Detaljerad miljöinformation

Identification and characterisation

CAS number: 738-70-5 [1]

Molecular weight: 290.32 [1]

Remark: -

Brand name: Bactrim (Trimethoprim in combination with Sulfamethoxazole) [1]

Physico-chemical properties

Aqueous solubility 300 mg/l (20 °C) [1]

Aqueous solubility 400 mg/l (25 °C) experimental cited in: [2]

Dissociation constant, pK_a 6.6 [1]

Melting point 199–203 °C [1]

Vapour pressure ND

Boiling point 449.23 °C experimental cited in: [2]

K_H 1.247E-7 Pa*m3/mol QSAR [2]

Predicted Environmental Concentration (PEC)

PEC is calculated according to the formula:

PEC (μg/L) = (A x 1'000'000'000 x (100-R)) / (365 x P x V x D x 100) = 1.5 x 10-6 x A x (100 - R) = 0.09 μg/L

Where:

A Sold quantity = 581.8475 kg/y (sales data from IQVIA / LIF - kg consumption/2019)

R Removal rate = 0 % Default value [4]

P Population of Sweden = 9000000

V Volume of Wastewater = 200 l/day Default value [4]

D Factor for Dilution = 10 Default value [4]

Predicted No Effect Concentration (PNEC)

Ecotoxicological Studies

Green alga (Raphidocelis subcapitata): [5]

EC50 72 h (yield) = 40 mg/l (OECD 201)

NOEC 72 h (yield) = 16 mg/l (OECD 201)

Green alga (Raphidocelis subcapitata): [6]

EC50 72 h (growth) = 98 mg/l (OECD 201)

EC50 72 h (biomass) = 70 mg/l (OECD 201)

NOEC 72 h = 32 mg/l (OECD 201)

Green alga (Raphidocelis subcapitata): [7]

NOEC 96 h (yield) = 63.4 mg/l (OECD 201)

Cyanobacteria (Anabaena flos-aquae)

EC10 96 h (growth) = 18.3 mg/l (OECD 201) [8, 9]

EC10 72 h (growth) = 25.0 mg/l (OECD 201) [8, 9]

EC10 72 h (growth) = 0.008 mg/l (OECD 201) [8, 9]

EC10 72 h (growth) = 26.0 mg/l (OECD 201) [8, 9]

(The geometric mean of these four EC10 values as applied by the AMR Industry Alliance is 3124.5 μg/l. Using an assessment factor of 10, this results in a PNEC of 312.45 μg/l)

Algae, marine (Rhodomonas salina) [20]

EC50 72 h (growth rate) = 16 mg/l (ISO 8692)

Duckweed (Lemna minor ) [10]

EC50 7 d (growth) = 215 mg/l (OECD 221)

EC50 7 d (yield) = 133 mg/l (OECD 221)

NOEC 7 d = 53.5 mg/l (OECD 221)

Water-flea (Daphnia magna) [11]

EC50 48 h (immobilization) >100 mg/l (OECD 202)

NOEC 48 h (immobilization) = 100 mg/l (OECD 202)

Zebrafish (Danio rerio) [12]

NOEC 72 h (mortality) = 100 mg/l (OECD 203)

Daphnia magna Reproduction [13]

NOEC 21 d (overall) = 6 mg/l (OECD 211)

Fish, early-life stage toxicity test with zebrafish (Danio rerio) [14]

NOEC 35 d (overall) = 100 mg/l (OECD 210)

Activated sludge respiration inhibition test

EC50 3 h = 17.8 mg/l (OECD 209) [12]

EC50 3 h >200 mg/l (OECD 209) [15]

EC10 3 h = 0.435 mg/l (OECD 209) [15]

Nitrification inhibition test

EC10 4 h >96 mg/l (ISO 9509) [16]

NOEC 4 h = 96 mg/l (ISO 9509) [16]

NOEC = 0.05 mg/l (method not specified) [17]

Anaerobic inhibition [18]

NOEC = 100 mg/l (OECD 224)

Minimal inhibitory concentration [19]

MIC = 16 μg/l (EUCAST)

PNEC Derivation

The PNEC is based on the following data:

PNEC (μg/l) = EC10/10, where 10 is the assessment factor used. An EC10 of 3124.5 μg/l has been used for this calculation. This is a joint assessment performed by the AMR Industry Alliance. [8, 9]

PNEC = 3124.5 / 10 = 312.45 µg/l

Environmental Risk Classification (PEC/PNEC Ratio)

PEC Predicted Environmental Concentration = 0.09 µg/l

PNEC Predicted No Effect Concentration = 312.45 µg/l

Ratio PEC/PNEC = 0.00028

PEC/PNEC = 0.09/312.45 = 0.00028 for Trimethoprim which justifies the phrase 'Use of Trimethoprim has been considered to result in insignificant environmental risk.'

