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EC number: 235-120-4
CAS number: 12070-08-5
Bioelution data for TiC support read-across between TiO2 and TiC. Details are given in the attached read-across report. Titanium dioxide did not show adverse effects in a chronic oral repeated dose toxicity study in rats, with a NOAEL of 3,500mg/kg bw/day. Titanium dioxide is not absorbed to any relevant extent through human skin, thus no toxic effects can be expected via the dermal route of exposure. Titanium dioxide showed fibrogenic effects in a chronic inhalation repeated dose toxicity study in rats with a NOAEC of 10 mg/m³. This is considered a rodent specific overload effect with limited significance in human risk assessment.
In the female rats, C-cell adenomas or carcinomas of the thyroid occurred
at incidences that were dose related (P = 0.013), but were
not high enough (P = 0.043 for direct comparison of the high-dose group
with the control group) to meet the level of P = 0.025 required
by the Bonferroni criterion (controls 1/48, low- dose 0/47, high-dose
6/44). Thus, these tumors of the thyroid were not considered to be
related to the administration of the test chemical.
Inflammatory, degenerative, and hyperplastic lesions that occurred were
similar in number and kind to those naturally occurring lesions found in
aged Fischer 344 rats. Based on the histopathologic examination,
titanium dioxide was neither toxic nor carcinogenic to Fischer 344 rats
under the conditions of this bioassay.
In a chronic toxicity study Titanium dioxide (> 98%) was administered to
50 F344 rats per sex and dose in the diet at dose levels of 0, 25000,
and 50000 ppm for 103 weeks.
Administration of titanium dioxide had no appreciable effect on the mean
body weights of rats of either sex. With the exception of white feces,
there was no other clinical sign that was judged to be related to the
administration of titanium dioxide. Survival of the rats at the end of
the bioassay was not affected by the test chemical. Sufficient numbers
of dosed and control rats of each sex were at risk for development of
In the female rats, C-cell adenomas or carcinomas of the thyroid
occurred at incidences that were dose related (P = 0.013), but were not
high enough (P = 0.043 for direct comparison of the high-dose group with
the control group) to meet the level of P = 0.025 required by the
Bonferroni criterion (controls 1/48, low-dose 0/47, high-dose 6/44).
Thus, these tumors of the thyroid were not considered to be related to
the administration of the test chemical.
It is concluded that under the conditions of this bioassay, titanium
dioxide was not carcinogenic by the oral route for Fischer 344 rats. A
NOEL of 50000 ppm was established.
Table1: Lung and final body weights of rats exposed to TiO2at
0, 10, 50, or 250 mg/m³.
Final body weights
Lung/body weight ratio
0 mg/m³ (Control)
*Significantly different (p < 0.05) from control group by Dunnett`s test.
Table2: Incidence of main nonneoplastic lesions in the
nasal cavity and trachea
Sq. metaplasia, anterior
Sq. metaplasia, posterior
( ) the number of rats examined is in parentheses
Table3: Incidence of main nonneoplastic lesions in the
nasal cavity and trachea
Aggregates, foamy alveolar
Alveolar cell hyperplasia,
Anaplastic carcinoma, large cell
Squamous cell carcinoma
( ) In parentheses is the number of rats examined
In a combined repeated dose and carcinogenicity study
Titanium dioxide was administered to 400 male and female Crj:
CD(SD) rats by inhalation at nominal concentrations of 0, 10, 50,
and 250 mg/m³ 6 hours a day, 5 days a week for 24 month.
There were no abnormal clinical signs, body weight changes,
or excess mortality in any exposed group. Exposed groups showed
slight increases in the incidence of pneumonia, tracheitis, and
rhinitis with squamous metaplasia in the anterior nasal cavity.
The lung reaction was characterized by dust-laden macrophage (dust
cell) infiltration in the alveolar ducts and adjoining alveoli
with hyperülasia of type II pneumocytes. Exposure to 50 and 250
mg/m³ resulted in dose dependent dust cell accumulation, a foamy
macrophage response, type II pneumocyte hyperplasia, alveolar
proteinosis, alveolar brochiolarization, cholesterol granulomas,
focal pleurisy, and dust deposition in the tracheobronchial lymph
nodes. The pulmonary lesions with massive dust accumulation
appeared to be the result of an overwhelmed lung clearance
mechanism at 250 mg/m³ exposure., Bronchioloalveolar adenomas and
cystic keratinizing squamous cell carcinomas occurred at 250 mg/m³
Based on the findings at the low dose (alveolar cell
hyperplasia, broncho/bronchiolar pneumonia) the concentration of
10 mg/m³ is considered as NOEC for non-neoplastic changes in this
Bronchioloalveolar adenomas and cystic keratinizing squamous cell
carcinoma occurred at 250 mg/m³ TiO2 exposure (the tumours
produced were ultimately characterized as primarily benign
pulmonary keratin cysts (Warheit and Frame,2006)), while no
compound-related lung tumors were found in rats exposed either to
10 or 50 mg/m³. Thus, the concentration of 50 mg/m³ represents the
NOEC for carcinogenicity in rats.
