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Naprosyn® Entero

Pharmanovia

Enterotablett 250 mg
(vit, rund, kupad, märkt "NPR EC 250" på ena sidan)

Antiflogistikum med analgetisk och antipyretisk effekt

Aktiv substans:
ATC-kod: M01AE02
Läkemedel från Pharmanovia omfattas av Läkemedelsförsäkringen.
  • Vad är miljöinformation?

Miljöinformation

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]

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.