Ranke and co-workers are pioneers in cytotoxic evaluation of ILs. Their first study of cytotoxicity of ILs was reported in 2002 and concerned 1-butyl-3-methylimi- dazolium chloride [164]. J774A.1 macrophage cells were used and the authors determined the LC-50 (lethal concentration leaving 50 % cells alive): 0.50 mg. mL-1 after 48 h of incubation. They also showed that an augmentation of the incubation time increases the cytotoxicity of BmimCl. These results highlighted the importance of wider evaluations of ILs cytotoxicities.

Jastorff et al. proposed a SAR study based on the alkylimidazolium scaffold. They showed that long alkyl chains increase the global toxicity of imidazoliums (evaluation on IPC-81 leukemia cell lines) [44]. The year after, the same team proposed a detailed biological study of methyl — and ethylimidazoliums on IPC-81 (leukemia cells) and C6 (glioma cells) rat cell lines [151]. Again, they observed that long alkyl chains increase toxicity against cell lines involved. In this case, the anion (here PF6~, BF4~ and Br~) seems to have a few influence whereas another study published by Stepnowski et al. showed that the anion bulk, especially NTf2~, has a preponderant role in toxicity towards HeLa cell lines [165]. These results involved that the cytotoxicity of ILs depended on several parameters: IL structure, concen­trations and cell lines To rationalize the cytotoxic behavior of alkylimidazoliums, Ranke’s team studied the cellular distribution of some ILs and correlated cytotox­icity and lipophilicity [150,162,166]. Indeed, most hydrophobic ILs are more toxic and exhibit higher cellular sorption (C8MimBF4 > C6MimBF4 > C4MimBF4). C10MimBF4 was too toxic and further evaluations were not purchased. After HPLC analysis, they determined cellular distribution (~80 % in cytosol, ~12 % in membrane and ~8 % in nucleus). It is commonly assumed that cytotoxicity of ILs is partially due to interactions between ILs and cell lipidic membranes [167].

On another hand, this same team demonstrated that lipophilic properties of the anion side chains and his chemical stability are widely involved in cytotoxicity but the anions tested do not exhibit intrinsic cytotoxicity towards IPC-81 cell lines [168].

Another group investigated cytotoxicity of ILs. Their studies based on varied ILs (pyrrolidiniums, piperidiniums, imidazoliums…) showed the same tendencies (longer alkyl chains involve higher cytotoxicities) and pyridiniums seems to be more toxic than other ILs [169]. They also showed that functionalized ILs (ethers,…) exhibit significantly lower cytotoxicities [170].

Several exhaustive reports were published in 2010 and 2011 and summarize all known studies concerning cytotoxicity of ILs towards mammalian cell lines (HeLa, CaCo-2, IPC-81, HT-29, C6, MCF-7, NCI60, V79). They confirmed the interdependence between lipophilicity, structure, concentration and cytotoxicity [110, 142, 171]. About 230 ILs with various structures were evaluated on IPC-81 (mammalian cell lines derived from a model of acute myelogenic leukemia) and a QSTR profile was established, confirming the tendencies previously mentioned [172]. Some results are summarized in the next table (see Table 12.3) [162, 172].

However, cytotoxic potential of ILs is a crucial parameter to develop industrial processes, it is not a latent obstacle. For example, some pharmaceuticals (e. g. lidocaine) have been grafted on ILs to increase solubility or biodisponibility [173, 174]. In the aim to set up industrial applications, moreover in pharmaceu­tical industry, establishing cytotoxic profile of ILs is necessary and will represent an important field of search for the future.