Ibuprofen pnec derivation June 2015

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Ibuprofen PNEC Derivation June 2015

Acute and chronic data are available for ibuprofen, including many micro-organism minimal inhibitory concentrations. [IUCLID, Chowdhury et al. 1996, Sanyal et al. 1993]. There is no explicit information on ibuprofen being inhibitory or not to sewage sludge micro-organisms in the biodegradation tests. However, as significant degradation was reached in both ready tests [both cited in IUCLID], it is assumed that the applied concentration of 20 mg/L was not inhibitory. In view of the comparatively high concentrations in all tests, no disruption of the biological step in sewage works is expected, nor is there an indication for toxicity towards micro-organisms in the environment. In freshwater cyanobacteria (Synechocystis species), ibuprofen at 1 µg/l up to 1 mg/l (the highest tested concentration) stimulated growth as compared to controls and therefore was certainly not inhibitory [Pomati et al. 2004].

Acute Toxicity Data
For the marine diatom, Skeletonema costatum, an EC50 of 7.1 mg/L was reported in a 96-hr study, and an EC50 of 39.9 mg/L with a NOEC of 20.5 mg/L was reported for a 5 day exposure with a 9 day recovery period [cited in IUCLID].
Ibuprofen showed moderate to low toxicity against freshwater green algae and no obvious difference between the sodium salt and the acid. Two studies reported 72-hr EC50 values of 315 and 342 mg/L for Desmodesmus subspicatus [Cleuvers, 2003, Cleuvers, 2004]. There is also a 72-hr EC05 of 72.9 mg/L based on growth rate, which is analogous to a NOEC [Cleuvers 2004] and a 72-hr IC25 of >32 μg/L with a 10 μg/L NOEC in Selenastrum capricornutum based on a decrease in biomass [Brun et al. 2006]. When this latter value is compared to the 96-hour IC50 value of >30 mg/L for Selenastrum capricornutum [cited in IUCLID], the difference in effect cannot be explained.
In several acute ecotoxicity tests with invertebrates, ibuprofen had 48-hour EC50 values of 9.06–132.6 mg/L and NOECs of 3–66 mg/L in Daphnia magna [IUCLID, Cleuvers 2004, Han et al. 2006, Cleuvers 2003]. Two EC50 values of approximately 10 mg/L are cited in IUCLID but the original data cannot be assessed. The other four studies [Heckmann et al. 2005, Han et al. 2006, Cleuvers 2003 and 2004] follow international protocols and have EC50 values consistently >100 mg/L. An acute test with the freshwater snail, Planorbis carinatus, resulted in a 96-hour LC50 of 17.1 mg/L [Pounds et al. 2004]. There is one marine invertebrate test, with a 96-hour EC50 >100 mg/L and a NOEC of 30 mg/L in Mysidopsis (Americamysis) bahia [cited in IUCLID]. Based on these data, ibuprofen is of low toxicity to invertebrates.
Acute, 96-hour toxicity of ibuprofen to fish is given by two citations in IUCLID. A LC50 of 173 mg/L and a NOEC of 10 mg/L was reported for the freshwater sunfish, Lepomis macrochirus, and a study with the estuarine species, Cyprinodon variegates, resulted in an LC50 >300 mg/L and a NOEC of 300 mg/L. A 48-hr LC50 of 23.9 mg/L was reported for Danio rerio embryos (Kehrer and Nagel, 2006), and a 24-hr LC50 of 142 mg/L (ppm) was reported for Cirrhinus mrigala [Saravanan 2012]. Based on these data, ibuprofen is of low acute toxicity to fish.
The 96-hr LC50 of ibuprofen for pre-metamorphic Rana catesbeiana tadpoles is 41.5 mg/L

(Veldhoen in press).

