Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

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 is no explicit fertility study with androstendione available. However, data on reproductive toxicity/fertility are cited in RTECS database (April 2013):

The subcutaneous administrations of androstendione 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 androstendione 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 androstendione 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)]

Androstendione 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 androstendione 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.

Short description of key information:
No explicit fertility study with androstendione available.

Data on reproductive toxicity/fertility are cited in RTECS database (April 2013):

Subcutaneous, 25 days (rat, male): TDLo: 10500 µg/kg (25D pre)
[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)]

Subcutaneous, 14 days (rat, female): 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)]

Implantat, 16 days (rat, female): 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)]

Effects on developmental toxicity

Description of key information
No explicit study on developmental toxicity with androstendione available. 
Data on developmental toxicity are cited in RTECS database (April 2013): see text in discussion
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 is no explicit developmental toxicity study with androstendione available. However, data on developmental toxicity are cited in RTECS database (April 2013):

The daily subcutaneous administration of androstendione 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 androstendione 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)]

Androstendione 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 androstendione 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 androstendione 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 androstendione 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)]

Androstendione 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 androstendione 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)]

Androstendione 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 androstendione 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.

Justification for classification or non-classification

For reproductive toxicity classification warranted as Repr. Cat. 1, R60/61 (May impair fertility/May cause harm to the unborn child) according to Directive 67/548/EEC or as Repr. 1A (H360F/D: May damage fertility or the unborn child) according to Regulation (EC) 1272/2008. Additionally classification is warranted for effects on or via lactation (R64 according to Directive 67/548/EEC or H362 according to Regulation (EC) 1272/2008 (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).