Detaljerad miljöinformation

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 occurring 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 applications 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.

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) = 1.37 * 10^-6 * A * (100-R) = 0.3057 μg/L

Where:

A = 2231.521 kg diclofenac acid (1532.15 kg diclofenac diethylamin equals 1228.66 kg diclofenac acid; 436.49 kg diclofenac potassium equals 386.79 kg diclofenac acid; 661.8 kg diclofenac sodium equals 616.07 kg diclofenac acid) (total sold amount API in Sweden year 2022, data from IQVIA).

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 = 10 *10⁶

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

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

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae:

EC₅₀ = 72 mg/L           (Desmodesmus subspicatus, 3 d, based on average growth rate; EEC Directive 92/69/EEC, Annex V, C.3) (Cleuvers, 2003)

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 23°C, 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 increase at 550 nm with a Bausch & Lomb spectronic 20 colorimeter.) (Ferrari et al., 2003).

Aquatic plants:

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

Crustacean:

Acute toxicity

EC50 (immobilisation) = 68.0 mg/L                  (Daphnia magna, waterflea; 48 h ; EEC Directive 92/69/EEC, 1992 Annex V, C.2) (Cleuvers, 2003)

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

Chronic toxicity

NOEC (reproduction) = 1.0 mg/L       (Cerodaphnia dubia, 7 d; test method: AFNOR T90-376 (2000a)) (Ferrari et al., 2003)

Fish:

Acute toxicity

LC50 96 h (mortality) = 82.0 mg/L       (Danio rerio, zebrafish; OECD203) (Ciba-Geigy, Ecotoxicology, Project No.81 17 95)

Chronic toxicity

NOEC 95 days (histopathological alterations in gills) = 0.368 mg/L (OECD 210, Oncorhynchus mykiss, rainbow trout) (Harlan Laboratories Study D24046)

NOEC 34 days (survival of larvae and juvenile fish) = 0.32 mg/L (OECD 210, Danio rerio, zebrafish) (Harlan Laboratories Study D33507)

NOEC 10 days = 4 mg/L (ISO 12890 (1999) early-life stage test, Danio rerio, zebrafish) (Ferrari et al., 2003).

Other ecotoxicity data:

Bacterial respiration inhibition

EC₅₀ 3 h > 100.0 mg/L            (activated sludge respiration inhibition; OECD209) (Ciba-Geigy, Ecotoxicology, Test No: 900010)

PNEC derivation:

PNEC = 0.032 mg/L = 32.0 µg/L

PNEC (μg/L) = lowest NOEC/10, where 10 is the assessment factor used, based on the fact that three chronic toxicity studies were available, covering three trophic levels. The most sensitive species in the chronic studies was the fish species Danio rerio. The NOEC for Danio rerio survival of larvae and juvenile fish was therefore used for PNEC derivation.

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.3057 μg/L / 32.0 µg/L = 0.0096, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase "Use of diclofenac has been considered to result in insignificant environmental risk."

Degradation

Biotic degradation

Ready degradability:

55.5 % degradation in 28 days, not readily biodegradable (OECD301D) (Ciba-Geigy, Ecotoxicology, Project No. 81 17 94)

Simulation studies:

Significant depletion by sediment microbial activity (93 % depletion of diclofenac after 5 days); non-standardised method, fixed-bed column bioreactor with high sediment/water ratio and a long operation time. The whole system was light-protected and operated at 20°C ±2°C. (Gröning et al., 2007)

t½ = 5.5 – 18.6 days in sediment systems (Kunkel and Radke 2008)

Bench-scale annular flume; flat sediment surface vs. moving sediment; 18°C, in the dark. Sediment and water from the river Roter Main. Initial test item concentration of approximately 30-50 μg/L 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 quadrupole mass spectrometer (1200 L)

Photolysis:

t½ = 2.4 days (in salt and organic-free water, 50° N in winter) (Andreozzi et al., 2003)

t½ = 39 min (in natural water and Milli-Q water, 45° N in summer) (Packer et al., 2003)

Justification of chosen degradation phrase:

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.

Bioaccumulation

Partitioning coefficient:

log P (neutral spezies) = 4.51                 

log D (pH 7.4) = 1.31                                                    

(pH-metric technique; Avdeef et al., 1998)                  

log D (pH 7.0) = 1.9            (Shake-flask experiment, OECD107, Scheytt et al., 2005)               

Bioaccumulation:

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

BCF (plasma) = 5 - 11            (mean measured plasma concentration / mean exposure concentration in rainbow trout (Oncorhynchus mykiss) exposed to sewage effluents at three sites) (Brown et al., 2007)

BCF (plasma) = 2.5 - 29         (measured fish plasma levels / average measured water concentration after 14 days of exposure) (Fick et al., 2010)

                                                                

Justification of chosen bioaccumulation phrase:

Based on the low BCF found in a standard OECD305 fish bioconcentation study, the phrase 'Diclofenac has low potential for bioaccumulation' is justified for the risk assessment on diclofenac.

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 (Voltaren^® Core Data Sheet).                                                                                                                                                                                             

PBT/vPvB assessment

Diclofenac does not fulfil the criteria for a PBT substance, as it is not bioaccumulative, according to the EU criteria for PBT.

References

ECHA 2008, European Chemicals Agency. 2008 Guidance on information requirements and chemical safety assessment.http://guidance.echa.europa.eu/docs/guidance_document/information_requirements_en.htm

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

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, 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.

Ciba-Geigy, Ecotoxicology, Test No: 900010, Final report: 06.04.1990

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

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. 

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

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.                                                                                                                                                    

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.

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.

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

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.

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.

Voltaren^® (diclofenac sodium) Core Data Sheet. Version 2.1. 05. February 2018.