Norethisterone

Detailed information

Comment on Fass environmental information

Norethisterone has different classifications on fass.se. According to Lif (the trade association for the research-based pharmaceutical industry in Sweden) the various pharmaceutical companies compile environmental information for their active substances based on internal studies and published data. Based on data, which may thus differ between different pharmaceutical companies, the companies assess the environmental risk with guidance from “Environmental classification of pharmaceuticals at www.fass.se – Guidance for pharmaceutical companies 2012”. The Swedish Environmental Institute (IVL) reviews the assessment but does not have the task of coordinating/harmonizing environmental information from different pharmaceutical companies for the same active substance.

Fass environmental information for Primolut-Nor (norethisterone) from Bayer (downloaded 2021-04-21)

Hazard

Persistence: "Ready degradability: not ready biodegradable. The biodegradability was studied in a CO₂ evolution test (OECD 301B). [...] No degradation was observed within 28 days of incubation. The results of the study on ready biodegradability justifies the phrase: Norethisterone/norethisterone acetate is potentially persistent." 

Bioaccumulation: Log P 2.7 at pH 7 and 25 °C.

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 2018. PEC = 0.0020 microg/L, PNEC = 0.0005 microg/L. PEC/PNEC = 4 which gives the risk moderate."PNEC = 0.0005 μg/L (Lowest chronic NOEC fish = 0.005 µg/L; AF 10). An assessment factor of 10 has been used despite only two tests (algae and fish) were set up as chronic tests, while for invertebrates (Daphnia magna) only an acute test has been performed. Because fish are known to be generally the most sensitive species for effects of steroid hormones and invertebrates like daphnids lack a physiological function of sex steroids, it is highly unlikely that a chronic test with Daphnia magna would result in a lower NOEC than in fish. Therefore, it is justified to use the lower assessment factor of 10."

According to the guidelines, AF 50 would be used in two chronic tests. If AF 50 (PEC = 0.0020 microg/L, PNEC = 0.0001 microg/L) is used, PEC/PNEC = 20 which gives the risk high.

Fass environmental information for norethisterone from Activelle (estradiol, norethisterone) (downloaded 2021-04-21)

Hazard

Persistence: "NETA (norethisterone acetate, editoral note) is not readily biodegradable under “modified Sturm test” conditions since less than 10% of the substance was biodegraded within 28 days."

Bioaccumulation: Log P_ow = 3.7. "Since Log P_ow < 4, it indicates that NETA has low potential for bioaccumulation."

Toxicity: There are data for 2 trophic levels, most sensitive green alga 600 microg/L.

Risk

Risk of environmental impact of norethisterone cannot be excluded due to lack of eco-toxicity data.

Fass environmental information for Mini-Pe (norethisterone) from Pfizer (downloaded 2021-04-21)

Hazard

Persistence: It cannot be excluded that norethisterone is persistent, due to the lack of data.

Bioaccumulation: It cannot be excluded that norethisterone bioaccumulates, due to the lack of data.

Toxicity: No data.

Risk

Risk of environmental impact of norethisterone cannot be excluded, due to the lack of environmental toxicity data.

Concentrations in the aquatic environment and impact on fish

In various international studies, the reported level of norethisterone in purified wastewater ranges from undetectable to 188 ng/L (the latter appears to be unreasonably high) and in surface water from 1 to 7.5 ng/L.

Effects on fish has been shown in various studies at levels from 1 ng/L. Based on prescribing data, expected levels downstream Swedish watewater treatment plants could be around 2.6 ng/L.

Report on progestogens from Goodoint

A substance's ability to activate the androgen receptor in fish is believed to also contribute to increased risk of environmental impact. Norethisterone, levonogestrel and etonogestrel activate the androgen receptor in fish at very low concentrations, whereas, for example, drospirenone is a much less potent androgen receptor agonist. The risk is likely to be lower for norethisterone than for levonorgestrel seen from the risk of affecting fish via the androgen receptor.

Based on binding to the androgen receptor, binding to SHBG (Sex Hormone Binding Globulin) and studies on fish, norethisterone and levonogestrel are a higher environmental risk than medroxyprogesterone. Binding to SHBG is believed to contribute to increased bioconcentration (and thus potency) in fish.

The dosage form, patches versus oral formulations, is also important.