## 4 Conclusions and Future Perspective  
The toxicity of a wide variety of DESs has been evaluated. Different biomodels have been used for this purpose, and in vitro studies have been carried out to a higher extent than in vivo studies. In general, several key factors have been identified as being relevant to the cytotoxic effects of some DESs, such as the selection of different HABs or HBDs, the presence of organic acids as HBDs (pH alteration), the molar ratios of the components, the occurrence of synergistic toxicity, and the incorporation of components that alter metabolic pathways or viscosity levels. Fewer studies have been conducted using in vivo models, and more such studies would be an important step for the future development of DESs and their possible applications in the health field.  
Moreover, different sensitivities of diverse biomodels have been found in ecotoxicity studies of DESs. The composition of DESs (e.g., HBA/HBD components or the ability to cross cell barriers, among others) also influences ecotoxicity results. It can be highlighted that the individual toxicity of the initial components cannot be used as a predictive factor of DES ecotoxicity. Nevertheless, the starting materials are indicative of the biodegradability properties of the final DES.  
DESs are still promising solvents with many applications, but their safety should be deeply checked prior to their generalized use. A lack of predictive methods for (eco)toxicity behavior has also been identified. As mentioned, the large number of possible combinationsof DES components makes it difficult to characterize and generalize their properties. Future investigations should address this problem. A comprehensive database for the (eco)toxicological properties of DESs, covering several endpoints and as many HBA/HBD combinations as possible, is needed as a first step. Secondly, computational predictive methods must be developed, supporting the variability of components of the mixtures and different prediction conditions.  
Conceptualization, B.G., L.L., M.P.R., C.B.G.; formal analysis, M.P.R., C.B.G., B.G., J.C., E.S., M.P.G., D.E. and L.L.; methodology: L.L., E.S., J.C., M.P.G. and D.E.; writing--original draft preparation, M.P.R., C.B.G., B.G., J.C., E.S., M.P.G., D.E. and L.L.; writing--review and editing, B.G. and L.L.; investigation, M.P.R., C.B.G., B.G., J.C., E.S., M.P.G., D.E. and L.L.; visualization, E.S., J.C., D.E. and M.P.G.; supervision, L.L.; funding acquisition, L.L. and B.G. All authors have read and agreed to the published version of the manuscript.  
Gobierno de Aragon E31_17R, EEE53 SL, Pinares de Venecia Division Energetica, Brial (ENATICA), Novalti, Banco Sabadell, Industrias Quimicas del Ebro.  
Not applicable.  
The PLATON research group acknowledges financial support from the Gobierno de Aragon and the Fondo Social Europeo \"Construyendo Europa desde Aragon\" E31_17R. Furthermore, we thank EEE53 SL and the business groups Pinares de Venecia Division Energetica and Brial (ENATICA) for their support. Both business groups are committed to sustainable development through respect for the environment. [PERSON], [PERSON], [PERSON], and [PERSON] thank Novalti, Banco Sabadell, and Industrias Quimicas del Ebro for their financial support.  
Authors declare no conflict of interest in the results of this work.