potassium titanium oxide (K2Ti6O13)

Endpoint summary

Description of key information

The oral and inhalation routes were chosen as the most appropriate routes of administration for acute toxicity studies for the substance, having regard to the likely route of human exposure.

The acute toxicity of the test material was investigated, by the (i) oral and (ii) inhalation routes, in studies which were conducted under GLP conditions and in accordance with the standardised guidelines.

The acute oral median lethal dose (LD50) of the test material in male/female Wistar rat was estimated to be greater than 2000 mg/kg bodyweight in two studies. In the acute inhalation study, the acute inhalation median lethal concentration (4 h LC50) of the substance in the male/female Fisher 344 strain rat was greater than 1.9 mg/L (aerosol of the substance).  No deaths occurred in neither of the studies.

In a study via intra-tracheal installation,the biological half-life of TOFIX-S in the rat lung after a single intra-tracheal instillation was found to be 2.3 months, consistent, the author noted, with particulate materials having little biological effect. No production of 8-hydroxydeoxyguanosine (an indicator of oxidative damage caused by active oxygen species) was observed, no significant differences in gene expression of TIMP-2 (Tissue Inhibitors of MetalloProteins) was found (suggesting that the substance has little effect on inflammation and fibrosis), and no significant changes were noted in histopathological examination of the lungs.

Data from the literature show that the shape of the fibers is relevant in determinig lung effects after intratracheal instillation (Ishihara et al, 2002). Moreover, acute inflammatory response may reflect the effects observed after reapeated dose exposure to fibrous material (Morimoto et al, 2001).

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

13 December 1989 to 31 January 1990

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results.

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

(1987)

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Slc:Wistar, Japan SLC Co., Ltd., Koto-cho, Hamamatsu-shi, Shizuoka, Japan.
- Age at study initiation: 6 weeks old.
- Weight at study initiation: 134 - 145 g for males, 109 - 112 g for females.
- Fasting period before study: Not reported.
- Housing: The animals were housed in groups of 5 in a hanging stainless cage (26 X 38 X 18 cm, Toyo Riko k.k.).
- Diet (e.g. ad libitum): MF (Oriental Yeast Industry k.k.), at libitum.
- Water (e.g. ad libitum): UV sterilised / filtred tap water, ad libitum.
- Acclimation period: 1 week.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 ± 2ºC.
- Humidity (%): 55 ± 10%.
- Air changes (per hr): 13 changes per hour.
- Photoperiod (hrs dark / hrs light): Twelve hours continuous light (06:00 to 18:00) and 12 hours darkness.

IN-LIFE DATES: From: Day 0 To: Day 14.

Route of administration:

oral: gavage

Vehicle:

other: Carboxymethyl Cellulose Sodium

Details on oral exposure:

VEHICLE
- Concentration in vehicle: (suspended in 0.5% Carboxymethyl Cellulose Sodium)
- Amount of vehicle (if gavage): 10 mg/kg

MAXIMUM DOSE VOLUME APPLIED: 2000 ml/kg (limited test).

Doses:

2000 mg/kg.

No. of animals per sex per dose:

5 animals per sex per dose.

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days

- Frequency of observations and weighing:
(clinical signs and mortality) Immediately after and at 1, 3 and 6 hours after administration, and every 24 hours for 14 days.
(body weight gain) Day 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 14.

- Necropsy of survivors performed: yes. All animals were exsanguinated to death under ether anaesthesia after the 14-day observation period and postmortem pathological examinations were performed. Gross examination was performed for abnormal organs or tissues.

Statistics:

Not reported.

Preliminary study:

Not applicable.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No deaths occurred in both sexes at the dose tested.
Male: 2000 mg/kg bw; Number of animals: 5; Number of deaths: 0
Female: 2000 mg/kg bw; Number of animals: 5; Number of deaths: 0

Clinical signs:

other: No significant changes were observed. During the 14-day observation period, only mild soft stools were observed in one male rat from 50 minutes to 3 hours after the administration, and in one female rat at 3 hours post dose administration.

Gross pathology:

No abnormalities were noted at necropsy of animals killed at the end of the study period.

