Introduction
According to the European Cosmetic Regulation 1223/2009/EC, the responsibility for the safety and legal compliance of cosmetics is with the “Responsible Person” (RP) (Regulation No.1223/20, 21/12/
2009). The latter can be a natural or legal person, established in the EU, but is in most cases the manufacturer or importer. The RP must take care that the cosmetic product under consideration is safe for human health when used under normal or foreseeable conditions of use (Regulation No. 1223/20, 21/12/2009). This is done through safety assessment, performed by a qualified safety assessor, and being an integral part of the product information file (PIF) of that particular product. Impurities or traces present in the composing ingredients and raw materials need to be stated in the PIF, along with their characterization and concentration. They are, however, not considered as ingredients and must not be labeled on the product. In the Notes of GuidanceoftheScientificCommitteeonConsumerSafety(SCCS), it is further clarified that the RP must ensure that neither other impurities nor increases in the identified impurities are present in the representative commercial material (SCCS’s Notes of Guidance). This can be realized by monitoring all different batches. In case impurities come from their presence in a natural substance, it still needs to be demonstrated that the cosmetic product, containing these impurities, does not pose a threat to the health of the consumer. In any case, it must be shown that the quantities of the
impurities are as low as possible and technically unavoidable (Regulation No. 1223/20, 21/12/2009).
As risk assessment of impurities present in cosmetics may be a difficult exercise, the case of Dead Sea mud is taken here as an example of a natural material that may contain, because of its natural origin, traces of metals such as nickel and chrome. It further needs to be considered that due to human industrial activities and environmental pollution, these concentrations could potentially increase over time.
Since ancient times, Dead Sea mineral mud has been used as well for health reasons(atopic or psoriatic skin, rheumatic patients) as for beauty purposes (Halevy and Sukenik, 1998; Hodak et al., 2003; Moses et al., 2006). The mineral-rich mud is harvested from lakes’ banks and is topically applied either as warm relaxing mudpacks at local resorts or marketed worldwide after industrial processing, mixing, and filtering (Halevy and Sukenik,1998; Hodak et al., 2003; Moses et al., 2006; Ma’or et al., 2006; Abdel-Fattah and
Pingitore, 2009). One to 4 packs are used per week, usually for a limited time period. In skin care cosmetics, it may be present as a natural humectant, but it also has protective effects against UV-B-induced stress (Ma’or et al., 1996; Ma’or, 2008; Portugal-Cohen et al., 2009). Mineral mud has also been reported to display some anti-microbial properties (Ma’or et al., 2006). the drainage pattern. The sample density was about 1 sample per 1 km2.Around1kgsamplesweretakenanddried,splitandsievedto
a final size of <0.15 mm, and this fraction was analyzed for major and trace elements by inductively coupled plasma mass spectrometry (ICP-MS), used in kinetic energy discrimination mode (KED). The Dead Sea mineral mud (dry weight 77.5% weight to weight (w/w)) was analyzed by inductively coupled plasma atomic emission spectrometry (ICP-AES) and ICP-MS as described earlier (Kafri et al., 2002). The samples were decomposed by sintering with sodium peroxide, followed by dissolution in nitric acid.
Results
3.1. Nickel and chromium content in crude and commercial Dead Sea mud Collected samples, commercially available mud bags, and interstitial water from both preparations were analyzed for their Cr- and Ni-contents. Their levels are shown in Table 1.