Potential titanium ion release by different routes of human
exposure can be compared for different titanium substances by using in
vitro bioelution testing. Bioelution has been assessed for TiC in four
artificial body fluids. These data support read-across between TiO2 and
TiC. Details are given in the attached read across report. A
bioassay of titanium dioxide for possible carcinogenicity was conducted
by the National Cancer Institute (1979). Titanium dioxide was
administered via feed to Fischer 344 rats and B6C3F1 mice. It was
concluded that under the conditions of this assay the test substance was
not carcinogenic by the oral route for Fisher 344 rats or B6C3F1 mice.
In a publication of Lee et al. (1985) cystic keratinizing squamous
lesions were reported to be produced in rats after chronic exposures to
high concentrations of pigment-grade TiO2 particles. Furthermore chronic
inhalation exposure of rats to very high doses of particles can result
in inflammation, fibrosis, and some lung tumors. Exposures to TiO2
resulted in impairment of alveolar macrophage clearance functions,
sustained persistent pulmonary inflammation, and enhanced cell
proliferative responses. The keratin cysts are a species specific lesion
that is unique to the rat under conditions of particle overload.
A more comprehensive histopathological evaluation determined that the
keratinizing lesions were not neoplastic (IARC Monograph 93).
Bermudez et al. (2002 and 2004) showed the species specific response to
chronic exposure with TiO2. Rats, hamster, and mice were exposed to 0,
10, 50 and 250 mg/m³ TiO2 for 13 weeks. The lung burdens of the species
were equivalent, but rats had more severe and persistent inflammatory
response than mice and hamster. The major species specific reactions to
TiO2 exposure were described to be a faster pulmonary clearance of dust
in hamsters than in rats and mice, particle overload was observed in
mice and rats, pulmonary cellular and tissue responses to particle
overload were different in the species. Rats developed greater and
sustained lung inflammatory response and a significantly more intensive
epithelial and fibroproliferative response. These results were also
shown by a companion study with ultra-fine titanium dioxide.
Warheit et al. (1997) showed that the lungs of particle-overloaded rats
are characterized by impaired pulmonary clearance, sustained pulmonary
inflammation, cellular hypertrophy, and hyperplasia. These effects are
likely to result in the development of overload-related pulmonary tumors.
In summary, the results of the studies show that pulmonary tumors in
TiO2-exposed rats are developed only after chronic, 2-year inhaled doses
which produced massive particle overload in the lung (250 mg/m³)
associated with marked, sustained inflammation. Despite particle
overload and persistent pulmonary inflammation was observed after a two
year exposure to 50 mg/m³ TiO2 no lung tumors were observed.
The tumorigenic response observed in the rat lung was shown to be
species specific and restricted to doses in which there is an overload
to the particle clearance mechanism. The species-specific response to
particulate exposure is not relevant for extrapolating results to humans
for purposes of determining human cancer risk.
The publication by the National Cancer Institute (1979) is considered as
the key study for repeated dose toxicity via oral application and will
be used for classification. Based on the lack of adverse effects, the no
observed adverse effect level (NOAEL) via oral application for titanium
dioxide was established to be 3500 mg/kg bw/day.
The classification criteria according to regulation (EC) 1272/2008 as
specific target organ toxicant (STOT) repeated exposure, oral are not
met since no reversible or irreversible adverse health effects were
observed immediately or delayed after exposure and the no observed
adverse effect level (NOAEL) via oral application is above the guidance
value for a Category 2 classification (100 mg/kg bw/day). Therefore, no
classification for specific target organ toxicant (STOT) repeated
exposure via the oral route is required.
The species specific sensitivity of rats to the exposure with titanium
dioxide and lung damage under conditions of particle overload was
In the rat particle overload finally results in fibroproliferative
disease, septal fibrosis, hyperplasia and eventually lung tumours.
However, similar pathological changes are not observed in other common
laboratory rodents, non-human primates or in exposed humans. According
to regulation (EC) 1272/2008, a classification for specific target organ
toxicity repeated exposure shall be taken into account only when
reliable evidence associating repeated exposure to the substance with a
consistent and identifiable toxic effect demonstrates support for the
classification. These adverse health effects include consistent and
identifiable toxic effects in humans, or in experimental animals,
toxicologically significant changes which have affected the function or
morphology of a tissue/organ, or have produced serious changes to the
biochemistry or haematology of the organism and these changes are
relevant for human health.
No systemic toxicity was shown from the results of chronic inhalation
exposure to high concentrations of pigment grade titanium dioxide.
Particle overload was observed with the rat being the most sensitive
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