Subchronic Toxicity of Orally Administered (Gavage and Dosed-Feed) Theophylline in Fischer 344 Rats and B6C3F2 13 Mice

Subchronic Toxicity of Orally Administered (Gavage and Dosed-Feed)Theophylline in Fischer 344 Rats and B6C3F, Mice.COLLINS, J.J., ELWELL, M. R., LAMP, J. C, IV, MANUS, A. C, HEATH, J. E.,and MAKOVEC, G. T. (1988). Fundam Appl Toxicol. 11, 472—484.Theophylline, a methylated xanthine closely resembling caffeineand theobromine, is a widely used pharmaceutical agent for thetreatment of respiratory disorders and certain acute cardiovascularconditions. The National Toxicology Program has conducted 13-weeksubchronic toxicity studies in F344 rats and B6C3F₁ mice (10animals/group) following administration of theophylline viathe diet or by gavage. Administration of theophylline in thefeed (0, 1000, 2000, and 4000 ppm) resulted in no mortalityor body weight effects in F344 rats, but did induce periarteritisof the arteries adjacent to mesenteric lymph nodes and the pancreas,particularly arterioles in the latter. Also observed in ratsdosed with theophylline via the diet was an increased severityof chronic nephropathy in males, especially at the high dose.Administration of theophylline at the same concentrations inthe feed to B6C3Fi 2 mice resulted in no mortality, but terminalbody weights were significantly decreased in all dosed groups.An increased incidence of hepatocellular glycogen depletionwas observed in male and female mice, and this change is believedto represent a physiological alteration exacerbated by the administrationof theophylline. Administration of theophylline by gavage toF344 rats (0, 37.5, 75, and 150 mg/kg) resulted in the earlydeath of one high-dose male and female and significantly decreasedor increased terminal body weights of high-dose males and females,respectively. Similar to the results of the dosed-feed study,male and female rats receiving theophylline by gavage demonstrated a dose-related increase in the incidence and severityof perivascular inflammation of mesen teric arteries. Gavageadministration of theophylline to B6C3F, mice (0, 75, 150, and300 mg/kg) resulted in the early death of all high-dose femalesand 3/10 high-dose males and significant depres sion of terminalbody weights in high- and mid-dose males and low-dose females.As in the dosed feed study, the primary histopathologk changein the mouse subchronic gavage study was hepatocel lular glycogendepletion, although in this case it was seen only in females.In summary, the major target organs for orally administeredtheophylline in 13-week subchronic toxicity studies appear tobe the mesenteric arteries in F344 rats and the liver in B6C3F₁mice. On the basis of organ weight changes and/or minor histopathologiceffects, many other tissues were also affected, particularlythe kidneys in dosed-feed male rats and the uterus in gavage-dosedfemale rats.