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MiljöinformationFörmånsstatus
McNeil

Kapsel, mjuk 400 mg
(genomskinliga, svagt gula med flytande innehåll, 10,0 x 17,0 mm)

Icke-steroida antiinflammatoriska/antireumatiska medel, NSAID

Aktiv substans:
ATC-kod: M01AE01
Utbytbarhet: Ej utbytbar
Läkemedel från McNeil omfattas av Läkemedelsförsäkringen.
  • Vad är miljöinformation?

Miljöpåverkan (Läs mer om miljöpåverkan)

Ibuprofen

Miljörisk: Användning av ibuprofen har bedömts medföra medelhög risk för miljöpåverkan.
Nedbrytning: Ibuprofen bryts ned i miljön.
Bioackumulering: Ibuprofen har låg potential att bioackumuleras.


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Detaljerad miljöinformation

1. PREDICTED ENVIRONMENTAL CONCENTRATION (PEC):

PEC is based on the following data:


A = 124 592 kg (total sold amount API (Ibuprofen, Dexibuprofen and Ibuprofen-D,L-lysin) in Sweden year 2018, data from IQVIA/LIF)

R = 87.3% (based on SimpleTreat model results)

P = 9 × 106 inhabitants

V = 200 L inh-1 d-1

D = 10


bild 1


2. ECOTOXICOLOGICAL STUDIES1

The following section includes a short summary of acute (short-term) and chronic (long-term) studies showing ecologically relevant adverse effects of ibuprofen exposure. Because of the large number of studies that have been conducted, any studies using less sensitive species and/or reporting only effects that are not considered to be ecologically relevant under FASS guidance are not included below.


Studies with algae (all studies considered both acute and chronic):2

Green alga (Desmodesmus subspicatus) (Methods for determination of

ecotoxicity; Annex V, C.3, Algal inhibition test. European Guideline. Commission of the European Communities, 1993):

NOECr 72 h= 30 mg/L


ErC50 72 h = 323.4 mg/L

Cleuvers (2003)


Green alga (Pseudokirchneriella subcapitata, formerly Selenastrum capricomutum) (Environment Canada. 1992. Growth inhibition test using the freshwater alga Selenastrum capricornutum. EPS 1/RM/25):

NOECy 72 h = 10 µg/L

EC25y 72 h > 32 µg/L

Brun et al. (2006).


Acute and chronic studies with crustaceans:

Water-flea (Daphnia magna) (OECD 202):

Acute EC50 48 h = 31 mg/L

NOEC not reported

Yamamoto et al. (2007)


Water-flea (Daphnia magna) (Environment Canada. 1990. Biological test method: Acute lethality test using Daphnia spp. EPS 1/RM/11):

Acute LC50 48 h > 32 µg/L

Brun et al. (2006).


Water-flea (Daphnia magna) Methods for determination of ecotoxicity; Annex V, C.2, Daphnia acute immobilisation test’European Guideline (Commission of the European Communities, 1992):

Acute EC50 48h = 95.6 mg/L

Cleuvers (2004)


Water-flea (Daphnia magna) (Author-derived method used, described in the reference cited):

Measured concentrations used to derive endpoints

Chronic EC10 14d (reproduction) = 2.04 mg/L

Chronic NOEC 14d (survival) = 20 mg/L

Chronic NOEC 14d (population growth) = <20 mg/L

Heckmann et al., (2007)


Water-flea (Daphnia magna):

Static renewal exposure according to test method EPA/600/4-91/002

Chronic NOEC 21d (reproduction) = 20 mg/L

Han et al. (2006)


Acute and chronic studies with fish:

Japanese medaka (Oryzias latipes) (OECD 203):

Acute LC50 96 h = 89 mg/L

Yamamoto et al. (2007)


Fathead minnow (Pimephales promelas) (OECD 210):

Measured concentrations used to derive endpoints

No adverse effects at the maximum concentration tested – 680 µg/L

Endpoints: survival, growth, abnormalities

Overturf et al. (2012)


Japanese medaka (Oryzias latipes) (Author-derived 6-week reproduction and chronic effects method used, described in the reference cited):

Endpoints: reproduction, histology.

Static renewal exposure (solution renewal every 24 hours)

No adverse effects to reproductive output or histology occurred at the maximum concentration tested – 100 µg L-1

Reproduction timing patterns significantly differed from control in a concentration-dependent relationship.

Endpoints: reproduction, histology.

