Toxicology and carcinogenesis studies of chlorpheniramine maleate (99% pure), a widely used antihistaminic drug in human and veterinary medicine, were conducted by administering this chemical in deionized water by gavage to groups of 50 male and 50 female F344/N rats and B6C3F1 mice, 5 days per week for 103 weeks. The doses used were: male rats-- 0, 15, or 30 mg/kg; female rats-- 0, 30, or 60 mg/kg; male mice-- 0, 25, or 50 mg/kg; female mice-- 0, 100, or 200 mg/kg. The selection of these doses was based largely on data from 14-day or 16-day studies and 13-week studies in which reduced body weight gain and reduced survival occurred at higher doses. Doses used in the 2-week studies ranged from 40 to 640 mg/kg in rats and 25 to 800 mg/kg in mice; in the 13-week studies, doses ranged from 3.75 to 60 mg/kg in rats and 12.5 to 200 mg/kg in mice. The recommended human adult daily oral dose of chlorpheniramine maleate is up to 0.32 mg/kg.
Doses originally selected for male mice in the 2-year study were 0, 100, or 200 mg/kg; however, because of poor survival, that study was stopped and a new study was started at doses of 0, 25, or 50 mg/kg. At the termination of the study (week 104), survival of high dose female rats (6/50) and high dose male mice (15/50) was lower than that of the vehicle controls (29/50 and 39/50, respectively). Survival of all other dosed groups was comparable to that of respective vehicle control groups. Mean body weights of dosed rats were about 10%-15% (male) or about 10%-25% (female) lower than those of vehicle controls; mean body weights of female mice were generally 20%-35% lower than those of vehicle controls.
No compound-related gross or microscopic pathologic effects were observed in either species in the 16-day or 13-week studies. Hyperactivity and hyperexcitability associated with dosing were frequently noted in the 13-week and 2-year studies. There were no significant positive trends or increases in the incidences of neoplasms in either male or female rats dosed with chlorpheniramine maleate for 103 weeks. Marginal increases in the incidences of adrenal gland capsule adenomas in male mice (vehicle control, 2/50; low dose, 7/49; high dose, 4/49) were not considered to be compound related, since there was not a corresponding increase in the incidence of adrenal gland capsule hyperplasia (46/50; 33/49; 22/49). A positive trend was seen for subcutaneous tissue tumors in male mice (4/50; 5/49; 8/50); this marginal effect was not considered to be compound related.
The incidences of thyroid gland follicular cell cysts (2/48; 10/49; 13/47), thyroid gland follicular cell hyperplasia (3/48; 29/49; 36/47), and thyroid gland follicular cell adenomas (0/48; 4/49; 2/47) were greater in dosed female mice than in vehicle controls. This finding is toxicologically important,since thyroid gland neoplasms are uncommon in mice and are often preceded by hyperplasia of the follicular epithelium.
The major route of excretion of chlorpheniramine or its metabolites is in the urine. In male F344 rats orally administered 14C-chlorpheniramine maleate at doses of 2 or 20 mg/kg, there was essentially no difference in the percentage of urinary or fecal excretion of radioactivity between these dose levels.
Chlorpheniramine maleate was not mutagenic to Salmonella strains TA98, TA100, TA1535, or T1537 in the presence or absence of S9 metabolic activation systems prepared from the liver of Aroclor 1254-treated male Sprague-Dawley rats or male Syrian hamsters. Chlorpheniramine maleate did not induce forward mutations at the TK locus of L5178Y mouse lymphoma cells with or without metabolic activation. In Chinese hamster ovary cells in culture, chlorpheniramine maleate induced a weak but reproducible increase in sister-chromatid exchanges in the absence of exogenous metabolic activation. Chromosomal aberrations were induced at the highest dose tested but only in the presence of S9 from Aroclor 1254-induced Sprague-Dawley male rat liver.
An audit of the experimental data was conducted for these 2-year carcinogenesis studies on chlorpheniramine maleate. No data discrepancies were found that influenced the final interpretations.
Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenicity for F344/N rats or B6C3F1 mice of either sex administered chlorpheniramine maleate in deionized water, 5 days per week for 2 years. Due to high mortality in high dose female rats and high dose male mice, the sensitivity of these groups to detect a carcinogenic response was reduced. Chlorpheniramine maleate had a proliferative effect in the thyroid gland of female mice, as shown by the increased incidences of follicular cell cysts and hyperplasia in both low dose and high dose groups.