Phenylephrine hydrochloride

Endpoint summary

Description of key information

Target organs of phenylephrine hydrochloride upon long-term (2-year), repeated exposure via the diet are the liver and prostate and, possibly the lung, in rats (in the affected organs the incidence of inflammation was increased), and the liver (increased incidence of focal cellular change) in mice. These effects occurred from the lowest dose tested in rats, namely 620 mg/kg diet (22 and 26 mg/kg bw/day in male and female rats, respectively) and at the highest dose tested in mice, namely 2,500 mg/kg diet. The lowest dose tested in mice was a NOAEL (1,250 mg/kg diet, corresponding to  
130 and 140 mg/kg bw/day in male and female mice, respectively). In the 12-week feeding studies preceding the 2-year studies dietary levels up to 20,000 mg/kg feed were tested. At these higher doses growth retardation (from 1,250 mg/kg feed in rats and and mice) and mortality (from 5,000 g/kg feed in rats and 10,000 mg/kg feed in mice) occurred but no specific target organs were identified.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

LOAEL

22 mg/kg bw/day

Study duration:

chronic

Species:

rat

Additional information

Oral

 

The repeated dose toxicity 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.

 

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 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.

Since there were no significant adverse effects at the lowest dose tested in mice, 1,250 mg/kg in the diet (corresponding to about 130 and 140 mg/kg bw/day in males and females, respectively), was a NOAEL in the 2-year mouse study. In the 2-year rat study, adverse effects (including increased incidences of inflammation in the liver and prostate) occurred at both dose levels. Hence, the lowest dose tested (620 mg/kg diet, corresponding to 22 and 26 mg/kg bw/day in males and females, respectively) was a LOAEL in the 2-year rat study. As rats showed adverse effects at lower doses of phenylephrine hydrochloride than mice, the 2-year rat study was considered the key study for repeated dose toxicity.

 

Prior to the above 2-year studies, phenylephrine hydrochloride was examined in 14-day and 12-week dose-range finding studies with rats and mice (National Toxicology Program, 1987). In the 14-day study, rats received diets containing 125, 250, 500, 1,000 or 2,000 mg/kg diet and mice received diets containing 63, 125, 250, 500 or 1,000 mg/kg diet (5 animals/sex/dose of each species). Endpoints to assess toxicity included mortality, clinical observations, body weight, food consumption, necropsy and limited histopathology. Since no adverse effects were evident in the 14-day studies, higher dietary concentrations were tested in the 12-week studies, namely: 1,250, 2,500, 5,000, 10,000 and 20,000 mg/kg diet for both species (10 animals/sex/dose of each species). Mortality, clinical observations, body weight, food consumption, pupil diameter, weight of adrenals and heart (at highest dose only), necropsy and histopathology of a large number of organs and tissues were used to assess toxicity. No specific target organ toxicity was observed in the 12-week studies. At the higher levels, several male animals died (1 rat at 5,000 mg/kg, 2 rats and 2 mice at 10,000 mg/kg, 4 rats and 3 mice at 20,000 mg/kg). In both species, a dose-related decrease in body weight was observed. Mean terminal body weight was decreased by about 10% at the lowest dose (in male rats and female mice) and up to 65% (male rats) or 32% (female mice) at the highest dose. In rats, but not in mice, food consumption was decreased dose-dependently. Thus, decreased body weight gains in rats are considered to be a sign for an unpalatable diet mixture and not a test item related adverse effect. In fact, high dose mice apparently consumed more food than controls. The weights of the adrenals and heart in the 20,000 mg/kg groups differed from controls, but interpretation of these findings was compromised by the marked growth depression at this dose level. Pupil size was not affected in mice whereas dosed rats generally had smaller pupil sizes than controls. Histopathology revealed inflammatory eye lesions at 10,000 mg/kg in rats and at 20,000 mg/kg in both species These eye lesions were considered secondary to the pharmacologic drying action of the substance. In addition, rats fed 20,000 mg/kg showed atrophy of the testes, seminal vesicles and ovaries; these findings may be secondary to the severe effect on body weight in at 20,000 mg/kg. No other compound related histopathological changes were observed.

 

Dermal and Inhalation

No repeated dose studies are available.

Justification for classification or non-classification

In the 2-year feeding study, rats showed an increased incidence and severity of chronic focal inflammation of the liver (both sexes) and of inflammation of the prostate at dietary levels from 620 mg/kg (corresponding to 22 and 26 mg/kg bw/day in male and female rats, respectively). These histopathological changes are considered not to be a sign of significant toxicity because they were not associated with decreased survival or other obvious signs of toxicity. Moreover, similar lesions occurred in untreated controls. The results of the 2-year feeding study with mice and those of the preliminary 12-week feeding studies with rats and mice revealed no significant specific target organ toxicity either. Therefore, based on the results of the oral repeated dose toxicity studies in rats and mice, classification according to EU Directive 67/584/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 is not warranted.