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Administrative data

Link to relevant study record(s)

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.

The clinical pharmacology and the absorption, distribution, metabolism and excretion of norethisterone and its ester derivates are well characterized as described in the current label of approved drugs.

 

Key value for chemical safety assessment

Additional information

There are no experimental data on norethisterone (ZK 5378) available. All data on ADME are cited in RTECS/HSDB database (Jan 2010):

Adsorption/Distribution/Excretion

Norethisterone appears to bind to intestinal walls and are then slowly released into the bloodstream [1]
In women given 15,16,3H- norethisterone acetate 20 muci IV in 10 % ethanol-water vehicle, norethisterone had biphasic disappearance with rapid initial disappearance in 1st 6 hr followed by slow disappearance phase (34.8 hr). Results are compared with other progestins data [2]
In 25 BALB/c mice implanted subcutaneously with pellets containing 40% norethisterone and 60% cholesterol for 76-77 wk, absorption of norethisterone was estimated to be between 3.6 and 15.9 ug/day (mean, 7.7 ug/day).[3]

Rabbits excrete norethisterone metabolites predominantly in the urine ... while rats excrete them to 80% in bile [4]
When 3H- or 14C-norethisterone was given orally to men, about half of the dose was excreted in the urine [5]

Although norethisterone is absorbed almost completely, it undergoes first-pass metabolism, which decreases its bioavailability to an average of 64%. There is wide inter individual variation in its absorption, which is estimated to be as high as three- to fivefold. Norethisterone is absorbed rapidly, achieving maximum serum concentrations within 1-4 hours. After doses of 0.5, 1 and 3 mg, the serum concentrations peaked at 2-5, 5-10 and up to 30 ng/ml, respectively.[6]

Metabolism

Metabolic removal of 17 alpha-ethynyl group from antifertility drug norethindrone, 17 alpha-ethynyl-17 -beta-hydroxyester-4 -en-3 -one affords ester-4 -ene-3,17 -dione. In earlier study, 17 alpha-ethynyl-5 alpha-19 -norandrostan-17 beta-ol-3 -one and 17 alpha-ethynyl-5 alpha-19 -norandrostan-3beta, 17 beta-diol were urinary metabolites [7]

After incubation of norethisterone with dog liver microsomes the 4beta,5beta-epoxide of norethisterone and a 6-oxygenated norethisterone derivative were obtained as minor metabolites [4]

Rabbit liver homogenates ... catalyze the deethinylation of norethisterone, giving rise to the metabolite oestr-4-ene-3,17-dione. [4]

When 3H- or 14C-norethisterone was given orally to men ...50-65% of the urinary radioactivity was sulfate conjugates. The major sulfate conjugate was that of 5beta-oestrane-3beta,17beta-diol; the major glucuronide conjugate was that of 5beta-oestrane-3alpha,17beta-diol. The other metabolites in the glucuronide and sulfate fraction were produced by reduction of norethisterone at C-3 and at the double-bond of ring A ... . Norethisterone is transformed by reductive enzymes to four isomeric ring-A-reduced (5alpha and 5beta) 3alpha- or 3beta-hydroxy metabolites ..[5]

The major metabolites of norethisterone are isomers of 5alpha-dihydronorethisterone and tetrahydronorethisterone, which are excreted largely as glucuronides. Because of steric hindrance of the bulky ethinyl group at position 17alpha, only a small percentage of norethisterone metabolites are conjugated at the 17beta-hydroxy group.The ethinyl group remains intact in 90% of metabolites.[6]

[1] The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3.London: The Chemical Society, 1975., p. 166

[2] Singh H et al. AM J Obstet Gynecol 135(10) 409 (1979)

[3] 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)., p. V21 452 (1979)

[4] 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)., p. V21 453 (1979)

[5] 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)., p. V21 454 (1979)

[6] 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)., p. V72 232 (1999)

[7] The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 1: A Review of the Literature Published Between 1960 and 1969.London: The Chemical Society, 1970., p. 244