Environmental risk assessment of metformin and its transformation product guanylurea: II. Occurrence in surface waters of Europe and the United States and derivation of predicted no-effect concentrations.

Metformin (MET), CAS 1115-70-4 (Metformin hydrochloride), is an antidiabetic drug with high usage in North America and Europe and has become the subject of regulatory interest. A pharmaceutical industry working group investigated environmental risks of MET. Environmental fate and chronic effects data were collated across the industry for the present risk assessment. Predicted environmental concentrations (PECs) for MET were modeled for the USA and Europe using the PhATE and GREAT-ER models, respectively. PECs were compared with measured environmental concentrations (MECs) for the USA and Europe. A predicted no effect concentration (PNEC) of 1 mg/L for MET was derived by deterministic procedures, applying an assessment factor of 10 to the lowest no observed effect concentration (i.e., 10 mg/L) from multiple chronic studies with algae, daphnids and fish. The PEC/PNEC and MEC/PNEC risk characterization ratios were <1, indicating no significant risk for MET with high Margins of Safety (MOS) of >868. MET is known to degrade during wastewater treatment to guanylurea (GUU, CAS 141-83-3), which we have shown to further degrade. There are no GUU toxicity data in the literature; hence, chronic studies for GUU were conducted to derive a PNEC of 0.16 mg/L. PECs were derived for GUU as for MET, plus MECs were retrieved from the literature. The PEC/PNEC and MEC/PNEC risk characterization ratios for GUU were also <1, with an MOS of >6.5. Based on standard risk assessment procedures for both MET and its transformation product GUU, there is no significant risk to aquatic life.

Environmental risk assessment of metformin and its transformation product guanylurea. I. Environmental fate.

Metformin (MET) is a pharmaceutical with very high use worldwide that is excreted in unchanged form, leading to concern about potential aquatic life impacts associated with MET, and its primary transformation product guanylurea (GUU). This study presents, in two companion papers, a risk assessment following internationally accepted guidelines of MET and GUU in surface water based on literature data, previously unpublished studies, and a new degradation test that resolves conflicting earlier results. Previous studies have shown that MET is removed during sewage treatment, primarily through transformation to GUU. In addition, measurements in WWTPs suggest that MET is not only transformed to GUU, but that GUU is further biodegraded. A prolonged inherent biodegradation test strongly suggests not only primary transformation of MET to GUU, but also subsequent full mineralization of GUU, with both degradation phases starting after a clear lag phase. MET may partition from surface water to sediment, where both transformation to GUU and in part mineralization is possible, depending on the presence of competent degrading microorganisms. In addition, MET may form non-extractable residues in sediments (12.8-73.5%). Both MET and GUU may be anaerobically degraded during sludge digestion, in soils or in sediments. Bioconcentration factor (BCF) values in crops and most plants are close to 1 suggesting low bioaccumulation potential, moreover, at least some plants can metabolize MET to GUU; however, in aquatic plants higher BCFs were found, up to 53. Similarly, neither MET nor GUU are expected to bioaccumulate in fish based on estimated values of BCFs ≤3.16.

Use of computer-assisted prediction of toxic effects of chemical substances.

The current revision of the European policy for the evaluation of chemicals (REACH) has lead to a controversy with regard to the need of additional animal safety testing. To avoid increases in animal testing but also to save time and resources, alternative in silico or in vitro tests for the assessment of toxic effects of chemicals are advocated. The draft of the original document issued in 29th October 2003 by the European Commission foresees the use of alternative methods but does not give further specification on which methods should be used. Computer-assisted prediction models, so-called predictive tools, besides in vitro models, will likely play an essential role in the proposed repertoire of "alternative methods". The current discussion has urged the Advisory Committee of the German Toxicology Society to present its position on the use of predictive tools in toxicology. Acceptable prediction models already exist for those toxicological endpoints which are based on well-understood mechanism, such as mutagenicity and skin sensitization, whereas mechanistically more complex endpoints such as acute, chronic or organ toxicities currently cannot be satisfactorily predicted. A potential strategy to assess such complex toxicities will lie in their dissection into models for the different steps or pathways leading to the final endpoint. Integration of these models should result in a higher predictivity. Despite these limitations, computer-assisted prediction tools already today play a complementary role for the assessment of chemicals for which no data is available or for which toxicological testing is impractical due to the lack of availability of sufficient compounds for testing. Furthermore, predictive tools offer support in the screening and the subsequent prioritization of compound for further toxicological testing, as expected within the scope of the European REACH program. This program will also lead to the collection of high-quality data which will broaden the database for further (Q)SAR approaches and will in turn increase the predictivity of predictive tools.