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EC number: 416-510-5 | CAS number: -
The objective of the study was to evaluate the potential toxicity and toxicokinetic profile of the test item when administered orally, by gavage, to Sprague Dawley rats for a minimum of 91 days. In addition, a 28-day recovery period assessed the reversibility, persistence, or delayed occurrence of potential test item-related effects. The protocol was designed to be in general accordance with the OECD Guidelines for the Testing of Chemicals (Guideline 408). The study was conducted in accordance with appropriate GLP guidelines except for the evaluation report of the bioanalytical plasma data that was written by the Sponsor.
The test item in the vehicle (deionized water) was administered orally by gavage once daily for a minimum of 91 consecutive days to 3 groups (Groups 2-4) of Crl:CD(SD) rats. Dosage levels were 250, 500, and 1000 mg/kg/day for Groups 2, 3, and 4, respectively. A concurrent control group (Group 1) received the vehicle (deionized water) on a comparable regimen. The dose volume was 10 mL/kg for all groups. Groups 1 and 4 each consisted of 15 animals/sex and Groups 2 and 3 each consisted of 10 animals/sex. Following approximately 13 weeks of dose administration, 10 rats/sex/group were euthanized; the remaining ≤ 5 rats/sex in the control and high-dose groups were euthanized following a 28-day nondosing (recovery) period. All animals were observed twice daily for mortality and moribundity. Clinical examinations were performed daily, and detailed physical examinations were performed approximately weekly. Individual body weights and food consumption were recorded approximately weekly. Functional observational battery (FOB) and locomotor activity data were recorded for all animals prior to the initiation of dose administration, and for 10 animals/sex/group during study week 12. Ophthalmic examinations were performed during study weeks -2, 12, and 16. Clinical pathology parameters (hematology, coagulation, serum chemistry, and urinalysis) were analyzed for animals at the primary (study week 13) and recovery (study week 17) necropsies. Daily vaginal lavages for estrous cycle determination were performed on all females beginning 2 weeks prior to the primary necropsy. Complete necropsies were conducted on all animals, and selected organs were weighed at the scheduled necropsies. Selected tissues were examined microscopically. Microscopic examination was performed on a wide range of listed tissues from the animal found dead and all animals in the control and 1000 mg/kg/day groups at the scheduled primary necropsy. The liver was examined from all females in the 250 and 500 mg/kg/day groups at the primary necropsy and from all females in the control and 1000 mg/kg/day groups at the recovery necropsy. Gross lesions were examined from all animals at the primary and recovery necropsies. Spermatogenic endpoints were evaluated for all males at the primary necropsy.
For plasma bioanalysis, blood samples were collected from 4 animals/sex/group at approximately 6 hours after dose administration on study days 7, 28, and 84.
There were no test item-related effects on survival, body weight, food consumption, FOB or locomotor activity assessment, hematology, coagulation, urinalysis, ophthalmic examinations, estrous cycle, macroscopic examinations, or spermatogenic endpoints. Yellow staining on the ventral trunk and/or around the anogenital and/or urogenital areas was noted in the 1000 mg/kg/day group females beginning on study day 11 and sporadically throughout the dosing period.
Nonadverse test item-related higher calcium values were noted in the 500 and 1000 mg/kg/day group males at the primary necropsy. Nonadverse test item-related higher mean liver and kidney weights (absolute and relative to body and brain weights) were noted in the 1000 mg/kg/day group females at the primary necropsy and higher mean liver weight relative to final body weight was noted in the 1000 mg/kg/day group males at the primary and recovery necropsies. In the females from the 1000 mg/kg/day group at the primary necropsy, 3 of 10 animals had mild vacuolation of hepatocytes, which for 2 of these animals was further specified as microvesicular hepatocellular vacuolation. From the extension of histological evaluations, minimal to mild microvesicular hepatocellular vacuolation was also noted at the primary necropsy in 3 of 10 females in the 250 mg/kg/day group and in 4 of 10 females in the 500 mg/kg/day group. No instances of vacuolation were noted in the control or 1000 mg/kg/day group females examined at the recovery necropsy. Taking into account the mild nature of the vacuolation at the primary necropsy, the lack of associated liver enzyme alterations, the lack of persistence of the vacuolation at the recovery necropsy, and historical data, the hepatocellular vacuolation, mainly evident as microvesicular hepatocellular vacuolation, was considered to be an adaptive change and nonadverse.
Plasma concentrations of the test item and the two metabolites ranged from the lower limit of quantitation (LLQ) to 41,700 ng/mL (178.7μM) for the test item, from the LLQ to 16,600 ng/mL (80.9μM) for metabolite 1, and from 198 ng/mL to 21,600 ng/mL (1.2 - 98.5μM) for metabolite 2. The mean plasma concentrations for all 3 analytes increased with dosage on all 3 sampling days in both genders. In females the mean test item plasma concentrations were generally higher than the mean male value of the corresponding group and day of sampling. In contrast, the mean values for the 2 metabolites were lower in females than the corresponding male values. Regarding the sum of the 3 analytes (the test item, 2 metabolites) a dose-dependent increase in analyte concentrations was visible. For both genders a plasma level of the combined analytes of approximately 50, 100, and 200μM was observed respectively at a daily dosage of 250, 500, and 1000 mg/kg body weight, both on days 7 and 28. These data underline the linear dose dependence of plasma levels which are not evident from looking at the test item data alone due to its rapid metabolism. There was a slight decline of combined plasma levels on study day 84, which was more apparent in males than in females; this may indicate some sort of adaptation of the animals to the prolonged test item administration. In summary, plasma data showed dose dependence of test item absorption, metabolism and no indication of bioaccumulation over time.
Based on the results of this study, oral administration of the test item to Crl:CD(SD) rats over a period of 91 or 92 days resulted in a No-Observed-Adverse-Eeffect Level (NOAEL) of 1000 mg/kg/day, the highest dosage level investigated.
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