Theophylline, a widely prescribed antiasthmatic, was evaluated for toxic and teratogenic effects in timed-pregnant CD rats. THEO (0, 0.150, 0.300, or 0.400%) was administered continuously in the feed on gestational days 6 through 15. Females were weighed and observed daily for clinical signs of toxicity. At sacrifice, a total of 2021 dams (i.e., confirmed pregnant females) per treatment group were evaluated. The gravid uterus of each dam was weighed, and the status of each uterine implantation site (i.e., resorption, dead fetus, or live fetus) recorded. Each live fetus was weighed and examined for external, visceral, and skeletal malformations.
During THEO treatment, dams exhibited clinical signs of toxicity consisting primarily of piloerection, weight loss, and rough coat. No dose related maternal deaths occurred during this investigation. Maternal body weight on gd 15, maternal weight gain during gestation (i.e., gd 0 through 20) and treatment (i.e., gd 6 through 15), and corrected maternal weight gain (i.e., maternal weight gain during gestation minus gravid uterine weight) decreased in a dose related manner and exhibited a significant difference among treatment groups with the high dose group significantly below controls. A trend toward decreasing maternal body weight with respect to increasing dose was exhibited on gd 11, with a significant main effect for dose, but there was no significant difference between controls and any individual dose group. Maternal body weight on gd 20, gravid uterine weight, and absolute maternal liver weight each exhibited a decreasing trend with respect to increasing dose, but no significant treatment effect or pairwise differences between controls and any dose group were detected. Relative maternal liver weight (i.e., percent body weight) was unaffected by treatment. Maternal food consumption (g/day or g/kg/day), did not differ among treatment groups prior to onset of treatment. However, during treatment and during the entire gestation period maternal food consumption decreased in a dose related manner and was significantly below controls in both the 0.300% and 0.400% dose groups during treatment, and in the 0.400% dose group for the entire gestation period. Observation of the animals provided no evidence of food wastage; calculation of theophylline intake indicated that the dams were receiving 0, 123.8, 217.5, and 258.6 mg/kg/day in the 0, 0.150%, 0.300% and 0.400% dose groups, respectively. Maternal food consumption (g/day) after treatment had been completed (gd 15-20) exhibited no treatment effect; when calculated as g/kg/day, maternal food consumption during gestational days 15-20 tended to increase with respect to increasing treatment level. Maternal water consumption during treatment (g/day or g/kg/day) increased in a dose related manner, with all theophylline treated groups significantly above controls. After treatment ceased, there was no difference among dose groups in water consumption, calculated as g/day. When calculated as g/kg/day, maternal water consumption was significantly higher in the 0.400% treatment group.
There were no differences among treatment groups in the number of corpora lutea or implantation sites per dam, or in the percent preimplantation loss. THEO treatment had no effect on the percent of dead fetuses per litter (i.e., fetuses weighing greater than 0.8 g, having discernible digits and exhibiting no vital signs at uterine dissection on gd 20), or on the percent of litters with one or more resorptions, dead fetuses, nonlive implants (i.e., resorptions and dead fetuses), or adversely affected implants (i.e., resorptions, dead fetuses, and malformed live fetuses) or on the percent of resorptions, dead fetuses, nonlive implants, or adversely affected implants per litter. THEO treatment resulted in a significant difference among dose groups in the number of live fetuses per litter, with the high dose group significantly below controls. Average fetal body weight per litter (male, female, and combined) decreased in a dose-related manner and exhibited a significant main effect for dose with the 0.300% and 0.400% dose groups significantly below controls. THEO (0%, 0.150%, 0.300%, or 0.400% in feed) administered continuously from gd 6 to gd 15 had no effect on the percent of live fetuses malformed per litter or the percent of live male or female fetuses malformed per litter. Malformed fetuses per litter occurred with an incidence of 1.38%, 0.92%, 0.33%, and 1.57% for the vehicle control, low, medium, and high dose groups, respectively. The incidence of litters with one or more malformed live fetuses was unaffected by treatment. The incidence of litters with one or more external, skeletal, or visceral malformations was also unaffected by THEO treatment.
In conclusion, THEO administered continuously in the feed to timed-pregnant CD rats from gd 6 through gd 15 at levels of 0%, 0.150%, 0.300% or 0.400% produced at the high dose level a decrease in maternal body weight and maternal body weight gain and decreased maternal food consumption and had no effect on the percent of resorptions, nonlive implants, adversely affected implants or malformations per litter. However, THEO exposure resulted in significant dose-related fetotoxicity as evidenced by decreased average fetal body weight per litter at dose levels of 0.3 and 0.4% and reduced number of live fetuses per litter at the high dose. In a companion study in which THEO was administered in the drinking water to pregnant CD-1 mice (0%, 0.075%, 0.150%, or 0.200%) on gd 6 through 15, treatment at the 0.150% or 0.200% level resulted in an increase in the percent of resorptions, nonlive implants, and adversely affected implants per litter, and a decrease in the average fetal body weight per litter, and a dose related increasing trend in the proportion of litters with malformed fetuses and for the incidence of external malformations. Maternal toxicity was observed at 0.15% and 0.20% THEO in that study.