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EC number: 236-675-5 | CAS number: 13463-67-7
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
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Repeated dose toxicity: inhalation
Administrative data
- Endpoint:
- short-term repeated dose toxicity: inhalation
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- not specified
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
Data source
Reference
- Reference Type:
- publication
- Title:
- Inhalation of high concentrations of low toxicity dusts in rats results in impaired pulmonary clearance mechanisms and persistent inflammation
- Author:
- Warheit, D.B. et al.
- Year:
- 1 997
- Bibliographic source:
- Toxicology and Applied Pharmacology 145: 10 - 22.
Materials and methods
Test guideline
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- Male rats were exposed to titanium dioxide particles 6 hours/day, 5 days/week for 4 weeks at concentrations of 5, 50, and 250 mg/m³ and evaluated at selected intervals through 6 months postexposure (0 hour, 1 week, and 1, 3, and 6 months). Indices of pulmonary inflammation as well as alveolar macrophage clearance functions (morphology, in vivo and in vitro phagocytosis, and chemotaxis), cell proliferation, and histopathology endpoints were measured at several post-exposure time periods through 6 months. In addition, amounts of TiO2 in lungs and tracheobronchial lymph nodes were measured to allow an evaluation of particle clearance and translocation patterns.
- GLP compliance:
- not specified
- Limit test:
- no
Test material
- Reference substance name:
- Titanium dioxide
- EC Number:
- 236-675-5
- EC Name:
- Titanium dioxide
- Cas Number:
- 13463-67-7
- Molecular formula:
- O2Ti
- IUPAC Name:
- dioxotitanium
- Test material form:
- solid: particulate/powder
- Details on test material:
- - Name of test material (as cited in study report): pigment-graded titanium dioxide particles (obtained from the DuPont Co. (Wilmington, DE))
- Particle size (mean diameters of individual particles): 0.25 µm (generally forms 1.0 µm agglomerates)
- Crystal structure: rutile
Constituent 1
- Specific details on test material used for the study:
- TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: particles were heated to 200 °C for 4 hours to eliminate the possibility of endotoxin contamination.
Test animals
- Species:
- rat
- Strain:
- other: Crl:CDBR
- Details on species / strain selection:
- not specified
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Laboratories, Kingston, NY
- Age at study initiation: 7 - 8 weeks
Administration / exposure
- Route of administration:
- inhalation
- Type of inhalation exposure:
- nose only
- Vehicle:
- air
- Mass median aerodynamic diameter (MMAD):
- >= 1.4 - <= 1.9 µm
- Details on inhalation exposure:
- The methods utilized for aerosol generation of titanium dioxide particles have previously been reported (Warheit et al., 1991)*.
*Reference:
- Warheit, D.B., Carakostas, M.C., Hartsky, M.A., and Hansen, J.F. (1991). Development of a short-term inhalation bioassay to assess pulmonary toxicity of inhaled particles: Comparisons of pulmonary responses to carbonyl iron and silica. Toxicol. Appl. Pharmacol. 107, 350 - 368. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Overall mean atmospheric concentrations were very close to the design concentrations.
- Duration of treatment / exposure:
- 4 weeks
- Frequency of treatment:
- 6 hours/day, 5 days/week
Doses / concentrationsopen allclose all
- Dose / conc.:
- 5.4 mg/m³ air (analytical)
- Remarks:
- Standard deviation: 6 mg/m³
- Dose / conc.:
- 51.9 mg/m³ air (analytical)
- Remarks:
- Standard deviation: 16 mg/m³
- Dose / conc.:
- 252.2 mg/m³ air (analytical)
- Remarks:
- Standard deviation: 86 mg/m³
- No. of animals per sex per dose:
- not specified
- Control animals:
- yes, sham-exposed
- Details on study design:
- not specified
- Positive control:
- not specified
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: not specified
DETAILED CLINICAL OBSERVATIONS: not specified
BODY WEIGHT: not specified
FOOD CONSUMPTION AND COMPOUND INTAKE: not specified
FOOD EFFICIENCY: not specified
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): not specified
OPHTHALMOSCOPIC EXAMINATION: not specified
HAEMATOLOGY: not specified
CLINICAL CHEMISTRY: not specified
URINALYSIS: not specified
NEUROBEHAVIOURAL EXAMINATION: not specified
IMMUNOLOGY: not specified
LUNG EVALUATIONS:
Following exposures, the lungs of TiO2 exposed animals and aged-matched sham controls were subsequently evaluated by bronchoalveolar lavage fluid analysis, BrdU cell labeling, lung clearance analysis, and in vitro macrophage function at 0 hour, 1 week, and 1, 3 and 6 months postexposure.
Bronchoalveolar lavage procedures and biochemical assays on lavaged fluids were conducted according to methods previously described (Warheit et al ., 1991)*.
- Phagocytosis:
Alveolar macrophage cell culture and phagocytosis assay methods have previously been reported (Warheit et al., 1984a,b)*. For the phagocytic assay for TiO2-exposed macrophages, a suspension of carbonyl iron particles was incubated with normal rat serum for 1 hour at 40°C and sonicatecl to reduce aggregations of particles. A final concentration of 1.75 mg/mL was added to monolayers.
