Norethisterone

Carcinogenicity

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.

 

Overall, in chronic studies both esters indicate a higher incidence of benign tumors in rats and mice at sufficient high dosages.  It should be kept in mind that in general sexual steroids might stimulate the growth of hormone-dependent tissues and tumors and by this may have a promoting effect on pre-existing preneoplastic lesions. This is considered in the TRGS 905 (Technische Richtlinien für Gefahrstoffe/Technical Rule for Hazardous Substances 905, published by the German Federal Institute for Occupational Safety and Health, last update 13.03.2020) which concludes a possible cancerogenic potential (GHS Carc. 2, H351) for Norethisterone and its esters. Despite that, due to a positive benefit versus risk profile, Norethisterone and its enantate have been listed since decades for its contraceptic effect in the WHO Model List of Essential Medicines.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

other information

Study period:

Nov. 1975 to Nov 1977

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

documentation insufficient for assessment

Qualifier:

no guideline available

Principles of method if other than guideline:

In this 80 weeks study mice (40/sex/group) were treated after with norethisterone enanthate in feed in doses of 0, 0.25, 1.5, and 10.0 mg/kg bw/d. All animals were observed daily for clinical signs. Surviving animals were sacrificed after 80 weeks application and examined macro- and microscopically.

GLP compliance:

no

Species:

mouse

Sex:

male/female

Route of administration:

oral: feed

Duration of treatment / exposure:

80 weeks

Frequency of treatment:

continuously

Post exposure period:

no

Dose / conc.:

0.25 mg/kg bw/day (actual dose received)

Dose / conc.:

1.5 mg/kg bw/day (actual dose received)

Dose / conc.:

10 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

40/sex/dose

Control animals:

yes, concurrent vehicle

Relevance of carcinogenic effects / potential:

There was no macroscopic evidence of treatment-related tumour formation. Statistically significant changes in tumour incidences were recorded without dose-relationship, a higher incidence of pituitary adenomas and liver affection was noticed in males at a dose of 10 mg/kg bw/day.

Dose descriptor:

NOAEL

Effect level:

10 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no macroscopic evidence of treatment-related tumour formation

Conclusions:

There was no macroscopic evidence of treatment-related tumour formation. Statistically significant changes in tumour incidences were recorded without dose-relationship, a higher incidence of pituitary adenomas and liver affection was noticed in males at a dose of 10 mg/kg bw/day.

Executive summary:

No carcinogenicity studies were conducted with ZK 5378 (norethisterone). Results of studies conducted with an ester of norethisterone (norethisterone acetate, ZK 5422) are regarded as representative as most likely ester cleavage occurs in vivo after administration.

In this study of norethisterone acetate for potential carcinogenicity in prolonged administration to mice, dietary concentrations providing daily dosages of 0.25, 1.5 and 10.0mg/kg bw were fed over a period of 80 weeks.

Weight-gain in males receiving l0 mg/kg was slightly but consistently reduced, without effect on food intake with this exception, growth performance and survival were unaffected by treatment.

Macroscopic evidence of response to treatment at l0 mg/kg included reduction of testes, ovaries, seminal vesicles and prostate glands, apart from reduced seminal vesicles at 1.5 mg/kg, lower dosage-groups were unaffected.

There was no macroscopic evidence of treatment-related tumour formation. Statistically significant changes in tumour incidences were recorded without dose-relationship, a higher incidence of pituitary adenomas and liver affection was noticed in males at a dose of 10 mg/kg bw/day.

Reference 2

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: well reported study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)

GLP compliance:

no

Species:

rat

Strain:

other: Holtzman

Sex:

male/female

Route of administration:

oral: feed

Duration of treatment / exposure:

105 weeks

Frequency of treatment:

continuously

Post exposure period:

no

Dose / conc.:

0.4 mg/kg bw/day (actual dose received)

Dose / conc.:

4 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

50/sex/dose; 100/sex in control

Control animals:

yes, plain diet

Relevance of carcinogenic effects / potential:

basically no difference with respect to tumour incidence between substance treated animals and control

Dose descriptor:

dose level:

Effect level:

4 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no differences between treated or untreated animals with regard to tumor incidences. A high incidence of pituitary adenoma and liver affection was noted at a dose of 4 mg/kg

Conclusions:

In general, no differences were revealed between treated or untreated animals with regard to tumor incidences. A high incidence of pituitary adenoma and liver affection was noted at a dose of 4 mg/kg

Executive summary:

No carcinogenicity studies were conducted with ZK 5378 (norethisterone). Results of studies conducted with an ester of norethisterone (norethisterone acetate, ZK 5422) are regarded as representative as most likely ester cleavage occurs in vivo after administration.

