Environmental Risk Assessment Summary Sulfamethoxazole

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1 r Environmental Risk Assessment Summary Sulfamethoxazole Introduction The publication of environmental risk assessment summaries is part of Roche s engagement on developing a better understanding of issues regarding pharmaceuticals in the environment (PIE). New pharmaceutical substances are investigated for biodegradability and initial ecotoxicity during their development. For registration, a full state-of-the-art environmental risk assessment is developed based on chronic environmental effects and advanced environmental fate data, as required by the pertinent regulations. While not a regulatory requirement, Roche also investigates older pharmaceutical substances, normally at a simpler scale, in order to assess their environmental risks. For pharmaceutical substances, the potential environmental risk is calculated from the ratio between the Predicted Environmental Concentration (PEC) of the substance in the aquatic environment based on a conservative emission scenario and the Predicted No Effect Concentration (PNEC), a concentration below which no adverse effects on the environment have to be expected. If Measured Environmental Concentrations (MECs) are available, these can also be compared with the PNEC. Summary Sulfamethoxazole is a sulphonamide antimicrobial agent. It is commonly used in combination with Trimethoprim. Sulfamethoxazole competitively inhibits dihydropteroate synthase preventing the formation of dihydropteroic acid, a precursor of folic acid which is required for bacterial growth [16]. Sulfamethoxazole is the active pharmaceutical ingredient used in combination with Trimethoprim in the Roche product Bactrim. Sulfamethoxazole (SMX) is rapidly absorbed on oral administration; metabolism is mainly hepatic, with the formation of predominantly N4-acetyl-SMX (NAcSMX) and glucuronide conjugates (GluSMX). Excretion is renal, with a half-life of 7 h to 12 h, most of the excreted substance being NAcSMX (30 70% of administered), followed by Sulfamethoxazole (10 40%) and GluSMX [17]. Sulfamethoxazole is neither readily nor inherently biodegradable in standard OECD tests over 28 days [17]. However, based on 190 data of full-scale working sewage treatment plants (STP) the median removal rate amount to 49% [17]. The PEC/ PNEC SW ratio for ecotoxicology is With reference to the Guideline on the Environmental Risk Assessment on Medicinal Products for Human Use of the European Medicines Agency [6], a PEC/PNEC SW ratio of 1 means that Sulfamethoxazole and/or its metabolites are unlikely to represent a risk to the aquatic environment. F. Hoffmann-La Roche Ltd, Group SHE (LSO), ANH, page 1/6

2 Also when considering a provisional PEC/PNEC R ratio of (i.e. 1) for antimicrobial resistance selection, Sulfamethoxazole and/or its metabolites are unlikely to represent a risk to the aquatic environment. Predicted Environmental Concentration (PEC) The PEC is based on the following data: PEC (μg/l) = (A x 10 9 x (1-R)) / (365 x P x V x D) A Total patient consumption of Sulfamethoxazole in the European country with the highest yearly per capita use in the period (data from IQVIA [12]) R Removal rate in sewage treatment plant (STP): 0.49 (median removal rate for full-scale working STP of 49% [17] P Number of inhabitants in the country with the highest per capita use in the respective year of the period [7]; resulting in a consumption of 332 mg/inhabitant V Volume of wastewater per inhabitant and day (default value) = 200 L day -1 [6] D Dilution factor of wastewater by surface water flow (default value) = 10 [6] PEC = μg/l Note: Sulfamethoxazole is metabolised in the body to an extent of up to 90%. Since little is known about the ecotoxicity of these metabolites, it is assumed as a worst case that they have the same ecotoxicological relevance as Sulfamethoxazole. Measured Environmental Concentration (MEC) Based on about 5000 MEC data for Europe the calculated 50th and 95th percentiles (MEC 50 and MEC 95, respectively) for Sulfamethoxazole were μg/l and μg/l, respectively [17]. The MEC 95 of μg/l is in good agreement with the calculated PEC for Sulfamethoxazole of μg/l. Predicted No Effect Concentration for Aquatic Ecosystem Function (PNEC SW ) Acute and chronic data for species from three trophic levels, partially assessed based on OECD Test Guidelines, but also taken from the literature, have been used to calculate the PNEC SW The lowest No Observed Effect Concentration (NOEC) or chronic effective concentration (EC 10 ) is 5.9 μg/l of the 96 h NOEC growth for the cyanobacterium Synechococcus leopoliensis. Applying an assessment factor of 10 according to the EMA Guideline [6], this results in a PNEC SW of 0.6 μg/l. PNEC SW = 5.9 μg/l / 10 = 0.6 μg/l F. Hoffmann-La Roche Ltd, Group SHE (LSO), ANH, page 2/6

