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EC number: 200-164-5 | CAS number: 53-16-7
Carcinogenicity
Administrative data
Description of key information
A registration of estrone was already submitted earlier and is public available on the ECHA website. Chapter 7, which is still valid from today's perspective, was amended to fulfill the current information requirements. Consequently the migrated data (IUCLID 5 to IUCLID 6) was kept unchanged and only modified if there was a need for further information and/or to pass the technical completeness check (TCC).
Estrone is an endogenous sex hormone and an approved drug since several decades. The active ingredient, synthetic estrone, is similar both chemically and biologically to endogenously produced human estrone. Estrone belongs to the category “steroidal estrogens” and is one of the pharmacologically less-active metabolites of 17β-estradiol which is the most potent of the naturally occurring estrogens (17ß-estradiol, estrone, estriol). The toxic effects of steroidal estrogens like estradiol <-> estrone are an exaggeration of the normal pharmacological effects and result in an increase of female characteristics. Animal experiments with estrogens are of only limited predictive value for qualitative and even more so for quantitative extrapolation to humans because of the large diversity in factors responsible for endocrine regulation betwee animals and man. Estradiol and estrone are widely used for oral contraception and in post-menopausal hormonal therapy. Therefore a wide base of clinical experience is available pointing out various types of adverse effects.
Several evaluations* of carcinogenicity are public available which provide a good overview of the scientific opinion on steroidal estrogens in general and in particular for ß-estradiol <-> estrone.
*
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Oestradiol-17-B. [6]. 1974.
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Oestradiol-17-B, oestradiol 3-benzoate, oestradiol dipropionate, oestradiol-17B-valerate and polyoestradiol phosphate. [21]. 1979. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Overall Evaluations of Carcinogenicity: An Updating of IARC MonographsVolumes 1 to 42. [Supplement 7]. 1987.
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Hormonal Contraception and Post-Menopausal Hormonal Therapy. [72]. 1999.
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: 19.04.2016, only available in German,URLhttp://www.baua.de/de/Themen-von-A-Z/Gefahrstoffe/TRGS/Begruendungen- 905-906.html.
The associated documentation and justification for grouping steroid hormones and their classification was published in 09/1999. Estrone is mentioned in attachment 2 on page 16.
Health Council of the Netherlands, 2013; publication no. 2013/23
Key value for chemical safety assessment
Mode of Action Analysis / Human Relevance Framework
Estradiol-17ßis the most active naturally occuring estrogenic hormone. Estradiol and its metabolite estrone are essential for the growth and normal maintenance of the lining of the uterus, for the development of the accessory and secondary female sex characteristics, and for pregnancy. The toxic effects of steroidal estrogens like estradiol <-> estrone are an exaggeration of the normal pharmacological effects and result in an increase of female characteristics. Estradiol and estrone are widely used for oral contraception and in post-menopausal hormonal therapy. Therefore a wide base of case reports is available pointing out various types of adverse effects.
Justification for classification or non-classification
The following self classification for estrone is recommended according to Regulation (EC) No.1272/2008 (CLP) :
Carc. 2 (H351)
The classification is in accordance with German legislation for classification of estrogenic steroid hormones. The German Committee on Hazardous Substances (AGS) recommended for estrogenic steroid hormones classification as:
Toxicity to reproduction - Fertility: Category 1A
Toxicity to reproduction - Development: Category 2
Carcinogenicity: Category 2
See 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: 19.04.2016, only available in German,URLhttp://www.baua.de/de/Themen-von-A-Z/Gefahrstoffe/TRGS/Begruendungen- 905-906.html.
The associated documentation and justification for grouping steroid hormones and their classification was published in 09/1999. Estrone is mentioned in attachment 2 on page 16.
Additional information
A registration of estrone was already submitted earlier and is public available on the ECHA website. Chapter 7, which is still valid from today's perspective, was amended to fulfill the current information requirements. Consequently the migrated data (IUCLID 5 to IUCLID 6) was kept unchanged and only modified if there was a need for further information and/or to pass the technical completeness check (TCC).
