Environmental Risk Assessment Data Metformin hydrochloride

Transcription

1 Environmental Risk Assessment Data Metformin hydrochloride Metformin hydrochloride is an oral antihyperglycemic drug used in the management of type 2 diabetes. Metformin hydrochloride is an active pharmaceutical ingredient used in the following AstraZeneca products: Kombiglyze, Kombiglyze XR, Xigduo and Xigduo XR. Metformin hydrochloride is eliminated as unchanged drug in the urine. Metformin hydrochloride is not readily biodegradable. Based on the degradation studies, it is predicted that metformin hydrochloride entering the aquatic environment will partition into, and degrade within, aquatic sediments. The Predicted Environmental Concentration (PEC) / Predicted No Effect Concentration (PNEC) ratio is 0.93, which means use of metformin is predicted to present a low risk to the environment. Predicted Environmental Concentration (PEC) The PEC is based on the following data: PEC (µg/l) = (A*10 9 *(100-R))/(365*P*V*D*100) A (kg/year) = total patient consumption of metformin (active moiety) in the European country with the highest per capita use in 2016 (Source: IMS Health 1 ) R (%) = % removal during wastewater (sewage) treatment (due to loss by adsorption to sludge particles, by volatilisation, hydrolysis or biodegradation). For metformin, it is assumed that R = 0 as a worst case. P = number of inhabitants in the European country with the highest per capita use in 2016 (Source: Eurostat 2 ). A/P = 6.8 x 10-2 kg/inhabitant V (L/day) = volume of wastewater per capita and day = 200 (European Medicines Agency (EMA) default value, Ref. 1) D = factor for dilution of waste water by surface water flow = 10 (EMA default value, Ref 1) (Note: The factor 10 9 in the equation above converts the quantity used from kg to μg) PEC = 93 µg/l Predicted No Effect Concentration (PNEC) Long-term tests have been undertaken for species from three trophic levels, based on internationally accepted guidelines. Therefore, the PNEC is based on the lowest No Observed Effect Concentration (NOEC) 1 mg/l (equivalent to 100 µg/l) which was reported for the water flea (Ceriodaphnia dubia) reproduction test, and an assessment factor of 10 is applied, in accordance with the EMA guidance (Ref 1). PNEC = 100 µg/l /10 = 10 µg/l PEC/PNEC 1 IMS Health, MIDAS International Data for 2016, available for 22 European markets 2 The number of persons having their usual residence in a country on 1 January Available from Accessed: 20/4/1

2 PEC = 93 µg/l PNEC = 10 µg/l PEC/PNEC = 0.93 The PEC/PNEC ratio of 0.93 corresponds to the phrase Use of the substance has been considered to result in low environmental risk in the scheme (Ref 2). Environmental Fate Summary Results from the aerobic biodegradation test show that metformin hydrochloride is not readily biodegradable. The evidence from the OECD 308 study is that metfromin hydrochloride is likely to dissipate from the aqueous phase and partition into the sediment phase and will degrade within the aquatic environment, both via biotic and abiotic transformation. There metformin hydrochloride is not considered to be persistent. The octanol-water partition coefficient study shows that the risk of bioaccumulation in aquatic organisms is low. Aquatic Toxicity Data for Metformin Hydrochloride Toxicity to green algae, Pseudokirchinella subcapitata, growth inhibition test OECD hour NOEC (growth rate) 100 mg/l 2 hour EC50 (growth rate) > 100 mg/l 3 2 hour NOEC (biomass area under curve) 100 mg/l 2 hour EC50 (biomass area under curve) > 100 mg/l Acute toxicity to Daphnia magna Document hour EC50 (immobility) = 130 mg/l 4 Acute toxicity to bluegill sunfish, Lepomis macrochirus Document hour LC50 (mortality) >982 mg/l 5 Chronic toxicity to Daphnia magna OECD day NOEC (survival, reproduction and growth) = 6 mg/l 6 21 day NOEC (survival, reproduction and growth) (Note 1) = 54.1 mg/l Chronic toxicity to Ceriodaphnia dubia ISO d NOEC (Reproduction) = 1 mg/l Fish Early-Life Stage Toxicity with fathead minnows Pimephales promelas, OECD day NOEC (hatch, survival, growth) = 10 mg/l 32 day NOEC (hatch, survival, (Note 2) growth) = 2.2 mg/l 8

