# Has the Toxicity of Therapeutic Deep Eutectic Systems
###### Abstract
DESs can have a variety of applications including human health [26]. Biomedical potential applications of hydrophobic THEDESs based in menthol and saturated fatty acids with different chain lengths are studied by different authors, and for example, [PERSON] et al. found a huge versatility of THEDESs as an approach toward the development of many effective therapies [27]. THEDESs are used as an alternative to enhance the therapeutic action of certain antibiotics [28], and also to increase the antibacterial action [29]. [PERSON] et al. [30] showed that the production of new THEDESs involves combining terpen with anticancer properties, such as safranal, menthol, and linalool, with nonsteroidal anti-inflammatory drugs, such as ibuprofen and ketoprofen. To evaluate the therapeutic potential of these THEDESs, it is necessary to carry out the evaluation of their physicochemical properties and bioactivity. Moreover, [PERSON] et al. observed that the combination of limonene with ibuprofen as a THEDES formulation presented anticancer activities, associated with increased ibuprofen solubility [31]. Different THEDESs of ibuprofen with several terpen such as thymol and menthol were already reported. Menthol/ibuprofen (3:1) is able to increase Ibuprofen solubility, while THEDESs with thymol did not increase its solubility. Moreover, menthol and stearic acid were used to formulate a THEDES for wound healing [27]. Interestingly, it is rather promising to develop API-NADESs (Natural Deep Eutectic Solvents) formulations based on various components from Chinese herbal medicines to improve their targeted properties, such as solubility, bioavailability, stability, or fast drug delivery capacity to the target site [32]. THEDESs have been also used in the formulation of pharmaceuticals, including creams and suppositories, due to their ability to improve skin permeability or drug absorption, or even to provide controlled drug release or as an alternative strategy for drugs' delivery [33; 34; 35; 36; 37]. In some other cases, the formulation could also improve the stability of APIs and even promote a controlled release to achieve the therapeutic effect. In the work from [PERSON] et al. (2017) [38], the THEDES formed by ChCl-mandelic acid (1:2) and encapsulated in gelatin showed a fast-dissolving release profile in phosphate-buffered saline without cytotoxicity. The formulation also maintained the antibacterial effect of mandelic acid on both Gram-positive and -negative bacteria. Additionally, one THEDES based on a NADES (ChCl/ascorbic acid) and sunitinib malate as a drug was used to obtain an ion-gel system that could be used as a novel carrier for this anticancer drug. In addition, no cytotoxicity was found for the NADES mixture toward HN-5 cells [39]. The same NADES (ChCl/ascorbic acid) was also used to solubilize dexamethasone and a supercritical fluid sintering process was followed to obtain a controlled drug delivery system for this glucocorticoid with low water solubility. The authors highlighted the potential applications of this THEDES in biomaterials science beyond the pharmaceutical industry involving drugs [40]. To sum up, the potential advantages and main applications of THEDESs are collected in Table 1.  
The main objective of this paper is to gather different studies regarding the toxicity of THEDESs and to check if there is enough supporting information to confirm their safety to be used for human therapies. Previously, [PERSON] et al. carried out an exhaustive review of similar information regarding DESs [41]. Therefore, the most attention was paid on the toxicity results of THEDESs including cell lines, animal models, and human trials, as shown in Figure 1.