Estrone

Endpoint summary

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).

Estradiol-17ß is 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. The most frequent adverse dermatologic reaction associated with estrogen therapy is chloasma, melasma and erythema. An increased risk of thromboembolic and thrombotic disorders including thrombophlebitis, pulmonary embolism, stroke, subarachnoid hemorrhage, and myocardial infarction was reported for the use as oral contraceptive as well as breakthrough bleeding, spotting, changes in menstrual flow, missed menses (during use), or amenorrhea (after use). Dysmenorrhea and a premenstrual-like syndrome also occurred.

No repeated dose toxicity studies were conducted with estrone. But data on estradiol can be also used for the toxicological characterization, because estrone is the major metabolite of estradiol. Thus for repeated dose toxicity results of studies conducted with estradiol are taken as surrogate of estrone to fulfill formally the standard information requirement. Since the first introduction of drug preparations containing this steroidal estrogen dates back more than five decades, the major part of its preclinical characterization does not fulfil the requirements applicable today to studies used for safety assessment. However, these limitations are more than compensated for by the vast amount of clinical experience gained with estradiol <-> estrone in their continued and widespread therapeutic use. Therefore in conclusion the results of the preclinical characterisation of estradiol <-> estrone confirm its properties as a steroidal estrogen but they are not used for the safety assessment (systemic/local effects). The dose desriptor starting point is taken from human experience.

As known from an extensive data base animal experiments with estrogens are only of limited predictive value for qualitative and even more for quanatitative extrapolation tu humans because of a large diversity in factors responsible for endocrine regulation between experimental animals and man.

Therefore the most sensitive endpoint to consider is the lowest oral daily dose with pharmacological effects in humans (SSTmin) of estradiol which is used as surrogate for estrone.

Key value for chemical safety assessment

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Mode of Action Analysis / Human Relevance Framework

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 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. Estradiol and estrone are widely used for oral contraception and in post-menopausal hormonal therapy for many years. Therefore a wide base of clinical experience is available pointing out various types of adverse effects.

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).

The toxicity of estrogens in laboratory animals has been well characterized as described in the literature:

Dorfman RI. Pharmacology of Estrogens-General. In: Chaudhury RR ed. Pharmacology of Estrogens. New York: Pergamon Press. 1981: 49-61.

Heywood R, Wadsworth PF. The experimental toxicology of estrogens. In: Chaudhury RR ed. Pharmacology of Estrogens. New York: Pergamon Press. 1981:125-142.

Lehmann M, Putz B, Poggel HA, Gunzel P. Experimental toxicity studies with contraceptive steroids and their relevance for human risk estimation. In: Dayan AD, Paine AJ eds. Advances in Applied Toxicology. New York: Taylor & Francis Ltd. 1989

No internal repeated dose toxicity studies of estrone available.

