Norethisterone

Endpoint summary

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 repeated dose toxicity studies were conducted with ZK 5378 (norethisterone). But data on its ester derivatives norethisterone acetate and/or 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. However, since the first introduction of drug preparations containing this steroidal progestin dates back more than five decades, the major part of its preclinical characterization does not fulfil the requirements applicable today to studies used for safety assessment. However, these limitations are more than compensated for by the vast amount of clinical experience gained with norethisterone and its esters in their continued and widespread therapeutic use. Therefore in conclusion the results of the preclinical characterisation of norethisterone and its esters confirm its properties as a steroidal progestin.

 

As known from an extensive data base animal experiments with progestins are only of limited predictive value for qualitative and even more for quanatitative extrapolation to humans because of a large diversity in factors responsible for endocrine regulation between experimental animals and man.

Therefore the most sensitive endpoint that would be considered in risk assessment is the lowest oral daily dose with pharmacological effects in humans of norethisterone.

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: oral, other

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

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 oral toxicity studies were conducted with ZK 5378 (norethisterone), experiments with its ester derivate norethisterone acetate 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

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

clinical biochemistry

histopathology: non-neoplastic

Dose descriptor:

dose level:

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: depression of body weight gain, decrease of total cholesterol and atrophy of prostate, seminal vesicle and ovary

Remarks on result:

other: Effects observed after 56 weeks´treatment and end of the test

Critical effects observed:

yes

Lowest effective dose / conc.:

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

System:

other: male/female reproductive system

Organ:

ovary

seminal vesicle

other: prostate

Treatment related:

yes

Executive summary:

The results show that the maximum non-effective dose of the test item in 85 weeks´(male) or 104 weeks´(female) oral administration was estimated at dose of slightly less than 1.25 mg/kg/day. The toxic effects recognized in rats of the highest dose group (31.25 mg/kg/day) are those generally found after administration of synthetic progestin hormones and not specific to the test item.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

Study duration:

chronic

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

No repeated dose toxicity studies were conducted with ZK 5378 (norethisterone).  

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, a large number of experimental studies have been conducted during the pharmacological development to evaluate the systemic tolerance and tumorigenic potential of Norethisterone and its esters Norethisterone acetate and Norethisterone enantate after repeated administration (oral, subcutaneous or intramuscular) to mice, rats, dogs and monkeys. Data of the esters Norethisterone acetate and Norethisterone enantate can be used for the toxicological assessment of Norethisterone, because both esters are rapidly 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 here, especially if the type of study suggests a relevance with regard to REACH. As rodents (rats and mice), according to REACH, are the preferred species in repeated dose 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.

Based on the studies with Norethisterone acetate chronic oral administration led in rats generally to an increased survival rate, decreased feed consumption and body weight gain, transient hair loss, atrophy of testes, dilatation, inflammation, polyps and squamous metaplasia in the uterus. In the high dose groups additionally increased liver weights, mastopathy (in males and females) and a decrease in adrenal weights were observed. In mice brown degeneration of the zona reticularis, ovulation inhibition and, only in males, hypertrophy and increase of activity in the mammary gland, as well as atrophy of the accessory sexual glands were found.

Atrophy of gonads and accessory sex organs and increase of activity in mammary glands are known typical gestagenic effects. Thus, with respect to worker safety the effects on reproductive toxicity revealed the most critical effects following repeated systemic exposure to Norethisterone.

 

 

Rat studies

In a repeated dose toxicity study Norethisterone acetate was administered to 30 JCL-SD rats/sex/dose by gavage at dose levels of 0, 0.05, 1.25, 31.25 mg/kg bw/day for 85 weeks (male) or 104 weeks (female). General conditions were checked every day. Food and water consumptions and body weight were measured once a week and recorded. Urin analysis and hematological and pathological examinations were carried out three times (at 28 weeks, 56 weeks and end of test).

The results show that the maximum non-effective dose of the test item in 85 weeks´ (male) or 104 weeks´ (female) oral administration was estimated at dose of slightly less than 1.25 mg/kg/day. The toxic effects recognized in rats of the highest dose group (31.25 mg/kg/day) are those generally found after administration of synthetic progestin hormones and not specific to the test item.

 

The subacute toxicity of Norethisterone acetate was investigated in JCL-SD rats. The substance was administered orally to the rats at dose levels of 1000 mg/kg and 5000 mg/kg bw for 30 days except for Sundays.

Within fourth week of test all animals died at 5000 mg/kg and 1/20 male and 2/20 females at 1000 mg/kg.

The particular findings were the decrease of body weight gain, decrease of hemoglobin and WBC, increase of GPT activity and total, bilirubin, atrophy of thymus, spleen, testis, prostate and seminal vesicle, follicular cystic change of ovary, papillary proliferation of uterus and proliferation of gland tissue with lactation of mammary gland.

