Norethisterone

Repeated dose toxicity: oral

Administrative data

Endpoint:

repeated dose toxicity: oral, other

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From Jan. 1969 until 1971

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1979

Report date:

1979

Materials and methods

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

The substance was administered orally by oral tube to rats of both sexes for 85 weeks (male) or 104 weeks (female). general conditions were checked every day. Food and water consumptions and body weight were measured once a week and recorded. Urinanalysis and hematological and pathological examinations were carried out three times (at 28 weeks, 56 weeks and end of test).

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Norethisterone acetate

EC Number:

200-132-0

EC Name:

Norethisterone acetate

Cas Number:

51-98-9

Molecular formula:

C22H28O3

IUPAC Name:

17-ethynyl-3-oxoestr-4-en-17-yl acetate

Specific details on test material used for the study:

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: micronized
- Final preparation of a solid: suspension

Test animals

Species:

rat

Strain:

other: JCL-SD

Sex:

male/female

Details on test animals or test system and environmental conditions:

no data available

Administration / exposure

Route of administration:

other: oral tube

Vehicle:

other: 1 g tragant per 100 ml distilled water

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

85 weeks (male); 104 weeks (female)

Frequency of treatment:

daily

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

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

Doses / concentrations 2

Dose / conc.:

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

Doses / concentrations 3

Dose / conc.:

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

No. of animals per sex per dose:

30

Control animals:

yes

Positive control:

no

Examinations

Observations and examinations performed and frequency:

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: once a week

FOOD CONSUMPTION: YES
- Time schedule for examinations: once a week
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Not specified
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Not specified

WATER CONSUMPTION: Yes
- Time schedule for examinations: once a wwek

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for examinations: at 28 weeks, 56 weeks and end of test (no further informnation available)

CLINICAL CHEMISTRY: Not specified

URINALYSIS: Yes
- Time schedule for examinations: at 28 weeks, 56 weeks and end of test (no further informnation available)

NEUROBEHAVIOURAL EXAMINATION: Not specified

IMMUNOLOGY: Not specified

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
- Time schedule for examinations: at 28 weeks, 56 weeks and end of test (no further informnation available)
HISTOPATHOLOGY: Yes
- Time schedule for examinations: at 28 weeks, 56 weeks and end of test (no further informnation available)

Statistics:

no data available

Results and discussion

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

ca. 1.25 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

clinical biochemistry

histopathology: non-neoplastic

2

Dose descriptor:

dose level:

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: depression of body weight gain, decrease of total cholesterol and atrophy of prostate, seminal vesicle and ovary

Remarks on result:

other: Effects observed after 56 weeks´treatment and end of the test

Target system / organ toxicity

Critical effects observed:

yes

Lowest effective dose / conc.:

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

System:

other: male/female reproductive system

Organ:

ovary

seminal vesicle

other: prostate

Treatment related:

yes

Applicant's summary and conclusion

Executive summary:

No repeated dose toxicity studies were conducted with ZK 5378 (norethisterone). Results of studies conducted with an ester of norethisterone (norethisterone acetate, ZK 5422) are regarded as representative as most likely ester cleavage occurs in vivo after administration.

In a repeated dose toxicity study Norethisterone acetate was administered to 30 JCL-SD rats/sex/dose by gavage at dose levels of 0, 0.05, 1.25, 31.25 mg/kg bw/day for 85 weeks (male) or 104 weeks (female). General conditions were checked every day. Food and water consumptions and body weight were measured once a week and recorded. Urin analysis and hematological and pathological examinations were carried out three times (at 28 weeks, 56 weeks and end of test).

 

The results show that the maximum non-effective dose of the test item in 85 weeks´ (male) or 104 weeks´ (female) oral administration was estimated at dose of slightly less than 1.25 mg/kg/day. The toxic effects recognized in rats of the highest dose group (31.25 mg/kg/day) are those generally found after administration of synthetic progestin hormones and not specific to the test item.