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

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

There is no internal fertility study available with the target substance estrone methyl ether or the source substance estrone. However results of fertility studies with estrone are cited in RTECS database (Aug 2011):

Subcutaneous, 1 day (rabbit, female): TDLo: 200 ug/kg (1D pre)
("Control of Ovulation, Proceedings of the Conference, Dedham, MA, 1960," Villee, C.A., ed., Oxford, UK, Pergamon Press Ltd., 1961 -,37,1961 (13OPAL))

Route unreported, 1 day (rat, female): TDLo: 500 ug/kg (1D pre)
(Agents Affecting Fertility, a Symposium, 1964," Austin, C.R., and J.S. Perry, eds., Boston, Little, Brown and Co., 1965 -,195,1965 (15QWAW)

Oral, 14 days (rat, male): TDLo: 560 ug/kg (14D male)
(Annals of the New York Academy of Sciences. (New York Academy of Sciences, 2 E. 63rd St., New York, NY 10021) V.1- 1877- v. 71, p. 500, 1958 (ANYAA9))

Oral, 14 days (rat, male): TDLo: 2240 ug/kg (14D male)
(Annals of the New York Academy of Sciences. (New York Academy of Sciences, 2 E. 63rd St., New York, NY 10021) V.1- 1877- v. 71, p. 500, 1958 (ANYAA9))

Subcutaneous, 3 days (mouse, female): TDLo: 8 ug/kg (3D pre)
(Arzneimittel-Forschung. Drug Research. (Editio Cantor Verlag, Postfach 1255, W-7960 Aulendorf, Fed. Rep. Ger.) V.1- 1951- v. 36, p. 1069, 1986 (ARZNAD))

Intrauterin, 1 day (rat, female): TDLo: 120 ng/kg (1D pre)
(Biology of Reproduction. (Soc. for the Study of Reproduction, 309 W. Clark St., Champaign, IL 61820) V.1- 1969- v. 31, p. 705, 1984 (BIREBV).

Implantat, 60 days (human, male): TDLo: 1586 ug/kg (60D male)
(Contraception. (Geron-X, Inc., POB 1108, Los Altos, CA 94022) V.1- 1970- v. 25, p. 591, 1982 (CCPTAY))

Subcutaneous, 60 days (rat, male): TDLo: 500 ug/kg (60D male)
(Endokrinologie. (Leipzig, Ger. Dem. Rep.) V.1-80, 1928-82. For publisher information, see EXCEDS. v. 49, p. 55, 1965 (ENDKAC))

Implantat, 58 weeks (hamster, male): TDLo: 160 mg/kg (58W male)
(Endocrinology (Baltimore). (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21203) V.1- 1917- v. 57, p. 255, 1955 (ENDOAO))

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 internal fertility study available with the target substance estrone methyl ether (ZK 5512) or the source substance estrone (ZK 5019) . However results of fertility studies are cited in RTECS database (Aug 2011):

 Female rats were treated subcutaneously with estrone 1 day prior to mating. Effects on fertility: not further specified; TDLo: 200 ug/kg (1D pre) ["Control of Ovulation, Proceedings of the Conference, Dedham, MA, 1960," Villee, C.A., ed., Oxford, UK, Pergamon Press Ltd., 1961 -,37,1961 (13OPAL)]

 Female rats were treated with estrone 1 day prior to mating. The application route and effects on fertility were not further specified; TDLo: 500 ug/kg (1D pre) [Agents Affecting Fertility, a Symposium, 1964," Austin, C.R., and J.S. Perry, eds., Boston, Little, Brown and Co., 1965 -,195,1965 (15QWAW]

 The oral application of estrone to male rats over 14 days prior to mating results in paternal effects on prostate, seminal vessicle, Cowper's gland and accessory glands; TDLo: 560 ug/kg (14D male) [Annals of the New York Academy of Sciences. (New York Academy of Sciences, 2 E. 63rd St., New York, NY 10021) V.1- 1877- v. 71, p. 500, 1958 (ANYAA9)]

