Registration Dossier

Diss Factsheets

Administrative data

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Effects on fertility

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.


 


 

Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

There are no internal fertility studies with norethisterone available. However, 49 fertility studies with norethisterone are cited in RTECS database (accessed 04/2021), describing similar effects. The most representative results are reported here:


 


Single oral application to rabbits results in effects on fertility not further specified, TDLo: 125 ug/kg (1D pre) ["The Control of Fertility," Pincus, G., New York, Academic Press, 1965 -,57,1965 (85GRAA)]


 


Daily oral administration of norethisterone to unpregnant women over 52 weeks results in menstrual cycle changes or disorders; TDLo: 2190 ug/kg (52W pre) [Acta Endocrinologica, Supplementum (Copenhagen). (Periodica, Skolegade 12 E, DK-2500 Valby, Denmark) No.1- 1948- v. 144, p. 7, 1970 (ACEDAB)]


 


Single oral application to rabbits one day prior to mating results in effects on the mating performance (e.g., number of sperm positive females per number of females mated; number of copulations per number of estrus cycles); TDLo: 313 ug/kg (1D pre) [Acta Endocrinologica, Supplementum (Copenhagen). (Periodica, Skolegade 12 E, DK-2500 Valby, Denmark) No.1- 1948- v. 73, p. 17, 1963 (ACEDAB)]


 


Oral application to men over 25 days result in paternal effects on spermatogenesis (including genetic material, sperm morphology, motility, and count) and impotence; TDLo: 7143 ug/kg (25D male) [Acta Endocrinologica (Copenhagen). (Periodica, Skolegade 12 E, DK-2500 Valby, Denmark) V.1- 1948- v. 37, p. 75, 1961 (ACENA7)]


 


Oral administration of norethisterone to unpregnant women over 20 days results in maternal effects on uterus, cervix and vagina and in other effects on fertility not further specified; TDLo: 4 mg/kg (20D pre) [American Journal of Obstetrics and Gynecology. (C.V. Mosby Co., 11830 Westline Industrial Dr., St. Louis, MO 63146) V.1- 1920- v. 85, p. 427, 1963 (AJOGAH)]


 


Male rats received norethisterone orally daily for 14 days. This results in paternal effects on prostate, seminal vessicle, Cowper's gland and accessory glands; TDLo: 28 mg/kg (14D male) [Annals of the New York Academy of Sciences. (New York Academy of Sciences, 2 E. 63rd St., New York, NY 10021) V.1- 1877- v. 71, p. 500, 1958 (ANYAA9)]


 


Daily inhalation of norethisterone of male monkeys over 60 days results in paternal effects on spermatogenesis (including genetic material, sperm morphology, motility, and count) testes, epididymis and sperm duct ; TCLo: 30 ug/kg/30M (60D male) [Biology of Reproduction. (Soc. for the Study of Reproduction, 309 W. Clark St., Champaign, IL 61820) V.1- 1969- v. 22, p. 935, 1980 (BIREBV)]


 


Intramuscular applications for 3 days to female monkeys result in menstrual cycle changes or disorders; TDLo: 3 mg/kg (3D pre)


[Biology of Reproduction. (Soc. for the Study of Reproduction, 309 W. Clark St., Champaign, IL 61820) V.1- 1969- v. 30, p. 886, 1984 (BIREBV)]


 


Daily subcutaneous application to female rabbits for 7 days result in effects on female fertility index (e.g., number of females pregnant per number of sperm-positive females, number of females pregnant per number of females mated); TDLo: 17500 ug/kg (7D pre) [Contraception. (Geron-X, Inc., POB 1108, Los Altos, CA 94022) V.1- 1970- v. 12, p. 511, 1975 (CCPTAY)]


 


Daily subcutaneous application to male rabbits for 7 days result in effects on male fertility index (e.g., number of males impregnating females per number of males exposed to fertile non-pregnant females); TDLo: 5250 ug/kg (7D male) [Contraception. (Geron-X, Inc., POB 1108, Los Altos, CA 94022) V.1- 1970- v. 12, p. 511, 1975 (CCPTAY)]


