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Description of key information

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 (norethisterone). 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 (ZK 5410) are taken as surrogate of norethisterone. For the dermal route no studies are available for the esters, too. Because the substance has shown to be non-toxic via the oral route with an LD50 > 3000 mg/kg and no compound-related clinical signs, it may be expected with high certainty that it is also non-toxic via the dermal route.


 


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 (norethisterone).


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
Reference
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 (norethisterone), 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 for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 3 000 mg/kg bw
Based on:
test mat.
Mortality:
males: no mortality
females: 1/10 died on day 3
Clinical signs:
males: no clinical signs
females: 1/10 was comatose on day 1-2 and died on day 3; the other animals did not show any clinical signs
Gross pathology:
males: unremarkable
females: 1/10 showed stomach overloading, stomach hyperaemia, enteritis; no other effects were noted at necropsy
Interpretation of results:
GHS criteria not met
Executive summary:

No acute toxicity studies were conducted with ZK 5378 (norethisterone). 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 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 single oral administration of the test item to 10 female rats 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.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
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

Additional information

No acute toxicity studies were conducted with Norethisterone. Instead, data of its ester derivatives Norethisterone acetate and Norethisterone enantate can be used for acute toxicity assessment of Norethisterone, because both esters are rapidly cleaved in vivo with release of Norethisterone as the actual pharmacologically active ingredient. However, the available acute studies of the esters (with oral, s.c., i.p., and i.m. administration) do not fulfil current guideline requirements as they were conducted decades ago during the pharmacological development of the substances. Nevertheless, the endpoint can be reliably assessed for Norethisterone based on read across for the following reasons:


-         For the majority of studies sufficient documentation is available to enable at least allocation to Klimisch reliability category 2.


-         The studies were conducted and reviewed in the highly regulated context of pharmaceutical development.


-         Several studies exist with rats and mice that differ only e.g. in the formulation used. The results, however, per exposure route and species, revealed to be in good agreement, thus confidence is achieved by means of a weight of evidence evaluation.


With respect to acute oral toxicity, it was shown to be low for Norethisterone acetate and Norethisterone enantate with e.g. rat LD50 oral of > 2000 mg/kg.


Following p.o. and i.p. administration in mice clinical signs were dominated by apathy, spasms, alterations of the gastric mucosa and the liver. Following s.c. administrations the only clinical sign was apathy; the difference can be attributed to the slower absorption of the substance following s.c. admin. Similar clinical signs were observed in rats following p.o. administration, with the exception of spasms, that did not occur. Additionally, in rat discoloration of liver and heart, clouded urine and atrophy of testes, seminal vesicle and prostate were observed.


 


Oral Studies 


The single oral administration of Norethisterone enanthate (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: 1064, 1969-03-27]


 


The single oral administration of Norethisterone enantate 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. [Schering, study no. 1063, 27.03.1969]


 


The single oral administration of Norethisterone enanthate (ZK5410) 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, study no. 1048, 27.03.1969]


 


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, study no. 1199, 30.05.1969]


 


The single oral administration of a norethisterone enanthate (2000 mg/kg) to 10 male mice 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, study no. 1059, 24.02.1969]


 


The single oral administration of a norethisterone enanthate (2000 mg/kg) to 10 female mice 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, study no. 1060, 27.03.1969]


 


Male mice (10/group) treated with a single oral application of norethisterone enanthate (ZK 5410) at doses of 1000, 1400, 2000, 2800, 5000 and 7500 mg/kg developed apathy. Some animals died 2 -6 days after application. In macroscopic pathology no effects could be observed in sacrificed animals. Died animals had haemorrhages in the stomach. The LD50 oral is 5300 mg/kg body weight. [Schering, study no. 1052, 25.06.1969]


 


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, study no. 1053, 21.05.1969]


 