- Chemotaxis:
Alveolar macrophages were collected from TiO2- or sham-expmed rats by lavage as described above. The chemotaxis assay was carried out as described previously using three concentrations (1, 5, and 10%) of zymosan-activated sera as the chemotactic stimulus (Warheit er al., 1984b, 1992)*
- Pulmonary cell proliferation studies:
Pulmonary cell proliferation experiments were conducted according to methods previously described (Warheit et ed., 1992)*.
*References:
- Warheit, D. B., Carakostas, M. C., Hartsky, M.A., and Hansen, J. F. (1991). Development of a short-term inhalation bioassay to assess pulmonary toxicity of inhaled particles: Comparisons of pulmonary responses to carbonyl iron and silica. Toxicol. Appl. Pharmacol. 107, 350-368.
- Warheit, D. B., Hill, L. H ., and Brody, A. R. (1984a). Surface morphology and correlated phagocytic capacity of pulmonary macrophages lavaged from the lungs of rats. Exp. Lung Res. 6, 71-82.
- Warheit, D.B., and Chang, L.Y., Hill, L.H., Hook, G.E.R., Crapo, J.D., and Brody, A.R. (1984b). Pulmonary macrophage accumulation and asbestos-induced lesions at sites of fiber deposition. Am. Rev. Respir. Dis. 129, 301-310.
- Warheit, D.B., Kellar, K.A., and Hartsky, M.A. (1992). Pulmonary cellular effects in rats following aerosol exposures to ultrafine Kevlar aramid fibrils: Evidence for biodegradability of inhaled fibrils. Toxicol. Appl. Pharmacol. 116, 225-239. - Sacrifice and pathology:
- GROSS PATHOLOGY: No data
HISTOPATHOLOGY: Yes
Histopathology was performed at 0 hour, 1 week and 1, 3, and 6 months postexposure.
The lungs of rats exposed to TiO2 for 4 weeks were prepared for light microscopy by airway infusion using methods previously reported (Warheit et al., 1984b, 1991)*. Analyses of lung and lymph node burdens were conducted by digesting tissue specimens in hydrofluoric acid and analyzing for titanium using the method of inductively coupled plasma (ICP-AES) spectroscopy.
*References:
- Warheit, D. B., Carakostas, M. C., Hartsky, M.A., and Hansen, J. F. (1991). Development of a short-term inhalation bioassay to assess pulmonary toxicity of inhaled particles: Comparisons of pulmonary responses to carbonyl iron and silica. Toxicol. Appl. Pharmacol. 107, 350-368.
- Warheit, D.B., and Chang, L.Y., Hill, L.H., Hook, G.E.R., Crapo, J.D., and Brody, A.R. (1984b). Pulmonary macrophage accumulation and asbestos-induced lesions at sites of fiber deposition. Am. Rev. Respir. Dis. 129, 301-310. - Other examinations:
- not specified
- Statistics:
- Statistics were carried out using two-tailed Student t-test on a Microsoft Exel software program (p<0.05).
Results and discussion
Results of examinations
- Clinical signs:
- not specified
- Mortality:
- not specified
- Body weight and weight changes:
- not specified
- Food consumption and compound intake (if feeding study):
- not specified
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- not specified
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- - lesions in the respiratory system varied with exposure concentration and duration of post-exposure recovery.
- 5 mg/m³ concentration: concentration produced only minimal effects. Particle-laden macrophages and a minimal diffuse increase in alveolar macrophages (histiocytosis) were evident at 0 days of recovery. The histiocytosis was no longer evident at 1 week postexposure. Individual particle-laden macrophages could be found in very low numbers within air spaces and lymphoid tissue throughout the entire 6-month postexposure period.
- 50 and 250 mg/m³: concentrations produced a wide spectrum of effects within the lung. Free granular pigment of TiO2 was present on the mucosal surfaces of bronchioles and bronchi at 0 days of recovery. Particle-laden macrophages, found individually, were numerous throughout the air spaces at this same time period. Beginning at 1 week post-exposure and persisting thereafter, many dense aggregates of particle-laden macrophages were within alveoli and alveolar ducts. Cellular hypertrophy and hyperplasia were evident at alveolar wall and duct bifurcations that were adjacent to macrophage aggregates. Mucosal hypertrophy and hyperplasia were also observed within the bronchi and bronchioles.
- number of pigment-laden macrophages found individually and in aggregates was much greater in animals exposed to the highest concentration, and occupied a greater portion of the lung.
- severity of cellular hypertrophy and hyperplasia at alveoli and alveolar duct bifurcations was significantly greater in animals exposed to the highest concentration of TiO2 particles.
