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Voltaren®

MiljöinformationReceptstatusFörmånsstatus
Novartis

Enterotablett 25 mg
(Tillhandahålls för närvarande ej) (7 mm, gul, märkt CG/BZ)

Icke-steroida antiinflammatoriska/antireumatiska medel, NSAID

Aktiv substans:
ATC-kod: M01AB05
Läkemedel från Novartis omfattas av Läkemedelsförsäkringen.
  • Vad är miljöinformation?

Miljöpåverkan (Läs mer om miljöpåverkan)

Diklofenak

Miljörisk: Användning av diklofenak har bedömts medföra försumbar risk för miljöpåverkan.
Nedbrytning: Diklofenak bryts ned långsamt i miljön.
Bioackumulering: Diklofenak har låg potential att bioackumuleras.


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Detaljerad miljöinformation

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 1,152 µg/L / 32,0 µg/l = 0,036

Use of diclofenac has been considered to result in insignificant environmental risk.










Predicted Environmental Concentration (PEC)


PEC is calculated according to the following formula:

PEC (μg/L) = (A*109*(100-R)/(365*P*V*D*100) = 1,5*10-6*A(100-R)

PEC = 1,5*10-6 * 7680,868 kg * 100 = 1,152 µg/l


Where:

A = 7680,868 (total sold amount of diclofenac, including sodium, potassium and diethylamine salt forms, in Sweden in year 2015, data from IMS Health).

R = 0% removal rate (conservatively, it has been assumed there is no loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation)

P = number of inhabitants in Sweden = 9*106

V (L/day) = volume of wastewater per capita and day = 200 (ECHA default; EHCA 2008)

D = factor for dilution of waste water by surface water flow = 10 (ECHA default; EHCA 2008)


Predicted No Effect Concentration

Ecotoxicological studies:

Green algae: EC50 = 72 mg/L (Desmodesmus subspicatus, 3 d, based on average growth rate; EEC Directive 92/69/EEC, Annex V, C.3)

NOEC = 10 mg/L (Pseudokirchneriella subcapitata, 96 h, non-standardised test method: Inocula: 10 000 or 100 000 cells/mL from laboratory cultures in mid-exponential phase, grown in 100-mL Erlenmeyer flasks in Bold´s Basal Medium (BBM). Flasks were incubated on a shaking apparatus. Tests were carried out in triplicate and in axenic conditions at 23oC, light intensity: 8300 lux, 16-h light-8-h dark photoperiod. Algal growth measured either by counting the cell number with a Burker blood-counting chamber or by measuring the absorbance increased at 550nm with a Bausch & Lomb spectronic 20 colorimeter.)


Aquatic plants: EC50 = 7.5 mg/L (Lemna minor, 7 d; test method: ISO/WD 20079, ISO, 2001) (Cleuvers 2003)


Daphnia acute toxicity: EC50 = 68 mg/L (Daphnia magna, 48 h; EEC Directive 92/69/EEC, 1992 Annex V, C.2) (Cleuvers 2003)

EC50 = 22.7 mg/L (Cerodaphnia dubia, 48 h; test method: EPA 600/4_90/027 1991)) (Ferrari 2003)


Aquatic invertebrates chronic toxicity: NOEC = 1.0 mg/L (Cerodaphnia dubia, 7 d; test method: AFNOR T90-376 (2000a)) (Ferrari 2003)


Fish acute toxicity: LC50 = 82 mg/L (OECD203, Brachydanio rerio, 96 h) (Ciba-Geigy, Ecotoxicology, Project No.81 17 95)


Fish chronic toxicity:

NOEC = 0.369 mg/L (OECD210, Oncorhynchus mykiss, 95 days) (Harlan Laboratories Study D24046) based on histopathological alterations in gills

NOEC = 0.320 mg/L (OECD210, Danio rerio, 34 days) (Harlan Laboratories Study D33507) based on survival of larvae and juvenile fish

NOEC = 4 mg/L (Dani rerio, 10 d, early-life stage test; test method: ISO 12890 (1999)) (Ferrari 2003)


Bacterial Respiration Inhibition: EC50 > 100 mg/L (OECD209, activated sludge, 3 h) (Ciba-Geigy, Ecotoxicology, Test No: 900010)


The PNEC is based on the following data:

PNEC (µg/l) = lowest chronic NOEC / 10, where 10 is the assessment factor used.

