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Levonorgestrel

Information

This summary information on persistence, toxicity and risk comes from Fass. The risk is also supported by the reports from Goodpoint. Information on bioaccumulation comes from the reports from Goodpoint.

Persistence. Levonorgestrel is persistent. See comment below on "potential peristence" under Fass environmental information.
Bioaccumulation. Levonorgestrel is below the limit value for high potential to bioaccumulate, but the substance binds to Sex Hormone Binding Globulin (SHBG) and just binding to SHBG is assumed to contribute to the exceptionally high bioconcentration ability (and thus potency) observed in fish for levonorgestrel.
Toxicity. Levonorgestrel has very high chronic toxicity.
Risk. The use of levonorgestrel (sales data Sweden 2019) has been judged to entail a high risk of environmental impact.

Detailed information

Fass environmental information

Fass environmental information for Jaydess (levonorgestrel) from Bayer (downloaded 2020-11-05).

Hazard

Persistence: OECD 308: "Levonorgestrel was incubated in glass vessels containing sediment and overlaying water over 100 days. [...] The degradation rate was 6–7% at the end of the incubation period. The DT50 (disappearance half-life from the water phase) for parent compound in water was estimated with 2.5 and 3.2 days for the fine and coarse sediment, respectively. The overall disappearance half-life from the system exceeded the threshold of 120 days described in the FASS guidance. Therefore, levonorgestrel can be classified as being potentially persistent." The database, Pharmaceuticals and Environment, reference group believes that based on these results, a drug substance is persistent and not potentially persistent, hence the information that levonorgestrel is persistent in the initial summary information.

Bioaccumulation: "Log POW 3.55 (Shake flask method, FDA TAD 3.02). [...] According to the BCF of 119 to 250, levonorgestrel has low potential for bioaccumulation."

Toxicity: There are data for 3 trophic levels, most sensitive fish fathead minnow Pimephales promelas) NOEC 21 days (fish reproduction test; fecundity, sexual reversal) = 0.0001 microg/L (EC10) (OECD 229).

Risk

PEC/PNEC is based on sales data in Sweden in year 2019. PEC/PNEC = 141 which gives the risk high.

Report Goodpoint 2016

Estimated levels in Swedish surface water may be sufficient to interfere with reproduction in fish. Fish exposed to purified effluent accumulates levonorgestrel to concentrations exceeding the serum concentrations achieved in women using birth control pills.

Levonorgestrel is included in Region Stockholm's table of pharmaceuticals with risk for negative environmental impact according to the environmental program 2017–2021 based on lowest effect concentration, LOEC = 0.8 ng/L, and concentrations found in the environment.

Report on progestogens from Goodoint

Levonorgestrel has a BCF value that is below the limit value for a substance to be considered to have a high potential to bioaccumulate. However, the substance binds to SHBG, and binding to SHBG is supposed of contributing to the exceptionally high bioconcentration ability (and thus potency) observed in fish.

In comparison between levonorgestrel, norethisterone and medroxyprogesterone, medroxyprogesterone is preferred from an environmental point of view.

When using combination preparations with gestagen and estrogen, the estrogen component must also be considered. In particular, levonogestrel stands out as a drug with increased environmental risk. Environmental risk assessment is therefore relevant for both the gestagen and the estrogenic component. In total, levonorgestrel + ethinylestradiol and etonogestrel + ethinylestradiol are considered to be the highest environmental risk, drospirenone + ethinylestradiol lower risk (based on gestagen component) and nomegestrol and estradiol lowest risk (based primarily on the gestagen component but also the estrogen component).

The method, tablets versus long-acting reversible contraception (LARC), is also important, see below under "Concrete proposal for levonorgestrel".

The Wise list

Levonorgestrel 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 the emissions of levonorgestrel

Concrete proposals on how to work to reduce emissions of environmentally harmful pharmaceuticals on the list have been developed in close cooperation with Region 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 levonorgestrel

  • Levonorgestrel is recommended in the Wise list.
  • Individual adjustment of contraception is important to optimize treatment and avoid side effects.
  • When using oral combined hormonal contraceptives, the amount of levonorgestrel administered per day is multiply higher than the dose given by the long-acting levonorgestrel-releasing hormone spirals. Jaydess, Mirena and Kyleena (recommended in the Wise list) can therefore be an alternative to combined contraceptives from an environmental point of view. The long-acting Nexplanon p-implant with etonogestrel is another option (recommended in the Wise list).
  • Ensure that you, in your own business, discard any leftover pharmaceuticals and use the hormone spirals and p-implants correctly.
  • Inform the patient about the importance of discarding the leftover pharmaceutical correctly. Order the folder for patients "Protect the Environment – Throw in the Right Way".

References

  1. Fass.se för vårdpersonal
  2. Goodpoint. Prioritering av läkemedel med miljörisk inom SLL. Stockholm: Goodpoint; 2016. Rapport LS 2016–0634.
  3. Googpoint. Miljöhänsyn vid förskrivning av gestagena preparat. 2017.
  4. Zeilinger J, Steger-Hartmann T, Maser E, Goller S, Vonk R, Länge R. Effects of synthetic gestagens on fish reproduction. Environ Toxicol Chem. 2009;28:2663-70.
  5. Fick J, Lindberg RH, Parkkonen J, Arvidsson B, Tysklind M, Larsson DG. Therapeutic levels of levonorgestrel detected in blood plasma of fish: results from screening rainbow trout exposed to treated sewage effluents. Environ Sci Technol. 2010;44:2661-6.
  6. Miguel-Queralt S, Hammond GL. Sex hormone-binding globulin in fish gills is a portal for sex steroids breached by xenobiotics. Endocrinology. 2008;149:4269-75.
  7. Friel PN, Hinchcliffe C, Wright JV. Hormone replacement with estradiol: conventional oral doses result in excessive exposure to estrone. Altern Med Rev. 2005;10:36-41.
  8. Fent K. Progestins as endocrine disrupters in aquatic ecosystems: Concentrations, effects and risk assessment. Environ Int. 2015;84:115-30.
  9. Runnalls TJ, Beresford N, Kugathas S, Margiotta-Casaluci L, Scholze M, Scott AP et al. From single chemicals to mixtures--reproductive effects of levonorgestrel and ethinylestradiol on the fathead minnow. Aquat Toxicol. 2015;169:152-67.
  10. Region Stockholm. Förteckning över miljöbelastande läkemedel med åtgärdsförslag framtagen inom ramen för Region Stockholms miljöprogram 2017–2021.
  11. Region Stockholms läkemedelskommitté. Kloka listan (the Wise list).
  12. Region Stockholm. The Wise list 2015.

Author: Health and Medical Care Administration, Region Stockholm