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 acute toxicity studies were conducted with ZK 5378 (norethiosterone). But data on its ester derivatives norethisterone acetate and 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 studies conducted with norethisterone enanthate (K 5410) are taken as surrogate of norethisterone. For the dermal route no studies are available for the esters, too. Because scientific analysis of available data from in vivo acute toxicity studies have shown that substances that are not toxic via the oral route may be expected with high certainty to be also non-toxic via the dermal route the dermal test was waived.

Acute oral toxicity

The single oral administration of the surrogate to 10 rats/sex at a dose of 3000 mg/kg was tolerated without any compound-related clinical signs. One female rat died on day 3. In all sacrificed animals no macroscopic pathological signs were observed. The acute oral toxicity of the test item in rats is >3000 mg/kg body weight.

Acute dermal toxicity

No acute toxicity studies were conducted with ZK 5378 (norethiosterone).

The discriminating dose is predicted to be in the same order of magnitude as reported for the oral route.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
4. to 31. Dec 1968
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Reference:
Composition 0
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
not specified
GLP compliance:
no
Test type:
standard acute method
Limit test:
yes
Test material information:
Composition 1
Species:
rat
Strain:
Wistar
Sex:
female
Route of administration:
oral: gavage
Vehicle:
castor oil
Doses:
3000 mg/kg
No. of animals per sex per dose:
10 female
Control animals:
no
Sex:
female
Dose descriptor:
LD50
Effect level:
> 3 000 mg/kg bw
Based on:
test mat.

The test substance was tolerated without any compound-related clinical signs. One female rat died on day 3. In all sacrifices animals no macroscopic pathological signs were observed

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
LD50 female rat (oral) norethisterone enanthate > 3000 mg/kg body weight
Executive summary:

No acute 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 oral administration of ZK 5410 to 10 rats/sex at a dose of 3000 mg/kg was tolerated without any compound-related clinical signs. One female rat died on day 3. In all sacrificed animals no macroscopic pathological signs were observed.

The acute oral toxicity of ZK 5410 in rats is >3000 mg/kg body weight. [Schering AG, report no: 1063/1064, 1969-03-27]
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
4. to 31. Dec 1968
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Reference:
Composition 0
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
not specified
GLP compliance:
no
Test type:
standard acute method
Limit test:
yes
Test material information:
Composition 1
Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Dr. Hagemann
- Age at study initiation: no data
- Weight at study initiation: 115- 130 g
- Fasting period before study: 18 hours
- Housing: conventional
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 17 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-23 °C
- Humidity (%): 55 - 65%

Route of administration:
oral: gavage
Vehicle:
other: benzylbenzoate + castor oil (4+6)
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 50 g/100 ml
- Amount of vehicle (if gavage): 0.6 ml/kg bw
Doses:
3000 mg/kg
No. of animals per sex per dose:
10 male
Control animals:
no
Details on study design:
- Duration of observation period following administration: 22 days
- kind of observations: clinical signs, mortality
- Necropsy of survivors performed: yes
Statistics:
not applicable
Sex:
male
Dose descriptor:
LD50
Effect level:
> 3 000 mg/kg bw
Based on:
test mat.
Mortality:
no mortality
Clinical signs:
no clinical signs
Body weight:
not examined
Gross pathology:
unremarkable

No compound-related clinical and macroscopic pathological signs were observed.

Interpretation of results:
other: no substance related mortality observed
Conclusions:
LD50 male rat (oral) norethisterone enanthate > 3000 mg/kg body weight
Executive summary:

The single oral administration of the test item to 10 male rats at a dose of 3000 mg/kg was tolerated without any compound-related clinical signs. In all sacrificed animals no macroscopic pathological signs were observed.

The acute oral toxicity of the test item in rats is >3000 mg/kg body weight.
Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
Norethisterone is a synthetic steroidal progestin, first synthesized in the 1950s, that is used in oral form in preparations for the field of gynecological therapy. Norethisterone has progestogenic properties resembling those of the naturally occuring progesterone but is a more potent inhibitor of ovulation. Apart from the data on norethisterone (No acute toxicity studies were conducted with ZK 5378 (norethiosterone), experiments with its ester derivate norethisterone enanthate can be used for characterization of the biological activity of the progestin, because the ester is rapidly cleaved within the mammalian organism and thus, norethisterone is the systemically active metabolite irrespective of the form which is administered.
Reason / purpose:
read-across source
Related information:
Composition 1
Reason / purpose:
read-across source
Related information:
Composition 1
Test material information:
Composition 1
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 3 000 mg/kg bw
Based on:
test mat.
Mortality:
males: no moratality
females:
Clinical signs:
males: no clinical signs
females:
Body weight:
males: not examined
females:
Gross pathology:
males: unremarkable
females:
Interpretation of results:
other: no substance related mortality observed
Executive summary:

The single oral administration of the test item to 10 male rats at a dose of 3000 mg/kg was tolerated without any compound-related clinical signs. In all sacrificed animals no macroscopic pathological signs were observed. The acute oral toxicity of the test item in rats is >3000 mg/kg body weight.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
3 000 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
Conclusion and the amount of non-lethal dosage by analogy to the oral route.