 The oral application of estrone to male rats 14 days prior to mating results in paternal effects on testes, epididymis and sperm duct; TDLo: 2240 ug/kg (14D male) [Annals of the New York Academy of Sciences. (New York Academy of Sciences, 2 E. 63rd St., New York, NY 10021) V.1- 1877- v. 71, p. 500, 1958 (ANYAA9)]

 Female rats were treated subcutaneously 3 days prior to mating. Maternal effects were reported on uterus, cervix and vagina; TDLo: 8 ug/kg (3D pre) [Arzneimittel-Forschung. Drug Research. (Editio Cantor Verlag, Postfach 1255, W-7960 Aulendorf, Fed. Rep. Ger.) V.1- 1951- v. 36, p. 1069, 1986 (ARZNAD)]

 The intrauterin application of estrone to female rats 1 day prior to mating results in maternal effects on uterus, cervix and vagina; TDLo: 120 ng/kg (1D pre) [Biology of Reproduction. (Soc. for the Study of Reproduction, 309 W. Clark St., Champaign, IL 61820) V.1- 1969- v. 31, p. 705, 1984 (BIREBV]

Men were treated with estrone via implantat over 60 days prior to mating. This results in paternal effects on spermatogenesis (including genetic material, sperm morphology, motility, and count) and impotence; TDLo: 1586 ug/kg (60D male) [Contraception. (Geron-X, Inc., POB 1108, Los Altos, CA 94022) V.1- 1970- v. 25, p. 591, 1982 (CCPTAY)]

 Male rats were treated subcutaneously over 60 days prior to mating. Paternal effects on testes, epididymis, sperm duct, prostate, seminal vessicle, Cowper's gland and accessory glands were reported; TDLo: 500 ug/kg (60D male) [Endokrinologie. (Leipzig, Ger. Dem. Rep.) V.1-80, 1928-82. For publisher information, see EXCEDS. v. 49, p. 55, 1965 (ENDKAC)]

 The application of estrone via implantat to male hamsters over 58 weeks results in paternal effects on testes, epididymis and sperm duct; TDLo: 160 mg/kg (58W male) [Endocrinology (Baltimore). (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21203) V.1- 1917- v. 57, p. 255, 1955 (ENDOAO)]

Female mice were treated once with estrone on the day prior to mating. The route of application and the effects on fertility were not further specified; TDLo: 40 mg/kg (1D pre) [Fertility and Sterility. (American Fertility Soc., 608 13th Ave. S, Birmingham, AL 35282) V.1- 1950- v. 12, p. 346, 1961 (FESTAS)]

The subcutaneous application of estrone to female mice 3 days prior to mating results in maternal effects on uterus, cervix and vagina; TDLo: 2520 ng/kg (3D pre) [Fertility and Sterility. (American Fertility Soc., 608 13th Ave. S, Birmingham, AL 35282) V.1- 1950- v. 20, p. 211, 1969 (FESTAS)]

 The oral application of estrone to female rats once on the day prior to mating results in maternal effects of uterus, cervix and vagina;

TDLo: 100 ug/kg (1D pre] [Indian Journal of Experimental Biology (publications and Information Directorate, CSIR, Hillside Rd, New Delhi 110 012, India) V.1 -1963- v. 15, p. 1144, 1977 (IJEBA6)]

 Female monkeys were treated daily orally with estrone over 5 days prior to mating. Maternal effects on uterus, cervix and vagina;

TDLo: 6250 ug/kg (5D pre) [Indian Journal of Experimental Biology (publications and Information Directorate, CSIR, Hillside Rd, New Delhi 110 012, India) V.1 -1963- v. 15, p. 1144, 1977 (IJEBA6)]

The daily subcutaneous application to female rats over 3 days prior to mating results in maternal effects on uterus, vagina and cervix; TDLo: 1500 ng/kg (3D pre) [International Journal of Fertility. (Allen Press, 1041 New Hampshire, St., Lawrence, KS 66044) V.1- 1955- v. 24, p. 188, 1979 (INJFA3)]

