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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
2003-01-22 to 2003-04-03
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study. However, measurements of the excretion were not conducted until 95% of the administered dose had been excreted or for 7 days.
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2003
Report Date:
2003

Materials and methods

Objective of study:
absorption
distribution
excretion
Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Deviations:
yes
Principles of method if other than guideline:
Measurements of the excretion were not conducted until 95% of the administered dose had been excreted or for 7 days.
GLP compliance:
yes (incl. certificate)
Remarks:
signed 2001-04-03

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report):Titanium dioxide
- Molecular formula (if other than submission substance): TiO2
- Molecular weight (if other than submission substance): 79.90 g/mol

Rutile (thin platelet):
- Physical state: Slightly coloured powder
- Analytical purity: 98.7%
- Lot No.: 1038
- Expiry date: 2003-07-02
- Storage: ambient temperature in dry conditions

Rutile (thick platelet):
- Physical state: Slightly coloured powder
- Analytical purity: 99.2%
- Lot No.: 1016
- Expiry date: 2003-03-08
- Storage: ambient temperature in dry conditions

Rutile (amorphous):
- Physical state: White powder
- Analytical purity: 99.3%
- Lot No.: 5216514
- Expiry date: 2003-07-03
- Storage: ambient temperature in dry conditions

Anatase (amorphous):
- Physical state: White powder
- Analytical purity: 99.2%
- Lot No.: 5218414
- Expiry date: 2003-07-03
- Storage: ambient temperature in dry conditions

No further information on test material was stated
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Ltd. Margate, UK
- Age at study initiation: 6-10 weeks
- Weight at study initiation: 117g-151g
- Housing: steel cages
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): yes
- Water (e.g. ad libitum): yes
- Acclimation period: 5d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21°C (+-2°C)
- Humidity (%): 55% (+-15%)
- Air changes (per hr): >=15
- Photoperiod (hrs dark / hrs light): 12h/12h

Administration / exposure

Route of administration:
oral: feed
Vehicle:
other: diets
Details on exposure:
The test animals were fed with diets with different forms of TiO2 at approx. 200 ppm (equivalent to ca. 30 mg/kg bw) for 7 days after which the diets were replaced by control diet.
Diets were available to the animals ad libitum. Groups of animals were sacrificed at 1, 24 and 72 hours after withdrawal of the treated diets.
Duration and frequency of treatment / exposure:
7d
Doses / concentrations
Remarks:
Doses / Concentrations:
200ppm titanium dioxide in the diet (estimated to be equivalent to 30mg/kg bw/day, assuming daily consumption of 30g diet by a 200g rat)
No. of animals per sex per dose:
3m, 3f
Control animals:
yes
Positive control:
no
Details on study design:
- Dose selection rationale: dose level is lower than the NOAEL in a 103 week dietary study (=2500mg/kg bw/day)
Details on dosing and sampling:
METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine, faeces, whole-blood, liver, kidney, muscle
- Time and frequency of sampling: 1, 24, 72h after withdrawal of the treated diets
- Method type(s) for identification ICP-AES
- Limits of detection and quantification: LOQ=2ng/mL
Statistics:
two-way analysis of variance (ANOVA)

Results and discussion

Main ADME resultsopen allclose all
Type:
excretion
Results:
The total amount of titanium excreted in faeces accounted for means of 1.1-2.2 mg for male rats and 1.1-1.3 mg for female rats during 0 – 72 hours after withdrawal of the treated diets.
Type:
excretion
Results:
Titanium concentrations in urine were below the limit of quantification (<0.04 mg/l equivalent to <2% daily dose/l) in all but one sample: 0-24 hour urine from one male rat (0.05 mg/l).
Type:
distribution
Results:
Ti concentrations in liver, kidney and muscle were mainly below the limit of detection (<0.1 - <0.2 mg/kg wet weight) or in the range of 0.1 – 0.3 mg/kg wet weight for all groups including controls.
Type:
absorption
Results:
Whole-blood concentrations of titanium were <0.04 mg/ml for all animals and treatments.

Metabolite characterisation studies

Metabolites identified:
no
Details on metabolites:
Titanium dioxide as an inorganic substance is not metabolised.

Any other information on results incl. tables

The total amount of titanium excreted in faeces accounted for means of 1.1-2.2 mg for male rats and 1.1-1.3 mg for female rats during 0 – 72 hours after withdrawal of the treated diets.

Titanium concentrations in urine were below the limit of quantification (<0.04 mg/l equivalent to <2% daily dose/l) in all but one sample: 0-24 hour urine from one male rat (0.05 mg/l). 

Whole-blood concentrations of titanium were <0.04 mg/ml for all animals and treatments.

Titanium concentrations in liver, kidney and muscle were mainly below the limit of detection (<0.1 - <0.2 mg/kg wet weight) or in the range of 0.1 – 0.3 mg/kg wet weight for all groups including controls. The limit of detection was expressed as a range of values as a consequence of the variability in weights of individual samples taken for analysis.

The results suggest that there is no substantial accumulation of titanium in tissues following administration of diets with different forms of titanium dioxide.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
The results suggest that there is no substantial accumulation of titanium in tissues following administration of diets with different forms of titanium dioxide.