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Effects on fertility

Description of key information
No data available.
Additional information

Ther are no internal fertility studies with ethisterone available. However, some results of studies with ethisterone were cited in RTECS database (May 2010):

The single subcutaneous injection of ethisterone to female rabbits prior to mating result in effects on fertility: TDLo: 5 mg/kg (1D pre)

(Acta Endocrinologica, Supplementum (Copenhagen). [Periodica, Skolegade 12 E, DK-2500 Valby, Denmark) No.1- 1948- v. 28, p. 18, 1956 (ACEDAB)]

The oral administration of ethisterone to women over 3 weeks result in menstrual cycle changes or disorder: TDLo: 168 mg/kg (3W pre)

(American Journal of Obstetrics and Gynecology. [C.V. Mosby Co., 11830 Westline Industrial Dr., St. Louis, MO 63146) V.1- 1920- v. 76, p. 626, 1958 (AJOGAH)]

The administration of esthrone subcutaneously to female rats over 14 days results in maternal effects on ovaries and fallopian tubes (TDLo: 140 mg/kg) and effects on fertility at TDLo: 280 mg/kg [Contraception. (Geron-X, Inc., POB 1108, Los Altos, CA 94022) V.1- 1970- v. 5, p. 57, 1972 (CCPTAY)]

A single oral application to female rats influenced the mating performance (e.g., number of sperm positive females per number of females mated; number of copulations per number of estrus cycles): TDLo: 10 mg/kg (1D pre) [Fertility and Sterility. (American Fertility Soc., 608 13th Ave. S, Birmingham, AL 35282) V.1- 1950- v. 5, p. 282, 1954 (FESTAS)]

The oral adminstration to male rats over 9 days results in effects on prostate, seminal vessicle, Cowper's gland, accessory glands : TDLo: 288 mg/kg (9D male) [Proceedings of the Society for Experimental Biology and Medicine. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1903/04- v. 100, p. 540, 1959 (PSEBAA)]

daily subcutaneous administration of ethisterone to male rats over 10 days have effects on prostate, seminal vessicle, Cowper's gland, accessory glands: TDLo: 10 mg/kg (10D male) [Proceedings of the Society for Experimental Biology and Medicine. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1903/04- v. 100, p. 540, 1959 (PSEBAA)]


Short description of key information:
Ther are no internal fertility studies with ethisterone available. However, some results of studies with ethisterone were cited in RTECS database (May 2010):

Subcutaneous, single inj. (rabbit, female): TDLo: 5 mg/kg (1D pre)
(Acta Endocrinologica, Supplementum (Copenhagen). (Periodica, Skolegade 12 E, DK-2500 Valby, Denmark) No.1- 1948- v. 28, p. 18, 1956 (ACEDAB))

Oral, 3 weeks (woman): TDLo: 168 mg/kg (3W pre)
(American Journal of Obstetrics and Gynecology. (C.V. Mosby Co., 11830 Westline Industrial Dr., St. Louis, MO 63146) V.1- 1920- v. 76, p. 626, 1958 (AJOGAH))

Subcutaneous, 14 days (rat, female): TDLo: 280 mg/kg (14D pre)
(Contraception. (Geron-X, Inc., POB 1108, Los Altos, CA 94022) V.1- 1970- v. 5, p. 57, 1972 (CCPTAY))

Oral, single (rat, female): TDLo: 10 mg/kg (1D pre)
(Fertility and Sterility. (American Fertility Soc., 608 13th Ave. S, Birmingham, AL 35282) V.1- 1950- v. 5, p. 282, 1954 (FESTAS))

Oral, 9 days (rat, male): TDLo: 288 mg/kg (9D male)
(Proceedings of the Society for Experimental Biology and Medicine. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1903/04- v. 100, p. 540, 1959 (PSEBAA))

Subcutaneous, 10 days (rat, male): TDLo: 10 mg/kg (10D male)
(Proceedings of the Society for Experimental Biology and Medicine. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1903/04- v. 100, p. 540, 1959 (PSEBAA))