 


In women receiving norethisterone via implantat over 26 weeks effects on fertility index (e.g., number of females pregnant per number of sperm-positive females, number of females pregnant per number of females mated) were observed; TDLo: 230 ug/kg (26W pre) [Contraception. (Geron-X, Inc., POB 1108, Los Altos, CA 94022) V.1- 1970- v. 18, p. 411, 1978 (CCPTAY)]


 


The application of norethisterone via implantat to monkeys on day 1-31 of pregnancy results in abortions; TDLo: 186 ug/kg (1-31D preg) [Contraception. (Geron-X, Inc., POB 1108, Los Altos, CA 94022) V.1- 1970- v. 25, p. 97, 1982 (CCPTAY)]


 


Daily oral application to men over 42 days results in paternal effects on spermatogenesis (including genetic material, sperm morphology, motility, and count), testes, epididymis, sperm duct and in impotence and breast development; TDLo: 18 mg/kg (42D male) [Federation Proceedings, Federation of American Societies for Experimental Biology. (Bethesda, MD) V.1-46, 1942-87. v. 18, p. 1057, 1959 (FEPRA7)]


 


In mice receiving norethisterone via implant on day 1-3 of pregnancy effects on litter size (e.g., number of fetuses per litter, measured before birth) were observed; TDLo: 12 mg/kg (1-3D preg) [Journal of Endocrinology. (Biochemical Soc. Book Depot, POB 32, Commerce Way, Colchester, Essex CO2 8HP, UK) V.1- 1939- v. 20, p. 299, 1960 (JOENAK)]


 


Subcutaneous application to pregnant mice on day 6-7 of pregnancy results in pst-implantation mortality (e.g., dead and/or resorbed implants per total number of implants); TDLo: 2 mg/kg (6-7D preg) [Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- v. 15, p. 955, 1978 (OYYAA2)]

Effects on developmental toxicity

Description of key information

Embryotoxicity/teratogenicity studies with Norethisterone are not available, but with the esters Norethisterone acetate and/or Norethisterone enantate. Data of the esters 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.These studies with administration of the esters during the period of organogenesis were conducted in mice, rats, rabbits and monkeys. The high dose levels in these studies were selected with the aim of reaching the embryolethal and/or maternal toxic dose range. No teratogenic effects of the test substance were observed under the established test conditions, with the exception of masculinization in female monkeys at high doses (> / = 60 mg/kg/day Norethisterone acetate) that also led to embryo lethality.


It is known from the endocrine-pharmacological profile of norethisterone or its esters that they might be partially androgenic. Treatment of pregnant rats during the sensitive phase of fetal gonads differentiation/development following relatively high subcutaneous doses (ca. 3 mg/kg) did also lead to mascularization in the female pubs: following s.c. administration of Norethisterone or its esters during the last trimester of gestation indications of virilisation at the external genital organs of female fetuses were observed. The systemic exposure to the substance which is necessary for induction of these effects in rats exceeds the body burden resulting from therapeutic doses in humans.


Embryotoxic effects were observed in developmental toxicity studies with substance administration during the relevant period of organogenesis. In these studies, teratogenic effects were not observed, with the exception of virilization at doses that also led to embryolethality. The reproductive toxic potential 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 classification for reproductive toxicity for Norethisterone and its esters (GHS-classifications as Repr. 1A (H360F), Repr. 1B (H360D)).