 Female rats were treated once orally 1 day prior to mating resulting in maternal effects on uterus, cervix and vagina; TDLo: 4945 ng/kg (1D pre) [Journal of Medicinal Chemistry. (American Chemical Soc., Distribution Office Dept. 223, POB POB 57136, West End Stn., Washington, DC 20037) V.6- 1963- v. 23, p. 329, 1980 (JMCMAR)]

 A single intravaginal application of estrone to female mice one day prior to mating results in maternal effects on uterus, cervix and vagina; TDLo: 48 ng/kg (1D pre) [Journal of Endocrinology. (Biochemical Soc. Book Depot, POB 32, Commerce Way, Colchester, Essex CO2 8HP, UK) V.1- 1939- v. 20, p. 198, 1960 (JOENAK)]

Female hamsters were treated once parenterally prior to mating. The resulting effects on fertility were not further specified; TDLo: 2 mg/kg (1D pre) [Journal of Reproduction and Fertility. (Biochemical Soc. Book Depot, POB 32, Commerce Way, Colchester, Essex CO2 8HP, UK) V.1- 1960- v. 35, p. 612, 1973 (JRPFA4)]

 Female mice were treated orally 3 days prior to mating. Maternal effects on uterus, cervix and vagina were reported: TDLo: 40 ug/kg (3D pre) [Journal of Reproduction and Fertility. (Biochemical Soc. Book Depot, POB 32, Commerce Way, Colchester, Essex CO2 8HP, UK) V.1- 1960- v. 5, p. 331, 1963 (JRPFA4)]

 Daily intravenous application of estrone to female rats 3 days prior to mating results in maternal effects on uterus, cervix and vagina; TDLo: 3 ug/kg (3D pre) [Jitchuken Zenrinsho Kenkyuho. Central Institute for Experimental Animals, Research Reports. (Jikken Dobutsu Chuo Kenkyusho, 1433 Nogawa, Takatsu-ku, Kawasaki 211, Japan) V.1- 1975- v. 5, p. 63, 1979 (JZKEDZ)]

Daily dermal application of estrone to male rats over 30 days until mating results in paternal effects on testes, epididymis, sperm duct prostate, seminal vessicle, Cowper's gland and accessory glands; TDLo: 12 mg/kg (30D male) [Steroids. (Holden-Day Inc., 4432 Telegraph Ave., Oakland, CA 94609) V.1- 1963- v. 10, p. 687, 1967 (STEDAM)]

 Female rats were treated once with estrone intraperitoneally prior to mating resulting in maternal effects on uterus, cervix and vagina; TDLo: 1250 ng/kg (1D pre) [Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 18, p. 348, 1971 (TXAPA9)]

 Single intraperitoneal application of estrone to female mammals (not further specified) prior to mating results in maternal effects on uterus, cervix and vagina; TDLo: 12500 ng/kg (1D pre) [Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 18, p. 348, 1971 (TXAPA9)]

 The daily intraperitoneal administration of estrone to rabbits on day 3-4 of pregnancy results in pre-implantation mortality (e.g., reduction in number of implants per female; total number of implants per corpora lutea); TDLo: 225 ug/kg (3-4D preg) [American Journal of Physiology. (American Physiological Soc., 9650 Rockville Pike, Bethesda, MD 20814) V.1- 1898- v. 115, p. 219, 1936 (AJPHAP)]

Daily administration (route unreported) of estrone to rabbits on day 1-3 of pregnancy results in pre-implantation mortality (e.g., reduction in number of implants per female; total number of implants per corpora lutea); TDLo: 3 ug/kg (1-3D preg) [Contraception. (Geron-X, Inc., POB 1108, Los Altos, CA 94022) V.1- 1970- v. 2, p. 85, 1970 (CCPTAY)]

 Estrone is administered subcutaneously to rats on day 2 of pregnancy. This results in pre-implantation mortality (e.g., reduction in number of implants per female; total number of implants per corpora lutea); TDLo: 50 ug/kg (2D preg) [Endocrinology (Baltimore). (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21203) V.1- 1917- v. 63, p. 566, 1958 (ENDOAO)]

 Rats were treated with estrone subcutaneously on day 3 of pregnancy leading to effects on fertility not further specified; TDLo: 10 ug/kg (3D preg) [Endocrinology (Baltimore). (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21203) V.1- 1917- v. 77, p. 873, 1965 (ENDOAO)]

