Detaljerad miljöinformation

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

PEC is calculated according to the following formula:

PEC (μg/L) = (A*10⁹*(100-R))/(365*P*V*D*100) = 1.37*10^-6*A(100-R)

PEC = 0.00164 μg/L

Where:

A = 11.9804 kg. (Total amount of estriol sold in Sweden year 2022, data from IQVIA).

R = 0 % removal rate.

P = number of inhabitants in Sweden = 10*10⁶

V (L/day) = volume of wastewater per capita and day = 200 (ECHA default) (Ref. 1)

D = factor for dilution of wastewater by surface water flow = 10 (ECHA default) (Ref. 1)

According to the European Medicines Agency guideline on environmental risk assessment of medicinal products (EMA/CHMP/SWP/4447/00), use of estriol is unlikely to represent a risk for the environment, because the predicted environmental concentration (PEC) at the time of registration was below the action limit 0.01 µg/L.

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae (Chlorella vulgaris) (OECD 201) (Ref. 2)

EC50 72 h (growth inhibition) >100 mg/L

Crustacean

No toxicity data for crustaceans has been found. 

Fish (several species)

Fish has been reported to be the most sensitive aquatic species (Ref. 3-5)

Chronic toxicity

Varying results for NOEC in fish have been reported (Ref. 3-6) but none of these studies were performed entirely according to standardized OECD methods.

The pharmaceutical company Novo Nordisk applies a PNEC of 4.7 ng/L for estriol (published on fass.se, Ref 3) based on a study of the induction of vitellogenin in Oryzias latipes (Ref. 6). An assessment factor of 10 was applied.

The relevance of this PNEC is questioned in a position paper on the environmental risk assessment for estriol (Ref. 4) as effects on reproduction was not included in this study.

Caldwell et al. reports a PNEC of 60 ng/L for estriol based on a large set of reproduction studies on 17α-ethinylestradiol, estradiol and estriols and the compounds potency to induce vitellogenin (VTG). The added uncertainty due to extrapolation includes an assessment factor of 10 (Ref. 6).

Environmental risk classification (PEC/PNEC ratio)

Based on the PEC calculated from volumes of Estriol sold in Sweden 2022 (0.00164 μg/L) and a value of PNEC of 0.060 μg/L, PEC/PNEC=0.027. According to the guideline for Environmental classification of pharmaceuticals at www.fass.se, a PEC/PNEC ratio ≤ 0.1 means that the substance is considered to result in insignificant environmental risk. However, the spread in the reported results for NOECs and lack of conclusive data justifies the phrase ’Risk of environmental impact of Estriol cannot be excluded, since there is not sufficient ecotoxicity data available’.

Degradation

No degradation data are available.

Bioaccumulation

Partitioning coefficient:

Log K_ow = 2.45 (Ref. 7)

Since log K_ow < 4, estriol has low potential for bioaccumulation.

References

1. ECHA (2008). Guidance on information requirements and chemical safety assessment. European Chemicals Agency. http://guidance.echa.europa.eu/docs/guidance_document/information_requirements_en.htm

2. Czarny, K. Szczukocki, D., Krawczyk, B., Skrzypek, S., Zieliński, M. and Gadzała-Kopciuch, R. (2019). "Toxic effects of single animal hormones and their mixtures on the growth of Chlorella vulgaris and Scenedesmus armatus." Chemosphere 224: 93-102.

https://doi.org/10.1016/j.chemosphere.2019.02.072

3. Vagifem. Miljöinformationen för estradiol framtagen av Novo Nordisk för Activelle®, Estrofem, Eviana, Kliogest®, Novofem®, Trisekvens®, Vagifem® (Estradiol and its metabolites). Publicerat på Fass.se. Vagifem® - FASS Allmänhet

4. Cardinaals, H. (2021). Position paper on the environmental risk assessment for estriol. Test Facility Study No. 20299966. Sponsor Ref. No. ITFE 2026. Charles River Laboratories, The Netherlands, on behalf of Italfarmaco, S. A., Spain.

5. Caldwell, D. J., Mastrocco, F., Anderson, P. D., Länge, R. and Sumpter J. P. (2012). Predicted-no-effect concentrations for the steroid estrogens estrone, 17β-estradiol, estriol, and 17α-ethinylestradiol. Environ. Toxicol. Chem. 31(6), 1396-1406. https://doi.org/10.1002/etc.1825

6. Lei, B., Kang, J., Yu, Y., Zha, J., Li, W., Wang, Z., Wang, Y. and Wen Y. (2014). Long-Term Exposure Investigating the Estrogenic Potency of Estriol in Japanese Medaka (Oryzias latipes). Comp. Biochem. Physiol. C: Toxicol. Pharmacol. 160, 86-92. https://doi.org/10.1016/j.cbpc.2013.11.001

7. Hansch, C., Leo, A. and Hoekman D. (1995). Exploring QSAR: Hydrophobic, electronic, and steric constants. ACS professional reference book. Washington, DC. American Chemical Society. 2, 158. As cited on https://pubchem.ncbi.nlm.nih.gov