Norethisterone

Detailed information

Assessment report

Assessment report for norethisterone from Ryego (relugolix, estradiol, norethisterone), 20 May 2021, EMA/CHMP/127692/2021.

Hazard

Persistence: No data.

Bioaccumulation: "3.66 for norethindrone acetate (norethisterone acetate, ed. note) , 2.52 for norethindrone. Conclusion: Potential PBT: No because lower than 3 for the active metabolite norethindrone."

Toxicity: No data.

Risk

No data.

"Norethindrone acetate (NETA) may cause reproductive effects in vertebrates and/or lower animals. The action limit of 0.01 μg/L does not apply, a Phase II assessment is triggered based on the mode of action. ... The ERA is incomplete, and the applicant commits to submit the following studies as post-authorisation measures:
• Adsorption-desorption using a batch equilibrium method (OECD 106) using 3 soil types and 2 types of sewage sludge;
• Ready biodegradability test (OECD 301);
• Aerobic and anaerobic transformation in aquatic sediment systems (OECD 308);
• Daphnia sp. reproduction test (OECD 211, use version 2012);
• A fish, full life cycle study: either a Medaka extended one generation reproduction test (OECD 240), or a Zebrafish extended one generation reproduction test (ZEOGRT);
• Activated sludge, respiration inhibition test (OECD 209, use version 2010).
It is agreed that the algal toxicity test can be waived (OECD 201)."
No such information was found when searching the EMA website (2025-03-27).

Fass environmental information for Primolut-Nor

Fass environmental information for Primolut-Nor (norethisterone) from Bayer (downloaded 2025-03-27).

Hazard

Persistence: "Norethisterone (acetate) was not readily biodegradable, is hydrolytically stable and as there is no higher tier transformation study the half-life is considered to be DT₅₀ > 120 d, which qualifies for the phrase “Norethisterone (acetate) is potentially persistent.”"

Bioaccumulation: Log D_ow 2.7 vid pH 7 (OECD 117).

Toxicity: There are data for 3 trophic levels, most sensitive fish (Danio rerio) NOEC 28 days = 0.005 microg/L.

Risk

PEC/PNEC is based on sales data in Sweden in year 2021. PEC = 0.0018 microg/L, PNEC = 0.0005 microg/L. PEC/PNEC = 3.57 which gives the risk moderate."PNEC = 0.0005 μg/L (Lowest chronic NOEC fish = 0.005 µg/L; AF 10). The PNEC was calculated by division of the lowest effect level (NOEC) of the most sensitive taxonomic group considering an appropriate assessment factor (AF). There is no chronic study with daphnids but as norethisterone (acetate) is a hormone fish can be expected to be the most sensitive taxonomic group and the respective NOEC = 0.005 µg/L. The regulatory default standard AF of 10 was used, which is applicable when there are chronic aquatic toxicity studies representing the three trophic levels (algae, crustaceans, and fish)."

According to the guidelines, AF 50 would be used in two chronic tests. If AF 50 (PEC = 0.0018 microg/L, PNEC = 0.0001 microg/L) is used, PEC/PNEC = 18 which gives the risk high.

Fass environmental Activelle

Fass environmental information for norethisterone from Activelle (estradiol, norethisterone) (downloaded 2025-03-27).

Hazard

Persistence: "Since less than 10 % was degraded in the biodegradation test, NETA (norethisterone acetate, editoral note) is not readily biodegradable. It cannot be excluded that NETA is potentially persistent in the aquatic environment according to ref. 1."

Bioaccumulation: Log P_ow = 3.7. "Since Log P_ow < 4 and since the BCF most likely is below 500, NETA is assessed to have a low potential for bioaccumulation according to ref. 1."

Toxicity: There are data for 3 trophic levels, most sensitive fish 0.0041 microg NET/L (egg production).

Risk

PEC/PNEC is based on sales data in Sweden in year 2023. PEC/PNEC = 4.7 which gives the risk moderate. "No NOEC for algae is available. As NETA/NET is a hormone, fish is expected to be the most sensitive taxonomic group, which also available data for chronic toxicity indicate. The lowest NOEC for fish is identified at 0.0041 µg NET/L (egg production), which indeed is several factors lower than the NOEC of 0.5 mg NET/L for Daphnia magna. The regulatory default standard AF of 10 was used for the derivation of PNEC, which is applicable when there are chronic aquatic toxicity studies representing the three trophic levels (algae, crustaceans, and fish)." Two chronic tests if AF 50 (PEC = 0.0022 microg/L, PNEC = 0.000093 microg/L) PEC/PNEC = 23 which gives the risk high.

Report Goodpoint 2024

In general, all progestogens occur in very low or undetectable concentrations in environments affected by municipal wastewater. Based on sales, the PEC is below 3 ng/L for all studied progestogens except for progesterone, medroxyprogesterone and drospirenone, but credible international measurements show that these three progestogens are also detected in concentrations around 1 ng/L in treated wastewater. At the same time, some progestogens are exceptionally potent with effects observed at exposures below 1 ng/L. However, only progestogens that bind strongly to the androgen receptor appear to be so potent in fish. Of the progestogens recommended in the Wise list (the formulary in Region Stockholm, Sweden), levonorgestrel, norethisterone, desogestrel and etonogestrel meet these criteria, while the other progestogens are considered to be less environmentally hazardous given the current state of knowledge. It is difficult, based on existing data, to stratify with certainty which of the androgenic progestogens are the most or least environmentally hazardous, even though norethisterone and levonorgestrel are somewhat better studied than desogestrel and etonogestrel. It is possible to point out norethisterone (and lynestrenol, which is not covered in this report) as being a little more environmentally hazardous as they also contribute to the levels of EE2 (ethinylestradiol) in the environment through metabolism. See also the report, which lists various recommended alternatives in the Wise list, from best to worst from an environmental point of view.