Ephedrine hydrochloride

Endpoint summary

Description of key information

Based on repeated dosing schemes (NIH, 1986), two chronic carcinogenicity studies with Ephedrine sulfate (read across from analogous substance) were performed in rodents (see chapter 7.7). No evidence for carcinogenicity of the test substance was demonstrated in rats or mice (NIH, 1986). In case of rats (i.e. key study), the NOAEL was >9 mg/kg bw/day (males) and >11 mg/kg bw/day (females). In case of mice (i.e. supporting study), the NOAEL was >29 mg/kg bw/day (males) and >25 mg/kg bw/day (females). Since no adverse and treatment-related carcinogenic effects or other adverse effects were observed in rats, as systemic NOAEL for repeated toxicity 9 mg/kg bw/day is derived based on this reliable chronic study.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

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 based on a chronic 2-year diet study in rat (NIH, 1986). Doses for this study are based on dose-finding process using sub-acute (14-days) studies and sub-chronic (13-weeks) study in rats. Same study scheme was applied in mice. Detail on dose-finding studies in rodents are presented in the discussion below.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Repeated dose toxicity studies in rat (key study), read across:

13 weeks feed consumption study (dose-finder for 2 yr study)

In this subchronic repeated dose toxicity study (NIH, 1986), F344/N rats of each sex received diets containing 0, 125, 250, 500, 1,000 or 2,000 mg/kg (ppm) test substance for 13 weeks. Rats that received 2,000 ppm were hyperexcitable and had rough coats.None of the rats died before the end of the study. Final mean body weights of rats that received 1,000 or 2,000 ppm were 20% and 23% lower than those of the controls for males and 10% and 17% lower for females. Feed consumption by dosed and control groups was generally comparable. At necropsy, adrenal gland and heart weight were measured for control and highest dose groups. The following tissues were examined: Tissue masses, regional lymph node, blood smear, skin, mandibular lymph node, mammary gland, salivary gland, thigh muscle, sciatic nerve, bone marrow, costochondral junction (rib), thymus, larynx, trachea, heart, thyroid gland, parathyroids, esophagus, stomach, duodenum, jejunum, ileum, colon, rectum, mesenteric lymph node, liver, pancreas, spleen, kidneys, adrenal glands, urinary bladder, seminal veaicles/prostate/testes or ovaries/uterus, nasal cavity, brain, pituitary gland, eyes, external and middle ear and spinal cord. The relative adrenal gland weight of male rats that received 2,000 ppm was significantly greater than that of the controls, and the adrenal gland weight and heart weight of female rats that received 2,000 ppm were significantly lower than those of the controls. No compound-related histopathologic effects were observed. Futhermore, pupil diameter was measured also before sacrifrice, obtained mean pupil diameters for dosed and control animals were comparable. The mean packed cell volume of male rats that received 2,000 ppm was 6% greater than that of the controls. The major response that occurred during the 13-week study was compound-associated reduction in weight gain. With regard to the feed consumption in males, 12.1 - 14.8 grams were consumed per animal per day (week 12). In case of females, 12.1 - 13.1 grams were consumed per animal per day (week 12). This study serves as a basis for the concentrations selected for a 2-year study (i.e. 125 and 250 mg/kg test substance in feed); the reduced weight gain that occurred at higher concentrations was felt to be potentially life threatening over the duration of a 2-year study. Under the conditions of this study, the NOAEL is deemed as 500 ppm (diet) for toxicity (body weight decreased by less than 20 % compared to control animals, cf. OECD Guidance Document No. 19, November 2000). Thus, resulting in a NOAEL of 22 mg/kg bw/day for males and 35 mg/kg bw/day for females, respectively. This subchronic study in the rat is well-documented and scientifically acceptable.

2 -year feed consumption study

The 2-year chronic study (NIH, 1986) is considered to be the best available base for setting of relevant toxicological parameters. Based on this study, a systemic NOAEL of 9 mg/kg bw/day for repeated dose toxicity is derived. Study details are given in IUCLID chapter 7.7 (carcinogenicity).