Flippin et al. (2007)


Japanese medaka (Oryzias latipes) (OECD 210 test method modified by the author as described in the reference cited)3:

Measured concentrations used to derive endpoints

NOEC 144 d (reproduction) < 1.23 mg/L

NOEC 144 d (survival) = 33.3 mg/L

Han et al. (2010)


Studies with other species:

Mollusc (Planorbis carinatus) (Author-derived method used, described in the reference cited):

Flow-through exposure

Measured concentrations used to derive endpoints

Chronic NOEC 21 d = 1.02 mg/L

Endpoints: survival, growth, reproduction

Pounds et al. (2008)


Duckweed (Lemna minor) (ISO 20079):

Chronic EC50 7 d = 21 mg/L

NOEC not reported

Cleuvers (2003)


Duckweed (Lemna minor) (OPPTS 850.4400):

Chronic EC50 7 d = 4 mg/L

NOEC not reported4

Pomati et al. (2004)


Duckweed (Lemna gibba) (ASTM 7 d test method modified by the author as described in the reference cited):

No adverse effects at the maximum concentration tested – 1 mg/L

Endpoints: wet mass, number of fronds, chlorophylls a and b, and carotenoids

Brain et al. (2004)


Acute aquatic toxicity studies have been conducted for ibuprofen, with reported toxicological benchmarks greater than that in the critical chronic study listed above, and so are not reviewed here (Gravel et al., 2009; Han et al. 2006, Kim et al., 2009; Kim et al., 2010; Láng and Kőhidai, 2012; Mattozzo et al., 2012; Quinn et al. 2008).


1 In this section, if the study report referenced indicated that measured concentrations were used rather than nominal concentrations to derive the endpoint(s), it is noted in the study summary. If the study report does not specifically indicate that measured concentrations were used, it is assumed that nominal concentrations were used for calculations, and no note is made in the study summary.

2 Growth rate-based endpoints are used preferentially from studies that report both yield- and rate-based endpoints. Yield-based endpoints considered only if no rate-based value were available for a given species.

3 Han et al. (2010) performed a study in which Japanese medaka (O. latipes) were exposed to ibuprofen concentrations ranging from 0.01 µg/L to 1000 µg/L for 144 days. The endpoints examined included hatchability, fry survival, juvenile survival, adult survival, number of eggs, broods per pair, eggs per brood, fertility, and time-to-hatch. The authors report the lowest NOEC for the adult survival endpoint, equal to 0.1 µg/L. This result is unusual because reproduction endpoints and juvenile survival are typically more sensitive endpoints than adult survival. An unbiased independent panel of multinational experts (i.e,, the Scientific Committee on Health and Environmental Risks, or SCHER) was asked to evaluate the reliability of this study for setting an EU Environmental Quality Standard (EQS) for ibuprofen. The panel issued an opinion document in 2011 rejecting the use of these data for establishing an EQS (SCHER, 2011) because of shortcomings in the study, including: exposure intervals too broad, measurement intervals too infrequent, lack of adequate numbers of organisms and eggs, and insufficient statistical treatment of the data. Note that Flippin et al. (2007) also investigated reproductive effects in the same fish species, and found results that conflict with those of Han et al. 2010. Hence the results of Han et al. (2010) are neglected for setting the PNEC.

4 Pomati et al. (2004) investigated the growth of L. minor exposed to ibuprofen concentrations ranging from 1 to 1000 µg/L for 7 d, and the authors reported a decrease in growth at every concentration. However, no significance tests were conducted so a NOEC could not be determined. Also, growth stimulation followed an initial period of inhibition at all treatment levels except 1000 µg/L making interpretation of the study results problematic.


2.1. Calculation of Predicted No Effect Concentration (PNEC)

PNEC (µg/L) = lowest NOEC/10, where 10 is the assessment factor used, reflecting that data are available from chronic studies (e.g. EC10 or NOECs) from at least three species (fish, Daphnia and algae) representing three trophic levels. The NOEC for the green algae Pseudokirchneriella subcapitata (formerly Selenastrum capricornutum) 10 µg/L has been used for this calculation because it is the most sensitive of the tested species (i.e., yielded the lowest NOEC)


PNEC = 10 µg/L/10 = 1 µg/L


2.2. Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 2.34 µg/L / 1 µg/L = 2.34, i.e., 1 < PEC/PNEC ≤ 10 which justifies the phrase “Use of ibuprofen has been considered to result in moderate environmental risk.”


3. DEGRADATION

Ready biodegradation (OECD 301B) (Lavin, 2011)

Pass level reached within 28 days. Uncertain whether 10-day window criterion was achieved.


