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Description of key information

An OECD 420 study is available on TiO2. LD0 = 5000 mg/kg bw. 

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
no data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study
Qualifier:
according to
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
GLP compliance:
not specified
Test type:
fixed dose procedure
Limit test:
yes
Species:
mouse
Strain:
CD-1
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Beijing Vitalriver Experimental Animal Technology Co. Ltd.
- Age at study initiation: not reported
- Weight at study initiation: 19g (+- 2g)
- Fasting period before study: over night
- Housing: steel cage
- Individual metabolism cages: no
- Diet (e.g. ad libitum): yes, ad libitum
- Water (e.g. ad libitum): yes, ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20°C (+-2°C)
- Humidity (%): 60% (+-10%)
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12h/12h
Route of administration:
oral: gavage
Vehicle:
other: HPMC
Details on oral exposure:
VEHICLE: 0.5% hydroxypropylmethylcellulose K4M (HPMC, K4M) was used as a suspending agent; no data on justification
- 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

MAXIMUM DOSE VOLUME APPLIED: 3 g of the test substance per 12 ml of vehicle; 5 g per kg body weight

CLASS METHOD (if applicable)
- 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
Doses:
5 g/kg bw
No. of animals per sex per dose:
10 males and 10 females per dose
Control animals:
yes
Details on study design:
- 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
Statistics:
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.
Preliminary study:
no data
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Mortality:
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.
Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Titanium dioxide is not considered toxic after oral application. A LD50 > 5000 mg/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%) in 0.5 % hydroxypropylmethylcellulose K4M (HPMC, K4M) at a dose of  5 g/kg body weight and were observed for 14 days. An oral LD50 (males/females) of more than 5 g/kg body weight could be established. As none of the animals died the LD0 is 5 g/kg body weight.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
5 000 mg/kg bw
Quality of whole database:
The study was conducted according to accepted scientific standards and is well documented.

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

In an acute oral toxicity study according to OECD 420, groups off 10 mice/sex/dose were given a single oral dose of Titanium dioxide (5000 mg/kg bw) and were observed for 14 days. No mortality occurred. The bioaccessibility of TiC in artificial interstitial fluid is below the limit of detection (< 50µg/g sample). Thus, systemic exposure via inhalation is expected to be even lower than via the gastro-intestinal route.


Justification for selection of acute toxicity – oral endpoint
An OECD 420 study is available on TiO2.

Justification for classification or non-classification

Titanium carbide is considered to have a very low potential for acute toxic effects.