A NOEC of 0.32 mg/l for chronic fish toxicity has been used for this calculation

PNEC = 0.32 mg/L /10 = 32.0 µg/l


Environmental fate studies:

Degradation: 55.5%, not readily biodegradable (OECD301 D, 1981) (Ciba-Geigy, Ecotoxicology, Project No.81 17 94) (Gröning 2007)

Significant depletion by sediment microbial activity (93 % depletion of diclofenac after 5 days); non-standradised method, fixed-bed column bioreactor with high sediment/water ratio and a long operation time. The whole system was light-protected and operated at 20oC ± 2oC.


= 5.5 – 18.6 days in sediment systems (Kunkel 2008) (bench-scale annular flume; flat sediment surface vs moving sediment; 18oC, in the dark. Sediment and water from the river Roter Main. Initial test item concentration of approximately 30-50 µg L-1 in the surface water. 2-3 replicates per surface water sampling. Pharmaceuticals were determined with a HPLC-MS/MS system (VARIAN Inc., Palo Alto, CA, U.S.A.) consisting of two HPLC pumps (Prostar 210), an autosampler (Prostar 410), and a triple quadropole mass spectrometer (1200 L).


In their study on transformation of diclofenac in sediment systems, Kunkel and Radke (2008) report a half-life of 5.5-18.6 days. “Slow degradation” is moreover supported by other studies, such as the one from Gröning and coworkers (2007), also cited above. The classification "slow degradation" is justified using criteria for OECD308 studies according to Fass guidance Table 7 (2012). While the results from Kunkel 2008 would even justify the statement "diclofenac is degraded in the environment", the fact that no standard OECD308 study is available has led to a more conservative assumption.


Photolysis: = 2.4 days (in salt and organic-free water, 50° N in winter) (Andreozzi 2003)

= 39 min (in natural water and Milli-Q water, 45° N in summer) (Packer 2003)

Bioaccumulation:

BCFss = 3-5 (OECD305, 1996, Harlan Laboratories Study D24068)

5 -11 (Brown et al. 2007)

2.5 - 29 (Fick et al. 2010)


Based on the low BCF found in a standard OECD305 fish bioconcentration study, the phrase “diclofenac has low potential for bioaccumulation” is justified for the risk assessment on diclofenac (see table 8 of 2012 www.fass.se guidance)


Vulture populations in India and Pakistan were exposed to comparatively high concentrations of diclofenac via the very exceptional pathway of extensive diclofenac use in cattle. The pathway: veterinary use in cattle - leaving of dead cattle for vultures to feed upon (for cultural reasons) and the consequently occuring acute toxic events in vultures are not applicable to the situation in Sweden, as a) according to our knowledge diclofenac is not used extensively in veterinary application in Europe and b) we assume cattle is not left for raptorial birds to feed on in Sweden.

Based on the low bioconcentration factor found in our study (Harlan Laboratories Study D24068) on bioconcentration in fish, similar effects are not expected in fish eating birds, as the bioaccumulation via the pathway “patients use as human pharmaceutical - excretion/wash-off to sewer systems - intake into surface waters - bioconcentration in fish - accumulation in fish-eating birds” is not expected to be significant and consequently not expected to lead to acute toxic effects in birds.


Excretion/ Metabolism: Biotransformation of diclofenac takes place partly by glucuronidation of the intact molecule, but mainly by single and multiple hydroxylation and methoxylation, resulting in several phenolic metabolites, most of which are converted to glucuronide conjugates. Two of these phenolic metabolites are biologically active, but to a much smaller extent than diclofenac. About 60 % of the administered dose is excreted in the urine as the glucuronide of the intact molecule and as metabolites, most of which are also converted to glucuronide conjugates. Less than 1% is excreted as unchanged substance. The rest of the dose is eliminated as metabolites through the bile in the faeces.


