Registration Dossier

Administrative data

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).

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

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.

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.