Toxicology and carcinogenesis studies of USP-grade phenylephrine hydrochloride were conducted by administering diets containing the chemical (99% pure) to F344/N rats and B6C3F1 mice of each sex in studies of 14 days, 12 weeks, and 2 years. In the 14-day studies, no toxic effects were seen in rats or mice fed diets containing up to 2,000 ppm phenylephrine hydrochloride. Doses were increased in the 12-week studies, and deaths of male rats and male mice were observed in groups fed diets containing 10,000 or 20,000 ppm; 1/10 male rats in the 5,000-ppm group died. Other than inflammatory eye lesions (considered secondary to the pharmacologic drying action of the chemical), no specific organ toxicity was noted. Body weights decreased as concentrations of phenylephrine hydrochloride in the diet were increased, and feed consumption was lower in dosed rats. Doses of 0, 620, and 1,250 ppm for rats and 0, 1,250, and 2,500 ppm for mice were selected for the 2-year studies because of the decreased body weight gains in animals given higher doses in the 12-week studies. In the 2-year studies, the approximate amount of phenylephrine hydrochloride consumed per day was 24 mg/kg for low dose rats, 50 mg/kg for high dose rats, 133 mg/kg for low dose mice, and 270 mg/kg for high dose mice.
Body weight differences in rats appeared to be dose related, and dosed animals were 3%-15% lighter than controls. Body weights of dosed mice averaged 3%-14% lower than those of controls throughout the 2-year studies. Survival of high dose male rats was greater than that of the controls (control, 30/50; low dose, 33/50; high dose, 42/50); differences in survival were not significant for female rats (42/50; 34/50; 36/50), male mice (35/50; 38/50; 43/50), or female mice (37/50; 34/50; 34/50).
Few nonneoplastic lesions were related to phenylephrine hydrochloride dosing in rats or mice. Chronic focal inflammation of the liver was observed at increased incidences in dosed rats (male: 2/50; 13/50; 17/50; female:17/50; 28/50; 35/50). Inflammation of the prostate was seen more frequently in dosed than in control males (10/50; 24/50; 24/50). The incidence of focal cellular change in the liver was increased slightly in high dose male mice (0/50; 2/50; 7/50).
In male rats, mononuclear cell leukemia (24/50; 9/50; 5/50) and pheochromocytomas of the adrenal gland (14/49; 11/50; 2/50) occurred with negative trends, and the incidences in the high dose group were lower than those in the controls. No increases in neoplasia were seen in dosed male or female rats or mice.
Phenylephrine hydrochloride was not mutagenic in four strains of Salmonella typhimurium < (TA100, TA1535, TA1537, and TA98) with or without Aroclor 1254-induced liver S9 from male Sprague-Dawley rats or male Syrian hamsters. The results of mutagenicity studies of phenylephrine hydrochloride were equivocal in the mouse lymphoma L5178Y/TK+/- assay in the absence of S9; it was not tested in the presence of S9. Phenylephrine hydrochloride induced sister-chromatid exchanges (SCEs) but not chromosomal aberrations in Chinese hamster ovary cells. The increase in SCEs was seen only in the absence of metabolic activation with S9.
An audit of the experimental data was conducted for the 2-year studies of phenylephrine hydrochloride. No data discrepancies were found that influenced the final interpretations.
Under the conditions of these 2-year studies, there was no evidence of carcinogenicity of phenylephrine hydrochloride for male or female F344/N rats given 620 or 1,250 ppm in feed or for male or female B6C3F1 mice given 1,250 or 2,500 ppm in feed. Survival of high dose male rats was greater than that of controls, and the incidences of mononuclear cell leukemia and pheochromocytomas were lower in dosed than in control male rats. Inflammation was observed more frequently in the liver and prostate gland of dosed male rats than in controls.