No internal carcinogenicity studies of estrone (ZK 5019) are available. Some studies have been cited in RTECS database (Aug 2011):
Guinea pigs treated with estrone via implantat developed tumors in uterus (equivocal tumorigenic agent by RTECS criteria); TDLo: 640 ug/kg [Boletin de la Sociedad de Biologia de Santiago de Chile. (Santiago, Chile) V.1-12, 1943-55. Discontinued. v. 8, p. 142, 1951 (BSBSAS)]
In rats treated with estrone applied via implantat developed tumors not further specified (equivocal tumorigenic agent by RTECS criteria); TDLo: 16 mg/kg [Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 13, p. 147, 1953 (CNREA8)]
In hamsters treated with estone via implant over 38 weeks kidney tumors could be observed (equivocal tumorigenic agent by RTECS criteria); TD :640 mg/kg/38W-I [Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 43, p. 5200, 1983 (CNREA8)]
After parenteral application of estrone daily for 1 week mice developed tumors not further specified (equivocal tumorigenic agent by RTECS criteria); TDLo: 1200 ug/kg/1W-I [Comptes Rendus Hebdomadaires des Seances, Academie des Sciences. (Paris, France) V.1-261, 1835-1965. For publisher information, see CRASEV. v. 195, p. 630, 1932 (COREAF)]
After subcutaneous application of estrone to guinea pigs for 18 weeks uterine tumors could be observed (equivocal tumorigenic agent by RTECS criteria); TDLo: 40 mg/kg/18W-I [Comptes Rendus des Seances de la Societe de Biologie et de Ses Filiales. (SPPIF, B.P.22, F-41353 Vineuil, France) V.1- 1849- v. 130, p. 9, 1939 (CRSBAW)]
Estrone was applied subcutaneously over 24 weeks to mice developing tumors not further specified and not seen sponanously (equivocal tumorigenic agent by RTECS criteria); TD :48 mg/kg/24W-I [Journal of the National Cancer Institute. (Washington, DC) V.1-60, 1940-78. For publisher information, see JJIND8. v. 1, p. 119, 1940 (JNCIAM)]
Estron was applied to hamsters continously as implantat for 59 weeks. Tumors of the kidneys could be observed (equivocal tumorigenic agent by RTECS criteria); TDLo: 320 mg/kg/59W-C [National Cancer Institute, Monograph. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) No.1- 1959- v. 1, p. 1, 1959 (NCIMAV)]
Rats treated with estrone via implantat developed tumors not further specified (equivocal tumorigenic agent by RTECS criteria); TD :80 mg/kg [Proceedings of the Canadian Cancer Research Conference. (Toronto, Ont., Canada) V.1-11, 1954-76. Discontinued. v. 6, p. 50, 1966 (PCCRA4)]
Estrone was applied via implantat to guinea pigs developing uterine tumors (equivocal tumorigenic agent by RTECS criteria); TD :2 mg/kg [Revista Brasileira de Biologia. Brazilian Review of Biology. (Academia Brasileira de Ciencias, Caixa Postal 229, ZC-00 Rio de Janeiro, Brazil) V.1 - 1941 - v. 5, p. 1, 1945 (RBBIAL)]
Guinea pigs treated with estrone via implantat developed tumors at site of application (equivocal tumorigenic agent by RTECS criteria); TD :1800 ug/kg [Revue Canadienne de Biologie. (Montreal, Quebec, Canada) V.1-40, 1942-81. v. 3, p. 108, 1944 (RCBIAS)]
Estrone was applied via implantat to mice developing lymphoma including Hodgkin's disease (equivocal tumorigenic agent by RTECS criteria); TDLo: 48 mg/kg [Yale Journal of Biology and Medicine. (333 Cedar St., New Haven, CT 06510) V.1- 1928- v. 17, p. 75, 1944 (YJBMAU)]
Mice treated subcutaneously over 90 weeks developed lymphoma including Hodgkin's disease (neoplastic by RTECS criteria); TDLo: 108 mg/kg/90W-I [Zeitschrift fuer Krebsforschung. (Berlin, Fed. Rep. Ger.) V.1-75, 1903-71. For publisher information, see JCROD7. v. 56, p. 482, 1949 (ZEKBAI)]
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