 

 

Repeated dose toxicity studies in rat and mouse (supporting studies):

14 day range-finding feed consumption study (rat)

To estimate appropriate doses for a subchronic study with the test substance, two sub acute repeated dose toxicity studies (feeding study/drinking water study) were performed in rats (NIH ,1986). In the following, the feeding study is described: F344/N rats of each sex (five per dose) received diets containing 0, 90, 190, 380, 750 or 1,500 mg/kg test substance for 14 days. Hyperexcitability and rough hair coats were observed in rats that received 380, 750, or 1,500 ppm. Final mean body weights of males that received 1,500 ppm were 10% lower than that of the controls. Final mean body weights of dosed females were not affected by Ephedrine sulphate. Feed consumption by rats that were given diets containing 1,500 ppm test substance was 76% to that of the controls for males and 87% for females. None of the rats died before the end of the studies. After the regular study period, necropsy performed on on all animals. 10% of animals were examined histologically and packed cell volume was determined on blood taken at terminal kill. The mean packed cell volume was not affected by ephedrine sulphate. No clear compound-related effects were observed at necropsy. Under the given experimental conditions, a NOAEL of 190 ppm (diet) is deemed based on the clinical signs observed at higher doses in the feeding study. Thus, resulting in a NOAEL of 16 mg/kg bw/day for males and 23 mg/kg bw/day for females, respectively. This sub-acute study in the rat is well-documented and scientifically acceptable. Conclusive remarks: F344/N rats of each sex received diets containing 0-1,500 ppm Ephedrine sulfate or drinking water containing 0-1,200 ppm Ephedrine sulphate. The average feed consumption by dosed rats was comparable to that of their respective controls. The average water consumption by rats decreased with increasing concentration of Ephedrine sulfate in the drinking water. Thus, subsequent studies used the feed route of administration.

 

14 day range-finding water consumption study (rat)

To estimate appropriate doses for a subchronic study with the test substance, two sub acute repeated dose toxicity studies (feeding study/drinking water study) were performed in rats (NIH ,1986). In the following, the drinking water study is described: F344/N rats of each sex (five per dose) received water containing 0, 75, 150, 300, 600, or 1,200 mg/kg test substance. Hyperexcitability and rough hair coats were observed in rats that received 300, 600, or 1,200 ppm for 14 days. Dehydration was observed for rats that received 600 or 1,200 ppm. The final mean body weights were not significantly affected. Average water consumption decreased with increasing dose. Water consumption by male rats that received 1,200 ppm was 50% that of the controls. Water consumption by female rats that received 1,200 ppm was 25% that of the controls. None of the rats died before the end of the study. The mean packed cell volume of female rats that received 1,200 ppm was 8% lower than that of the controls. No compound-related effects were observed at necropsy. Under the given experimental conditions, as a proposal a NOAEL of 150 ppm (diet) is deemed based on the clinical signs observed at higher doses in the drinking water study. This sub-acute study in the rat is well-documented and scientifically acceptable. Conclusive remarks: F344/N rats of each sex received diets containing 0-1,500 ppm Ephedrine sulfate or drinking water containing 0-1,200 ppm Ephedrine sulphate. The average feed consumption by dosed rats was comparable to that of their respective controls. The average water consumption by rats decreased with increasing concentration of Ephedrine sulfate in the drinking water. Thus, subsequent studies used the feed route of administration.

14 day range-finding feed consumption study (mouse)

To estimate appropriate doses for a subchronic study with the test substance, two sub acute repeated dose toxicity studies (feeding study/drinking water study) were performed in mice (NIH ,1986). In the following, the feeding study is described: Five B6C3F1 mice of each sex per dose received diets containing 0, 300, 600, 1,250, 2,500 or 5,000 mg/kg test substance for 14 days. Hyperactivity, rough hair coats, dehydration, and arched backs were observed in both sexes at doses of 500, 1,000 and 2,000 ppm. Final mean body weights of mice that received 5,000 ppm were 11% Iower than those of the controls for males and 10% lower for females. Feed consumption was not adversely affected by application of the test substance. One male and one female that received 2,500 ppm died before the end of the study. After the regular study period, necropsy performed on on all animals. 10% of animals were examined histologically and packed cell volume was determined on blood taken at terminal kill. The mean packed cell volume was not notably affected by administration of test substance. No compound-related effects were observed at necropsy. Under the given experimental conditions, a NOAEL of 600 ppm (diet) is deemed based on the clinical signs observed at higher doses in the feeding study (since in the water drinking study clinical signs were described, but doses were not clearly specified). Thus, resulting in a NOAEL of 80 mg/kg bw/day for males and 98 mg/kg bw/day for females, respectively. This sub-acute study in the mouse is well-documented and scientifically acceptable. Conclusive remarks: B6C3F1 mice received diets or drinking water containing 0-5,000 ppm Ephedrine sulfate. In the feeding study, the average feed consumption by dosed mice was comparable to that of their respective controls. The average water consumption by mice decreased with increasing concentration of Ephedrine sulfate in the drinking water. Thus, subsequent studies used the feed route of administration.

