Ephedrine sulfate is a sympathomimetic amine that affects both the central and peripheral nervous systems. An effective bronchiodilator and weak vasoconstrictor, ephedrine sulfate is used extensively in nonprescription pharmaceutical preparations such as nose drops, cold tablets, cough syrups, and, in particular, asthma relief medicines. Ephedrine sulfate was nominated for carcinogenesis studies by the National Cancer Institute because of its widespread and long-term use for the relief of symptoms associated with asthma.
In 14-day repeated-exposure studies, F344/N rats of each sex received diets containing 0-1,500 ppm ephedrine sulfate or drinking water containing 0-1,200 ephedrine sulfate; B6C3F1 mice received diets or drinking water containing 0-5,000 ppm ephedrine sulfate. In the feed studies, the average feed consumption by dosed rats and mice was comparable to that of their respective controls. The average water consumption by rats and mice decreased with increasing concentration of ephedrine sulfate in the drinking water. Thus, subsequent studies used the feed route of administration.
Doses for the 2-year studies were selected on the basis of results from 13-week studies in which F344/N rats of each sex were given diets containing 0, 125, 250, 500, 1,000, or 2,000 ppm ephedrine sulfate and B6C3F1 mice of each sex were given diets containing 0, 310, 630, 1,250, 2,500, or 5,000 ppm ephedrine sulfate. The major response that occurred during the 13-week studies was compound-associated reduction in weight gain. Toxicology and carcinogenesis studies of ephedrine sulfate were conducted by administering diets containing 0, 125, or 250 ppm ephedrine sulfate to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex for 103 weeks. The estimated average amount of ephedrine sulfate consumed per day during the 2-year study was 4 mg/kg and 9 mg/kg for low dose and high dose male rats, 5 mg/kg and 11 mg/kg for female rats, 14 mg/kg and 29 mg/kg for male mice, and 12 mg/kg and 25 mg/kg for female mice.
Survival of chemically exposed female rats during the 2-year study was greater than that of the controls (control, 27/50; low dose, 39/50; high dose, 39/50); survival of exposed male rats and male and female mice was comparable to that of controls. Throughout most of the 2-year studies, mean body weights of rats and mice of each sex receiving diets containing ephedrine sulfate were lower than those of controls.
Neoplasms that occurred in these studies were not considered to be related to administration of ephedrine sulfate. Two high dose female mice had ovarian granulosa cell tumors, and luteomas were found in one low dose and one high dose female mouse. Because of the low incidence, these uncommon, benign tumors could not be clearly related to ephedrine sulfate administration.
Ephedrine sulfate was not mutagenic in four strains of Salmonella typhimurium (TA100, TA1535, TA97, or TA98) with or without Aroclor 1254-induced male Sprague-Dawley rat or Syrian hamster liver S9 activation. Ephedrine sulfate did not induce sister-chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells.
An audit of the experimental data was conducted for these 2-year studies of ephedrine sulfate. No data discrepancies were found that influenced the final interpretations.
Under the conditions of these studies, there was no evidence of carcinogenicity for F344/N rats or B6C3F1 mice of either sex receiving 125 or 250 ppm ephedrine sulfate in the diet for 2 years.