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Estradiol

Summary

Persistence. Estradiol is slowly degraded in the environment.
Bioaccumulation. Estradiol has low potential to bioaccumulate.
Toxicity. Estradiol has very high chronic toxicity.
Risk. "Overall, E1‒E4 occur in water bodies in a few ng/L or even lower concentrations. At the same time, estrogens, especially EE2, are very potent and can interfere with reproduction in fish. The greatest evidence for effects in the environment is for EE2 with measured concentrations that relatively often exceed safe effect levels. How the risk would change when replacing EE2 with E2 or E4 is discussed under the heading "risk assessment when replacing." E1 = estrone, EE2 = ethinylestradiol, E2 = estradiol, E3 = estriol och E4 = estetrol. For more information see the report from Goodpoint 2024.

 

This summary information about estradiol comes from assessment reports and fass.se. The information about risk comes from the report from Goodpoint 2024.

 

Suggestions on how to reduce emissions of estradiol

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). The environmental aspect is not considered in the benefit/risk assessment for human medicinal products.

Assessment report Ryeqo

Assessment report for Ryeqo (relugolix, estradiol, norethisterone acetate), Gedeon Richter Plc., 20 May 2021, EMA/CHMP/127692/2021.

Hazard

Persistence: OECD 308: 58.3, 42.5, 32.3, 52.3 days. Geometric mean: 45.2 days.

Bioaccumulation: Log Kow = 3.73.

Chronic toxicity: There is data for 1 trophic level full life cycle study, 2.86 ng/L.

Risk

PEC = "PECsw is not agreed upon, a question on Fpen refinement is asked."

"Conclusions on studies for 17β-estradiol
17β-Estradiol 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. 17β-Estradiol is not PBT nor vPvB. The applicant is requested to include this indication in the ERA for estradiol and to update the ERA accordingly. The ERA is incomplete, and the applicant commits to perform the following studies as postauthorisation commitments:
• A bioconcentration study (OECD 305):
• Adsorption-desorption using a batch equilibrium method (OECD 106) for at least 1 type of sewage
sludge;
• Daphnia sp. reproduction test (OECD 211, use version 2012);
• Activated sludge, respiration inhibition test (OECD 209, use version 2010).
The CHMP agrees that the algal toxicity test can be waived (OECD 201)." No such data has been found when searching the EMA website (2025-01-24).

Assessment report Zoely

Assessment report for estradiol, Zoely (nomegestrol, estradiol) from 2011, procedure No. EMEA/H/C/001213.

Hazard

Persistence: No data.

Bioaccumulation: "The results of the bioconcentration studies in fish indicate that bioconcentration is not a significant environmental concern for these species. In most of the non-fish species a similar conclusion can be reached based on relatively low BCFs. The results from the studies in zebra mussels are interesting, but seem to indicate that E2 (estradiol, ed. remark) is taken up by these organisms and stored in an inactive form. There is less data available concerning the effect of E2 on sediment organisms. However, based on analogy to EE2 (etinylestradiol, ed. remark), a much more potent estrogen, it is not expected to have significant effects on sediment species."

Chronic toxicity: Data for 3 trophy levels are not reported, but it is interpreted as based on used AF 10. Fish "the lowest NOEC (2.6 ng/L)."

Risk

"In conclusion, based on the above results, NOMAC (nomegestrol, ed. remark)-E2 does not appear to present a specific risk to the aquatic environment. However, given the hormonal activity of both components, nomegestrol acetate and estradiol, a warning has been included in the relevant section of the product SmPC and in the package leaflet as follows: Zoely tablets no longer required should not be disposed via wastewater or the municipal drainage system. The hormonal active compounds in the tablet may have harmful effects if reaching the aquatic environment. Return them to a pharmacy or dispose them in another safe way according to local requirements. These measures will help to protect the environment.”

Fass environmental information Novo Nordisk

Fass environmental information for estradiol, Activelle (estradiol, noretisteron) from Novo Nordisk (downloaded 2025-01-24).

"17β-estradiol and its main metabolites estrone and estriol." For more information see fass.se.

Hazard

Persistence: "Activated sludge test according to OECD guideline no. 302A has shown that 17β-estradiol is inherently biodegradable under aerobic conditions in activated sludge ... 17β-estradiol is thus slowly degraded in the environment. In a 100 days simulation study of 17β-estradiol (OECD Test Method no. 308), an aerobic mineralisation (marine) of 61±1% respectively 62±3% mineralisation (freswater) was found ... Thus, 17β-estradiol is found to be biodegradable in both marine and fresh water. In addition, an activated sludge tests (OECD 302 ...) show that 17β-estradiol is inherently biodegradable under aerobic conditions."