Groups of 50 Holtzman albino rats, 7-8 weeks-of-age, were daily given doses of Norethisterone acetate mixed with the diet for 105 weeks. Diet levels used were 0.00075% and 0.0075%, corresponding to approx. 0.4 and 4 mg/kg bw/d. Control groups of 100 animals of each sex were held under identical conditions, except that they were given standard ration only.

In comparison to untreated rats, the treated groups showed reduced food intake and weight gain, and a notable increased survival, but with no significant alteration in types of spontaneous disease. Animals in all treated groups had transient hair loss.

Male and female rats given the substance, as compared to untreated animals had no significant difference in total crude tumor incidence in cumulative probability of tumor development, or in tumors per animal. F'urther, female rats had a significant delay in onset of tumor development. Both male and female rats given the higher dosage had mastopathy, a relative increase in liver weight, an increased incidence of hepatic cell hyperplasia, regenerative nodules, and adenomas. There was a dose-related gonadal atrophy in males and uterine lesions and polyps in females.

Reference 3

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

other information

Study period:

Jan 1969 - Nov 1971

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

documentation insufficient for assessment

Qualifier:

no guideline available

Principles of method if other than guideline:

In this 85 weeks(male) or 104 weeks(female) study rats (40/sex/group) were treated with norethisterone acetate via gavage in doses of 0.05, 1.25, and 31.25 mg/kg bw/d. General conditions were checked every day. Food and water consumption and body weight were measured once a week. Urinalysis and hematological (in peripheral blood and bone marrow) blood chemical (in serum) and pathological (macroscopy, microscopy, organ weight) examinations were carried out three times (at 28 weeks, 56 weeks and end of test). Surviving animals were sacrificed after 85 weeks(male) or 104 weeks(female) and examined macro- and microscopically.

GLP compliance:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

other: 1g tragant per 100 mL distilled water

Duration of treatment / exposure:

85 weeks(male) or 104 weeks(female)

Frequency of treatment:

daily

Post exposure period:

no

Dose / conc.:

0.05 mg/kg bw/day (actual dose received)

Dose / conc.:

1.25 mg/kg bw/day (actual dose received)

Dose / conc.:

31.25 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

30/sex/dose

Control animals:

yes, concurrent vehicle

Relevance of carcinogenic effects / potential:

Relevant effects: increase of benign hepatocellular adenoma and nodular hyperlasia and decrease of incidence of pituitary adenomas
No malign tumours

In some rats of each group including control, fibroadenoma, adenocarcinoma or adenoma with lactation of mammary gland and adenoma of pituitary gland were found.

Conclusions:

In some rats of each group including control, fibroadenoma, adenocarcinoma or adenoma with lactation of mammary gland and adenoma of pituitary gland were found.

Executive summary:

No carcinogenicity studies were conducted with ZK 5378 (norethisterone). Results of studies conducted with an ester of norethisterone (norethisterone acetate, ZK 5422) are regarded as representative as most likely ester cleavage occurs in vivo after administration.

Chronic toxicity of Norethisterone acetate was investigated in JCL-SD rats. The rats were administered orally the substance by oral tube at dose levels of 0.05, 1.25 and 31.25 mg/kg/day for 85 weeks(male) or 104 weeks(female). General conditions were checked every day. Food and water consumption and body weight were measured once a week. Urinalysis and hematological (in peripheral blood and bonemarrow) blood chemical (in serum) and pathological (macroscopy, microscopy, organ weight) examinations were carried out three times (at 28 weeks, 56 weeks and end of test).

Particular findings recognized as influence of the substance were depression of body weight gain, decrease of total cholesterol and atrophy of prostate, seminal vesicle and ovary.

These changes were found in rats of the 31.25 mg/kg/day dose group after 56 weeks treatment and end of test and not found in rats of the other dose groups in anytime.

Furthermore in some rats of each group including control, fibroadenoma, adenocarcinoma or adenoma with lactation of mammary gland and adenoma of pituitary gland were found.

The results show that the maximum non-effective dose of norethisterone acetate in 85 weeks (male) or 104 weeks (female) oral administration was estimated at dose of slightly less than 1.25~

mg/kg/day. The 1.25 mg/kg/day dose corresponds to about 21 times the human dose, assuming that therapeutic dose in human is 3 mg/50 kg human. The toxic effects recognized in rats of highest dose group (31.25 mg/kg/day) are those generally found after administration of synthetic progestin hormones and not specific effect to the substance.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

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 (Technische Richtlinien für Gefahrstoffe/Technical Rule for Hazardous Substances 905, published by the German Federal Institute for Occupational Safety and Health, last update 13.03.2020).

