Läs upp

Cookies

Den här webbplatsen använder så kallade cookies. Cookies är små textfiler som lagras i din dator och sparar information om olika val som du gjort på en webbsida – t ex språk, version och statistik – för att du inte ska behöva göra dessa val en gång till. Tekniken är etablerad sedan många år tillbaka och används idag på väldigt många webbplatser på Internet.

Du kan när som helst ändra cookieinställningarna för denna webbplats.

FASS logotyp
Receptbelagd

Peka på symbolerna och beteckningarna till vänster för en förklaring.

Kontakt

Sök apotek med läkemedlet i lager

Sök lagerstatus

Bactrim®

Roche

Tablett 400 mg/80 mg
(11 mm, vita, runda, brytskåra, prägling ROCHE)

Antibakteriellt medel, sulfonamid+trimetoprim

ATC-kod: J01EE01
Utbytbarhet: Ej utbytbar
Läkemedel från Roche omfattas av Läkemedelsförsäkringen.
  • Vad är miljöinformation?

Miljöinformation

Miljöpåverkan (Läs mer om miljöpåverkan)

Sulfametoxazol

Miljörisk: Användning av sulfametoxazol har bedömts medföra låg risk för miljöpåverkan.
Nedbrytning: Sulfametoxazol är potentiellt persistent.
Bioackumulering: Sulfametoxazol har låg potential att bioackumuleras.


Läs mer

Detaljerad miljöinformation

Identification and characterisation

CAS number: 723-46-6 [1]

Molecular weight: 253.3 [1]

Remark: -

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


Physico-chemical properties

Aqueous solubility: 136 mg/l (37 °C) [1]

Aqueous solubility: 610 mg/l (37 °C) experimental cited in: [2]

Dissociation constant, pKa: pKb ~ 1.39, pKa ~ 5.81 QSAR

Melting point: 168–172 °C [1]

Vapour pressure: ND

Boiling point: 414.01 °C experimental cited in: [2]

KH: 1.114E-6 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) = 0.264 μg/L


Where:

A Sold quantity = 1761.0276 kg/y (total sold amount API in Sweden year 2017, data from IQVIA)

R Removal rate = 0 % Default value [4]

P Population of Sweden = 9000000

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

D Factor for Dilution = 10 Default value [4]


*Based on 190 data of full-scale working sewage treatment plants (STP) the median removal rate amounts to 49%. [3]


Predicted No Effect Concentration (PNEC)


Ecotoxicological Studies

Green alga (Raphidocelis subcapitata) [5]

EC50 96 h = 0.146 mg/l (method not specified)

NOEC 96 h = 0.090 mg/l (method not specified)


Green alga (Raphidocelis subcapitata) [12]

EC50 72 h (growth rate) = 3.4 mg/l (OECD 201)

EC50 72 h (yield) = 0.81 mg/l (OECD 201)

EC10 72 h (growth rate) = 0.4 mg/l (OECD 201)

EC10 72 h (yield) = 0.17 mg/l (OECD 201)


Green alga (Raphidocelis subcapitata) [6]

EC50 72 h = 1.12 mg/l ISO 8692


Green alga (Chlorella vulgaris) [7]

EC50 48 h = 0.98 mg/l (OECD 201)

EC50 72 h = 1.51 mg/l (OECD 201)


Diatom (Cyclotella meneghiniana) [5]

EC50 96 h = 2.4 mg/l (method not specified)

NOEC 96 h = 1.25 mg/l (method not specified)


Diatom (Skeletonema marinoi) [6]

EC50 72 h = 5.35 mg/l (ISO 10253)


Cyanobacteria (Synechococcus leopoliensis) [5]

EC50 96 h = 0.0268 mg/l (method not specified)

NOEC 96 h = 0.0059 mg/l (method not specified)


The applied test conditions were described by Ferrari et al. (2004) as follows: Inocula, corresponding to 10,000 or 100,000 cells/ml from laboratory cultures in midexponential phase, were grown in 100-ml conical flasks containing Bold’s basal medium. The test was carried out in triplicate in axenic conditions at 28 ± 1 °C, with lighting of 8,300 lux under a 16:8 h light:dark photoperiod. After 96 h of incubation, algal growth was followed either by counting the cell number with a Burker bloodcounting chamber or by measuring the absorbance increase at 550 nm with a colorimeter. [5]


(NOEC used by the AMR Industry Alliance to derive the PNEC) [11]


Duckweed (Lemna gibba) [8]

EC50 7 d (frond number) = 0.249 mg/l (ASTM)

EC50 7 d (wet weight) = 0.081 mg/l (ASTM)

EC10 7 d (frond number) = 0.011 mg/l (ASTM)