Other findings:

Not reported.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

It was concluded that the potassium titanate fibre has no toxic effects at the dose of 2000 mg/kg, and the minimum dose of potassium titanate fibre in rats was more than 2000 mg/kg. The test material does not meet the criteria for classification according to EU classification system (Council Directive 67/548/EEC and Regulation (EC) No 1272/2008).

Executive summary:

To determine the acute toxicity of potassium titanate fiber, an oral dose limiting study in rats using 2000 mg/kg was conducted. The results were summarised as follows.

2000 mg/kg of the substance was dosed to 5 male and 5 female rats, being fasted from the previous night to 3 hours after the administration. No death has occurred in all male and female rats. In the observations of clinical signs, soft stools were found in one male rat from 50 minutes until 3 hours after the administration, and one female rat at 3 hours after the administration. No other significant changes were observed.

Both of all male and female rats gained body weight normally.

Any abnormal changes were not found at the postmortem pathological examinations following the 14-day observation period.

It was concluded that the minimum lethal dose of the substance was more then 2000 mg/kg.

The test material does not meet the criteria for classification according to EU classification system (Council Directive 67/548/EEC and Regulation (EC) No 1272/2008).

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

June 2011 to July 2011

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: performed in accordance with OECD 423 (Acute Oral toxicity - Acute Toxic Class Method). GLP compliant study

Qualifier:

according to guideline

Guideline:

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

Deviations:

yes

Remarks:

Concerning: General Information According to the Study Plan: TOHO MATERIARL CO, LTD. Deviation: TOHO MATERIAL CO, LTD. Reason: Typing error. This deviation is considered not to have had an impact on the objectives of the study

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

other: RjHan:WI rats

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Laboratoire Elevage Janvier, B.P. 4105, Route des Chénes Secs, 53940 Le Genest-St-Isle, CEDEX, FRANCE (Date of receipt: 09 June 2011)

- Age at study initiation: Young healthy adult rats, 10 and 11 weeks old (at dosing)

- Weight at study initiation: 233 - 242 g (at treatment)

- Housing: 3 animals/cage
- Cage type: Type II polypropylene/polycarbonate
- Bedding: Lignocel Bedding was available to animals during the study. A copy of the Certificate of Analysis is retained in the archive at LAB Research Ltd.

- Diet (e.g. ad libitum) Animals received ssniff® SM R/M-Z+H “Autoclavable complete feed for rats and mice "breeding and maintenance” produced by ssniff Spezialdiäten GmbH, D-59494 Soest Germany. The food is considered not to contain any contaminants that could affect the validity or integrity of the study. Appendix 5 of attached report contains a certificate of the diet test report and analytical certificate for the batch used.

- Water (e.g. ad libitum): Tap water was via the municipal supply as for human consumption. Water quality analysis was performed once every three months and microbiological assessment was performed monthly, by Veszprém County Institute of State Public Health and Medical Officer Service (ÁNTSZ, H-8201 Veszprém, József A.u.36., Hungary). Results are retained in the archives at LAB Research Ltd.

- Acclimation period: At least 19 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 30 - 70
- Air changes (per hr): 15-20
- Photoperiod (hrs dark / hrs light): 12 hours daily, from 6.00 am. to 6.00 p.m.

- Other details:
- Hygienic level at arrival: SPF
- Hygienic level during the study: Standard housing conditions
- Animal health: Only healthy animals were used for the test.
The veterinarian certified health status.
- Enrichment: Animals were housed by group to allow social interaction and with deep wood sawdust bedding to allow digging and other normal rodent activities. The temperature and relative humidity were recorded twice daily throughout the duration of the study.

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

The limit dose of 2000 mg/kg bw (200 mg/mL @ a dose volume of 10 mL/kg) was selected in accordence with current guidence (OECD 423 and Commision Regulation (EC) NO 440/2008 of 30 May 2008, B.1. Tris) in RjHan:WI rats).

Doses:

Justification for the initial starting dose (as selected by the Study Director) was that which was most likely to produce mortality in some of the dosed animals. Therefore, in the absence of any preliminary toxicological information, 2000 mg/kg bw was selected as the starting dose.

Initially, three female animals were treated with 2000 mg/kg bw of TOFIX-SNR. No mortality was observed, therefore further 3 animals were treated at the dose level of 2000 mg/kg bw. As no mortality was observed in this second dose group, further testing was not required according to the test guidelines (OECD 423, Commission Regulation (EC) NO 440/2008 of 30 May 2008, B.1.Tris).

