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Toxicological information

Carcinogenicity

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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.

No carcinogenicity 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 occursin vivoafter administration.

Weekly intramuscular injections of norethisterone enanthate over 78 weeks to mice (40/sex/dose) at doses of 0, 10, 30 and 100 mg/kg results in swelling of the perigenital region of males, slightly increased weight gain, increased severity in inflammatory reaction at appliaction site, distribution of liver noduli, increased heart and kidney weight, hyperplasia of mammary gland, increase in hepatoma , transitional cell carcinomata of urinary epithelium. LOAEL: 10 mg/kg [Schering AG, Report No. 3708/70/520, 1971-10-22]

Single intramuscular injections of ZK 5410 were applied to female rats every fortnightfor2 years at doses of 0, 1, 10 and 50 mg/kg (60 rats/dose). At 12 and 18 months interim sacrifice of 5 animals/group was carried out. Treatment results in slight reduce of body weight gain and foodconsumption and serum total protein and albumin (after 6/12 months) and colesterol (after 12/18/24 months). Serum AP was increased at 50 mg/kg. At interim sacrifice rats of mid and high dose had nonsecretory mammary glands, lack of ovarian luteal tissue and onset of liver tumours. At termination increase of benign hepatocellular adenoma and nodular hyperlasia and decrease of incidence of pituitary adenomas were observed at high dose. Toxic level (carcinogenicity) > 50 mg/kg [Schering AG, Report No. 3194, 1978-05-10]

Single intramuscular injections of ZK 5410 were applied to female rats (60/group) every 12 weeks for 14 months in doses of 0, 6, 60 and 300 mg/kg bw and every 8 weeks for the rest of the 2 years study period in doses of 0, 4, 40 and 200 mg/kg bw. At 12 and 18 months interim sacrifice of 5 animals/group were carried out. Treated rats showed a dose dependent decrease in body weight gain and colesterol. At interim sacrifice no corpora lutea were seen in the high dose rats. At termination at high dose an incidence of increase in nodular hyperplasia and hypertrophy in liver occurred. A decrease of incidence of pituitary adenomas were observed. Toxic level (carcinogenicity) > 200 mg/kg[Schering AG, Report No. 3666, 1978-11-30]

Weekly Intramuscular injections over two years to rats (40/sex/group) at a dose of 0, 10, 30 and 100 mg/kg bw result in alopecia and reduced grooming activities, increased mortality, reduced food intake and weight gain (female only at high dose) and increased food intake and bw gain in females at low and mid dose. Also depression of erythrocytic parameter, increase of blood and urine proteins were observed. Cataracts and decreased weight in testis, prostate and ovaries occures. Both sexes showed increased incidences of hepatoma and mammary gland carcinoma, mammary gand tumours and pituitary adenomas in males. Histological changes in liver,adrenals, pituitary, seminal vesicles, uterus and mammary gands (males) were observed. LOAEL: 10 mg/kg [Schering AG, Report No. 4253/71/411, 1975-06-06]

Beagle dogs received for 7 years ZK 5410 intramuscular in following doses: 0, 1, 10 and 25 times of human contraceptive dose. At terminal sacrifice gross lesions in the liver suspicious of being proliverative processes have been observed in some animals of control and treatment group and assumed to be of no relevance for human. [Shering AG, Report No. 5553, 1983 -08 -02]

Female monkeys were treated with single intramuscular injections every 8 (12) weeks for 10 years with ZK 5410 doses of 0/ 4 (6)/ 40 (60)/ 200 (300) mg/kg. Slight changes in biochemistry (cholesterol, albumin, blood protein, alanin aminotransferase, fibrinogen) and organ weights were observed at high dose animals. Also changes in endocrine dependent organs (ovaries, accessory sexual organs, mammary and pituitary gland) and the skin were reported in mid and high dose groups related to the pharmacological action of the compound. In high dose animals two cases of endometrial carcinoma and pituitary adenoma were reported. [Schering AG, Report No. 8015, 1988 -05 -03]