EC10 7 d (wet weight) = 0.017 mg/l (ASTM)


Water-flea (Daphnia magna) [5]

EC50 48 h (immobilization) >100 mg/l (AFNOR T90-301)


Water-flea (Daphnia magna) [6]

EC50 48 h (immobilization) = 98.01 mg/l (ISO 6341)


Water-flea (Daphnia magna) [13]

EC50 24 h (immobilization) = 89 mg/l (OECD 202)

EC50 48 h (immobilization) = 75 mg/l (OECD 202)

NOEC 48 h (immobilization) = 36 mg/l (OECD 202)


Water-flea (Ceriodaphnia dubia) [5]

EC50 48 h (immobilization) >100 mg/l (EPA/600/4-90/027F)


Ceriodaphnia dubia Reproduction and Survival [5]

NOEC 7 d (overall) = 0.25 mg/l (AFNOR T90-376)


Rainbow trout (Oncorhynchus mykiss) [14]

NOEC 96 h (mortality) = 1000 mg/l (OECD 203)


Fish embryo toxicity test with zebrafish (Danio rerio) [5]

NOEC 10 d = 8 mg/l (ISO 12890)


Zebrafish (Danio rerio), partial life-cycle study [15]

NOEC 150 d (survival, 1st generation) = 0.2 mg/l (method not specified)

NOEC 150 d (length, 1st generation) = 0.2 mg/l (method not specified)

NOEC 150 d (weight, 1st generation) = 0.02 mg/l (method not specified)

NOEC 150 d (egg production, 1st generation) = 0.02 mg/l (method not specified)

96 h NOEC (overall, next generation) = 0.02 mg/l (method not specified)


Microorganisms [16]

NOEC 28 d (toxicity control) = 3.8 mg/l (OECD 301 D)


Anaerobic inhibition [9]

NOEC = 100 mg/l (OECD 224)


Minimal inhibitory concentration [10]

MIC = 1000 μg/l (EUCAST)


PNEC Derivation

The PNEC is based on the following data:

PNEC (mg/l) = lowest chronic NOEC/10, where 10 is the assessment factor used. A NOEC of 5.9 μg/l for the cyanobacterium Synechococcus leopoliensis has been used for this calculation. This is a joint assessment performed by the AMR Industry Alliance. [11]


PNEC = 5.9 / 10 = 0.6 μg/l


Environmental Risk Classification (PEC/PNEC Ratio)

PEC Predicted Environmental Concentration = 0.264 μg/l

PNEC Predicted No Effect Concentration = 0.6 μg/l

Ratio PEC/PNEC = 0.440


PEC/PNEC = 0.264/0.6 = 0.440 for Sulfamethoxazole which justifies the phrase 'Use of Sulfamethoxazole has been considered to result in low environmental risk.'


Degradation


Biotic Degradation

Ready biodegradability: [16]

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

13% after 28 days of incubation BOD/ThOD (OECD 301 D with co-metabolism)


Inherent biodegradability:

-10% after 28 days of incubation CO2/TOC (OECD 302 B) [17]

13% after 28 days of incubation DOC (OECD 302 B) [17]

0% after 28 days of incubation DOC (OECD 302 B) [14]


Other degradation information


Elimination in sewage treatment plants:

Based on 190 data of full-scale working sewage treatment plants (STP) the median removal rate amounts to 49%. cited in: [3]


Abiotic Degradation

Photodegradation: half-lives: 10 h to 15 h to well over 100 h cited in: [3]


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


Bioaccumulation/Adsorption


logKOW 0.89 experimental, method unknown cited in: [2]

logKOW 0.48 QSAR [2]


Sulfamethoxazole has low potential for bioaccumulation (log KOW <4).


Excretion/metabolism


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. [3]


References

1. F. Hoffmann-La Roche Ltd (2019): Safety Data Sheet for Sulfamethoxazole, 10.01.2019; https://www.roche.com/sustainability/what_we_do/for_communities_and_environment/environment/safety_data_sheetsrow. htm

2. US Environmental Protection Agency (2012). EPI Suite™-Estimation Program Interface v4.11.

3. Straub JO (2016). Aquatic environmental risk assessment for human use of the old antibiotic sulfamethoxazole in Europe. Environ Toxicol Chem. 35(4):767-779.

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. Ferrari B, Mons R, Vollat B, Fraysse B, Paxéus N, Lo Giudice R, Pollio A, Garric J (2004). 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):1344-1354.

6. Minguez L, Pedelucq J, Farcy E, Ballandonne C, Budzinski H, Halm-Lemeille MP (2016). Toxicities of 48 pharmaceuticals and their freshwater and marine environmental assessment in northwestern France. Environ Sci Pollut Res Int. 23(6):4992-5001.

