Dermal and mucosal system References Crystal phase composition (particle size in nm) Type of exposure Type and number of animals/subjects Results Tan et al., 1996 [112 ] Sunscreen containing 8% microfine TiO2 Cutaneous application: 2 times/day for 2–6 wks.13 male and female volunteer patients TiO2 absorption: levels of Ti in dermis were higher in treated patients compared to controls, but not significantly. Lademann et al., 1999 [113 ] W/O emulsion UV-Titan M 160 Cutaneous application: 2 mg/cm2 on the volar forearm, 5 times on the first 3 days, and once on the 4th.Human volunteers TiO2 absorption: mostly located in the upper st. corneum. Pflücker et al., 2001 [107 ] W/O emulsion T805 coated with trimethyl octylsilane TiO2 (20) 2 coated with Al2 O3 and SiO2 (10–15) 2 coated with Al and SiO2 (100) Cutaneous application: 4 mg/cm2 on forearm skin for 6 hr.Human volunteer TiO2 absorption: TiO2 solely localized on the outermost surface of the st. corneum, not in the deeper subcutaneous layers. Schulz et al., 2002 [108 ] See Pflücker et al., 2001 [107 ] TiO2 absorption: located on the outermost surface of the st. corneum and not in the deeper subcutaneous layers. Menzel et al., 2004 [105 ] Sunscreen containing TiO2 (length: 45–150; width: 17–35) Cutaneous application: on the back pig skin for 8–48 hr.Pigs TiO2 absorption: TiO2 penetrated through intercellular spaces of the st. corneum into the st. granulosum. Kertész et al., 2005 [106 ] Hydrophobic emulsion TiO2 NPs. Cutaneous application: on human foreskin grafts for 1–48 hr.Human grafts transplanted into SCID mice TiO2 absorption: corneocyte layers of the st. corneum. Mavon et al., 2007 [109 ] Emulsion with 3% T805 Degussa TiO2 coated with trimethyl octylsilane (20) Cutaneous application: 2 mg/cm2 on upper arms.3 human volunteers TiO2 absorption: 93% of the TiO2 applied was recovered in the st. corneum. Kiss et al., 2008 [110 ] Hydrophobic emulsion containing micronized TiO2 . Cutaneous application: 2 mg/cm2 on human foreskin grafts for 24 hr.Human grafts transplanted into SCID mice TiO 2 absorption: outermost layers of the st. corneum. Yanagisawa et al., 2009 [114 ] Rutile TiO2 (15, 50, 100) Intradermal injections: of 20 μ g TiO2 with or without mite allergen on the ears.11 male C/NgaTndCrj (NC/Nga) mice per group Atopic dermatitis: allergen + TiO2 enhanced ear thickening. Inflammatory action: allergen + TiO2 increased EOSs, IL-4, MCs and decreased IFN-γ ; TiO2 increased IL-13. Wu et al., 2009 [115 ] Anatase TiO2 (
5
±
1
,
1
0
±
1
) 2 (
2
5
±
5
,
6
0
±
1
0
) 2 (~21) 2 (0.3–0.5 μ m) Cutaneous application : 24 mg TiO2 formulations on the pig ear for 30 days and on the mouse interscapular skin for 60 consecutive days.3 male reared pigs per group 6 hairless mice (BALB/c/nu/nu) per group TiO2 absorption in pigs: TiO2 detected in the st. corneum, granulosum, prickle and basal cell layer, not in the dermis; TiO2 absorption in mice: increased MDA, reduced HYP content, and excessive keratinisation in skin. Sadrieh et al., 2010 [104 ] P25 Degussa TiO2 (30–50) 2 coated with aluminium hydroxide/dimethicone copolymer (diameter: 20–30, length: 50–150) 2 (300–500) Cutaneous application: 2 mg cream/cm2 skin for 4 times/day, 5 days/week, 4 weeks of.3 female Yucatan minipigs per group TiO2 absorption: TiO2 detected in the upper st. corneum and follicular lumen, with few particles observed in dermal layers as a contamination results. Adachi et al., 2010 [111 ] W/O emulsion containing anatase TiO2 (
2
6
.
4
±
9
.
5
) Cutaneous application: 4 mg/cm2 TiO2 on dorsal skin.Male hairless Wistar Yagi rats TiO2 absorption: TiO2 detected in the horny layer of the interfollicular epidermis. Moon et al., 2011 [116 ] TiO2 (<25; <100) Intraperitoneal injections: once a day for 28 consecutive days before subcutaneous implantation with B16F10 melanoma cells.Mice Tumor growth: increasedFurukawa et al., 2011 [117 ] Coated TiO2 (long axis: 50–100; short axis: 10–20) Cutaneous application : 5–20 mg TiO2 in the postinitiation phase in a skin carcinogenesis model.10–20 CD1 (ICR) female mice per group Carcinogenicity: no increased development of skin nodules