No. of animals per sex per dose:

Number of animals: 6 (3 females/group)

Control animals:

not specified

Details on study design:

A single oral gavage administration was followed by a fourteen-day observation period. All treated animals were fasted from food (not water) overnight the day before treatment. Animals were weighed just before treatment, following which the test item was administered by oral gavage. Food was returned 3 hours after treatment.

Statistics:

No details referenced within report.

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks:

TOFIX-SNR

Mortality:

No mortality was observed throughout the 14-day duration of the study

Clinical signs:

other: No test item related adverse effects were observed throughout the 14-day duration of the study

Other findings:

No macroscopic observations noted.

Interpretation of results:

study cannot be used for classification

Remarks:

Migrated information

Conclusions:

The acute oral LD50 value of the test item TOFIX-SNR was found to be above 2000 mg/kg bw in female RjHan:WI rats. Therefore, in accordence with the Globally Harmonised Classification System for Chemical Substances and Mixtures (GHS), TOFIX-SNR was assigned a category of “Category 5” or “Unclassified”.

Executive summary:

The single-dose oral toxicity of TOFIX-SNR was performed according to the acute toxic class method (OECD 423 and Commission Regulation (EC) NO 440/2008 of 30 May 2008, B.1.Tris) in RjHan:WI rats. Two groups of three female RjHan Wistar rats (Group 1 and Group 2) were treated with TOFIX-SNR at 2000 mg/kg bw. Three females (Group 1) were initially treated at 2000 mg/kg bw. As no mortality was observed, a confirmatory group (Group 2) was therfore treated at the same dose level. As no mortality was observed in the confirmatory group, no further testing was required.   For each group animal a single treatment was performed by gavage. TOFIX-SNR was administered as a homogenous suspension in distilled water.   Clinical observations were performed at 30 minutes, 1, 2, 3, 4 and 6 hours after dosing and daily for 14 days thereafter. Body weight was measured on Days -1, 0 and 7 and before necropsy (day 14). All animals were subjected to necropsy and macroscopic examination. TOFIX-SNR did not cause any test item related adverse effect or mortality during the 14 day observation period following administration at the limit dose of 2000 mg/kg bw. The body weight gain observed in treated animals showed no indication of any treatment-related effect. No macroscopic observations were noted in any animal. The acute oral LD50 value of the test item TOFIX-SNR was found to be above 2000 mg/kg bw in female RjHan:WI rats. Therefore, in accordance with the Globally Harmonised Classification System for Chemical Substances and Mixtures (GHS), TOFIX-SNR was assigned a category of “Category 5” or “Unclassified”.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

> 2 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

7 January 1992 to 24 September 1992

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results.

Justification for type of information:

According to Column 2 of Section 8.5 of Annex VIII details specific rules for adaptation, notably requiring information on at least one other route of exposure depending on the nature of the substance and the likely route of human exposure.
Considering the chemico-physical characteristics of the substance and the likely route of human exposure, it was judged as priority and essential to submit information related to acute toxicity by inhalation route.

Qualifier:

according to guideline

Guideline:

EPA OTS 798.1150 (Acute inhalation toxicity)

Version / remarks:

(1985)

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratory.

- Age at study initiation: 5 - 7-week old.

- Weight at study initiation: 71.9 - 86.2 g (males), 71.0 - 82.2 g (females).

- Fasting period before study: Not reported (food withheld during the 4-hour exposure period).

- Housing: The animals were individually housed in stainless steel wire cages.

- Diet: Purina Certified Rodent Chow (pellets) ad libitum.

- Water: Water from the City of Columbus municipal supply and was not further treated at the testing facility. Ad libitum.

- Acclimation period: 7 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 22°C

- Humidity (%): 47 - 73%.

- Photoperiod (hrs dark / hrs light): 12 hours light/12 hours dark each day.

IN-LIFE DATES: From: Day 1 To: Day 15.

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

other: breathing zone

Vehicle:

air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure chamber volume: 0.5 m3.

- Source and rate of air: Approximately 500 liters per minute, airflow rate through the plenum.

- System of generating particulates/aerosols: Aerosol generator consist of two-part system.