Norethisterone acetate was applied orally at dose levels of 500, 720, 1000, 1400, 2000 mg/kg. Apathy was observed immediately after administration of the substance, later some animals developed clonic convulsions. Animals died 3 h to 8 d after administration of the substance. The oral LD50 = 1400 mg/kg in mice. [Schering, study no. 497, 02.01.1968]


 


The single oral administration of norethisterone acetate in sesame oil to male and female rats resulted in a LD50 of 2800 mg/kg body weight. When administered as microcrystalline suspension, the LD50 was 4000 mg/kg bw. [Schering, study no. 220, 25.04.1966]


 


Norethisterone acetate was applied orally at a single dose at levels from 2000 to 8000 mg/kg in male rats and from 1000 -8000 mg/kg in female rats. Apathy and decrease of spontaneous movement were observed in all animals. The oral LD50 in male rat was 3470 mg/kg; the LD50 in female rat was 3120 mg/kg. [Nihon Schering, study no. 4301, 22.12.1978]


 


Subcutaneous studies


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 period (21 days). At necropsy alle male animals showed reduced size of the testis.


The TD50 (subcutaneous) of norethisterone enanthate in rats is >10 g/kg body weight.[Schering, study no. 866, 16.09.1968]


 


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 observed. No animal died during observation period.


The LD50 (subcutaneous) > 4000 mg/ kg body weight.[Schering, study no. 1219, 23.05.1969]


 


Norethisterone acetate was applied subcutaneously to rat (10/sex) at a single dose of 10000 mg/kg. All animals showed signs of apathy after application. No mortality occurred during the study. The LD50 was >10000 mg/kg.[Nihon Schering, study no 4301, 22.12.1978]


 


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, study no. 868, 16.09.1968]


 


After the single subcutaneous administration of norethisterone enanthate (ZK 5410) at the doses of 2500, 3750, 5000 and 7500 mg/kg to male mice (10/dose) the animals showed transient signs of apathy and some developed abscesses at the application site. 2/10 mice died at 2500 mg/kg and 1/10 at 3750 mg/kg and at high dose. LD50 > 7500 mg/kg body weight.[Schering, study no. 1069, 04.07.1969]


 


The single subcutaneous administration of norethisterone acetate (2.5 g/kg) to mice (5/sex) was tolerated without any compound-related clinical or macroscopic pathological signs. The LD50 (subcutaneous) in mice is above 2.5 g/kg body weight.[Schering, study no. 414 B, 10.01.1968]


 


After the single subcutaneous administration of norethisterone enanthate (ZK 5410) at the doses of 2500, 3750, 5000 and 7500 mg/kg to female mice (10/dose) the animals showed transient signs of apathy and some developed abscesses at the application site. At 3750 mg/kg died 3/10 and at high dose 1/10 animals, respectively. LD50 > 7500 mg/kg body weight.[Schering, study no. 1070,26.06.1969]


 


Intramuscular Studies


The single intramuscular administration of a norethisterone enanthate (1000 mg/kg) to rats (10/sex) caused weight loss in 2 animals after 6 - 9 days after application. 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, study no. 867, 16.09.1968]


 


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


LD50 > 200 mg/kg body weight.[Schering, study no. 1220, 03.06.1969]


 


Intraperitoneal Studies


Norethisterone enanthate (ZK5410) was applied to rats (5/sex/group) at the dose of 500, 1000, 1400, 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, study no. 1218, 28.05.1969]


 


A single intraperitoneal administration of norethisterone enanthate (1000 mg/kg) to rats (10 male) was tolerated without any clinical signs. At necropsy 6 animals showed peritonitis with adherence of organs. Also atrophy of the testes and seminal vesicle as well as swelling of the liver was found. LD50 > 1000 mg/kg body weight. [Schering, study no. 1061, 21.02.1969]


 


A single intraperitoneal administration of norethisterone enanthate (1000 mg/kg) to rats (10 female) was tolerated without any compound-related clinical signs. One animal died on day 3. At necropsy animals showed adherent inner organs and peritonitis. The LD50 in female rats is >1000 kg/kg body weight. [Schering, study no. 1062, 16.06.1969]