3 Provisional Predicted No Effect Concentration for Antimicrobial Resistance Development (PNEC R ) In the discussion about antimicrobial resistance (AMR) development, provisional PNEC R are derived. An approach is to use the 1 st percentile of the minimal inhibitory concentrations (MIC) for different bacteria genera, corresponding to the value containing the bottom 1% of the MIC values and by applying a safety factor of 10. With this approach a provisional PNEC R of 16 μg/l was derived [3]. PNEC R = 16 μg/l PEC/PNEC ratios PEC = μg/l PNEC SW = 0.6 μg/l PNEC R = 16 μg/l (provisional) PEC/PNEC SW = PEC/PNEC R = (provisional) With reference to the Guideline on the Environmental Risk Assessment on Medicinal Products for Human Use of the European Medicines Agency [6], a PEC/PNEC SW ratio of (i.e. 1) means that Sulfamethoxazole and/or its metabolites are unlikely to represent a risk to the aquatic environment. Also when considering a provisional PEC/PNEC R ratio of (i.e. 1) for AMR selection, Sulfamethoxazole and/or its metabolites are unlikely to represent a risk to the aquatic environment. F. Hoffmann-La Roche Ltd, Group SHE (LSO), ANH, page 3/6

4 Aquatic Toxicity Data for Sulfamethoxazole Study Guideline Results Ref. green alga Raphidocelis subcapitata not specified ISO h EC50 = mg/l 96 h NOEC = mg/l 72 h EC50 = 1.12 mg/l [15] OECD h EC50 = 0.98 mg/l [4] green alga Chlorella vulgaris 72 h EC50 = 1.51 mg/l not specified 96 h EC50 = 2.4 mg/l diatom Cyclotella meneghiniana 96 h NOEC = 1.25 mg/l diatom Skeletonema marinoi ISO h EC50 = 5.35 mg/l [15] cyanobacteria Synechococcus leopoliensis duckweed Lemna gibba Acute immobilisation test with Daphnia magna not specified ASTM AFNOR T ISO 6341 EPA/600/4-90/027F 96 h EC50 = mg/l 96 h NOEC = mg/l 7 d EC50 (frond no.) = mg/l 7 d EC50 (wet weight) = mg/l 7 d EC10 (frond no.) = mg/l 7 d EC10 (wet weight) = mg/l 48 h EC50 >100 mg/l 48 h EC50 = mg/l [15] Acute immobilisation test with 48 h EC50 >100 mg/l Ceriodaphnia dubia Acute immobilisation test with not specified 48 h EC50 >100 mg/l [15] Artemia salina Ceriodaphnia dubia, reproduction AFNOR 7 d NOEC = 0.25 mg/l and survival test T Fish embryo toxicity test with ISO d NOEC = 8 mg/l zebrafish (Danio rerio) Anaerobic inhibition OECD 224 NOEC = 100 mg/l [10] [5] EC50 NOEC concentration of the test substance that results in 50% effect No Observed Effect Concentration F. Hoffmann-La Roche Ltd, Group SHE (LSO), ANH, page 4/6

