Absorption, Distribution and Excretion
When male and female rats were fed a diet containing titanium dioxide (100 g/kg) for a period of about 32 days, a significant retention of titanium of 0.06 and 0.11 mg/kg wet weight was found only in the muscles; no retention was observed in the liver, spleen, kidney, bone, plasma, or erythrocytes
The kinetics of TiO2 elimination in the rat lung following its deposition after 7 hr exposure at 10 and 50 mg/cu m were determined for periods up to 140 days.The retention half-time was 14 days for the first clearance phase and 88 days thereafter.
Six hours after titanium dioxide was administered to rats through IV injection at 250 mg/kg body weight, the highest concentration appeared in the liver; after 24 hours, the highest concentration was detected in the celiac lymph nodes, which filter the lymph from the liver.
The clearance of titanium dioxide from the lungs was studied in rats after inhalation of 15 or 100 mg/cu m. The average median aerodynamic diameter of the titanium dioxide particles was 1.48 um. After a single exposure, about 40-45% of the deposited particles were cleared from the lung in 25 days. At 15 mg/cu m, 0.7% was found in the hilar lymph nodes indicating penetration of titanium dioxide particles from alveoli into the lymphatic system and partial clearance by the lymphatic route. The clearance rate was similar after intra-tracheal administration of titanium dioxide. At an exposure of 100 mg/cu m, the clearance rate decreased drastically. /Other researchers/ demonstrated the presence of titanium dioxide in the lymphatic systems of 3 workers employed in processing titanium dioxide pigments.
The deposition of titanium dioxide dust in the lungs of rats is similar to that observed for other particles. Titanium dioxide is found in the lymphocytes and regional nodes in the lungs, indicating that a slow rate of removal occurs by this process. Clearance is also significantly decreased, or even ceases, at high exposure over a period of time because of overload. It is suggested that small amounts of titanium dioxide can enter the general circulation from the lungs.
The case of a 53-year-old man with pneumoconiosis due to approximately 13 years of occupational exposure to 'high' concentrations of titanium dioxide /is reported/. The patient died of lung cancer, which was possibly associated with a 34 pack-year smoking history and not attributed to exposure to titanium dioxide. At autopsy, about 9-10 years after the exposures to titanium dioxide, particle deposition was found to be diffuse in the lung and particles were typically found in interstitial and alveolar macrophages. Examination of lung tissue in the right upper lobe and right hilar lymph nodes showed deposits of crystalloid substances that had a high titanium content and measured 0.2-0.3 um by 0.7 um.
Six hours after titanium dioxide was administered to rats through IV injection at 250 mg/kg body weight, the highest concentration appeared in the liver; after 24 hours, the highest concentration was detected in the celiac lymph nodes, which filter the lymph from the liver.
/Researchers/ studied lung specimens from three factory workers exposed for 9 years to the processing of titanium dioxide pigments; they found deposits in the pulmonary interstitium with cell destruction and slight fibrosis. Clearance of titanium dioxide through the lymphatic system was demonstrated by the observation of particles in the lymph nodes.
For more Absorption, Distribution and Excretion (Complete) data for TITANIUM DIOXIDE (13 total), please visit the HSDB record page.

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Metabolism / Metabolites
Rats were intraperitoneal injected with 1.60 g/100 g body wt of TiO(2) in saline solution. Organs (liver, spleen, lung) were processed for histological evaluation. Reactive oxygen species (ROS) in alveolar macrophages obtained by bronchoalveolar lavage (BAL) were evaluated using the nitroblue tetrazolium test and quantitative evaluation by digital image analysis. The histological analysis of organs revealed the presence of titanium in the parenchyma of these organs with no associated tissue damage. Although in lung alveolar macrophages TiO(2) induced a significant rise in ROS generation, it failed to cause tissue alteration. This finding may be attributed to an adaptive response.

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Biological Half-Life
The kinetics of TiO2 elimination in the rat lung following its deposition after 7 hr exposure at 10 and 50 mg/cu m were determined for periods up to 140 days...The retention half-time was 14 days for the first clearance phase and 88 days thereafter.
The kinetics of TiO2 elimination in the rat lung following its deposition after 7 hr exposure at 10 and 50 mg/cu m were determined for periods up to 140 days...The retention half-time was 14 days for the first clearance phase and 88 days thereafter.

