Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

A registration of norethisterone 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).

Norethisterone is a synthetic sex hormone and active ingredient of approved drugs since several decades. Norethisterone belongs to the category “steroidal progestins” and has progestogenic properties resembling those of the naturally occuring progesterone but is a more potent inhibitor of ovulation. Apart from the data on norethisterone, information from its ester derivates (norethisterone enanthate and acetate) can be used for characterization of the biological activity of progestin, because both esters are rapidly cleaved within the mammalian organism and thus, norethisterone is the systemically active metabolite irrespective of the form which is administered.

There are no internal fertility studies with norethisterone available. However, 49 fertility studies with norethisterone are cited in RTECS database (Jan 2010), describing similar effects. The most representative results are reported here:

Single oral application to rabbits results in effects on fertility not further specified, TDLo: 125 ug/kg (1D pre) ["The Control of Fertility," Pincus, G., New York, Academic Press, 1965 -,57,1965 (85GRAA)]

Daily oral administration of norethisterone to unpregnant women over 52 weeks results in menstrual cycle changes or disorders; TDLo: 2190 ug/kg (52W pre) [Acta Endocrinologica, Supplementum (Copenhagen). (Periodica, Skolegade 12 E, DK-2500 Valby, Denmark) No.1- 1948- v. 144, p. 7, 1970 (ACEDAB)]

Single oral application to rabbits one day prior to mating results in effects on the mating performance (e.g., number of sperm positive females per number of females mated; number of copulations per number of estrus cycles); TDLo: 313 ug/kg (1D pre) [Acta Endocrinologica, Supplementum (Copenhagen). (Periodica, Skolegade 12 E, DK-2500 Valby, Denmark) No.1- 1948- v. 73, p. 17, 1963 (ACEDAB)]

Oral application to men over 25 days result in paternal effects on spermatogenesis (including genetic material, sperm morphology, motility, and count) and impotence; TDLo: 7143 ug/kg (25D male) [Acta Endocrinologica (Copenhagen). (Periodica, Skolegade 12 E, DK-2500 Valby, Denmark) V.1- 1948- v. 37, p. 75, 1961 (ACENA7)]

Oral administration of norethisterone to unpregnant women over 20 days results in maternal effects on uterus, cervix and vagina and in other effects on fertility not further specified; TDLo: 4 mg/kg (20D pre) [American Journal of Obstetrics and Gynecology. (C.V. Mosby Co., 11830 Westline Industrial Dr., St. Louis, MO 63146) V.1- 1920- v. 85, p. 427, 1963 (AJOGAH)]

Male rats received norethisterone orally daily for 14 days. This results in paternal effects on prostate, seminal vessicle, Cowper's gland and accessory glands; TDLo: 28 mg/kg (14D male) [Annals of the New York Academy of Sciences. (New York Academy of Sciences, 2 E. 63rd St., New York, NY 10021) V.1- 1877- v. 71, p. 500, 1958 (ANYAA9)]

Daily inhalation of norethisterone of male monkeys over 60 days results in paternal effects on spermatogenesis (including genetic material, sperm morphology, motility, and count) testes, epididymis and sperm duct ; TCLo: 30 ug/kg/30M (60D male) [Biology of Reproduction. (Soc. for the Study of Reproduction, 309 W. Clark St., Champaign, IL 61820) V.1- 1969- v. 22, p. 935, 1980 (BIREBV)]

Intramuscular applications for 3 days to female monkeys result in menstrual cycle changes or disorders; TDLo: 3 mg/kg (3D pre)

[Biology of Reproduction. (Soc. for the Study of Reproduction, 309 W. Clark St., Champaign, IL 61820) V.1- 1969- v. 30, p. 886, 1984 (BIREBV)]

Daily subcutaneous application to female rabbits for 7 days result in effects on female fertility index (e.g., number of females pregnant per number of sperm-positive females, number of females pregnant per number of females mated); TDLo: 17500 ug/kg (7D pre) [Contraception. (Geron-X, Inc., POB 1108, Los Altos, CA 94022) V.1- 1970- v. 12, p. 511, 1975 (CCPTAY)]

Daily subcutaneous application to male rabbits for 7 days result in effects on male fertility index (e.g., number of males impregnating females per number of males exposed to fertile non-pregnant females); TDLo: 5250 ug/kg (7D male) [Contraception. (Geron-X, Inc., POB 1108, Los Altos, CA 94022) V.1- 1970- v. 12, p. 511, 1975 (CCPTAY)]

