Absorption, Distribution and Excretion
When male and female rats were fed a diet containing titanium dioxide (100 g/kg) for approximately 32 days, significant titanium retention was observed only in muscle, at 0.06 and 0.11 mg/kg wet weight, respectively; no retention was observed in the liver, spleen, kidneys, bones, plasma, or erythrocytes. Clearance kinetics of titanium dioxide were determined over a period of up to 140 days after exposure of the rat lungs to concentrations of 10 and 50 mg/m³ for 7 hours. The retention half-life during the first clearance phase was 14 days, followed by 88 days. The highest concentration of titanium dioxide was observed in the liver 6 hours after intravenous administration of 250 mg/kg body weight; the highest concentration was detected in the peritoneal lymph nodes, which filter lymph fluid from the liver, 24 hours later. The clearance of titanium dioxide from the rat lungs was investigated after inhalation of titanium dioxide at concentrations of 15 or 100 mg/m³. The median aerodynamic diameter of titanium dioxide particles is 1.48 μm. Following a single exposure, approximately 40-45% of deposited particles are cleared from the lungs within 25 days. At a concentration of 15 mg/m³, 0.7% titanium dioxide was detected in the hilar lymph nodes, indicating that titanium dioxide particles infiltrate the lymphatic system from the alveoli and are partially cleared via the lymphatic pathway. Clearance of titanium dioxide after intratracheal administration was similar to that at inhaled concentrations. At a concentration of 100 mg/m³, clearance decreased significantly. Other researchers have confirmed the presence of titanium dioxide in the lymphatic systems of three workers involved in the processing of titanium dioxide pigments. The deposition of titanium dioxide dust in the lungs of rats is similar to that of other particulate matter. Titanium dioxide was found in lymphocytes and regional lymph nodes in the lungs, indicating a slow rate of clearance via this process. Long-term exposure to high concentrations leads to a significant decrease or even cessation of clearance due to excessive lung load. Studies have shown that small amounts of titanium dioxide may enter systemic circulation from the lungs. This article reports a case of pneumoconiosis in a 53-year-old male due to approximately 13 years of occupational exposure to high concentrations of titanium dioxide. The patient died of lung cancer, which was likely related to his 34-pack-year smoking history rather than titanium dioxide exposure. Autopsy revealed diffuse particulate matter deposits in the lungs approximately 9-10 years after titanium dioxide exposure; these particles were typically found in the interstitium and alveolar macrophages. Examination of lung tissue from the right upper lobe and right hilar lymph nodes revealed high-titanium crystalline deposits measuring 0.2-0.3 μm × 0.7 μm. In rats, the highest titanium dioxide concentration was observed in the liver 6 hours after intravenous injection of 250 mg/kg body weight of titanium dioxide; the highest concentration was detected in the peritoneal lymph nodes after 24 hours of filtering liver lymph. Researchers studied lung tissue samples from three factory workers who had been exposed to titanium dioxide pigment processing for 9 years; they found deposits in the lung interstitium accompanied by cell damage and mild fibrosis. Observation of particles in lymph nodes confirmed that titanium dioxide can be cleared through the lymphatic system. For more complete data on the absorption, distribution, and excretion of titanium dioxide (13 types), please visit the HSDB record page. Metabolites/Metabolites: Rats were intraperitoneally injected with 1.60 g/100 g body weight of titanium dioxide saline. Histological evaluation of organs (liver, spleen, lung) was performed. Reactive oxygen species (ROS) in alveolar macrophages in bronchoalveolar lavage fluid (BAL) were quantitatively assessed using the nitroblue tetrazolium test and digital image analysis. Organ histological analysis showed the presence of titanium in the parenchyma of these organs, but no associated tissue damage was found. Although TiO₂ induced a significant increase in ROS production in alveolar macrophages, it did not cause tissue alterations. This finding may be attributed to an adaptive response.

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Biological Half-Life
Clearance kinetics of TiO₂ were determined over a period of up to 140 days after 7 hours of lung exposure in rats at concentrations of 10 and 50 mg/m³… The retention half-life during the first clearance phase was 14 days, followed by 88 days.
Clearance kinetics of TiO₂ were determined over a period of up to 140 days after 7 hours of lung exposure in rats at concentrations of 10 and 50 mg/m³… The retention half-life during the first clearance phase was 14 days, followed by 88 days.

