Gestonorone

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Thre are no reproductive toxicity studies conducted with ZK 5686, read across with results of studies with ZK 5623 (gestonorone caproate):
subcutaneous (Rat, non-GLP, Doses: 0/ 2/ 20/ 200 mg/kg, Days 17 and 20 p.c., Days 1, 4, 7, 10, 13, 16 and 19 p.p.): NOEL = 20 mg/kg
[Schering AG, Report 3217, 1978-05-31]

Additional information

There are no reproductive toxicity studies conducted with ZK 5686 (gestonorone). Results of studies conducted with a different ester of gestonorone (ZK 5623, gestonorone caproate) are regarded as representative as most likely ester cleavage occurs in vivo after administration.

Effects of ZK 5623 on female fertiliy was assessed in rats with subcutaneous administration (twice weekly, two weeks premating and up to two weeks mating) of doses of 2, 20, and 200 mg/kg. Dose-dependently increased disturbance of fertility was seen at 20 mg/kg and higher. Reversibility of effects was shown in two subgroups at 20 and 200 mg/kg which were mated for up to six weeks after end of treatment. No effects on duration of pregnancy and embryofetal development was seen in pregnant animals. [Schering AG, Report 3299, 1978-07-27]

Effects of ZK 5623 on male fertility was assessed in rats with subcutaneous administration (0/ 2/ 20/ 60 mg/kg, twice weekly, 10 weeks premating plus up to two weeks mating period). Male fertility was decreased dose dependently from 20 mg/kg onwards. Also a slight increase in resorption rate was observed. [Schering AG, Report 4057, 1979-11-15]

Effects of ZK 5623 on male fertility was assessed in rats with subcutaneous administration (twice weekly, ten weeks premating and up to two weeks mating) of doses of 2, 20, and 200 mg/kg. Dose-dependently decreased male fertility was seen at the dose of 20 mg/kg and higher, including decreased weights of male reproductive organs. In addition, increased numbers of total resorptions were seen at 20 mg/kg and higher. However, results of a dominant lethal test in rats up to the highest tested dose of 60 mg/kg did not indicate a dominant-lethal effect of ZK 5623. [Schering AG, Report 3253, 1978-05-31]

In a study in mice, the effect of ZK 5623 on embryofetal development including peri/ postnatal development of F1 generation and embryonic develoment of F2 generation was studied after subcutaneous administraton on Days 1, 7 and 14 p.c. at a dose of 0.3 mg/animal (appr. 12 mg/kg). There were no compound-related findings in this study. ZK 5623 was not teratogenic. [Schering AG, 1968-07-10]

The effects observed on male and female fertility are regarded as exaggerated pharmacodynamic effects as a consequence of the progestenic activity of ZK 5623.

Short description of key information:
There are no fertility studies conducted with ZK 5686, read across with results of studies with ZK 5623 (gestonorone caproate):

subcutaneous (Rat, females, non-GLP, Doses: 0/ 2/ 20/ 200 mg/kg, twice weekly, two weeks premating plus up to two weeks mating period): NOEL = 2 mg/kg
[Schering AG, Report 3299, 1978-07-27]

subcutaneous (Rat, males, non-GLP, Doses: 0/ 2/ 20/ 60 mg/kg, twice weekly, 10 weeks premating plus up to two weeks mating period): NOEL = 2 mg/kg
[Schering AG, Report 4057, 1979-11-15]

subcutaneous (Rat, males, non-GLP, Doses: 0/ 2/ 20/ 200 mg/kg, twice weekly, ten weeks premating plus up to two weeks during mating): NOEL = 2 mg/kg
[Schering AG, Report 3253, 1978-05-31]

subcutaneous (Mouse-NMRI, non-GLP, Doses: 0/ appr. 12 mg/kg, Days 7 to 13 p.c.): NOEL > 12 mg/kg
[Schering AG, 1968-07-10]

Effects on developmental toxicity

Description of key information

There are no reproductive toxicity studies conducted with ZK 5686, read across with results of studies with ZK 5623 (gestonorone caproate):
subcutaneous (Mouse-NMRI, non-GLP, Doses: 0/ appr. 12 mg/kg, Days 1, 7 and 14 p.c.): NOEL > 12 mg/kg
[Schering AG, 1968-07-10]
subcutaneous (Mouse-NMRI, non-GLP, Doses: 0/ appr. 12 mg/kg, Days 1, 7 and 14 p.c.): NOEL > 12 mg/kg
[Schering AG, 1968-07-10]
subcutaneous (Rat, non-GLP, Doses: 0/ 2/ 20/ 200 mg/kg, Days 0 and 4 p.c.): NOEL = 200 mg/kg.
[Schering AG, Report 3219, 1978-05-30] 
subcuatenous (Rat, non-GLP, Doses: 0/ 2/ 20/ 200/ 500, Days 7, 10, 13, 16 p.c.): NOEL (embryotoxicity) = 20 mg/kg; NOEL (maternotoxicity and teratogenicity) > 500 mg/kg
[Schering AG, Report No. 3218, 1978-05-31]
subcutaneous (Rabbit, non-GLP, Doses: 0/ 2/ 20/ 200 mg/kg, days 6, 9, 12, 15 p.c.): NOEL (embryotoxicity) = 20 mg/kg; NOEL (maternotoxicity and teratogenicity) > 200 mg/kg
[Schering AG, Report No. 3254, 1978-05-31]
subcutaneous (Rabbit, non-GLP, Doses: 0/ 20/ 200 mg/kg, days 6, 9, 12, 15 p.c.): NOEL (embryotoxicity) = 20 mg/kg; NOEL (maternotoxicity and teratogenicity) > 200 mg/kg
[Schering AG, Report No. 3975, 1979-09-26]

Additional information

Thre are no reproductive toxicity studies conducted with ZK 5686 (gestonorone). Results of studies conducted with an ester of gestonorone (ZK 5623, gestonorone caproate) are regarded as representative as most likely ester cleavage occurs in vivo after administration.