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 acute 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 oral administration of a norethisterone enanthate (2000 mg/kg) to 10mice/sex was tolerated without any compound-related clinical or macroscopic pathological signs. The acute oral toxicity of ZK 5410 in mice is >2000 mg/kg body weight. [Schering AG, Report No. 1060/1059, 1969-03-27 and 1969-02-24]

Norethisterone enanthate (ZK5410) was applied orally at a dose of 1000, 2000, 2800 and 5000 mg/kg to 10 female mice/dose group. One high dose animal developed apathy after application and died. All other mice were without any compound-related clinical and macroscopic pathological signs. The oral LD50 >5000 mg/kg in female mice. [Schering AG, Report No. 1053, 1969-05-21]

Male mice (10/group) treated with a single oral application of ZK5410 at doses of 1000, 1400, 2000, 2800,5000 and 7500 mg/kg developed apathy. Some animals died 2 -6 daysafter application. In macroscopic pathology no effects could be observed in sacrified animals. Died animals had haemorrhages in the stomach. The LD50 oral is 5300 mg/kg body weight. [Schering AG, Report No. 1052, 1969-06-25]

The single oral administration of ZK 5410 to 10 female rats at a dose of 6000 mg/kg caused transient clinical signs (apathy) on day one after application. One animal died on day 3. All other animals were without compound-related clinical signs from day 2 onwards. No compound-related macroscopic pathological signs were observed. The acute oral toxicity of ZK 5410 in female rats is >6000 mg/kg body weight. [Schering AG, Report No. 1048, 1969-03-27]

The single oral administration of ZK 5410 to 10 rats/sex at a dose of 3000 mg/kg was tolerated without any compound-related clinical signs. One female rat died on day 3. In all sacrificed animals no macroscopic pathological signs were observed.

The acute oral toxicity of ZK 5410 in rats is >3000 mg/kg body weight. [Schering AG, Report No. 1063/1064, 1969-03-27]

Norethisterone enanthate (ZK5410) was applied orally at a dose of 4000 mg/kg to 10 male rats. The animals developed apathy after application. One rat died. The acute oral LD50 in male rats is >4000 mg/kg body weight. [Schering AG, Report No. 1199, 1969-05-30]

After the single subcutaneous administration of ZK5410 at the doses of 2500, 3750, 5000 and 7500 mg/kg to mice (10/sex/dose) the animals showed transient signs of apathy and some developed abscesses at the application site. Male mice died at 2500 (2/10). At 3750 mg/kg died 3/10 female, 1/10 male and at high dose 1/10 male and female animals, respectively. LD50 > 7500 mg/kg body weight. [Schering AG, Report No. 1069/1070, 1969-07-04 and 1969-06-26]

The single subcutaneous administration of norethisterone enanthate (12.5 g/kg) to mice (10/sex) was tolerated without any compound-related clinical or macroscopic pathological signs. The TD50 (subcutaneous) of ZK 5410 in mice is above 12.5 g/kg body weight. [Schering AG, Report No. 868, 1968 -09 -16]

Norethisterone enanthate (ZK5410) was applied subcutaneously to rats (5/sex) at a dose of 4000 mg/kg. The animals showed transient signs of apathy and developed abscess at the application size. In pathology reduced testes size was obsserved. No animal died during observation period.

The LD50 (subcutaneous) > 4000 mg/ kg body weight. [Schering AG, Report No. 1219, 1969-05-23]

The single subcutaneous administration of norethisterone enanthate (10 g/kg) to rats (10/sex) was tolerated without any compound-related clinical signs. All animals survived the observation periode (21 days). At necropcy alle male animals showed reduced size of the testis. The TD50 (subcutaneous) of ZK 5410 in rats is above 10 g/kg body weight. [Schering AG, Report No. 866, 1968-09-16]

Norethisterone enanthate (ZK5410) was applied as single intramuscular injection to rats (5/sex) at a dose of 200 mg/kg. No substance was tolerated without any compound-related clinical signs. In pathology reduced testes size was obsserved. No animal died during observation period.

LD50 > 200 mg/kg body weight. [Schering AG, Report No. 1220, 1969-06-03]

The single intramuscular administration of a northisterone enanthate (1000 mg/kg) to rats (10/sex) caused weight loss in 2 animals after 6 - 9 days after applicaction. All male animals showed minimal decrease in testis size. All animals survived the observation period (21 days). The LD50 (intramuscular) of acute toxicity of ZK 5410 in rats is above 1000 mg/kg body weight. [Schering AG, Report No. 867, 1968-09 -16]

A single intraperitoneal administration of norethisterone enanthate (1000 mg/kg) to mice (10/sex) induced apathy in male mice 3 to 5 days after application. Two male animals died on day 3 and 4. At necropsy in one female mouse liver and stomach were adhered, in one male testes size was reduced. In two female and one male mice the liver showed single gray-yellow-white foci. LD50 > 1000 mg/kg body weight. [Schering AG, Report No. 1058 and 1057, 1969-02-06/07]

