(a) Experimental systems

(ii) Toxic effects

The acute intraperitoneal LD50 of theophylline in rats was reported to be 206 mg/kg bw, and accompanying clinical signs were delayed convulsions and tetanic spasm. Acute studies in mice showed an oral LD50 of 332 mg/kg bw and an intraperitoneal LD50 of 217 mg/kg bw; clinical signs included convulsions, profuse salivation and emesis (Tarka, ).

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A single oral dose of 400 mg/kg bw theophylline was acutely toxic to rats and mice. Administration of the same daily dose as two separate doses of 200 mg/kg bw was acutely toxic to rats but not to mice (Lindamood et al., ). In dogs, the minimal oral toxic concentration of theophylline appears to be higher (37&#;60 µg/ml plasma) than in man (> 20 µg/ml) (Munsiff et al., b). Theophylline has been reported to be more toxic than caffeine or theobromine to the heart, bronchi and kidneys (Tarka, ).

Two weeks&#; feeding 800 ppm (mg/kg) theophylline in the diet to rats induced no significant toxicity except for dose-related uterus hypoplasia (Lindamood et al., ).

(iii) Effects on reproduction and prenatal toxicity

Reproductive toxicity: Feeding theophylline to immature (five to six weeks old) Osborne-Mendel rats at 0.5% in the diet [approximately 300 mg/kg bw per day] for 75 weeks produced severe testicular atrophy in 50% of animals, oligo-spermatogenesis and aspermatogenesis. These results were confirmed in Holtzman rats fed 0.5% theophylline for 19 weeks: 86% showed testicular atrophy (Friedman et al., ).

In 13-week toxicity studies, weanling B6C3F1 mice and Fischer 344 rats were administered theophylline by gavage or in the diet. Gavage with 300 mg/kg bw per day led to a slight but significant decrease in testicular weight in mice, but 150 mg/kg bw or less had no effect. In rats, a significant decrease in testicular weight was observed after gavage with 150 mg/kg bw per day but not with 75 mg/kg bw or less. No effect on sperm motility, sperm density or the number of abnormal sperm was observed in male rats or mice, and no effect was seen on the mean length of the oestrous cycle in females. Daily administration of 184&#;793 mg/kg bw theophylline in the diet to mice had no effect on sperm, whereas abnormal sperm were seen in rats given 258 mg/kg in the diet but not at lower doses (Morrissey et al., ).

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In a reproductive study, Swiss CD-1 mice were administered 0.075, 0.15 or 0.30% theophylline in the diet (average daily doses, 125, 265 or 530 mg/kg bw) for one week before mating and during 13 weeks of cohabitation. Litters were removed one day after birth, except for the last litter which was raised to 21 days of age. Among all treated groups, there was a dose-related decrease in the number of live pups per litter; in the high-dose groups, there was a significant decrease in the number of litters per breeding pair and a significant decrease in live pup weight. In the high- and mid-dose groups, a significant decrease in the percentage of pups born alive was observed. Only mild toxicity was observed in adults at these doses. In a cross-over mating trial at the end of a 19-week exposure to 0.3% theophylline, animals of each sex were found to be affected, although females were more severely affected than males. The decrease in reproductive capacity was considered by the authors to be related partially to embryotoxicity (Morrissey et al., ).

Developmental toxicity. IRC-JCL mice received a single intraperitoneal injection of 175, 200 or 225 mg/kg bw theophylline on day 12 of gestation. Subsequently, 40% of dams in the high-dose group died, and dyspnoea and convulsions were observed in those in the low- and mid-dose groups. Fetal body weight was decreased with the high and medium doses, and the incidence of resorptions was significantly increased with the high dose. Malformations were observed in all treated groups; these included cleft palate, digital defects and macrognathia. Subcutaneous haematomas were also seen (Fujii & Nishimura, ).

ICR mice received an intraperitoneal injection of 100, 150 or 200 mg/kg bw theophylline on one of gestation days 10&#;13. A dose-related increase in the incidence of resorptions and malformations &#; mostly cleft palate &#; was observed, with a peak embryotoxic response in fetuses treated on day 11 (Tucci & Skalko, ).

Sprague-Dawley rats were fed theophylline in the diet (average daily dose, 124, 218 or 259 mg/kg bw) on days 6&#;15 of gestation. In parallel, Swiss CD-1 mice received theophylline in the drinking-water (daily doses, 282, 372 or 396 mg/kg bw) on the same gestation days. Slight maternal toxicity (decreased weight gain) was observed in high-dose rats and in mid- and high-dose mice. In rats, fetal body weight was significantly decreased with the medium and high doses, and live litter size was decreased with the high dose; no malformation was observed. In mice, fetal body weight was significantly decreased in the mid- and high-dose groups, and the incidence of resorptions was increased in the mid-dose group (Lindström et al., ).

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