Androsta-1,4-diene-3,17-dione

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Neither fertility nor multigeneration studies are available for androstadiendion or the read-across substance androstendion. Data waiver is claimed.

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

There are no explicit fertility or multigeneration studies available for androstadiendion (CAS No. 897-06-3) or the read-across substance androstendion (CAS No.63-05-8). However, the following not assignable data (abstracts/handbooks), cited in the RTECS database (April 2013), suggest a possible reproductive toxicity potential of androstendion:

The subcutaneous administrations of androstendion to male rats over 25 days prior to mating result in no further specified effects on spermatogenesis (including genetic material, sperm morphology, motility, and count) testes, epididymis and sperm duct; TDLo: 10500 µg/kg (25D male) [Acta Medica Turcica. (Dr. Ayhan Okcuoglu, Cocuk Hastalikari Klinigi, c/o Ankara Univ., Tip Facultesi, Cebeci, Ankara, Turkey) V.1-10/11, 1948-58: New series: V.1- 1964- v. 8, p. 68, 1971 (AMTUA3)]

The subcutaneous administrations of androstendion to female rats over 14 days prior to mating result in maternal effects on ovaries, fallopian tubes, uterus, cervix and vagina and not further specified effects on fertility; TDLo: 7 mg/kg (14D pre) [Contraception. (Geron-X, Inc., POB 1108, Los Altos, CA 94022) V.1- 1970- v. 5, p. 489, 1972 (CCPTAY)]

The administration of androstendion to female rats via an implantat over16 days prior to mating results in menstrual cycle changes or disorders and not further specified effects on fertility ; TDLo: 5056 µg/kg (16D pre) [Journal of Reproduction and Fertility. (Biochemical Soc. Book Depot, POB 32, Commerce Way, Colchester, Essex CO2 8HP, UK) V.1- 1960- v. 56, p. 675, 1979 (JRPFA4)]

Androstendion is an endogenous intermediate in steroid hormone synthesis and as such an endogenous precursor of testosterone and estrone, which can be metabolized to estradiol. In accordance with the androgenic effect of androstendion signs of masculinisation as well as disturbances to the cycle and fertility are to be expected in women following long-term exposure to doses which are pharmacologically effective. Impairment of the endogenous hormone production as well as disturbances to fertility (impairment of spermiogenesis) are also to be expected in men following long-term exposure due to the pharmacologically proven androgenic effects.

For an assessment of steroid hormones see also the argumentation for steroid hormones related to the Technical Rule for Hazardous Substances 905, which was elaborated by the German Committee on Hazardous Substances (AGS) and published by the German Federal Ministry of Labour and Social Affairs (version of 2008/2005/1999, only available in German, http://www.baua.de/de/Themen-von-A-Z/Gefahrstoffe/TRGS/ Begruendungen-905-906.html). In this argumentation 73 steroid hormones or precursors of steroid hormones were each allocated to one of seven hormone classes based on their predominant pharmacological activity (i.e. androgenic, mild androgenic, anabolic, estrogenic, gestagenic, mild gestagenic or glucocorticoide), and recommendations for their classification were elaborated. Androstendion was allocated to group 1 (androgenic steroids) resulting in a classificationwith Repr. Cat. 1 according to criteria of Directive 67/458/EEC.

This classification is also taken for androstadiendion. Therefore, the reproduction toxicity data waiver of androstadiendion is based on the classification of the read-across substance androstendion.

Effects on developmental toxicity

Description of key information

No developmental toxicity or teratogenicity studies are available for androstadiendion or the read-across substance androstendion. Data waiver is claimed.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

There are no explicit developmental toxicity studies available for androstadiendion or the read-across substance androstendion. However, the following not assignable data (abstracts/handbooks), cited in the RTECS database (April 2013), suggest a possible developmental toxicity potential of androstendion:

The daily subcutaneous administration of androstendion to hamsters on day 1-4 of pregnancy results in pre-implantation mortality (e.g., reduction in number of implants per female; total number of implants per corpora lutea); TDLo: 35 mg/kg (1-4D preg) [Endocrinology (Baltimore). (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21203) V.1- 1917- v. 80, p. 1152, 1967 (ENDOAO)]

The daily subcutaneous administration of androstendion to hamsters on day 1 -4 of pregnency results in maternal effects in ovaries, and fallopian tubes not further specified; TDLo: 17500 ug/kg (1-4D preg) [Endocrinology (Baltimore). (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21203) V.1- 1917- v. 80, p. 1152, 1967 (ENDOAO)]

Androstendion is administered subcutaneous to hamsters on day 1-4 of pregnancy. This leads in unspecified maternal effects of uterus, cervix and vagina; TDLo: 70 mg/kg (1-4D preg) [Endocrinology (Baltimore). (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21203) V.1- 1917- v. 80, p. 1152, 1967 (ENDOAO)]

