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 (desogestrel + etonogestrel) = 0,00102 μg/L.

Where:

A = 3,6832 kg + 3,7338 kg = 7,4170 kg (total amount of desogestrel and etonogestrel sold in Sweden year 2023, data from IQVIA). The volumes for the two compounds are summarized as desogestrel are metabolized to etonogestrel.

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)

The factor 10⁹ in the equation converts the quantity used from kg to μg.

The factor 365 in the denominator converts from annual to daily quantity used.

According to the European Medicines Agency guideline on environmental risk assessment of medicinal products (EMA/CHMP/SWP/4447/00), use of desogestrel is unlikely to represent a risk for the environment, because the predicted environmental concentration (PEC) at the time of registration on Fass.se was below the action limit 0,01 µg/L.

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Desogestrel was first synthesized in 1972 by Organon International and introduced for medical use in 1981 (ref. 2,3). Desogestrel is a prodrug which is rapidly metabolized to the active drug substance 3-keto-desogestrel, also known as etonogestrel (ref. 4-6). There is very limited ecotoxicological data for desogestrel available in scientific literature and open data sources. Organon, and also the European Directorate for the Quality of Medicines & HealthCare (EDQM), refer to studies on etonogestrel for the ecotoxicity information in the safety data sheet for desogestrel (ref. 7-9). The ecotoxicological data used in this risk assessment are based on etonogestrel, as published in Organon's and EDQM’s safety data sheet for desogestrel (ref. 7-9).

Toxicity (fish):

LC50 (Oncorhynchus mykiss (rainbow trout)): 4 mg/L. Exposure time: 96 h. Method: FDA 4.11

LC50 (Lepomis macrochirus (Bluegill sunfish)): 1,3 mg/L. Exposure time: 96 h. Method: OECD Test Guideline 203. Remark: No toxicity at the limit of solubility.

Toxicity (daphnia):

EC50 (Daphnia magna (Water flea)): > 3,9 mg/L. Exposure time: 48 h. Method: OECD Test Guideline 202. Remark: No toxicity at the limit of solubility.

Chronic toxicity (fish):

NOEC (Pimephales promelas (fathead minnow)): 0,059 mg/L. Exposure time: 32 d.

Method: OECD Test Guideline 210.

NOEC (Oryzias latipes (Japanese medaka)): 0,0000027 mg/L. Exposure time: 183 d.

Chronic toxicity (daphnia):

NOEC (Daphnia magna (Water flea)): 1,2 mg/L. Exposure time: 21 d.

Chronic toxicity (algae): NOEC (Microcystis aeruginsa): 4,5 mg/L. Exposure time: 8 days.

PNEC calculations

The lowest NOEC for chronic toxicity studies was found for fish (Oryzias latipes): 2,7 ng/L (ref. 8,9).

EC₅₀ = 2,7 μg/L (fish)

An assessment factor of 10 should be used when there are long-term results from species representing three trophic levels (fish and/or daphnia and/or algae)) according to ECHAs guideline for chemical safety assessment (ref. 10). As the studies are based on the metabolite etonogestrel, a higher assessment factor, 1000, has been used in the PNEC calculation.

Assessment factor 1000 -> PNEC = 2,7 μg/L / 1000 = 0,0027 μg/L

Environmental risk classification (PEC/PNEC ratio)

PEC = 0,00102 μg/L, PNEC = 0,0027 μg/L

-> risk quotient PEC/PNEC = 0,00102/0,0027 = 0,38

Justification of chosen phrase for the environmental risk:

Even though the highest assessment factor (1000) has been used as a worst case senario for the calculations of the risk quotient, the risk ratio is low, 0,38, which justifies the phrase “Use of desogestrel has been considered to result in low environmental risk.”

Degradation

Biotic degradation

No data are available.

Abiotic degradation

No data are available.

Justification of chosen degradation phrase:

There are no data for biotic and abiotic degradation in the environment for desogestrel which justifies the phrase “The potential for persistence of desogestrel cannot be excluded, due to lack of data” is chosen.