Results of repeated dose toxicity studies are cited in RTECS database (Aug 2011): Oral, 90 days (rat): TDLo: 135 mg/kg/90D-I (Acta pharmacologica Sinica (Shanghai : Shanghai Institute of Materia Medica : Chinese Academy of Science : Carlton, VIC, Australia : Blackwell Publishing Asia, 2005) V.21- 2000- v. 24, p. 599, 2003 (ACPSI*)) Intravaginal, 8 weeks (rat): TDLo: 784 ug/kg/8W-I (Farmakologiya i Toksikologiya (Moscow). For English translation, see PHTXA6 and RPTOAN. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.2- 1939- v. 44, p. 117, 1981 (FATOAO)) Subcutaneous, 8 weeks (rat): TDLo: 784 ug/kg/8W-I (Farmakologiya i Toksikologiya (Moscow). For English translation, see PHTXA6 and RPTOAN. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.2- 1939- v. 44, p. 117, 1981 (FATOAO)) Subcutaneous, 8 weeks (rat): TDLo: 33.6 mg/kg/8W-I (Farmakologiya i Toksikologiya (Moscow). For English translation, see PHTXA6 and RPTOAN. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.2- 1939- v. 44, p. 117, 1981 (FATOAO)) Oral, 4 days, continous application (mouse): TDLo: 50 ug/kg/4D-C (Journal of Agricultural and Food Chemistry. (American Chemical Soc., Distribution Office Dept. 223, POB 57136, West End Stn., Washington, DC 20037) V.1- 1953- v. 10, p. 410, 1962 (JAFCAU)) Subcutaneous, 3 days (mouse): TDLo: 2.5 ug/kg/3D-I (Journal of Endocrinology. (Biochemical Soc. Book Depot, POB 32, Commerce Way, Colchester, Essex CO2 8HP, UK) V.1- 1939- v. 34, p. 215, 1966 (JOENAK)) Dermal, 3 weeks (rat): TDLo: 0.021 mg/kg/3W-I (Toksikologicheskii Vestnik. (18-20 Vadkovskii per. Moscow, 101479, Russia) History Unknown v. (6), p. 25, 1994 (TOVEFN)) Subcutaneous, 8 days (rat): TDLo: 40 ug/kg/8D-I (Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 90, p. 330, 1987 (TXAPA9)) Subcutaneous, 3 days (rat): TDLo: 6 mg/kg/3D-I (Toxicology. (Elsevier Scientific Pub. Ire... No internal repeated dose toxicity studies of estrone are available. Results of repeated dose toxicity studies are cited in RTECS database (Aug 2011): The daily oral application of estrone to rats over 90 days results in changes in uterine weight and musculoskeletal changes not further specified; TDLo: 135 mg/kg/90D-I [Acta pharmacologica Sinica (Shanghai : Shanghai Institute of Materia Medica : Chinese Academy of Science : Carlton, VIC, Australia : Blackwell Publishing Asia, 2005) V.21- 2000- v. 24, p. 599, 2003 (ACPSI*)] Intravaginal application of estrone to rats over 8 weeks results in changes in liver and effects on uterus, cervix and vagina; TDLo: 784 ug/kg/8W-I [Farmakologiya i Toksikologiya (Moscow). For English translation, see PHTXA6 and RPTOAN. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.2- 1939- v. 44, p. 117, 1981 (FATOAO)] Subcutaneous, application of estrone to rats over 8 weeks leads to maternal effects in uterus, cervix and vagina; TDLo: 784 ug/kg/8W-I [Farmakologiya i Toksikologiya (Moscow). For English translation, see PHTXA6 and RPTOAN. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.2- 1939- v. 44, p. 117, 1981 (FATOAO)] Subcutaneous administration to rats over the period of 8 weeks results in changes in adrenal weight; TDLo: 33.6 mg/kg/8W-I [Farmakologiya i Toksikologiya (Moscow). For English translation, see PHTXA6 and RPTOAN. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.2- 1939- v. 44, p. 117, 1981 (FATOAO)] Continous oral application of estrone for 4 days to mice results in estrogenic effects not further specified and changes in uterine weight; TDLo: 50 ug/kg/4D-C [Journal of Agricultural and Food Chemistry. (American Chemical Soc., Distribution Office Dept. 223, POB 57136, West End Stn., Washington, DC 20037) V.1- 1953- v. 10, p. 410, 1962 (JAFCAU)] Daily subcutaneous administration of estrone to mice over 3 days results in endocrine estronic effects and maternal effects in uterus, cervix and vagina and in changes in uterine weight; TDLo: 2.5 ug/kg/3D-I [Journal of Endocrinology. (Biochemical Soc. Book Depot, POB 32, Commerce Way, Colchester, Essex CO2 8HP, UK) V.1- 1939- v. 34, p. 215, 1966 (JOENAK)] Dermal application of estrone to rats daily over 3 weeks leads to effect on menstrual cycle; TDLo: 0.021 mg/kg/3W-I [Toksikologicheskii Vestnik. (18-20 Vadkovskii per. Moscow, 101479, Russia) History Unknown v. (6), p. 25, 1994 (TOVEFN)] Estrone is applied daily subcutaneously to rats over 8 days resulting in maternal effects in uterus, cervix and vagina; TDLo: 40 ug/kg/8D-I [Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 90, p. 330, 1987 (TXAPA9)] Subcutaneous application to rats over 3 days results in maternal effects in uterus, cervix and vagina; TDLo: 6 mg/kg/3D-I [Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 170, p. 21, 2002 (TXCYAC)] Oral application to rats over 10 days results in: - weight loss or decreased weight gain; TDLo: 2704 ug/kg/10D-I - not further specified effects on lipids including transport and plasma proteins not involving coagulation; TDLo: 270.4 µg/kg/10D-I - changes in serum composition (e.g. TP, bilirubin, cholesterol); TDLo: 27.04 µg/kg/10D-I [Steroids. (Holden-Day Inc. 4432 Telegraph Ave., Oakland, CA 94609) V.1- 1963- v. 70, p. 667, 2005 (STEDAM)]

Justification for classification or non-classification

According to CLP Annex I, 3.9.1.1, specific toxic effects covered by other hazard classes are not included in STOT-RE. STOT-RE should only be assigned where the observed toxicity is not covered more appropriately by another hazard class. For example specific effects like tumours or effects on the reproductive organs should be used for classification for carcinogenicity (see chapt. 7.7) or reproductive toxicity (see chapt. 7.8), respectively, but not for STOT-RE.

Therefore there is no classification required for SPECIFIC TARGET ORGAN TOXICITY – REPEATED EXPOSUREa according to Regulation (EC) No. 1272/2008 (CLP).