Chronic Toxicity Data
Three publications on toxicity to macrophytes give 7-day EC50 values to Lemna gibba of >1 mg/L [Brain et al., 2004], and an extrapolated 4 mg/L [Pomati et al. 2004] and a measured 22 mg/L in Lemna minor [Cleuvers, 2003].  These values are in reasonable agreement, but Brain and colleagues noted an EC10 >1 mg/l (and a NOEC of 1 mg/L) [Brain et al. 2004], while Pomati and co-workers set their NOEC or LOEC at a very low 1 µg/L based on an observation that growth was 14% lower than control on day 7 at 1 μg/L [Pomati et al. 2004]. Pomati has a very flat dose-response, and their no-effect level was not a statistical no-effect level, since their statistical section just describes probit analysis. The coefficient of variation was not presented so it is impossible to determine if that is a real NOEC. Cleuvers did not indicate a NOEC [Cleuvers, 2003].  Brain et al. changed the media daily, used five different endpoints (wet weight, frond number, chlorophyll a, chlorophyll b and carotenoids) and consistently found no significant effect of ibuprofen at 1 mg/L, the highest treatment level. Pomati and colleagues replaced the test solutions just once on day 5, used only frond number as the endpoint and found a decrease of 25% compared to controls at 1 mg/l, the highest treatment level. Cleuvers used five concentrations, 1, 3.2, 10, 32 and 100 mg/L, did not change the media, used number and area of fronds as the endpoints and did not report any untoward effects at lower concentrations. In view of daily media exchanges and more endpoints studied by Brain and co-workers, making for the most consistent exposure and for the most sensitive effects evaluation, and in view of no significant adverse effects seen by Cleuvers at 1 mg/L, the NOEC of 1 mg/L in the study by Brain et al. is the most robust for Lemna
In a battery of five basic mode-of-action test systems with Ibuprofen using photosynthetic bacteria, green algae and genetically modified yeasts and Escherichia coli bacteria, there was no indication or evidence for any general, specific, unspecific or reactive toxicity other than minimal (narcotic or baseline) toxicity [Escher et al. 2005]. The strongest effect found was an inhibition of photosystem II quantum yield in algae at an EC50 of 92.1 mg/L, which falls in the reported range of algal effects data. Overall, this result supports a relatively low level of toxicity of ibuprofen, which in turn supports choosing the higher chronic NOEC for Lemna.
The NOECs of 1 mg/L for L. gibba and L. minor were selected for use in the Species Sensitivity Distribution (SSD).

Chronic survival NOECs of 20 -33 mg/L (21-d) [Han 2006; Heckmann 2007; Han 2010] and 40 mg/L (10 to 12-d) [Heckmann 2005; Hayashi 2008] were reported for Daphnia magna. A boundary estimate of >32 μg/L (the highest concentration tested) was observed in a 7-d Ceriodaphnia study (Brun et al. 2006).
After 21 d exposure with D. magna, the NOEC based on survival of the initial neonate was 33.3 mg/L, while the LOEC based on reproduction was 1.23 mg/L which was the lowest concentration tested [Han 2010]. The PGR decreased but the magnitude of the effect was not expected to result in negative population growth [Han 2010]. A previous study by G. Han [2006] reported a reproduction NOEC of 20 mg/L, and Heckmann [2007] reported a reproduction EC10 of 2.04 mg/L. Hayashi [2008] reported the number of offspring returned to control levels in the 20 mg/L group exposed for 10-d after a 10-d recovery period. Hayashi was determined to be a reliable study (Reliability 2 assigned by wca.)
The Geometric mean of the conservative NOECs of 1.23 mg/L and 2.04 mg/L was selected for use in the SSD.
The NOEC for reproduction of M. macrocopa was 25 mg/L [Han 2010], which was selected for the SSD. The NOEC based on survival of M. macrocopa was >50.0 mg/L [Han et al. 2010].

A chronic test with the freshwater snail, Planorbis carinatus, resulted in a 21-day NOEC of 1.02 mg/L with a LOEC of 2.43 mg/L [Pounds et al. 2004]. (Reliability 2 assigned by wca.)
The NOEC of 1.02 mg/L was selected for use in the SSD.
Quinn et al. (2008) investigated the acute and chronic toxicity of ibuprofen to the cnidarian