In women receiving norethisterone via implantat over 26 weeks effects on fertility index (e.g., number of females pregnant per number of sperm-positive females, number of females pregnant per number of females mated) were observed; TDLo: 230 ug/kg (26W pre) [Contraception. (Geron-X, Inc., POB 1108, Los Altos, CA 94022) V.1- 1970- v. 18, p. 411, 1978 (CCPTAY)]

The application of norethisterone via implantat to monkeys on day 1-31 of pregnancy results in abortions; TDLo: 186 ug/kg (1-31D preg) [Contraception. (Geron-X, Inc., POB 1108, Los Altos, CA 94022) V.1- 1970- v. 25, p. 97, 1982 (CCPTAY)]

Daily oral application to men over 42 days results in paternal effects on spermatogenesis (including genetic material, sperm morphology, motility, and count), testes, epididymis, sperm duct and in impotence and breast development; TDLo: 18 mg/kg (42D male) [Federation Proceedings, Federation of American Societies for Experimental Biology. (Bethesda, MD) V.1-46, 1942-87. v. 18, p. 1057, 1959 (FEPRA7)]

In mice receiving norethisterone via implant on day 1-3 of pregnancy effects on litter size (e.g., number of fetuses per litter, measured before birth) were observed; TDLo: 12 mg/kg (1-3D preg) [Journal of Endocrinology. (Biochemical Soc. Book Depot, POB 32, Commerce Way, Colchester, Essex CO2 8HP, UK) V.1- 1939- v. 20, p. 299, 1960 (JOENAK)]

Subcutaneous application to pregnant mice on day 6-7 of pregnancy results in pst-implantation mortality (e.g., dead and/or resorbed implants per total number of implants); TDLo: 2 mg/kg (6-7D preg) [Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- v. 15, p. 955, 1978 (OYYAA2)]


Effects on developmental toxicity

Description of key information

A registration of norethisterone 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 developmental toxicity studies were conducted with ZK 5378 (norethiosterone). Results of studies conducted with an ester of norethisterone (norethisterone enanthate, ZK 5410) are regarded as representative as most likely ester cleavage occurs in vivo after administration.

The single subcutaneous administration of norethisterone enanthate on day 6 p.c. to female rat (12/group) in the doses of 0, 6 and 60 mg/kg was tolerated well. Only the body weight gain of high dose females was reduced. The NOEL for maternal toxicity was 6 mg/kg body weight. [Schering AG, Report No. 1380, 1970-04-10]

The single subcutanous administration of norethisterone enanthate on day 6 p.c. to female rabbits (10 or 11 /group) in the doses of 0, 6 and 60 mg/kg resulted in reduced body weight gain of the dams and high embryo lethality in the high dose group. NOEL (embryotoxicity, maternal toxicity): 6 mg/kg [Schering AG, Report No. 1296, 1971 -08 -03

A single subcutanous dose of norethisterone enanthate was administered on day 6. p.c. to female rabbits (0/10/20/40 mg/kg body weight). At 10 mg/kg 66% and at higher dose levels 100% of the embryos died. LOAEL: 10 mg/kg [Schering AG, Report No. 2022, 1975-10-28]

Additionally 17 developmental toxicity studies with norethisterone are cited in RTECS database (Jan 2010), describing similar effects. The most representative results are reported here: Daily oral application to women on week 5 -25 of pregnancy results in specific developmental abnormalities of the urogenital system in the offsprings; TDLo: 28 mg/kg (5-25W preg) [American Journal of Diseases of Children. (AMA, 535 N. Dearborn St., Chicago, IL 60610) V.1-80(3), 1911-50: V.100- 1960- v. 106, p. 586, 1963 (AJDCAI)] Subcutaneous application to guinea pigs on day 18-60 of pregnancy result in specific developmental abnormalities of the endocrine and urogenital system; TDLo: 86 mg/kg (18-60D preg) [Fertility and Sterility. (American Fertility Soc., 608 13th Ave. S, Birmingham, AL 35282) V.1- 1950- v. 19, p. 606, 1968 (FESTAS)] Oral application of norethisterone to female rats on day 15-17 of pregnancy results in fetotoxicity (except fetal death) and specific developmental abnormalities on skin, skin appendages and musculoskeletal system; TDLo: 188 mg/kg (15-17D preg) [Indian Journal of Experimental Biology. (Publications and Information Directorate, CSIR, Hillside Rd., New Delhi 110 012, India) V.1- 1963- v. 21, p. 591, 1983 (IJEBA6)] daily application of norethisterone (route unreported) to women during week 6-20 of pregnancy results in behavoural changes of the newborn;TDLo: 12 mg/kg (6-20W preg) [Science. (American Assoc. for the Advancement of Science, 1333 H St., NW, Washington, DC 20005) V.1- 1895- v. 211, p. 1171, 1981 (SCIEAS)]

