Reaction mass of disodium hexatitanium tridecaoxide and disodium trititanium heptaoxide

Endpoint summary

Description of key information

Acute toxicity, oral:

LD50 > 2000 mg/kg bw  for rat

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2010-05-06 to 2010-05-28

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

GLP guideline study reliable without restrictions

Justification for type of information:

Disodium titanate substance (EC 234-802-9) has the molecular formula Na2TiO3 and its composition is expressed as (Na2O)x(TiO2), where x is ranging from 0.1 to 6 according to the SIP. This substance, Reaction mass of Disodium Hexatitanate and Sodium Metatitanate, has a value of x = 0.21, calculated from XRF results, has been identified as a mixture of two specific types of disodium titanate and is therefore within the scope of the disodium titanate SIP.
It is assessed therefore that disodium titanate is an acceptable read-across substance for Reaction mass of Disodium Hexatitanate and Sodium Metatitanate

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Version / remarks:

, 2001-12-17

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

signed 2008-11-12

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Laboratories B.V., Kreuzelweg 53, 5961 NM Horst / The Netherlands
- Age at study initiation: 10 weeks
- Weight at study initiation: 183.8 g – 199.0 g
- Fasting period before study: rats were fasted for approximately 16 to 19 hours, but with free access to water. Food was presented approximately 3 hours after dosing.
- Housing: In groups of three in Makrolon type-4 cages with wire mesh tops and standard softwood bedding (‘Lignocel’, J. Rettenmaier&Söhne GmbH&CoKG, 73494 Rosenberg / Germany, imported by Provimi Kliba AG, 4303 Kaiseraugst / Switzerland). including paper enrichment (Enviro-dri from Lillico, Biotechnology, Surrey, UK).
- Diet (ad libitum): Pelleted standard Provimi Kliba 3433 rat/mouse maintenance diet, batch no. 83/09 (Provimi Kliba AG, 4303 Kaiseraugst / Switzerland) (except for the overnight fasting period prior to intubation and approximately 3 hours post dose).
- Water (ad libitum): Community tap water from Füllinsdorf
- Acclimation period: Five to eight days under laboratory conditions, after health examination. Only animals without any visible signs of illness were used for the study.
Music played during the daytime light period.

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 3 °C
- Relative humidity: 30-70%
- Air changes: 10-15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12/12
No further information on the test animals was stated.

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

VEHICLE
- Source: Carl Roth GmbH & Co., 76185 Karlsruhe / Germany
- Justification for choice of vehicle: The vehicle was chosen after a non-GLP solubility trial which was performed before the study initiation date. The test item formulated at 20% (w/w) in corn oil was described as a clear yellow solution and was considered to be suitable for an oral application.
- Batch no.: 049103168
- Expiry Date: 31-Jan-2014
- Stability of the Vehicle: Stable under storage conditions
- Storage Conditions: At room temperature (range of 20 ± 5 °C), light protected.
- Description: Yellowish oily liquid

MAXIMUM DOSE VOLUME APPLIED: The application volume was 10 mL/kg body weight.

DOSAGE PREPARATION: The dose formulations were prepared shortly before each dosing occasion using a magnetic stirrer and a spatula as homogenizers.
The test item was weighed into a tared glass beaker on a suitable precision balance and the vehicle added (weight:volume).
Homogeneity of the test item in the vehicle was maintained during administration using a magnetic stirrer.
No further information on the oral exposure was stated.

Doses:

2000 mg/kg

No. of animals per sex per dose:

2 x 3 female rats (Total: 6 female rats)

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Viability/mortality was checked daily during acclimatization. Then it was checked once before treatment
and within the first 30 minutes and at approximately 1, 2, 3 and 5 hours after treatment on test day 1 (in common with the clinical signs). After test day 1, viability/mortality was checked twice daily during days 2 – 15. Clinical signs were checked daily during acclimatization. Then clinical signs were checked once before treatment and within the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1. After test day 1, clinical signs were checked once daily during days 2 – 15. Body weight was measured on test days 1 (prior to administration), 8 and 15.
- Necropsy of survivors performed: Yes
All animals were sacrificed at the end of the observation period by carbon dioxide asphyxiation and discarded after macroscopic examinations were performed. An external examination and opening of the abdominal and thoracic cavities for examinations of major organs was performed. The appearance of any macroscopic abnormalities was recorded. No organs or tissues were retained.
No further information on the study design was performed.

Statistics:

No statistical analysis was performed.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No intercurrent deaths occurred during the course of the study.

Clinical signs:

other: No clinical signs were observed throughout the entire observation period.

Gross pathology:

No macroscopic findings were recorded at necropsy.

Other findings:

No data

Interpretation of results:

not classified

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

The median lethal dose of disodium titanate after single oral administration to female rats, observed over a period of 14 days, is:
LD50 (female rat): > 2000 mg/kg body weight
Based upon regulation (EC) No 1272/2008 and its subsequent amendments, disodium titanate is not classified with respect to acute oral toxicity in the rat.
Also, based upon the Directive 67/548/EEC and its subsequent amendments, disodium titanate is not classified with respect to acute oral toxicity in the rat.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

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.

