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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Description of key information

No studies are available for Estradiol and therefore, all data presented are based on the result of a literature search (references are stated in the tables). Estradiol and its esters were tested in mice, rats, hamsters and guinea-pigs by oral and subcutaneous administration. Administration to mice increased the incidences of several tumors including mammary, uterine or renal tumors. In rats, there was an increased incidence of mammary and/or pituitary tumours and an increased incidence of hepatocellular adenomas in males. In hamsters, a high incidence of malignant kidney tumours occurred in intact and castrated males and in ovariectomized females, but not in intact females. In guinea-pigs, diffuse fibromyomatous uterine and abdominal lesions were observed. A report of the IARC Working Group stated that a number of studies, utilizing a variety of designs, have shown a consistent, strongly positive association between exposure to a number of oestrogenic substances and risk of endometrial cancer in human, with evidence of positive dose-response relationships both for strength of medication and duration of use. Users of postmenopausal estrogen therapy had no excess risk for cancers at other sites. The evidence for the carcinogenicity of postmenopausal combined estrogen-progestogen therapy was deemed to be limited.

Key value for chemical safety assessment

Justification for classification or non-classification

The following self classification for estradiol 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. Estradiol is mentioned in attachment 2 on page 16.

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



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


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.


B6C3F1


mice, 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.


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.


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, 


Orchiectomized



Estradiol



Implants


every three


months



20 mg



Renal-cell dysplasia


and infiltrating and


non-infiltrating renal


carcinoma were


observed.



Goldfarb & Pugh,


1990. Cancer Res.,


50, 113¿119 as


cited by IARC


Monographs,


Volume 72,


Hormonal


Contraception and


Post-Menopausal


Hormonal Therapy,


1999.



Rat, male and

female


Combinations

of various

estrogens

and

progestogens


Diet



 


Increased incidence

of hepatocellular

 

Adenomas in males


Schuppler. &

Gunzel, 1979.

Arch. Toxicol.,

Suppl. 2, 181¿195

as cited by IARC

Monographs,

Volume 72,

Hormonal

Contraception and

Post-Menopausal

Hormonal Therapy,

1999.


Sprague-

Dawley rats,

female


mestranol +

norethynodrel


Diet



100 µg + 25 mg for


nine months (daily


intakes of 0.02¿


0.03 and 0.5¿0.75


mg/kg bw.)



A statistically


significant increase in


the number of altered


g-glutamyl


Transpeptidase-


positive hepatic foci


was observed



Yager & Yager,

1980. Cancer Res.,

40, 3680¿3685 as

cited by IARC

Monographs,

Volume 72,

Hormonal

Contraception and

Post-Menopausal

Hormonal Therapy,

1999.


Fischer 344

rats, female


Estradiol

dipropionate


Subcutaneous

injection


5 mg once every

two weeks for 13

weeks


Pituitary adenomas


and carcinomas were


observed.



Satoh et al., 1997


Toxicol. Pathol.,


25, 462¿469 as


cited by IARC


Monographs,


Volume 72,


Hormonal


Contraception and


Post-Menopausal


Hormonal Therapy,


1999.



ACI rats



Estradiol



Subcutaneous


implantation



27.5 mg (crystalline


estradiol)



rapid development of


palpable mammary


tumours (carcinomas,


100% of the animals),


which were first


observed 99 days


after treatment



Shull et al., 1997.


Carcinogenesis, 18,


1595¿1601 as cited


by IARC


Monographs,


Volume 72,


Hormonal


Contraception and


Post-Menopausal


Hormonal Therapy,


1999.



Guinea-pigs



Estradiol,


Estradiol 3-


benzoate



Subcutaneous


injection



20-80 µg


 


3 times a week



Multiple tumors,


described as fibromas


and fibromyomas



Lipschütz et al.,


1938. C.R. Soc.


Biol. 130, 9-11 as


cited by IARC


Monographs,


Volume 72,


Hormonal


Contraception and


Post-Menopausal


Hormonal Therapy,


1999.



Nonhuman



17ß-


Estradiol



 



 



In vivo


carcinogenicity


studies


 


Positive



Panel Report:


EMICBACK/67174


; Mutat. Res.


