Estetrol

Detailed information

Assessment report Drovelis

Assessment report for Drovelis (drospirenone, estetrol) about estetrol, 25 March 2021, EMA/212533/2021.

Hazard

Persistence: "Whole system DT₅₀ (20°C) = 3.99 d–7.3 d, water DT₅₀ (12°C) = 8.1 d–25.7 d, sediment DT₅₀ (12°C) = 8.7 d–14.3 d." According to expert estetrol is degraded in the environment (C. Coll, Department of Environmental Chemistry, Eawag, 2023-10-04).

Bioaccumulation: Log D_ow = 1.65.

Toxicity: There are data for 3 trophic levels, most sensitive fish NOEC 0.69 microg/L.

"Although the FFLC concentration hatching response relation is not fully monotonic, considering that there are statistically significant differences in hatching in the middle concentrations (and partly supported by statistically significant changes in anal papillae at the highest concentration), and that E4 is an endocrine active substance which is expected to be effective on reproductive endpoints at very low concentrations, the lowest concentration (0.69 ug/L) is chosen as the basis for the risk assessment."

Risk

The risk, PEC/PNEC, calculated from data in the assessment report from a European perspective:

Default PEC_sw = 0.071 mikrog/L.

PNEC = Lowest NOEC, 0.69 microg/L/10 (Assessment Factor (AF) for 3 chronic studies) = 0.069 microg/L

PEC/PNEC = 1.0289 which gives the risk moderate.

"The proposed E4 PEC_sw is 0.0312 ug/L based on a refined Fpen of 0.0044. The Applicant is committed to submit an updated ERA with this PEC_sw as a basis. For the surface water compartment, this is stated to give a risk quotient of < 1, but the final conclusion can only be made with the submission of the updated ERA." No such information has been found on the EMA website. A question has been sent to EMA 2023-09-21. New documentation was received from EMA (Estetrol/drospirenone (15 mg/3 mg) 1.6.1 Non-GMO environmental risk assessment phase IIA, Smithers report number: 3200557_Version 3.0_final report, date of current version: 31 March 2021). Estetrol is metabolized and the main metabolites are glucuronides. The parent compound, estetrol, was selected to represent all estetrol components entering the environment (conservatively). The environmental risk, PEC/PNEC, calculated from the data in the new report from a European perspective:

PEC_sw = 0.031 microg/L.

PNEC = Lowest NOEC, 0.69 microg/L/10 (Assessment Factor (AF) for 3 chronic studies) = 0.069 microg/L

PEC/PNEC = 0.45, which gives the risk low.

Assessment report Lydisilka

Assessment report for Lydisilka (drospirenone, estetrol) about estetrol, 25 March 2021, EMA/212535/2021.

Corresponding information as for Drovelis above can be found in this assessment report. The following has also been written: "The proposed E4 PEC_sw is 0.0312 ug/L based on a refined Fpen of 0.0044. The Applicant is committed to submit an updated ERA with this PEC_sw as a basis. For the surface water compartment, this is stated to give a risk quotient of < 1, but the final conclusion can only be made with the submission of the updated ERA."No such information has been found on the EMA website (2024-12-10).

Fass environmental information Drovelis

Fass environmental information about estetrol from Drovelis from pharmaceutical company Gedeon Richter (downloaded 2024-12-10).

Hazard

Persistence: "Ready biodegradability (guideline OECD 301B) ThCO2 = 3% (< 60%) degradation after 28 days. Estetrol is therefore considered to be not readily biodegradable. ... Estetrol did not pass the ready degradability test. The phrase "Estetrol is potentially persistent" is thus chosen."

Bioaccumulation: Log K_ow = 1.65 at pH 7. As the log K_ow was < 4 estetrol is not considered bioaccumulative which qualifies for the phrase “Estetrol has low potential for bioaccumulation”.

Toxicity: There are data for 3 trophic levels, most sensitive fish (Japanese Medaka) NOEC 0.69 microg/L.

Risk

PEC/PNEC is based on sales data in Sweden in year 2022. PEC/PNEC = 0.0025 which gives the risk insignificant.