3 Fish Early-Life Stage Toxicity with 32 day NOEC (hatch, survival, Zebra fish, Danio rerio growth) = 11.1 mg/l Toxicity to Chironomus riparius OECD day NOEC (total emergence, development rate, sex ratio) = 100 mg/kg dry weight Growth inhibition of fungi: Aspergillus clavatus Penicillium canescens Chaetomium globosum Growth inhibition of bacteria: Pseudomonas fluorescens Bacillus megaterium Growth inhibition of Nitrogen fixing bacteria, Azobacter chroococcum Growth inhibition of blue-green algae, Anabaena flos-aquae Note 1 Note 2 NOEC LOEC EC50 LC50 Document day LOEC (total emergence, development rate, sex ratio > 100 mg/kg dry weight 6 day Microbial Inhibitory Concentartion (MIC) = 800 mg/l = 400 mg/l 6 day Microbial Inhibitory Concentartion (MIC) = 100 mg/l = 80 mg/l Geometric average of 4 data points Geometric average of 3 data points No Observed Effect Concentration Lowest Observed Effect Concentration the concentration of the test substance that results in a 50% effect the concentration of the test substance that results in a 50% mortality Environmental Fate Data for Metformin Hydrochloride Aerobic biodegradation FDA 3.11 Degradation after 28 days 0.6 % 11 Not readily biodegradable 9 10

4 Water-sediment transformation study OECD 308 DT50 (Total System) (High Organic Matter Sediment) = 6.59 days DT50 (Total System) (Low Organic Matter Sediment) = 55.0 days 12 Hydrolysis FDA 3.09 % hydrolysis after 5 days at ph 5, and 9 < 1% Hydrolysis half-life at 25 C 1 year Photolysis FDA 3.10 % photolysis after 5 days = 15% Photolysis half-life =28.3 days Activated sludge FDA 3.08 Kd = 10.3 Sorption/Desorption K oc = 32.1 Kd Distribution coefficient for adsorption Koc Organic carbon normalized adsorption coefficient Physical Chemistry Data for Metformin Hydrochloride Solubility Water Unknown mg/l at 25 o C 16 Partition Coefficient Unknown Log Kow = Octanol-Water References 1. Committee for Medicinal Products for Human Use (CHMP); Guideline on the Environmental Risk Assessment of Medicinal Products for Human Use. 1 June 2006, EMEA/CPMP/SWP/444/00 corr2. C pdf 2. Fass.se (2012). Environmental classification of pharmaceuticals at Guidance for pharmaceutical companies 3. Metformin Hydrochloride - Acute Toxicity to the Freshwater Green Alga, Pseudokirchneriella subcapitata OECD 201, Springborn Smithers Laboratories, Inc.:Report No , Acute Toxicity of Metformin HCl to Daphnia magna ABC Laboratories, Inc. Report No. 418, Jul 14, Static Acute Toxicity of Metformin HCl to Bluegill (Lepomis macrochirus) ABC Laboratories, Inc. Report number 419, July Metformin Hydrochloride - Full Life-Cycle Toxicity Test with Water Fleas Daphnia magna, Under Static-Renewal Conditions OECD 211, Springborn Smithers Laboratories, Inc.: Report No , Environmental Risk Assessment for metformin and its transformation product guanylurea in surface water. Caldwell.D, et al. SETAC Europe 24th Annual Meeting, Basle, Switzerland, May 11th 15th, 2014). 8. Metformin (BMS 20150) Early Life-Stage Toxicity Test with Fathead Minnow, (Pimephales promelas), Following OECD Guideline 210. Smithers Viscient: Report No , Metformin Hydrochloride Toxicity Test with Sediment-Dwelling Midges (Chironomous riparius) Under Static Conditions, Following OECD Guideline 218. Smithers Viscient: Report No , 2011.

5 10. Microbial Growth Inhibition with Metformin HCl, ABC Laboratories, Inc. Report No. 416, Jul 13, Aerobic Biodegradation of 14C-Metformin HCl in Water, ABC Laboratories, Inc. Report No. 415, Aug 10, [14C]Metformin Hydrochloride [14C](BMS 20150) Aerobic Transformation in Aquatic Sediments Following OECD Guideline 308. Smithers Viscient: Report No , Hydrolysis of Metformin HCl as a function of ph, ABC Laboratories, Inc. Report No. 414, Aug 10, Determination of the Aqueous Photodegradation of 14C-Metformin HCl, ABC Laboratories, Inc. Report No , Aug 11, Sorption / Desorption Springborn Smithers Laboratories FDA July AstraZeneca Environmental Risk Assessment of Saxagliptin/Metformin Fixed Dose Combination [CV ], June 2010.