Estradiol

Endpoint summary

Description of key information

A registration of estradiol 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).

A study in Spraque-Dawley rats revealed transient decrease in body weight gain and water consumption at 20 and 300 mg/kg, but no liver toxicity (Research Report No. AG69). Application of Estradiol (1.28 mg/kg or 2.4 mg/kg every third day or 1.28 mg/kg once a week) to beagle dogs showed clinical, haematological, biochemical and histopathological effects but not indication of neoplastic or anaplastic processes (Research Report No. 3102). Only few real repeated dose studies were found for Estradiol in the literature, most reports focussed on carcinogenic effects. Nevertheless, effects on several organs, hematopoiesis, centrilobular hepatocellular hypertrophy, diffuse hyperplasia of the pituitary gland, feminization of the male mammary gland, mammary gland hyperplasia in females, cystic ovarian follicles, hypertrophy of the endometrium and endometrial glands in the uterus, degeneration of the seminiferous epithelium, and atrophy of the testes and accessory sex glands were reported. The toxic effects of Estradiol are an exaggeration of the normal pharmacological effects and result in an increase of female characteristics. Estradiol is 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.

Additional information

A registration of estradiol 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).

Animal Data

Test system	Substance	Application	Test concentration	End point/Effect	Literature
Spraque- Dawley rats, 3 male and 3 female	Estradiol	Intragastric application on 5 consecutive days.	20 and 300 mg/kg	Transient decrese in water consumption (males) and body weight gain (both sexes) was observed in both doses.   No liver toxicity	Research Report No. AG69, Schering AG, Ethinylestradiol, estradiol, megastrol acetate, drospirenone, chlormadinone acetate, dexamethasone, flutamide, tamoxifen citrate ¿ Systemic tolerance study with special regard to liver toxicity in juvenile Spraque-Dawley rats after daily per os (intragastric) administration over 5 days, dated 05 Nov. 1997.
Crl:CD Rat, male and Female	Ethinyl Estradiol (EE), Estradiol valerate (EV)	Oral	EE: 0.005 ¿ 0.09 mg/kg bw/d EV: 1.2 - 12 mg/kg bw/d for 80-105 weeks	Increased incidence of adenocarcionoma, nodular hyperplasia, cervix epithelial carcinoma, mammary gland cancer	Seibert, 1996. Endocrinically active Chemicals in the environment, UBA Texte, 88-93.
Crl:CD BR rat, female	Estradiol	Oral	0. 0.003, 0.17, 0.69, or 4.1 mg/kg bw/d for 90 d	The end-points were chosen to evaluate both short-term and reproductive toxicity and several mechanistic and biochemical parameters. Doses > 0.17 produced dose- dependent increases in body weight, food consumption, and feed efficiency. Evidence of ovarian malfunction (reduced corpora lutea and large antral folicles) was found.   At 0.69 and 4.1 mg/kg bw/d, minimal to mild non- regenerative anaemia, lymphopenia, decreased serum cholesterol (at the high dose only), and altered splenic lymphocyte subtypes were observed. Changes in the weights of several organs were noted. Centrilobular hepatocellular hypertrophy, diffuse hyperplasia of the pituitary gland, feminization of the male mammary gland, mammary gland hyperplasia in females, cystic ovarian follicles, hypertrophy of the endometrium and endometrial glands in the uterus, degeneration of the seminiferous epithelium, and atrophy of the testes and accessory sex glands.	Biegel et al., 1998b. Toxicol. Sci., 44, 143-154 as cited by Toxicological Evaluation of certain Veterinary Drug Residues in Food. WHO Food Additives Series: 43, prepared by the Fifty-second meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA), 2000.