 


Norethisterone acetate was applied intraperitoneally to rat (10/sex/group) at dose levels of 500, 720, 1000, 1400, 2000 mg/kg in males and 360, 500, 720, 000, 1400, 2000 mg/kg in females. All animals showed signs of apathy after application. Mortality was observed from 500 mg/kg in females and from 720 mg/kg in males. The LD50 in male rat is 1033 mg/kg and in female rat 816 mg/kg. [Nihon Schering, study no. 4301, 22.12.1978]


 


LD50 mouse (intraperitoneal) norethisterone acetate is 500 mg/kg body weight (95% c.i. 440 - 570) [Schering, 11.09.1963]


 


A single intraperitoneal administration of norethisterone enanthate (1000 mg/kg) to 10 male mice induced apathy 3 to 5 days after application. Two animals died on day 3 and 4. At necropsy in one male testes size was reduced and in one other mouse the liver showed single yellow foci. LD50 > 1000 mg/kg body weight. [Schering, study no. 1057, 07.02.1969]


 


A single intraperitoneal administration of norethisterone enanthate (1000 mg/kg) to 10 female mice were without any substance-related clinical signs. At necropsy in one mouse liver and stomach were adhered. In two mice the liver showed single gray-white foci. LD50 > 1000 mg/kg body weight. [Schering, study no. 1058, 06.02.1969]


 


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. At high dose of 2500 mg/kg all animals died within 3 days after treatment. LD50 in male mice is 1200 mg/kg body weight. [Schering, study no. 1074, 21.05.1969]


 


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, study no. 1075, 17.07.1969]


 


Norethisterone acetate was applied to mice (5/sex/group) at dose levels of 250, 360, 500, 1000, 1400, 1800, 2500 mg/kg intraperitoneally. All animals showed signs of apathy after application. Clonic convulsions and mortality were observed from 500 mg/kg bw. The LD50 in mice is 619 mg/kg [Schering, study no. 441, 10.01.1968]


 


 


Rat studies






































































































Exposure route


 

Norethisterone acetate


 


 

Norethisterone enantate


 

oral


 

LD50 Rat (♂+♀):


2800 mg/kg bw


(formulated in sesame oil)


4000 mg/kg bw


(microcrystalline suspension)


[Schering, study no. 220, 25.04.1966]


 

LD50 Rat (♂):


> 3000 mg/kg


(formulated in benzyl benzoate/castor oil)
[Schering, study no. 1063, 27.03.1969]


 

 


 

LD50 Rat
(♂): 3470 mg/kg bw


(♀): 3120 mg/kg bw


(formulated in aqueous CMC)


[Nihon Schering, study no. 4301, 22.12.1978]


 

LD50 Rat (♀):


> 3000 mg/kg


(formulated in benzyl benzoate/castor oil)
[Schering, study no. 1064, 27.03.1969]


 

 


 

 


 

LD50 Rat (♂):


> 4000 mg/kg


(microcrystalline suspension)
[Schering, study no. 1199, 30.05.1969]


 

 


 

 


 

LD50 Rat (♀):


> 6000 mg/kg


(microcrystalline suspension)
[Schering, study no. 1048, 27.03.1969]


 

s.c.


 

LD50 Rat
(♂): 10000 mg/kg bw; (♀): 816 mg/kg bw


(formulated in aqueous CMC)


(♂+♀): 7500 mg/kg bw


(formulated in benzyl benzoate/castor oil)


[Nihon Schering, study no 4301, 22.12.1978]


 

LD50 Rat (♂+♀):


> 10000 mg/kg bw


(formulated in benzyl benzoate/castor oil)


[Schering, study no. 866, 16.09.1968]


 

 


 

 


 

LD50 Rat (♂+♀):


> 4000 mg/kg bw


(microcrystalline suspension)


[Schering, study no. 1219, 23.05.1969]


 

i.p


 

