The Developmental Toxicity of Orally Administered Theophylline in Rats and Mice

The Developmental Toxicity of Orally Administered Theophyllinein 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 fordevelopmental toxicity. It was administered continuously onGestational 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 gestationand treatment, as well as corrected weight gain) decreased at0.40%. While food consumption was lower only in the 0.40% treatmentgroup, water consumption was higher in all treated groups. Therewas a dose-related decreasing trend in gravid uterine weight.The number of live fetuses per litter decreased at 0.40% andthe average male and female fetal weight per litter decreasedat 0.30 and 0.40%. There was no increase in malformations. Inmice, maternal corrected body weight and weight gain duringgestation decreased at 0.15 and 0.20%, and weight gain duringtreatment and gravid uterine weight decreased at 0.20%. Waterconsumption was reduced by as much as 30-45% of controls at0.15 and 0.20%, respectively, while food consumption did notchange with THEO treatment There was an increase in percentageresorp-tions per litter and a decrease in the average male andfemale fetal weight per litter at 0.15 and 0.20%. An increasingtrend was noted for percentage malformed fetuses per litter,and percentage litters with externally malformed fetuses wereslightly 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 adversedevelopmental effects in mice were observed at doses that causedreduced maternal water consumption and body weight gain. Itis possible that water deprivation contributed to the effectsseen in mice after THEO treatment. For maternal toxicity, noobservable adverse effect levels (NOAELs) were 218 mg/kg forrats and 282 mg/kg for mice. NOAELs for developmental toxicitywere 124 mg/kg for rats and 282 mg/kg for mice. These NOAELsare approximately 10-to 30-fold greater than doses requiredto maintain humans on serum THEO concentrations that are clinicallyuseful.