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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
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
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
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
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.
1) Prediction model
Ti (IV) isopropoxide
Ti (IV) bis(ammonium lactato) dihydroxide solution
Ti (IV) oxide
Note: The prediction model states that if 2/3 independent runs results
in ≥ 5 fold increase in IL-18 secretion at RhE viability ≤40% compared
to vehicle then the chemical scores as a sensitizer. The maximum IL-18
SI observed in the dose response at a cell viability ≤ 40% relative to
the vehicle is shown. Note the chemical concentration at which the
maximum IL-18 SI
occurs may differ between independent runs due to batch and donor
variation in RhE (see detailed prediction model in Materials and Methods
of the original paper). Chemical concentrations in the dose response
were 2 fold serial dilutions with highest concentration being 200 mg/ml.
(−) No values obtained at cell viability≤ 40% relative to the vehicle
and/or IL-18 was below the detection limit of the ELISA.
2) Comparision of in vivo data with RhE EC50 and IL-18 SI2
according to LLNA
Human NOEL (µg/cm2)
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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