Syrian hamsters, male, castrated	various steroidal and non-steroidal estrogens	Subcutan implantation	Release rate: 110 µg/d for 9 months	Good correlation among the hormonal parameters progesterone receptor induction and serum prolactin and relative estrogenic potency (estrogen receptor binding) in hamster kidney. All animals trested with estradiol developed renal tumours.	Li et al., 1995. Cancer Res., 55, 4347-4351 as cited by Toxicological Evaluation of certain Veterinary Drug Residues in Food. WHO Food Additives Series: 43, prepared by the Fifty-second meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA), 2000.
Syrian hamsters, male, castrated	Estradiol	Subcutaneous pellets	Release rate: Estradiol, 96 µg/d for 8 months	tumour incidence of 100%, completely abolished by concurrent treatment with ethinylestradiol	Li et al., 1998 Carcinogenesis, 19, 471-477 as cited by Toxicological Evaluation of certain Veterinary Drug Residues in Food. WHO Food Additives Series: 43, prepared by the Fifty-second meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA), 2000.
Syrian hamsters, male	Estradiol	subcutaneous implantation	25 mg,sacrified after 175 d	Renal tumours in 4/5 animals	Liehr et al., 1986 J. Steroid Biochem.,24, 353-356as cited by Toxicological Evaluation of certain Veterinary Drug Residues in Food. WHO Food Additives Series: 43, prepared by the Fifty-second meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA), 2000.
Syrian hamsters, male, castrated	Estradiol	subcutaneous implantation	released 100- 210 µg/d for 9 months	Renal tumour incidence: 75- 100%,	Li et al., 1983. Cancer Res., 43, 5200-5204356 as cited by Toxicological Evaluation of certain Veterinary Drug Residues in Food. WHO Food Additives Series: 43, prepared by the Fifty-second meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA), 2000.
B6C3F1mice, both sexes	Catechol estrogens	intraperitoneal injection	Treatment on days 12-15 after birth, monitored for 18 months	Estrone-3,4-quinone was significantly carcinogenic in the livers of male mice. It was also highly toxic, as most of the mice died from unknown causes shortly after treatment. Estrone was protective against liver tumour formation in this system, and few tumours were induced in female mice	Cavalieri et al., 1997. Proc. Natl Acad. Sci. USA, 94, 10937- 10942 as cited by Toxicological Evaluation of certain Veterinary Drug Residues in Food. WHO Food Additives Series: 43, prepared by the Fifty-second meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA), 2000.
C3H/HeJ mice, female	Estradiol	Oral	0.015, 0.15, or 0.75 mg/kg bw/d from week 6 to week 110.   Sacrified after 52 weeks	Preneoplastic and neoplastic findings in mice sacrificed after up to 104 weeks on the estrogenic diets.   High doses of estradiol increased the incidence of adenosis but did not affect the incidence of ovarian tubular adenomas. After 66- 91 weeks of treatment, high doses of estradiol also increased the incidence of mammary gland hyperplastic alveolar nodules	Highman et al., 1980. J. Environ. Pathol. Toxicol., 4, 81-95 as cited by Toxicological Evaluation of certain Veterinary Drug Residues in Food. WHO Food Additives Series: 43, prepared by the Fifty-second meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA), 2000.
C3H/HeJ mice, female	17ß-Estradiol	In drinking- water	0.5 mg/l for 1 y	17ß-Estradiol caused tumours	Welsch, 1976. J. Toxicol. Environ. Health, Suppl. 1, 161- 175as cited by Toxicological Evaluation of certain Veterinary Drug Residues in Food. WHO Food Additives Series: 43, prepared by the Fifty-second meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA), 2000.
Mouse	Estradiol			Adverse affect on hematopoiesis, resulting in marrow hypocelluarity and depressed numbers of colony-forming units. Decreased erythropoiesis, although a compensatory splenic increase occurs several days following cessation of estrogen administration.	Thomas et al., 1985. Toxicology. New York,: Raven Press, Ltd., p. 72 as cited by the Hazardous Substances Data Bank (HSDB), Estradiol on November 23, 2009.