 

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.

 

Single intramuscular injections of Norethisterone enanthate (ZK 5410) were given weekly to female rats (16 rats/dose group) over 90 days at the doses of 0, 1, 10 and 50 mg/kg. At 1 and 10 mg/kg bw the rats developed disorder of the cycle and the uterus weights (10 mg/kg) of the rats were reduced. At 50 mg/kg bw the animals were in a constant diestrus with growth depression. The organ weights of hypophysis, ovaries, uterus and thymus were reduced. Additionally hyperplasia/proliferation of granulosa cells were observed. LOAEL: 1 mg/kg

 

The subacute toxicity study of Norethisterone acetate was studied in JCL-SD rats. The rats were given subcutaneously Norethisterone acetate at dose levels of 100, 300 and 1000 mg/kg/day respectively for 30 days except for Sunday. The death occurred in 3 males and 4 females in the 1000 mg/kg dose group. The particular findings were suppression of body weight gain, increase of blood glucose, decrease of total protein, atrophy of thymus, spleen, testis and epididymis, follicular cystic change of ovary, vacuole formation of epithelium of

mucosa of oviducts, papillary proliferation of endometrium of uterus and proliferation of gland tissue with lactation of the mammary gland.

 

The subchronic toxicity of Norethisterone enanthate was investigated in JCL-SD rats. The substance was subcutaneously administered to the rats daily at dose levels of 1, 10 and 100 mg/kg/day for 14 weeks.

Particular findings were suppression of body weight gain, decrease of white blood cells, proliferation of gland tissue with lactation of mammary gland and atrophy of sexual organs. These findings were observed in many rats of 100 mg/kg dose group and in some rats of the 10 mg/kg dose group.

 

 

In a two year study of the effects of norethisterone enantate in repeated intramuscular injection in rats, dosages of 10,30 and 100 mg/kg were administered once weekly.

Observations in treated rats may be summarized as follows:

- mild to moderate alopecia and reduced grooming activity,

- deterioration in the general physical condition of rats receiving 30 or 100 mg/kg,

- increased mortality among both males and females receiving 30 or 100 mg/kg, and among males receiving 10 mg/kg,

- in males, depression of food intake end impairment of weight gain, and in females, increased food intake, associated with elevated weight gain during the first 18 months of the study in those receiving 10 or 30 mg/kg, but depressed weight gain in those receiving 100 mg/kg,

- reduced food conversion efficiency in males of all three treated groups and in females receiving 100 mg/kg;

- sporadic elevation of urinary protein concentration;

- depression of erythrocytic parameters in rats receiving 100 mg/kg, and, less consistently, in males receiving 10 or 30 mg/kg;

- sporadic elevation of serum protein concentration in rats receiving 100 mg/kg;

- extensive posterior polar, anterior, or equatorial lens opacities, dense cataracts, retinal pallor, and abnormal twisting of retinal blood vessels, seen at first in rats, especially females, treated with 100 mg/kg, but later appearing in rats receiving 10 or 30 mg/kg;

- decreased weights of testes, prostate and ovaries in rats receiving 30 mg/kg, and of testes and ovaries in rats receiving 10 mg/kg;

- histological changes in the liver, adrenal, pituitary, seminal vesicles, uterus, mammary gland (in males), end injection sites;

- increased incidence of hepatomas in both sexes at all three dosage levels, and of mammary gland tumours and pituitary adenomas in males; increased incidence of mammary gland carcinomas in both sexes receiving 30 or 100 mg/kg.

 

4 groups of 60 female Charles River CD rats were injected with 0 (controls), 1, 10 and 50 mg/kg norethisterone enantate intramuscularily every two weeks for up to 2 years. Interim sacrifice of 5 rats was carried out after 12 and 18 months treatment. Surviving animals were sacrificed after 2 years treatment and examined macro- and microscopically.

Changes were observed that can be ascribed to the gestagenic and inherent estrogenic activity of the substance.

Mortality was not influenced. Neither toxic organ lesions nor unexpected findings were noted. A slight decrease in body weight gain as well as a decrease in serum cholesterol might indicate some inherent estrogenic effects in rats, whereas the described changes of the ovaries, cervix and vagina are considered as progestogenic pharmacological effects.

Hypertrophic and/or hyperplastic changes in the liver are typical for rats.

 

Single intramuscular injections of 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.