185:1-195,1987 as


cited by


GENETOX


database, Beta-


Estradiol, last


update 1998



 


 


Human data


 






















End point/Effect



Literature














































































































































































































































































































Pooled relative risks and 95% confidence intervals derived in a meta-analysis of studies of post-menopausal estrogen therapy and endometrial cancer



 



 



 



 



Any use of estrogens



 



 



 



Analysis



Relative Risk



95% Confidence Interval



No. Of Studies



All eligible studies



2.3



2.1-2.5



29



Cohort studies



1.7



1.3-2.1



4



Case-control studies



2.4



2.2-2.6



25



Hospital controls



2.2



2.0-2.5



10



Gynaecologcial controls



3.3



2,7-4.0



6



Community controls



2.4



2.0-2.9



10



 



 



 



 



 



 



 



 



Dose of conjugated estrogens (mg)



 



 



Analysis



Relative Risk



95% Confidence Interval



No. Of Studies



0.3



3,9



1.6-9.5



3



0.625



3.4



2.0-5.6



4



>1.25



5.8



4.5-7.5



9



 



 



 



 



 



 



 



 



Duration of use (years)



 



 



Analysis



Relative Risk



95% Confidence Interval



No. Of Studies



<1



1.4



1.0-1.8



9



 1 - 5



2.8



2.3-3.5



12



 5 - 10



5.9



4.7-7.5



10



>10



9.5b



7.4-12



10



 



 



 



 



 



 



 



 



Regimen



 



 



 



Analysis



Relative Risk



95% Confidence Interval



No. Of Studies



Intermittent and cyclic



3



2.4-3.8



8



Continuous



2.9



2.2-3.8



8



 



 



 



 



Type of estrogen



 



 



 



Analysis



Relative Risk



95% Confidence Interval



No. Of Studies



Conjugated



2.5



2.1-2.9



9



Synthetice



1.3



1.1-1.6



7



 



 



 



 



Time since last use (years)



 



 



 



Analysis



Relative Risk



95% Confidence Interval



No. Of Studies



<1



4.1



2.9-5.7



3



 1 - 4



3.7



2.5-5.5



3



>5



2.3



1.8-3.1



5



 



 



 



 



Stage of tumour



 



 



 



Analysis



Relative Risk



95% Confidence Interval



No. Of Studies



0-1



4.2



3.1-5.7



3



39848



1.4



0.8-2.4



3



Not invasive



6.2



4.5-8.4



4



Invasive



3.8



2.9-5.1



6



Death from endometrial cancer



2,7



0.9-8.0



3



 



Grady et al., 1995. Obstet. Gynecol., 85, 304-313 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.



It was determined that there is sufficient evidence in humans for the carcinogenicity of postmenopausal estrogen therapy, largely based on the clear evidence and substantial strength of the association with risk for endometrial cancer. The rise and fall of incidence of endometrial cancer in several areas of the USA was compatible with trends in estrogen use. The association with breast cancer is weak but consistent with biological mechanisms such as the adverse effects of delay in age at menopause and obesity in postmenopausal women. Users of postmenopausal estrogen therapy had no excess risk for cancers at other sites. The evidence for the carcinogenicity of postmenopausal combined estrogen-progestogen therapy was deemed to be limited.



IARC Working Group, 1999 as cited byToxicological 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.



It was determined that there was sufficient evidence in humans for the carcinogenicity of combined oral contraceptives. Conversely, the evidence for the carcinogenicity of progestogen-only contraceptives was deemed inadequate. It is impossible to infer whether the association between breast cancer and use of combined oral contraceptives is due to earlier diagnosis of breast cancer in users, to the biological effects of contraceptives, or to a combination.



IARC Working Group, 1999 as cited byToxicological 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.



 


 


 


































Determination of the estrogen and estrogen metabolite profiles in prospectively collected serum from post-menopausal women with and without breast cancer who reported no use of exogenous hormones at the time of blood collection. There was a statistically significant association of unconjugated estradiol, unconjugated estrone, conjugated estrone, and many estrogen metabolites with an increased beast cancer risk.