C3H HeJ (MTV + ) mice	17ß-Estradiol	Diet	0, 100, 1000 and 5000 µg/kg  for 24 months starting at 6 weeks of age	Mammary adenocarcinomas after 52 weeks and other malignant tumors in high doses	Highman et al., 1977. J. Environ. Pathol. Toxicol., 1, 1-30 as cited by IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Geneva: World Health Organization, International Agency for Research on Cancer, 1972- PRESENT. (Multivolume work), V21 (1979).
Strong A Mice, male	estradiol 3- benzoate	Subcutaneous injection	16.6 or 50 µg for at least 6 months	Interstitial-cell tumors of the testis occurred	Hooker & Pfeiffer,1942. Cancer Res. 2, 759-769 as cited by IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Geneva: World Health Organization, International Agency for Research on Cancer, 1972- PRESENT. (Multivolume work), V21 (1979).
Marsh Buffalo mice, female	17ß-Estradiol	Subcutaneous or Intramuscul ar injection	80 pg for twice weekly for 6 months	Lymphosarcomas occurred earlier (between 3 and 10 months) and in a higher incidence (28% in intact, 47% in ovariectomized) than in controls.	Bischoff et al, 1942. Cancer Res. 2, 52- 55769 as cited by IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man.: World Health Organization, International Agency for Research on Cancer, 1972- PRESENT. (Multivolume work), V21 (1979).
C3H x RIII F1 mice (MTV+), male	17ß-Estradiol	subcutaneous implantation	0.5-1 mg	Mammary cancer.	Rudali er al., 1971. Rev. Eur. Etud. Clin. Biol., 16, 425-429 as cited by IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Geneva: World Health Organization, International Agency for Research on Cancer, 1972- PRESENT. (Multivolume work), V21 (1979).
(C3H x RIII) Fl mice, male	17ß-Estradiol	subcutaneous implantation	0, 1, 2.5, 5, 10 or 100 ug	Mammary tumors	Rudali er al., 1971. Biomedicine, 29, 45- 46 as cited by IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Geneva: World Health Organization, International Agency for Research on Cancer, 1972- PRESENT. (Multivolume work), V21 (1979).
C3H/MS mice, neonatally	17ß-Estradiol			Increased mammary tumorigenesis, hyperplastic nodules or metaplastic lesions have also been found in various accessory sex organs, including prostatic lobes.	Mori, 1967. Annot. Zool. Jpn., 41, 43-52 as cited by IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Geneva: World Health Organization, International Agency for Research on Cancer, 1972- PRESENT. (Multivolume work), V21 (1979).
guinea-pigs, female, ovaritectomized	Etradiol 3- benzoate	Subcutaneous injection	20-80 µg	Multiple tumors, described as fibromas or fibromyomas, arose in the uterus and mesentery at several locations.	Lipschütz & Iglesias, 1938. C.R. Soc.Biol. 129, 519-524 as cited by IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Geneva: World Health Organization, International Agency for Research on Cancer, 1972- PRESENT. (Multivolume work), V21 (1979).
Beagle dog, 24 female	Estradiol valerate or 17ß Estradiol	Intramuscular application	1.28 or 2.4 mg/kg every third day and 1.28 mg/kg once weekly for a period of 52 or 66 weeks	Morphological changes do not indicate neoplastic or anaplastic processes. Benign proliverative lesions of the mesothelial lining of genital organs together with other changes known to be related to Estrogen effects (clinical, haematological, biochemical and histopathological indices).	Research Report No. 3102, Schering AG, Systemic tolerance study of ZK Nr. 5018 and ZK Nr. 5104 in beagle dogs by repeated intramuscular application over a period of 65 weeks, with special regards to ovarian carcinoma, dated 03March 1978.
Macaca mulatta, female	17ß-Estradiol	subcutaneous implantation	Total doses of 575-825 mg at intervals of 5-6 weeks	Cystic hyperplasia of the mammary gland but no tumors was found.	Engle et al., 1943. Cancer Res., 3, 858- 866429 as cited by IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man.: World Health Organization, International Agency for Research on Cancer, 1972- PRESENT. (Multivolume work), V21 (1979).

