Cytotoxicity towards CCO cells of imidazolium ionic liquids with functionalized side chains: Preliminary QSTR modeling using regression and classification based approaches Marina Cvjetko Bubalo a , Kristina Radošević a , Višnja Gaurina Srček a , Rudra Narayan Das b , Paul Popelier c , Kunal Roy b,c,n a Laboratory for Cell Technology, Application and Biotransformations, Faculty of Food Technology and Biotechnology, University of Zagreb, Pierottijeva 6, HR-10000 Zagreb, Croatia b Drug Theoretics and Cheminformatics Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India c Manchester Institute of Biotechnology, University of Manchester, Manchester M1 7DN, United Kingdom article info Article history: Received 24 July 2014 Received in revised form 13 October 2014 Accepted 20 October 2014 Keywords: Imidazolium ionic liquids CCO cell line In vitro toxicity Quantitative structure–toxicity relationship Predictive toxicology abstract Within this work we evaluated the cytotoxicity towards the Channel Catfish Ovary (CCO) cell line of some imidazolium-based ionic liquids containing different functionalized and unsaturated side chains. The toxic effects were measured by the reduction of the WST-1 dye after 72 h exposure resulting in dose- and structure-dependent toxicities. The obtained data on cytotoxic effects of 14 different imidazolium ionic liquids in CCO cells, expressed as EC 50 values, were used in a preliminary quantitative structure–toxicity relationship (QSTR) study employing regression- and classification-based approaches. The toxicity of ILs towards CCO was chiefly related to the shape and hydrophobicity parameters of cations. A significant influence of the quantum topological molecular similarity descriptor ellipticity (ε) of the imine bond was also observed. & Elsevier Inc. All rights reserved. 1. Introduction Over the past decades, ionic liquids (ILs) have been intensively studied as a green replacement for standard volatile and flam- mable organic solvents, which is reflected in the more than 30,000 scientific papers related to their preparation, characterization, application and impact on the environment. However, it was de- monstrated that ILs were not intrinsically green (Cvjetko Bubalo et al., 2014a; Egorova and Ananikov, 2014) and could become potent water and soil contaminants if not handled properly. Con- sequently, their persistence in the environment, (bio)degradation, migration, bioaccumulation, and (eco)toxicity should be proac- tively assessed prior to their large-scale application (Cvjetko Bu- balo et al., 2014a; Pham et al., 2010). So far, toxicity studies on ILs have been conducted by performing a series of tests on bacteria (Ranke et al., 2004; Matzke et al., 2007; Ventura et al., 2012), yeast (Zhu et al., 2013), algae (Cho et al., 2008; Latala et al., 2010), ne- matode (Swatloski et al., 2004), mammals (Yu et al., 2009), plants (Matzke et al., 2007; Zhang et al., 2013; Cvjetko Bubalo et al., 2014b; Wang et al., 2009) as well as in different mammalian (Ranke et al., 2004; Stepnowski et al., 2004, Stolte et al., 2007; Wang et al., 2007) and fish cell lines (Radošević et al., 2013), where depending on the used test-system and chemical structure, ILs showed moderate to high toxicity, in general. Nevertheless, ILs present a group of exceptional chemicals with vast possible var- iations in their structure, and thus it is crucial to understand the chemical and environmental factors controlling the behavior of ILs in the environment in order to design them as environmentally benign (Cvjetko Bubalo et al., 2014a). The development of predictive chemometric models con- stitutes an essential part of the toxicity assessment of different chemicals including ILs. It helps in predicting the toxicity of un- tested compounds and it aids in deriving a rational basis for cor- relating the toxicity of chemicals with their structural attributes while reducing the number of experiments involving animals. Structure-toxicity relationship studies for ILs have already prompted scientists to develop a variety of predictive models in order to estimate the toxicity of ILs, while avoiding the costs as- sociated with the production and testing of new ILs (Luis et al., 2007, 2010; García-Lorenzo et al., 2008; Torrecilla et al., 2010; Fatemi and Izadiyan, 2011; Alvarez-Guerra and Irabien, 2011; Cho Contents lists available at ScienceDirect journal homepage: www.elsevier.com/locate/ecoenv Ecotoxicology and Environmental Safety http://dx.doi.org/10.1016/j.ecoenv.2014.10.029 0147-6513/& Elsevier Inc. All rights reserved. n Corresponding author at: Jadavpur University, Department of Pharmaceutical Technology, Drug Theoretics and Cheminformatics Laboratory, Raja S C Mullick Road, Kolkata 700032, India. Fax: þ91 33 28371078. E-mail address: kroy@pharma.jdvu.ac.in (K. Roy). Ecotoxicology and Environmental Safety 112 (2015) 22–28