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Acute Aquatic Toxicity and Biodegradability of Fluorinated Ionic Liquids Nicole S. M. Vieira, Stefan Stolte, João M. M. Araújo, Luis Paulo N. Rebelo, Ana B. Pereiro, and Marta Markiewicz ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.8b03653 • Publication Date (Web): 10 Jan 2019 Downloaded from http://pubs.acs.org on January 12, 2019

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ACS Sustainable Chemistry & Engineering

Acute Aquatic Toxicity and Biodegradability of Fluorinated Ionic Liquids Nicole S. M. Vieira†,‡, Stefan Stolte‖,§, João M. M. Araújo†, Luís Paulo N. Rebelo†, Ana B. Pereiro†,, Marta Markiewicz‖,§, †

LAQV, REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia,

Universidade Nova de Lisboa, Campus da Caparica, 2829-516 Caparica, Portugal ‡

Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa

(ITQB NOVA), Avenida da República, 2780-157 Oeiras, Portugal

‖

UFT - Centre for Environmental Research and Technology, University of Bremen,

Leobener Straße, D-28359, Bremen, Germany §

Institute of Water Chemistry, Technische Universität Dresden, Bergstraße 66, 01062

Dresden, Germany AUTHOR INFORMATION Corresponding Authors  [email protected]

(A.B. Pereiro)

ACS Paragon Plus Environment

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ACS Sustainable Chemistry & Engineering 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

 [email protected]

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(M. Markiewicz)

KEYWORDS Fluorosurfactants; Pharmaceuticals; Ecotoxicity; Aquatic Environment; Vibrio fischeri; Daphnia magna; Lemna minor; Biodegradation.


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ABSTRACT

Several novel fluorinated ionic liquids (FILs), fully miscible with water and with excellent surfactant behavior, have been studied for pharmacological applications. The use of these novel FILs as drug delivery systems can improve the bioavailability, stability, structure and efficacy of therapeutic proteins. An initial screening of toxicity in four different human cell lines indicated that some of the FILs possess low cytotoxicity. An environmental hazard assessment of these compounds, in the context of Green Pharmacy, is necessary before a pharmaceutical application takes place. In this work, ecotoxicity tests have been performed in aquatic species with different levels of biological organization (Vibrio fischeri, Daphnia magna and Lemna minor) to evaluate intrinsic hazard that these FILs might pose after being released to the aquatic environment from the human body or from industrial processes. Additionally, the biodegradability of these compounds has been evaluated using microorganisms from wastewater treatment plant.


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INTRODUCTION Pharmaceutical industry is the sector with the highest R&D investments compared to their revenues, with increasing safety standards and a need to not only show the efficacy of new drugs but to also show that they offer a significant improvement in comparison to existing therapeutics.1 Therefore, the design of new sustainable pharmaceuticals is expected to integrate lower environmental harmfulness of both products and processes as one of the screening criteria in drug development. Many novel and existing drugs are poorly soluble in water, instable in vivo, have poor pharmacokinetics/biodistribution or require delivery to the target tissue.2 To overcome these concerns, drug delivery systems (DDS) are being intensively studied to improve solubility, stability, distribution, and pharmacokinetics while limiting the side effects associated with some therapies.2-5 Fluorinated ionic liquids (FILs) are fluorosurfactants that can be a very promising drug delivery platform in biomedical applications. These compounds allow the development of stable and self-assembled structures for a nano-scale delivery system to encapsulate and protect the biomolecules (especially proteins) from enzymatic degradation prior to their delivery,5 improving their therapeutic mechanism on the target site of action. FILs based on

the

imidazolium,

pyridinium

and

cholinium

cation

conjugated

with

the

perfluorobutanesulfonate anion are fully miscible with water, show excellent surfactant behavior and preserve the activity, stability and secondary structure of a model therapeutic protein, lysozyme.5 The numerous advantages regarding the use of FILs for


4

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the development of novel pharmaceuticals are counterbalanced by the negative impacts of fluorocarbons including high bioaccumulation potential and resistance to (bio)degradation.6,7 Although the ecotoxicity of ILs has been studied for some time now, the knowledge of ecotoxicity of FILs is limited. Several studies were performed regarding the toxicity of traditional ionic liquids in different human cell lines.8-10 Only two studies, evaluate the cytotoxicity of FILs in human cell lines (Caco-2, HepG2, Ea.hy926 and HaCa-T).11,12 These studies were performed in several families of FILs based on imidazolium, pyridinium, ammonium,

cholinium

perfluorobutanesulfonate,

and

pyrrolidinium

cations

conjugated

perfluoroctanesulfonate

with

the and

bis(nonafluorobutylsulfonyl)imide anions. The results established that the compounds possessing relatively long (>6) hydrogenated or fluorinated alkyl moieties (in either the anion or the cation) were cytotoxic. It was shown that the tetrabutylammonium bromide IL is one to two orders of magnitude more toxic than tetrabutylammonium perfluorobutyl- and perfluorooctylsulfonate, respectively.11,13 On the other hand, the replacement of the long chain fluorinated anions,7 such as perfluorooctanesulfonate by short chain equivalents, such as perfluorobutanesulfonate, started in the beginning of 2000.14,15 The surfactant properties and hydro-/lipophobicity, which are essential in industrial applications, remain present in the short chain PFCs while the toxicity and bioaccumulation appear to be relatively low.14-20 However, the persistence of these


