No adverse effects on dietary intake or food efficiency were detected for Subgroup A animals during the treatment period, or for Subgroup B females during the pre-mating, gestation and lactation phases of the study.
Water consumption: No intergroup differences were detected for treated animals from both Subgroup A and Subgroup B when compared to their concurrent controls.
Ophthalmoscopy:No ocular effects were detected for high dose Subgroup A animals.
Urinalysis: There were no treatment-related effects detected in the urinalytical parameters investigated for Subgroup A animals.
Haematology:No toxicologically significant effects were detected for treated Subgroup A animals when compared to concurrent controls.
Blood chemistry: No toxicologically significant effects were detected for treated Subgroup A animals when compared to concurrent controls.
Oestrus cycle assessments: No significant differences in oestrus cycles were detected for treated Subgroup B females when compared to their concurrent controls.
Mating performance: There were no treatment-related differences in mating performance.
Fertility & pregnancy: There were no treatment-related effects detected on fertility or pregnancy status for treated animals when compared to controls.
Gestation length: No treatment-related effects on gestation lengths were detected for treated Subgroup B females when compared to controls.
Litter responses: There were no treatment-related effects detected for litters from treated animals when compared to controls. There were no differences in corpora lutea or pre/post implantation losses for treated animals when compared to controls.
No treatment-related effects were detected for offspring during the daily observations, litter weights or offspring bodyweights. Reflexological assessments did not reveal any significant differences between litters from treated and control dams. No treatmentrelated macroscopic abnormalities were detected at termination.
Semen assessment: No treatment-related effects were detected in sperm motility, morphology or homogenisation resistant spermatid counts from treated Subgroup A males when compared to concurrent controls.
Organ weights: No toxicologically significant intergroup differences were detected for both Subgroup A animals and Subgroup B females.
Necropsy: No treatment-related macroscopic abnormalities were detected for both Subgroup A and Subgroup B animals at terminal kill.
Histopathology: No treatment-related microscopic abnormalities were detected for animals from both Subgroup A and Subgroup B.
Conclusion: Oral administration of EA 2854 by gavage to rats for either a period of one hundred and eight consecutive days or at least twenty-eight days prior to mating and through the gestation and lactation phases of the reproductive cycle for female rats, did not result in toxicologically significant effects at dose levels of up to 1000 mg/kg/day. The 'No Observed Adverse Effect Level' (NOAEL) was therefore considered to be 1000 mg/kg/day for both systemic and reproductive toxicity.
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