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The test substance was administered by daily oral gavage to male and female Sprague Dawley rats at dose levels of 0, 100, 300 or 1000 mg/kg bw/day according to the OECD 421 guideline. Males were exposed for 2 weeks prior to mating, during mating and up to termination (total of 29 doses). The females were exposed for 2 weeks prior to mating, during mating, during post-coitum, and during 3 days of lactation (53-57 doses).
All F0 males and females in the control, 100, 300, and 1000 mg/kg/day groups survived to the scheduled necropsies. Test substance-related clinical findings were noted for males and females in the 300 and 1000 mg/kg/day groups. Clear material around the mouth was noted for 11 of 12 males and all females at 1000 mg/kg/day and to a lesser extent (5 males and 6 females) at 300 mg/kg/day at 1-2 hours following dose administration generally throughout the respective treatment periods. The clinical findings noted for males and females in the 300 and 1000 mg/kg/day groups were considered non-adverse. Body weight and food consumption were unaffected by test substance administration.
Slightly higher mean liver weights (absolute, relative to final body weight, and relative to brain weight) were noted in the 1000 mg/kg/day F0 group males [5.9%, 5.9%, and 3.8% (values not statistically significant)] and females [14.2% (p<0.05), 13.8% (p<0.01), and 13.5% (p<0.05)]. These changes were of a minimal magnitude. Slightly higher mean liver weights were also noted at 1000 mg/kg/day in a previous 28-day study (Haas, 2013, WIL-537026) (approximately 12% higher in males and females) and in a concurrent 90-day study (Haas, Draft, WIL-537030) (9.5% and 8.1% higher in males and females, respectively) of the same test substance with no correlating adverse clinical pathology or histologic changes. Based on the lack of any correlating adverse clinical pathology or histologic changes in two additional studies on the same test substance with similar minimal liver weight elevations, microscopic examination of the liver was not performed in the current study and the slightly higher mean liver weights were considered toxicologically irrelevant. Therefore, the NOAEL for F0 male and female systemic toxicity was considered to be 1000 mg/kg/day.
No test substance-related effects were noted on F0 reproductive endpoints, including male and female mating and fertility, male copulation, and female conception indices, mean number of days between pairing and coitus, gestation length, and the process of parturition at any dosage level. Therefore, the no-observed-adverse-effect level (NOAEL) for F0 male and female reproductive toxicity was considered to be 1000 mg/kg/day (the highest dosage level evaluated) when the test substance was administered orally by gavage to Crl:CD(SD) rats.
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