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compounds in the environment remains due to their high resistance to degradation.16,20 The ecotoxicological screening of FILs is a first step in the assessment of possible adverse biological effects in aquatic organisms. Once the structural aspects of FILs that contribute to (eco)toxicity are established, it will be possible to minimize their intrinsic environmental hazard by avoiding such molecular structures. The main purpose of this study is to screen for possible negative impacts of these compounds in the aquatic environment. To this end, studies of ecotoxicity using different aquatic species and biodegradability have been performed. Different aquatic species were chosen according to their different levels of biological organization. The compounds were tested using a luminescence inhibition test with a marine bacterium Vibrio fischeri, a 48h acute immobilization test with freshwater crustacean Daphnia magna as well as subchronic growth inhibition test with Lemna minor. Additionally, the ready biodegradability experiments were performed using manometric respirometry tests and an inoculum from wastewater treatment plant.

EXPERIMENTAL SECTION Ionic

Liquids

Synthesis

and

Characterization.

1-Ethyl-3-methylimidazolium

perfluorobutanesulfonate, [C2C1Im][C4F9SO3] (> 97 % mass fraction purity), and cholinium ((2-hydroxyethyl)trimethylammonium) perfluorobutanesulfonate, [N1112(OH)][C4F9SO3] (>


6

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97 % mass fraction purity), were supplied by IoLiTec GmbH. 1-Ethyl-3-methylimidazolium perfluoropentanoate, [C2C1Im][C4F9CO2] (> 99 % mass fraction purity), and 1-ethyl-3methylpyridinium perfluoropentanoate, [C2C1py][C4F9CO2], (> 99 % mass fraction purity), were previously synthesized and characterized in our laboratory.21,22 The

synthesis

of

cholinium

perfluoropentanoate,

[N1112(OH)][C4F9CO2],

1-(2-

hydroxyethyl)-3-methylimidazolium perfluorobutanepentanoate, [C2(OH)C1Im][C4F9CO2], and

1-(2-hydroxyethyl)-3-methylimidazolium

perfluorobutanesulfonate,

[C2(OH)C1Im][C4F9SO3], was made through the ion exchange resin method, as previously described.21,22 In this synthetic procedure, cholinium chloride ([N1112(OH)]Cl, 99% mass fraction

purity,

IoLiTec,

Heilbronn,

Germany)

and

1-(2-hydroxyethyl)-3-

methylimidazolium chloride ([C2(OH)C1Im]Cl, ≥98% mass fraction purity, Sigma-Aldrich, St. Louis, EUA) were first transformed into hydroxides using an ionic exchange column (SUPELCO AMBERLITE IRN78) in aqueous solutions. For [C2(OH)C1Im][C4F9SO3] synthesis, the aqueous solution of imidazolium hydroxide was neutralized with nonafluoro-1butanesulfonic acid (≥98% mass fraction purity, TCI, Tokyo, Japan). In the case of perfluoropentanoate based FILs, the aqueous solutions of respective hydroxides were neutralized with perfluoropentanoic acid (≥97% mass fraction purity, Fluorochem, Hadfield, UK). The excess of water and acid were eliminated by evaporation and washing, respectively, to obtain pure FILs in the final stage. All the isolated products were completely


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characterized by 1H and 19F NMR, and CHN elemental analysis to check their final purities. The 1H and

19F

NMR spectra were carried out on a Bruker AVANCE 400 spectrometer

operated at room temperature with 16 and 32 scans, respectively. Elemental analysis was done on an element analyzer (Thermo Finnigan-CE Instruments Flash EA 1112 CHNS series). Additionally, the quantitative integration of their characteristic 1H and

19F

NMR

resonance peaks elucidates the expected cation/anion correlations, using 1,4difluorobenzene (99% mass fraction purity, Alfa Aesar, Karlsruhe, Germany) as internal standard. Also, there were no peaks assigned to impurities in the 1H or 19F NMR spectra. The characterization of [N1112(OH)][C4F9CO2], 1H NMR (400 MHz, (CD3)2CO): δ 4.10 (m, 2H, OHCH2CH2N); 3.73 (t, 2H, CH2CH2N); 3.42 (s, 9H, (CH3)3N) .