Protein Binding
Researchers determined the concentration of titanium dioxide (anatase) in the blood of six adult men (24-66 years old) after oral administration of titanium dioxide capsules and/or powder. The absorption of titanium dioxide in the gastrointestinal tract is related to particle size: smaller particles (0.16 μm) are more easily absorbed than larger particles (0.38 μm). Before the experiment, the background concentration of titanium dioxide in the blood of these men was approximately 6 to 18 μg/L. Four to 12 hours after administration of 23 mg or 46 mg of titanium dioxide, the blood concentrations reached approximately 50 μg/L and 100 μg/L, respectively. Interactions Nanoparticles (NPs) have been reported to penetrate human skin through skin lesions or hair follicle structures. Therefore, this study explored their interaction capabilities with monocyte-derived dendritic cells (mono-DCs). The results showed that the titanium dioxide/p-aminobenzoic acid (TiO₂/PABA) hybrid nanoparticles were not cytotoxic. The nanoparticles entered dendritic cells (DCs) via macropinocytosis rather than receptor-mediated mechanisms. Confocal microscopy revealed no nanoparticles within the cell nucleus. Electron microscopy confirmed these results, indicating that the hybrid nanoparticles rapidly contacted the cell membrane and localized within cytoplasmic vesicles, without co-localizing with clathrin-coated vesicles. The hybrid nanoparticles did not induce CD86 or HLA-DR overexpression, nor did they induce the secretion of cytokines (IL-8 and TNF-α), indicating that they did not activate DCs. Internalization of the hybrid nanoparticles did not alter the response of dendritic cells (DCs) to sensitizers such as nickel, thimerosal, or lipopolysaccharide (LPS) (used as positive controls). Furthermore, the hybrid nanoparticles did not induce any oxidative stress associated with DC activation. After monolayer dendritic cells (DCs) were irradiated with ultraviolet A (UVA), cells treated with the mixed nanoparticles did not produce UVA-induced reactive oxygen species (ROS) and showed higher cell viability compared to UVA-irradiated control cells, indicating that the mixed TiO₂/PABA nanoparticles have a protective effect against UVA-induced ROS. /Mixed TiO₂/PABA nanoparticles/
Reduce UV penetration into the epidermis by absorbing UV radiation within a specific wavelength range. The absorption amount and wavelength of UV radiation are affected by the molecular structure of sunscreen agents. /Sunscreen agent, topical/
A large amount of white gas containing titanium dioxide and hydrogen chloride was accidentally generated during an experiment in a chemical laboratory. Fourteen students and faculty members experienced nausea, difficulty breathing, or respiratory irritation symptoms immediately after inhaling the gas. Upon arrival at St. Luke's International Hospital, more than half of the patients developed a low-grade fever. The symptoms quickly subsided spontaneously after admission, but the low-grade fever persisted until the following morning. Inhalation of hydrogen chloride could not explain the low-grade fever, so it was speculated that it was caused by inhalation of titanium dioxide, manifesting as metal fume fever. Titanium dioxide is considered to have no significant toxicity to humans and is clinically considered safe. To our knowledge, this is the first reported case of metallic fume fever in humans caused by titanium dioxide inhalation. The correlation between the degree of fever and the amount and concentration of inhaled titanium dioxide remains to be determined. Male long-Evans-hooded rats were exposed to cadmium chloride at concentrations of 1.5 or 5.0 mg/m³ for 30 minutes via nasal administration only. Subsequently, cadmium-treated rats were exposed to titanium dioxide dust at concentrations of 12 to 15 mg/m³ for 6 hours, and their pulmonary clearance and lymphatic absorption were measured. Initial titanium dioxide deposition was reduced by 40% due to pre-exposure to 5 mg cadmium chloride. Overall titanium dioxide clearance was unchanged, but the lymph node load in cadmium-exposed animals was 2.7 times higher than in the control group. Exposure to 1.5 mg/m³ cadmium chloride had no effect on pulmonary clearance or lymphatic absorption of titanium dioxide. The same results were obtained when the exposure order was reversed, with animals exposed to titanium dioxide first and then to cadmium chloride: increased lymphatic absorption of titanium dioxide. The authors concluded that when the phagocytic activity of alveolar macrophages decreased, the lymphatic system's absorption of dust particles increased. Twenty-four male and twenty-four female Syrian golden hamsters (6-7 weeks old) were divided into two groups and treated weekly for 15 weeks. The treatment group received an intratracheal infusion of either 3 mg titanium dioxide (purity not specified; particle size: 97% <5 μm; 51% <0.5 μm) plus 3 mg benzo[a]pyrene (dissolved in 0.2 mL of physiological saline) or 3 mg benzo[a]pyrene (dissolved in physiological saline, control group). Animals were observed until natural death; all hamsters in the control and treatment groups died at 90-100 weeks and 60-70 weeks, respectively. In 48 hamsters treated with titanium dioxide and benzo[a]pyrene, tumors (sex not specified) appeared in the larynx (11 papillomas, 5 squamous cell carcinomas), trachea (3 papillomas, 14 squamous cell carcinomas, 1 adenocarcinoma), and lungs (1 adenoma, 1 adenocarcinoma, 15 squamous cell carcinomas, 1 undifferentiated carcinoma). In the control group treated with benzo[a]pyrene, 2 papillomas appeared in the trachea. In the same study, the tumor profile induced by iron oxide (3 mg) and benzo[a]pyrene was similar to that induced by the combination of titanium dioxide and benzo[a]pyrene.

