Ephedrine hydrochloride

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

1979 - 1980

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Well-documented, scientifically acceptable study report. As the toxicity of (-)-Ephedrine-Hydrochloride is predominantly mediated by the alkaloid with its phenethylamine skeleton read-across to Ephedrine sulphate has been done and is scientifically justified.

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1986

Report date:

1986

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Version / remarks:

(adopted 12 May 1981)

Principles of method if other than guideline:

13 weeks study in rats as part of the National Toxicology Program/National Institutes of Health.
The study was performed from 1979 to 1980 previously to OECD 408.

GLP compliance:

no

Remarks:

(initiated before the requirement of compliance to Good Laboratory Practices)

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Bis[[R-(R*,S*)]-β-hydroxy-α-methylphenethyl)methylammonium] sulphate

EC Number:

205-154-4

EC Name:

Bis[[R-(R*,S*)]-β-hydroxy-α-methylphenethyl)methylammonium] sulphate

Cas Number:

134-72-5

Molecular formula:

C10H15NO.1/2H2O4S

IUPAC Name:

2-(methylamino)-1-phenylpropan-1-ol sulfate (2:1) (salt)

Test material form:

other: White microcrystalline powder

Details on test material:

- Name of test material: Ephedrine sulphate

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS (feeding study)
- Source: Charles River Breeding Laboratories (rats at 4-5 weeks of age)
- Age at study initiation: 7-8 weeks
- Weight at study initiation: 133-160 g (males), 106-117 g (females)
- Fasting period before study: Not mentioned
- Housing: Polycarbonate cages, 5 animals per cage
- Diet: Rodent Laboratory Chow 5001, ad libitum
- Water: ad libitum
- Acclimation period: Not mentioned
- Quarantine: Animals were quarantined for 18-19 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.0-26.6
- Humidity (%): 20-48
- Air changes (per hr): 120
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: To: 1979-12-31 to 1980-04-04

Administration / exposure

Route of administration:

oral: feed

Details on oral exposure:

DIET PREPARATION (feeding study)
- Premix mixed with feed in a twin-shell blender for 5 min with intensifier bar and then 10 min without intensifïer bar
- Rate of preparation of diet (frequency): no data
- Maximum storage time: 14 days
- Mixing appropriate amounts with: Diet
- Storage temperature of food: Room temperature

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

daily

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0, 125, 250, 500, 1,000 or 2,000 mg/kg (ppm)
Basis:
nominal in diet

Doses / concentrations 2

Remarks:

Doses / Concentrations:
Males: 0, 4.6, 9.6, 22.2, 43.4, 87.4 mg/kg bw/day (mean)
Basis:
actual ingested

Doses / concentrations 3

Remarks:

Doses / Concentrations:
Females: 0, 8.1, 16.6, 35.6, 67.2, 144.9 mg/kg bw/day (mean)
Basis:
actual ingested

No. of animals per sex per dose:

10 rats of each sex

Control animals:

yes, concurrent no treatment

Details on study design:

- Dose selection rationale: Estimate applicable doses for chronic study.
- Animal distribution: Assigned to weight distribution classes and then to dosed group according to a table of random numbers.

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: two times per day

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: two times per day

BODY WEIGHT: Yes
- Time schedule for examinations: individual animal weights determined 1 x week

FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Feed consumption measured 1 x week
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No

FOOD EFFICIENCY: No

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: at the end of the study
- Dose groups that were examined: all groups

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

- At the end of the 13-week studies, survivors were killed.
- A necropsy was performed on all animals except those excessively autolyzed or cannibalized.
- Adrenal gland weight, heart weight, and packed cell volume were measured for controls and for the 2,000-ppm groups of rats.

Necropsy and histologic examination were performed on all animals.
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.

Statistics:

No data given.

Results and discussion

Results of examinations

Details on results:

CLINICAL SIGNS AND MORTALITY:
- None of the rats died before the end of the studies.
- Rats that received 2,000 ppm were hyperexcitable and had rough coats.

BODY WEIGHT AND WEIGHT GAIN
- 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.
- Final body weight males, 0 ppm: 359+/-5 grams; 125 ppm: 347+/-6 grams; 250 ppm: 339+/-5 grams, 500 ppm: 315+/-2 grams; 1,000 ppm: 286+/-8 grams; 2,000 ppm: 277+/-4 grams
Final body weight females, 0 ppm: 201+/-3 grams; 125 ppm: 189+/-5 grams; 250 ppm: 184+/-3 grams, 500 ppm: 184+/-3 grams; 1,000 ppm: 180+/-4 grams; 2,000 ppm: 167+/-2 grams

FOOD CONSUMPTION AND COMPOUND INTAKE:
- Feed consumption by dosed and control groups was generally comparable.
- Males:
12.7 - 15.1 grams of feed consumed per animal per day (week 6) [500 ppm: 15.4 grams]
12.1 - 14.8 grams of feed consumed per animal per day (week 12) [500 ppm: 14.0 grams]
- Females:
8.5 - 9.7 grams of feed consumed per animal per day (week 6) [500 ppm: 8.9 grams]
12.1 -13.1 grams of feed consumed per animal per day (week 12) [500 ppm: 13.1 grams]

OPHTHALMOSCOPIC EXAMINATION:
- The mean pupil diameters for dosed and control animals were comparable

HAEMATOLOGY / CLINICAL CHEMISTRY:
The mean packed cell volume of male rats that received 2,000 ppm was 6% greater than that of the controls.

GROSS PATHOLOGY / ORGAN WEIGHTS:
- The relative adrenal gland weight of male rats that received 2,000 mg/kg bw/day 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.

HISTOPATHOLOGY:
- No compound-related histopathologic effects were observed.

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

500 other: ppm (nominal in diet)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Clinical signs at 2000 ppm and loss of body weight >20% at 1000 and 2000 ppm (nominal in diet).

2

Dose descriptor:

NOAEL

Effect level:

22 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: Clinical signs and loss of body weight.

3

Dose descriptor:

NOAEL

Effect level:

35 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: Clinical signs and loss of body weight.

Target system / organ toxicity

Critical effects observed:

not specified