Table 1
Ni-and Cr concentrations in crude and commercial Dead Sea mud.
| metals | (Ma’or et al., | (Abdel-Fattah and | mud pack Israel | (Abdel-Fattah and Pingitore, | Israel/Jordan (Abdel-Fattah and | mud pack Israel/Jordan (Abdel- |
| 2006) n ¼ 3 | Pingitore, 2009) n ¼ 4 | (*) n ¼ 1 | 2009) n ¼ 3 | Pingitore, 2009) | Fattah and Pingitore, 2009) | |
| Ni | 0.0040 | 0.0023 | 0.0017 | 0.0014 | 0.0000028 | 0.000008 |
| Cr | 0.0075 | 0.0038 | 0.0032 | 0.0025 | <0.000001 | <0.000001 |
Materials and methods
Dead Sea mud is a natural suspension consisting of a water and solid phase. The latter is mainly composed of various clay minerals: illite-smectite, kaolinite, illite, calcite, quartz, and small concentrations of chlorite, palygorskite, dolomite, and halite (Ma’or et al.,1996; Kafri et al., 2002). Some metal traces are present, including nickel (Ni) and chromium (Cr). Both are metals, present in Annex II of the
Cosmetic Regulation 1223/2009 (Regulation No. 1223/20, 21/12/ 2009), and thus not allowed as ingredients in cosmetic products. It is, however, not surprising to detect traces of these inmineralmudas
it is known that Ni naturally occurs in soils and volcanic dust (Sunderman, 1988). Likewise, Cr is an element found in rocks, soils, volcanic dust, gasses, animals, and plants (Hamilton and Wetterhahn, 1988), predominantly as Cr3þ.Cr3þ is also an essential element in man that plays a role in glucose metabolism (Hamilton and Wetterhahn, 1988; ICH Guideline, 2015). Cr6þ is in particular produced by industrial processes and its potential increase, if detected in the Dead Sea mud, could give an indication of ongoing pollution (Hamilton and Wetterhahn, 1988; ICH Guideline, 2015). 2.2. Analysis data available on mud and stream sediment Over the last 10 years some analyses on mud and stream sediments have been carried out. As a part of the results were already published, the sampling procedure and analytical methods used could be retrieved (Ma’or et al., 2006; Abdel-Fattah and Pingitore, 2009). Mud samples from mining points around the Dead Sea Lake were collected. Stream sediment sample sites were selected according to Dead Sea crude mud, dried to 77.5%, w/w, commercial mud packs samples, and interstitial water of crude and commercial mud samples were analyzed. The results are expressed as % (w/w);
n ¼number of repetitions. Precision of measurements’ determination is about ±10%.
(*) inspection sample by French Inspection in 2014. The Ni-content varies in crude and commercialized mud between 0.0023% (w/w) to 0.0040% (w/w), and 0.0014% (w/w) to 0.0017% (w/w), respectively. In interstitial water, obtained by centrifugation, the Ni-content is less than 0.000008% (w/w). The Cr content of mud varies in crude and commercialized samples between 0.0075% (w/w) and 0.0038% (w/w), and 0.0032% and 0.0025%, respectively. Cr-concentration in interstitial water is less than 0.000001%.
3.2. Nickel and chromium content in stream sediments More than 400 samples of stream sediments were collected in a survey from different spots at the Dead Sea area (Gil and Halicz, 1992). Stream sediments from 400 different points in the area of the city of Jerusalem were also sampled (Wolfson et al., 1992). Chemical analysis of stream sediment samples was performed using conventional methods as described earlier (Kafri et al., 2002). The results for Ni-and Cr concentrations are presented in Table 2. Table 2 shows that the mean Ni-concentration at the Dead Sea area and in stream sediments at Jerusalem is 0.0051% (w/w) and 0.0062% (w/w), respectively. The mean Cr concentration is 0.0096% (w/w) and 0.0103% (w/w), respectively. 3.3. Exposure to nickel 3.3.1. Evaluation of the systemic toxicity following topical application of Dead Sea mud The systemic toxicity was determined according to the margin of safety (MoS) principle as explained in the SCCS Notes of Guidance (SCCS’s Notes of Guidance). The systemic exposure dosage (SED) for Ni was calculated as SED ¼ A (mg/kg body weight/day) X C(%)/100 Dap (%)/100; with C ¼ concentration and Dap ¼ dermal absorption of the compound under study, respectively. In a conservative way, the dermal absorption is taken as 100%. The concentration of Ni, found in commercial mud is 0.0017% (w/w) (Table 1). SED is 0.000007 mg/kg body weight/day for one application per week and 0.000030 mg/kg body weight/day for four applications per week. A no observed adverse effect Level (NOAEL) is usually obtained in vivo through amoral repeateddosetoxicitystudy in experimental animals. It is the maximum concentration of a substance that is found to have no adverse systemic effects after repeated exposure. The mostly used NOAEL for Ni is 5 mg/kg body weight/day, measured for NiSO4ina2-yearoralratstudy(DEFRAandEA,2002). For oral absorption, it is known that soluble Ni-compounds are
more absorbable than insoluble ones. In the fasted state up to 50% can be absorbed from the gastrointestinal tract, but the extent of absorption can be reduced dramatically in the presence of several
food constituents. Thus most Ni in food remains unabsorbed; about 10% of Ni in food is absorbed (European Medicines Agency EMEA, 2007). Since no precise absorption data is available, the conservative default value of 50% is used as recommended by the SCCS (SCCS’s Notes of Guidance).