Norethisterone enanthate (ZK5410) was applied to female mice (10/dose) at the dose of 250, 500, 750, 1000, 1500 and 2500 mg/kg intraperitoneally. All animals showed signs of apathy after application. Some animals died 4 hours up to 19 days after application. Sacrificed animals showed peritonitis and adherence of inner organs as well as grayish foci in liver at macroscopic pathology. LD50 is 1000 mg/kg body weight. [Schering AG, Report No. 1075, 1969-07-17]

Norethisterone enanthate (ZK5410) was applied to male mice at the dose of 250, 500, 750, 1000, 1500 and 2500 mg/kg intraperitoneally. All animals showed signs of apathy after application. At dose 1000 mg/kg and 1500 mg/kg 4/10 and 7/10 mice, respectively died during observation period. LD50 in male mice is 1200 mg/kg body weight. [Schering AG, Report No. 1074, 1969-05-21]

A single intraperitoneal administration of norethisterone enanthate (1000 mg/kg) to rats (10/sex) was tolerated without any compound-related clinical signs. One female rat died on day 3. At necropsy animals showed adherent inner organs and peritonitis. Also athrophy of the testes and seminal vesicle as well as swelling of the liver was found. The LD50 in rats is >1000 kg/kg body weight. [Schering AG, Report No. 1062/1061, 1969-06-16 and 1969-02-21]

Norethisterone enanthate (ZK5410) was applied to rats (5/sex/group) at the dose of 500, 1000, 1400, 2000, 2800 and 4000 mg/kg intraperitoneally. All animals showed signs of apathy after application. From dose 2000 mg/kg onwards animals died during observation period. LD50 in rats is 3200 mg/kg [Schering AG, Report No. 1218, 1969-05-28]

No acute toxicity studies were conducted with ZK 5378; read across with results of studies with norethisterone enanthate (ZK 5410): Oral (mouse, non-GLP): LD50 > 2000 mg/kg (Schering AG, report no: 1060/1059, 1969-03-27 and 1969-02-24) Oral (mouse-female, non-GLP): LD50 > 5000 mg/kg (Schering AG, report no: 1053, 1969-05-21) Oral (mouse-male, non-GLP): LD50 5300 mg/kg (Schering AG, report no: 1052, 1969-06-25) Oral (rat-female, non-GLP): LD50 > 6000 mg/kg (Schering AG, report no: 1048, 1969-03-27) Oral (rat, non-GLP): LD50 > 3000 mg/kg (Schering AG, report no: 1063/1064, 1969-03-27) Oral (rat-male, non-GLP): LD50 > 4000 mg/kg (Schering AG, report no: 1199, 1969-05-30) Subcutaneous (mouse, non-GLP): LD50 > 7500 mg/kg (Schering AG, report no: 1069/1070, 1969-07-04 and 1969-06-26) Subcutaneous (mouse, non-GLP): LD50 > 12500 mg/kg (Schering AG, report no: 868, 1968-09-16) Subcutaneous (rat, non-GLP): LD50 > 4000 mg/kg (Schering AG, report no: 1219, 1969-05-23) Subcutaneous (rat, non-GLP): LD50 > 10000 mg/kg (Schering AG, Report No. 866, 1968-09-16) Intramuscular (rat, non-GLP): LD50 > 200 mg/kg (Schering AG, Report No. 1220, 1969-06-03) Intramuscular (rat, non-GLP): LD50 > 1000 mg/kg (Schering AG, Report No. 867, 1968-09-16) Intraperitoneal (mouse, non-GLP): LD50 > 1000 mg/kg (Schering AG, Report No. 1058 and 1057, 1969-02-06/07) Intraperitoneal (mouse-female, non-GLP): LD50=1000 mg/kg (Schering AG, Report No. 1075, 1969-07-17) Intraperitoneal (mouse-male, non-GLP): LD50 1200 mg/kg (Schering AG, Report No. 1074, 1969-05-21) Intraperitoneal (rat, non-GLP): LD50 > 1000 mg/kg (Schering AG, Report No. 1062/1061, 1969-06-16 and 1969-02-21) Intraperitoneal (rat, non-GLP): LD50 = 3200 mg/kg (Schering AG, Report No. 1218, 1969-05-28)

Additionally, results of acute toxicity studies with norethisterone were cited from RTECS database (Jan 2010):

Acute oral toxicity study in woman results in androgenic effects and dermatitis; TDLo: 42 mg/kg [TAmerican Journal of Obstetrics and Gynecology. (C.V. Mosby Co., 11830 Westline Industrial Dr., St. Louis, MO 63146) V.1- 1920- v. 84, p. 962, 1962 (AJOGAH)]

The acute oral toxicity study in mice results in LD50: 6 g/kg [Drugs in Japan (Ethical Drugs). (Yakugyo Jiho Co., Ltd., Tokyo, Japan) v. -, p. 809, 1990 (NIIRDN)]

Justification for classification or non-classification

Based on the data for surrogate no classification for acute toxicity according to Regulation (EC) No. 1272/2008 (CLP) is required for norethisterone.