Phenylephrine hydrochloride

Carcinogenicity

Description of key information

There was no evidence of carcinogenicity of phenylephrine hydrochloride in 2-year oral carcinogenicity studies (non-GLP, according to NTP protocol) with F344/N rats and B6C3F1 mice which received this substance at dietary concentrations up to 1250 mg/kg (rat; 47 and 54 mg/kg bw/day in males and females, respectively) or 2500 mg/kg  (mouse; 260 and 280 mg/kg bw/day in males and females, respectively).

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Dose descriptor:

NOAEL

47 mg/kg bw/day

Study duration:

chronic

Species:

rat

Justification for classification or non-classification

Based on the absence of evidence of carcinogenicity in the 2-year carcinogenicity studies with rats and mice, the substance does not need to be classified according to Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.

Additional information

Carcinogenicity of USP-grade phenylephrine hydrochloride (99% pure) was examined in 2-year feeding studies (non-GLP, NTP protocol) with F344/N rats and B6C3F1 mice (National Toxicology Program, 1987). Groups of 50 male and 50 female animals of each species received the test material in their diet for 2 years. Concurrent control groups of the same size were kept on plain diet. Rats received the test material at dietary concentrations of 620 and 1,250 mg/kg (corresponding to 22 (males)/26 (females) and 47 (males)/54 (females) mg/kg bw/day, respectively). Mice received the test material at dietary concentrations of 1,250 and 2,500 mg/kg (corresponding to 130 (males)/140 (females) and 260 (males)/280 (females) mg/kg bw/day, respectively). Endpoints to assess toxicity included mortality, cllinical signs, palpable masses, ophthalmologic examination, body weight, food consumption, necropsy and histopathology.

Results:

Survival of the rats and mice was not adversely affected by treatment. Survival of high dose male rats was even greater than that of 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). Body weights of dosed animals were slightly lower than those of controls (on averge 3-15% in rats and 3-14% in mice) and this effect was dose related. Food consumption was not significantly different among dosed and control rats, whereas dosed mice consumed about 6-10% less feed than did controls.

Few non-neoplastic 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 association with treatment of the higher incidence of perivascular cuffing in the lung of male rats was less clear (control 2/50; low dose 12/50; high dose 8/50). In mice, the incidence of focal cellular change in the liver was increased slightly in high dose males (0/50; 2/50; 7/50).

No increases in neoplasia were seen in dosed male or female rats or mice. In fact, the lower incidences of a few proliferative lesions in rats were considered to be associated with treatment. 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 high dose males were statistically significantly lower than those in controls. Further, adrenal medullary hyperplasia (male rats), adrenal cortical focal hyperplasia (rats of both sexes) and bile duct hyperplasia (rats of both sexes) occurred less frequently in dosed rats than in controls.

 

In conclusion, under the conditions of these 2-year studies, there was no evidence of carcinogenicity (chemically related increases in malignant or benign neoplasms) of phenylephrine hydrochloride for male or female F344/N rats given 620 or 1,250 mg/kg feed or for male or female B6C3F3 mice given 1,250 or 2,500 mg/kg 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.