Estetrol

Detailed information

General information about assessment reports

Since 2006, an Environmental Risk Assessment (ERA) for the active pharmaceutical substance shall accompany an application for a marketing authorisation in EU for a medicinal product for human use. Parts of environmental data can be found in the public investigation report (PAR/EPAR for medicinal product through a centralized procedure). Since the benefit/risk assessment for human medicinal products at present does not include environmental effects, an update of the environmental risk assessment is not required for renewals of marketing authorizations. There is thus no requirement for companies to stay informed about the development of their substances from an environmental point of view and consequently to update the environmental risk assessment as new data are published.

Assessment report

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

Hazard

Persistence: "Whole system DT₅₀ (20°C) = 3.99d–7.3d, water DT₅₀ (12°C) = 8.1d–25.7d, sediment DT₅₀ (12°C) = 8.7d–14.3d." 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.

Fass environmental information

Environmental information is missing for estetrol on fass.se (2024-06-04).