- Method of particle size determination: Scanning Electron Microscopy (SEM).

- Temperature, humidity, pressure in air chamber: See 'details on test animals and environmental conditions'.

TEST ATMOSPHERE
- Brief description of analytical method used:Concentration was monitored by gravimetric technique. The.test atmosphere temperature and humidity were monitored in the exposure chamber during the
actual exposure. Chamber concentration uniformity was determined by gravimetric concentration sampling on the horizontal plane of the chamber where the animals were exposed.

- Samples taken from breathing zone: No

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: Mean fiber lengths of 20, 18, 21, and 11 μm for the plenum bottom, middle, top and exposure chamber, respectively. The mean fiber width for each location was 6.5, 6,0, 7.2, and 4.2 μm for the plenum bottom, middle, top and exposure chamber, respectively.

- MMAD (Mass median aerodynamic diameter for liq.+solid aerosol):
1st sample: mean fibre length = 16.2 µm
mean fibre width = 7.4 µm
2nd sample: mean fibre length = 14.5 µm
mean fibre width = 7.6 µm

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

1.9 mg/L.

No. of animals per sex per dose:

5 per sex.

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days

- Frequency of observations and weighing:
Mortality & clinical observations: Twice daily.
Body weight: On Days 1, 8 and 15.

- Necropsy of survivors performed: yes, on Day 15.

Statistics:

In-life and postmortem data (necropsy findings) were collected using the Xybion® Path/Tox System, (Xybion Medical Systems Corporation, Cedar Knolls, NJ) for body weights, daily clinical observations, and gross findings.
Individual animal body weight data was collected weekly and summarized by sex. Data were not analyzed statistically since there were no group to group comparisons.

Preliminary study:

Chamber uniformity measurements were completed during the pre-study validation of the inhalation system. The data show that the variability, as defined by the Relative Standard Deviation of all samples, was less than 2.5%. The mean concentration was 1.94 mg/L, which was 97% of the 2.0 mg/L target value. This pre-study analysis showed a uniform distribution of the atmosphere within the chamber.

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 1.9 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Mortality:

Male: 1.9 mg/L; Number of animals: 5; Number of deaths: 0
Female: 1.9 mg/L; Number of animals: 5; Number of deaths: 0

Clinical signs:

other: Signs of toxicity related to dose levels: Clinical signs of nasal discharge, ocular discharge and ruffled fur occurred after exposure and persisted for several days. There were no other visible effects.

Body weight:

Animals gained weight at a rate consistent with that expected of this age and strain of rat.

Gross pathology:

Effects on organs: Necropsy findings revealed no gross lesions or abnormalities of any kind.

Other findings:

Not reported.

Interpretation of results:

other: classified for STOT-SE Category 3 / R37 - irritating to respiratory system

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

Under the conditions of the study, the LD50 of the test material was determined to be > 1.9 mg/L air (4h): the substance is not classified for acute toxicity by inhalation in accordance to CLP criteria.

Executive summary:

Under the conditions of the study, the LD50 of the test material was determined to be > 1.9 mg/L air (4h): the substance is not classified for acute toxicity by inhalation in accordance to CLP criteria.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating conc.

Value:

> 1 900 mg/m³ air

Physical form:

inhalation: aerosol

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because the physicochemical and toxicological properties suggest no potential for a significant rate of absorption through the skin

the study does not need to be conducted because inhalation of the substance is likely

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

The acute toxicity tests described above via oral and inhalation routes meet the requirements of OECD Test Guidelines and are assigned to be reliabilityscore of1 according to the scoring system of Klimisch et al (Klimischet al., 1997). This ranking was deemed appropriate because the studies were conducted at the GLP certified laboratory and were in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of relevant results.

Justification for classification or non-classification

Justification for selection of acute toxicity – oral endpoint
Under the conditions of the reported study, the LD50 of the test material was determined to be > 2000 mg/kg bw: the substance is not classified, in accordance to CLP criteria.

Justification for selection of acute toxicity – inhalation endpoint
Under the conditions of the reported study, the LD50 of the test material was determined to be > 1.9 mg/L air (4h): the substance is not classified, in accordance to CLP criteria

Justification for selection of acute toxicity – dermal endpoint
data waiving