19F

NMR (376 MHz,

(CD3)2CO): δ -81.96 (CF3); -114.73 (CF2CO2); -123.51 (CF3CF2CF2); -126.37 (CF3CF2). Elemental analysis calculated (found): %C 32.71 (32.43); %H 3.84 (3.79); %N 3.81 (3.52), with a standard uncertainty of ±0.1. The characterization of [C2(OH)C1Im][C4F9CO2], 1H NMR (400 MHz, (CD3)2CO): δ 9.13 (s, 1H, N=CH-N); 7.79 (s, 1H, N-CH); 7.73 (s, 1H, N-CH); 4.47 (t, 2H, CH2C1Im); 4.11 (s, 3H, CH3N); 3.96 (t, 2H, CH2CH2C1Im).

19F

NMR (376 MHz, (CD3)2CO): δ -81.84 (CF3); -115.49

(CF2CO2); -122.00 (CF3CF2CF2); -126.58 (CF3CF2). Elemental analysis calculated (found): %C 33.86 (34.05); %H 2.84 (3.03); %N 7.18 (7.02), with a standard uncertainty of ±0.2.


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The characterization of [C2(OH)C1Im][C4F9SO3], 1H NMR (400 MHz, (CD3)2CO): δ 9.07 (s, 1H, N=CH-N); 7.78 (s, 1H, N-CH); 7.74 (s, 1H, N-CH) 4.47 (t, 2H, CH2C1Im); 4.11 (s, 3H, CH3N); 3.97 (t, 2H, CH2CH2C1Im).

19F

NMR (376 MHz, (CD3)2CO): δ -81.84 (CF3); -115.50

(CF2CO2); -122.05 (CF3CF2CF2); -126.60 (CF3CF2). Elemental analysis calculated (found): %C 28.18 (27.92); %H 2.60 (2.66); %N 6.57 (6.26); %S 7.52 (7.45), with a standard uncertainty of ±0.3. All the fluorinated ionic liquids were dried under vacuum (3 × 10-2 Torr) and vigorously stirred at 313.15 K for at least 2 days, prior to use. The water content, determined by Karl Fischer titration, was less than 500 ppm. The chemical structures of the ionic liquids used in this work are presented in Table 1. Table 1. Chemical Structure and Acronyms of the Fluorinated Ionic Liquids (FILs) used in this Work. IL Designation Cholinium perfluorobutanesulfonate [N1112(OH)][C4F9SO3] Cholinium perfluoropentanoate [N1112(OH)][C4F9CO2] 1-Ethyl-3methylimidazolium perfluorobutanesulfonate [C2C1Im][C4F9SO3] 1-Ethyl-3methylimidazolium perfluoropentanoate [C2C1Im][C4F9CO2]

Chemical Structure O H3C

CH3 N+

OCH3

HO

S

CF2CF2CF2CF3

O

O H3C

CH3 N+

HO

OCH3

C

CF2CF2CF2CF3

O S

H3C

N

OO N CH3

+

CF2CF2CF2CF3

O

H3C

N

+

ON

C

CF2CF2CF2CF3

CH3


9


1-(2-hydroxyethyl)-3methylimidazolium perfluorobutanesulfonate [C2(OH)C1Im][C4F9SO3] 1-(2-hydroxyethyl)-3methylimidazolium perfluoropentanoate [C2(OH)C1Im][C4F9CO2] 1-Ethyl-3methylpyridinium perfluorobutanepentanoat e [C2C1py][C4F9CO2]

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O S

H3C

N

O-

+

CF2CF2CF2CF3

O

N

OH

O

H3C

N

O-

+

N

C

CF2CF2CF2CF3 OH

CH3

O C

O+

N

CF2CF2CF2CF3

CH3

Vibrio fischeri luminescence inhibition test. LCK 482 test kit (Dr. Lange GmbH, Duesseldorf, Germany) was used to access the toxicity of FILs to the marine luminescent bacterium Vibrio fischeri (strain: NRRL-B-11177). This test is based on the measurement of the bacteria luminescence after exposure to the test substance. A decrease in luminescence is an indicator of the toxicity of the tested compounds. To exclude pHeffects, all substances were prepared at phosphate-buffered solutions (0.02 M, pH 7.0, including 2% NaCl) and pH was measured before the test start. The assay was carried out independently at least three times for each substance with concentration levels ranging from 125 µmol L-1 - 300 mmol L-1. For each test, negative control (2% NaCl solution, phosphate-buffered) and positive control (standard solution of NaCl 7.5%) were performed. The assay was performed at 15°C using thermostats (LUMIStherm, Dr. Lange GmbH, Duesseldorf, Germany). The freeze-dried bacteria were rehydrated with the reactivation solution according to the test protocol. Then, 500µL aliquots of the bacterium


