Acetaminophen (ACET), a common over-the-counter analgesic agent, 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 0.25%, 0.5%, and 1.0% in the diet. Feed consumption was reduced only in females at the top dose level, by 10-20%. Measured body weight and feed consumption allowed exposure to be estimated as nearly equal to 370, 770, and 1400 mg/kg/d.
During Task 2, 4 animals died: 2, 1, and 1 each in the low, middle, and high dose groups. During Task 2, the number of litters/pair decreased by 3% for the high dose group. No changes were noted in the number of pups/litter, viability, or in adjusted pup weight. The slight reduction in number of litters/pair was judged to be too small to yield a detectable change during the statistically-less-powerful Task 3 crossover mating, so no crossover test was conducted.
For the F1 evaluation, the last litter in Task 2 from all dose groups was nursed to weaning, and reared on the diet consumed by their parents. F1 pup body weights were reduced at all doses for both sexes by nearly equal to 6-18% . Pup body weight gain to weaning was also reduced for the medium and high dose males (17% and 34%), and for females at all doses (10-28%).
All dose groups were reared consuming the same diet provided to their parents. The body weight differences that were seen during nursing were reduced, but still present, at the time of mating.
At the F1 mating, the F2 pup weight adjusted for litter size was decreased by 11% at the high dose level. No other reproductive endpoints were affected.
After the F2 pups were delivered and evaluated, the F1 adults from only the control and high dose groups were killed and necropsied. Compared to controls, the high dose males weighed 10% less, while organ weights were not affected. Sperm abnormalities increased from 7% (controls) to 16% at the high dose. High dose females weighed 8% less, while adjusted liver weight was increased by 10%.
In summary, the greatest toxicity produced by acetaminophen in the diet of Swiss mice was on the growing neonate (reduced weight gain during nursing). Fertility endpoints (ability to bear normal numbers of normal-weight young) were generally not affected.
NTIS #PB85204667/AS