Protein Binding
The researchers/ determined blood levels of titanium dioxide (anatase) following oral ingestion of titanium-dioxide capsules and/or powder in six adult men (24-66 years of age). Titanium dioxide was absorbed by the gastrointestinal tract in a size dependent manner: smaller particles (0.16 um) were more readily absorbed than larger ones (0.38 um). Before the experiment, the background blood levels of titanium dioxide in these men ranged from approximately 6 to 18 ug/L. Blood levels reached up to approximately 50 ug/L or 100 ug/L between 4 and 12 hours after intake of 23 mg or 46 mg titanium dioxide, respectively

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Interactions
Nanoparticles (NPs) have been reported to penetrate into human skin through lesional skin or follicular structures. Therefore, their ability to interact with dendritic cell (DC) was investigated using DCs generated from monocytes (mono-DCs). Hybrid titanium dioxide/para-amino benzoic acid (TiO(2)/PABA) NPs did not induce any cell toxicity. NPs were internalized into DCs through macropinocytosis and not by a receptor-mediated mechanism. Confocal microscopy showed that NPs were not detected in the nucleus. These data are confirmed by electronic microscopy which demonstrated that hybrid NPs were rapidly in contact with cellular membrane and localized into cytoplasmic vesicles without colocalization with clathrin-coated vesicles. Hybrid NPs did not induce CD86 or HLA-DR overexpression or cytokine secretion (IL-8 and TNF-alpha) indicating no DC activation. Internalization of hybrid NPs did not modify DC response towards sensitizers such as nickel and thimerosal or /lipopolysaccharide/ LPS used as positive controls. Moreover, hybrid NPs did not induce any oxidative stress implicated in DC activation process. After mono-DC irradiation by ultraviolet A (UVA), hybrid NP-treated cells did not produce UVA-induced reactive oxygen species (ROS) and exhibited a better cell viability compared with UVA-irradiated control cells, suggesting a protecting effect of hybrid TiO(2)/PABA NPs against UVA-induced ROS. /Hybrid TiO(2)/PABA Nanoparticles/
Diminish the penetration of ultraviolet (UV) light through the epidermis by absorbing UV radiation within a specific wavelength range. The amount and wavelength of UV radiation absorbed are affected by the molecular structure of the sunscreen agent. /Sunscreen agents, topical/
A large quantity of white gas containing titanium dioxide and hydrogen chloride was generated unexpectedly during an experiment in a chemical laboratory. Fourteen students and staff complained of nausea, dyspnea, or respiratory irritation immediately after inhaling the gas. On arrival at Saint Luke's International Hospital, more than half of the patients presented with low-grade fever. Symptoms spontaneously resolved soon after admission, although the low-grade fever persisted until the following morning. Low-grade fever after inhalation exposure is not explicable by hydrogen chloride inhalation and therefore appeared to be caused by titanium dioxide inhalation, manifesting as metal fume fever. Titanium dioxide is thought to have no remarkable human toxicity and is considered to be safe clinically. To our knowledge, this is the first report of titanium dioxide inhalation as the potential cause of metal fume fever in humans. Correlations between the degree of fever and quantity and concentration of inhaled titanium dioxide remain to be determined.
Male Long-Evans-hooded-rats were exposed in a nose only setting to cadmium-chloride at concentrations of 1.5 or 5.0 mg/cu m cadmium ... for 30 minutes. Lung clearance and lymphatic uptake were determined after exposing the cadmium treated rats to titanium-dioxide at dust concentrations of 12 to 15 mg/ cu m for 6 hours. The initial deposition of titanium-dioxide was decreased by 40 percent due to the pre-exposure to 5 milligrams cadmium-chloride. The overall clearance of titanium-dioxide was not changed, but the lymph node burden was 2.7 times higher in cadmium exposed animals as compared to controls. The 1.5 mg/cu m cadmium-chloride exposure did not influence lung clearance nor lymphatic uptake of titanium-dioxide. When the order of exposures was reversed and the animals were first exposed to titanium-dioxide followed by cadmium-chloride, the same results were obtained; lymphatic uptake of titanium-dioxide was increased. The authors concluded that dust particle uptake by the lymphatic system is increased when phagocytosis by alveolar macrophages is decreased.
Groups of 24 male and 24 female Syrian golden hamsters, 6-7 weeks of age, received intratracheal instillations of 3 mg titanium dioxide ((purity unspecified); particle size: 97% <5 um; 51% <0.5 um) plus 3 mg benzo(a)pyrene in 0.2 mL saline or 3 mg benzo(a)pyrene alone in saline (controls) once a week for 15 weeks. Animals were observed until spontaneous death; all control and treated hamsters had died by 90- 100 and 60-70 weeks, respectively. In the 48 hamsters treated with titanium dioxide plus benzo[a]pyrene, tumors (number of tumors per sex unspecified) occurred in the larynx (11 papillomas, five squamous-cell carcinomas), trachea (three papillomas, 14 squamouscell carcinomas, one adenocarcinoma) and lung (one adenoma, one adenocarcinoma, 15 squamous-cell carcinomas, one anaplastic carcinoma). Two papillomas occurred in the trachea of benzo(a)pyrene-treated controls. In the same study, ferric oxide (3 mg) and benzo(a)pyrene induced a similar spectrum of tumors to that induced by the combination with titanium dioxide.

