Registration Dossier

Administrative data

Description of key information

No repeat-dose studies were conducted with gestonorone acetate (ZK 5624); results of studies with gestonorone caproate (ZK 5623):
Subcutaneous, 4 weeks (Rat-Spraque-Dawley, non-GLP, doses: 0/ 125 / 500 mg/kg, 6 times/week): NOEL < 125 mg/kg
(Anonymous 1967)
Subcutaneous, 28 weeks, (Rat-Spraque-Dawley, non-GLP, doses: 0/ 5/ 25/ 125 mg/kg, once weekly): < 5 mg/kg
(Anonymous 1967)
Intramuscular, up to 78 weeks (rat-CD, non-GLP, doses: 0/ 1.25/ 8.75/ 17.5, up to 5 injections/week): NOEL < 1.25 mg/kg
(Anonymous 1966)
Intramuscular, up to 52 weeks (dog-Beagle, non-GLP, doses: 0/ 1.25/ 8.75/ 17.5 mg/kg, up to 5 injections/week): NOEL < 1.25 mg/kg
(Anonymous 1966)


Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

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

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 subcutaneous (6 applications / week) administration of gestonorone caproate (ZK 5623) to rats at doses of 125 and 500 mg/kg over 4 weeks resulted in increased body weight gain and food consumption in females. Post mortem examination revealed the expected exaggerated pharmacodynamic effects of a gestagen from the lowest tested dose upwards and include dose-dependent effects on prostate (decreased weights, slight to severe atrophy), seminal vesicles (decreased weight, slight to severe atrophy), ovary (decreased weights, moderate to severe atrophy) and uterus (decreased weight, slight ot severe atrophy). At the high dose, additional effects on epididymides (decreased weight), vagina (vacuolation) and mammary gland (slight to moderate proliferation of glandular tissue; females only) were seen. Increased liver weight was described from the low dose upwards without corresponding findings in clinical pathology and histopathology examination. No clear signs of organtoxicity were observed. The NOEL is < 125 mg/kg after subcutaneous administration. (Anonymous 1967)

The subcutaneous, once weekly administration of gestonorone caproate (ZK 5623) to rats at doses of 5, 25 and 125 mg/kg over 28 weeks resulted in increased body weight gain and food consumption in females at the mid dose and higher. Post mortem examination revealed the expected exaggerated pharmacodynamic effects of a gestagen from the lowest tested dose upwards and include dose-dependent effects on prostate (decreased weights, slight atrophy), ovary (decreased weight, atrophy, cystic follicles, disappearance of corpus luteum), vagina (vacuolation) and uterus (decreased weights, light to severe atrophy, disappearance of uterine gland, papillomatous hyperplasia of endometrium and nodular hyperplasia of longitudinal muscle layer) at 5 mg/kg; seminal vesicle (decreased weights, atrophy) at 25 mg/kg, and in addition on testis (reduced weight) at 125 mg/kg. No clear signs of organtoxicity were observed. Two fibroadenoma were detected without a dose-dependency in one female each at the doses of 5 and 25 mg/kg. The NOEL is < 5 mg/kg after once weekly subcutaneous administration. (Anonymous 1967)

The intramuscular administration of gestonorone caproate (ZK 5623) to male and female rats at doses of 1.25, 8.75 and 17.5 mg/kg over up to 59 weeks with necropsies in weeks 15 and 78 resulted in increased body weight gain from the low dose upwards. At necropsy in week 15, dose-dependent effects on uterus (decreased weight, hypoplasia), ovary (decreased weight, hypoplasia) at the mid dose of 8.75 mg/kg, and in addition on liver (degenerative changes without corresponding findings in clinical pathology) and kidneys (tubular changes in upper nephron) at the high dose of 17.5 mg/kg were seen. Treatment-related findings in week 78 (19 weeks after last treatment) were decreased prostate and uterus organ weights from the low dose upwards without corresponding histological findings. Dose-dependent local intolerance reactions were observed in all dose groups (inflammatory infiltration, abscess formation) from the low dose upwards. Effects on endocrine organs are regarded as exaggerated pharmacodynamic effects. The NOEL is < 1.25 mg/kg. (Anonymous 1966)

The intramuscular administration of 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. (Anonymous 1966)

Justification for classification or non-classification

Based on the results there is no classification required according to Regulation (EC) 1272/2008 (CLP).