7. Borecka M, Białk-Bielińska A, Haliński ŁP, Pazdro K, Stepnowski P, Stolte S (2016). The influence of salinity on the toxicity of selected sulfonamides and trimethoprim towards the green algae Chlorella vulgaris . J Hazard Mater. 308:179-186.

8. Brain RA, Johnson DJ, Richards SM, Sanderson H, Sibley PK, Solomon KR (2004). Effects of 25 pharmaceutical compounds to Lemna gibba using a seven-day static renewal test. Environ Toxicol Chem. 23(2):371-382.

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

10. 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.

11. Tell J, Caldwell DJ, Häner A, Hellstern J, Hoeger B, Journel R, Mastrocco F, Ryan JJ, Snape J, Straub JO, Vestel J (2019). Science-based Targets for Antibiotics in Receiving Waters from Pharmaceutical Manufacturing Operations. Integr Environ Assess Manag. 15(3):312-319. doi: 10.1002/ieam.4141.

12. NOTOX B.V., on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (1996). Fresh Water Algal Growth Inhibition Test with Sulfamethoxazole. NOTOX study no. 180045.

13. NOTOX B.V., on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (1996). Acute Toxicity Study inD aphnia magna with Sulfamethoxazole. NOTOX study no. 179966.

14. F. Hoffmann-La Roche Ltd (1980). Internal assessment no. 16, 21.03.1980.

15. Yan Z, Lu G, Ye Q, Liu J (2016). Long-term effects of antibiotics, norfloxacin, and sulfamethoxazole, in a partial life-cycle study with zebrafish (Danio rerio ): effects on growth, development, and reproduction. Environ Sci Pollut Res Int. 23(18):18222-8.

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

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

Trimetoprim

Miljörisk: Användning av trimetoprim har bedömts medföra försumbar risk för miljöpåverkan.
Nedbrytning: Trimetoprim är potentiellt persistent.
Bioackumulering: Trimetoprim har låg potential att bioackumuleras.


Läs mer

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, pKa 6.6 [1]

Melting point 199–203 °C [1]

Vapour pressure ND

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

KH 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) = 0.08 μg/L


Where:

A Sold quantity = 520.1523 kg/y (total sold amount API in Sweden year 2017, data from IQVIA)

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) [7]

EC10 96 h (yield) = 18.3 mg/l (OECD 201)

NOEC 96 h (yield) = 13.6 mg/l (OECD 201)


Cyanobacteria (Anabaena flos-aquae) [31]

EC50 72 h (growth) = 99 mg/l (OECD 201)

EC10 72 h (growth) = 25 mg/l (OECD 201)

NOEC 72 h (growth) = 3.2 mg/l (OECD 201)

EC10 72 h (yield) = 3.3 mg/l (OECD 201)

NOEC 72 h (yield) = 1.0 mg/l (OECD 201)

NOEC 72 h (yield) of 1.0 mg/l was used by the AMR Industry Alliance to derive the PNEC [8]


Diatom (Phaeodactylum tricornutum) [9]

EC10 72 h = 2.4 mg/l (ISO 10253) Algae, marine (Rhodomonas salina) [20] EC50 72 h (growth rate) = 16 mg/l (ISO 8692)


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 (mg/l) = lowest chronic NOEC/10, where 10 is the assessment factor used. A NOEC of 1 mg/l (1000 μg/l) for cyanobacteria (endpoint: yield) has been used for this calculation. This is a joint assessment performed by the AMR Industry Alliance. [8]

PNEC = 1000 / 10 = 100 μg/l


Environmental Risk Classification (PEC/PNEC Ratio)

PEC Predicted Environmental Concentration = 0.08 μg/l

PNEC Predicted No Effect Concentration = 100 μg/l

Ratio PEC/PNEC = 0.0008


PEC/PNEC = 0.08/100 = 0.0008 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 KOW <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. US Environmental Protection Agency (2012). EPI Suite™-Estimation Program Interface v4.11.

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. Tell J, Caldwell DJ, Häner A, Hellstern J, Hoeger B, Journel R, Mastrocco F, Ryan JJ, Snape J, Straub JO, Vestel J (2019). Science-based Targets for Antibiotics in Receiving Waters from Pharmaceutical Manufacturing Operations. Integr Environ Assess Manag. 15(3):312-319. doi: 10.1002/ieam.4141.

9. Claessens M, Vanhaecke L, Wille K, Janssen CR (2013). Emerging contaminants in Belgian marine waters: single toxicant and mixture risks of pharmaceuticals. Mar Pollut Bull. 71(1-2):41-50.

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.

31. Data provided by GSK to the AMR Industry Alliance.