In a 100-day sediment/water study similar to an OECD 308 test, using a loamy sand solid phase, the 90% dissipation time was less than six days, with mineralization of ibuprofen beginning after an eight-day lag time. At the end of the 100-day study, 77% of the ibuprofen evolved as CO2. Parent ibuprofen was “totally transformed into volatile degradation products, mainly CO2” by the end of the study. (Loffler et al., 2005) Unextractable residues totaled 17% of the applied 14C at a maximum, occurring on day 14, where the extraction used was a four stage sequential process (15 min each stage, 50g sediment:45mL acetone/acetic acid 20:1 (v/v) for stage one, and ethyl acetate for stages two through four) under ultrasonic treatment. According to FASS guidance, ibuprofen can be designated with the phrase “Ibuprofen is degraded in the environment” because the DT50 in this study (< 6 d) is less than the criterion value of 32 days.


SimpleTreat, Version 3.1, dated March 14, 2003 was used to determine the percent removal for use in the PEC calculation. Default values for all parameters were used in the model, with the exception of the following:


Table 1 Input Values Used in SimpleTreat Modeling

Model Input (units)

Value Used

Notes/Source

Molecular weight (Da)

206.3

Value for ibuprofen acid (IBU-H)

Kow (n/a)

9337.5

Value for IBU-H from Avdeef et al., (1998)

Vapour pressure (Pa)

3.56 × 10-7

Daubert and Danner (1989) as cited in the US National Institutes of Health Hazardous Substances Data Bank (HSDB)

Solubility (mg L-1)

21

At 25 ºC from Yalkowsky and Dannenfelser (1992) as cited in HSDB

Ka (n/a)

3.55 × 10-5

Avdeef et al., (1998)

k biodeg1 (hr-1)

1

Recommendation in the model. See text below for details.


For estimating biodegradation in SimpleTreat, when the result of a standard laboratory test is to be used as the basis for estimating the extent of biodegradation in the treatment plant, the recommended values for the parameter, k biodeg1, are:

  • 1 to 3 h-1 when the substance is readily biodegradable and fulfills the 10-day window criterion

  • 0.3 to 1 hr-1 when the substance is readily biodegradable and does not fulfill the 10-day window criterion


The value selected is 1 hr-1 based on the ready biodegradability test performed by Lavin (2011), which shows IBU to be readily biodegradable in an OECD guideline 301B test, but with uncertainty around whether the 10-day window was fulfilled, due to the frequency of sampling.


The fraction of IBU removed in the wastewater treatment plant was predicted to be 91.5% in the 6-box model, and 87.3% in the 9-box model. Based on this result, the R parameter in the PEC equation was set equal to 87.3%.

Ibuprofen passes the ready biodegradation test (with uncertainty around the 10-day window criterion due to sampling frequency) and has a DT50 < 32 days in a sediment dissipation study. The phrase “Ibuprofen is degraded in the environment” is thus chosen.


4. BIOACCUMULATION

BCF in rainbow trout (Oncorhynchus mykiss) after 8-d exposure with 3 µg/L ibuprofen = 1.50 (muscle) and 23.69 (fat).

Zhang et al., (2010)


Maximum BCF in rainbow trout (Oncorhynchus mykiss) muscle after an 8-day exposure to 2.79 mg/L ibuprofen = 6.6

Togunde et al. (2012)


Maximum BCF in fathead minnow (Pimephales promelas) tissue after 28 d exposure and 14‑d depuration (OECD 305), and in channel catfish (Ictalurus punctatus) after 7 d exposure and 7 d depuration with 250 µg/L ibuprofen = 1.4.

Nallani et al. (2011)


Since BCF < 500, the substance has low potential for bioaccumulation.


5. REFERENCES

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 Res 15(2):209-215.


Brain, RA; Johnson, DJ; Richards, SM; Sanderson, H; Sibley, PK; Solomon, KR. 2004. “Effects of 25 Pharmaceutical Compounds to Lemna gibba Using a Seven-Day Static Renewal Test” Environ Toxicol Chem 23(2):371-382.


Cleuvers, M. 2003. "Aquatic Ecotoxicity of Pharmaceuticals Including the Assessment of Combination Effects" Toxicology Letters 142:185-194.


Cleuvers, M. 2004. "Mixture Toxicity of the Anti-inflammatory Drugs Diclofenac, Ibuprofen, Naproxen, and Acetylsalicylic Acid" Ecotoxicology and Environmental Safety 59:309–315.


Flippin, JL; Huggett, D; Foran, CM. 2007. “Changes in the timing of reproduction following chronic exposure to ibuprofen in Japanese medaka, Oryzias latipesAquatic Toxicol, 81:73-78.


Gravel, A; Wilson, JM; Pedro, DF; Vijayan, MM. 2009. “Non-steroidal anti-inflammatory drugs disturb the osmoregulatory, metabolic and cortisol responses associated with seawater exposure in rainbow trout.” Comp Biochem Physiol C Toxicol Pharmacol. 149(4):481-90.


