© 1990 Oxford University Press
other |
The Developmental Toxicity of Orally Administered Theophylline in Rats and Mice1
Systemic Toxicology Branch, National Institute of Environmental Health Sciences, National Toxicology Program P.O. Box 12233, Research Triangle Park, North Carolina 27709
*Chemistry and Life Sciences, Research Triangle Institute P.O. Box 12194, Research Triangle Park, North Carolina 27709
Reproductive and Developmental Toxicology Branch/HHAG/OHEA (RD 689), US Environmental Protection Agency 401 M Street, S W., Washington, D.C. 20460
Received March 13, 1989; accepted June 19, 1989
The Developmental Toxicity of Orally Administered Theophylline in Rats and Mice. LIND-STRÖM, P., MORRISSEY, R. E., GEORGE, J. D., PRICE, C. J., MARR, M. C, KJMMEL, C. A., AND SCHWETZ, B. A. (1990). Fundam. Appl. Toxicol. 14, 167–178. Theophylline (THEO), a widely prescribed anti-asthmatic, was evaluated for developmental toxicity. It was administered continuously on Gestational Days 6 through 15 to pregnant Sprague-Dawley (CD) rats in the feed (0,0.15,0.30, or 0.40%) and to pregnant Swiss (CD-1) mice in the drinking water (0,0.075, 0.15, or 0.20%). Estimated intake of THEO for rats was 0, 124, 218, or 259 mg/kg/day, while for mice it was 0, 282, 372, or 396 mg/kg/day. In rats, maternal weight gain parameters (weight gain during gestation and treatment, as well as corrected weight gain) decreased at 0.40%. While food consumption was lower only in the 0.40% treatment group, water consumption was higher in all treated groups. There was a dose-related decreasing trend in gravid uterine weight. The number of live fetuses per litter decreased at 0.40% and the average male and female fetal weight per litter decreased at 0.30 and 0.40%. There was no increase in malformations. In mice, maternal corrected body weight and weight gain during gestation decreased at 0.15 and 0.20%, and weight gain during treatment and gravid uterine weight decreased at 0.20%. Water consumption was reduced by as much as 30-45% of controls at 0.15 and 0.20%, respectively, while food consumption did not change with THEO treatment There was an increase in percentage resorp-tions per litter and a decrease in the average male and female fetal weight per litter at 0.15 and 0.20%. An increasing trend was noted for percentage malformed fetuses per litter, and percentage litters with externally malformed fetuses were slightly increased in the mid- and high-dose groups. However, these increases were not statistically significant. In summary, there were developmental effects seen in rats at a dose (0.30%) that did not produce overt maternal toxicity, but the adverse developmental effects in mice were observed at doses that caused reduced maternal water consumption and body weight gain. It is possible that water deprivation contributed to the effects seen in mice after THEO treatment. For maternal toxicity, no observable adverse effect levels (NOAELs) were 218 mg/kg for rats and 282 mg/kg for mice. NOAELs for developmental toxicity were 124 mg/kg for rats and 282 mg/kg for mice. These NOAELs are approximately 10-to 30-fold greater than doses required to maintain humans on serum THEO concentrations that are clinically useful.