Effects on developmental toxicity

Description of key information
There is no teratogenicity study with ethisterone available. Results of  studies  were cited in RTECS database (May 2010):
Oral, 6 to 28 week of preg. (woman): TDLo: 386 mg/kg (6-28W preg)
(American Journal of Obstetrics and Gynecology. (C.V. Mosby Co., 11830 Westline Industrial Dr., St. Louis, MO 63146) V.1- 1920- v. 84, p. 962, 1962 (AJOGAH))
Oral, 17 to 20 day of preg. (rat): TDLo: 200 mg/kg (17-20D preg)
(Endocrinologia Japonica. (Japan Pub. Trading Co., Ltd., POB 5030, Tokyo International, Tokyo, Japan) V.1- 1954- v. 24, p. 77, 1977 (ECJPAE))
Route unreported, 7 to 39 week of preg. (woman): TDLo: 92 mg/kg (7-39W preg)
(Fertility and Sterility. (American Fertility Soc., 608 13th Ave. S, Birmingham, AL 35282) V.1- 1950- v. 11, p. 148, 1960 (FESTAS))
Oral, 8 to 26 week of preg. (woman): TDLo: 79800 ug/kg (8-26W preg)
(Journal of Clinical Endocrinology and Metabolism. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.12- 1952- v. 18, p. 559, 1958 (JCEMAZ))
Route unreported, 15 to 39 week of preg. (woman): TDLo: 56 mg/kg (15-39W preg)
(Journal of Clinical Endocrinology and Metabolism. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.12- 1952- v. 18, p. 559, 1958 (JCEMAZ))
Oral, 11 to 15 week of preg. (woman): TDLo: 21 mg/kg (11-15W preg)
(Journal of Clinical Endocrinology and Metabolism. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.12- 1952- v. 19, p. 1369, 1959 (JCEMAZ))
Oral, 16 to 28 week of preg. (woman): TDLo: 81900 ug/kg (16-28W preg)
(Journal of Clinical Endocrinology and Metabolism. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.12- 1952- v. 19, p. 1369, 1959 (JCEMAZ))
Additional information

There is no internal teratogenicity study with ethisterone available. However results of different studies are cited in RTECS database (May 2010):

Daily oral application of ethisterone to pregnant women in week 6 to 28 of pregnancy results in developmental abnormalities of the fetal urogenital system: TDLo: 386 mg/kg (6-28W preg) [American Journal of Obstetrics and Gynecology. (C.V. Mosby Co., 11830 Westline Industrial Dr., St. Louis, MO 63146) V.1- 1920- v. 84, p. 962, 1962 (AJOGAH)]

Pregnant rats were treated orally with ethisterone on day 17 to 20 of pregnancy. This results in specific fetal abnormalities of the urogenital system: TDLo: 200 mg/kg (17-20D preg) [Endocrinologia Japonica. (Japan Pub. Trading Co., Ltd., POB 5030, Tokyo International, Tokyo, Japan) V.1- 1954- v. 24, p. 77, 1977 (ECJPAE)]

Fetuses of women treated with ethisterone during pregnancy weeek 7 to 39 week developed abnormalities of the Urogenital system: TDLo: 92 mg/kg (7-39W preg) [Fertility and Sterility. (American Fertility Soc., 608 13th Ave. S, Birmingham, AL 35282) V.1- 1950- v. 11, p. 148, 1960 (FESTAS)]

Women treated with ethisterone during pregnancy weeks 8 to 26 or 15 to 39 had fetuses with specific developmental abnormalities of the urogenital system: TDLo: 79800 ug/kg (8-26W preg) and TDLo: 56 mg/kg (15-39W preg) [Journal of Clinical Endocrinology and Metabolism. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.12- 1952- v. 18, p. 559, 1958 (JCEMAZ)]

Oral treatment of women during pregnancy weeks 11 to 15 or weeks 16 to 28 results in specific abnormalities of the fetal urogenital system: TDLo: 21 mg/kg (11-15W preg) or TDLo: 81900 ug/kg (16-28W preg) [Journal of Clinical Endocrinology and Metabolism. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.12- 1952- v. 19, p. 1369, 1959 (JCEMAZ)]

Toxicity to reproduction: other studies

Additional information

No data available.

Justification for classification or non-classification

No experimental data in the reproductive toxicity of ZK 4957 are available. However, several animal studies are cited in RTECS database (May 2010) showing toxic effects of reproductive toxicity.

Corresponding to the progestogenic efficacy of the compound 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.Similarly to other progesterons a risk of embryotoxic effects should be taken into consideration if exposure to high loads of ethisterone occurs during pregancy. This assumption is supported by the study results scited in RTECS. In particular the risk of masculinisation of female offsprings has to be taken into account. in addition, it should be prudently assumed that the compound might be transfered into the milk of brest-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 1272/2008/EC (CLP).

According to the Directive 67/548 EEC ethisterone 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

Additional information