Structure of diclofenac sodium: CAS-Nr. 15307-79-6


Phys.-chem. properties:

Water Solubility 53.1 g/L (Novartis internal data)

Partition Coefficient: logP (neutral spezies) = 4.51 (Avdeef et al. 1998)

log D (pH 7.4) = 1.31 (Avdeef et al. 1998)

log D (pH 7.0) = 1.9 (Scheytt et al. 2005)


Literature:

  • Andreozzi R, Marotta R, Paxéus N (2003). Pharmaceuticals in STP effluents and their solar photodegradation in aquatic environment. Chemosphere; 50: 1319-1330.

  • Avdeef A, Box KJ, Comer JEA, Hibbert C, Tam KY (1998). pH-metric logP 10. Determination of liposomal membrane-water partition coefficients of ionizable drugs. Pharmaceutical Research; 15 (2): 209-215.

  • Brown JN, Paxéus N, Förlin L, Larsson DGJ (2007). Variations in bioconcentration of human pharmaceuticals from sewage effluents into fish blood plasma. Environmental Toxicology and Pharmacology; 24: 267-274.

  • Ciba-Geigy, Ecotoxicology, Project No.81 17 95. Final report: 24.2.1982

  • Ciba-Geigy, Ecotoxicology, Test No: 900010, Final report: 06.04 .1990

  • Ciba-Geigy, Ecotoxicology, Project No:81 17 94, Final report: 22.2.1982

  • Cleuvers M (2003). Aquatic ecotoxicity of pharmaceuticals including the assessment of combination effects. Toxicology Letters; 142 (3): 185-194.

  • ECHA, European Chemicals Agency, 2008. Guidance on information requirements and chemcial safety assessment. http://echa.europa.eu/guidance-documents/guidance-on-information-requirements-and-chemical-safety-assessment

-Ferrari B, Paxéus N, Giudice RL, et al (2003). Ecotoxicological impact of pharmaceuticals found in treated wastewaters: study of carbamazepine, clofibric acid, and diclofenac. Ecotoxicology and Environmental Safety; 55: 359-370.

  • Fick J, Lindberb RH, Parkkonen J, Arvidsson B, Tysklind M, Larsson DGJ (2010). Therapeutic levels of levonorgestrel detected in blood plasma of fish: results from screening rainbow trout exposed to treated sewage effluents. Environmental Science and Technology, article in press.

  • Gröning J, Held C, Garten C, et al (2007). Transformation of diclofenac by the indigenous microflora of river sediments and identification of a major intermediate. Chemosphere; 69: 509-516.

  • Harlan Laboratories Study D24046. Diclofenac Na: Toxic Effects to Rainbow Trout (Oncorhynchus mykiss) in an Early-Life stage Toxicity Test. Final report: 16.12.2011.

  • Harlan Laboratories Study D24068. [14C]-Diclofenac Na: Bioconcentration Flow-Through Test in the Rainbow Trout (Oncorhynchus mykiss). Final report: 21.11.2011.

  • Harlan Laboratories Study D33507. Diclofenac Na: Toxic Effects to Zebra Fish (Danio rerio) in an Early-Life Stage Toxicity Test. Final report 13.12.2011.

  • Kunkel U and Radke M (2008). Biodegradation of acidic pharmaceuticals in bed sediments: insight from a laboratory experiment. Environmental Science and Technology; 42: 7273-7279.

  • Packer JL, Werner JL, Latch DE, McNeill K, Arnold W (2003). Photochemical fate of pharmaceuticals in the environment: Naproxen, diclofenac, clofibric acid, and ibuprofen. Aquatic Sciences; 65: 342-351.

  • Scheytt T, Mersmann P, Lindstädt R and Heberer T (2005a). 1-octanol/water partition coefficients of 5 pharmaceuticals from human medical care: carbamezipine, clofibric acid, diclofenac, ibuprofen, and propyphenazone. Water, Air, and Soil Pollution; 165: 3-11.


Miljöinformationen för diklofenak är framtagen av företaget Novartis för Voltaren®