Additional information

In general, for the assessment of hazard in human clinical human data have precedence over experimental animal data. For Norethisterone and its esters clinical information is available due to their long-standing pharmaceutical use.

Nevertheless, for the assessment of long-term toxicity and/or tumorigenicity a variety of studies with oral or intramuscular administration with the esters Norethisterone acetate and enantate, respectively, can be taken into account. Such studies are available with mice, rats, dogs and monkeys and a study duration of up to 10 years (monkey). Data of the esters Norethisterone acetate and Norethisterone enantate can be used for the toxicological assessment of Norethisterone, because both esters arerapidly cleaved within the mammalian organism to release the active ingredient Norethisterone, irrespective of the form which is administered. Some of the available information is provided in the dossier, especially if the type of study suggests a relevance with respect to REACH. As rodents (rats and mice), according to REACH, are the preferred species in carcinogenicity studies, and as further the non-rodent studies often were conducted with females only (for the purpose of a women’s health drug development program), the focus of the tabulated summary below is on the rodent studies.

 

In rodents, the applied oral doses in the chronic studies ranged from 0.05 to 31.25 mg/kg bw/dayin rats and 0.25 to 10 mg/kg bw/day in mice (Norethisterone acetate). In the chronic studies with i.m. administration the applied doses were about 1 (every second week) to 100 (once weekly) mg/kg bw in rats and 10 to 100 mg/kg bw (once weekly) in mice. Thus, taking into account the molecular weight and the dose regimen the dose ranges investigated does not essentially differ between Norethisterone acetate and enantate.

 

Mouse studies

In mice, chronic oral administration of Norethisterone acetate led to a higher incidence of lymphatic lymphomas in females starting at a dose of 1.5 mg/kg bw/day and a higher incidence of reticulum cell tumours starting at a dose 0.25 mg/kg bw/day, but without dose dependency, thus a relation to substance administration was considered questionable. At a dose of 10 mg/kg bw/day hyperplasia of the bile ducts was seen. Additionally, only in males decreased body weight gain, hypertrophy of liver cells, a higher incidence of benign liver tumours, pituitary adenomas, bladder carcinoma and testes atrophy were noted. In females, additionally atrophy of the ovaries, lipoidosis of the liver, adenomyositis uteri and a higher incidence of uterus cysts were reported.

 

Chronic i.m. injection of Norethisterone enantate to mice showed no statistically significant differences with respect to tumor incidences between controls and test substance-treated animals up to 30 mg/kg/week (eq. to 4.3 mg/kg/day). Only at a high dose of 100 mg/kg/week (eq. to 14 mg/kg/day) the overall tumor incidence was significantly increased, as was the transitional-cell carcinomas of the urinary bladder. On the other hand, the incidences of tumors of the lympho-reticular system was significantly decreased at this level, if compared with controls.

With respect to urinary bladder carcinoma in mice, it is considered that this only occurs at particularly high doses in the genetically predisposed mice, due the inherent estrogenic effects of the substance. The increase in benign liver cell adenomas in rats is considered as a consequence of a promoting effect of the substance on pre-existing preneoplastic lesions to which the rat is particularly sensitive.

 

Norethisterone acetate – oral admin.	Norethisterone enantate – i.m. admin.
Chronic studies
Mouse(♂+♀), 80 weeks, Doses: 0.25, 1.5, and 10.0 mg/kg bw (feed study) [Huntingdon Research Center, Report nos 3405/70/217, 3410/70/222, 3406/70/218, 27.01.1971 and Schering commentary of 30.10.1970] There was no macroscopic evidence of treatment-related tumour formation. Statistically significant changes in tumour incidences were recorded without dose-relationship, a higher incidence of pituitary adenomas and liver affection was noticed in males at a dose of 10 mg/kg bw/day.	Mouse(♂+♀), 78 weeks, Doses: 10, 30, and 100 mg/kg bw, Dose regimen: 1/week (formulated in benzyl benzoate/castor oil) [Huntingdon Research Center, Report no. 3708/70/520, 22.10.1971 and Schering commentary of 15.11.1971] With respect to tumor incidences no statistically significant differences between controls and substance-treated females at 10 or 30 mg/kg/week; only at 100 mg/kg/week there were significant differences compared to controls: increased overall tumor incidence, increased incidence of transitional-cell carcinomas of the urinary bladder, decreased incidence of tumors of the lympho-reticular system. A slight statistically non-significant increase in liver-cell adenomas and mammary gland adenocarcinomas might indicate some tumor promoting activity of the substance in these organs in mice.