Adrostendion is administered subcutaneous to rats on day 2-5 of pregnancy leading to maternal effects in uterus, cervix and vagina as well as pre-implantation mortality (e.g., reduction in number of implants per female; total number of implants per corpora lutea) and further unspecified effects on fertility; TDLo: 80 mg/kg (2-5D preg) [Endocrinology (Baltimore). (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21203) V.1- 1917- v. 81, p. 1091, 1967 (ENDOAO)]

The daily oral application of androstendion to rats two weeks prior to mating and 0-20 day of pregnancy results in specific developmental abnormalities of the urogenital system; TDLo: 280 mg/kg (2W pre/0-20D preg) [Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 42, p. 917, 2004 (FCTOD7)]

The daily oral adminsitration of androstendion to female rats 14 day pre-mating and until day 19 after conception led to specific developmental abnormalities (central nervous system); TDLo: 1980 mg/kg (14D pre/-19D preg) [Toxicology and Industrial Health. (Princeton Scientific Pub. Co., POB 2155, Princeton, NJ 08540) V.1 -1985- v. 23,p. 65, 2007 (TIHEEC)]

Intramuscular application of androstendion to rats on day 14-21 of pregnancy results in specific developmental abnormalities on skin and skin appendages as well as effects on newborn: Live birth index (similar to fetuses per litter, except measured after birth) and delayed effects; TDLo: 80 mg/kg (14-21D preg) [Journal of Comparative and Physiological Psychology. (Washington, DC) V.40-96, 1947-82. v. 92, p. 13, 1978 (JCPPAV)]

Intramuscular administration of androstendion to rats on day 14-21 day of pregnancy leads to specific developmental abnormalities of the urogenital system and effects on newborn (e.g., reduced weight gain); TDLo: 40 mg/kg (14-21D preg [Journal of Comparative and Physiological Psychology. (Washington, DC) V.40-96, 1947-82. v. 92, p. 13, 1978 (JCPPAV)]

Androstendion administered subcutaneously to rats on day 5 of pregnancy results in pre-implantation mortality (e.g., reduction in number of implants per female; total number of implants per corpora lutea); TDLo: 20 mg/kg (5D preg) [Journal of Endocrinology. (Biochemical Soc. Book Depot, POB 32, Commerce Way, Colchester, Essex CO2 8HP, UK) V.1- 1939- v. 18, p. 271, 1959 (JOENAK)]

Subcutaneous application of androstendion to rats on day 8 of pregnancy results in post-implantation mortality (e.g., dead and/or resorbed implants per total number of implants); TDLo: 20 mg/kg (8D preg) [Journal of Endocrinology. (Biochemical Soc. Book Depot, POB 32, Commerce Way, Colchester, Essex CO2 8HP, UK) V.1- 1939- v. 18, p. 271, 1959 (JOENAK)]

Androstendion is an endogenous intermediate in steroid hormone synthesis and as such an endogenous precursor of testosterone and estrone, which can be metabolized to estradiol. Exposure during pregnancy may lead to signs of masculinization in the sex organs of a female child. If taken by nursing women androstendion may reach into the mother's milk and thus impair the development of the infant.

For an assessment of steroid hormones see also the argumentation for steroid hormones related to the Technical Rule for Hazardous Substances 905, which was elaborated by the German Committee on Hazardous Substances (AGS) and published by the German Federal Ministry of Labour and Social Affairs (version of 2008/2005/1999, only available in German, http://www.baua.de/de/Themen-von-A-Z/Gefahrstoffe/TRGS/ Begruendungen-905-906.html). In this argumentation 73 steroid hormones or precursors of steroid hormones were each allocated to one of seven hormone classes based on their predominant pharmacological activity (i.e. androgenic, mild androgenic, anabolic, estrogenic, gestagenic, mild gestagenic or glucocorticoide), and recommendations for their classification were elaborated. Androstendion was allocated to group 1 (androgenic steroids) resulting in a classification with Repr. Cat. 1 according to criteria of Directive 67/458/EEC.

This classification is also taken for androstadiendion. Therefore, the developmetal toxicity data waiver of androstadiendion is based on the classification of the read-across substance androstendion.

Justification for classification or non-classification

In analogy to the read-across substance androstendion the following self classification for androstadiendion is recommended according to Regulation (EC) No.1272/2008 (CLP) :

Repr. 1A (H360FD: May damage fertility or the unborn child) - Additional category for effects on or via lactation (H362: May cause harm to breast-fed children).

The classification is in accordance with German legislation for classification of androgenic steroids. The German Committee on Hazardous Substances (AGS) recommended for androgenic steroids classification as Repr. Cat. 1 for effects on fertility and Repr. Cat. 2 for developmental toxicity each according to criteria of Directive 67/458/EEC (see argumentation for the assessment of steroid hormones, Technical Rule for Hazardous Substances 905; elaborated by the German Committee on Hazardous Substances (AGS) and published by the German Federal Ministry of Labour and Social Affairs, version of 2008/2005/1999, only available in German, http://www.baua.de/de/Themen-von-A-Z/Gefahrstoffe/TRGS/Begruendungen- 905-906.html).