Estradiol

Detailed information

Comment on Fass environmental information

Estradiol 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 Novo Nordisk

Fass environmental information for estradiol, Activelle (estradiol, noretisteron) from Novo Nordisk (downloaded 2021-08-16).

"17β-estradiol is metabolized during human metabolism into the major transformation products estrone, estriol, estrone sulfate and estrone glucoronide. Se vidare Fass-informationen."

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. Therefore, 17β-estradiol and its metabolites are assessed not to fulfil the criteria of persistence in the aquatic environment."

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 2016. PEC/PNEC = 2.75 which gives the risk moderate.

Fass environmental information Bayer

Fass environmental information for estradiol, Angemin (drospirenone, estradiol) från Bayer (downloaded 2021-08-16).

Hazard

Persistence: "Biotic degradation. Ready degradability: not readily biodegradable, but significant mineralization. Estradiol was studied for aerobic biodegradability in a study according to OECD 301 B and in two studies according to FDA TAD 3.11. In all studies, estradiol was determined to degraded to more than 60 % after 28 days, however, failing the criterion for ready biodegradation. Abiotic degradation. Hydrolysis: Estradiol is hydrolytically stable. Due to the high mineralization rate in the ready biodegradability test, the phrase “estradiol (as valerate or hemihydrate) is slowly degrading in the environment” applies."

Bioaccumulation: "The log K_OW of 4.03 fulfills the screening criterion, while the BCF of 108.8 is clearly below the threshold of
500. Therefore, the phrase “The substance has a low potential for bioaccumulation” applies."

Chronic toxicity: There are data for 3 trophic levels, most sensitive fish (fathead minnow Pimephales promelas) EC₁₀ 56 d (weight) = 0.008 μg/L.

Risk

PEC/PNEC is based on sales data in Sweden in year 2019. PEC/PNEC = 4.5 which gives the risk moderate.

Fass environmental information Pfizer

Fass environmental information for Oestring (estradiol) from Pfizer (downloaded 2021-08-16).

Hazard

Persistence: No data.

Bioaccumulation: No data.

Toxicity: No data.

Risk

Risk of environmental impact of estradiol cannot be excluded, since no ecotoxicity data are available. It is voluntary for manufacturers to provide information about environmental impact on fass.se.

Fass environmental information from MSD

Fass environmental information forEstradiol SUN (estradiol) from SUN Pharmaceutical (downloaded 2021-08-16). The environmental information for estradiol is produced by the company MSD for IOA. IOA was deregistered on 2014-07-31 according to the Swedish Medical Products Agency's "Läkemedelsfakta" (2021-08-16).

Hazard

Persistence: "Biotic degradation. Biodegradation in Wastewater Treatment Systems 84% mineralized over 24 hrs (Non-guideline) (Ref. VIII) Ready Biodegradation (OECD 301B) 68% degradation in 28 days (Ref. IX) Justification of chosen degradation phrase: Estradiol is quickly degraded in wastewater treatment systems and undergoes significant degradation in an OECD 301B test, but does not pass the criteria for ready biodegradation. Thus, the phrase “Estradiol is slowly degraded in the environment” is chosen."

Bioaccumulation: "Fish Bioaccumulation (OECD 305) A bioaccumulation study determined the steady state BCF to be 108.8."

Chronic toxicity: There are data for 3 trophic levels, most sensitive fish (Oryzias latipes) NOEC (160 day, fertility) = 0.003 μg/L.

Risk

PEC/PNEC is based on sales data in Sweden in year 2018. PEC/PNEC = 0.89 which gives the risk low.

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 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 K_ow = 3.73.

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

Risk

PEC = "PEC_sw 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)."

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.”

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

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.

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.