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solution were pre-incubated for 15 min at 15 °C. After the initial luminescence had been measured, 500 µL of the diluted samples were added to the bacteria and after contact time of 30 min another measurement of luminescence was performed. The relative toxicity of the samples was expressed as a percentage inhibition compared to the controls. The dose-response curves were fitted and the EC50 values were calculated as the concentration responsible for 50 % inhibition of luminescence as described below. Growth inhibition assay with Daphnia magna. The 48h acute immobilization test with the freshwater crustacean Daphnia magna was conducted using the commercially available Daphtoxkit F (MicroBioTest Incorporation, Gent, Belgium) according to OECD guideline 202.23 The assays were performed in glass vials with neonates less than 24h old at 20°C in the dark. For the test, five pre-fed young daphnids, were exposed to minimum five concentrations levels ranging from 75 - 20000 µmol L-1 of the test substance in four replicates for 48 h. Each test was repeated at least two times. Control solutions free of test samples, with only mineral medium, were tested in parallel. The number of immobilized animals was checked after 24 h and 48 h and compared with controls in order to obtain dose-response curves for each compound. The EC50 values were obtained as described below. Growth inhibition assay with Lemna minor (duckweed). This growth inhibition assay was designed to evaluate the toxicity of substances to freshwater aquatic plants (duckweed) and was performed accordingly to a modified version of the OECD guideline


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221.24 The objective of the test is to quantify substance-related effects on growth over a period of seven days based on assessments of different measurement variables (frond area is the main variable assessed, but also the total frond number and the frond color were analyzed). The Lemna minor plants were grown in open Erlenmeyer flasks in sterilized Steinberg medium (pH 5.5 ± 0.2) in a climate chamber with a constant temperature of 25 ± 2 °C under constant illumination (maximum of 6klx). Tests were performed in six-well cell culture plates, at six different concentrations levels ranging from 31.16- 3869 µmol L-1 in three replicates. Each test, contained negative controls with only medium and the positive controls with several concentrations of benzalkonium chloride and was repeated three times. The pH was measured at the beginning and at the end of each test. To start the test, one duckweed plant with three fronds was placed inside each well. The frond number, area and color were evaluated using a Scanalyzer from Lemnatec GmbH (Wuerselen, Germany) at the beginning and at the end of the test. The growth rate was calculated based on frond area and compared to controls. The EC50 values were obtained as described below. Biodegradation. Ultimate biodegradation was measured by the manometric respirometry method according to the OECD Test Guideline 301F using the automated, thermostatically controlled OxiTop® set (WTW, Weilheim, Germany).25 The activated sludge from the municipal wastewater treatment plant in Delmenhorst (Germany) was used as a source of inoculum. The flocs were allowed to settle and the remaining


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supernatant was aerated for 4-7 days prior to use to removed residual organics. The inoculum concentration was 104 cells/L as measured using Paddle test (Hach Lange, Germany). The test lasted at least 28 days and was performed in standard OECD medium supplemented with a nitrification inhibitor (allylthiourea). The solutions of target compounds were added to the test vessels to yield a biological oxygen demand of 40 mgO2L-1. Both cation and anion biodegradability potential were taken into account. Two replicates were run for each compound accompanied by two blanks and two positive controls (sodium benzoate BOD = 40 mgO2L-1). The test was repeated at least twice. Accordingly to this test, the substance could be classified as “readily biodegradable” if 60% of biodegradation is exceeded within 28 days. Data analysis. The results of each experiment were inspected for violations of quality criteria given in corresponding guidelines (e.g. mortality in controls, growth rates in controls, response in positive controls, standard deviation of response etc.). Tests which did not match the quality criteria where discarded and the test was repeated. The data of each experiment were log-normal transformed and plotted together. Subsequently probit, logit or linlogit models were fitted to obtain the EC50 value with confidence intervals using the drfit package (version 3.1.0) for R (version 3.4; http://www.rproject.org). The data was visually inspected to see if the model adequately represents the data. The LemnaTec software (LemnaLaucher version 6.4.0.19788) was used for plant phenotyping in the Lemna minor test.


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RESULTS AND DISCUSSION Ecotoxicity of Fluorinated Ionic Liquids towards Bacteria, Crustaceans and Plants a.

