Registration Dossier

Administrative data

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 repeated dose toxicity studies were conducted with ZK 5378 (norethiosterone). But data on its ester derivatives norethisterone acetate and/or norethisterone enantate can be also used for the toxicological characterization, because both esters are rapidly cleaved in vivo and norethisterone as the actual pharmacologically active metabolite is released. Thus for the oral route results of a study conducted with norethisterone acetate (K 5422) is taken as surrogate of norethisterone to fulfill formally the standard information requirement. Since the first introduction of drug preparations containing this steroidal progestin dates back more than five decades, the major part of its preclinical characterization does not fulfil the requirements applicable today to studies used for safety assessment. However, these limitations are more than compensated for by the vast amount of clinical experience gained with norethisterone and its esters in their continued and widespread therapeutic use. Therefore in conclusion the results of the preclinical characterisation of norethisterone and its esters confirm its properties as a steroidal progestin but they are not used for the safety assessment (systemic/local effects). The dose desriptor starting point is taken from human experience.

As known from an extensive data base animal experiments with progestins are only of limited predictive value for qualitative and even more for quanatitative extrapolation tu humans because of a large diversity in factors responsible for endocrine regulation between experimental animals and man.

Therefore the most sensitive endpoint to consider is the lowest oral daily dose with pharmacological effects in humans (SSTmin) of norethisterone.

Key value for chemical safety assessment

Mode of Action Analysis / Human Relevance Framework

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 repeated dose 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.

Single intramuscular injections of ZK 5410 were given weekly to female rats (16 rats/dose group) over 90 days at the doses of 0, 1, 10 and 50 mg/kg. At 10 mg/kg bw the rats developed disorder of the cycle and the uterus weights of the rats were reduced. At 50 mg/kg bw the animals were in a constant diestrus with growth depression. The organ weights of hypophysis, ovaries, uterus and thymus were reduced. Additionally hyperplasia/proliveration of granulosa cells were observed. LOAEL: 1 mg/kg [Schering AG, Report No. 1590, 1975-01-21]

In a 52 weeks study K 5410 was administered into the muscle of dogs (4/sex/dose) once weekly up to 8 weeks and then every third week in doses of 0, 10, 30 and 100 mg/kg. The animals of the treatment groups showed local reaction (swelling, abscess) at the muscle and oedema of the limbs. In males reduced testicles growth and increased mammary growth (male and female) as well as slight vulva swelling in females was observed. In haematology erythrocyte sedimentation rate was increased and platelet count decreased mainly at high dose. Total protein and alpha-2 -globulin was increased in blood and albumin (30 and 100 mg/kg) and calcium (100 mg/kg) was reduced. Macroscopic findings were dose dependent dilatation of the uterus with mucous or purulent content and endometrium with noduli and convoluted appearance combined with enlargement of vulva and clitoris. Weight of ovaries, testis and prostate were reduced, uterus weight increased. LOAEL: 10 mg/kg [Schering AG, Report No. 3782/70/604, 1971-02-15]

Female monkeys were treated with single intramuscular injections on day 1 and 45 of a 90 day study period with 0, 6, 60 and 300 mg/kg (1 animal/dose). Decrease of body weight gain, irregular menstrual cycle or acyclic effects,increased uterus size and weight and decreased ovaries size were observed. Additionally, decidual cell reaction were induced in the uterine endometrium and the proportion of acidophil cells in anterior pituitary was increased. LOAEL: 6 mg/kg [Schering AG, Report No. 1605, 1975 -02 -07]

Additionally results of repeated dose toxicity studies with norethisterone are cited in RTECS database (Jan 2010):

The daily intramuscular application of norethisterone to rats over 15 days results in changes in serum composition (e.g., TP, bilirubin, cholesterol) and lipid intermediar metabolism including transport; TDLo: 30 mg/kg/15D-I

[Shengzhi Yu Biyun. Reproduction and Contraception. (China International Book Trading Corp., POB 2820, Beijing, Peop. Rep. China) 1980- v. 11(3), p. 17, 1991 (SCYYDZ)]

The daily subcutaneous administration of ZK 5378 to rats over 3 days results in maternal effects on uterus, cervix and vagina; TDLo: 60 mg/kg/3D-I [Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 170, p. 21, 2002 (TXCYAC)]

The subcutaneous application over 3 days to rats results in maternal effects on uterus, cervix and vagina and weight loss or decreased weight gain; TDLo: 600 mg/kg/3D-I [Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 170, p. 21, 2002 (TXCYAC)]

Justification for classification or non-classification

According to CLP Annex I, 3.9.1.1, specific toxic effects covered by other hazard classes are not included in STOT-RE. STOT-RE should only be assigned where the observed toxicity is not covered more appropriately by another hazard class. For example specific effects like tumours or effects on the reproductive organs should be used for classification for carcinogenicity (see chapt. 7.7) or reproductive toxicity (see chapt. 7.8), respectively, but not for STOT-RE.

Therefore there is no classification required for SPECIFIC TARGET ORGAN TOXICITY – REPEATED EXPOSURE according to Regulation (EC) No. 1272/2008 (CLP).