Toxicology12


Although the information about physical, thermodynamic, kinetic or engineering data had been extended continuously, only little data with regard to the toxicity and ecotoxicity of ionic liquids have been available until now.
The “green character” of ionic liquids has usually been justified with their negligible vapour pressure, but even if ionic liquids will not evaporate and will not contribute to air pollution most of them are water soluble and might enter the environment by this path (e.g. accidental spills, effluents). Until now we do not know what the consequences are in these cases.

(Eco)Toxicological studies' results


Methodology
Studies performed
Conclusions

Methodology

In general there are different ways to approach the question of toxicity.

  • On the one side properties as (eco)toxicity, metabolism and degradability of ionic liquids could be discussed considering the chemical structures and using the knowledge on Structure-Activity-Relationships (T-SAR, QSAR) or Structure-Property-Correlations.
  • On the other side (eco)toxicological test methods will be always necessary to corroborate these working hypothesis and to get information about the potential effects of new compounds in complex systems which can be predicted only with great uncertainty.

Continuous interaction of both approaches result in a mutual optimisation process.

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Studies performed
  • Referring to their chemical structure Wasserscheid et al. (2002) pointed out that in the case of ionic liquids consisting of halogen containing anions with poor stability in water, toxic and corrosive species such as HF or HCl might be liberated. Therefore they suggest the use of halogen-free and relatively hydrolysis-stable anions such as octylsulfate-compounds.
  • Gathergood et al. (2004) synthesised ionic liquids with functionalised side chains. These modifications should allow enzymatic hydrolysis. Using the OECD - “Closed Bottle Test” an increase in biodegradability could be shown.
  • Stock et al. (2004) presented initial results on molecular toxicity of ionic liquids with the acetylcholinesterase inhibition assay using the purified enzyme from electric eel (Electrophorus electricus). The results indicate that longer alkyl chain length (position R2) of imidazolium ionic liquids resulted in a stronger inhibition of the enzyme. Furthermore the strongest inhibition was obtained with ionic liquids containing positively charged nitrogen (pyridinium and imidazolium). The ionic liquids based on imidazolium were slightly less inhibitory and the phosphonium compounds showed the smallest inhibition potential.
  • Other studies showed that in certain cases ionic liquids might even be used as reaction media for enzymatic reactions or other biotransformations. For example, lipases are active in ionic liquids containing BF4 or PF6 anions and higher yields in respect to biocatalysis could be realised due to better enzyme stability, substrate and/or product selectivity and suppression of side reactions. (Schöfer et al. 2001, Kragl et al 2002).
  • The antimicrobial activity of a series of 3-alkoxymethyl-1-methylimidazolium salts of Cl-, BF4- and PF6- on different bacteria (Cocci, rods) and fungi had been tested by Pernak et al. (2002). The results showed that elongation of the alkyl chain length in the alkoxymethyl substituent increased the antimicrobial activity. Further the antimicrobial activity had not been affected by the type of anion. Ranke et al. (2004) exposed the marine bacterium Vibrio fischeri to different concentrations of alkylimidazolium salts of BF4-, PF6-, o Cl- and Br-. The inhibition of luminescence as well increased with increasing n-alkyl chain length in R2-position but no systematic influence of the anion could be determined.
  • Higher loss of cell viability with increasing chain length of alkyimidazolium ionic liquids had been also observed using mammalian cells (IPC 81 leukemia cells, C6 glioma cells) (Ranke et al. 2004).
  • Even experiments with the soil nematode Caenorhabditis elegans showed that lethality of these organisms increased in the presence of alkylimidazolium salts of Cl- with increasing alkyl chain length (Swatlowski et al. 2004).
  • Acute toxicity studies are reported for [3-hexyloxymethyl-1-methylimidazolium][BF4-]: an LD50 = 1400 mg/kg and 1370 mg/kg, for male and female rats, respectively, are reported. 4


  • At the University of Notre Dame (IN, USA) research in respect to ecological impacts on aquatic ecosystems has already commenced (see below).

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    IL's impact on aquatic ecosystems 16

    The impact ionic liquids have on aquatic ecosystems is particularly important, given their non-volatile nature and mild to high solubility in water of some of them.
    A research performed in collaboration with Prof. Joan Brennecke at the University of Notre Dame (IN, USA) in 2004 provides the LC50 levels for two imidazolium-based ionic liquids with Daphnia magna.
    Daphnia are a common fresh water crustaceans. They are filter feeders, and are at the base of the aquatic foodchain. Their response to ionic liquids is therefore crucial for assessing how these new solvents will impact an environmental ecosystem.

Image of a water flea (Daphnia magna)

Image of a water flea (Daphnia magna)

The following LC50 values were obtained for 1-n-butyl-3-methylimidazolium cations with PF6 and BF4 anions:

Table: LC50 values for 1-n-butyl-3-methylimidazolium cations with PF6 and BF4 anions

As can be seen, these two ionic liquids are about as toxic to Daphnia as benzene, and are far more toxic than acetone.

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Conclusions

The first results of (eco)toxicological effects of ionic liquids indicate that due to the structure of the compounds similar trends might occur in test systems of different biological complexity (e.g. enzymes, micro organisms, organisms) and with different endpoints (e.g. lethality, reproduction) although the absolute effect levels might be distinct.
These corresponding effects might be explained with the more lipophilic properties of longer alkyl chains and the similarity of imidazolium compounds to cationic surfactants. Cationic surfactants are known to increase membrane permeability and therefore cause narcotic effects with increasing chain length (Cross, 1994).

First results give reason to be optimistic that with increasing data of (eco-) toxicological properties of selected ionic liquids it might be possible to reduce the complexity of chemical structures of ionic liquids which could be synthesised by chemists by means of theoretical assessment of possible biological activities with help of T-SAR prior to synthesis.

At least it should be mentioned that for all (eco)toxicological assays attention has to be paid to the purity of the ionic liquids used. Otherwise side effects of substances which had been used in access during the synthesizing or following purification processes (Swatloski et al. 2004) cannot be excluded. Therefore different authors (Swatloski et al. 2004, Stepnowski et al. 2003) attached significant importance to proper analysing techniques.12

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