Hydra attenuata. The 96-hour LC50 for ibuprofen was 22.36 mg/L, the EC50 based on feeding was 3.85 mg/L and the NOEC based on growth (hydranth number) was 1 mg/L. The study did not follow a standard guideline or GLP, but the methods were clearly documented. Therefore, the study is considered to be reliable (Reliability 2 assigned by wca).
Pascoe et al. (2003) determined a NOEC of 1 mg/L for feeding & budding from a 17-d study in H. vulgaris. There was also a >10 μg/L NOEC for polyp regeneration but only one concentration was studied.
The NOECs of 1 mg/L for both H. attenuate and H. vulgaris were selected for the SSD.
Algal NOECs of 72.9 mg/L (EC05, growth rate, Desmodesmus subspicatus, Cleuvers, 2004), >30 mg/L (Selenastrum capricornutum, IUCLID, 2000) and 10 μg/L (biomass, Selenastrum capricornutum, Brun et al. 2006) have been reported. A Skeletonema NOEC of 20.5 mg/L was also reported [IUCLID, 2000].
A new study from Aguirre-Martinez et al. (2015) on toxicity to freshwater algae (Pseudokirchneriella subcapitata) and marine algae (Isochrysis galbana) has been assessed as reliable with restrictions by the JRC. The EC10 for Pseudokirchneriella subcapitata at 72 h and 96 h (40.7 and 162.1 mg/L, respectively) are several orders of magnitude higher than the NOEC of 0.01 mg/L reported in the study which had been included in the previous dossier (from Brun et al. 2006). The NOECs from Aquirre-Martinez et al. are in line with Cleuvers’ Desmodesmus subspicatus data, the Selenastrum capricornutum NOEC reported in IUCLID, and the NOEC of reported in Scenedesmus rubescens by Moro et al. 2014. The Moro study showed no effect of ibuprofen on growth in a 30 d study until day 18 (250 μg/L and above) with a NOEC of 62.5 μg/L at day 30. While this study does not conform to standard guidelines, it does provide useful data to put the other studies, including Brun et al., into context.
The NOECs of 72.9 and 40.7 mg/L were selected for use in the SSD.

Chronic NOECs were reported for medaka, Oryzias latipes (Flippin 2007; Han 2010) and for fathead minnow, Pimephales promelas (Overturf 2012; Gallagher 2010/Maack 2011). These are discussed below.

Oryzias latipes
Flippin et al. (2007) evaluated effects of ibuprofen on Oryzias latipes (Japanese medaka) exposed for 6 weeks prior to reproduction assessment via water to three concentrations of ibuprofen (1–100 μg/L nominal concentrations). Each day 100% of the water was changed and fresh ibuprofen solution was administered in (nominal) concentrations of 1, 10 and 100 μg/L. Reproductive parameters, including frequency of spawning, fecundity, egg size, and rate of fertilization, were measured for each pair of adult medaka following 6 weeks of exposure. Increasing exposure to ibuprofen significantly increased the number of eggs per reproductive event, but decreased the number of spawning events per week. The total number of eggs produced by pairs over the week of assessment did not differ with exposure (Kruskal–Wallis test, H= 1.792, p = 0.62). As ibuprofen treatment increased, the frequency of egg production (eggs/day) decreased at 100 μg/L. The number of days with eggs decreased at 10 μg/L. On days when they did reproduce, pairs exposed to 100 μg/L of ibuprofen produced nearly twice as many eggs as those in the control group. Spawning events decreased with increasing concentration, althoμgh the frequency of egg production increased resulting in a higher number of eggs produced per spawning event for no net change. No difference was observed in the rate of fertilization and was generally greater than 90% in all treatment groups. No difference was observed in the rate of fertilization between treatment groups (Kruskal–Wallis test, H= 2.278, p = 0.52). No pathological damage was evident the in the gills, livers and head kidneys of animals from the highest exposure group. The temporal pattern of spawning, but not egg production or reproductive success, changed with increasing exposure.
A conservative NOEC of 10 μg/L is derived from this study and used in the SSD.

Han et al. (2010) evaluated effects of ibuprofen on O. latipes at concentration up to 1000 μg/L for 144 days. The authors report a NOEC for survival at 0.1 μg/L. Examination of the data indicates no consistent dose response for a number of parameters and a NOEC is more appropriately in the range of 1 to 10 μg/L based on survival, number of eggs per brood, and time to hatch of fertilized eggs. This study raises an important question: Since no lethality observed in fry or juveniles, why do adults have a 1000-fold lower NOEC than the juveniles? This result is in stark contrast to what was observed by Flippin [2007].

The European Commission’s SCEHR reviewed the Han study and determined it was unsuitable for use in deriving a PNEC [SCHER (Scientific Committee on Health and Environmental Risks). 2011. “Opinion on ‘Chemicals and the Water Framework Directive: Draft Environmental Quality Standards’ Ibuprofen” 30 March].

