Methylphenidate (M, Ritalin®) is used in the pharmacologic management of hyperactive children, using doses from 0.5 - 2 mg/kg/d. Since there are few published reports on the reproductive toxicity of this compound, this study was performed using the RACB protocol in Swiss CD-1 mice. In a previous NTP subchronic study of M in B6C3F1 mice, dietary levels of greater than 125 ppm reduced sperm motility, while hepatitis was observed at levels greater than or equal to 250 ppm. Thus, dietary concentrations of 0.012, 0.05, and 0.1% in feed were selected for the current study (125, 500, and 1000 ppm).
Body weight was occasionally reduced for males at the high dose (by nearly equal to 6%), but not for females at any dose. Feed consumption was not affected by M addition. Body weights and feed consumption measures permit the calculation of daily dose estimates: 18, 75, and 160 mg/kg/d. The 9 deaths during the study all showed differing patterns of effects, and were judged to be not treatment-related.
These levels of M in the feed did not change the number of litters/pair, the number of pups/litter, pup viability, or pup weight. Cumulative days to litter were not changed by M treatment.
The last litter from Task 2 was reared and began M treatment after weaning. Pup viability and growth to weaning was not affected by maternal M consumption.
After the last litter was weaned, the high dose and control F0 mice were killed and necropsied. Female terminal body weights were unchanged, while adjusted liver weight was increased in the treated mice by nearly equal to 20%. Ante-mortem cyclicity measures found no M-related change in the estrous cycle.
Male terminal body weight was reduced by nearly equal to 10%, and adjusted liver weight was increased by nearly equal to 19%. There were no changes in other organ weights. Epididymal sperm abnormalities were reduced from a control value of nearly equal to 5% to nearly equal to 3% in the M-treated males; while statistically significant, this is probably of little or no biological import.
Since there were no adverse reproductive effects in Task 2, only the high dose group and controls were evaluated in the second generation. During this mating trial, there were no treatment-related changes in the percent of pairs mating or delivering young, just as there were no reductions in the number of live pups/litter, their viability, or their body weight.
Once the F2 litters had been evaluated, all mice were killed, and the F1 parents necropsied. Female terminal body weight was unchanged by 0.1% M consumption, but adjusted liver, kidney, and ovary weights were increased, by 17%, 6%, and 18%, respectively. There was no M-related ante-mortem change in estrous cycliclty. Male body weights were unaffected by 0.1% M consumption, though adjusted liver weight was increased by nearly equal to 20%, and seminal vesicle weight was reduced by 13%. There were no changes in epididymal sperm measures.
These data show that these levels of Methylphenidate in the diet of Swiss mice caused effectively no change in reproductive endpoints, despite changes in liver weights and male body weights. Although hepatic and body weight changes seen in the previous 90 day subchronic study were mirrored in this RACB study, the previous reductions in sperm motility were not reproduced. One possible explanation for this is the use of different mouse strains, but this is hypothetical, and deserves further investigation.
NTIS# PB89178057