Bromoform, which is present in drinking water supplies at low mg-ng levels, was tested for its effects on reproduction and fertility in CD-1 mice, following the RACB protocol. Data on body weights, clinical signs, and food and water consumption from a 2 week dose-range-finding study (Task 1) were used to set exposure levels for the Task 2 continuous cohabitation phase at 50, 100, and 200 mg/kg/d by gavage. With a single exception, dosing formulations were 90% - 110% of nominal concentrations.
Six animals died during Task 2: parturition complications, infection, and skin wounds inflicted by the partner accounted for the deaths, which occurred in all dose groups, and were not related to treatment. Water consumption was increased for high dose animals by nearly equal to 16%. Starting with the first litter, post-partum dam weights were lower in the high dose group, compared to controls, by 3-8%. Female body weights at other dose levels, and male body weights, were unaffected.
In Task 2, there were no treatment-related changes in reproductive endpoints: number of litters/pair, live pups/litter, viability, and pup body weights were all unaffected by these levels of bromoform exposure. The average study day for litter delivery was not affected by treatment. In the absence of a reproductive effect to investigate, no crossover test was performed.
The last litters from all dose groups were nursed by their dams until weaning. Bromoform exposure increased neonatal mortality by 15-20% at the high dose only in the first 4 days postnatally. Pup body weight was occasionally significantly reduced in high-dose pups prior to weaning.
After weaning, the F0 mice were killed and discarded without necropsy. Following the protocol of a "negative" study, at weaning the pups from the low and middle dose groups were killed and discarded, and the pups from the control and high dose groups were reared and dosed through the mating period (at 74 ± 10 days of age) until necropsy.
During the F1 mating trial, there were no differences between the two groups with respect to mating or fertility index. The number, viability, and weight of pups were not affected by bromoform exposure.
After the F2 pups were delivered and evaluated, the F1 adults were killed and necropsied. While female body weights were unaffected by exposure to 200 mg/kg/d bromoform, relative liver weight was increased by 8%, and relative kidney weight was decreased by 6%. Vaginal cyclicity was not examined in these mice. In males, body weights of the exposed mice were reduced by 6%, while weight-adjusted liver weights were increased by 6% and adjusted kidney weights were reduced by 6%. There were no changes in other organ weights, or in epididymal sperm parameters.
Microscopically, varying degrees of hepatocellular degeneration was seen in all treated male and female mice. No treatment-related alterations were noted in kidney, thryoid, lung, or sex organs.
In summary, bromoform caused a slight increase in postnatal mortality, but no changes in other reproductive indices, at doses that caused significant hepatotoxicity.
NTIS# PB89169254