**5. Conclusions**

Elemental impurities in medicinal products have to be controlled within safety limits with different guidelines and normatives being useful from a pharmaceutical quality perspective. The essential role of clay minerals in drug products and cosmetics is widely known. Nanoclay/natural spring water hydrogels have been prepared by mixing a sepiolite and a palygorskite with local spring water (Alicún de las Torres, Granada, Spain). Clay hydrogels are traditionally used in balneotherapy or as natural cosmetics (masks, shampoos, etc.). Since these formulations are intended to establish an intimate contact with the skin (either healthy, sensitive, or damaged skin) their composition is of high importance in terms of safety. In this study, special attention has been paid to the presence of heavy metals and other hazardous elements. As expected, pristine materials possessed a wide variety of hazardous elements such as Cd, Pb, or P, among others. Since these elements are specifically forbidden in cosmetics according to the European Regulation (EC 1223/2009), pristine materials do not accomplish cosmetic regulations on their own. Nonetheless, the presence of certain substances in a cosmetic does not imply that they are able to be absorbed or enter in contact with the skin. In order to discern the potential bioavailability of these elements, their mobility was evaluated by using Franz cells in vitro tests. Among all the specifically forbidden elements in cosmetics, only As and Cd were detected as mobile, though in very low amounts. Their mobility was so low that, taking into account the corresponding PDE for the parenteral route and assuming 100% of bioavailability through the skin, the calculated safe doses were approximately 1 kg of hydrogel per day. In conclusion, the present study demonstrates that the composition and nature of the solid phases of the hydrogel determine the mobility of the elements. Legally speaking, the mobility of As and Cd could hinder the authorization of ALIPS9 and ALIG30 hydrogels as cosmetic products. Nonetheless, there is no sufficient evidence to confirm that the presence of these elements is detrimental to their safety and, though further studies are still necessary, ALIPS9 and ALIG30 hydrogels could be used in practice. Finally, it is worth to mention that, despite that ALIG30 showed higher ability to reduce the elements mobility, the ALIPS9 hydrogel would be easier to authorize as a medicine or cosmetic, since the mobility of As and Cd in this hydrogel was minimum or absent. Future perspectives of this particular study include the assessment of the percutaneous mobility of the elements (bioavailability) both in vitro and in vivo. These kinds of studies would help to better define the best techniques to apply fibrous clay-based hydrogels to maximize benefits by minimizing the risks.

**Author Contributions:** Data curation, F.G.-V.; Funding acquisition, P.C. and C.V.; Investigation, F.G.-V.; Methodology, R.S.-E.; Supervision, C.V.; Writing–original draft, F.G.-V.; Writing–review & editing, R.S.-E., A.B.-S., L.P. and C.V. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by Ministerio de Ciencia e Innovación, CGL2016–80833-R; Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía, P18-RT-3786 and Ministerio de Educación, Cultura y Deporte, who awarded a predoctoral grant (FPU15/01577).

**Acknowledgments:** This project was supported by the Spanish research group CTS-946. Technical support was provided by the CIC (Centro de Instrumentación Científica, University of Granada) and the IACT (Instituto Andaluz de Ciencias de la Tierra, CSIS-UGR). Special thanks to TOLSA group (Madrid), who kindly gifted clay minerals samples, and Alicún de las Torres thermal station, who provided spring water samples for the study.

**Conflicts of Interest:** The authors declare no conflict of interest.