Structure effects on acute toxicity of different aquatic organisms. The effect

of the cation (cholinium, imidazolium and pyridinium substituted with short alkyl chains) conjugated

with

perfluorobutanesulfonate

([C4F9SO3]⁻)

or

perfluoropentanoate

([C4F9CO2]⁻) anions were studied. Furthermore, the imidazolium cations substituted with a hydroxyethyl side chain and coupled with the fluorinated anions mentioned above were also included in the test set. Three test systems were used to test ecotoxicity of these FILs including Vibrio fischeri, Lemna minor and Daphnia magna. Dose-response curves are plotted in Figures S1 to S19 of Supporting Information and the corresponding EC50 values are shown in Table 2. The EC50 values of all tested FILs to Vibrio fischeri were between 4786.3 and 37154 µmol L-1, demonstrating their very low toxicity. The EC50 values for imidazolium, hydroxylated imidazolium and cholinium perfluoropentanoates were generally higher than the same cations paired with perfluorobutanesulfonate, showing that the latter is more toxic. The introduction of the hydroxyethyl group in the side chain of the imidazolium cation decreases the overall toxicity of the compound. The EC50 values for hydroxylated imidazoliums are a factor of 2-3 higher than for imidazoliums substituted with nonfunctionalised side chains. This functionalization of the side chain with the hydroxyl in the


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cation core decreases the hydrophobicity, decreasing the toxicity to Vibrio fischeri, green algae Scenedesmus vacuolatus, and Lemna minor.26,27 A decrease of toxicity to Vibrio fischeri and Daphnia magna was also observed when an ether group was introduced into the side chain.28,29 The cholinium and imidazolium FILs show comparable toxicity toward marine bacterium. Furthermore, FILs based on the [C4F9SO3]⁻ are less toxic than [C2C1Im]+ coupled

with

the

most

commonly

used

fluoroorganic

anion,

bis(trifluoromethanesulfonyl)imide [(CF3SO2)2N]⁻ (EC50 = 844 µmol L-1).30 The EC50 values for Daphnia magna were high again proving rather low toxicity of all tested compounds. The highest EC50 values were obtained for both non-aromatic (i.e. cholinium based) FILs followed by hydroxylated imidazoliums (all EC50 values above 2700 µmol L-1). The non-functionalised imidazoliums were slightly more toxic to Daphnia magna than their hydroxylated equivalents (EC50 values within a factor of two) as it was the case in in Vibrio fischeri test system. The most toxic FIL was [C2C1py] [C4F9CO2], yet the EC50 value was still high showing generally moderate toxicity. This is in line with previous studies which established that the toxicity of imidazolium and pyridinium ILs substituted with the same side chains is generally comparable.26,31 Also in this test system the fluoroorganic anion derived from carboxylic acid is slightly less toxic than the one derived from sulfonic acid for choliniums and non-functionalised imidazoliums yet the differences are less pronounced that it was the case for Vibrio fischeri. In the case of the functionalized imidazoliums-based

FILs

the

differences

between

perfluoropentanoate

and


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perfluorosulfonate are almost negligible. These anions also seem to be less toxic than the [(CF3SO2)2N]⁻ anion which, when paired with [C2C1Im]+ cation, has the EC50 = 230 µmol L-1 for Daphnia magna.27


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Table 2. EC50 Values* for the Studied Fluorinated Ionic Liquids with 2.5-97.5% Confidence Intervals in Brackets.

FIL Designation

[N1112(OH)][C4F9SO3] [N1112(OH)][C4F9CO2] [C2C1Im][C4F9SO3]

[C2C1Im][C4F9CO2]

[C2(OH)C1Im][C4F9SO3] [C2(OH)C1Im][C4F9CO2] [C2C1py][C4F9CO2]

Bacteria

Crustacean

Vibrio fischeri

Daphnia magna

Plant Lemna minor

EC50 (µmol L-1)

EC50 (mg L-1)

EC50 (µmol L-1)

EC50 (mg L-1)

EC50 (µmol L-1)

EC50 (mg L-1)

15488

6245.1

4897.8

1974.9

n.a.

n.a.

(13490-17378)

(5439.3-7007.2)

(4897.8-n.a.)

(1974.9-n.a.)

33113

12158

5495.4

2017.7

n.a.

n.a.

(26915-39811)

(9882.5-14617)

(4786.3-7762.5)

(1757.4-2850.1)

5754.4

2360.5

812.83

333.43

512.86

210.38

(5011.9-6456.5)

(2055.9-2648.5)

(794.33-870.96)

(325.84-357.28)

(478.63562.34)

(196.34-230.68)

14125

5285.2

1071.5

400.92

645.65

241.58

(13490-14791)

(5047.3-5534.2)

(1000.0-1202.3)

(374.16-449.84)

(575.44707.95)

(215.31-264.88)

11482

4893.5

2884.0

1229.2

1380.4

588.33

(10233-13183)

(4361.4-5618.5)

(2630.3-3162.3)

(1121.0-1347.8)

(1288.2-n.a.)

(549.06-n.a.)

37154

14496

2754.2

1074.6

1318.0

514.00

(30200-44668)

(11783-17428)

(2630.3-2951.2)

(1026.2-1151.4)

(n.a.)

(n.a.)

