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Toxicological information

Repeated dose toxicity: other routes

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Administrative data

Endpoint:
sub-chronic toxicity: other route
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
other information
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: well reported study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1975
Report Date:
1975

Materials and methods

Test guideline
Qualifier:
no guideline available
Deviations:
not applicable
Principles of method if other than guideline:
Every second weekly single intramuscular injections of norethisterone enanthate were given to female rats (16 rats/dose group) over 90 days at the doses of 0, 1, 10 and 50 mg/kg.
At beginning of the study rats were 45 days old, bw 121-151 g.
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): norethisterone enanthate (ZK5410)

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
female

Administration / exposure

Route of administration:
intramuscular
Vehicle:
castor oil
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
90 days
Frequency of treatment:
every fortnight
Doses / concentrations
Remarks:
Doses / Concentrations:
1, 10 and 50 mg/kg.
No. of animals per sex per dose:
16/dose
Control animals:
yes, concurrent no treatment

Results and discussion

Effect levels

Dose descriptor:
LOAEL
Effect level:
>= 1 mg/kg bw/day
Based on:
test mat.
Sex:
female
Basis for effect level:
other: disorders in sexual cycle

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

At 1 and 10 mg/kg bw the rats developed disorder of the cycle and the uterus weights (10 mg/kg) of the rats were reduced. At 50 mg/kg bw the animals were in a constant diestrus with growth depression. The organ weights of hypophysis, ovaries, uterus and thymus were reduced. Additionally hyperplasia/proliveration of granulosa cells were observed.

Applicant's summary and conclusion

Conclusions:
LOAEL: 1 mg/kg based on disorder of the cycle
Executive summary:

No repeated dose toxicity studies were conducted with ZK 5378 (norethiosterone). Results of studies conducted with an ester of norethisterone (norethisterone enanthate, ZK 5410) are regarded as representative as most likely ester cleavage occurs in vivo after administration.

Single intramuscular injections of ZK 5410 were given weekly to female rats (16 rats/dose group) over 90 days at the doses of 0, 1, 10 and 50 mg/kg. At 1 and 10 mg/kg bw the rats developed disorder of the cycle and the uterus weights (10 mg/kg) of the rats were reduced. At 50 mg/kg bw the animals were in a constant diestrus with growth depression. The organ weights of hypophysis, ovaries, uterus and thymus were reduced. Additionally hyperplasia/proliveration of granulosa cells were observed. LOAEL: 1 mg/kg