MoS ¼NOAEL=SED 50%
For one to four topical applications of Dead Sea mud, the calculated MoS is 357,143 and 833,333, respectively. As these values are much higher than 100, there is no toxicological concern for systemic toxicity, following topical exposure to Dead Sea mud.3.3.2. Evaluation of local toxicity following topical application of Dead Sea mud As Ni is a well-known sensitizer, the local toxicity to be examined is skin sensitization. In Table 1, the Ni-concentration is given for a commercial mud pack that was analyzed by the French Authorities upon legal inspection in 2014. It provides, as expected, somewhat lower values of 0.0017% (w/w) than those observed for crude mud samples and this seems to be in line with values made
available earlier (Abdel-Fattah and Pingitore, 2009). For topical Ni-exposure, a human threshold value of 0.2 ug/cm2/ week for dermal exposure is available for consumer products intended to be in direct and prolonged contact with the skin; for short-term contact 0.5 ug/cm2/week is applied (Regulation No.
1907/20, 2006; Regulation No 1907/200, 1907). Dead Sea comes for a short time in contact with the whole body surface (17,500 cm2, worst case scenario with head included) (SCCS’s Notes of Guidance) and per-application an amount of 18.67 g could be estimated, in analogy with the use of shower gel
(SCCS’s Notes of Guidance). Assuming that all Ni present in the Dead Sea mud would come
in contact with the skin (worst case scenario as most metal traces are adsorbed within the clay fraction of the mud), a single exposure to mud would give a Ni-exposure of 0.0181 ug/cm2/week, which is 28 times lower than the set threshold. When exposure is 4 times per week, Ni exposure would be 0.0725ug/cm2/week, which still is about 7 times lower than the threshold. Since Dead Sea mud is a rinse-off product with a skin contact of 20e30 min, it seems reasonable to assume that sensitizing effects
will not occur on healthy intact skin, knowing that traces in personal care products of the same order of magnitude are not the primary cause of sensitization (Marinovich et al., 2014). However, a consumer already sensitized to Ni via other sources, may react and consequently suffer from allergic contact dermatitis (Basketter et al., 2003; Travassos et al., 2011). Therefore, it is important that on the label a warning is present to protect already Ni-sensitized consumers for elicitation reactions.