Bioaccumulation: "Several measured BCFs are available for 17β-estradiol – all well below the cut-off value of 500. Therefore, 17β-estradiol is assessed not to have a high potential for bioaccumulation."

Chronic toxicity: There are data for 3 trophic levels, most sensitive fish. "The lowest no observed effect concentration for 17β-estradiol is a 35–50 d NOEC of 0.5 ng/L ... for the trout Onchorhynchus mykiss."

Risk

PEC/PNEC is based on sales data in Sweden in year 2022. PEC/PNEC = 3.00 which gives the risk moderate.

Fass environmental information Bayer

Fass environmental information for estradiol, Progynon (estradiol) from Bayer (downloaded 2025-01-24).

Hazard

Persistence: "The high ready biodegradation and elimination in sewage treatment plants qualifies for the phrase “Estradiol is slowly degraded in the environment.”."

Bioaccumulation: "As the BCF was < 500 estradiol is not considered bioaccumulative which qualifies for the phrase “Estradiol has low potential for bioaccumulation.”."

Chronic toxicity: There are data for 3 trophic levels, most sensitive fish NOEC = 0.00286 μg/L.

Risk

PEC/PNEC is based on sales data in Sweden in year 2022. PEC/PNEC = 3.57 which gives the risk moderate.

EU water legislation

Estradiol has previously been monitored within the framework of EU water legislation. There is now enough data to assess whether estradiol is to be proposed as a priority substance when the European parliament and the Council next time proposes a revised directive regarding priority substances in the field of water policy.

The Swedish Agency for Marine and Water Management

Estradiol is among special pollutants in the Swedish Agency for Marine and Water Management regulation HVMFS 2019:25.

Report Goopoint 2016

Estradiol is included in Region Stockholm's table of pharmaceuticals with a negative environmental impact according to the environmental programme 2017–2021.

Estradiol is more easily degraded than ethinyl estradiol in the body, in the wastwater treatment plant, in the environment and is less potent in fish. An oral dose of 1.5 mg estradiol gives an excreeted dose in the urine of only 100 micrograms. Therefore, the risk is probably lower with estradiol despite the often higher dosage.

Report Goodpoint 2024

The report from Goodpoint 2024 aims to present an overall, comparative assessment for the treatment options recommended for all indications under the therapeutic area of ​​gynecology and obstetrics in the 2024 Wise list (the formulary for Region Stockholm, Sweden) containing either estrogens or progestogens + estetrol. The risk assessment does not aim to assess absolute or quantitative risk (which, for example, strongly depends on dilution in different recipients) but is primarily of a comparative nature, i.e., a ranking of the risk between different treatment options. For more information see the report.

The Wise list

Estradiol is recommended in the Wise list. The Wise list is the drug formulary of essential medicines for common diseases in Region Stockholm from the Drug and Therapeutics Committee. Environmental classification of pharmaceuticals is taken into consideration, sometimes with other environmental aspects, when selecting pharmaceuticals for the Wise list. When comparable pharmaceuticals are equivalent to medical effects, safety and pharmaceutical efficacy, environmental impact and price are considered.

Suggestions on how to reduce emissions of estradiol

Concrete proposals on how to work to reduce emissions of environmentally harmful pharmaceuticals on the list have been developed in close cooperation with the Stockholm Drug and Therapeutics Committee's expert groups. The action proposals were developed from an environmental perspective. The patient's best always goes first and several pharmaceuticals on the list are also included in the Wise list. However, for such pharmaceuticals, there may be measures that could reduce the environmental impact.

Concrete proposal for estradiol

  • Estradiol is recommended in the Wise list.
  • Individual adaptation of contraceptives as well as pharmaceuticals for treatment of menopausal symptoms and symptomatic vaginal atrophy is important in order to optimize treatment and avoid side effects.
  • For topical application of patches with estradiol (Estradot, recommended in the Wise list) for menopausal symptoms, the amount of pharmaceutical administered to an individual is significantly lower than the dose required to give the corresponding effect with estradiol tablets.
  • Ensure that you, in your own business, discard leftover pharmaceuticals and used patches and vaginal inserts correctly.  
  • Inform the patient about the importance of discarding leftover pharmaceuticals, as well as used patches and vaginal inserts, correctly. Order the folder for patients "Protect the Environment – Throw in the Right Way".

Author: Health and Medical Care Administration, Region Stockholm