This summary information about persistence, bioaccumulation and toxicity comes from Fass. The risk comes from the report by Goodpoint.
Persistence. Drospirenone is persistent.
Bioaccumulation. Drospirenone has low potential for bioaccumulation.
Toxicity. Drospirenone has very high chronic toxicity.
Risk. See the report by Goodpoint.
Fass environmental information
Fass environmental information for Angemin (drospirenone, estradiol) from Bayer (downloaded 2021-04-21).
Persistence: "The overall disappearance half-life from the system exceeded the threshold of 120d described in the FASS guidance, if the isomere is considered. Therefore, drospirenone can be classified as being potentially persistent. (OECD 308) 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 drospirenone is persistent in the initial summary information.
Bioaccumulation: "Log P 3.1 at pH 7 and 25°C (Shake flask method , OECD 117). [...] Since Log POW (at pH 7) < 4, and the BCFss is 100–102, the phrase drospirenone has a low potential for bioaccumulation is justified."
Toxicity: There are data for 3 trophic levels, most sensitive fish (Danio rerio) NOEC 216 days (fecundity, sex ratio, histopathological changes of gonads) = 0.23 microg/L.
PEC/PNEC is based on sales data in Sweden in year 2018. PEC/PNEC = 0.54 which gives the risk low.
Report on progestogens from Goodoint
Based on the ability to bind to the androgen receptor, bind to SHBG (Sex Hormone Binding Globulin) and studies on fish, drospirenone is a lower environmental risk than levonorgestrel, etongestrel and norethisterone. Binding to SHBG is believed to contribute to increased bioconcentration (and thus potency) in fish. Drosperionone binds less to SHBG than, for example, levonorgestrel, norethisterone and etonogestrel.
A substance's ability to activate the androgen receptor in fish is believed to also contribute to increased risk of environmental impact. Levonogestrel, norethisterone and etonogestrel activate all the androgen receptor in fish at very low concentrations, whereas, for example, drosperionone is a much less potent androgen receptor agonist.
In a study by Zeilinger at al where levonorgestrel was compared with drospirenone, levonogestrel was shown to inhibit egg production in fish at 0.8 ng/L while requiring 6 500 ng/L of drosperionone to effect.
Comparison of combination preparation with estrogen
Studies show that levonogestrel and etonogestrel are the most environmental hazard of the progestogen component. Drosperinone is significantly less environment-affecting based on ecotoxicological studies, partly due to its low affinity for the androgen receptor and SHBG. For nomegestrel, both exposure data and effect data are missing in fish. However, nomegestrel binds poorly to both the androgen receptor and SHBG, which makes a low risk profile.
Of the oestrogens ethinyl estradiol causes high environmental risk while estradiol is less dangerous. At the same time, the amount of estradiol in pharmaceuticals is often higher, but estradiol is degraded more easily than ethinyl estradiol in the body, in the wastewater treatment plant and 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 higher dosage.
In total, levonorgestrel + ethinyl estradiol and ethonogestrel + ethinyl estradiol are considered to be of the highest environmental risk, drosperinone + ethinyl estradiol of lower risk (based on the gestagen component) and nomegestrol and estradiol of the lowest risk (based on the primary gestagen component but also the estrogen component).
- Fass.se för vårdpersonal
- Goodpoint. Miljöhänsyn vid förskrivning av gestagena preparat. Stockholm: Goodpoint; 2017.
- 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.
- Ellestad LE, Cardon M, Chambers IG, Farmer JL, Hartig P, Stevens K et al. Environmental gestagens activate fathead minnow (Pimephales promelas) nuclear progesterone and androgen receptors in vitro. Environ Sci Technol. 2014;48:8179-87.
- Bain PA, Kumar A, Ogino Y, Iguchi T. Nortestosterone-derived synthetic progestogens do not activate the progestogen receptor of Murray-Darling rainbowfish (Melanotaenia fluviatilis) but are potent agonists of androgen receptors alpha and beta. Aquat Toxicol. 2015;163:97-101.
- 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.
Author: Health and Medical Care Administration, Region Stockholm