The effect of ZK 5623 on embryofetal development was studied in mice with once daily subcutaneous administration from day 7 to 13 p.c. at a dose of 0.3 mg/animal (appr. 12 mg/kg). There were no compound-related findings in this study. ZK 5623 was not teratogenic.[Schering AG, 1968 -07 -10]

In a second study in mice, the effect of ZK 5623 on embryofetal development including peri/ postnatal development of F1 generation and embryonic develoment of F2 generation was studied after subcutaneous administraton on Days 1, 7 and 14 p.c. at a dose of 0.3 mg/animal (appr. 12 mg/kg). There were no compound-related findings in this study. ZK 5623 was not teratogenic. [Schering AG, 1968-07-10]

The effect of ZK 5623 on early embryonic development was studied in rats after subcutaneous administration of doses of 0/ 2/ 20/ 200 mg/kg on Days 0 and 4 p.c. No effects on pregnancy and embryo-fetal development were seen in this study. [Schering AG, Report 3219, 1978-05-30]

The effect of ZK 5623 on embryofetal development including peri-/postnatal development of F1 generation and embryonic development of F2 generation was studied in rats with subcutaneous administration of doses of 2, 20, 200 and 500 mg/kg on Days 7, 10, 13 and 16 p.c. At the dose of 200 mg/kg an higher, fetolethal effects were described due to prevention of spontaneous delivery. These findings are a consequence of the progestational activity of the ZK 5623. No compound-related findings were observed at lower doses in the dams, the F1 and the F2 generations. ZK 5623 was not teratogenic in this study. [Schering AG, Report No. 3218, 1978-05-31]

In rabbits, the effect of ZK 5623 on embryofetal development was studied in two independent studies with subcutaneous administration of doses of 2, 20, and 200 mg/kg on Days 6, 9, 12 and 15 p.c. Results of both studies indicated retardational and embryolethal effects in the fetuses at the high dose of 200 mg/kg. No malformations were seen. ZK 5623 was not teratogenic in rabbits.[Schering AG, Report No. 3254, 1978-05-31; Schering AG, Report No. 3975, 1979-09-26]

Toxicity to reproduction: other studies

Additional information

there are no reproductive toxicity studies conducted with ZK 5686 (gestonorone). Results of studies conducted with an ester of gestonorone (ZK 5623, gestonorone caproate) are regarded as representative as most likely ester cleavage occurs in vivo after administration.

The effect of ZK 5623 on peri- and postnatal development (effects on dams, reared pups of F1 generation and F2 fetuses) was assessed by subcutaneous treatment of rats (P generation) at end of pregnancy (Days 17 and 20 p.c.) and during the weaning period (Days 1, 4, 7, 10, 13, 16 and 19 p.p.) with doses of 2, 20 and 200 mg/kg. At the high dose, spontenous delivery was prevented by treatment in nearly all animals. Only dead fetuses were detected in high dose animals sacrificed on Day 24 p.c. No effects of ZK 5623 were seen on any of the other parameters assessed in this study at the two lower doses tested.[Schering AG, Report 3217, 1978-05-31]

Effects on peri- and postnatal development were also assessed within embryofetal toxicity studies in mice and rats (see above). No effects were seen in mice at the high dose of 12 mg/kg. Prevention of spontaneous delivery and secondary fetolethality was the only effect in rats at high subcutaneous doses of 200 and 500 mg/kg.

Prevention of sponteous delivery by ZK 5623 is a consequence of its progestational acitivity.

Justification for classification or non-classification

There are no experimental data on the reproductive toxicity of ZK 5686 available. Corresponding to the progestogenic efficacy of the compound and based on experimental results with ZK 5623 (gestonorone caproate) the repeated exposure to pharmacologically active doses may result in disturbances of endogenous hormone production and consequently to reversible inhibition of fertility in men and women. No indication of a teratogenic potential even after partially embryolethal doses were observed during embryotoxicity studies with gestonorone caproate (ZK 5623) in mice, rats and rabbits. Furthermore, no adverse effects on the development of the offspring were recorded in peri/postnatal studies with gestonorone caproate in rats. Still as a precaution a risk of embryotoxic effects in humans should be taken into consideration if exposure to high loads of the drug occurs during pregnancy. In addition, it should be prudently assumed that the compound might be transferred into the milk of breast-feeding women and might lead to a disturbance of the development of the infant.

Classified according to German legislation (TRGS-905) as Repr. (F) Cat. 1 and Repr. (E) Cat. 2 (EEC criteria).

Classified as Category 1A according to Regulation (EC) 1272/2008 (CLP).

According to the Directive 67/548/EEC gestonorone is classified:

Category 1; R60 - May impair fertility.

Category 2; R61 - May cause harm to the unborn child.

R64 - May cause harm to breastfed babies