Dose Range-Finding Developmental Toxicity (Segment II) Study of WR242511 in Rabbits
Abstract
This dose range-finding study evaluated the developmental toxicity of WR242511 tartrate in time- mated New Zealand female rabbits. Doses were 0, 1, 2.5. 6 and 14 ma base/ka/day administered by gavage during gestation days (GD) 6-18 (GD0 - day of mating). Maternal toxic manifestations included the fatalities of all animals at 14 mg base/kg/day by GD8 and all animals at 6 mg base/kg/day by GD12. In the 6 rag base/kg/day dose, activity was decreased in one animal the day prior to death. A marginal lack in weight gam and decrease in food consumption were observed at least in one of the surviving pregnant females in the 2.5 mg base/kg/day dose. The 2.5 mg base/kg/day dose was therefore considered at or near the maternal no observable adverse effect level (LOAEL). Fetal toxicity was seen in 2.3 mg base/kg/day as significant decreases in fetal body weights and one non-viable ferns. A biologically significant decrease in the female fetal body weights was observed at the 1 mg base/kg/day dose. The 1 mg base/kg/day dose was considered at or near the low observable adverse effect level for developmental toxicity. The results of this study and a previous dose range-finding developmental toxicity study in rats (UIC/TRL No. 143) suggested direct developmental toxicity of WR242511 tartrate. and a higher sensitivity in rabbits than rats. In addition, it was evident in rats and rabbits that there is an increased sensitivity of female ictuses to the test article in comparison to the males. The high dose for the definitive developmental toxicity study m rabbits should not exceed 3.5 mg base/kg/day to produce enough surviving females at the high dose to assess toxicity. Accordingly. O.5. 1.3 and 3.5 mg base/kg/day are suggested as doses for the definitive developmental toxicity (segment II) study in rabbits.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 26, 1994
- Accession Number
- ADA640509
Entities
People
- Ashraf F. Youssef
- Barry S. Levine
Organizations
- University of Illinois Urbana–Champaign