LD50 Rat
(♂): 1033 mg/kg bw


(♀): 816 mg/kg


(formulated in aqueous CMC)


[Nihon Schering, study no. 4301, 22.12.1978]


 

LD50 Rat (♂):


> 1000 mg/kg bw


(formulated in benzyl benzoate/castor oil)


[Schering, study no. 1061, 21.02.1969]


 

 


 

 


 

LD50 Rat (♀):


> 1000 mg/kg bw


(formulated in benzyl benzoate/castor oil)


[Schering, study no. 1062, 16.06.1969]


 

 


 

 


 

LD50 Rat (♂+♀):


Ca. 3200 mg/kg bw


(microcrystalline suspension)


[Schering, study no. 1218, 28.05.1969]


 

i.m.


 

 


 

LD50 Rat (♂+♀):


> 1000 mg/kg bw


(formulated in benzyl benzoate/castor oil)
[Schering, study no. 867, 16.09.1968]


 

 


 

 


 

LD50 Rat (♂+♀):


> 200 mg/kg bw


(microcrystalline suspension)
[Schering, study no. 1220, 03.06.1969]


 

 


Mouse studies






































































































 


Exposure route


 

Norethisterone acetate


 


 

Norethisterone enantate


 

Oral


 

LD50 Mouse (♂+♀):


1400 mg/kg


(microcrystalline suspension)


[Schering, study no. 497, 02.01.1968]


 

LD50 Mouse (♂):


> 2000 mg/kg bw


(formulated in benzyl benzoate/castor oil)


[Schering, study no. 1059, 24.02.1969]


 

 


 

 


 

LD50 Mouse (♀):


> 2000 mg/kg bw


(formulated in benzyl benzoate/castor oil)


[Schering, study no. 1060, 27.03.1969]


 

 


 

 


 

LD50 Mouse (♂):


> 5000 mg/kg bw


(microcrystalline suspension)


[Schering, study no. 1052, 25.06.1969]


 

 


 

 


 

LD50 Mouse (♀):


> 5000 mg/kg bw


(microcrystalline suspension)


[Schering, study no. 1053, 21.05.1969]


 

s.c.


 

LD50 Mouse (♂+♀):


> 2500 mg/kg bw


(microcrystalline suspension)


[Schering, study no. 414 B, 10.01.1968]


 

LD50 Mouse (♂+♀):


> 12500 mg/kg bw


(formulated in benzyl benzoate/castor oil)


[Schering, study no. 868, 16.09.1968]


 

 


 

 


 

LD50 Mouse (♀):


> 7500 mg/kg bw


(microcrystalline suspension)


[Schering, study no. 1069, 04.07.1969]


 

 


 

 


 

LD50 Mouse (♀):


> 7500 mg/kg bw


(microcrystalline suspension)


[Schering, study no. 1070,26.06.1969]


 

i.p.


 

LD50 Mouse (♂+♀):


500 mg/kg bw


(formulated in gum arabic)


[Schering, 11.09.1963]


 

LD50 Mouse (♂):


> 1000 mg/kg bw


(formulated in benzyl benzoate/castor oil)


[Schering, study no. 1057, 07.02.1969]


 

 


 

LD50 Mouse (♂+♀):


619 mg/kg bw


(microcrystalline suspension)


[Schering, study no. 441, 10.01.1968]


 

LD50 Mouse (♀):


> 1000 mg/kg bw


(formulated in benzyl benzoate/castor oil)


[Schering, study no. 1058, 06.02.1969]


 

 


 

 


 

LD50 Mouse (♂):


Ca. 5000 mg/kg bw


(microcrystalline suspension)


[Schering, study no. 1074, 21.05.1969]


 

 


 

 


 

LD50 Mouse (♀):


1000 mg/kg bw


(microcrystalline suspension)


[Schering, study no. 1075, 17.07.1969]


 

 


 


Additionally, results of acute toxicity studies with norethisterone were cited from RTECS database (accessed 04/2021):


 


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.

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