 


 


 

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
other information
Study period:
02/1970 - 07/1970
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: well reported study
Qualifier:
no guideline available
Principles of method if other than guideline:
After appropriate acclimation period female rabbits were mated with male animals. 20 Pregnant mice per dose group were orally administered norethisterone acetate at doses of 12 and 48 mg/kg bw/day during GD 7-13, in each group 5/20 dams were allowed to deliver spontaneously. The other dams were sacrificed on day 18 of gestation, fetuses were removed from dams via section. All animals were examined macroscopically.
GLP compliance:
no
Limit test:
no
Species:
mouse
Strain:
ICR
Route of administration:
oral: unspecified
Vehicle:
other: tragacant 1%
Duration of treatment / exposure:
day 7- 13 of gestation
Frequency of treatment:
daily
Dose / conc.:
12 mg/kg bw/day (actual dose received)
Dose / conc.:
48 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
20 (15 caesarean section, 5 spontaneous delivery)
Control animals:
yes, concurrent vehicle
Dose descriptor:
NOAEL
Effect level:
>= 48 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: no effects observed
Abnormalities:
no effects observed
Dose descriptor:
NOAEL
Effect level:
12 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reduction in number of live offspring
changes in postnatal survival
Abnormalities:
no effects observed
Developmental effects observed:
not specified
Executive summary:

No prenatal developmental toxicity 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 a test where pregnant mice of Day 7-13 received doses of 48 and 12 mg/kg p.o., the number of perinatal death increased at a dose of 48 mg/kg. No teratogenic effects were observed at both doses.

Endpoint:
developmental toxicity
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:
no guideline available
Principles of method if other than guideline:
After appropriate acclimation period female rabbits were mated with male animals. 15-20 Pregnant rabbits per dose group were orally administered norethisterone acetate at doses of 0.1, 1.0, and 10 mg/kg bw/day during GD 6-18. On day 28 of pregnancy, fetuses were removed from dams via section. All animals were examined macroscopically.
GLP compliance:
no
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Route of administration:
oral: gavage
Vehicle:
physiological saline
Duration of treatment / exposure:
day 6-18 of gestation
Frequency of treatment:
daily
Dose / conc.:
0.1 mg/kg bw/day (actual dose received)
Dose / conc.:
1 mg/kg bw/day (actual dose received)
Dose / conc.:
10 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
control: 15
low dose: 20
mid+high dose: 17
Control animals:
yes, concurrent vehicle
Dose descriptor:
LOAEL
Effect level:
0.1 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
early or late resorptions
Abnormalities:
no effects observed
Developmental effects observed:
not specified
Executive summary:

No prenatal developmental toxicity 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, New Zealand white rabbits were administered Norethisterone acetate (ZK 5422) at dose levels of 0.1, 1.0 or 10.0 mg/kg bw/d during GD 6-18. The test item led dose-dependently to embryolethal effects. Toxic effects (decrease in body weight gain) were observed for the dams during the period of administration from a dose of 1.0 mg/kg onwards. At doses of 0.1 and 1.0 mg/kg a slight (29 %) or distinct (71 %) degree of fetal resorption was observed, and 100% resorption at 10 mg/kg, but no indications for a teratogenic potential was observed for the test substance.

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
other information
Study period:
7.10.1975 - 4.2.1976
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: well reported study
Qualifier:
no guideline available
Principles of method if other than guideline:
20 Pregnant rats per dose group were orally administered norethisterone acetate at doses of 12 and 48 mg/kg bw/day during GD 7-13, in each group 5/20 dams were allowed to deliver spontaneously. The other dams were sacrificaed on day 19 of gestation, fetuses were removed from dams via section. All animals were examined macroscopically.
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Route of administration:
oral: gavage
Vehicle:
other: tragacanth 1%
Duration of treatment / exposure:
day 7 - 13 of gestation
Frequency of treatment:
daily
Dose / conc.:
12 mg/kg bw/day (actual dose received)
Dose / conc.:
48 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
20 (15 caesarean section, 5 spontaneous delivery)
Control animals:
yes, concurrent vehicle
Dose descriptor:
LOAEL
Effect level:
12 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
food consumption and compound intake
water consumption and compound intake
Abnormalities:
no effects observed
Dose descriptor:
LOAEL
Effect level:
12 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
fetal/pup body weight changes
Abnormalities:
not specified
Developmental effects observed:
not specified
Executive summary:

No prenatal developmental toxicity 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 a test where pregnant rats of Day 7-13 received doses of 48 and 12 mg/kg bw/day of norethisterone acetate by oral gavage, fetal mortality was increased at doses of 48 and 12 mg/kg and increase of body weight in dams was suppressed and mean body weight of live fetuses was decreased at a dose of 48 mg/kg. No teratogenic effects were observed at both doses.