4786.3

1843.6

316.23

121.81

549.54

211.68

(4265.2-5370.3)

(1681.4-2068.6)

(295.12-363.08)

(113.68-139.85)

(512.86575.44)

(197.55-221.65)

* The 7.5 % NaCl solution was used as a positive control in Vibrio fischeri test and the luminescence inhibition was within 40-60%; the potassium dichromate was used as reference substance for Daphnia magna with an EC50 = 1.1 (0.96-1.17) mg L-1 after 24 h exposure. This value is in accordance to OCDE guideline


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1 2 3 -1 4 202. Benzalkonium chloride was used as reference for Lemna minor test with an EC50 = 6.6 (4.5-10.2) mg L . This result is within the laboratory long term 5 range. 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 ACS Paragon Plus Environment 45 46 18 47

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Low acute toxicity of [C4F9SO3]⁻ and [C4F9CO2]⁻ anions to Daphnia magna is in accordance with literature on PFCs where the EC50 values of perfluorobutanesulfonate and perfluoropentanoate were within 6440-7301 µmol L-1 and higher than 424-467 µmol L-1, respectively.32,33 Similar trends discussed for Daphnia magna were observed in Lemna minor test system. The imidazolium based FIL with sulfonate anion ([C2C1Im][C4F9SO3]) was slightly more toxic than the one possessing the same cation but carboxylate-based anion i.e. [C2C1Im][C4F9CO2] (EC50 of 512.86 and 645.65 µmol L-1 respectively). The only pyridinium based FIL in the test set ([C2C1py][C4F9CO2]) was more toxic than imidazolium FIL containing the same cation substituents and anion ([C2C1Im][C4F9CO2]) but the difference in EC50 values was less pronounced than in case of Daphnia magna. In both Daphnia magna and Lemna minor test systems, the EC50 values obtained for hydroxylfunctionalised FILs clearly show their lower toxicity but also a reversed trend in the toxicity of the anion as compared to non-functionalised equivalents. In these cases, the [C4F9SO3]⁻ anion was less toxic than [C4F9CO2]⁻. However, the differences are small. Again the toxicitymitigating impact of the terminal hydroxyl group was reported for 1-ethyl-3methylimidazolium chlorides, where the EC50 value for Lemna minor increased from 700 to 3350 µmol L-1 when the alkyl chain was substituted for 3-hydroxypropyl.8,26,27 Furthermore, another parameter used to evaluate the effect of FILs on duckweed was the modification of fronds pigmentation. The exposure to higher concentrations of some


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FILs induced a change on the fronds pigmentation from green to light yellow / white. This discoloration, known as chlorosis, was evident for three out of seven tested FILs: [C2C1Im][C4F9SO3], [C2C1Im][C4F9CO2] and [C2(OH)C1Im][C4F9SO3] where the green pigmentation was lost at the concentrations equal or higher than 316, 630 and 2500 µmol L-1, respectively. To sum up, we have observed that: a) imidazolium FILs were marginally less toxic than pyridinium based FIL; b) carboxylate anions are less toxic than sulfonated based ones for the non-functionalised cations; c) the cation functionalization with terminal OH group reduces the overall toxicity of the compounds. The choliniums and hydroxylated imidazoliums were generally less toxic to Vibrio fischeri, Daphnia magna and Lemna minor than non-functionalised imiadazoliums and pyridinium FILs. b. Aquatic microorganism response to fluorinated ionic liquids: The “species” effect. The aquatic organisms were chosen as the main target because they are most likely to be exposed due to high water solubility of FILs. The FILs could be released to the aquatic environment after being excreted by the human body, with process effluents from industrial plants or by accidental releases. Herein, the toxicity of FILs was tested in: Vibrio fischeri bacteria; Daphnia magna crustacean; and the freshwater higher plant Lemna minor. These data complete our previous study regarding the cytotoxicity of a series of FILs in four different human cell lines.12


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The results obtained in these studies demonstrate that the gram-negative bioluminescent bacteria Vibrio fischeri are the least sensitive organism (Table 2). The EC50 values to Vibrio fischeri were generally an order of magnitude higher than the EC50 values to Daphnia magna or Lemna minor. The lower sensitivity of Vibrio fischeri compared to other species (including Daphnia magna, algae and different cell lines) was already noticed by other authors.8,29,30 This lower toxicity could be explained by the length of the exposure time (the shortest for Vibrio fischeri, the longest to Lemna minor) or the differences in cell structure.8,34 Gram-negative bacteria possess a very complex cell envelope, composed of different membrane layers, including the outer membrane, the peptidoglycan cell wall and the cytoplasmatic membrane which provide better protection against external stimuli,35 as ILs.32 The aquatic plant Lemna minor was the most sensitive species, with the only exception of [C2C1py][C4F9CO2] which had marginally higher toxicity to Daphnia magna. This together with chlorosis caused by test compounds suggests that FILs might act though a specific mode of action on plants apart from showing baseline toxicity (Figure 1). Indeed, decrease in photosynthetic pigments (chlorophyll a, chlorophyll b or carotenoids) content caused by ILs was observed before in Lemna minor36 and terrestrial plants37. This was linked to formation of reactive oxygen species.36,37