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Non-human toxicity values
Hamster dermal LD50 ≥ 10,000 mg/kg body weight
Rats oral LD50 > 10,000 mg/kg body weight

[1]. Augustynski J. Aspects of photo-electrochemical and surface behaviour of titanium (IV) oxide[M]//Solid Materials. Berlin, Heidelberg: Springer Berlin Heidelberg, 2005: 1-61.
[2]. Elder DP, et al. Pharmaceutical excipients - quality, regulatory and biopharmaceutical considerations. Eur J Pharm Sci. 2016 May 25;87:88-99.

According to California labor law, titanium dioxide (airborne particulate matter) may be carcinogenic. Titanium dioxide is a tasteless, odorless white powder with a pH of 7.5, existing in three crystalline forms. (NTP, 1992) Titanium dioxide is a titanium oxide with the chemical formula TiO₂. It is a naturally occurring oxide derived from ilmenite, rutile, and anatase, and has a wide range of uses, including as a food coloring agent. Titanium dioxide, also known as titanium tetroxide or titanium dioxide, is the natural oxide of titanium. It is used as a pigment, with names including titanium white, pigment white 6 (PW6), or CI 77891. It is typically extracted from ilmenite, rutile, and anatase. Anatase is a mineral with the chemical formula Ti₄O₂ or TiO₂. The corresponding IMA (International Mineralogical Association) number is IMA1962 sp. The IMA symbol is Ant.
Brockite is a mineral with the chemical formula Ti₄+O₂ or TiO₂. Its IMA symbol is Brk.
Rutile is a mineral with the chemical formula Ti₄+O₂ or TiO₂. Its IMA symbol is Rt.
See also: Ensulizine; Titanium Dioxide (Ingredient); Padimat O; Titanium Dioxide (Ingredient); Salicylic Acid; Titanium Dioxide (Ingredient)...See more...

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Drug Indications
Titanium dioxide, similar to zinc oxide, is used in most sunscreens to block UVA and UVB rays.

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Mechanism of Action
By absorbing ultraviolet radiation within a specific wavelength range, it reduces the penetration of ultraviolet rays into the epidermis. The molecular structure of sunscreens affects the amount and wavelength of ultraviolet radiation absorbed.
By absorbing ultraviolet radiation within a specific wavelength range, it reduces the penetration of ultraviolet rays into the epidermis. The molecular structure of sunscreens affects the amount and wavelength of ultraviolet radiation absorbed. /Sunscreen, Topical/

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Therapeutic Use
Photosensitizer; Sunscreen
Titanium dioxide acts on the skin similarly to zinc oxide, and its uses are also similar. Titanium peroxide and titanium salicylate are often used together with titanium dioxide to treat diaper rash. Titanium dioxide reflects ultraviolet rays and is a physical sunscreen agent, also an ingredient in some cosmetics.
Physical compounds titanium dioxide and zinc oxide can reflect, scatter, and absorb UVA and UVB rays. Using new technologies, the particle size of zinc oxide and titanium dioxide has been reduced, making them more transparent without affecting their ability to block ultraviolet rays.

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Drug Warning
Manufacturers of sunscreens using propellants warn that inhaling the fumes produced by these formulations may be harmful or even fatal. /Propellant/
Because the skin absorption characteristics of infants under 6 months of age may differ from those of adults, and their metabolic and excretory pathways are not yet mature, which may limit their ability to clear transdermal sunscreens, sunscreen products should only be used on infants under 6 months of age under the guidance of a clinician. Older adults may have different skin characteristics than younger adults, but these characteristics and the special considerations for this age group when using sunscreen are not fully understood. Sunscreen: Limited information is available regarding the safety of long-term sunscreen use, but commercially available physical and chemical sunscreens appear to have a low incidence of adverse reactions. Derivatives of para-aminobenzoic acid (PABA), benzophenone, cinnamic acid, salicylic acid, and 2-phenylbenzimidazole-5-sulfonic acid can cause skin irritation, including burning, stinging, itching, and erythema, in rare cases. Sunscreen should not be used as a means of prolonging sun exposure, such as extended sunbathing, nor should it replace clothing on normally unexposed areas such as the torso and buttocks. For more complete data on drug warnings for titanium dioxide (11 in total), please visit the HSDB records page.

O2TI

79.87

79.937

13463-67-7

26042

White, tetragonal crystals
White powder in two crystalline forms, anatase and rutile
AMORPHOUS, INFUSIBLE POWDER
White powder

4.26 g/mL at 25 °C(lit.)

2900 °C

1840 °C

2500-3000°C

2.61

0

2

0

3

18.3

0

[Ti](=O)=O

GWEVSGVZZGPLCZ-UHFFFAOYSA-N

InChI=1S/2O.Ti

dioxotitanium

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: (1). This product requires protection from light (avoid light exposure) during transportation and storage.  (2). Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)