5 Environmental Fate Data for Sulfamethoxazole Study Guideline Results Ref. Ready Biodegradability Test OECD 301 D 2% after 14 days with respect to BOD 4% after 28 days with respect to BOD 0% after 28 days with respect to BOD [2] [1] 0% after 40 days with respect to BOD not readily biodegradable Inherent Biodegradability Test OECD 302 B 0% after 28 days with respect to TOC [11] (mineralization) 13% after 28 days with respect to TOC (DOC elimination) not inherently biodegradable Anaerobic Biodegradability test ISO % after 60 days with respect to TOC [10] (biogas production) 0% after 60 days with respect to TOC (DOC elimination) not anaerobically biodegradable Sludge adsorption coefficient Average and standard deviation Kd = 256 ± 169 L/kg Grap samples Kd = 114 L/kg Kd = 400 L/kg [13] 1) BOD Biochemical oxygen demand TOC Total organic carbon 1) Sorption to activated sewage sludge was found to be of minor importance In general, compounds with a Kd of <500 L/kg are eliminated by less than 10% through sorption on to activated sludge [12]. Physical Chemical Data for Sulfamethoxazole Study Guideline Results Ref. Water solubility 136 mg/l (37 C) [8] n-octanol/water Partition Coefficient log P OW = 0.89 [8] F. Hoffmann-La Roche Ltd, Group SHE (LSO), ANH, page 5/6

6 References [1] Al-Ahmad A, Daschner FD, Kummerer K Biodegradability of cefotiam, ciprofloxacin, meropenem, penicillin G, and sulfamethoxazole and inhibition of waste water bacteria. Arch Environ Contam Toxicol. 37(2): [2] Alexy R, Kümpel T, Kümmerer K Assessment of degradation of 18 antibiotics in the Closed Bottle test. Chemosphere, 57: [3] Bengtsson-Palme J, Larsson DG Concentrations of antibiotics predicted to select for resistant bacteria: Proposed limits for environmental regulation. Environ Int. 86:140-9 [4] Borecka M, Białk-Bielińska A, Haliński ŁP, Pazdro K, Stepnowski P, Stolte S The influence of salinity on the toxicity of selected sulfonamides and trimethoprim towards the green algae Chlorella vulgaris. J Hazard Mater. 308: [5] Brain RA, Johnson DJ, Richards SM, Sanderson H, Sibley PK, Solomon KR Effects of 25 pharmaceutical compounds to Lemna gibba using a seven-day static-renewal test. Environ Toxicol Chem. 23(2): [6] European Medicines Agency (EMA) (2006/2015): Guideline on the environmental risk assessment of medicinal products for human use. European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP), 01 June 2006, EMA/CHMP/SWP/447/00 corr 2 [7] Eurostat. Population data. [8] F. Hoffmann-La Roche Ltd (2017): Safety data sheet for Sulfamethoxazole, 20 September data_sheets-row.htm Ferrari B, Mons R, Vollat B, Fraysse B, Paxéus N, Lo Giudice R, Pollio A, Garric J Environmental risk assessment of six human pharmaceuticals: are the current environmental risk assessment procedures sufficient for the protection of the aquatic environment? Environ Toxicol Chem. 23(5): [10] Gartiser S, Urich E, Alexy R, Kümmerer K. 2007a. Anaerobic inhibition and biodegradation of antibiotics in ISO test schemes. Chemosphere. 66(10): [11] Gartiser S, Urich E, Alexy R, Kümmerer K. 2007b. Ultimate biodegradation and elimination of antibiotics in inherent tests. Chemosphere. 67(3): [12] Göbel A, McArdell CS, Joss A, Siegrist H, Giger W Fate of sulfonamides, macrolides, and trimethoprim in different wastewater treatment technologies. Sci Total Environ. 372(2-3): [13] Göbel A, Thomsen A, McArdell CS, Joss A, Giger W Occurrence and sorption behavior of sulfonamides, macrolides, and trimethoprim in activated sludge treatment. Environ Sci Technol. 39(11): [14] IQVIA MIDAS Quantum, Q [15] Minguez L, Pedelucq J, Farcy E, Ballandonne C, Budzinski H, Halm-Lemeille MP Toxicities of 48 pharmaceuticals and their freshwater and marine environmental assessment in northwestern France. Environ Sci Pollut Res Int. 23(6): [16] National cancer Institute (NIH). NCI Thesaurus (NCIt). [17] Straub JO Aquatic environmental risk assessment for human use of the old antibiotic sulfamethoxazole in Europe. Environ Toxicol Chem. 35(4): F. Hoffmann-La Roche Ltd, Group SHE (LSO), ANH, page 6/6

Environmental Risk Assessment Summary Ganciclovir / Valganciclovir

Environmental Risk Assessment Summary Ganciclovir / Valganciclovir Introduction The publication of environmental risk assessment summaries is part of Roche s engagement on developing a better understanding