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.

Neither in vivo studies in animals nor in vivo studies on skin sensitisation are available for norethisterone. Data waivers are claimed. The vast amount of clinical experience gained with this approved drug substance over many decades gives no evidence that norethisterone and related substances (norethisterone enanthate/acetate) have a significant skin sensitizing potential.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Reference 1

Endpoint:

skin sensitisation: in vitro

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Justification for type of information:

JUSTIFICATION FOR DATA WAIVING
Norethisterone and its ester derivates (norethisterone enanthate/acetate) are well-known drug substances and constituents of numerous approved drug products which have been in therapeutic use for many decades and therefore the formal data gap is more than compensated by the vast amount of clinical experience gained in their continued and widespread therapeutic use.
Overall there is proven broad exposure related to the therapeutic topical use of norethisterone related substances in transdermal therapeutic systems and there is only one isolated positive patch test reaction of unclear relevance published, compared to the substantial therapeutic use in postmenopausal patients.
Therefore based on the available reliable and relevant human data the assessment of the skin sensitization potential (hazard identification) is possible. Based on all available data there is no evidence of skin sensitization properties of norethisterone and structurally related substances.

Reference 2

Endpoint:

skin sensitisation: in vivo (LLNA)

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Justification for type of information:

JUSTIFICATION FOR DATA WAIVING
Norethisterone and its ester derivates (norethisterone enanthate/acetate) are well-known drug substances and constituents of numerous approved drug products which have been in therapeutic use for many decades and therefore the formal data gap is more than compensated by the vast amount of clinical experience gained in their continued and widespread therapeutic use.

Overall there is proven broad exposure related to the therapeutic topical use of norethisterone related substances in transdermal therapeutic systems and there is only one isolated positive patch test reaction of unclear relevance published, compared to the substantial therapeutic use in postmenopausal patients.
Therefore based on the available reliable and relevant human data the assessment of the skin sensitization potential (hazard identification) is possible. Based on all available data there is no evidence of skin sensitization properties of norethisterone and structurally related substances.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

For additional information see expert opinion " Assessment of the skin sensitization potential of Norethisterone (CAS 68-22-4) and related substances" in chapter 7.10.4 Sensitisation data (humans).

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information:

With respect to skin sensitizing effects, experimental studies in animals or in vitro alternatives with Norethisterone are not available. However, according to GHS, existing human experience is a first line information for the analysis of this endpoint, as it directly observes possible effects on human skin.

Transdermal therapeutic systems with Norethisterone acetate are in therapeutic use for decades e.g. in the treatment of climacteric symptoms in post-menopausal women. A number of clinical trials and a broad clinical experience is therefore available that allows the assessment of the skin sensitization potential for norethisterone and related substances. Humans were exposed continuously and over years dermally via dermal patches that guarantee intense skin contact and transdermal delivery as well as systemic availability of the active ingredient in therapeutic use.

The clinical data confirm the good tolerability of the transdermal therapeutic systems and based on the available data there is no evidence of a skin sensitization potential.

Overall, there is proven broad exposure related to the therapeutic topical use of norethisterone related substances in transdermal therapeutic systems and there is only one isolated positive patch test reaction of unclear relevance published, compared to the substantial therapeutic use in postmenopausal patients.

Therefore, based on the available reliable and relevant human data the assessment of the skin sensitization potential (hazard identification) is possible. Based on all available data there is no evidence of skin sensitization properties of norethisterone and the structurally related substances.

Justification for classification or non-classification

In the light of the clinical experience no classification is required according to Regulation (EC) No. 1272/2008 (CLP).