Ephedrine hydrochloride

Carcinogenicity

Description of key information

No evidence for carcinogenicity of Ephedrine sulphate was demonstrated in two chronic studies in rodents (rat or mice).
In case of rats, the NOAEL was >9 mg/kg bw/day (males) and >11 mg/kg bw/day (females).
In case of mice, the NOAEL was >29 mg/kg bw/day (males) and >25 mg/kg bw/day (females).
No adverse and treatment-related carcinogenic effects were observed.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

9 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

Reliable dataset, read-across study with Ephedrine sulphate.

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Since there is no evidence for a carcinogenic potential, Ephedrine sulphate and in consequence also Ephedrine hydrochloride is not subject to classification as being carcinogenic according to Directive 67/548/EEC and Regulation(EC) No 1272/2008.

Additional information

Chronic studies in rodents

Rat:

In a chronic carcinogenicity study (NIH, 1986), Ephidrine sulfate (99 %; read-across) was administered by diet to F344/N rats at concentrations of 0, 125 or 250 ppm for 103 weeks (50 animals/sex/group). Doses are based on a 13-week study in which F344/N rats of each sex received diets containing 0, 125, 250, 500, 1,000 or 2,000 ppm test substance (the major response that occurred during the 13-week studies was compound-associated reduction in weight gain). In the 2 year study performed prior to GLP, the estimated average amount of Ephedrine sulfate consumed per day was 4 mg/kg bw/day and 9 mg/kg bw/day for low dose and high dose male rats, 5 mg/kg bw/day and 11 mg/kg bw/day for female rats. Survival of 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 was comparable to that of controls. Throughout most of the study period, mean body weights of rats of each sex receiving diets containing the test substance were lower than those of controls (about 10%). At necropsy, the following tissues were examined: gross lesions, skin, mandibular lymph node, mammary gland, salivary gland, thigh muscle, sciatic nerve, sternebrae, vertebrae or femur including marrow, costochondral junction (rib), oral cavity, thymus, larynx and pharynx, trachea, lungs and bronchi, heart and aorta, thyroid gland, parathyroids, esophagus, stomach, duodenum, jejunum, tongue, regional lymph nodes, ileum, colon, cecum, rectum, mesenteric lymph node, liver, pancreas, spleen, kidneys, adrenal glands, seminal vesicles, prostate, testes, epididymis or ovaries, uterus, nasal cavity and nasal turbinates, brain, pituitary gland, spinal cord, eyes, and preputial or clitoral gland. With regard to non-neoplastic lesions, the incidences in the low and high dose groups of male and female rats rats were comparable with the incidences of the control group in general. Neoplasms that occurred in this study (pituitary gland adenoma) were not considered to be related to administration of Ephedrine sulfate.Thus, at the doses tested, there was no evidence of increased incidence of carcinogenesis. Under the conditions of this study, the NOAEL was >9 mg/kg bw/day (male rats) and >11 mg/kg bw/day (female rats) for carcinogenicity. Conclusively, no evidence for carcinogenicity of ephedrine sulphate was postulated. This 2 year carcinogenicity study in the rat is well-documented and scientifically acceptable.

Mouse:

In a chronic carcinogenicity study (NIH, 1986), Ephidrine sulfate (99 %; read-across) was administered by diet to B6C3F1 mice at concentrations of 0, 125 or 250 ppm for 103 weeks (50 animals/sex/group). Doses are based on a 13-week study in which B6C3F1 mice of each sex received diets containing 0, 125, 0, 310, 630, 1,260, 2,600 or 5,000 ppm test substance (the major response that occurred during the 13-week studies was compound-associated reduction in weight gain). In the 2 year study performed prior to GLP, the estimated average amount of Ephedrine sulfate consumed per day was 14 mg/kg bw/day and 29 mg/kg bw/day for male mice, and 12 mg/kg bw/day and 25 mg/kg bw/day for female mice. Survival of exposed male and female mice was comparable to that of controls. The average daily feed consumption by both dosed male mouse groups was 100% that of the controls and by low dose and high dose female mice, 97% and 94% that of the controls. However, throughout most of the study period (after week 10 of the study time), mean body weights of mice of each sex receiving diets containing the test substance were lower than those of controls (at high doses up to ca. 20%). At necropsy, the following tissues were examined: gross lesions, skin, mandibular lymph node, mammary gland, salivary gland, thigh muscle, sciatic nerve, sternebrae, vertebrae or femur including marrow, costochondral junction (rib), oral cavity, thymus, larynx and pharynx, trachea, lungs and bronchi, heart and aorta, thyroid gland, parathyroids, esophagus, stomach, duodenum, jejunum, tongue, gallbladder, regional lymph nodes, ileum, colon, cecum, rectum, mesenteric lymph node, liver, pancreas, spleen, kidneys, adrenal glands, seminal vesicles, prostate, testes, epididymis or ovaries, uterus, nasal cavity and nasal turbinates, brain, pituitary gland, spinal cord, eyes, and preputial or clitoral gland. With regard to non-neoplastic lesions, the incidences in the low and high dose groups of male and female mice were comparable with the incidences of the control group in general. Furthermore, with regard to neoplasms in male mice, generally the incidences in the low and high dose groups were comparable with the incidences of the control group. Neoplasms that occurred in female mice 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. Thus, at the doses tested, there was no evidence of increased incidence of carcinogenesis. Under the conditions of this study, the NOAEL was >29 mg/kg bw/day (males) and >25 mg/kg bw/day (females) for carcinogenicity. Conclusively, no evidence for carcinogenicity of Ephedrine sulphate was postulated. This 2 year carcinogenicity study in the rat is well-documented and scientifically acceptable.

Justification for selection of carcinogenicity via oral route endpoint:
Read-across study with Epedrine sulphate. This chronic study in rats was chosen as leading study. In parallel, a chronic study in mice was performed, which is described below also.