Calcium wolframate

Endpoint summary

Key value for chemical safety assessment

Respiratory sensitisation

Endpoint conclusion

Additional information:

Read-across - calcium wolframate:

Calcium wolframate is the salt of wolframic acid. It is composed of calcium cations and wolframate anions so that calcium wolframate is electrically neutral (i.e. without a net charge). Any dissolution ofcalcium wolframatewill release the wolframate anion that is pH-dependent in equilibrium with undissociated wolframic acid (as based on the pKa of wolframic acid).

Thus, wolframate and wolframic acid, coexist in aqueous solution in adynamic pH-dependant equilibrium. Under neutral and basic conditions, the wolframate ion predominates whereas under more acidic conditions, the hydrogen wolframate anion and finally (below a pH of ca. 5) wolframic acid is more prevalent.

 

                                  H₂WO₄ HWO₄^-+ H⁺ WO₄^2-+ 2H⁺

The pKa values for wolframic acid is estimated to be 3.50 and 4.60 based on handbook data (Hollemann Wiberg, Lehrbuch der Anorganischen Chemie, 101.Auflage). The mean pKa value for calcium cations is estimated to be 12.6 based on handbook data (Lide, D.R., 2008).A Hägg-graph representing the equilibrium ofwolframic acid/ wolframateis provided below.

 

Due to its electronegativity E₀(Ca/Ca²⁺) = -2,84V calcium is present in the environment only in the divalent cationic form. At high solution pH, i.e. above 12, calcium hydroxide complexes are formed.

Other calcium species, potentially relevant for the environmental of human health hazard assessment, are not present at environmentally or physiologically relevant redox conditions and solution pH.

According to the Hägg-graph and the Pourbaix- diagram wolframate is the dominant species under ENV conditions (Seiler et al., 2005). Anthropogenic use of W utilizes W metal or WC, which are thermodynamically unstable and when introduced into environmental systems begins to alter to a more stable form (WO₄^2-) (Andersson and Bergstrom 2000).

Wolfram metal is (due to its negative potential (-0.09 to -1.074, pH0 -pH14)) transformed to wolframate which represents the most stable oxidation state of Wolfram(see Pourbaix Diagram below).

W + H₂O/1.5 O₂ --> 2 H⁺+ WO₄^2-

Hence, under physiological conditions wolframic acid, hydrogen wolframate and wolframate co-exist in a pH-dependent manner, irrespective of their origin.

Skin sensitisation - wolfram metal:

Wolfram metal does not possess a skin sensitisation potential and does not require classification as skin sensitiser according to Regulation (EC) No 1272/2008 and subsequent adaptations.

Skin sensitisation - calcium ion:

Evaluation of the sensitization potential of a substance was usually carried out in animal models. Nowadays, there is much interest in reducing and ultimately replacing current animal tests. The human cell line activation test (h-CLAT) and the ARE-Nrf2 luciferase test method were recently adopted as alternative methods for skin sensitization. Both test systems are based on human cell lines, such as the human monocytic leukaemia cells THP-1 and the KeratinoSens™ cells which are cultured either in RMPI-1640 medium or DMEM (OECD guideline No. 422D and 422E). Both media are supplemented with calcium salts at concentrations ranging from 2.5 to 5.0 mM. These methods were validated and accepted under these conditions and demonstrate that in vitro cell culture systems are dependent on calcium containing media.

Calcium is known for its key role in many regulatory functions in the skin. Calcium is mostly found in the outermost layer, the epidermis, where it is involved in barrier function repair and skin homeostasis (Dendaet al.,2003). Within the epidermis, keratinocytes have a different need for calcium concentrations. Keratinocyte differentiation throughout the epidermis is in part mediated by a calcium gradient, increasing from the stratum basale until the outer stratum granulosum, where it reaches its maximum. “Calcium concentration in the stratum corneum (SC) is very low because the relatively dry SC, with its extracellular lipid content, is not able to dissolve the ions. After disruption of the permeability barrier, an influx of water into the SC occurs and the calcium ion gradient is lost. This depletion of calcium regulates lamellar body exocytosis (Lee et al., 1992; Menon et al., 1985; Menon et al., 1991). Disturbed regulation of calcium metabolism and increased transepidermal water loss (Lavrijsen et al., 1993) is observed in Darier’s and Hailey– Hailey diseases, which are both characterized by loss of adhesion between suprabasal epidermal cells” (Prokschet al.,2008). Beside the fact, that calcium is a very important regulator of protein synthesis in the epidermis, including regulation of transglutaminase 1 activity (Hitomi, 2005) and cell–cell adhesion, the calcium gradient described above is involved in keratinocyte differentiation and as such considered as a key regulator in the formation of the epidermal layers (Proksch et al., 2008).

The turnover rate of the keratinocytes slows down with increasing age which is associated with thinning of the epidermis, elastosis and a decreased barrier function. Since the differentiation of the keratinocytes is calcium dependent, calcium plays a crucial role in the aging epidermis. Therefore, many calcium containing cosmetic products, especially anti-ageing products, are on the market. For example one of the long-lasting synthetic semi-permanent dermal fillers is calcium hydroxylapatite suspended in an aqueous carboxymethylcelluose gel carrier or calcium pantothenicum cream for regeneration of damaged skin. Radiesse® is one of these subdermal fillers, whose principal component is synthetic calcium hydroxylapatite (CaHA). Depending on injection site up to 4 mL of this product is injected (Jacovella, 2008). “The semi-solid nature of the product is created by suspending CaHA microspheres of 25–45 micron diameter in a gel carrier that consists primarily of sterile water and glycerin. The gel structure is formed by the addition of a small amount of carboxymethylcellulose (USP). The gel is dissipated in vivo and replaced with soft tissue growth, while the CaHA remains at the site of injection (Bioform Medical Inc. 2007)” (Jacovella, 2008). According to Flaharty (2000) the biocompatibility of CaHA has been tested in preclinical studies, and it has been shown to be non-toxic and non-mutagenic (Flaharty 2000).

Calcium hydroxide, calcium phosphate as well as calcium stearate are known ingredients of many commercial available products. “Calcium stearate was reported to be in 23 preparations in 1976, with the largest single use occurring in eyebrow pencils; concentrations ranged from >25 % to 50 %. In 2001, calcium stearate was reportedly used in 107 cosmetic preparations (FDA, 2001), with the largest single use occurring in eye shadow at concentrations that range from 0.2 % to 10 % (CTFA, 2001)” (The Cosmetic Ingredient Review (CIR) Expert Panel, 2001). The CIR Expert Panel evaluated the scientific data and concluded that calcium stearate and other stearates were safe for use in cosmetics and personal care products. In 2001, as part of the scheduled re-evaluation of ingredients, the CIR Expert Panel considered available new data on the stearate compounds and reaffirmed the above conclusion. According to the Regulation No. 1223/2009 of the European Parliament and of the Council on Cosmetic Products the use of calcium stearate is allowed in colorants and preservatives (EC No. 1223/2009 Annex IV and V).

Justification for classification or non-classification

Calcium wolframate is not expected to show signs of dermal sensitisation, since the two moieties calcium and wolframate have not shown any skin sensitisation potential in experimental testing. Thus, calcium wolframate is not to be classified according to regulation (EC) 1272/2008 as skin sensitising.