Subchronic toxicity of orally administered (gavage and dosed-feed) theophylline in Fischer 344 rats and B6C3F1 mice.

Theophylline, a methylated xanthine closely resembling caffeine and theobromine, is a widely used pharmaceutical agent for the treatment of respiratory disorders and certain acute cardiovascular conditions. The National Toxicology Program has conducted 13-week subchronic toxicity studies in F344 rats and B6C3F1 mice (10 animals/group) following administration of theophylline via the diet or by gavage. Administration of theophylline in the feed (0, 1000, 2000, and 4000 ppm) resulted in no mortality or body weight effects in F344 rats, but did induce periarteritis of the arteries adjacent to mesenteric lymph nodes and the pancreas, particularly arterioles in the latter. Also observed in rats dosed with theophylline via the diet was an increased severity of chronic nephropathy in males, especially at the high dose. Administration of theophylline at the same concentrations in the feed to B6C3F1 mice resulted in no mortality, but terminal body weights were significantly decreased in all dosed groups. An increased incidence of hepatocellular glycogen depletion was observed in male and female mice, and this change is believed to represent a physiological alteration exacerbated by the administration of theophylline. Administration of theophylline by gavage to F344 rats (0, 37.5, 75, and 150 mg/kg) resulted in the early death of one high-dose male and female and significantly decreased or 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 severity of perivascular inflammation of mesenteric arteries. Gavage administration of theophylline to B6C3F1 mice (0, 75, 150, and 300 mg/kg) resulted in the early death of all high-dose females and 3/10 high-dose males and significant depression of terminal body weights in high- and mid-dose males and low-dose females. As in the dosed-feed study, the primary histopathologic change in the mouse subchronic gavage study was hepatocellular glycogen depletion, although in this case it was seen only in females. In summary, the major target organs for orally administered theophylline in 13-week subchronic toxicity studies appear to be the mesenteric arteries in F344 rats and the liver in B6C3F1 mice. On the basis of organ weight changes and/or minor histopathologic effects, many other tissues were also affected, particularly the kidneys in dosed-feed male rats and the uterus in gavage-dosed female rats.

Reproductive effects of theophylline in mice and rats.

Theophylline was administered by gavage in 13-week studies to B6C3F1 mice (0, 75, 150, 300 mg/kg/day) and F344 rats (0, 37.5, 75, 150 mg/kg/day) with significant reductions in male mouse terminal body and testicular weights. Male rats also displayed reduced testicular weight, as well as nonsignificant but dose-related decreases in body weight. There was a significant but non-dose-related decrease in female mouse body weight. In parallel studies of B6C3F1 mice and F344 rats, theophylline administered in the diet (0, 0.1, 0.2, 0.4%) produced significantly decreased terminal body weights in male and female mice, but not rats. In rats, cauda epididymis weight was reduced at the high dose compared to the control group, and there was an increase in abnormal sperm. These studies were followed by continuous breeding reproductive assays in CD-1 mice in which theophylline was administered in feed (0.0, 0.075, 0.15, and 0.30%; calculated doses of 0, 125, 265, and 530 mg/kg/day, respectively) to breeding pairs for 14 weeks. There was a dose-dependent decrease in the number of live pups produced per litter, a significant decrease in the number of litters produced per pair (0.30%) and in the adjusted live pup weight (0.30%), a decrease in the percentage of pups born alive (0.15 and 0.30%), and an increase in the number of days needed to produce each litter (0.30%). After 19 weeks of continuous treatment at 0.30%, a crossover mating trial indicated that females and males were adversely affected by theophylline, as judged by the decreased percentage of pups born alive, the decreased live pup weight, and the decreased number of live pups per litter relative to matings within the control group, but the effects in females were more extensive. Based on other studies, there is a suggestion that the observed changes in fertility may be partially attributed to embryotoxicity.

Toxicological evaluation of 4-vinylcyclohexene. I. Prechronic (14-day) and subchronic (13-week) gavage studies in Fischer 344 rats and B6C3F1 mice.

4-Vinylcyclohexene (VCH), a dimer of 1,3-butadiene present in the gases discharged during tire curing, was examined for its toxic effects in Fischer 344 (F344) rats and B6C3F1 mice by 14-d prechronic and 13-wk subchronic testing. In the 14-d studies, VCH was administered orally by gavage in corn oil at doses of 0 (vehicle control), 300, 600, 1250, 2500, or 5000 mg/kg body weight to groups of five F344 rats and B6C3F1 mice of each sex, while the doses for the 13-wk studies (10 animals/group; 5 d/wk) were 0 (vehicle control), 50, 100, 200, 400, or 800 mg/kg body weight for rats and 0 (vehicle control), 75, 150, 300, 600, or 1200 mg/kg body weight for mice. All rats and most mice in the 14-d studies died when administered doses greater than or equal to 1250 mg/kg, although no compound-related gross or histopathologic effects were observed. In the 13-wk studies, extensive mortality was observed only in mice dosed at 1200 mg/kg. Final body weights were reduced in the 13-wk studies in male rats receiving doses greater than or equal to 400 mg VCH/kg, in female rats receiving 800 mg/kg, and in female mice receiving 600 mg/kg. Compound-related histopathologic effects in the 13-wk studies included hyaline droplet degeneration of the proximal convoluted tubules of the kidney in dosed male rats, the severity of which was dose-related, and a reduction in the number of primary follicles and mature graafian follicles in the ovaries of female mice receiving 1200 mg VCH/kg. No compound-related gross or histopathologic effects were evident in dosed female rats or male mice in the 13-wk studies.