 

14 day range-finding water consumption study (mouse)

To estimate appropriate doses for a subchronic study with the test substance, two sub acute repeated dose toxicity studies (feeding study/drinking water study) were performed in mice (NIH ,1986). In the following, the drinking water study is described: Five B6C3F1 mice of each sex per dose received water containing 0, 312.5, 625, 1,260, 2,500 or 5,000 mg/kg test substance. Compound-related clinical signs observed were hyperexcitability, arched backs, rough hair coats, and dehydration. Cachexia was observed at dosing of 5,000 ppm. The final mean body weights of mice that received 5,000 ppm were 12% lower than those of the controls for males and 5% lower for females. The mean water consumption was lower than that of the controls for all but the lowest dose group of males and for all dosed groups of females. None of the mice died before the end of the study. The mean packed cell volumes of males and females that received 5,000 ppm were 22% and 16% lower than those of the controls. No compound-related gross lesions were observed at necropsy. Since in the water drinking study clinical signs were described, but doses were not clearly specified, no NOAEL was deemed. Nevertheless, this sub-acute study in the mouse is scientifically acceptable. Conclusive remarks: B6C3F1 mice received diets or drinking water containing 0-5,000 ppm Ephedrine sulfate. In the feeding study, the average feed consumption by dosed mice was comparable to that of their respective controls. The average water consumption by mice decreased with increasing concentration of Ephedrine sulfate in the drinking water. Thus, subsequent studies used the feed route of administration.

 

13 weeks feed consumption study (dose-finder for 2 yr study) (mouse)

In this subchronic repeated dose toxicity study (NIH, 1986), B6C3F1 mice of each sex received diets containing 0, 310, 630, 1,260, 2,600 or 5,000 ppm test substance. Rough coats, hyperexcitability, and fighting among males were compound-related. The deaths that occurred in male mice receiving 1,250, 2,500, or 5,000 ppm were the result of fighting. All female mice survived to the end of the studies. Compared to the controls, final mean body weights of males that received 1,250, 2,500, or 5,000 ppm were 14%, 17%, and 12% lower and final mean body weights of females were more than 13% lower (up to 21% at 1,250 ppm). Estimated feed consumption by dosed groups was greater than that of the controls. At necropsy, adrenal gland and heart weight were measured for control and highest dose groups. The following tissues were examined: Tissue masses, regional lymph node, blood smear, skin, mandibular lymph node, mammary gland, salivary gland, thigh muscle, sciatic nerve, bone marrow, costochondral junction (rib), thymus, larynx, trachea, heart, thyroid gland, parathyroids, esophagus, stomach, duodenum, jejunum, ileum, colon, rectum, mesenteric lymph node, liver, gallbladder, pancreas, spleen, kidneys, adrenal glands, urinary bladder, seminal veaicles/prostate/testes or ovaries/uterus, nasal cavity, brain, pituitary gland, eyes, external and middle ear and spinal cord. The relative heart weight and adrenal gland weight of mice receiving 5,000 ppm were comparable to those of the controls. No compound-related histopathologic effects were observed. Futhermore, pupil diameter was measured also before sacrifrice, as a result mean pupil diameter was not affected by the test substance. The mean packed cell volume of male mice that received 5,000 ppm was 9% lower than that of the controls. The major response in mice that occurred during the 13-week study was compound-associated reduction in weight gain. With regard to the feed consumption in males, 2.8 – 4.1 grams were consumed per animal per day (week 12). In case of females, 2.8 – 4.4 grams were consumed per animal per day (week 12). This study serves as a basis for the concentrations selected for a 2-year study (i.e. 125 and 250 mg/kg test substance in feed); the reduced weight gain that occurred at higher concentrations was felt to be potentially life threatening over the duration of a 2-year study. Under the conditions of this study, the NOAEL is deemed as 630 ppm (diet) for toxicity with regard to the loss of bodyweight (up to 21 % at higher doses) at the end of the study period. Thus, resulting in a NOAEL of 69 mg/kg bw/day for males and 78 mg/kg bw/day for females, respectively. This subchronic study in the mouse is well-documented and scientifically acceptable.

2 -year feed consumption study (mouse)

Details of this supporting study (NIH, 1986) are presented in IUCLID chapter 7.7 (carcinogenicity).

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Two year chronic study in rats (Key.NIH_56-2563.Carcinogenicity. 2 year rat, oral, referenced in chapter 7.7 (Carcinogenicity).
Furthermore, two year Chronic study in mice (Supporting.NIH_56-2563.Carcinogenicity. 2 year mouse, oral (diet) is available also.

Justification for classification or non-classification

Based on the results of the chronic dose toxicity study in rat with regard to specific target organ toxicity, Ephedrine sulphate and in consequence also Ephedrine hydrochloride is not subject to classification and labelling according to Directive 67/548/EEC and Regulation (EC) No 1272/2008.