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
other information
Study period:
13. Jun 1975 to 26. Aug 1975
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: well reported study
Qualifier:
no guideline available
Principles of method if other than guideline:
25 Pregnant rats per dose group were orally administered norethisterone acetate at doses of 12 and 48 mg/kg bw/day during GD 7-13, in each group 5/20 dams were allowed to deliver spontaneously. The other dams were sacrificaed on day 19 of gestation, fetuses were removed from dams via section. All animals were examined macroscopically.

GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Route of administration:
oral: gavage
Vehicle:
physiological saline
Duration of treatment / exposure:
day 6-15 of gestation
Frequency of treatment:
daily
Dose / conc.:
0.1 mg/kg bw/day (actual dose received)
Dose / conc.:
1 mg/kg bw/day (actual dose received)
Dose / conc.:
10 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
25
Control animals:
yes, concurrent vehicle
Dose descriptor:
NOAEL
Effect level:
1 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
Abnormalities:
no effects observed
Dose descriptor:
NOAEL
Effect level:
1 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
skeletal malformations
Abnormalities:
not specified
Developmental effects observed:
not specified
Executive summary:

No prenatal developmental toxicity 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, 25 female Sprague-Dawley rats per dose were administered Norethisterone acetate (ZK 5422) at dose levels of 0.1, 1.0 or 10.0 mg/kg bw/d during GD 6-15.


No effects on the development were noted following oral administration of up to 1 mg/kg to the dams. At the high dose of 10 mg/kg, at which slightly toxic effects on the mothers (depression in weight gain) could not be excluded, developmental toxicity was observed (sign. increase of fetuses with skeletal anomalies), but no teratogenic or lethal effects.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Embryotoxicity/teratogenicity studies with Norethisterone are not available, but with the esters Norethisterone acetate and/or Norethisterone enantate. Data of the esters 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.These studies with administration of the esters during the period of organogenesis were conducted in mice, rats, rabbits and monkeys. The high dose levels in these studies were selected with the aim of reaching the embryolethal and/or maternal toxic dose range. No teratogenic effects of the test substance were observed under the established test conditions, with the exception of masculinization in female monkeys at high doses (> / = 60 mg/kg/day Norethisterone acetate) that also led to embryo lethality.


It is known from the endocrine-pharmacological profile of norethisterone or its esters that they might be partially androgenic. Treatment of pregnant rats during the sensitive phase of fetal gonads differentiation/development following relatively high subcutaneous doses (ca. 3 mg/kg) did also lead to mascularization in the female pubs: following s.c. administration of Norethisterone or its esters during the last trimester of gestation indications of virilisation at the external genital organs of female fetuses were observed. The systemic exposure to the substance which is necessary for induction of these effects in rats exceeds the body burden resulting from therapeutic doses in humans.


Embryotoxic effects were observed in developmental toxicity studies with substance administration during the relevant period of organogenesis. In these studies, teratogenic effects were not observed, with the exception of virilization at doses that also led to embryolethality. The reproductive toxic potential 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 classification for reproductive toxicity for Norethisterone and its esters (GHS-classifications as Repr. 1A (H360F), Repr. 1B (H360D)).


Some of the available information is provided in the table below, especially if the type of study suggests a relevance with respect to REACH. As rodents and rabbits, according to REACH, are the preferred species in reproductive toxicity studies, the focus of the tabulated summary below is on these species.With respect to embryotoxicity in primates see Hendricks et al., Teratology 35: 119-127, 1987 (referring to studies with Norethisterone acetate in Rhesus monkey, Baboon and Cynomolgus).


 


Mouse studies


In a test where pregnant mice of Day 7-13 received doses of 4 and 2 mg/kg s.c., fetal mortality and perinatal mortality increased at a dose of 4 mg/kg. No teratogenic effects were observed in the respective treated groups.