Pimephales promelas
Overturf et al. (2012) assessed the effects of ibuprofen to the fathead minnow (Pimephales promelas) in an OECD 210 early life stage test under semi-static exposure conditions. Mean measured concentrations were 68% of nominal across all exposures and the results were expressed as mean measured concentrations. No significant effects on survival, growth or incidence of abnormalities were observed; therefore the NOEC was determined to be >680 μg/L (the highest concentration tested). The study followed a standard guideline and was well documented. Therefore, it was therefore assigned a reliability score of 1 (reliable without restrictions) by wca.
However, Gerd Maack (UBA) questioned the reliability of the Overturf study:
“According to the updated OECD 210 (The Fish Early Life Stage Test) (July 2013) a minimum of 18 mm fish length is recommended for fathead minnow control fish. This was not reached in the Ibuprofen study by Overturf et al, where the control fish had an average length of just 15 mm. This means that potential growth effects could not have been detected, mainly due to much too small tanks, where 25 fish were living in a 600 ml tank. The updated guideline however recommended much larger tanks: “The dimensions of the vessels should be large enoμgh to allow proper growth in the control, maintenance of dissolved oxygen concentration (e.g. for small fish species, a 7 L tank volume will achieve this) and compliance with the loading rate criteria given in paragraph 19”. Even if the study was conducted prior the update, the actual guideline needs to be used to assess the study. Due to too high density in the tank and therefore no chance for the control fish to grow, the Ibuprofen part of the study can only be assessed with a reliability score of 3 (unreliable).
It is noted that the length of the fish in the controls were claimed to be normal by the author. Overturf et al (2012) describes the results as:
“Dilution water and solvent control larval weights and lengths at 28 days were within the range of FHM values reported in the literature (Bogers et al. 2006; Lizotte et al. 1999).
However, Figure 3 in the paper shows that the length of the controls in the ibuprofen experiment (15 cm) were smaller than the fish length in the controls for other tested substances (18-20 cm). In fact, exposure of the fish to norethindrone at 0.74 μg/L results in a reduction in growth down to 15 cm (which is considered significant) that corresponds to the growth of the control fish in the ibuprofen experiment.

Dan Caldwell (J&J) agrees with the wca reliability rating of 1 and disagrees with the UBA arguments and their reliability assessment for the following reasons:

First, the study was conducted according to the guideline in effect at the time of the study. The results are valid; if the points made by UBA (e.g., tank dimension/density) had any effect, it would be expected to result in an adverse effect to the fish. No adverse effects were demonstrated in this study.
Second, there was no impact of ibuprofen on length of the exposed fish compared to the control fish for the ibuprofen study.
Comparison of the ibuprofen study to the norethindrone study is irrelevant and potentially misleading.
The NOEC of 680 μg/L was selected for use in the SSD. This NOEC was the highest concentration tested and is supported by the Gallagher et al. 2010 / Maack et al. 2011 study described below.

The Gallagher et al. 2010 draft report, reported in summary form by Maack et al. 2011, supports the NOEC reported by Overturf et al.(2012). This is an Early Life-Stage Toxicity Test with the Fathead Minnow (Pimephales promelas) conducted by Wildlife International, Ltd. for UBA, the German Federal Environment Agency. This study was conducted according to the OECD 210 Fish Early Life Stage study protocol in compliance with Good Laboratory Practice Standards as published by the U.S. Environmental Protection Agency (40 CFR Parts 160 and 792); OECD Principles of Good Laboratory Practice (ENV/MC/CHEM (98) 17); and Japan MAFF (11 NohSan, Notification No. 6283, Agricultural Production Bureau, 1 October 1999).

The study exposed four replicates of 20 fathead minnow embryos (< 24 hours old at test initiation) for 33 Days (5-Day Hatch and 28-Day Post-Hatch) to one of 6 ibuprofen treatment concentrations from 0.0091 to 3.0 mg/L (mean measured) plus negative control under flow throμgh conditions with 6 exchanges per day. After a 5-d embryo hatching period, the larvae were released into the test chambers, where exposure continued during a 28-d juvenile growth period. There were no effects of ibuprofen on the time to hatch, hatching success, larval survival, and growth (length and weight) of fathead minnows during early life-stage development. The study NOEC was 3.0 mg/L, the highest concentration tested. This study is assigned a Reliability of 1 (Caldwell).
The NOEC of 3.0 mg/L (3000 μg/L) was selected for use in the SSD.