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Non-Human Toxicity Values
LD50 Hamster dermal > or = 10,000 mg/kg body weight
LD50 Rat oral > 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.

Titanium dioxide (airborne, unbound particles of respirable size) can cause cancer according to California Labor Code.
Titanium dioxide is an odorless white powder. Tasteless. pH 7.5. Occurs in three crystalline forms. (NTP, 1992)
Titanium dioxide is a titanium oxide with the formula TiO2. A naturally occurring oxide sourced from ilmenite, rutile and anatase, it has a wide range of applications. It has a role as a food colouring.
Titanium dioxide, also known as titanium(IV) oxide or titania, is the naturally occurring oxide of titanium. It is used as a pigment under the names titanium white, Pigment White 6 (PW6), or CI 77891. It is typically extracted from ilmenite, rutile and anatase.
Anatase is a mineral with formula of Ti4+O2 or TiO2. The corresponding IMA (International Mineralogical Association) number is IMA1962 s.p.. The IMA symbol is Ant.
Brookite is a mineral with formula of Ti4+O2 or TiO2. The IMA symbol is Brk.
Rutile is a mineral with formula of Ti4+O2 or TiO2. The IMA symbol is Rt.
See also: Ensulizole; titanium dioxide (component of); Padimate O; titanium dioxide (component of); OCTISALATE; Titanium Dioxide (component of) ... View More ...

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

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Mechanism of Action
Diminish the penetration of ultraviolet (UV) light through the epidermis by absorbing UV radiation within a specific wavelength range. The amount and wavelength of UV radiation absorbed are affected by the molecular structure of the sunscreen agent.
Diminish the penetration of ultraviolet (UV) light through the epidermis by absorbing UV radiation within a specific wavelength range. The amount and wavelength of UV radiation absorbed are affected by the molecular structure of the sunscreen agent. /Sunscreen agents, topical/

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Therapeutic Uses
Photosensitizing Agents; Sunscreening Agents
Titanium dioxide has an action on the skin similar to that of zinc oxide and has similar uses. Titanium peroxide and titanium salicylate are used with titanium dioxide for nappy rash. Titanium dioxide reflects ultraviolet light and is used a physical sunscreen. It it also an ingredient of some cosmetics.
The physical compounds titanium dioxide and zinc oxide reflect, scatter, and absorb both UVA and UVB rays. ... Using new technology, the particle sizes of zinc oxide and titanium dioxide have been reduced, making them more transparent without losing their ability to screen UV.

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Drug Warnings
The manufacturers of sunscreen preparations with propellants warn that concentrating and subsequently inhaling the fumes from these preparations may be harmful or fatal. /Propellants/
Because the absorptive characteristics of skin of children younger than 6 months of age may differ from those of adults and because the immaturity of metabolic and excretory pathways of these children may limit their ability to eliminate any percutaneously absorbed sunscreen agent, sunscreen products should be used in children younger than 6 months of age only as directed by a clinician. It is possible that the characteristics of geriatric skin also differ from those of skin in younger adults, but these characteristics and the need for special considerations regarding use of sunscreen preparations in this age group are poorly understood. /Sunscreens/
Little information is available regarding the safety of chronic sunscreen usage, but commercially available physical and chemical sunscreens appear to have a low incidence of adverse effects. Derivatives of PABA, benzophenone, cinnamic acid, and salicylate and 2-phenylbenzimidazole-5-sulfonic acid have caused skin irritation including burning, stinging, pruritus, and erythema on rare occasions. /Sunscreens/
Sunscreens should not be used as a means of extending the duration of solar exposure, such as prolonging sunbathing, and should not be used as a substitute for clothing on usually unexposed sites, such as the trunk and buttocks. /Sunscreens/
For more Drug Warnings (Complete) data for TITANIUM DIOXIDE (11 total), please visit the HSDB record 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.)