 

Rat studies

Single intramuscular injections of norethisterone enanthate were applied to female rats every fortnight for 2 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, food consumption, 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

 

Single intramuscular injections of Norethisterone enanthate (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. After 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

 

Weekly Intramuscular injections of Norethisterone enanthate 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

 

Groups of 50 Holtzman albino rats, 7-8 weeks-of-age, were daily given doses of Norethisterone acetate mixed with the diet for 105 weeks. Diet levels used were 0.00075% and 0.0075%, corresponding to approx. 0.4 and 4 mg/kg bw/d. Control groups of 100 animals of each sex were held under identical conditions, except that they were given standard ration only.

In comparison to untreated rats, the treated groups showed reduced food intake and weight gain, and a notable increased survival, but with no significant alteration in types of spontaneous disease. Animals in all treated groups had transient hair loss.

Male and female rats given the substance, as compared to untreated animals had no significant difference in total crude tumor incidence in cumulative probability of tumor development, or in tumors per animal. F'urther, female rats had a significant delay in onset of tumor development. Both male and female rats given the higher dosage had mastopathy, a relative increase in liver weight, an increased incidence of hepatic cell hyperplasia, regenerative nodules, and adenomas. There was a dose-related gonadal atrophy in males and uterine lesions and polyps in females.

 

Chronic toxicity of Norethisterone acetate was investigated in JCL-SD rats. The rats were administered orally the substance by oral tube at dose levels of 0.05, 1.25 and 31.25 mg/kg/day for 85 weeks(male) or 104 weeks(female). General conditions were checked every day. Food and water consumption and body weight were measured once a week. Urinalysis and hematological (in peripheral blood and bonemarrow) blood chemical (in serum) and pathological (macroscopy, microscopy, organ weight) examinations were carried out three times (at 28 weeks, 56 weeks and end of test).

Particular findings recognized as influence of the substance were depression of body weight gain, decrease of total cholesterol and atrophy of prostate, seminal vesicle and ovary.

These changes were found in rats of the 31.25 mg/kg/day dose group after 56 weeks treatment and end of test and not found in rats of the other dose groups in anytime.

Furthermore in some rats of each group including control, fibroadenoma, adenocarcinoma or adenoma with lactation of mammary gland and adenoma of pituitary gland were found.

The results show that the maximum non-effective dose of of teh substance in 85 weeks (male) or 104 weeks (female) oral administration was estimated at dose of slightly less than 1.25 mg/kg/day. The 1.25 mg/kg/day dose corresponds to about 21 times the human dose, assuming that therapeutic dose in human is 3 mg/50 kg human. The toxic effects recognized in rats of highest dose group (31.25 mg/kg/day) are those generally found after administration of synthetic progestin hormones and not specific effect to the substance.

 

Norethisterone acetate – oral admin.		Norethisterone enantate – i.m. admin.
Rat(♂+♀), 105 weeks, Doses: 0.4, and 4.0, mg/kg bw (feed study) [Parke Davis, 15.05.1969] In general, no differences were revealed between treated or untreated animals with regard to tumor incidences. A high incidence of pituitary adenoma and liver affection was noted at a dose of 4 mg/kg.		Rat(♂+♀), 2 years, Doses: 10, 30, and 100 mg/kg bw, Dose regimen: 1/week (formulated in benzyl benzoate/castor oil) [Huntingdon Research Center, Report no. 4253/71/411, 06.06.1975 and Schering commentary 1969 of 13.11.1975] In female rats mammary gland carcinomas were increased indicating a considerable compound cumulation in the animals due to weekly intervals. The incidence of proliferative liver lesions including benign adenomas was increased.
Rat, 85 (♂)/104 (♀) weeks, Doses: 0.05, 1.25, and 31.25 mg/kg bw (formulated in aq. “Tragant”) [Nihon Schering, Report no. 1/1/4703, 02.03.1979] In some rats of each group including control, fibroadenoma, adenocarcinoma or adenoma with lactation of mammary gland and adenoma of pituitary gland were found.		Rat(♀), 2 year Doses: 1, 10, and 50 mg/kg bw, Dose regimen: every 2 weeks (formulated in benzyl benzoate/castor oil) [IRDC, Report no. 367-001, 21.04.1978 and Schering commentary 3194 of 10.05.1978] In female rats a decrease in pituitary adenomas and mammary gland fibroadenoma was observed at the mid and high dose levels (2-week injection interval), whereas cystic adenomas increased suggesting a transition from one into another form of adenoma rather than opposite changes of incidences of two tumor types. The incidence of proliferative liver lesions including benign adenomas was increased.
		Rat(♀), 2 year Doses: 6(4), 60(40), and 300 (200) mg/kg bw, Dose regimen: every 12(8) weeks for 5(6) intervals (formulated in benzyl benzoate/castor oil) [IRDC, Report no. 367-006, 30.11.1978 and Schering commentary 3666 of 06.03.1979] Study outcome as above, see IRDC, report no. 367-001.