 


In a test where pregnant mice of Day 7-13 received Norethisterone acetate at doses of 48 and 12 mg/kg p.o., the number of perinatal death increased at a dose of 48 mg/kg. No teratogenic effects were observed at both doses.


 


Rat studies


In a test where pregnant rats of Day 7-13 received Norethisterone acetate at doses of 48 and 12 mg/kg bw/day by oral gavage, fetal mortality was increased at doses of 48 and 12 mg/kg and increase of body weight in dams was suppressed and mean body weight of live fetuses was decreased at a dose of 48 mg/kg. No teratogenic effects were observed at both doses.


 


In this study, 25 female Sprague-Dawley rats per dose were administered Norethisterone acetate (ZK 5422) at dose levels of 0.1, 1.0 or 10.0 mg/kg bw/d during GD 6-15 by oral gavage.


No effects on the development were noted following oral administration of up to 1 mg/kg to the dams. At the high dose of 10 mg/kg, at which slightly toxic effects on the mothers (depression in weight gain) could not be excluded, developmental toxicity was observed (sign. increase of fetuses with skeletal anomalies), but no teratogenic or lethal effects.


 


In a test where pregnant rats of Day 7-13 received Norethisterone acetate at doses of 4 and 2 mg/kg s.c., all newborns under fostering died at a dose of 4 mg/kg and the increase in body weight of dams was supressed at doses of 4 and 2 mg/kg. No embryotoxic effects were observed in the treated groups.


 


The single subcutaneous administration of norethisterone enanthate on day 6 p.c. to female rats (12/group) in the doses of 0, 6 and 60 mg/kg was tolerated well. Only the body weight gain of high dose females was reduced. The NOEL for maternal toxicity was 6 mg/kg body weight.


 


Rabbit studies


In this study, New Zealand white rabbits were administered Norethisterone acetate (ZK 5422) at dose levels of 0.1, 1.0 or 10.0 mg/kg bw/d during GD 6-18 by oral gavage. The test item led dose-dependently to embryolethal effects. Toxic effects (decrease in body weight gain) were observed for the dams during the period of administration from a dose of 1.0 mg/kg onwards. At doses of 0.1 and 1.0 mg/kg a slight (29 %) or distinct (71 %) degree of fetal resorption was observed, and 100% resorption at 10 mg/kg, but no indications for a teratogenic potential was observed for the test substance.


 


A single subcutaneous dose of norethisterone enanthate was administered on day 6. s.c. to female rabbits (0/10/20/40 mg/kg body weight). At 10 mg/kg 66% and at higher dose levels 100% of the embryos died. LOAEL = 10 mg/kg bw


 


The single subcutanous administration of norethisterone enanthate on day 6 p.c. to female rabbits (10 or 11 /group) in the doses of 0, 6 and 60 mg/kg resulted in reduced body weight gain of the dams and high embryo lethality in the high dose group. NOEL (embryotoxicity, maternal toxicity): 6 mg/kg


 















































Norethisterone acetate



Norethisterone enantate



Mouse studies 



Doses: 12 and 48 mg/kg bw/day, oral admin. during GD 7-13, in each group 5/20 dams were allowed to deliver spontaneously


(formulated in aq. “Tragacanth”)


[Nihon Schering, Report no. 1/2/5304, 26.12.1978]


In a test where pregnant mice of Day 7-13 received doses of 48 and 12 mg/kg p.o., the number of perinatal death increased at a dose of 48 mg/kg. No teratogenic effects were observed at both doses.



 



Doses: 2 and 4 mg/kg bw/day, s.c. admin. during GD 7-13, in each group 5/20 dams were allowed to deliver spontaneously


(formulated in sesame oil)


[Nihon Schering, Report no. 1/2/5306, 26.12.1978]


In a test where pregnant mice of Day 7-13 received doses of 4 and 2 mg/kg s.c., fetal mortality and perinatal mortality increased at a dose of 4 mg/kg. No teratogenic effects were observed in the respective treated groups.



