Metformin

Detailed information

Assessment report

Below is Hazard and Risk according to data from the assessment report for Segluromet (ertugliflozin/metformin hydrochloride) 25 January 2018, EMA / 86928/2018.

Hazard

Persistence: "DT_{50, sediment} (20C) = 14d, DT_{50, water} (12C) = 12–43.3d, DT_{50, 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 K_ow -2, "Not B".

Chronic toxicity: There is NOEC for three trophic levels, lowest NOEC for fish 10 mg/L.

Risk

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."

Hazard

Persistence: DT_{50 (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.

Risk

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)

Hazard

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 K_ow = -1.43.

Toxicity: There are data for 3 trophic levels, most sensitive crustaceans (Ceriodaphnia dubia) NOEC 1000 microg/L.

Risk

PEC/PNEC is based on sales data in Sweden in year 2017. PEC/PNEC = 0.23 which gives the risk low.

Report Goodpoint

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’."