Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

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).

Test system

Substance

Application

Test concentration

End point/Effect

Literature

Crl:CD BR rats

Estradiol

Oral

0, 0.003, 0.17, 0.69, or 4.1 mg/kg for 90 d

one-generation study; serum hormones were evaluated after 7, 28, and 90 days of feeding.

 

No pups were born at the two highest doses. All doses produced a dose-dependent decrease in serum progesterone concentration on test day 90, which correlated with ovarian atrophy and lack of corpora lutea. The serum concentration of luteinizing hormone was decreased at all times at > 0.69 mg/kg bw/d and at 0.17 mg/kg bw/d on test day 90.

In the F1 generation on postnatal day 28, the serum estradiol concentration was increased and that of progesterone decreased at 0.27 mg/kg bw/d.

Dietary estradiol caused marked effects on the estrus cycle at 0.17 mg/kg bw/d (F0) and 0.27 mg/kg bw/d (F1).

Biegel et al., 1998. 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.

Crl:CD BR rats

Estradiol

Oral

0, 0.003, 0.17, 0.69, or 4.1 mg/kg for 90 d

No pups were born at the two highest doses. Dose depended reduction of pub weight. Parenteral administration of estradiol did not affect the anogenital distance in male or female pups. Delayed sexual maturation in male but hastned in female offspring. Some of the histopathological findings were more severe in the F1 generation than in the parent generation.

No NOEL identified

Biegel et al., 1998. Toxicol. Sci., 44, 116-142 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.

Crl:CD BR rats, male

Estradiol

Oral

10-50 mg¿/kg for 90 d

Decreased testis and epididymis weight, reduced sperm production, oligospermia, presence of germ cell debris in the lumen of the tubules and athropy of epididymal tubules.

Cook et al., 1998. Toxicol. Sci. 44, 155-168 as cited by Lai et al., 2002. Crit. Rev. Toxiocl. 32(2), 113-132.



Short 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). Treatment of rats caused dose dependently ovarian athropy, marked effects on the estrus cycle, delayed sexual maturation in male offspring and decreased testis and epididymis weight, reduced sperm production.

Effects on developmental toxicity

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 with dosing on days 6 to 15 with up to 1 µg/ml after conception revealed no toxicity and no teratogenicity (Study Report No. 1708). In New Zealand white rabbits, analogous treatment from day 6 to day 18 resulted in increased embryo resorption at 1 µg/ml (Study Report No. 2363). Treatment of mice caused dose dependently irreversible cornification or stratification of the vaginal epithelium in female and increased prostate weight in male offspring. Furthermore, an effect on the brain development and abnormal estrus cycles were detected. High doses of Estradiol led to complete resorption of embryos in rats, effects on brain development. An association between Estrogen exposure and cardiovascular defects, eye and ear abnormalities, and Down's syndrome was reported in humans. Conflicting results were obtained considering the occurrence of applied Estrogen in the milk of breastfeeding women.

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).

Test system

Substance

Application

Test concentration

End point/Effect

Literature

CF-1 mice,

female, pregnant

Estradiol

Subcutaneous inplantation

0, 25, 100, 200,

or 300 µg on

gestation day 13

Prostate weight was increased in F1 males at the low dose sacrificed at eight months but

was decreased at the high dose. The authors concluded that increased fetal serum estrogen concentrations affect androgen

regulation of prostate differentiation, resulting in a permanent increase in the number of prostatic androgen receptors and in prostate size.

 

No NOEL for effects on fetal prostate

vom Saal et al.,1997. Proc. Natl Acad. Sci. USA, 94, 2056-2061 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.

Mice, neonatal

pubs

Estradiol

Injection

0.5 mg, 14 daily

Effect on brain development

Grober et al., 1998. Gen. Comp Endocrinol., 122,

356-363 as cited by Lai et al., 2002. Crit. Rev. Toxiocl. 32(2), 113-132.

ICR mouse fetuses

17ß

Estradiol

Subcutaneous

injection

50 µg from the

15th or 17th day of gestation

Irreversible cornification or stratification of the vaginal epithelium was seen at birth. When examined at the age of 3 months, corpora lutea were absent in 4/12 treated on day 17 and in 5/6 mice treated on day 15. Administration on the day of birth or 3 days later to ICR mice resulted in absence of corpora lutea.

 

 

Kimura, 1975. Endocrinol. Jpn., 22, 497-502. 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.

BALB/cfC3H/Crgl

and C3H/Tw mice

17ß Estradiol

 

500 µg on day

15 of gestation

Abnormal estrus cycles in female offspring late in life and abnormalities of the cervicovaginal epithelium.

Mori, 1978. Int. Res.

Commun. Med. Sci., 6, 275 as cited by IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to:

World Health Organization,

International Agency for Research on Cancer, 1972 PRESENT. (Multivolume work), V21 (1979).