Toxicological evaluation of 4-vinylcyclohexene. II. Induction of ovarian tumors in female B6C3F1 mice by chronic oral administration of 4-vinylcyclohexene.

4-Vinylcyclohexene (VCH), a dimer of 1,3-butadiene present in the gases discharged during tire curing, was examined for its toxic and carcinogenic effects in Fischer 344 (F344) rats and B6C3F1 mice by 2-yr chronic testing. VCH was administered orally by gavage in corn oil at doses of 0 (vehicle control), 200, or 400 mg/kg body weight to groups of 50 F344 rats and B6C3F1 mice of each sex for 103 wk (5 d/wk). Because the studies of VCH in male and female rats and in male mice were considered to be inadequate studies of carcinogenicity due to the extensive and early mortality at the high dose or both doses tested, as well as the lack of conclusive evidence of a carcinogenic effect, the present article focuses on the results of the 2-yr study of VCH in female B6C3F1 mice. Survival of high-dose female mice was lower (p less than 0.001) than that of the vehicle controls, whereas survival of low-dose and survival of vehicle control female mice were comparable. Mean body weights of high-dose female mice were generally slightly lower than those of the vehicle controls, whereas the mean body weights of low-dose female mice were generally greater than or comparable to those of the vehicle controls. Oral administration of VCH by gavage to female B6C3F1 mice was associated with an increased incidence of a number of nonneoplastic lesions, including mild acute inflammatory lesions and epithelial hyperplasia of the forestomach, congestion of the lungs and adrenal glands at the high dose, and cytologic alteration of the adrenal cortex at both doses. However, the most striking finding was the markedly increased (p less than 0.01) incidences of uncommon ovarian neoplasms, including mixed benign tumors, granulosa-cell tumors, and granulosa-cell tumors or carcinomas (combined), in both groups of dosed female mice. In addition, the increased incidence of adrenal-gland capsular adenomas in high-dose female mice may have been compound-related.

Forestomach lesions in rats and mice administered 3-chloro-2-methylpropene by gavage for two years.

The carcinogenicity of 3-chloro-2-methylpropene (CMP), a chemical intermediate and insecticide, was studied because of possible human exposure and because of its structural relationship to vinyl chloride and allyl chloride. CMP in corn oil was administered by gavage to groups of 50 male and 50 female Fischer 344/N rats at 0, 75, or 150 mg/kg body weight and to groups of 50 male and 50 female B6C3F1 mice at 0, 100, or 200 mg/kg body weight, 5 times a week for 103 weeks. The body weights of the two CMP treated groups of rats were 3-15% lower than the controls; the survival rates were similar. The body weights and survival rates of the CMP-exposed male and female mice were not different from the respective controls throughout the study. CMP administration resulted in dose-related increases in the incidence and severity of forestomach basal cell hyperplasia and the incidence of forestomach squamous cell papillomas in both sexes of rats and mice. In the two groups of CMP-exposed male mice the incidences of squamous cell carcinoma of the forestomach were also increased. Invasion or metastasis of the squamous cell carcinomas to other organs was observed in 2 male mice treated at 100 mg/kg and in 3 male mice and one female mouse treated at 200 mg/kg. The data show that CMP is a carcinogen for the forestomach in rats and mice and acts at the tissue site of contact and support genetic toxicity findings that CMP is a direct-acting alkylating agent.

Lung neoplasms in rodents after chronic administration of dimethyl hydrogen phosphite.

Dimethyl hydrogen phosphite (DMHP), an intermediate in the production of insecticides or herbicides, was administered by p.o. gavage for 2 yr to male Fischer 344/N rats and male and female B6C3F1 mice at doses of 0, 100, or 200 mg/kg and to female Fischer 344/N rats at doses of 0, 50 or 100 mg/kg. Dose related toxicity was seen in the lungs of treated male and female rats. The lung lesions were most prevalent in the high dose male rat group which received a dose twice that given to the high dose female rats. Lung lesions included alveolar epithelial hyperplasia, chemically related pneumonia, alveolar-bronchiolar adenoma, alveolar-bronchiolar carcinoma, and squamous cell carcinoma. DMHP also caused neoplastic and nonneoplastic lesions of the forestomach in male rats; a similar but less pronounced effect was observed in female rats. Nonneoplastic lesions associated with administration of DMHP included mineralization of the cerebellum in male rat and focal calcification of the testis in male mice. Under the conditions of this study, there was clear evidence for carcinogenicity for male rats, equivocal evidence for carcinogenicity in female rats, and no evidence for carcinogenicity in either male or female mice. DMHP caused the highest incidence of lung tumors in the male rat of all chemicals studied to date in the National Cancer Institute-National Toxicology Program Carcinogenesis Testing Program.

Hematologic, biochemical, and physiologic indices of the sacred baboon (Papio hamadryas).

Hematologic, biochemical, and physiologic indices for a recently imported group of sacred baboons, Papio hamadryas, were studied over a 6-week period. Hematologic values were in agreement with results recorded for other species of baboons. Blood biochemical data were consistent with findings previously reported for other baboons and for man except that alkaline phosphatase levels were higher than previously for other baboons but similar to those reported for man; lactic dehydrogenase levels were higher than for man but lower than for other baboons; cholesterol levels were within the range for baboons but lower than for man; and creatinine and uric acid levels were lower and amylase levels were higher than those for man. Temperature and respiration and pulse rates were in agreement with those reported for other baboons.