 Intramuscular application of estrone to rabbits on day1-3 of pregnancy results in effects on fertility not further specified; TDLo: 5 ug/kg (1-3D preg) [Fertility and Sterility. (American Fertility Soc., 608 13th Ave. S, Birmingham, AL 35282) V.1- 1950- v. 10, p. 155, 1959 (FESTAS)]

 Rats were treated with estrone parenteral on day 2 of pregnancy. This results in effects on litter size (e.g., number of fetuses per litter, measured before birth) and other effects on fertility not further specified; TDLo: 25 ug/kg (2D preg) [Fertility and Sterility. (American Fertility Soc., 608 13th Ave. S, Birmingham, AL 35282) V.1- 1950- v. 12, p. 178, 1961 (FESTAS)]

 Oral application of estrone to rabbits on day 1-3 of pregnancy results in effects on fertility not further specified; TDLo: 300 ug/kg (1-3D preg) [Fertility and Sterility. (American Fertility Soc., 608 13th Ave. S, Birmingham, AL 35282) V.1- 1950- v. 16, p. 281, 1965 (FESTAS)]

Oral administration of estron to hamsters on pregnancy days 1-3 results in effects on female fertility index (e.g., number of females pregnant per number of sperm-positive females, number of females pregnant per number of females mated); TDLo: 24 mg/kg (1-3D preg) [Fertility and Sterility. (American Fertility Soc., 608 13th Ave. S, Birmingham, AL 35282) V.1- 1950- v. 16, p. 281, 1965 (FESTAS)]

In rabbits subcutaneously treated with estrone on pregnancy days 1-3 pre-implantation mortality (e.g., reduction in number of implants per female; total number of implants per corpora lutea) was observed; TDLo: 6 ug/kg (1-3D preg) [Fertility and Sterility. (American Fertility Soc., 608 13th Ave. S, Birmingham, AL 35282) V.1- 1950- v. 20, p. 211, 1969 (FESTAS)]

In rats subcutaneously treated with estrone on day 2 of pregnancy effects on female fertility index (e.g., number of females pregnant per number of sperm-positive females, number of females pregnant per number of females mated) were reported; TDLo: 25 ug/kg (2D preg) [International Journal of Fertility. (Allen Press, 1041 New Hampshire, St., Lawrence, KS 66044) V.1- 1955- v. 14, p. 56, 1969 (INJFA3)]

 Subcutaneous application of estrone to rabbits on pregnancy day 15-25 results in post-implantation mortality (e.g., dead and/or resorbed implants per total number of implants); TDLo: 5500 ug/kg (15-25D preg) [Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 49, p. 146, 1933 (JPETAB)]

Effects on developmental toxicity

Description of key information

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.

There is no internal teratogenicity study available with the target substance estrone methyl ether (ZK 5512) or the source substance estrone (ZK 5019) . But data on estradiol can be also used for the toxicological characterization, because estrone is the major metabolite of estradiol. Thus, 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.

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

No studies on reproductive toxicity were conducted with estrone-3-methylether. However, according to national guidelines (TRGS 905 and the supporting justification text for steroid hormones; BAUA, version of Sept. 1999) both estrone and estrone-3-methylether are listed as estrogenic substances and classified as Estrogens Group 6 with reproduction toxicity R_F= 1A and R_D=2.

A harmonized classification according to CLP/GHS is not yet concluded for both substances but there is broad agreement between ECHA-registrants that both substances raise concerns for reproductive toxicity.

In addition, a study examining adverse effects of estrone on chick embryogenesis is available. Fertilized eggs of white Leghorns were obtained within 24 h after laying. Embryos were administered 10, 100 nM, and 1 µM estrone, and incubated for 48 h at 37 ± 0.5°C and >80% relative humidity with one rotation per hour. The embryos were excised, fixed in 70% ethanol and viewed under a stereomicroscope.
Their morphological abnormalities and numbers of somites were recorded. There were no significant difference in the average number of somites. Abnormal embryogenesis, however, showed dose-related increases caused by estrone.

