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).

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.

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

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.