3.4. Exposure to chromium 3.4.1. Evaluation of the systemic toxicity following topical application of Dead Sea mud The safety for Criscalculated in a worst-case scenario, namely the
total exposure to Cr is measured without distinguishing between Cr3þ and Cr6þ (as if the exposure would be only to Cr6þ in a concentration as high as the sum of both), and the dermal absorption is
set at 100%. (C) ¼ is 0.0032% (Table 1). The SED calculation yields 0.000014 mg/kg body weight/day and 0.000057 mg/kg body weight for one or four applications per week, respectively. The most stringent NOAEL value found for Cr is 2.5 mg/kg body weight/day (U.S. Environmental Protection Agency, 1992) which was for Cr 6þ retrieved from a 1-year oral rat study. Intestinal absorption of Cr3þ is
low (up to 2%) in both humans and animals. For Cr6þ values of 5.7% were found in human studies (European Medicines Agency EMEA, 2007). As no precise absorption data is available, a conservative
bio-availability default of 50% is used (Regulation No.1907/20, 2006). The calculated MoS becomes as such is 89,286 and 21,930 for one or four applications per week, respectively. There is no systemic toxicity
concern following topical application of Dead Sea mud. 3.4.2. Evaluation of local toxicity following topical application of Dead Sea mud The local toxicity related to skin exposure to Cr is restricted to skin sensitization. For Cr, a threshold human dermal exposure value is not available under the actual REACH Regulation. Yet, in 2002 for certain consumer products (such as leather), the recommendation was made
by the Committee for Risk Assessment to have not more than 0.0003% Cr 6þ release from leather products upon direct and prolonged contact with the skin. Here only the total sum of Cr3þ and Cr6þ is available. In analogy with the previous, also the labeling needs to be on the package that Cr-sensitized people should not come in contact with the mud. This was recommended as Cr-sensitized people react to concentrations as low as 0.0007e0.0010% (U.S. Environmental Protection Agency, 1992). 3.5. Collected health reports during last five years of commercial marketing of Dead Sea mud More than half a million units of Dead Sea mud were commercially supplied worldwide during the last five years of marketing. Only two (less than 0.0004%) consumers had complained regarding skin reactions (Internal Quality Assurance Data). For both complaints consumers reported “sensitivity” and “stinging” leading to skin itching and local redness following topical application. Skin onset period was short and none of the consumers were hospitalized or needed further medical support (Internal Quality Assurance Data).
Discussion
Residues of Ni and Cr are likely to be found in Dead Sea mud samples since both are naturally occurring elements, generally found in soil and rocks (ATSDR, 2012; ATSDR, 2005). Background Ni-levels in different soils may vary widely depending on local geography, but typically concentration levels range between
0.0004 and 0.0080% (ATSDR, 2005). Background levels of Cr in different soils also vary significantly depending on local geography, but typically in trace concentrations (ATSDR, 2012). Veniale et al.
reported that mud, collected at the northern Italian spas, contained Ni and Cr in concentrations of 0.0049% and 0.0115%, respectively (Veniale et al., 2007), which is quite comparable to the values found
in stream sediments of the Dead Sea surrounding areas (Table 2). These values represent the typical concentrations of the metals naturally occurring in rocks and soil, which have been stabilized
over many years of erosion and water wash. It was found that during the last 15 years, the Ni-and Cr levels measured in mud samples have not increased over time (Ma’or). Based on these observations, it seems reasonable to conclude that the reported Ni- and Cr concentrations, detected in Dead Sea
mudsamples, are naturally occurring metal traces. Crude mud has been centrifuged and analyzed for the metal content of the interstitial water. The results are shown in Table 1. The low levels of Ni
and Cr measured demonstrate that these metals are mainly a part of the crystallographic structure or enclosed by the high surface area of solid mud particles, for which the metal release rate to the liquid phase is poor. This finding may dramatically affect the effective exposure level of skin to both elements following application of Dead Sea mud, even lower than the permitted limits of these metals in drinking water (Edition of Drinking Water Standards, 2012). The Ni- and Cr-concentrations found are in accordance with the scientific literature about clay usage being one of the most efficient methods, feasible and simple, to absorb metal ions, including Ni and Cr, from “contaminated” aqueous solutions (Celis et al., 2000; Lin and Juang, 2002; Bradl, 2004; Eba et al., 2010). Due to their high specific surface area, high cationic exchange capacity, and positive or negative surface’ charge, clays represent an effective
