17-hydroxy-19-norpregn-4-ene-3,20-dione 17-acetate

Repeated dose toxicity: other routes

Administrative data

Endpoint:

chronic toxicity: other route

Type of information:

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

Adequacy of study:

other information

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:

1966

Report date:

1966

Materials and methods

Test guideline

Qualifier:

no guideline available

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Gestonorone caproate

EC Number:

215-010-2

EC Name:

Gestonorone caproate

Cas Number:

1253-28-7

Molecular formula:

C26H38O4

IUPAC Name:

17-acetyl-3-oxoestr-4-en-17-yl hexanoate

Test animals

Species:

dog

Strain:

Beagle

Sex:

male/female

Administration / exposure

Route of administration:

intramuscular

Vehicle:

castor oil

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

52 weeks

Frequency of treatment:

twice weekly; for dogs of 17.5 mg/kg group during week 8 and 9 three weekly administration were given and from week 10 on these dogs received five weekly injections

Doses / concentrations

Remarks:

Doses / Concentrations:
0 - 1.25 - 8.75 - 17.5 mg/kg

No. of animals per sex per dose:

3/sex/group

Control animals:

yes, concurrent vehicle

Results and discussion

Effect levels

Dose descriptor:

NOEL

Effect level:

< 1.25 mg/kg bw/day

Based on:

not specified

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Treatment results in slightly increased body weight gain at the low dose and higher. Signs of local intolerance were observed in all animals including controls with increased severity at the high dose. Expected exaggerated pharmacodynamic effects on endocrine organs were observed from the low dose upwards and include effects on vagina (cornification), uterus (increased weight, endometrial glandular stimulation with endometrial necrosis and calcification), ovary (increased follicular activity, decrease in luteal tissue), testes (decreased weight), prostate (decreased weight, atrophy), and mammary gland (proliferation, both sexes).

Applicant's summary and conclusion

Executive summary:

No repeat-dose studies were conducted with ZK 5624 (gestonorone acetate). Results of studies conducted with a different ester of gestonorone (gestonorone caproate, ZK 5623) are regarded as representative as most likely ester cleavage occurs in vivo after administration.

The intramuscular administration of gestonorone caproate (ZK 5623) to male and female dogs at doses of 1.25, 8.75 and 17.5 mg/kg over up to 52 weeks with necropsies in weeks 15 and 53 resulted in slightly increased body weight gain at the low dose and higher. Signs of local intolerance were observed in all animals including controls with increased severity at the high dose. Expected exaggerated pharmacodynamic effects on endocrine organs were observed from the low dose upwards and include effects on vagina (cornification), uterus (increased weight, endometrial glandular stimulation with endometrial necrosis and calcification), ovary (increased follicular activity, decrease in luteal tissue), testes (decreased weight), prostate (decreased weight, atrophy), and mammary gland (proliferation, both sexes). The NOEL is < 1.25 mg/kg.