 



Rat studies 



Doses: 0.1, 1.0, and 10 mg/kg bw/day, p.o. admin. during GD 6-15


(microcrystalline suspension)


[Schering, Report no. 2330, Study no TX 75493 (Prot. no 493/75), 23.08.1976]


No effects on the development were noted following oral admin. of up to 1 mg/kg to the dams. At the high dose of 10 mg/kg, at which slightly toxic effects on the mothers (depression in weight gain) could not be excluded, developmental toxicity was observed (sign. increase of fetuses with skeletal anomalies), but no teratogenic or lethal effects.



Doses: 6.0 and 60 mg/kg, s.c. admin. on GD 6 (single dose, depot activity)


(formulated in benzyl benzoate/castor oil)


[Schering, Study no. 1380, 10.04.1970]


The only substance-related effect was a statistically significant decrease in body weight gain following s.c. admin. at 60 mg/kg. All fetal anomalies reported were only occasionally seen and were already known as spontaneous malformation in the rat strain used, thus a treatment-related effect was not concluded. In any dose group a virilizing or feminizing effect was seen.



Doses: 12 and 48 mg/kg bw/day, p.o. admin. during GD 7-13, in each group 5/20 dams were allowed to deliver spontaneously


(formulated in aq. “Tragacanth”)


[Nihon Schering, Report no. 1/2/5303, 26.12.1978]


In a test where pregnant rats of Day 7-13 received doses of 48 and 12 mg/kg bw/day, fetal mortality was increased at doses of 48 and 12 mg/kg and increase of body weight in dams was suppressed and mean body weight of live fetuses was decreased at a dose of 48 mg/kg. No teratogenic effects were observed at both doses.



 



Doses: 2 and 4 mg/kg bw/day, s.c. admin. during GD 7-13, in each group 5/20 dams were allowed to deliver spontaneously


(formulated in sesame oil)


[Nihon Schering, Report no. 1/2/5305, 26.12.1978]


In a test where pregnant rats of Day 7-13 received doses of 4 and 2 mg/kg s.c., all newborns under fostering died at a dose of 4 mg/kg and the increase in body weight of dams was supressed at doses of 4 and 2 mg/kg. No embryotoxic effects were observed in the treated groups.



 



Rabbit studies



Doses: 0.1, 1.0, and 10 mg/kg bw/day, p.o. admin. during GD 6-18


(microcrystalline suspension)


[Schering, Report no. 2300, Study no. 3959 (Prot. No. 494/75), 12.07.1976]


In rabbits the test item led dose-dependently to embryolethal effects. Toxic effects (decrease in body weight gain) were observed for the dams during the period of administration from a dose of 1.0 mg/kg onwards. At doses of 0.1 and 1.0 mg/kg a slight (29 %) or distinct (71 %) degree of fetal resorption was observed, respectively, but no indications for a teratogenic potential was observed for the test substance.



Doses: 6.0 and 60 mg/kg, s.c. admin. on GD 6 (single dose, depot activity)


(formulated in benzyl benzoate/castor oil)


[Schering, Report no. 186, Study no. 1296, 03.08.1971]


Administration of 60 mg/kg on Day 6 p.c. were clearly (100%) embryotoxic (embryolethal), whereas doses of 6 mg/kg were tolerated without symptoms. 



 



Doses: 10, 20, and 40 mg/kg bw, s.c. admin. on GD 6 (single dose, depot activity)


(formulated in benzyl benzoate/castor oil)


[Reprotox Muenster, Report of 28.10.1975 and Schering commentary no. 2022 of 06.01.1976]


The embryotoxic threshold in the rabbit was concluded to be between 6 (see previous study Report no 186) and 10 mg/kg following a single s.c. admin. with the substance, the threshold for a 100 % embryolethal effect between 10 and 20 mg/kg. 10 mg/kg was considered a partly embryolethal dose. A teratogenic effect could not be revealed at any dose.