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Figure 1. Plant phenotype image (top row) and colour classified image (bottom row) of Lemna minor. Images 1A and 1B show negative control (no growth inhibition and no chlorosis), in images 2A and 2B a growth inhibition is visible but without chlorosis for [C2(OH)C1Im][C4F9CO2] at concentrations levels ranging from 630-3324 µM, in images 3A and 3B both growth inhibition and chlorosis are visible for [C2(OH)C1Im][C4F9SO3] at concentrations levels ranging from 630- 3679 µM.

c.

Acute toxicity of fluorinated ionic liquids: GHS classification. The “Globally

Harmonized System of Classification and Labelling of Chemicals (GHS)” is a voluntary system used widely around the world to assure a clear, consistent communication of hazard associated with chemicals.38 Accordingly to GHS, EC50 obtained in acute tests with Daphnia magna and Lemna minor could be used for hazard classification. The classification encompasses three categories i) the “category acute 1” labels the compounds with EC50 values at concentrations equal or lower than 1 mg L-1; ii) with “category acute 2” are those with EC50 values at concentrations between 1 and 10 mg L-1; iii) finally, the compounds that have an EC50 values between 10 and 100 mg L-1 are include in the “category acute 3”. All the EC50 values obtained in this study for FILs are higher than 100 mg L-1 which falls above the upper limit of category acute 3 (Table 2). This means that


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based on present results they do not require labelling in terms of acute aquatic hazard, however, chronic test have not been performed yet. Biodegradation of Fluorinated Ionic Liquids. As mentioned before, the microbial degradation of FILs is a key parameter in their environmental hazard assessment. In this context, the microbial degradation of all FILs included in this study (Table 1) was investigated using a test set up that determines the biodegradability based on consumption of oxygen that is used to biologically oxidise the test compound. As shown in Figure 2, the biodegradation, taking into account measurement error, was close to 0% for the imidazolium cation substituted with a short alkyl chains ([C2C1Im]+) coupled with either [C4F9SO3]⁻ or [C4F9CO2]⁻ anions (results not shown). The introduction of the hydroxyl group in the alkyl side chain of this cation does not enhance the microbial degradability (results not shown). This lack of biodegradation of short chain imidazoliums was reported before.39-41 The imidazolium ring is generally resistant to degradation and there is a critical length of alkyl substituent (C>6) when the degradation of the chain occurs.39-41


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Figure 2. Ultimate biodegradability of [C2C1Im][C4F9SO3], [C2C1Im][C4F9CO2], [C2(OH)C1Im][C4F9SO3] and [C2(OH)C1Im][C4F9CO2] measured during 28 days. Four replicates obtained in two independent tests are shown.

However, for the pyridinium cation ([C2C1py]+), the biodegradation reached between 28 and 45% after 28 days (Figure 3). Relatively high variability between independent tests was observed while the maximum degradation achieved within one test was within 4-6% proving test valid.42 The degradation of pyridinium based ILs by the microorganisms from activated sludge has been subject of study by several groups40,43,44 where quite different results were attributed to different composition of microbial inoculum. The pyridinium based

ILs

substituted

with

butyl-

and

longer

chains

are

susceptible

to

biodegradation40,44,45 whereas those substituted with shorter alkyl chains were shown to


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be resistant to biodegradation46 unless pre-adapted inoculum is used.40,43,47 According to these works, the biodegradation of short chained pyridiniums based ILs is limited to the alkyl side chain and does not affect the pyridinium ring45 whereas in case of octylsubstituted pyridinium ring a full mineralization was achieved.40,44 The cation degradation through the hydroxylation of pyridinium ring or oxidation of the alkyl side chain was suggested.44,47 The biodegradation of cholinium based FILs [N1112(OH)][C4F9SO3] and [N1112(OH)][C4F9CO2] amounted to 46-56% and 46-68%, respectively (Figure 3). These results were expected because cholinium cation is a biogenic molecule and a capacity for its degradation evolved throughout the time.39,48,49 The fluorinated anions are highly resistance to biodegradation.14,16,50,51 In case of cholinium FILs over 75% of oxidizable carbon is in the cation. The fact that in none of the cases more than 70% degradation was achieved proves that it was indeed only the cation that underwent degradation.


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Figure 3. Ultimate biodegradability of [N1112(OH)][C4F9SO3] (top) and [N1112(OH)][C4F9CO2] (middle) and [C2C1py][C4F9CO2] (bottom) measured during 28 days. Four replicates obtained in two independent tests are shown.