 

Norethisterone acetate	Norethisterone enantate
oral or s.c. admin.	i.m. admin.
Subacute studies
Rat(♂+♀), 30 days, oral admin. Doses: 1000 and 5000 mg/kg bw (formulated in aq. “Tragant”) [Nihon Schering, Report no. 4305, 10.01.1979] Within fourth week of test all animals died at 5000 mg/kg and 1/20 male and 2/20 females at 1000 mg/kg. Particular findings were suppression of body weight gain, decrease of hemoglobin and WBC, increase of GPT activity and total bilirubin, atrophy of thymus, spleen, testis, prostate and seminal vesicle, follicular cystic change of ovary, papillary proliferation of uterus and proliferation gland tissue with lactation of mammary gland.
Rat(♂+♀), 30 days, s.c. admin. Doses: 100, 300 and 1000 mg/kg bw (formulated in benzyl benzoate/castor oil) [Nihon Schering, Report no. 4404, 10.01.1979] Deaths occurred in 3 males and 4 females at 1000 mg/kg. Particular findings were suppression of body weight gain, increase of blood glucose, decrease of total protein, atrophy of thymus, spleen, testis and epididymis, follicular cystic change of ovary, vacuole formation of epithelium of mucosa of oviducts, papillary proliferation of endometrium of uterus and proliferation of gland tissue with lactation of mammary gland.
Subchronic studies
Rat(♂+♀), 14 weeks, s.c. admin. Doses: 1, 10, and 100 mg/kg bw (formulated in benzyl benzoate/castor oil) [Nihon Schering, Report no. 4415, 16.01.1979] Particular findings were suppression of body weight gain, decrease of white blood cells, proliferation of gland tissue with lactation of mammary gland and atrophy of sexual organs. The max. non-effective dose was estimated between 1 and 10 mg/kg.	Rat– 13 weeks, i.m. admin. Doses: 1, 10, and 50 mg/kg bw Dose regimen: every 2 weeks (formulated in benzyl benzoate/castor oil) [Endocrine Laboratory of Madison Inc. and Schering histologic evaluation of 30.09.1974, further Schering Report nos. 1371, 06.06.1974 and 1590, 21.01.1975 and] 1 and 10 mg/kg did not lead to substance-related pathological findings except cycle disorders and decreased uterus weights at 10 mg/kg. At 50 mg/kg animals were in a constant diestrus with growth depression and reduced organ weights of hypophysis, ovaries, uterus and thymus. Histopathologically, inhibition of ovulation and hyperplasia/proliferation of granulosa cells were detected.
Chronic studies
Rat(♂+♀), 105 weeks, oral admin. (feed study) Doses: 0.4, and 4.0 mg/kg bw [Parke Davis, 15.05.1969] Besides typical gestagenic effects (atrophy of gonads, activity increase of mammary gland), a high incidence of pituitary adenoma and liver affection is revealed at 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] Findings, that were only noted in the study with substance administration at weekly intervals (indicating a considerable compound cumulation in the animals): Increase in mortality, unclarified ophthalmoscopic changes suggesting increase in the incidence of cataracts, alopecia, decrease in erythrocytic count, and an increase in absolute and relative liver weights. Further, in this study using weekly injection intervals, the local inflammatory reaction at the application sites was increased compared to controls.
Rat85 (♂)/104 (♀) weeks, oral admin. Doses: 0.05, 1.25, and 31.25 mg/kg bw (formulated in aq. “Tragant”) [Nihon Schering, Report no. 4703, 02.03.1979] Particular findings were depression of body weight gain, decrease of total cholesterol and atrophy of prostate, seminal vesicle and ovary; the max. non-effective dose slightly less than 1.25 mg/kg bw.	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] Changes were observed that can be ascribed to the gestagenic and inherent estrogenic activity of the substance. Mortality was not influenced. Neither toxic organ lesions nor unexpected findings were noted. A slight decrease in body weight gain as well as a decrease in serum cholesterol might indicate some inherent estrogenic effects in rats, whereas the described changes of the ovaries, cervix and vagina are considered as progestogenic pharmacological effects. Hypertrophic and/or hyperplastic changes in the liver are typical for rats.
	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.

 

 

Mouse studies

 

In an eight-week study of the effects of norethisterone acetate in mice, dietary concentrations were fed to provide dosages of approximately 2, 10 and 50 mg/kg bw/day.

There was no mortality on any dose group,

Weight gains were depressed in both sexes at 50 mg/kg bw/day, and in females only at 10 mg/kg bw/day.

These effects did not relate to reduced food intake, since in these groups consumption was regularly higher than in the untreated control group.

Treatment was associated with a decrease in the size of theseminal vesicles in males of Groupe 3 and 4. In females of Group 4, ovarian size was apparently reduced. A small incidence ofovarian cysts was observed, but these occurred equally in control and treated mice.

These findings suggest that an upper dosage to be tolerated by mice over an 80-week period should not exceed 10 mg/kg/day, and that 5 mg/kg/day would probably constitute a more appropriate level.

 

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

Weight-gain in males receiving 10 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 10 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.