Bioaccumulation

Bioconcentration factor (BCF), etonogestrel:

BCF (fish plasma) = 27 (calculated from log K_ow = 3,16 according to the formula log BCF = 0,73 log K_ow - 0.88) (ref. 11,13).

BCF (QSAR modelling) = 24,0 L/kg (ref. 12).

Partitioning coefficient:

Log K_ow (desogestrel) = 3,5 (ref. 8).

Log K_ow (etonogestrel) = 3,16 (experimental) (ref. 11,13).

Justification of chosen bioaccumulation phrase:

Desogestrel is metabolised to etonogestrel and thus does not bioaccumulate. Based on BCF < 500 and log K_ow < 4, etonogestrel has low potential for bioaccumulation.

Excretion (metabolism)

Desogestrel is metabolized to the active metabolite etonogestrel (ref. 5). Etonogestrel has a half-life of 30 h in humans (ref. 6) and 3,4 days in fish (QSAR modelling) (ref. 12).

PBT/vPvB assessment

Since desogestrel/etonogestrel has low potential for bioaccumulation it is not considered to be persistent, bioaccumulating and toxic (PBT) or very persistent and very bioaccumulating (vPvB).

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. Desogestrel. Wikipedia. https://en.wikipedia.org/wiki/Desogestrel 2025-01-15

3. Kuhl, H. Pharmacology of Progestogens. Journal of Reproductive Medicine and Endocrinology (2011), 8, 157-177. https://www.kup.at/kup/pdf/10168.pdf

4. Madden, S., Back, D.J., Martin, C. A. and Orme, M.L. Metabolism of the contraceptive steroid desogestrel by the intestinal mucosa. Br. J. clin. Pharmac. (1989), 27, 295-299. https://pubmed.ncbi.nlm.nih.gov/2524206/

5. Kuhl, H. Comparative pharmacology of newer progestogens. Drugs, (1996), 51, 188–215. doi:10.2165/00003495-199651020-00002

6. Product summary for desogestrel/Vinelle, originating from Campus Pharma and published on Fass.se. https://www.fass.se/LIF/product?userType=2&nplId=20130925000015&docType=6&scrollPosition=600#pharmacological (accessed 2024-10-07)

7. Personal mail communication with Mr/Mrs EHS Steward at Organon 2025-01-06.

8. Organon. Safety data sheet for Desogestrel Formulation. SDS No. 21970-00027. Version 6.1. Revision Date: 2024/04/06. https://www.organon.com/docs/product/safety-data-sheets/Desogestrel%20Formulation_ID_6N.pdf

9. European Directorate for the Quality of Medicines & HealthCare (EDQM). Safety data sheet for Desogestrel. V 2.0. Published 2023/09/26. https://sds.edqm.eu/pdf/SDS/EDQM_201600263_2.0_SDS_EN.pdf?ref=1709523099

10. ECHA Guidance on information requirements and chemical safety assessment Chapter R.10: Characterization of dose [concentration]-response for environment. https://echa.europa.eu/sv/guidance-documents/guidance-on-information-requirements-and-chemical-safety-assessment

11. Kumar, V., Johnson, A.C., Trubiroha, A., Tumová, J., Ihara, M., Grabic, R., Kloas, W., Tanaka, H., Kroupová, H.K. The Challenge presented by progestins in ecotoxicological research: A critical review. Environ. Sci. Technol. (2015), 49, 2625–2638. https://doi.org/10.1021/es5051343

12. The U.S. EPA Distributed Structure-Searchable Toxicity (DSSTox) Databasehttps://comptox.epa.gov/dashboard/chemical/env-fate-transport/DTXSID9046782(accessed 2024-09-25)

13. Rocha, M. J. and Rocha E. Synthetic Progestins in Waste and Surface Waters: Concentrations, Impacts and Ecological Risk. Toxics (2022), 10, 163. https://doi.org/10.3390/toxics10040163