- severity and character of the lesions changed with time. Free granular pigment was no longer apparent at 1 week post-exposure in any concentration group. Particle-laden macrophages, found individually, decreased in number with time, but were evident in small numbers within the pulmonary air spaces throughout the entire 6-month recovery period. The numbers and size of the dense aggregates of macrophages within alveoli and alveolar ducts, increased during the first month post-exposure but did not expand throughout the remaining 5-month post-exposure period. Minimal mucosal hypertrophy and hyperplasia in bronchi and bronchioles were evident at 1 month postexposure in the two highest concentration groups. Focal cellular hypertrophy and hyperplasia were associated with aggregates of pigmented macrophages, and were evident at alveoli and alveolar duct bifurcations for the entire 6-month postexposure period in the two higher concentration groups. Pigmented macrophages could also be observed within pulmonary lymphoid tissue throughout this time period. - Histopathological findings: neoplastic:
- not specified
- Other effects:
- effects observed, treatment-related
- Description (incidence and severity):
- LUNG BURDEN ANALYSIS
- four-week exposure to inhaled TiO2 particles produced significant exposure-related accumulations of particles in the lungs of exposed rats.
- animals exposed to 250 mg/m³ TiO2 had lung burdens of 1600 μg/g of fixed lung tissue or 12 mg/lung.
- ratio of mean lung burden/exposure concentration: 51, 54, and 46 µg/mg/m³ (5, 50, 250 mg/m³ dose level, respectively).
BRONCHOALVEOLAR LAVAGE DATA
- four-week exposure to inhaled TiO2 particles produced sustained pulmonary inflammatory responses in animals exposed to 250 mg/m³.
- nearly 100% of alveolar macrophages recovered by lavage from rats exposed to 250 mg/m³ TiO2 contained particles 6 months after the termination of exposures.
- substantial numbers of neutrophils were recovered in rats exposed to TiO2 at 250 mg/m³ dose level and this response was not significantly diminished until 6 months postexposure.
- rats exposed to 50 mg/m³ TiO2 demonstrated small but sustained inflammatory responses which reached control levels by 3 months postexposure.
- LDH and protein values in BAL fluids recovered from TiO2-exposed rats were elevated only in the 250 mg/m³ dose group.
PULMONARY CELL PROLIFERATION
- rats exposed to 250 mg/m³ TiO2 demonstrated substantial increases compared to controls in pulmonary cell proliferation indices measured on lung parenchymal and terminal bronchiolar surfaces and many of these effects were sustained through 3-6 months postexposure. - Details on results:
- BRONCHOALVEOLAR LAVAGE DATA
- no significant increases relative to controls in BAL alkaline phosphatase and N-acetylglucosaminidase values were measured for any exposure groups.
LUNG CLEARANCE
- following exposures to 250 mg/m³, clearance of TiO2 particles was evident during the time interval of 1 week through 1 month postexposure but appeared to be substantially diminished thereafter. A plot of the clearance data shows a typically rapid initial clearance followed by a slower phase. The amount measured in the lungs of exposed rats at the end of the 4-week exposure period was proportional to the exposure concentration for the three exposure concentrations. When fitted to a monoexponential clearance model (Morrow, 1977)*, the deposited TiO2 was found to clear with half-times of approximately 68, 110, and 330 days for the 5, 50, and 250 mg/m³ groups, respectively.
PARTICLE TRANSLOCATION TO TRACHEOBRONCHIAL LYMPH NODES
- evaluation of lymph node burdens of rats exposed to 250 mg/m³ TiO2 demonstrated that substantial amounts of TiO2 particles had translocated to tracheobronchial lymph nodes, particularly during the 1- to 3- and 3- to 6-month intervals.
- no appreciable translocation of TiO2 particles to lymph nodes at the other two concentrations.
ALVEOLAR MACROPHAGE FUNCTIONAL RESPONSES
- in vitro phagocytosis study demonstrated that alveolar macrophages exposed to 250 mg/m³ TiO2 were impaired in their phagocytic responses relative to controls and this effect was sustained through 1 month postexposure.
- Chemotaxis study: alveolar macrophages exposed to 250 mg/m³ TiO2 particles were impaired in their chemotactic responses to zymosan-activated sera when compared to controls. This effect was measured immediately after exposure, as well as 1 week and 3 months postexposure in TiO2-exposed animals.
*Reference:
- Morrow, P. E. ( 1977). Clearance kinetics of inhaled particles. In Respiratory Defense Mechanisms. Il. Lung Biology in Health and Disease (J. D.
Brain, Ed.), p. 493. Dekker, New York.
Effect levels
- Remarks on result:
- other:
- Remarks:
- 4-week inhalation exposures to high dust concentrations produced persistent pulmonary effects, many lasting throughout a 6-month post-exposure period. These included pulmonary inflammation, enhanced proliferation of pulmonary cells, impairment of particle clearance mechanisms, deficits in macrophage function, and morphological evidence of macrophage aggregation.
Target system / organ toxicity
- Critical effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- 4-week inhalation exposures to high dust concentrations produced persistent pulmonary effects, many lasting throughout a 6-month post-exposure period. These included pulmonary inflammation, enhanced proliferation of pulmonary cells, impairment of particle clearance mechanisms, deficits in macrophage function, and morphological evidence of macrophage aggregation.
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