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Acute Toxicity: oral

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acute toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Published data. Study conducted according to OECD guideline 420.

Data source

Reference Type:
Acute toxicity and biodistribution of different sized titanium dioxide particles in mice after oral administration
Wang, J
Bibliographic source:
Toxicol. Letters 168, 176-185

Materials and methods

Test guideline
according to guideline
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
GLP compliance:
not specified
Test type:
fixed dose procedure
Limit test:

Test material

Constituent 1
Reference substance name:
Titanium dioxide
EC Number:
EC Name:
Titanium dioxide
Cas Number:
Test material form:
other: nano-sized TiO2 and fine TiO2 particles
Details on test material:
- Name of test material (as cited in study report): Titanium dioxide; nano-sized TiO2 (Hangzhou Dayang Nanotechnology Co. Ltd., 80 and 25 nm) and fine TiO2 particles were used in this experiment
- Substance type: inorganic
- Physical state: solid
- Analytical purity: The nominal purity of TiO2 powder is >92%. The sodium and chlorine contents are both below 0.001% X-ray fluorescence analysis (XRF) was used to check up the purity of TiO2. A molybdenum X-ray tube was used to excite samples and the FWHM of the Si(Li) detector for Mn K-alpha peak was 146 eV. The results show that the purity of different sized particles is better than 99%.

Test animals

Details on test animals or test system and environmental conditions:
- Source: Beijing Vitalriver Experimental Animal Technology Co. Ltd.
- Age at study initiation: not reported
- Weight at study initiation: 19g (+- 2g)
- Fasting period before study: Before treatment: over night; after treatment: 2h
- Housing: stainless steel cages
- Individual metabolism cages: no
- Diet (e.g. ad libitum): yes, ad libitum
- Water (e.g. ad libitum): yes, ad libitum
- Acclimation period: 5 days

- Temperature (°C): 20 °C (+-2 °C)
- Humidity (%): 60% (+/- 10%)
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
other: HPMC (0.5% w/v)
Details on oral exposure:
- Concentration in vehicle: 3 g per 12 mL
- Amount of vehicle (if gavage): not reported
- Justification for choice of vehicle: not reported
- Lot/batch no. (if required): not reported
- Purity: no data

3 g of the test substance per 12 mL of vehicle; 5 g per kg body weight

- Rationale for the selection of the starting dose: Due to the low toxicity, a fixed large dose of 5 g/kg body weight of TiO2 suspensions was administrated by a single oral gavage according to the OECD procedure.
- Before treatment, animals were fasted over night
5 g/kg bw
No. of animals per sex per dose:
Control animals:
Details on study design:
- animals were randomly divided into four groups: control group and three experimental groups (25, 80 nm and fine). After vigorous stirring, TiO2 suspension was given to mice by a syringe via gastrointestinal tract in a minute.
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The symptoms and mortality were observed and recorded carefully during the first 24 h; body weight and organ weights were determined at the beginning and at the end of the study; Blood samples and serum was harvested after the study period of 14 days.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other: biodistribution
Results were expressed as mean ± standard deviation (S.D.). Multigroup comparisons of the means were carried out by one-way analysis of variance (ANOVA) test. Dunnett’s test was used to compare the differences between the experimental groups and the control group. Student’s t-test was used to compare the means of each nano-group and the corresponding fine group. The statistical significance for all tests was set at p < 0.05.

Results and discussion

Preliminary study:
no data
Effect levels
Dose descriptor:
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
No mortality associated to the application of the test material was observed.
Clinical signs:
see "other findings"
Body weight:
No obvious differences were found in the body weight of four groups.
Gross pathology:
No abnormal pathology changes in the heart, lung, testicle (ovary), and spleen tissues are reported
Other findings:
- Organ weights: No differences were observed in the coefficients of liver, spleen, and kidneys of the male mice. For the female mice, the coefficients of liver in the 80 and 25 nm groups were significantly higher (p < 0.05) than the control and fine groups. The increased coefficients indicate that the inflammation might be induced in the female mice after ingestion of TiO2 particles, which was confirmed by the further morphological examination of liver. There are no significant changes in the coefficients of spleen and kidneys.
- Histopathology: hepatic injury (hydropic degeneration around the central vein and the spotty necrosis of hepatocyte) and renal lesion (proteinic liquids in the renal tubule and swelling in the renal glomerulus) were observed in the histopathological examination.
- Potential target organs: liver
- Other observations: The changes of serum biochemical parameters (ALT/AST, LDH) and pathology (hydropic degeneration around the central vein
and the spotty necrosis of hepatocytes) of liver indicated that the hepatic injury was induced after exposure to mass different-sized
TiO2 particles. In addition, the nephrotoxicity like increased BUN level and pathology change of kidneys was also observed in
the experimental groups. The significant change of serum LDH and alpha-HBDH in 25 and 80 nm groups showed the myocardial
damage compared with the control group.
- Biodistribution experiment showed that TiO2 mainly retained in the liver, spleen, kidneys, and lung tissues, which
indicated that TiO2 particles could be transported to other tissues and organs after uptake by gastrointestinal tract.

Applicant's summary and conclusion

Interpretation of results:
not classified
Migrated information Criteria used for interpretation of results: EU
Based on the date from the read across partner Titanium dioxide, TiN is not considered toxic after oral application. An LD50 of greater than 5000 mg Ti/kg bw was established.
Executive summary:

In an acute oral toxicity study according to OECD guideline 420 (fixed dose procedure), groups of fasted CD-1 mice (10 males and 10 females) were given a single oral dose of titanium dioxide (>99% purity) in 0.5 % hydroxypropylmethylcellulose K4M (HPMC, K4M) at a dose of  5000 mg/kg bw and were observed for 14 days. No mortality occured. Based on the results from this study, the oral LD50 (males/females) in mice is considered to be greater than 5000 mg/kg bw.

This information is used in a read-across approach for the assessment of titanium nitride.