Miljöpåverkan
Naproxen
Miljörisk:
Användning av naproxen har bedömts medföra låg risk för miljöpåverkan.
Nedbrytning:
Naproxen bryts ned långsamt i miljön.
Bioackumulering:
Naproxen har låg potential att bioackumuleras.
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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]
Identification and characterisation |
|
CAS number |
26159-34-2 Naproxen sodium [1] 22204-53-1 Naproxen acid [2] |
Molecular weight |
252.24 Naproxen sodium [1] |
Brand name |
Naprosyn, Naprosyn Entero |
Stability/degradation (Naproxen acid) |
|
Ready biodegradability |
not readily, literature; readily, own data [5] |
Inherent biodegradability |
10% 13 d, >60% 17 d, 98% 28 d; OECD 302C [2] |
Other degradation information |
~67 (0–99)% removal/biodegradation in sewage works, literature [5] t½ surface waters (Aug–Oct, Switzerland) = 14 d [6] |
Photodegradation |
90% 72 h, algal medium, algal light cabinet, OECD 201 [5] |
Hydrolysis |
no hydrolysable bonds |
Accumulation/adsorption (Naproxen acid) |
|
logPow (pH < 2.18!) |
3.18 [2] |
logD (pH 6.5) |
0.98–1.06 [7] |
logD (pH 7.4) |
0.23–0.33 [8, 9] |
KOC |
<=727 pH sensitive QSAR |
Sorption |
no significant sorption in actual sewage works [10] |
BCF |
<10; <80 pH sensitive QSAR |
Physico-chemical properties |
|
Aqueous solubility |
250000 mg/l Naproxen-Na 15.9 mg/l Naproxen acid [2] |
Dissociation constant, pKa |
4.15 Naproxen acid [2] |
Melting point |
255 °C [2] |
Vapour pressure |
ND |
Boiling point |
ND |
KH |
3.39*E–10 atm*m3/mol QSAR Naproxen acid |
Ecotoxicological data (Naproxen acid) |
|
Algal growth inhibition |
31.82 mg/l 72h EbC50 ISO8692 Pseudokirchneriella subcap. [11] |
21/39 mg/l 72h Eb/rC50 OECD201 Desmodesmus subspicatus [5] |
|
3.9 mg/l 72h NOEC OECD 201 D. subspicatus [5] |
|
Daphnia acute immobilisation |
37 mg/l 48h EC50 OECD 202 Daphnia magna [5] |
10 mg/l 48h NOEC OECD 202 D. magna [5] |
|
0.032 mg/l 8d NOEC ECM Ceriodaphnia dubia chronic [12] |
|
Fish acute toxicity |
52 mg/l 96h LC50 OECD 203 Oncorhynchus mykiss [5] |
32 mg/l 96h NOEC OECD 203 O. mykiss [5] |
|
Micro-organism inhibition |
30 mg/l 14d NOEC OECD302C activated sludge [5] |
Aquatic macrophytes inhibition |
24.2 mg/l 7d EC50 Lemn a, Naproxen-Na [5] |
PBT/vPvB Assessment |
|
P: Freshwater half-life |
14 d, based on measured half-life in Swiss lake [6] |
Sediment half-life |
d, based on |
Persistence criteria fulfilled? |
not P |
B: BCF (experimental) | |
alternatively, base or acid? |
a |
alternatively, logDOW(p H 7) |
0.329387, logDow < 3 [7, 8, 9] |
Bioaccumulation criteria fulfilled? |
no significant bioaccumulation potential |
T: chronic NOEC < 0.01 mg/l? |
no data on T |
CMR substance? |
n not CMR [1, 2] |
Endocrine-disrupting effects? |
no data on ED |
T criteria fulfilled? |
no or incomplete data on T criteria |
PBT Assessment: |
not PBT |
Initial PEC according to fass.se |
|
Annual use in Sweden, A: |
11893.6 kg/a [information from LIF 2010] |
Excretion | |
Excretion as parent |
70 % (if not filled in/unknown, 100% is assumed by default) |
Excretion as metabolite 1 |
30 %, with 100 % pharmacological activity compared to parent |
Excretion total, E: |
100 %, calculated as pharmacological activity of parent |
Removal rate in STP, R: |
67 %, based on literature data [5] |
PEC = 1.5*10E–6*A*(E/100)*(100–R) = |
0.5887 μg/l |
Initial PNEC according to EU TGD |
|
Lowest ecotox effect value, LEEV: |
0.032 mg/l chronic NOEC Ceriodaphnia |
Assessment factor, AF: |
50 chronic NOECs for algae and daphnids available |
PNEC = LEEV/AF= |
0.64 μg/l |
PEC/PNEC ratio |
0.920 0.1 <PEC/PNEC <= 1 |
PBT Assessment |
not PBT |
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.