Detaljerad miljöinformation

PEC/PNEC =0.59/0.64 = 0.92 for Naproxen which means that the phrase 'Use of the medicine has been considered to

result in low environmental risk.' is used for Level 1 and 2.

The PEC is based on the following data:

A = 11893.6 kg Naproxen (use data from Läkemedelsstatistik AB, LSAB, 2010)

PEC = 1.5 × 10^–6 × 11893.6 × (100–67) = 0.59 μg/l

Ecotoxicological studies: [5]

Green alga (Desmodesmus subspicatus):

ErC50 72 h =39 000 μg/l (OECD 201)

NOEC 72 h = 3 900 μg/l (OECD 201)

Water-flea (Daphnia magna):

EC50 48 h = 37 000 μg/l (OECD 202)

Water-flea chronic (Ceriodaphnia dubia):

chronic NOEC 192 h = 32 μg/l (Environment Canada Method)

Rainbow trout (Oncorhynchus mykiss):

LC50 96 h = 52 000 μg/l (OECD 203)

Micro-organisms:

NOEC = 30 000 μg/l (toxicity control in inherent biodegradation test)

The PNEC is based on the following data:

The PNEC is based on the lower of two chronic NOECs available (water-flea, Ceriodaphnia) and 50 is the assessment factor used.

PNEC = 32/50 = 0.64 μg/l

Degradation:

Naproxen is not readily biodegradable, however, it is inherently biodegradable and actual, measured elimination rates in various sewage works range from 0% to >99%, with a median of approximately 67%. Moreover, naproxen in surface waters is short-lived, due to biodegradation and photolysis in superficial layers (which is not included in the above PEC calculation). A surface water half-life in late summer in Switzerland at ~47° N was determined at 14 days. Hence, naproxen is rapidly degraded in sewage works and surface waters and is nonpersistent. [5]

Bioaccumulation:

Naproxen has no significant bioaccumulation potential, with measured logD values below 1.1 at pH 6.5–7.4.

Excretion/metabolism:

Subsequent to oral application, naproxen shows rapid uptake, very high bioavailability (~99%) and equally high plasma protein binding. The plasma half-life is around 14 (12–15) h, longer in older people. Approximately 30% of absorbed naproxen undergoes Phase I metabolism through 6-O-demethlyation in liver microsomes, which is mediated by cytochrome P450 (CYP) enzyme isoforms CYP2C9 and CYP1A2. Both the approximately 70% native and the 30% 6-O-desmethyl naproxen subsequently undergo Phase II metabolism by conjugation. Excretion of naproxen in man is mainly (≥95%) by urinary pathway in the form of glucuronic acid or other conjugates of native and 6-O-desmethyl naproxen. [3, 4]

References

1. F. Hoffmann-La Roche Ltd (2005): Safety Data Sheet for Naproxen sodium, 19.12.2005.

2. F. Hoffmann-La Roche Ltd (2004): Safety Data Sheet for Naproxen, 20.12.2004.

3. Hradman JG, Limbird LE, Molinoff PB, Ruddon RW, Goodman Gilman A (1996): Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. McGraw-Hill, New York.

4. Miners JO, Coulter S, Tukey RH, Veronese ME, Birkett DJ (1996): Cytochromes P450, 1A2 and 2C9 are responsible for the human hepatic O-demethylation of R- and S-naproxen. Biochem Pharmacol 51(8):1003–1008.

5. Straub JO, Stewart KM (2007): Deterministic and Probabilistic Acute-Based Environmental Risk Assessment for Naproxen for Western Europe. Environ Toxicol Chem 26(4): 795–806.

6. Tixier C, Singer HP, Oellers J, Müller SR (2003): Occurrence and fate of carbamazepine, clofibric acid, diclofenac, ibuprofen, ketoprofen and naproxen in surface waters. Environ Sci Technol 37(6):1061–1068.

7. ACD/logD Suite (1997): Results of titrometric and shake-flask measurements on selected drugs compared to ACD/logD predictions. Poster, AAPS, Boston, Nov 1997,

http://www.acdlabs.co.uk/products/phys_chem_lab/logd/exp2.html.

8. Perlovich GL, Kurkov SV, Kinchin AN, Bauer-Brandl A (2004): Solvation and hydration characteristics of ibuprofen and acetylsalicylic acid. AAPS Pharm Sci 6(1):1–9.

9. Zhu C, Jiang L, Chen T–M, Hwang K–K. 2002. A comparative study of artificial membrane permeability assay for high throughput profiling of drug absorption potential. Eur J Med Chem 37:399–407.

10. Joss A, Alder AC, Felis E, Gödel A, Herrmann N, Hoffmann B, Löffler D, McArdell CS, Siegrist H, Ternes T, Zabczynski S, Clara M, Kreuzinger N, Strenn B (2005): fate of pharmaceuticals, hormones and fragrances in full scale wastewater treatment; are predictions based on lab-scale experiments reliable? Presentation, 15th SETAC Europe Annual Conference, Lille. // Joss A, Carballa M, Kreuzinger N, Siegrist H, Zabczynski S (2006): Wastewater treatment. In Ternes TA, Joss A, eds (2006): Human Pharmaceuticals, Hormones and Fragrances; The challenge of micropollutants in urban water management. IWA Publishing, London, pp. 243–292.

11. Isidori M, Lavorgna M, Nardelli A, Parelly A, Previtera L, Rubino M (2005) Ecotoxicity of naproxen and its phototransformation products. Sci Tot Envir 346: 87–98.

12. Brun GL, Bernier M, Losier R, Doe K, Jackman P, Lee H-B (2006): Pharmaceutically active compounds in Atlantic Canadian sewage treatment plant effluents and receiving waters, and potential for environmental effects as measured by acute and chronic aquatic toxicity. Environ Toxicol Chem 25(8): 2163–2176.

Note

ND = no data; QSAR = QSAR-modelled (EPISuite, SPARC, ACD Solaris); AMC = average measured concentration; ECM = Environment Canada method; NC = nominal concentration; SC = saturation concentration.