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EC number: 231-726-8 | CAS number: 7704-98-5
Metal hydride – Titanium hydride (CAS 7704-98-5; EC 231-726-8)
Background:To induce sensitization, metal ions need to penetrate through the outer stratum corneum barrier layer of the skin and reach the underlying viable epidermis. Then, to become immunologically reactive, metal ions must bind to macromolecules such as proteins to form a hapten complex. Antigen presenting cells display this hapten complex on their cell surfaces and when the hapten is recognized as foreign by naïve T-lymphocyte cells, these cells undergo differentiation to form hapten-specific effector and memory helper T-cells (e.g., a person becomes sensitized). Upon repeated contact with the offending metal, at exposure levels that result in sufficient metal ion release and stratum corneum penetration, memory T-cells are recruited to the site of skin contact and elicit an inflammatory reaction (Stefaniak et al., 2014; Gibbs et al., 2018).
Regarding skin sensitization of titanium hydride as requested under REACH regulation1907/2006, no data are currently available. To meet the skin sensitization endpoint requirement, read-across strategy with titanium salts and titanium dioxide has been used. It has to be noted that titanium dioxide at nanoform scale is extensively used in cosmetic (e.g. sunscreen, make-up), toothpastes and medical devices. Even if some papers in the literature raise sensitization concern regarding the use of TiO2 as nanoform, the related papers for these specific applications have been voluntary excluded from this dossier as titanium hydride is not intended to be used as nanoform for direct consumer use.
Titanium salts & Titanium oxide:
Testing of potential sensitizers of metals is traditionally carried out by applying the metal test chemical in the form of salt to the skin of animals or reconstructed skin under standard conditions. Preferably the salt should dissolve to form metal ions. In that respect, a couple of papers publicly available have been found and shortly described allowing to fulfill the sensitization requirement in the REACH dossier.
Ikarashi et al. 1996
Sensitization potency of a titanium salt (TiCl4) was studied using the guinea-pig maximization test (GPMT) and adjuvant and patch test (APT). In addition, a sensitive mouse lymph node assay was also ran (SLNA). As result, one of the five animals treated with TiCl4 showed a weak skin response with 5% challenge. When these animals were rechallenged, 3 of 5 (60%) responded to TiCl4, and the response intensity became stronger. TiCl4 was retested by using more animals. As a result, 5 of 10 (50%) animals showed skin reactions by challenge. After SLNA, it appears that TiCl4 caused mild increases in lymph node weight, LNC number and LNC proliferation. However, the SLNA defined TiCl4 as negative according to the criteria. According to the research team, titanium is not considered as skin sensitization while a "sensitization capacity" cannot be excluded.
Gibbs et al., 2018 (Review)
In the frame of testing the applicability domain of the in vitro reconstructed human epidermis (RhE) IL-18 assay developed to identify contact allergens. Twenty eight chemicals including 15 metal salts were topically exposed to RhE. Nickel, chrome, gold, palladium were each tested in two different salt forms, and titanium in 4 different salt forms. Metal salts were labelled (YES/NO) as sensitizer if a threshold of more than 5 fold IL-18 release was reached. Titanium salts (Titanium (IV) isopropoxide, Titanium (IV) bis(ammonium lactato) dihydroxide solution and Titanium (IV) oxide) were scored as extreme weak sensitizers/irritants. From analysis of the applicability domain of the assay, it appears that titanium ion do not penetrate the stratum corneum which may explain why titanium is a weak sensitizer.
Warheit et al., 2007
In this paper, ten different toxicity studies were conducted with newly developed ultrafine TiO2 particle-types. Part of this set of studies, askin sensitization study (LLNA, OECD guideline N°429) in mice was ran. Result of this test was not a dermal sensitizer to mice under the test conditions.
Conclusion:According to the papers found in the literature and publicly available, titanium salts and titanium oxide would not be classified as dermal sensitizer. On this basis, the non-sensitization of titanium dihydride has been extrapolated. In addition, water solubility of titanium hydride at various pH was assessed and showed that the test item is insoluble (<0.1 mg/L) in water at pH which maximises the solubilisation (pH 5.8). This argument strengthens the non-allergic property of titanium dihydride.
Gibbs S, Kosten I, Veldhuizen R, Spiekstra S, Corsini E, Roggen E, Rustemeyer T, Feilzer AJ, Cees J. Kleverlaan CJ. 2018. Assessment of metal sensitizer potency with the reconstructed human epidermis IL-18 assay. Toxicology 393: 62–72.
Ikarashi Y, Momma J, Tsuchiya T, Nakamura A. 1996. Evaluation of skin sensitization potential of nickel, chromium, titanium and zirconium salts using guinea-pigs and mice. Biomaterials 17: 2103–2108.
Stefaniak AB, Duling MG,Geer L, and Virji MA. 2014. Dissolution of the metal sensitizers Ni, Be, Cr in artificial sweat to improve estimates of dermal bioaccessibility. Environ Sci Process Impacts 16: 341–351.
Warheit DB, Hoke RA, Finlay C, Donner EM, Reed KL, Sayes CM. 2007. Development of a base set of toxicity tests using ultrafine TiO2 particles as a component of nanoparticle risk management. Toxicology Letters 171: 99–110.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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