Reaction mass of disodium hexatitanium tridecaoxide and disodium trititanium heptaoxide

Acute Toxicity: other routes

Administrative data

Endpoint:

acute toxicity: other routes

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

Sodium titanates are effectively the sodium salts of the unstable titanic acid (titanium hydroxide). Titanium hydroxide is hard to isolate without rapid hydrolysis to titanium dioxide and sodium chloride. It is therefore proposed to base environmental and health assessment on these two hydrolysis products. There has been extensive research on similar substances in the ‘titanate’ grouping and these all exhibit similar behaviour in that under acid biological conditions (eg if ingested) or if dispersed in water, there is dissociation of the ions and subsequent hydrolysis / oxidation. Read-across justification for the use of TiO2 data is available in section 13.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

2013

Report date:

2013

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

In this study, mice were injected intravenously with a single dose of TiO2 NPs at varying dose levels (0, 140, 300, 645, or 1387 mg/kg). Animal mortality, blood biochemistry, hematology, genotoxicity and histopathology were investigated 14 days after treatment.

GLP compliance:

not specified

Remarks:

No details given apart from the fact that animal study protocols were approved by the Ningbo University Institutional Animal Care and Use Committee.

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Titanium dioxide

EC Number:

236-675-5

EC Name:

Titanium dioxide

Cas Number:

51745-87-0

Molecular formula:

O2Ti

IUPAC Name:

Titanium dioxide

Test material form:

solid: particulate/powder

Specific details on test material used for the study:

TiO2 NPs were obtained from Hangzhou Wanjing new material Co, Ltd (Lot No. 20110228).
TiO2 NPs; form = 100% Anatase; purity = 99.99; particle size = 40±5 nm

Test animals

Species:

mouse

Strain:

ICR

Sex:

male/female

Details on test animals or test system and environmental conditions:

48 (24 male and 24 female) ICR mice were housed according to their sex in stainless steel cages in a ventilated animal room (Relative humidity at 60±10% and a 12 hour light/dark cycle). Room temperature was maintained at 20±2°C. Distilled water and sterilized food for mice were available ad libitum. Animal study protocols were approved by the Ningbo University Institutional Animal Care and Use Committee.

Administration / exposure

Route of administration:

intravenous

Vehicle:

other: fresh saline

Details on exposure:

Animals were randomly divided into 5 groups: 1 control group and 4 experimental groups (0, 140, 300, 645, and 1387 mg/kg BW of TiO2 NPs). Each group had 8 mice (4 male and 4 female). The remaining 8 mice (4 male and 4 female) were used as the positive control in the micronucleus test. TiO2 NPs dose setting was based on the principle of Horn's Method. After mixing with a vortex, a single injection of TiO2 NPs saline suspension was administered through the tail vein (28 G needle). Control group mice were given saline only. Behavior and mortality were monitored and recorded carefully after treatment.

Doses:

Single injection

No. of animals per sex per dose:

4 male, 4 female per group

Control animals:

yes

Details on study design:

A stock suspension of TiO2 NPs was prepared in saline (10 mg/ml) by sonication for 30 seconds using a Branson sonifier 450 (Branson Ultrasonics Corp., Danbury, CT). The particle suspensions were kept on ice for 15 seconds and sonicated again on ice for a total of 3 minutes at a power of 400 W. Before use, TiO2 NPs were diluted to desired concentrations in fresh saline. All samples were prepared under sterile conditions.

Statistics:

Results were expressed as mean ± standard deviation (SD). Multigroup comparisons of the means were carried out by one-way analysis of variance (ANOVA) test. Dunnett's test was used to compare the difference between the experimental groups and the control group. The statistical significance for all tests was set at P<0.05.

Results and discussion

Effect levels

Sex:

male/female

Dose descriptor:

LD50

Effect level:

>= 645 - <= 1 387 mg/kg bw

Based on:

test mat.

Remarks on result:

other:

Remarks:

Death of mice in the highest dose (1387 mg/kg) group was observed at day two after TiO2 NPs injection. At day 7, acute toxicity symptoms, such as decreased physical activity and decreased intake of food and water, were observed in the highest dose group. Hematological analysis and the micronucleus test showed no significant acute hematological or genetic toxicity except an increase in the white blood cell (WBC) count among mice 645 mg/kg dose group. However, the spleen of the mice showed significantly higher tissue weight/body weight (BW) coefficients, and lower liver and kidney coefficients in the TiO2 NPs treated mice compared to control. The biochemical parameters and histological tissue sections indicated that TiO2 NPs treatment could induce different degrees of damage in the brain, lung, spleen, liver and kidneys. However, no pathological effects were observed in the heart in TiO2 NPs treated mice.

Mortality:

7 days after treatment, difference in eating and drinking patterns and physical activity were observed in the 1387 mg/kg dose group. They showed decreased food and water intake and decreased physical activity than control group. At day 9, 2 males and 4 females in the 1387 mg/kg dose group died. 2 males survived at this dose level, leaving less than three mice at the end of the experiment. Therefore, in this dose group only the tissues were histopathologically analyzed.

Gross pathology:

The mice treated with TiO2 NPs showed significantly higher spleen organ weight/BW coefficients, and lower liver and kidney organ/BW coefficients compared to control.

Other findings:

Hematological analysis and micronucleus test showed no significant acute hematological or genetic toxicity except an increase of WBC count in mice at 645 mg/kg.

Applicant's summary and conclusion

Conclusions:

Intravenous injection of TiO2 NPs at high doses in mice could cause acute toxicity effects in the brain, lung, spleen, liver, and kidney.
No significant hematological or genetic toxicity was observed.
Death of mice in the highest dose (1387 mg/kg) group was observed at day two after TiO2 NPs injection. At day 7, acute toxicity symptoms, such as decreased physical activity and decreased intake of food and water, were observed in the highest dose group. Hematological analysis and the micronucleus test showed no significant acute hematological or genetic toxicity except an increase in the white blood cell (WBC) count among mice 645 mg/kg dose group. However, the spleen of the mice showed significantly higher tissue weight/body weight (BW) coefficients, and lower liver and kidney coefficients in the TiO2 NPs treated mice compared to control. The biochemical parameters and histological tissue sections indicated that TiO2 NPs treatment could induce different degrees of damage in the brain, lung, spleen, liver and kidneys. However, no pathological effects were observed in the heart in TiO2 NPs treated mice.
Whilst the test substance was administered via intravenous injection which is a non-physiological route of TiO2 administration, the results indicate that should TiO2 enter the bloodstream at high doses w.r.t. mice, some effect can be observed at levels above 645 mg/kg.