Han, GH; Hur, HG; Kim, SD. 2006. "Ecotoxicological Risk of Pharmaceuticals from Wastewater Treatment Plants in Korea Occurrence and Toxicity to Daphnia magna" Environ Toxicol Chem 25:265–271.


Han, S; Choi, K; Kim, J; Ji, K; Kim, S; Ahn, B; Yun, J; Choi, K; Khim, JS; Zhang, X; Giesy, JP. 2010. “Endocrine disruption and consequences of chronic exposure to ibuprofen in Japanese medaka (Oryzias latipes) and freshwater cladocerans Daphnia magna and Moina macrocopaAquatic Toxicol 98:256–264.


Heckmann, L-H; Callaghan, A; Hooper, HL; Connon, R; Hutchinson, TH: Maund, SJ; Sibly, RM. 2007. “Chronic Toxicity of Ibuprofen to Daphnia magna: Effects on Life History Traits and Population Dynamics” Toxicol Letters 172:137–145.


Kim, JW; Ishibashi, H; Yamauchi, R; Ichikawa, N; Takao, Y; Hirano, M; Koga, M; Arizono, K. 2009. “Acute toxicity of pharmaceutical and personal care products on freshwater crustacean (Thamnocephalus platyurus) and fish (Oryzias latipes).” J Toxicol Sci. 34(2):227-32.


Kim, J; Park, J; Kim, PG; Lee, C; Choi, K; Choi K. 2010. “Implication of global environmental changes on chemical toxicity-effect of water temperature, pH, and ultraviolet B irradiation on acute toxicity of several pharmaceuticals in Daphnia magna.” Ecotoxicology. 19:662-669.


Láng, J; Kőhidai, L. 2012. “Effects of the aquatic contaminant human pharmaceuticals and their mixtures on the proliferation and migratory responses of the bioindicator freshwater ciliate Tetrahymena.” Chemosphere. 89:592-601.


Loffler, D; Rombke, J: Meller, M; Ternes, TA. 2005. “Environmental Fate of Pharmaceuticals in Water/Sediment Systems” Environ. Sci. Technol. 39:5209-5218.


Mattozzo, V; Rova, S; Marin MG. 2012. “The nonsteroidal anti-inflammatory drug, ibuprofen, affects the immune parameters in the clam Ruditapes philippinarum.” Mar Environ Res. 79:116-121.


Nallani, GC; Paulos, PM; Constantine, LA; Venables, BJ; Huggett DB. 2011. “Bioconcentration of ibuprofen in fathead minnow (Pimephales promelas) and channel catfish (Ictalurus punctatus).” Chemosphere. 84:1371-1377.


Overturf, MD; Overturf, CL; Baxter, D; Hala, DN; Constantine, L; Venables, B; Huggett, DB. 2012. “Early Life-Stage Toxicity of Eight Pharmaceuticals to the Fathead Minnow, Pimephales promelasArch Environ Contam Toxicol 62:455–464.


Pomati F; Netting AG; Calamari D; Neilan BA. 2004. “Effects of erythromycin, tetracycline and ibuprofen on the growth of Synechocystis sp. and Lemna minor.” Aquat Toxicol 67(4):387–396


Pounds, N; Maclean, S; Webley, M; Pascoe, D; Hutchinson, T. 2008. "Acute and Chronic Effects of Ibuprofen in the Mollusk Planorbis carinatus (Gastropoda: Planorbidae)" Ecotoxicol Environ Safety 70:47–52.


Quinn, B; Gagné, F; Blaise, C. 2008. “An investigation into the acute and chronic toxicity of eleven pharmaceuticals (and their solvents) found in wastewater effluent on the cnidarian, Hydra attenuata.” Sci Total Environ. 389(2-3):306-14.


SCHER (Scientific Committee on Health and Environmental Risks). 2011. “Opinion on ‘Chemicals and the Water Framework Directive: Draft Environmental Quality Standards’ Ibuprofen” 30 March.


Togunde,OP; Oakes, KD; Servos, MR; Pawliszyn, J. 2012. “Determination of Pharmaceutical Residues in Fish Bile by Solid-Phase Microextraction Couple with Liquid Chromatography-Tandem Mass Spectrometry (LC/MS/MS)” Environ. Sci. Technol. 46:5302−5309.


Zhang, X; Oakes, KD; Cui, S; Bragg, L; Servos, MB; Pawliszyn, J. 2010. "Tissue-specific in vivo bioconcentration of pharmaceuticals in rainbow trout (Oncorhynchus mykiss) using space-resolved solid-phase microextration" Environ Sci Technol 44:3417-3422.