 


Peri- and postnatal toxicity












Rat studies



Studies with Norethisterone and Norethisterone acetate, Doses of 0.3, 1.0, 3.0, and 10 mg/animal/day, s.c. admin. on GD 22 (last trimester of pregnancy)


(formulated in benzyl benzoate/castor oil)


[Schering, Report no. 5127, 21.06.1982]


A lengthening of the anogenital distance in female fetuses was observed from a dose of 1mg/animal/day onwards (= approx.3 mg/kg bw/day)



 


 


Additionally, 17 developmental toxicity studies with norethisterone are cited in RTECS database (accessed 04/2021), describing similar effects.


The most representative results are reported here:


Daily oral application to women on week 5 -25 of pregnancy results in specific developmental abnormalities of the urogenital system in the offsprings; TDLo: 28 mg/kg (5-25W preg) [American Journal of Diseases of Children. (AMA, 535 N. Dearborn St., Chicago, IL 60610) V.1-80(3), 1911-50: V.100- 1960- v. 106, p. 586, 1963 (AJDCAI)]


 


Subcutaneous application to guinea pigs on day 18-60 of pregnancy result in specific developmental abnormalities of the endocrine and urogenital system; TDLo: 86 mg/kg (18-60D preg) [Fertility and Sterility. (American Fertility Soc., 608 13th Ave. S, Birmingham, AL 35282) V.1- 1950- v. 19, p. 606, 1968 (FESTAS)]


 


Oral application of norethisterone to female rats on day 15-17 of pregnancy results in fetotoxicity (except fetal death) and specific developmental abnormalities on skin, skin appendages and musculoskeletal system; TDLo: 188 mg/kg (15-17D preg) [Indian Journal of Experimental Biology. (Publications and Information Directorate, CSIR, Hillside Rd., New Delhi 110 012, India) V.1- 1963- v. 21, p. 591, 1983 (IJEBA6)]


 


Daily application of norethisterone (route unreported) to women during week 6-20 of pregnancy results in behavioural changes of the newborn; TDLo: 12 mg/kg (6-20W preg) [Science. (American Assoc. for the Advancement of Science, 1333 H St., NW, Washington, DC 20005) V.1- 1895- v. 211, p. 1171, 1981 (SCIEAS)]


 

Mode of Action Analysis / Human Relevance Framework

No internal experimental data to the reproductive toxicity of Norethisterone are available. Results of studies conducted with an ester of norethisterone (norethisterone enanthate, ZK 5410) and studies cited in RTECS database (accessed 04/2021) are regarded as representative.


 


In humans a dose of appr. 350 µg norethisterone/woman/day (administered alone without estrogens) is an effective dose for oral contraception. Thus, reversible fertility disorders are to be reckoned with in women after administration such doses. Embryotoxicity studies were carried out with the esters, norethisterone acetate and norethisterone enanthate, in mice, rats rabbits and monkeys. There was no indication of a teratogenic potential with the exception of signs of masculinization in female monkey fetuses after high doses of norethisterone acetate (from 60 mg/kg/day), which were sufficient to cause embryo-lethal effects. Treatment of pregnant rats during the sensitive phase of differentiation of the fetal sex organs also led to masculinization of female fetuses following relatively high subcutaneous doses (>1 mg/kg BW/day). Signs of masculinization of female embryos have been also described in humans after treatment with high doses of norethisterone or norethisterone acetate (10 to 40 mg/woman/day) during the sensitive phase of fetal sexual differentiation (from day 45 following conception). On the basis of available data, 10 mg/woman/day p.o. can be taken as the threshold dose for the occurrence of these anomalies in humans. At uptake by nursing mothers, norethisterone may pass into the milk and affect the development of the child.

Justification for classification or non-classification

The following self classification for norethisterone is recommended according to Regulation (EC) No.1272/2008 (CLP) :


 


Repr. 1A (H360FD)


Additionally norethisterone is allocated to the hazard category for effects on or via lactation (H362: May cause harm to breast-fed children).


 


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).


The associated documentation and justification for grouping steroid hormones and their classification was published in 09/1999. Norethisterone is mentioned in attachment 2 on page 17.

Additional information