Degradation

Biotic Degradation

Ready biodegradability:

0% after 28 days of incubation BOD/ThOD (OECD 301 F) [12]

4% after 28 days of incubation BOD/ThOD (OECD 301 D) [21]

27% after 28 days of incubation BOD/ThOD (OECD 301 D with co-metabolism) [21]

Inherent biodegradability: [22]

0% after 28 days of incubation CO2/TOC (OECD 302 B)

16% after 28 days of incubation DOC (OECD 302 B)

Other degradation information

Inherent biodegradability in reactors:

Half-life (total system) = 22–41 d (method not specified) [12]

Elimination = ~70% (method not specified) [23]

Half-life (total system) = 96 h (method not specified) [23]

Elimination in sewage treament plants:

The average and the median removal rates for full-scale working sewage treatment plants (STP) with 107 recorded removal rates, representing at least 63 STPs are 25% and 30%, respectively. [3]

Average removal range between 10% and 49% in Swedish investigation in the year 2010 [27]

Abiotic Degradation

Photodegradation:

no photodegradation 42d freshwater [24]

no photodegradation 21d natural seawater, natural light [25]

Hydrolysis:

no significant hydrolysis [26]

Trimethoprim is neither readily, nor inherently biodegradable. This justifies the phrase 'Trimethoprim is potentially persistent.'

Bioaccumulation/Adsorption

logKow	0.64 experimental, method unknown [1]
	0.91 experimental, method unknown, cited in: [2]
	0.73 QSAR [2]
Kd	208 ± 49 l/kg average in STP * [28]
	157 l/kg grap sample in STP * [28]
	375 l/kg grap sample in STP * [28]

* 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. [29]

Trimethoprim has low potential for bioaccumulation (log K_OW <4).

Excretion/metabolism

In humans, Trimethoprim was rapidly and almost completely absorbed (more than 95%) after oral administration. Trimethoprim was excreted chiefly by glomerular filtration and renal tubular secretion. 70–90% of an orally administered dose was recovered from the urine within 24 h and 92–102% within 3 d. Some hepatic transformation occurred with a small proportion of the dose excreted in the bile. 80% of the administered dose was excreted unmetabolised. Five metabolites were identified in the remaining 20%. [30]

References

1. F. Hoffmann-La Roche Ltd (2019): Safety Data Sheet for Trimethoprim, 14.02.2019; https://www.roche.com/sustainability/what_we_do/for_communities_and_environment/environment/safety_data_sheetsrow. htm

2. F. Hoffmann-La Roche Ltd (2016): Safety Data Sheet for Oseltamivir ethylester phosphate, 09.05.2016

3. Straub JO (2013). An Environmental Risk Assessment for Human-Use Trimethoprim in European Surface Waters. Antibiotics, 2, 115-162.

4. ECHA, European Chemicals Agency (2008). Guidance on information requirements and chemical safety assessment. http://guidance.echa.europa.eu/docs/guidance_document/information_requirements_en.htm

5. Yang LH, Ying GG, Su HC, Stauber JL, Adams MS, Binet MT (2008). Growth-inhibiting effects of 12 antibacterial agents and their mixtures on the freshwater microalga Pseudokirchneriella subcapitata. Environ Toxicol Chem. 27(5):1201-8.

6. NOTOX B.V., on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (1996). Fresh Water Algal Growth Inhibition Test with Trimethoprim. NOTOX study no. 180089.

7. Guo J, Selby K, Boxall AB (2016). Comparing the sensitivity of chlorophytes, cyanobacteria, and diatoms to major-use antibiotics. Environ Toxicol Chem. 35(10):2587-2596.

8. AMR Industry Alliance (2021): AMR Alliance Science-Based PNEC Targets for Risk Assessments, 1 February 2021. https://www.amrindustryalliance.org/wp-content/uploads/2020/01/AMR-Table-1-Update-February-2021.pdf

9. AMR Industry Alliance (2021): AMR Alliance Science-Based PNEC Targets for Risk Assessments. On-going Supplementary Table, 1 February 2021. https://www.amrindustryalliance.org/wp-content/uploads/2020/01/On-going-Supplementary-Table-February-2021.pdf

10. BMG Engineering Ltd, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2011). Growth inhibition test withL emna minor . BMG study no. A11-00372.

