3-methoxyoestra-1,3,5(10)-trien-17-one

Carcinogenicity

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

The following self classification for estrone methyl ether is recommended according to Regulation (EC) No.1272/2008 (CLP) :

 

Classified according to German legislation (TRGS-905) for estrogenic steroids as Carc. Cat. 2 (EEC criteria).

 

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: 02.05.2018, only available in German,URL:https://www.baua.de/DE/Angebote/Rechtstexte-und-Technische-Regeln/Regelwerk/TRGS/pdf/TRGS-905.pdf?__blob=publicationFile&v=7.

The associated documentation and justification for grouping steroid hormones and their classification was published in 09/1999. Estrone methyl ether is mentioned in attachment 2 on page 15.

Additional information

Although no genotoxic potential was found for estrone-3-methylether in the bacterial screening test, it should be kept in mind that exogenous steroid hormones might stimulate the growth of hormone-dependent tissues and tumors.

Additionally, literature data demonstrated estrone having a clastogenic potential in a sister-chromatid exchange assay in CHO cells (Kochar, 1988), and in a MNT and Comet assay in human breast cells (Yared, 2002). The potential to induce gene mutations by estrone was, however, found to be negative in an HPRT-like assay in V79 cells (Drevon, 1981).

 

The biological effects of estrone (E1) and its structurally similar metabolite, 2-OH-E1, on estrogen receptor-positive breast cancer cells (MCF-7) were assessed via detection of gene and protein levels of estrogen pathway proteins to compare their estrogen effects. Protein expression levels during the cell cycle, inflammation, mammalian target of rapamycin (mTOR) and protein kinase B (Akt) pathways were examined to compare the physiological effects of the two estrogens. In this study, the authors found that estrone could promote the proliferation of MCF-7 cells at concentrations ranging from 1E-12 mol/L to 1E-06 mol/L. The test item significantly increased ROS levels in cells at a concentration of 1E-08 mol/L compared to the control group and as the concentration increased, the promotion effect was more significant. Biomarkers for oxidative stress and inflammation were up-regulated (Xu et al., 2021).

 

Various concentrations of estrone (1E−04 to 1E−12 M) were applied alone or together with fluoruracil to murine MC38 colon cancer in vitro. Estrone inhibited the MC38 cancer growth and that estrone increased also the cytotoxic effect of FU, what confirms the role of female sex steroids in modulation of colon cancer growth (Motylewska E, Melen-Mucha G, 2009).

 

In clinical studies, serum concentrations of unconjugated estradiol, conjugated and unconjugated estrone, and many estrogen metabolites were statistically significantly associated with an increased risk of postmenopausal breast cancer (Fuhrman, 2012). As well the role of estrogen as a mitogen that stimulates breast cell proliferation through activation of the estrogen receptor as its role as a precursor to a potent mutagen are assumed to be mechanisms that contribute to estrogen-mediated carcinogenesis.

No animal studies with estrone-3-methylether were conducted to assess the carcinogenicity potential but the substance as well as estrone is mentioned to be carcinogenic (Cat 2) and reprotoxic (Cat 1) in RTECs.

Regarding TRGS 905 (version 12.03.2020 and the justification for Steroid Hormones, version Sept 1999) both estrone and estrone-3-methylether are listed and classified as member of Group 6/ Estrogens with carcinogenicity Cat 2 (acc. to Regulation (EC) no. 1272/2008 and being reprotoxic (Fertility: Category 1A, Development: Category 2).

 

Several carcinogenicity studies of estrone have been cited in RTECS database (Aug 2011), which further support the classification as carcinogenicity Category 2

 

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)]

 

 

Therefore, a hazard for carcinogenicity cannot be excluded for estrone-3-methylether.

 

 

References:

Drevon C. et al. 1981, Mutagenicity assays of estrogenic hormones in mammalian cells. Mutation Research, 89:83-90

 

Fuhrman B. et al, Estrogen Metabolism and Risk of Breast Cancer in Postmenopausal Women. J Natl Cancer Inst 2012;104:326–339

 

Kochhar T.S., Steroid hormones enhanced sister-chromatid exchange in cultured CHO cells. Experientia 44 (1988)

 

Motylewska E, Melen-Mucha G, 2009. Estrone and progesterone inhibit the growth of murine MC38 colon cancer line. Journal of Steroid Biochemistry and Molecular Biology, (JAN 2009) Vol. 113, No. 1-2, pp. 75-79. 

 

TRGS 905, URL:https://www.baua.de/DE/Angebote/Rechtstexte-und-Technische-Regeln/Regelwerk/TRGS/pdf/TRGS-905.pdf?__blob=publicationFile&v=7.

The associated documentation and justification for grouping steroid hormones and their classification was published in 09/1999. Estrone methyl ether is mentioned in attachment 2 on page 15.

 

Xu S et al., Opposite estrogen effects of estrone and 2-hydroxyestrone on MCF-7 sensitivity to the cytotoxic action of cell growth, oxidative stress and inflammation activity. Ecotoxicology and environmental safety, (2021 Feb) Vol. 209, pp. 111754. 

 

Yared E et al. Genotoxic effects of oestrogens in breast cells detected by the micronucleus assay and the comet assay. Mutagenesis, 17 (4), 345-352