The incidence of malformations was significantly higher in the estrone than their control groups. We observed malformed embryonic head, spoonshaped dysplasia, and disclosure of the neural tube. Malformations were observed in 58.33%, 63.66%, 50.00% of embryos administered 10 nM, 0.1 µM, and 1 µM estrone, respectively. In contrast, no malformations were observed in the control group, embryos administered dilutions of DMSO (Saito K et al., 2012. Bisphenol A and Estrone-Induced Developmental Effects in Early Chick Embryos. Environmental toxicology, (2012 Jan) Vol. 27, No. 1, pp. 58-62.).

 

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

 

There is no internal teratogenicity study with estrone (ZK 5019) available. However, results of different teratogenicity studies are cited in RTECS database (Aug 2011):

The intramuscular application of estrone to rabbits on day 9 of pregnancy results in occurence of extra embryonic structures (e.g., placenta, umbilical cord) and further effects on embryo not specified; TDLo: 13 iu/kg (9D preg) [American Journal of Obstetrics and Gynecology. (C.V. Mosby Co., 11830 Westline Industrial Dr., St. Louis, MO 63146) V.1- 1920- v. 111, p. 1083, 1971 (AJOGAH)]

 Rats were treated subcutaneously with estrone on day 9 of pregnancy, resulting in behavioral effects in newborns; TDLo: 50 ug/kg (9D preg) [Bulletin of Experimental Biology and Medicine (English Translation). Translation of BEBMAE. (Plenum Pub. Corp., 233 Spring St., New York, NY 10013) V.41- 1956- v. 74, p. 1255, 1972 (BEXBAN)]

In rabbits orally treated with estrone on days 6-8 of pregnancy pre-implantation mortality (e.g., reduction in number of implants per female; total number of implants per corpora lutea) and extra embryonic structures (e.g., placenta, umbilical cord) were reported; TDLo: 630 ug/kg (6-8D preg) [Fertility and Sterility. (American Fertility Soc., 608 13th Ave. S, Birmingham, AL 35282) V.1- 1950- v. 16, p. 281, 1965 (FESTAS)]

 Subcutaneous application of estrone to rats on day 2 of pregnancy results in fetal death; TDLo: 10 ug/kg (2D preg) [International Journal of Fertility. (Allen Press, 1041 New Hampshire, St., Lawrence, KS 66044) V.1- 1955- v. 14, p. 56, 1969 (INJFA3)]

Daily subcutaneous application of estrone to mice on pregnancy day 12-16 results in specific craniofacial developmental abnormalities (including nose and tongue) and abortion; TDLo: 28 mg/kg (12-16D preg) [Proceedings of the Society for Experimental Biology and Medicine. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1903/04- v. 97, p. 809, 1958 (PSEBAA)]

 In rats subcutaneously treated with estrone on pregancy day 11-20 fetotoxicity (except fetal death) and specific developmental abnormalities on endocrine system and urogenital system were observed; TDLo: 5 mg/kg (11-20D preg) [Toxicologist. (Soc. of Toxicology, Inc., 475 Wolf Ledge Parkway, Akron, OH 44311) V.1- 1981- v. 90, p. 82, 2006 (TOXID9)]

Mode of Action Analysis / Human Relevance Framework

There is no internal reproductive toxicity studies available with teh target substance estrone methyl ether or the source substance estrone. However, results of different studies are cited in RTECS database (Aug 2011) showing estrone derived effects on the fertility in several animal and one human study and limited effects in developmental toxicity in animal studies.

The possibility of reversible disturbances of fertility caused by impairment of the endogenous hormone production in both males and females has to be taken into consideration in case of repeated intake of high dosages of estrone. Following intake of estrone by pregnant women the risk of an embryolethal effect and the occurence of genital malformations is to be regarded as small. In case of an extremely high burden, however, the possibility of such effects does seem to exist in principle. Moreover, it can be assumed that intake of estrone by nursing mothers may lead the substance entering the mother's milk, thus possibly impairing the infant's development.

Justification for classification or non-classification

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

Repr. 1A (H360Fd)

Additionally estrone methyl ether is allocated to the hazard 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 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.