Persistence. Metformin is slowly degraded in the environment.
Bioaccumulation. Metformin has low potential for bioaccumulation.
Toxicity. Metformin has moderate chronic toxicity.
Risk. The use of metformin in Sweden has been considered to result in low environmental risk.
This summary information about persistence and bioaccumulation for metformin is from the assessment report Segluromet (ertugliflozin/metformin hydrochloride) 25 January 2018, EMA/86928/2018 and Fass. Information about toxicity comes from Fass environmental information for Komboglyze. The risk comes from the report of Goodpoint.
Metformin is included on the watch list of substances for Union-wide monitoring in the field of water policy pursuant to Directive 2008/105/EC of the European Parliament and of the Council.
Below is Hazard and Risk according to data from the assessment report for Segluromet (ertugliflozin/metformin hydrochloride) 25 January 2018, EMA / 86928/2018.
Persistence: "DT50, sediment (20C) = 14d, DT50, water (12C) = 12–43.3d, DT50, sediment (12C) = 38.8d, % shifting to sediment = 50.8–59.5% AR after 17d. TG218 test. Metformin can be considered persistent in water according to PBT criteria (DT50 > 40d)."
Bioaccumulation: log Kow -2, "Not B".
Chronic toxicity: There is NOEC for three trophic levels, lowest NOEC for fish 10 mg/L.
The risk, PEC/PNEC, calculated from data in the assessment report from a European perspective:
PEC = 5.0 mikrog/L
PNEC = Lowest NOEC, 10000 microg/L/10 (Assessment Factor (AF) for three chronic studies) = 1000 microg/L
PEC/PNEC = 0.005 which gives the risk insignificant.
Comment on Fass environmental information
Metformin 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 for Eucreas
Fass environmental information for Eucreas (metformin, vildagliptin) from Novartis (downloaded 2022-11-16)
"Disclaimer: With the exception of the literature studies and the Novartis Core data sheet, all studies used in this Environmental Assessment are the property of Janssen. Novartis has been authorised by Janssen to use the study reports for the purpose of contributing to the Swedish www.fass.se database."
Persistence: DT50 (total system) = 43.0–53.0 days (OECD 308, 101 days). [...] According to the pass criteria for OECD308 studies, metformin can be classified as ‘Metformin is slowly degraded in the environment' (DT50 for total system ≤ 120 days).
Bioaccumulation: Log P = -2.48 (OECD107).
Toxicity: There are data for 3 trophic levels, most sensitive fish (Pimephales promelas, fathead minnow) NOEC 32 days = 10300 microg/L.
PEC/PNEC is based on sales data in Sweden in year 2018. PEC/PNEC = 0.024 which gives the risk insignificant.
Fass environmental information for Komboglyze
Fass environmental information for Komboglyze (metformin, saxagliptin) from AstraZeneca (downloaded 2022-11-16)
Persistence: Percentage Aerobic Biodegradation (FDA 3.11) 10 mg/L 28 d 0.6%: Not readily biodegradeable. OECD 308: 102 d. 1.0 mg/L (High Organic Matter Sediment) DT50 = 6.59 days (Total System) 1.0 mg/L (Low Organic Matter Sediment) DT50 = 55.0 days (Total System). Results from the aerobic biodegradation test, showed that metformin hydrochloride is not readily biodegradable. Evidence from the OECD 308 study is that metfromin hydrochloride is likley to dissipate from the aqueous phase and partition into the sediment phase. [...] The phrase “Metformin hydrochloride is slowly degraded in the environment.” has been assigned.
Bioaccumulation: Log Kow = -1.43.
Toxicity: There are data for 3 trophic levels, most sensitive crustaceans (Ceriodaphnia dubia) NOEC 1000 microg/L.
PEC/PNEC is based on sales data in Sweden in year 2017. PEC/PNEC = 0.23 which gives the risk low.
Measured levels in Sweden are far below reported concentration of environmental impact. Abroad significant higher levels in wastewater are reported.
EU water legislation
"During 2021, the Commission gathered data on a range of other substances that could be included in the watch list. It took into account the different types of relevant information referred to in Article 8b(1) of Directive 2008/105/EC, and consulted experts from Member States and stakeholder groups. Substances for which doubt exists about their toxicity, or for which the sensitivity, reliability or comparability of the available monitoring methods are not adequate, should not be included in the watch list. The fungicide azoxystrobin, the herbicide diflufenican, the insecticide and veterinary pharmaceutical fipronil, the antibiotics clindamycin and ofloxacin, the human pharmaceutical metformin and its metabolite guanylurea, and a group of three sunscreen agents (butyl methoxydibenzoylmethane, also known as avobenzone; octocrylene; and benzophenone-3, also known as oxybenzone) were identified as suitable candidates. The addition of the pharmaceuticals is consistent with the EU Strategic Approach to Pharmaceuticals in the Environment (6), and the inclusion of the two antibiotics is also consistent with the European One Health Action Plan against Antimicrobial Resistance (AMR) (7), which supports the use of the watch list to ‘improve knowledge of the occurrence and spread of antimicrobials in the environment’."
- European Medicines Agency. European public assessment reports (EPAR) for Segluromet (ertugliflozin/metforminhydroklorid) 25 January 2018, EMA/86928/2018.
- Fass.se för vårdpersonal
- Goodpoint. Prioritering av läkemedel med miljörisk inom SLL. Stockholm: Goodpoint; 2016. Rapport LS 2016–0634.
- IVL Swedish Environmental Research Institute Ltd. Fick J, Lindberg RH, Kaj L, Brorström-Lundén E. Results from the Swedish National Screening Programme 2010. Subreport 3, B 2014 Pharmaceuticals.
- IVL Swedish Environmental Research Institute Ltd Fick J, Lindberg RH, Fång J, Magnér J, Kaj L, Brorström-Lundén E. Screening 2014. Analysis of pharmaceuticals and hormones in samples from WWTPs and receiving waters. Rapport C 135.
- Fick J, Lindberg RH, Tysklind M, Larsson DG. Predicted critical environmental concentrations for 500 pharmaceuticals. Regul Toxicol Pharmacol. 2010;58:516-23.
- Niemuth NJ, Jordan R, Crago J, Blanksma C, Johnson R, Klaper RD. Metformin exposure at environmentally relevant concentrations causes potential endocrine disruption in adult male fish. Environ Toxicol Chem. 2015;34:291-6.
- Official Journal of the European Union. Commission implementing decision (EU) 2022/1307 of 22 July 2022.
Author: Health and Medical Care Administration, Region Stockholm