Three metabolic pathway ratios were identified that were associated with the risk of breast cancer even after adjustment for circulating levels of unconjugated estradiol: the ratio of the 2-hydroxylation pathway to parent estrogens, the ratio of the 2-hydroxylation pathway to the 16-hydroxylation pathway, and the ratio of 4-hydroxylation pathway catechols to 4-hydroxylation pathway methylated catechols. The ratio of the 2-hydroxylation pathway to parent estrogens was associated with a statistically significantly decreased risk of breast cancer after adjustment for unconjugated estradiol. Compared with estrogens and other estrogen metabolites, 2-hydroxylation pathway catechols have relatively low affinities for estrogen receptors and are rapidly cleared from circulation.


Thus, 2-hydroxylation may result in a decrease in bioavailable estrogens and reduced estrogen receptor–mediated signaling in the breast. the ratio of catechols to methylated catechols in the 4-hydroxylation pathway was associated with statistically significantly increased risk of breast cancer. Catechols in both the 2- and 4-hydroxylation pathways can be oxidized to form quinones; these reactive electrophiles can then react with DNA to form a variety of adducts. Methylation of the catechols prevents their conversion to reactive quinones. Whereas the most common DNA adducts derived from 4-hydroxylation pathway catechols are depurinating and highly mutagenic, most of those derived from 2-hydroxylation pathway catechols are stable and can be repaired with little error; this difference may explain why 2-hydroxylation pathway catechols are not potent carcinogens in animal models of estrogen-mediated cancers and why their ratio to the corresponding methylated catechols was not statistically significantly associated with the risk of breast cancer in this study. The results point to three estrogen-related factors that may contribute to breast cancer pathogenesis in postmenopausal women: the quantity of available estrogens, the extent of 2-hydroxylation of parent estrogens, and the extent of methylation of 4-hydroxylation pathway catechols.


 


 


 



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



Published findings on breast cancer risk associated with different types of menopausal hormone therapy (MHT) are inconsistent, with limited information on long-term effects. The authors bring together the epidemiological evidence, published and unpublished, on these associations, and review the relevant randomised evidence. Every MHT type, except vaginal oestrogens, was associated with excess breast cancer risks, which increased steadily with duration of use and were greater for oestrogen-progestagen than oestrogen-only preparations. The oestrogen-progestagen risks during years 5–14 were greater with daily than with less frequent progestagen use. For a given preparation, the RRs during years 5–14 of current use were much greater for oestrogen-receptor-positive tumours than for oestrogen-receptor-negative tumours, were similar for women starting MHT at ages 40–44, 45–49, 50–54, and 55–59 years, and were attenuated by starting after age 60 years or by adiposity (with little risk from oestrogen-only MHT in women who were obese). After ceasing MHT, some excess risk persisted for more than 10 years; its magnitude depended on the duration of previous use, with little excess following less than 1 year of MHT use. Interpretation: for women of average weight in developed countries, 5 years of MHT, starting at age 50 years, would increase breast cancer incidence at ages 50–69 years by about one in every 50 users of oestrogen plus daily progestagen preparations; one in every 70 users of oestrogen plus intermittent progestagen preparations; and one in every 200 users of oestrogen-only preparations. The corresponding excesses from 10 years of MHT would be about twice as great. Among postmenopausal women in western countries, ER+ breast cancer accounts for about three-quarters of all breast cancer cases and deaths, and post menopausal oestrogenic activity is a strong determinant of the incidence of ER+ breast cancer. Among postmenopausal women, the incidence of ER+ breast cancer correlates with age at menopause 9 and with blood oestrogen levels, and randomised trials have shown that the incidence of ER+ breast cancer can be greatly reduced by anti-oestrogen drugs such as an aromatase inhibitor, or tamoxifen.


MHT use is associated with much greater proportional increases in ER+ than ER– disease. Moreover, the excess breast cancer risks in MHT users are strongly duration dependent. Although MHT users differ in various ways from non-users, these biologically plausible findings suggest that the excess of ER+ breast cancer associated with MHT use, which accounts for most of the overall excess of breast cancer associated with MHT use, is largely causal (ie, that some years of MHT use, starting at around the time of the menopause, increases the probability of developing ER+ breast cancer among otherwise similar women of the same age). In Sum, an increase in the risk of developing breast cancer after MHT use was provided, however, this increase is dependent on several factors such as type of MHT, duration of MHT, start of MHT and time after last use. Further, elevation of risk was also dependent on BMI. The lowest risk excess among the MHT users were found in oestrogen-only users, especially in obese women.



Lancet 2019; 394: 1159–68, Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence