*Article* **Safety of Nanoclay**/**Spring Water Hydrogels: Assessment and Mobility of Hazardous Elements**

**Fátima García-Villén 1, Rita Sánchez-Espejo 2, Ana Borrego-Sánchez 2, Pilar Cerezo 1, Luana Perioli <sup>3</sup> and César Viseras 1,2,\***


Received: 16 July 2020; Accepted: 7 August 2020; Published: 12 August 2020

**Abstract:** The presence of impurities in medicinal products have to be controlled within safety limits from a pharmaceutical quality perspective. This matter is of special significance for those countries and regions where the directives, guidelines, or legislations, which prescribe the rules for the application of some products is quite selective or incomplete. Clay-based hydrogels are quite an example of this matter since they are topically administered, but, in some regions, they are not subjected to well-defined legal regulations. Since hydrogels establish an intimate contact with the skin, hazardous elements present in the ingredients could potentially be bioavailable and compromise their safety. The elemental composition and mobility of elements present in two hydrogels have been assessed. Sepiolite, palygorskite, and natural spring water were used as ingredients. The release of a particular element mainly depends on its position in the structure of the hydrogels, not only on its concentration in each ingredient. As a general trend, elements' mobility reduced with time. Among the most dangerous elements, whose presence in cosmetics is strictly forbidden by European legal regulations, As and Cd were mobile, although in very low amounts (0.1 and 0.2 μg/100 g of hydrogel, respectively). That is, assuming 100% bioavailability, the studied hydrogels would be completely safe at normal doses. Although there is no sufficient evidence to confirm that their presence is detrimental to hydrogels safety, legally speaking, their mobility could hinder the authorization of these hydrogels as medicines or cosmetics. In conclusion, the present study demonstrates that hydrogels prepared with sepiolite, palygorskite, and Alicún spring water could be topically applied without major intoxication risks.

**Keywords:** heavy metal; hazardous element; element mobility; clay minerals; spring water; hydrogel; toxicity; sepiolite; palygorskite

#### **1. Introduction**

The concentration and bioavailability of impurities such as hazardous elements in both health products and medicines is a main preformulation concern during their development. Different health care products must comply with specific normatives and guidelines, depending on the administration route, and most of the times, on the region or country in which they are written and applied. It is generally accepted that levels of elemental impurities below toxicity thresholds could be considered as safe, with diverse limits depending on the consulted normative. In Canada, natural health products that do not require a medical prescription, are included in a guide in which heavy metals (Pb, As, Cd, Hg, and Sb, among others) are banned or limited to a maximum amount, in accordance with

the administration route [1]. In the USA, similar health products fail into FDA legislation, which only considers Hg as a forbidden element and limits the Pb concentration [2]. On the other hand, European cosmetic legislation is much more detailed and restrictive regarding the presence of elemental impurities [3].

Similar health products may also be considered into different categories depending on the country. The boundaries between medicinal products, natural health care products, cosmetics, and others, are not internationally normalized, even if generally accepted definitions have been achieved. In fact, the absence of clear boundaries made it necessary to address some products on a case-by-case basis. Particularly interesting is the cosmetic category, in which the presence of some ingredients, their origin, the administration route, and the scope of the product could raise doubts about their classification. A manual on the scope of the application of the cosmetics regulation EC 1223/2009 has been published by the working group on cosmetic products in order to shed some light on this matter [4]. The global cosmetics market have grown by an estimated 5.25% in 2019 [5], and, due to this continuous growth, the attention is being increasingly focused on the quality and safety of these products. Cosmetics are, according to the European Council Directive 2003/15/EC and the US Food Drug and Cosmetic Act, those products or mixtures of substances prepared and destined to be applied in different parts of the human body in order to clean, protect, maintain them in good conditions, improve their aspect, or relieve/eliminate body odors [6,7]. It has been recognized and demonstrated that, although cosmetics are intended to be applied on the surface of the body or mucous membranes, they may not remain there exclusively, since some topically applied substances may penetrate through the skin [8–10]. This fact is more pronounced for those cosmetics which are intended to remain at their application site for several hours or days, without subsequent rinse or wash. The European Union established a Regulation on Cosmetic Products (1223/2009) where it states that "cosmetic products should be safe under normal or reasonably foreseeable conditions of use. In particular, a risk-benefit reasoning should not justify a risk to human health" [3]. According to the European legislation, all cosmetic products should be subjected to safety assessments, taking into consideration the toxicology of all the ingredients used, as well as their chemical structure and their potential to produce local and systemic side effects.

The use of clay minerals in health care comes from prehistoric times, as reviewed in various paperwork and databases [11–15]. Some properties of these minerals have made them one of the most frequently used materials in pharmaceutical formulations and cosmetics, due to both their potential therapeutic activities and their useful properties as excipients. These features depend on colloidal dimensions and high surface areas of clay minerals, which give rise to optimal rheological and sorption capacities [13,16,17]. Kaolin, talc, smectites (montmorillonite and saponite), and fibrous clays (palygorskite and sepiolite) are some of the clay minerals most used in pharmacy. Hydrotherapy, and more particularly, balneotherapy, is one of the most frequent uses of clay minerals from a traditional and natural point of view. Clay minerals are used to prepare semisolid suspensions (frequently known as thermal muds or peloids) after the interposition of clays with spring waters, thus forming a nanoclay/spring water hydrogel. That is, thermal muds are semisolid, topical, natural medicinal hydrogels prepared by the interposition of organic and inorganic solids in mineral–medicinal water [11].

On the view of the uses and properties of these clay-based hydrogels, they could be considered as cosmetics with skin-care functions such as cleansing, degreasing, exfoliating, hydrating, invigorating, and firming activities [18–20]. These clay-based products could also be considered as medicinal products, as they have demonstrated activities against dermatological affections such as psoriasis [21–23], atopic dermatitis, vitiligo, eczemas, seborrhoeic dermatitis, fungal infections, or acne have also been treated by clay/spring water hydrogels [24–28]. Moreover, in view of the current Covid-19 worldwide state of emergency, Masiero et al. [29] have pointed out the already demonstrated positive effects of balneotherapy and thermal muds over the human immune system. Therefore, according to the guidelines of the borderline products manual [4], these formulations could fall either in the cosmetic or in the medicine category. Nonetheless, they are usually prepared in thermal stations, without a deep characterization of their therapeutical functions, activities, safety, or quality control. This unclear

boundary between cosmetic and medical products showed by thermal muds, justifies the necessity of a harmonized regulation that compel for a full characterization of these products. Either way, since clay-based hydrogel formulations are intended to be applied over the skin (either health, ill, or injured skin), safety assessments should be one of the main milestones to be accomplished.

A remarkable feature of materials such as clays is the wide spectrum of mineralogical and chemical composition they have, something that is inevitable when it comes to natural products, most of the time accompanied by other naturally-associated mineral phases. Even if nanoclay/spring water hydrogels (thermal muds) are not legally considered as cosmetics or medicines and, therefore, they are not subjected to any kind of compulsory regulation; their accomplishment would highlight their quality constancy attributes and safety. The use of pharmaceutical-grade minerals in the preparation of thermal muds would guarantee the compositional safety of the gel-like system. In this regard, the chemical composition of the substances present in the formulation is crucial, since hazardous elements such as heavy metals and other elements are prohibited or limited in cosmetic products by different regulations. For instance, the ICH Harmonized Guideline for elemental impurities Q3D(R1) [30] published by the European Medicines Agency and Regulation No 1223/2009, European Parliament [3] are some of the regulations in which the discussion of this paperwork will be based. The safety assessment of the elements, such as heavy metals in cosmetics should start from the knowledge of the type and concentration of ingredients contained in the product in order to evaluate their potential intrinsic hazard [31]. The next step would include the analysis and studies of the mobility of those elements, either beneficial or harmful, in order to understand the potential biological and therapeutical effects of the formulation. This is especially important when it comes to "technically unavoidable" elements.

Recently, sepiolite and palygorskite (two inorganic excipients mainly composed of clay minerals) were mixed with natural spring water to prepare hydrogels intended for topical application. In previous studies, these excipients have demonstrated remarkable purity in terms of mineralogical composition (> 92% and > 58% of sepiolite and palygorksite richness, respectively) and quality performance [32]. Moreover, these very same hydrogels have also proved to possess wound healing effects.

The aim of this paper was to prepare, characterize, and address the elemental composition of nanoclay/spring water hydrogels made of sepiolite and palygorskite clay minerals and natural spring water. Since the present hydrogels are intended to be applied over potentially damaged or wounded skin, the mobility of their elements was also characterized. The final objective of this study was to assess the safety attributes of these formulations on the basis of the content and bioavailability of the elemental impurities.