Additionally, results of carcinogenicity studies with norethisterone were cited in RTECS database (Jan 2010):

Mice were treated subcutaneously with norethisterone for 78 weeks developing ovarian tumours (equivocal tumorigenic agent by RTECS criteria); TDLo: 163 mg/kg/78W-C [British Journal of Cancer. (Macmillan Press Ltd., Houndmills, Basingstoke, Hants. RG21 2XS, UK) V.1- 1947- v. 21, p. 153, 1967 (BJCAAI)]

Mice were treated 77 weeks via implantat resulting in increased incidence of tumors in susceptible strain (equivocal tumorigenic agent by RTECS criteria); TDLo: 166 mg/kg/77W-C [Nature. (Nature Subscription Dept., POB 1018, Manasguan, NJ 08736) V.1- 1869- v. 212, p. 686, 1966 (NATUAS)]

Parenteral application of norethisterone to mice for 78 weeks result in ovarian tumours (equivocal tumorigenic agent by RTECS criteria); TDLo: 168 mg/kg/78W-C [Pakistan Medical Forum. (Karachi, Pakistan) V.1-8, 1966-73(?) Disc ontinued. v. 7, p. 21, 1972 (PMDFA9)]

Key value for chemical safety assessment

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 carcinogenicity studies were conducted with ZK 5378; read across approach of studies with norethisterone enanthate (ZK 5410): Intramuscular, 78 weeks (Mice-CD, non-GLP, doses: 0/ 10/ 30/ 100 mg/kg weekly) LOAEL: 10 mg/kg (Schering AG, Report No. 3708/70/520, 1971-10-22) Intramuscular, 2 years (Rat-CD, non-GLP, doses: 0/ 1/ 10/ 50 mg/kg, every 14 days) Toxic level (carcinogenicity) > 50 mg/kg (Schering AG, Report No. 3194, 1978-05-10) Intramuscular, 2 years (Rat-CD, non-GLP, doses: 0/ 6/ 60/ 300 mg/kg, every 12 w for 14 months; 0/4/40/200 mg/kg every 8 w for month 15-24) (Schering AG, Report No. 3666, 1978-11-30) Intramuscular, 104 weeks (Rat-CD, non-GLP, doses: 0/ 10/ 30/ 100 mg/kg weekly) LOAEL: 10 mg/kg (Schering AG, Report No. 4253/71/411, 1975-06-06) Intramuscular, 7 years (Dog-Beagle, non-GLP, doses: 0/ 1 / 10/ 25 times of human contraceptive dose) (Shering AG, Report No. 5553, 1983-08-02) Intramuscular, 10 years (Monkey-Rhesus, non-GLP, doses: 0/ 4 (6)/ 40 (60)/ 200 (300) mg/kg, every 8 (12) weeks) (Schering AG, Report No. 8015, 1988-05-03) Additionally results of carcinogenicity studies with norethisterone were cited in RTECS database (Jan 2010): Subcutaneous, 78 weeks (mouse): TDLo: 163 mg/kg (British Journal of Cancer. (Macmillan Press Ltd., Houndmills, Basingstoke, Hants. RG21 2XS, UK) V.1- 1947- v. 21, p. 153, 1967 (BJCAAI)) Implantat, 77 weeks (mouse): TDLo: 166 mg/kg (Nature. (Nature Subscription Dept., POB 1018, Manasguan, NJ 08736) V.1- 1869- v. 212, p. 686, 1966 (NATUAS)) Parenteral, 78 weeks (mouse): TDLo: 168 mg/kg (Pakistan Medical Forum. (Karachi, Pakistan) V.1-8, 1966-73(?) Disc ontinued. v. 7, p. 21, 1972 (PMDFA9))

Justification for classification or non-classification

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

Carc. 2 (H351)

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.