Qualifier:

no guideline followed

Principles of method if other than guideline:

Fischer 344 male rats were exposed either with whole-body or nose-only inhalation for 6 hrs. Control animals were exposed to fresh air only. After the exposue period of 6 hrs animals were immediately sacrificed by overdose of phenobarbital. The body weights were recorded, the lungs were collected and the wet lung weights measured. The right lung was used for determining the amounts of TiO2, while the left lung was used for histopathological examination

GLP compliance:

not specified

Remarks:

All procedures and animal handling were done according to the guidelines described in the Japanese Guide for the Care and Use of Laboratory Animals as approved by the Animal Care and Use Committee University of Occupational and Environmental Health Japan.

Limit test:

no

Specific details on test material used for the study:

Nano-scale TiO2 (MT-150AW, TAYCA, Japan)

Species:

rat

Strain:

Fischer 344

Sex:

male

Details on test animals or test system and environmental conditions:

Fifteen Fischer 344 male rats (11 weeks old) were purchased from Charles River Laboratories International, Inc. (Japan). The animals were kept in the Laboratory Animal Research Center of the University of Occupational and Environmental Health for 1 week with access to free-feeding of commercial diet and water. All procedures and animal handling were done according to the guidelines described in the Japanese Guide for the Care and Use of Laboratory Animals as approved by the Animal Care and Use Committee, University of Occupational and Environmental Health, Japan.

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

other: whole body and nose only

Vehicle:

air

Details on inhalation exposure:

Rats were divided into three groups of five rats each for whole-body inhalation and for nose-only inhalation of TiO2 for 6 h, and for controls exposed to fresh air only.
Titanium dioxide powder was suspended in ultra-pure water for nanoparticle generation. The TiO2 concentration in the chambers was measured every hour by weighing the filtered particles.

Analytical verification of test atmosphere concentrations:

yes

Remarks:

The TiO2 in each right lung were digested with lung tissues with HNO3 H2SO4, (NH4)2SO4 and H2O2 by microwave digestion under a high-temperature and highpressure condition for 30 min and the amounts of Ti ion in the digested solution were determined by ICP

Duration of exposure:

6 h

Concentrations:

The average mass concentration of the TiO2 aerosol was 4.01 ± 1.11 mg/m3 in the nose-only chamber and 4.10 ± 1.07 mg/m3 in the whole-body chamber, respectively.

No. of animals per sex per dose:

5 animals per group. Only male rats were used

Control animals:

yes

Details on study design:

All the rats were sacrificed by overdose of pentobarbital immediately after 6 h inhalation. The wet lung weights of each rat were measured, and each right lung was used for determining the amounts of TiO2, while each left lung was used for histopathological examination

Statistics:

Analysis of variance (ANOVA) and Dunnett’s test were applied where appropriate to determine individual differences using a computer statistical package (SPSS, SPSS Inc., Chicago, IL, USA).
The amounts of TiO2 in the lungs after the inhalation were 42.6 ± 3.5 μg in the whole-body inhalation group and 46.0 ± 7.7 μg in the nose-only inhalation group. There was no statistical difference between the two groups.

Sex:

male

Dose descriptor:

LC50

Remarks on result:

not measured/tested

Remarks:

No mortality was observed during the exposure time and histopathological examination showed no Infiltrations of inflammatory cells in the alveolar space and interstitium, fibrosis or tumorgenesis in any of the treatment groups or in the control group. Macrophages engulfed pigment-like components in both whole-body and nose-only exposure were the only observation in treatment groups.

Mortality:

None observed

Body weight:

Before the exposure, the body weights were almost the same in the three groups. After the exposure, that in the nose-only inhalation group was less, but the difference was not significant.

Gross pathology:

Infiltrations of inflammatory cells in the alveolar space and interstitium, fibrosis and tumorigenesis were not observed in any of the three groups. Macrophages engulfed pigment-like components in both whole-body and nose-only exposure

Conclusions:

A whole-body inhalation study and a nose-only inhalation study of the same TiO2 nanoparticles in almost the same experimental conditions was carried out and compared the particle deposition and histopathological changes in the lung. The two inhalation studies yielded almost the same results.
This study exposed rate for 6 hours at concentrations of 4 mg/m³ via whole body and nose only. The aim of this study was to investigate differences for the two exposure conditions. No mortality occurred and histopathological examination showed no Infiltrations of inflammatory cells in the alveolar space and interstitium, fibrosis or tumorgenesis in any of the animals. Macrophages engulfed pigment-like components in both whole-body and nose-only exposure were the only observation in treatment groups.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Additional information

A whole-body inhalation study and a nose-only inhalation study of the same TiO2 nanoparticles in almost the same experimental conditions was carried out and compared the particle deposition and histopathological changes in the lung. The two inhalation studies yielded almost the same results.

No significant effect was noticed in either study, but the levels of administration were very low, and there was no observation time utilised following the 6 hour exposure period

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.

Justification for classification or non-classification

Acute toxicity

Rats were treated with disodium titanate by single oral gavage administration at a dosage of 2000 mg/kg body weight.

During the course of the study, no intercurrent deaths occurred, no clinical signs were observed, no macroscopic findings were recorded at necropsy. Also, the body weight of the animals was within the range commonly recorded for this strain and age.

LD50 oral, rat > 2000 mg/kg bw

The classification criteria acc. to regulation (EC) 1272/2008 as acutely toxic are not met since the LD50 is above 2000 mg/kg body-weight, hence no classification is required.