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MiljöinformationFörmånsstatus
GlaxoSmithKline Consumer Healthcare

Gel 11,6 mg/g
(Vit eller nästan vit, mjuk, homogen, krämliknande gel.)

Antiinflammatoriska medel, icke-steroider för utvärtes bruk.

Aktiv substans:
ATC-kod: M02AA15
Läkemedel från GlaxoSmithKline Consumer Healthcare 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

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 = 1.02 μg/L


Where:

A = 6790.99kg (total sold amount API expressed as the free active, in Sweden year 2016, derived from sodium, potassium and ethylamine salt forms, data from Quintiles IMS). Reduction of A may be justified based on metabolism data.

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) (Reference 1)

D = factor for dilution of waste water by surface water flow = 10 (ECHA default) (Reference 1)


Predicted No Effect Concentration (PNEC)

Ecotoxicological studies:

Green Algae (Desmodesmus subspicatus):

IC50 72 h (average growth rate) = 72,000 μg/L (OECD 201) (Reference 5)


Green Algae (Pseudokirchneriella subcapitata):

NOEC 96 h (average growth rate) = 68,000 μg/L (OECD 201) (Reference 9)


Aquatic plants (Lemna minor):

EC50 7 days = 10,000 μg/L (OECD 201) (Reference 5)


Water flea (Daphnia magna):

Acute toxicity

EC50 48 h (immobility) = 68,000 μg/L (OECD 202) (Reference 5)


Water flea (Ceriodaphnia dubia):

Acute toxicity

EC50 48 h (immobility) = 22,700 μg/L (OECD 202) (Reference 9)


Water flea (Ceriodaphnia dubia):

Chronic toxicity

NOEC 7 days (reproduction) = 1,000 μg/L (OECD 211) (Reference 9)


Zebrafish (Danio rerio)

Acute toxicity

LC50 96 h (mortality) = 82,000 μg/L (OECD203) (Reference 6)


Fathead minnow (Oncorhynchus mykiss):

Chronic toxicity

NOEC 95 days (histopathological alterations in gills) = 369 μg/L (OECD 210) (Reference 7)


Zebrafish (Danio rerio)

Chronic toxicity

NOEC 34 days (survival) = 320 μg/L (OECD210) (Reference 8)


Zebrafish (Danio rerio)

Chronic toxicity

NOEC 10 days (development) = 4,000 μg/L (OECD210) (Reference 9)


Other ecotoxicity data:

Microorganisms in activated sludge

EC50 3 hours (Inhibition) > 100,000 μg/L (OECD 209) (Reference 10)


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 320 μg/l for chronic fish toxicity has been used for this calculation

PNEC = 320 µg/L /10 = 32.0 µg/l


PNEC (μg/L) = lowest NOEC/10, where 10 is the assessment factor applied for three long-term NOECs. NOEC for fish (= 320 ug/L) has been used for this calculation since it is the most sensitive of the three tested species.


Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 1.02/32 = 0.032, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase “Use of diclofenac has been considered to result in insignificant environmental risk.”


Environmental fate studies

Degradation: 55.5%, not readily biodegradable (OECD301 D, 1981) (Reference 11)

Significant depletion by sediment microbial activity (93 % depletion of diclofenac after 5 day (Reference 12)


= 5.5 – 18.6 days in sediment systems (bench-scale annular flume; flat sediment surface vs moving sediment) (Reference 14)

In the study on transformation of diclofenac in sediment systems, report a half-life of 5.5-18.6 days (Reference 14).

Significant primary degradation of diclofenac has also been shown in sediment studies (Reference 13).

Photolysis: = 2.4 days (in salt and organic-free water, 50° N in winter) (Reference 2)

= 39 min (in natural water and Milli-Q water, 45° N in summer) (Reference 15)


Justification of chosen degradation phrase:

Diclofenac is not readily biodegradable nor inherently biodegradable. A weight of evidence approach suggests that diclofenac is subject to biotic and abiotic degradation in various environmental niches. However, there is insufficient data on degradation products to warrant conclusion of slow degradation in the environment.Thus the phrase “Diclofenac is potentially persistent” is thus chosen.


Bioaccumulation

BCFss = 3-5 (Reference 16)

5 -11 (Reference 4)

2.5 - 29 (Reference 12)

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 (old world) 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 subsequent secondary poisoning leading to acute toxic effects in vultures are unlikely to be applicable to the situation 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.

Partition Coefficient: logP (neutral species) = 4.51 (Reference 3)

log D (pH 7.4) = 1.31 (Reference 3)

log D (pH 7.0) = 1.9 (Reference 17)


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 phenolic metabolites are biologically active, but to a much lesser extent than diclofenac.

About 60% of the administered dose is excreted in the urine in the form of the glucuronide conjugate 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 (Reference 2).


PBT/vPvB assessment

Diclofenac does not fulfil the criteria for PBT and/or vBvP.

All three properties, i.e. ‘P’, ‘B’ and ‘T’ are required in order to classify a compound as PBT (Reference 1). Diclofenac does not fulfil the criteria for PBT and/or vBvP based on BCF < 2,000.


References

  • ECHA, European Chemicals Agency. 2008 Guidance on information requirements and chemical safety assessment.

  • 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.

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

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

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

  • 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.

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

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

  • 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, 44(7): 2661-2666.

  • 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.

  • 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.

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

  • 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.

  • Pharmacokinetic properties: Metabolism and Elimination. Summary of Product Characteristics Voltarol ampoules. Novartios Pharmaceuticals Ltd, March 2017.