Other studies
An early development fish study conducted in Dario rerio by David & Pancharatna (2009) was assessed by the JRC. Although the authors fail to report some crucial information and no analytical measurements were done on ibuprofen, they reported that early embryonic stages may be sensitive to ibuprofen, with several developmental effects and increased mortality reported during the 7-d exposure period. However, they used distilled water to administer the ibuprofen and in the controls; and in their discussion indicate the observed effects may be due to “osmotic disturbances interfering with the activity of the hatching enzyme.”
Further, Ji et al. (2013) found the average number of eggs spawned and rate of hatching were reduced after 21-d exposure of adult D. rerio to concentrations of ibuprofen > 1 μg/L.
In contrast, Morthorst et al. (2013) found no effect on egg laying of adult D. rerio exposed to much higher concentrations of ibuprofen for 7-d, with a NOEC of 506 μg/L.
Given the conflicting results and methodological issues with these studies, all of which are considered to have a reliability code of 3, no conclusion can be reached and thus D. rerio is not included in the SSD.
The study from Aguirre-Martinez et al. (2015) reported effects on developmental endpoints for the sea urchin Paracentrotus lividus, where they found effects on embryo-larval development at the lowest concentration tested (0.00001 mg/L). However, this was a non-standard assay and is assigned a reliability rating of 3.
Taken as a whole, reports that ibuprofen may have developmental effects need to be put into perspective. Reliable studies in two species of fish indicate no effects at exposures from 10 μg/L up to 3,000 μg/L. There could be a unique sensitivity of D. rerio to ibuprofen, but in the absence of a definitive study in this species the reported findings remain speculative.
Further, He et al. (2014) reported that ibuprofen increased the lifespan of Saccharomyces cerevisiae (a yeast), Caenorhabditis elegans (a metazoan nematode), and Drosophila melanogaster (an insect), indicative of conserved eukaryotic longevity effects. If a way can be found to use these data, all the regulatory requirements for a SSD are met.
Acute toxicity values of ibuprofen range from 7 to over 300 mg/L while chronic algal, Lemna, daphnid, snail, fish, and Hydra NOECs have a much wider range between a possible, 10 µg/L to over 100 mg/L. The chronic NOECs for Lemna, snails, and Hydra are consistent at 1 mg/L. There is no evidence in a battery of 5 basic mode-of-action test systems for any toxicity other than baseline toxicity/narcosis; no evidence for specific or unspecific toxicity in a photosystem II inhibition test; no evidence for estrogen receptor-mediated toxicity; and no evidence for reactive toxicity in comparison of glutathione present/absent and DNA repair system present/absent micro-organisms [Escher et al., 2005]. The overall picture that emerges from these studies is the acute ecotoxicity potential of ibuprofen is a minor concern.
For chronic exposure, a PNEC based on chronic toxicity can be extrapolated by dividing the lowest NOEC from chronic studies by an assessment factor of 10. Using the NOEC from Flippin et al. (2007) of 10 µg/L and dividing by 10, a PNEC of 1 µg/L is derived. Note the NOEC from the Brun algae study is also 10 µg/L, but is based on biomass.
To maximize the use of the available data, a Species Sensitivity Distribution (SSD) can be constructed to statistically derive a PNEC. Procedures for this are given by the EU Technical Guidance Document and the US EPA.
Since there are reliable chronic studies in 10 species spread over multiple taxa, including two fish species, a SSD was constructed to derive the HC5 of 39 µg /L. The SSD is presented in the figure. The 95% Lower Confidence Limit of the HC5 was calculated according to Aldenberg and Slob (1993), where: log HC05 = mean - k x SD where k is based on sample size; mean and SD are from natural log of (GM NOECs). The 95% LCL of the HC5 is 2.3 µg /L, and is proposed as the PNEC.
The PNEC was derived from data that covers the early life stage development of aquatic organisms (e.g., fish). Wheeler et al. (2014) demonstrated through their analysis that fish ELS NOECs are sufficient to protect against the long-term toxicity of plant protection products in fish without the need for FLC or PLC tests as a standard requirement. This specific finding for plant protection product active substances agrees with the results for other substances (e.g., Woltering 1984 and others). This indicates that the PNEC of 2 μg/L (rounded value) is protective of aquatic life. Further, due to the cyclical nature of exposure and measured environmental concentrations lower than this value, an additional level of safety is inherent in the PNEC.

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