Additional information

A registration of norethisterone 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 teratogenicity studies were conducted with ZK 5378; read across approach with results of studies with norethisterone enanthate (ZK 5410): Subcutanous (Rat, non-GLP, doses: 0/6/60 mg/kg on day 6 p.c.): reduced bw gain at 60 mg/kg, NOEL: 6 mg/kg [Schering AG, Report No. 1380, 1970-04-10] Subcutanous (Rabbit, NZW; non-GLP, doses: 0/6/60 mg/kg on day 6 p.c.): embryolethal, reduced bw gain of dams at 60 mg/kg, NOEL: 6 mg/kg [Schering AG, Report No. 1296, 1971-08-03] Subcutanous (Rabbit, NZW; non-GLP, doses: 0/10/20/40 mg/kg on day 6 p.c.): embryolethal; LOAEL: 10 mg/kg [Schering AG, Report No. 2022, 1975-10-28] Additionally 17 results of developmental toxicity studies with norethisterone are cited in RTECS database (Jan 2010), describing similar effects. The most representaive results are reported here: Oral, week 5-25 of preg (woman): TDLo: 28 mg/kg (5-25W preg) (American Journal of Diseases of Children. (AMA, 535 N. Dearborn St., Chicago, IL 60610) V.1-80(3), 1911-50: V.100- 1960- v. 106, p. 586, 1963 (AJDCAI)) Subcutaneous, day 18-60 of preg (guinea pig, female): TDLo: 86 mg/kg (18-60D preg) (Fertility and Sterility. (American Fertility Soc., 608 13th Ave. S, Birmingham, AL 35282) V.1- 1950- v. 19, p. 606, 1968 (FESTAS)) Oral, day 15-17 of preg (rat, female): TDLo: 188 mg/kg (15-17D preg) (Indian Journal of Experimental Biology. (Publications and Information Directorate, CSIR, Hillside Rd., New Delhi 110 012, India) V.1- 1963- v. 21, p. 591, 1983 (IJEBA6)) Route unreported, week 6-20 of preg (woman):TDLo: 12 mg/kg (6-20W preg) (Science. (American Assoc. for the Advancement of Science, 1333 H St., NW, Washington, DC 20005) V.1- 1895- v. 211, p. 1171, 1981 (SCIEAS))

Mode of Action Analysis / Human Relevance Framework

A registration of norethisterone 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 internal experimental data to the reproductive toxicity of ZK 5378 are available.Results of studies conducted with an ester of norethisterone (norethisterone enanthate, ZK 5410) and studies cited in RTECS database (Jan 2010) are regarded as representative.

In humans a dose of appr. 350¿g norethisterone/woman/day (administered alone without estrogens) is an effective dose for oral contraception. Thus, reversible fertility disorders are to be reckoned with in women after administration such doses. Embryotoxicity studies were carried out with the esters, norethisterone acetate and norethisterone enanthate, in mice, rats rabbits and monkeys. There was no indication of a teratogenic potential with the exception of signs of masculinization in female monkey fetuses after high doses of norethisterone acetate (from 60 mg/kg/day), which were sufficient to cause embryo-lethal effects. Treatment of pregnant rats during the sensitive phase of differentiation of the fetal sex organs also led to masculinization of female fetuses following relatively high subcutaneous doses (>1 mg/kg BW/day). Signs of masculinization of female embryos have been also described in humans after treatment with high doses of norethisterone or norethisterone acetate (10 to 40 mg/woman/day) during the sensitive phase of fetal sexual differentiation (from day 45 following conception). On the basis of available data, 10 mg/woman/day p.o. can be taken as the threshold dose for the occurrence of these anomalies in humans. At uptake by nursing mothers, norethisterone may pass into the milk and affect the development of the child.

Justification for classification or non-classification

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

Repr. 1A (H360FD)

Additionally norethisterone 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 steroid hormones. The German Committee on Hazardous Substances (AGS) recommended for the group of progestin/progesteron ("Gestagene") classification as:

Toxicity to reproduction - Fertility: Category 1A

Toxicity to reproduction - Development: Category 1B

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. Norethisterone is mentioned in attachment 2 on page 17.