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The objective of the study was to evaluate the potential repeated-dose and reproductive toxicity of the test substance when administered by gavage to male and female rats during premating, cohabitation, gestation, and lactation up through day 3. Groups of 20 Crl:CD(SD) rats were dosed with vehicle (deionised water) containing 0, 10, 50, or 200 mg/kg/day test substance during the treatment period. The dose solutions were sampled and analysed during the course of the study and were confirmed to be at targeted concentrations and stable under the conditions of the study. Following 28 days of dosing, five rats/sex/group were selected and euthanized to collect data to satisfy the 28-day subchronic toxicity, clinical pathology, and histologic endpoints. Five remaining rats/sex/group were selected for a 28-day recovery group, and test substance administration was ceased, on test day 29, for the remainder of the recovery period. For the remaining ten rats/sex/group, test substance administration was continued until one day prior to scheduled euthanasia. These rats were co-housed within their respective treatment groups to produce F1 litters. Dams were allowed to deliver and rear their offspring until postnatal day 4. Clinical observations, body weight, and food consumption were determined at least weekly throughout the study. Clinical pathology evaluations were conducted for five rats/sex/group from the reproductive subset and five rats/sex/group from the 28-day with recovery subset (prior to cessation of test substance administration) on test day 29-30 (haematology and clinical chemistry), and then again at terminal sacrifice for rats from the reproductive subset (coagulation; test day 45 for males and 57-61 for females). Rats selected for haematology and clinical chemistry evaluations were fasted overnight prior to blood collection. Clinical pathology evaluations were not conducted on the 28-day with recovery rats at the end of the recovery period since there were no effects during treatment. Neurobehavioral evaluations were conducted during acclimation (baseline) and on test days 27-28 on five rats/sex/group from the reproductive subset and five rats/sex/group from the 28-day with recovery subset. Litter examinations (live, dead, or missing pups, individual pup weights, clinical observations) were determined at birth and on postnatal day (PND) 4. Gross postmortem examinations were performed on selected rats and selected organs were weighed and/or retained for histopathological examination. There were no test substance related deaths or clinical observations noted during the study. No test substance-related effects on body weight or nutritional parameters were observed. There were no test substance-related effects on neurobehavioral endpoints, clinical pathology, reproductive performance, or effects on offspring at any concentration tested. Test substance-related histopathologic changes occurred at 50 and 200 mg/kg/day, and consisted of effects in the kidneys of male rats and in the nose of both male and female rats. Increased hyaline droplets consistent with alpha2u globulin were noted at 50 and 200 mg/kg/day in the cortical tubules of males after 28 days of administration, and were also observed in the P1 males after 45 days of test substance administration. Increased hyaline droplet accumulation was not present in the recovery males. However, the presence of a slight increase in severity of chronic progressive nephropathy in two recovery males, one with minimal granular casts, suggests that the increased droplets at 200 mg/kg/day were adverse. Kidney effects at 50 mg/kg/day were considered non-adverse. Low incidences of degeneration/atrophy of nasal olfactory epithelium were present in the 28-day and/or P1 groups at 200 mg/kg/day in male rats, and at 50 and 200 mg/kg/day in female rats. Olfactory lesions were reversible as no test substance-related changes were present in the nose of the 200 mg/kg/day recovery groups. Under the conditions of this study, the no-observed adverse effect level (NOAEL) for systemic toxicity was 10 mg/kg/day based on histopathologic effects that were observed in the noses and kidneys of male rats at 200 mg/kg/day and in the noses of female rats at 50 and 200 mg/kg/day.
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