 

Overall, in chronic studies both esters indicate a higher incidence of benign tumors in rats and mice at sufficient high dosages. It should be kept in mind that in general sexual steroids might stimulate the growth of hormone-dependent tissues and tumors and by this may have a promoting effect on pre-existing preneoplastic lesions. This is considered in the TRGS 905 (Technische Richtlinien für Gefahrstoffe/Technical Rule for Hazardous Substances 905, published by the German Federal Institute for Occupational Safety and Health, last update 13.03.2020) which concludes a possible cancerogenic potential (GHS Carc. 2, H351) for Norethisterone and its esters. Despite that, due to a positive benefit versus risk profile, Norethisterone and its enantate have been listed since decades for its contraceptic effect in the WHO Model List of Essential Medicines.

 

The available documentation of Norethisterone, Norethisterone acetate and Norethisterone enantate indicates the following further studies being available; some of these have only limited information and were conducted with one sex only, however, the overall outcome does not contradict the outcome on cancerogenicity as already summarized above.

 

Further studies with Norethisterone (oral admin.)

 

2-year study with male rats, Huntingdon Research Center (study conducted on request of Dunlop Committee, Great Britain), feed study, doses 0.08, 0.8, and 8.0 mg/kg bw/day

80-week study with male and female mice (study conducted on request of Dunlop Committee, Great Britain), feed study, doses 0.1, 0.6, 4.0, and 8.0 mg/kg bw/day

 

7-year study in female beagle dog with Micronor, Ortho Research Laboratories (study initiation July 1969, animal sacrifice August 1976), supplemental review by Ortho Pharmaceutical Corp. of 08.04.1977, final report of 11.04.1977, oral admin., doses 0.007, 0.07, 0.175, and 0.35 mg/kg bw/day, formulation in 0.25 % agar solution

 

10-year study in female monkey with Micronor, Woodard Research Corp. (study initiation October 1969), oral admin., doses 0.007, 0.07, and 350 mg/kg bw/day, formulation in ethyl alcohol

 

Further studies with Norethisterone enantate (i.m. admin.)

 

2-year study in female rat, Schering, 6585, Study nos. TX81160/TX83100, 02.02.1985, i.m. admin., doses each 200 mg Norethisterone enantate i.m. or Norethisteron plus Mestranol orally, dose regimen 8 or 12 weeks

 

7-year study in female beagle dog, IRDC 367-002, 07.08.1985, and Schering commentary nos. 2702 of 10.06.77, 3141 of 10.04.1978, 5553 of 02.08.1983, 5790 of 15.12.1983 and 7134 (TX 80291) of 29.04.1986, i.m. admin., doses 6, 60, and 150 mg/kg bw, dose regimen once weekly up to 8 weeks and then every third week
“An increased Incidence of mammary tumors in dogs after chronic administration of ZK 5410 confirmed the results of many other investigators who showed that prolonged treatment with progestogens including the naturally occurring progesterone, enhances mammary tumor formation in the Beagle dog.”

 

10-year study in female monkey, IRDC 367-003, 11.03.1988 and Schering commentary nos. 2700 of 10.06.1977, 6055 (KI83050) of 05.06.1984, 6492 (KI84132) of 08.03.1985, 8015 (TX80292) of 03.05.1988, i.m. admin., doses 6 (4), 60 (40), and 300 (200) mg/kg, dose regimen every 12 weeks for 85 weeks and then every 8 weeks

“The only findings which might be related to a possible tumorigenic effect of ZK 5410 in monkeys were endometrial carcinomas in two animals and (questionable) one pituitary adenoma, all of which occurred in the high dose group.”

 

Additionally, results of carcinogenicity studies with norethisterone were cited in RTECS database (accessed 04/2021):

 

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)]