entrapping system for metals (Lin and Juang, 2002). From a mineralogical point of view, Dead Sea mud is a combination of different clays (Kafri et al., 2002). Therefore, the traces of Ni and Cr measured in DeadSea mud could be considered as being present in the total mud samples. They are, however, not those to which the consumers’ skin is exposed. When Dead Seamudisappliedonskin, Ni and Cr as well as other metals are retained by the clay, in the solid particles. They are either part of the crystallographic structure or attached to the solid clay surface area. Consequently, purification of mud to reduce its Ni- and Cr-levels by the most used technique, namely exposure to natural clay, would not make sense here as this is already occurring naturally. Therefore, the presence of Ni and Cr measured in Dead Sea mud should be regarded as technically unavoidable as defined in Article 17 of the Cosmetic EU Regulation
(Regulation No. 1223/20, 21/12/2009). The anticipated level of skin local exposure to Ni after mud
application in a worst-case scenario is nearly 7-fold lower than the local toxicity threshold and therefore local toxicity is not to be expected in case consumers have not been pre-sensitized to Ni. The REACH accepted threshold value for short-term nickel exposure is 0.5 mg/cm2/week. The Dead Sea mud is a rinse-off product and stays on the skin surface for about 20e30 min before being rinsed away with water. It seems therefore unlikely that local effects related to Ni will occur on healthy and intact skin.
As we are not aware of a formal accepted threshold value for human skin exposure to Cr3þ or Cr6þ, we have mentioned here the upper approved limit for Cr6þ for leather products upon direct and recommended by the EU Committee of Risk Assessment. This recommendation was made in view of the fact that Cr-sensitized people react to concentrations as low as 0.0007e0.0010%. It is mentioned in the literature, however, that Cr3þ elicitation concentrations are generally much higher (Basketter et al., 2003, 1993). Cr6þ is a pollutant; it is this fraction that should be measured in clay, since it will provide an indication whether the composition of the clay used remains the same over the years.
It should also be kept in mind that actually, the skin is exposed to much lower concentrations of nickel and chrome from mud, than estimated from the measured values in the samples. Indeed, the metals are under normal conditions taken up in the clay, attached to its surface and not bio-available via the water
fraction. Anyhow, as a preventive measure, it is necessary to label the Dead Sea mud and clearly indicate the Dead Sea mud allowed exposure should be limited to persons with intact skin. Although its safe history of usage by those with atopic dermatitis and psoriasis, persons with damaged skin, are advised to consult a medical expert before skin exposure to mud.
Conclusions
Nickel and chrome measured in Dead Sea mud are technically unavoidable as definedinArticle 17 of ECRegulation 1223/2009. The nickel and chrome concentrations actually measured in the mudare safe for human health with respect tosystemictoxicity, evenwhenworstcasescenario’sisconsidered;theyare alsosafe
for human health with respect to local toxicity when used on non-sensitized persons. Actually, skin exposure to nickel and chrome are much lower since both metals are mainly attached to the claycomponents of released constituting aquatic solution As Dead Seamudis used a sarinse-offproduct, skin contact time is limited. Using Dead Sea mud is not recommended for already Ni- or Cr sensitized persons. Skin sensitizing by exposure of normal healthy skin to Dead Sea mud is not expected. Consumers should, however, be aware of the presence of these metals through a clear product label for precaution not to be used by sensitized persons. As a preventive measure, regular monitoring of the Cr6þ-content of Dead Sea mud seems necessary in order to be able to guarantee that no increase in polluting metal concentration is generated. An annual sampling of the mud and its chemical analysis is anticipated. Changes in chrome concentrations in general and Cr6þ in particular if occurred should be seriously investigated.
Acknowledgments
Geological Survey: Dr. Moshe Shirav, Dr. Olga Yoffe, Yevgeni Zakon.