To sum up, a highest degradability was observed for the cholinium followed by pyridinium cation (Figure 3). However, the imidazolium based FILs showed negligible biodegradation (Figure 2). The results of biodegradation assays vary between studies and


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are often dependent on the experimental conditions e.g. composition of microbial community, biomass content, adaptation etc.40,44,46Although some positive results were achieved, they were associated with the degradation of the cation, and the anion resistance to biodegradation remains a problem to be solved. CONCLUSIONS The environmental assessment of fluorinated ionic liquids (FILs) is a critical step for their industrial application, including the biopharmaceutical industry where they have showed to be very promising. The acute ecotoxicity screening tests made herein have provided new insights into structure-toxicity patterns for this fluorinated ionic liquid family. The FILs studied in this work exhibit distinct response according to the different biological systems they are exposed to. However, none of them can be considered toxic under the tested conditions of the aquatic species involved. These FILs hardly have any impact on the gram-negative bacteria Vibrio fischeri, causing toxic effects in concentrations higher than 1.8 g L-1. Similarly, in Daphnia magna and Lemna minor test systems significant toxic effects were observed well above 100 mg L-1. These results were obtained with acute toxicity tests and the long-term effects of the compounds were not evaluated. The structure-activity conclusions taken from this work allow us to expect a lower toxicity associated to cholinium and hydroxylated imidazolium based FILs in comparison to non-functionalised imidazoliums and pyridinium-based ones. Additionally, perfluoropentanoates seem to be slightly less toxic than perfluorobutanesulfonates.


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In this work, the short chain imidazolium based FILs have shown not to be biodegradable, and the incorporation of hydroxyl groups did not have a significant impact on the results achieved. For these compounds, another route of degradation or separation processes must be applied in order to remove them from the waste streams. Choliniumand pyridinium-based FILs are biodegraded to a significant extent but the biodegradation seems to be limited to the cation. Thus, the biodegradation of the fluorinated anions seems unlikely and the concern regarding their persistence remains. This also shows that it is imperative for green design to make both the anion and the cation for highly biodegradable. Despite their relatively low ecotoxicity FILs cannot be perceived as environmentally acceptable due to resistance to biotic and abiotic degradation. In this regard, limiting exposure through preventing release and/or removal from waste streams seem to be the options for mitigating their impacts. On the other hand, their application in the biomedical field offers greater advantage over traditional surfactants and compounds used nowadays in the pharmaceutical industry mostly due to their greater surfactant and solubilisation power. Furthermore, their application as drug delivery systems leads to a reduction of the therapeutic drug dosage, which might reduce the emission of drug and transformation products into the environment.


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ASSOCIATED CONTENT Supporting Information: The Supporting Information is available free of charge on the ACS Publications website. Supplementary figures representing Vibrio fischeri viability, Daphnia magna and Lemna minor dose-response curve in the presence of several concentrations of FILs in study. AUTHOR INFORMATION Corresponding Author * Phone: (+351) 212948318; Fax: (+351) 212948550; E-mail: [email protected] (A.B. Pereiro). * Phone: +49 (351) 463-33872; Fax: +49 (351) 463-37271; E-mail: [email protected] (M. Markiewicz). Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Funding Sources Besides, the authors would like to thank the financial support from FCT/MEC (Portugal), through grant SFRH/BD/100563/2014

(N.S.M.V.) and “Investigador FCT

2014”

(IF/00190/2014 to A.B.P and IF/00210/2014 to J.M.M.A.), and projects PTDC/QEQEPR/5841/2014, PTDC/QEQ-FTT/3289/2014, IF/00210/2014/CP1244/CT0003. This work was also supported by the Associate Laboratory for Green Chemistry LAQV (financed by


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national funds from FCT/MEC (UID/QUI/50006/ 2013) and co-financed by the ERDF under the PT2020 Partnership Agreement (POCI-01-0145-FEDER - 007265). Financial support was also obtained through the STSM-CM1206-151216-081721 COST Action. The authors would also like to acknowledge the financial support of the University of Bremen and the European Union FP7 COFUND within Marie Curie Actions BremenTrac Program (grant agreement No.600411) and the “M8 Postdoc-Initiative PLUS”, funded by the German Excellence Initiative. Notes The authors declare no competing financial interest. ACKNOWLEDGMENT The authors of the work want to thank the members of the UFT team, U. Bottin-Weber and S. Bemowsky for their collaboration in biodegradation tests and lab work.


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Insert Table of Contents Graphic and Synopsis Here

Fluorinated ionic liquids with low acute toxicity and some biodegradability represent an advantage on the development of new “green” pharmaceuticals.


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73x47mm (150 x 150 DPI)


Acute Aquatic Toxicity and Biodegradability of ... - ACS Publications

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