Human data

End point/Effect	Literature
The most frequent adverse dermatologic reaction associated with estrogen therapy is chloasma or melasma. Other dermatologic reactions include erythema multiform, erythema nodosum, and hemorrhagic eruption. Hirsutism and alopecia have also occurred. Porphyria cutanea has reportedly been adversely affected in some women receiving estrogen therapy.	McEvoy, G.K. (ed.).Formulary Service - Drug Information 1999.,: American Society of Health-System Pharmacists, Inc. 1999 (Plus Supplements)., p. 2689 as cited by the Hazardous Substances Data Bank (HSDB), Estradiol on November 23, 2009.
Oral contraceptive use is associated with an increased risk of thromboembolic and thrombotic disorders including thrombophlebitis, pulmonary embolism, stroke, subarachnoid hemorrhage, and myocardial infarction. Retinal thrombosis and mesenteric thrombosis also have been reported in women receiving oral contraceptives. An increased risk of postsurgery thromboembolic complications has also been reported in patients receiving oral contraceptives.	McEvoy, G.K. (ed.).Formulary Service - Drug Information 1999.,: American Society of Health-System Pharmacists, Inc. 1999 (Plus Supplements)., p. 2689 as cited by the Hazardous Substances Data Bank (HSDB), Estradiol on November 23, 2009.
Estrogens may cause some degree of fluid retention and edema. Estrogen therapy should therefore be used with caution in patients with conditions that might be aggravated by fluid retention.	McEvoy, G.K. (ed.).Formulary Service - Drug Information 1999.,: American Society of Health-System Pharmacists, Inc. 1999 (Plus Supplements)., p. 2690 as cited by the Hazardous Substances Data Bank (HSDB), Estradiol on November 23, 2009.
Decreased glucose tolerance has occurred in women receiving estrogen-containing oral contraceptives and may occur in patients receiving large dosages of estrogens.	McEvoy, G.K. (ed.).Formulary Service - Drug Information 1999.,: American Society of Health-System Pharmacists, Inc. 1999 (Plus Supplements)., p. 2690 as cited by the Hazardous Substances Data Bank (HSDB), Estradiol on November 23, 2009.
Breakthrough bleeding, spotting, changes in menstrual flow, missed menses (during use), or amenorrhea (after use) may occur in women receiving estrogen therapy. Dysmenorrhea and a premenstrual-like syndrome also have been reported.	McEvoy, G.K. (ed.).Formulary Service - Drug Information 1999.,: American Society of Health-System Pharmacists, Inc. 1999 (Plus Supplements)., p. 2690 as cited by the Hazardous Substances Data Bank (HSDB), Estradiol on November 23, 2009.
Changes in cervical erosion and secretions may occur during estrogen therapy. In addition, preexisting uterine leiomyoma may increase in size in women receiving estrogens. A cystitis-like syndrome has been reported but has not been definitely attributed to estrogens. An increased incidence of Candida vaginitis has been associated with estrogen therapy.	McEvoy, G.K. (ed.).Formulary Service - Drug Information 1999.,: American Society of Health-System Pharmacists, Inc. 1999 (Plus Supplements)., p. 2690 as cited by the Hazardous Substances Data Bank (HSDB), Estradiol on November 23, 2009.
Headache, especially migraine headache, may occur during estrogen therapy.	McEvoy, G.K. (ed.).Formulary Service - Drug Information 1999.,: American Society of Health-System Pharmacists, Inc. 1999 (Plus Supplements)., p. 2690 as cited by the Hazardous Substances Data Bank (HSDB), Estradiol on November 23, 2009.
Breast changes, including tenderness, enlargement, and secretion, may occur during estrogen therapy. The incidence of breast pain may be increased in patients receiving estrogens in conjunction with progestins compared with those receiving estrogens alone; breast pain was reported in about 33% of women receiving conjugated estrogens concomitantly with medroxyprogesterone acetate compared to 12% of women receiving unopposed conjugated estrogen therapy.	McEvoy, G.K. (ed.).Formulary Service - Drug Information 1999.,: American Society of Health-System Pharmacists, Inc. 1999 (Plus Supplements)., p. 2690 as cited by the Hazardous Substances Data Bank (HSDB), Estradiol on November 23, 2009.
Use of estrogens, especially in large dosages, may be associated with an increased risk of several serious conditions including thromboembolism, stroke, myocardial infarction, liver tumor, gallbladder disease, visual disturbances, fetal abnormalities, malignancy, and hypertension. If a progestin is administered concomitantly with estrogen therapy, potential risks may include adverse effects on lipid metabolism, glucose tolerance, or possible enhancement of mitotic activity in breast epithelial tissue.	McEvoy, G.K. (ed.).Formulary Service - Drug Information 1999.,: American Society of Health-System Pharmacists, Inc. 1999 (Plus Supplements)., p. 2690 as cited by the Hazardous Substances Data Bank (HSDB), Estradiol on November 23, 2009.

Justification for classification or non-classification

Due to the outcome of reported repeated dose studies classification is not required according to Regulation (EC) 1272/2008 (CLP), Annex I.