 

Norethisterone acetate	Norethisterone enantate
oral or s.c. admin.	i.m. admin.
Subacute studies
Mouse(♂+♀), 8 weeks, Doses: 2, 10, and 50 mg/kg bw, oral admin. (feed study) [Huntingdon Research Center, Report no. 2276/68/154, 21.06.1968] Weight gains depressed in both sexes at 50 mg/kg, in females only at 10 mg/kg Macroscopic findings in sex organs ≥ 10 mg/kg and in females > 50 mg/kg.
Chronic studies
Mouse(♂+♀), 80 weeks, Doses: 0.25, 1.5, and 10 mg/kg bw, oral admin. (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] Weight-gain in males receiving 10 mg/kg slightly but consistently reduced, without effect upon food intake. Macroscopic evidence of response to treatment at 10 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 unaffected.	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] No signs of systemic intolerance or toxic effects were noted. Signs of systemic effects were the expected atrophic changes of the ovaries (increased incidence of absent corpora lutea at the high dose level), marginally Increased absolute and relative liver weights and a dose-dependent Increase in mammary gland hyperplasia. The latter two findings might indicate some growth promoting effects on hormone-sensitive tissue (for hepatomas and mammary tumors see chapter 4.8.)

 

 

The available documentation of Norethisteron, Norethisteron acetate and Norethisteron enantate indicates the following further studies being available; these have only limited information and were conducted with females only, however, the overall outcome does not contradict the conclusions on repeated dose toxicity as already summarized above.

 

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

52-week study in dog, HRC 3782/70/604, 15.02.1971 and Schering commentary of 17/18.02.1970 and 20.11 1970), doses 10, 30, and 100 mg/kg bwdose regimen once weekly up to 8 weeks and then every third week

In a 52 weeks study the substance was administered into the muscle of dogs (4/sex/dose) once weekly up to 8 weeks and then every third week in doses of 0, 10, 30 and 100 mg/kg. The animals of the treatment groups showed local reaction (swelling, abscess) at the muscle and edema of the limbs. In males reduced testicles growth and increased mammary growth (male and female) as well as slight vulva swelling in females was observed. In hematology erythrocyte sedimentation rate was increased and platelet count decreased mainly at high dose. Total protein and alpha-2 -globulin was increased in blood and albumin (30 and 100 mg/kg) and calcium (100 mg/kg) was reduced. Macroscopic findings were dose dependent dilatation of the uterus with mucous or purulent content and endometrium with noduli and convoluted appearance combined with enlargement of vulva and clitoris. Weight of ovaries, testis and prostate were reduced, uterus weight increased. LOAEL: 10 mg/kg

90-day study in monkey, Endocrine Lab. Of Madison Inc., 05.02.1973, and Schering commentary no. 1605 of 07.02.1975

Female monkeys were treated with single intramuscular injections on day 1 and 45 of a 90 day study period with 0, 6, 60 and 300 mg/kg (1 animal/dose). Decrease of body weight gain, irregular menstrual cycle or acyclic effects,increased uterus size and weight and decreased ovaries size were observed. Additionally, decidual cell reaction were induced in the uterine endometrium and the proportion of acidophil cells in anterior pituitary was increased. LOAEL: 6 mg/kg 

 

Additionally results of repeated dose toxicity studies with norethisterone are cited in RTECS database (accessed 04/2021):

 

The daily intramuscular application of norethisterone to rats over 15 days results in changes in serum composition (e.g., TP, bilirubin, cholesterol) and lipid intermediar metabolism including transport; TDLo: 30 mg/kg/15D-I

[Shengzhi Yu Biyun. Reproduction and Contraception. (China International Book Trading Corp., POB 2820, Beijing, Peop. Rep. China) 1980- v. 11(3), p. 17, 1991 (SCYYDZ)]

 

The daily subcutaneous administration of ZK 5378 to rats over 3 days results in maternal effects on uterus, cervix and vagina; TDLo: 60 mg/kg/3D-I [Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 170, p. 21, 2002 (TXCYAC)]

 

The subcutaneous application over 3 days to rats results in maternal effects on uterus, cervix and vagina and weight loss or decreased weight gain; TDLo: 600 mg/kg/3D-I [Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 170, p. 21, 2002 (TXCYAC)]

Justification for classification or non-classification

According to CLP Annex I, 3.9.1.1, specific toxic effects covered by other hazard classes are not included in STOT-RE. STOT-RE should only be assigned where the observed toxicity is not covered more appropriately by another hazard class. For example specific effects like tumours or effects on the reproductive organs should be used for classification for carcinogenicity (see chapt. 7.7) or reproductive toxicity (see chapt. 7.8), respectively, but not for STOT-RE.

Therefore there is no classification required for SPECIFIC TARGET ORGAN TOXICITY – REPEATED EXPOSURE according to Regulation (EC) No. 1272/2008 (CLP).