Spraque-Dawley

 

Rat

17ß Estradiol

Subcutaneous

0.1, 0.3 or
1 µg/kg on days
6 to 15 after
conception

No toxicity

No teratogenicity

Study Report No. 1708, Schering AG, Prüfung von ZK 5.018 auf embryo-toxische Wirkung an Ratten bei s.c.Verabreichung am 6. bis15. Tag post coitum, dated

14 April.. 1975.

Sprague-Dawley

rat, cultured whole

embryos

Estradiol

 

doses ranging

from 0.05 to 0.5

mmol/L

Dysmorphogenic effects at concentrations of

0.1-0.2 mmol/L. The commonest effect observed was hypoplasia of the prosencephalon. Estradiol was markedly and statistically significantly more toxic in the

presence of metabolic activation.

Beyer et al., 1989. Toxicol. Appl. Pharmacol., 98, 113- 127 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.

Sprague-Dawley

rat, female,

pregnant

Estradiol

Subcutaneous

implantation

10 mg on day 10
of pregnancy

Complete resorption of embryos in all treated animals

 

Sarkar et al., 1986. J.

Vet. Res., 50, 433-437 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.

New Zealand

White Rabbit

17ß Estradiol

Subcutaneous

0.1, 0.3 or
1 µg/kg on days6 to 18 after
conception

Increased embryo resorption at 1 µg/ml

No teratogenicity

Study Report No. 2363, Schering AG, ZK 5.018 

(17ß-Oestradiol)-Prüfung auf embryotoxische

Wirkung an Kaninchen bei s.c. Verabreichung am 6.

bis 18. Tag post coitum, dated 24 Sept. 1975.

Rabbits

17ß Estradiol

Intramuscular

injection

15 or 30 µg for
3-5 consecutive
days during
different periods
of gestation

15 µg terminated pregnancy when given before day 21 of gestation; later, 30 µg were required to terminate pregnancy.

Schofield, 1962. J.

Endocrinol. 25, 95-100 as cited by IARC Monographs

on the Evaluation of the Carcinogenic Risk of Chemicals to:

World Health Organization,

International Agency for Research on Cancer,1972- PRESENT. (Multivolume work), V21 (1979).

Human Data

Test system

Substance

Application

Test concentration

End point/Effect

Literature

 Humans

Estradiol

Accidental exposure

 

No effect reported on 7723 infants

Rothman & Louk, 1978.

 

Association between estrogen exposure and cardiovascular defects, eye and ear abnormalities, and Down's syndrome.

Young, L.Y., M.A. Koda-

Kimble (eds.). Applied

Therapeutics. The Clinical Use of Drugs. 6th ed. Vancouver, WA.,

Applied Therapeutics, Inc. 1995., p. 45-12 as cited by the Hazardous

Substances Data Bank (HSDB), Estradiol on

November 23, 2009.

Six women who were 6 or more months postpartum were given a vaginal suppository containing 50 or 100 mg of estradiol. Peak milk levels occurred between 3 and 11 hours after the dose. Peak milk levels were about 100 ng/L in 4 women, in one it was 300 ng/L and in the sixth, it was 1000 ng/L.

Nilsson et al., 1978. J

Obstet Gynecol. 132:653-7 as cited by the Drug and Lactation Database,

Estradiol, November 23,

2009.

Twenty-one women who were 20 weeks postpartum and breastfeeding their infants were randomized to receive a transdermal patch that released estradiol 50, 75 or 100 mg daily for 2 weeks. Breast milk and serum samples were collected at the beginning and end of the study. Serum estradiol levels increased slightly from baseline, but the differences were not statistically significant; serum levels were in the range of 25 to 45 ng/L. Estradiol was undetectable (< 6.8 ng/L) in all breast milk samples.

Perheentupa et al., 2004.Fertil Steril. 82:903-7 ascited by the Drug andLactation Database,Estradiol, November 23,2009.

A mother who had severe postpartum depression with 2 previous infants was prescribed a transdermal estradiol patch that released 50 mcg daily beginning on day 1 postpartum to prevent recurrence of depression. Decreased weight gain of the infant until day 28 when the estradiol was discontinued.

Ball & Morrison, 1999.

Central AfrJ Med. 45:68-707 as cited by the Drug and Lactation Database,

Estradiol, November 23, 2009.

Thirteen women who were 12 weeks postpartum and fully breastfeeding their infants were given a transdermal patch that released 100 mg of estradiol daily. The average number of breast feeds per day did not change significantly during 3 days of patch application.

Illingworth et al., 1995.

Hum Reprod. 10:1671-7 as cited by the Drug and Lactation Database,

Estradiol, November 23, 2009.

Justification for classification or non-classification

Corresponding to the efficacy of the estrogenic compound the repeated exposure may result in disturbance of engogenous hormon production resulting in a possible reversible impairment of the fertility in men and women.

With regard to the exposure during pregnancy the risk of feminisation effect on the sexual organs of a male child should be considered. Moreover, it can be assumed that intake of estradiol by nursing women may lead to the substance entering to mother's milk, thus impairing the infant's development.

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

Repr. 1A (H360Fd)

Additionally estradiol 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: 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.