11. NOTOX B.V., on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (1996). Acute Toxicity Study in Daphnia magna with Trimethoprim. NOTOX study no. 180001.

12. Halling-Sørensen B, Lützhøft HC, Andersen HR, Ingerslev F (2000). Environmental risk assessment of antibiotics: comparison of mecillinam, trimethoprim and ciprofloxacin. J Antimicrob Chemother. 46 Suppl 1:53-8.

13. Park S, Choi K (2008). Hazard assessment of commonly used agricultural antibiotics on aquatic ecosystems. Ecotoxicology. 17(6):526-38.

14. ECT Oekotoxikologie GmbH, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2011). Trimethoprim: a study on the toxicity to early-life stages of zebrafish according to OECD Guideline No. 210 “Fish, Early-life stage Toxicity Test”. ECT study no. 11AZ4FV.

15. BMG Engineering Ltd, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2011). Trimethoprim: Test for Inhibition of Oxygen Consumption by Activated Sludge. BMG study no. A11-00371

16. BMG Engineering Ltd, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2011). Trimethoprim: Test for Assessing the Inhibition of Nitrification of Activated Sludge Microorganisms: Nitrification Inhibition Test. BMG study no. A11-00764.

17. Ghosh GC, Okuda T, Yamashita N, Tanaka H (2009). Occurrence and elimination of antibiotics at four sewage treatment plants in Japan and their effects on bacterial ammonia oxidation. Water Sci Technol. 59(4):779-786.

18. Gartiser S, Urich E, Alexy R, Kümmerer K (2007). Anaerobic inhibition and biodegradation of antibiotics in ISO test schemes. Chemosphere. 66(10):1839-1848.

19. Bengtsson-Palme J, Larsson DG (2016). Concentrations of antibiotics predicted to select for resistant bacteria: Proposed limits for environmental regulation. Environ Int. 86:140-9.

20. Holten Lützhøft H-C, Halling-Sørensen B, Jorgensen SE (1999). Algal toxicity of antibacterial agents applied in Danish fish farming. Arch. Environ. Contam. Toxicol. 36:1-6.

21. Alexy R, Kümpel T, Kümmerer K (2004). Assessment of degradation of 18 antibiotics in the Closed Bottle test. Chemosphere, 57:505–512.

22. Gartiser S, Urich E, Alexy R, Kümmerer K (2007). Ultimate biodegradation and elimination of antibiotics in inherent tests. Chemosphere. 67(3):604-613.

23. Batt AL, Kim S, Aga DS (2006). Enhanced biodegradation of iopromide and trimethoprim in nitrifying activated sludge. Environ Sci Technol. 40(23):7367-7373.

24. Boxall ABA, Fogg LA, Blackwell PA, Kay P, Pemberton EJ, Croxford A (2004). Veterinary medicines in the environment. Rev Environ Contam Toxicol 180: 1-91.

25. Lunestad BT, Samuelsen OB, Fjelde S, Ervik A (1995). Photostability of 8 antibacterial agents in seawater. Aquaculture 134: 217-225.

26. Lam MW, Young CJ, Brain RA, Johnson DJ, Hanson MA, Wilson CJ, Richards SM, Solomon KR, Mabury SA (2004). Aquatic persistence of eight pharmaceuticals in a microcosm study. Environ Toxicol Chem 23(6): 1431–1440.

27. Fick, J.; Lindberg, R.H.; Kaj, L.; Brorström-Lundén, E. Results from the Swedish National Screening Programme 2010, Subreport 3, Pharmaceuticals, B2014; Swedish Environmental Research Institute (IVL): Stockholm, Sweden, 2011. Available online: http://www.ivl.se.

28. Göbel A, Thomsen A, McArdell CS, Joss A, Giger W (2005). Occurrence and sorption behavior of sulfonamides, macrolides, and trimethoprim in activated sludge treatment. Environ Sci Technol. 39(11):3981-3989.

29. Göbel A, McArdell CS, Joss A, Siegrist H, Giger W (2007). Fate of sulfonamides, macrolides, and trimethoprim in different wastewater treatment technologies. Sci Total Environ. 372(2-3):361-371.

30. European Medicines Agency (EMA). Committee for Medicinal Products for Veterinary Use (CVMP). Trimethoprim – Summary Report (2). EMEA/MRL/255/97 FINAL, September 1997.