Developmental Toxicity (Segment II) Study of WR6026 Dihydrochloride in Rabbits
Abstract
This study evaluated the developmental toxicity of WR6026 Dihydrochloride in time-mated New Zealand White (Pasteurella Free) female rabbits. Doses were 0, 3, 7, and 15/10 mg base/kg/day administered by gavage during gestation days (GD) 6-18 (GDO = day of observed mating). The high dose was reduced from 15 mg base/kg/day to 10 mg base/kg/day on gestation days 12 - 15 due to the death of four animals (the range of days reflects the study stagger-start over four days). A positive control group was administered retinol palmitate, 300 mg/kg/day, on GD9, and GDJ0 or GDI2 (in 5 females) by gavage. Toxic manifestations were only seen in the high dose group, and included an increase in respiratory rate associated with cyanosis. No biologically significant decreases in body weight/weight gain or in food consumption were observed at the high dose following dose level reduction. Ten mg base/kg/day was therefore considered at or near the maternal NOEL. This observation is supported by the results of a previously conducted dose range-finding study (UIC/TRL Study No. 172) in which no effects were seen at 10 mg base/kg/day, whereas maternal mortality occurred at 20 mg base/kg/day. Females in the positive control group did not show any significant drug-related effects. At the 15/10 mg base/kg/day level, two litters were observed with fetuses having vertebral anomalies. No statistically significant increases in the number of litters with skeletal malformations resulted. However, since the malformations observed for the fetuses from both litters were of a similar nature, it is unclear if the vertebral anomalies were or were not a result of treatment with WR6026 Dihydrochloride at 15/10 mg base/kg/day (a maternally lethal dose level\ Accordingly, 7 and possibly 15/10 mg base/kg/day was considered at or near the NOEL dose for developmental toxicity.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 07, 1995
- Accession Number
- ADA640651
Entities
People
- A. F. Youssef
- Barry S. Levine
- M. Mercieca
Organizations
- University of Illinois at Chicago