Registration Dossier

Administrative data

Description of key information

Oral:
The oral LD50 (rat; male) 7 500 mg/kg bw
Inhalation:
The inhalation LC50 (rat; male) 7 780 mg/m3
Dermal:
There is no valid data available for acute dermal toxicity.

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:
weight of evidence
Study period:
May 30, 1978 - August 7, 1978
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study is non-GLP and pre-guideline, deviates from current standards. Only male rats were tested. However, the study provides adequate information on acute oral toxicity for classification purposes.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Principles of method if other than guideline:
LD50 test; 5 groups of 10 males received a single oral gavage dose of the test substance; 14 day post administration observation period.
GLP compliance:
no
Test type:
other: LD50 test
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
Source of animals: Willi Gassner (WIGA), Versuchstierzuchtanstalt, 8741 Sultzfeld
Acclimatisation: 3 to 7 days
Cages: Conventional solid bottom cages
Temperature: 22±2°C
Humidity: 55±10%
Other: ad libitum tap water and standard pelleted rat & mouse feed; 12 hours light/dark; after treatment animals housed 5 per cage.
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
single intragastric gavage of undiluted test substance
Doses:
4.64, 5.62, 6.81, 8.25 and 10.0 g/kg bw (based on average group body weights)
No. of animals per sex per dose:
10 males
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Constant observation up to 6 hours after administration, then 24h after application and furthermore at least once a day up to 14 days. Weighing of animals was performed immediately prior to application and at 7 and 14 days after application.
- Necropsy of survivors performed: Yes, Surviving animals were sacrificed at the end of a 14 day observation period and necropsied
- Other examinations performed:clinical signs, lethality, body weights and gross necropsy.
Statistics:
Yes, probit analysis was performed to calculate the LD50 value
Sex:
male
Dose descriptor:
LD50
Effect level:
7 500 mg/kg bw
Based on:
test mat.
Mortality:
Individual mortality data, including time of death, are presented in Table 1, which is attached as background material.
Summary of mortality data:
Dose Mortality
4.64 g/kg - 0/10
5.62 g/kg - 2/10
6.81 g/kg - 3/10
8.25 g/kg - 6/10
10.0 g/kg - 10/10

Clinical signs:
Data on clinical signs is presented in Table 2, which is attached as background material.
Clinical signs occurred in all groups: reduced or no spontaneous activity or reaction to external stimuli; ataxia; decreased or no upright reflex response; reduced faeces; decreased muscle tone; decreased or no pain reflex; reduced or no corneal or pinna reflexes.
Surviving rats were free from clinical signs from 2 days after dosing.
Body weight:
Surviving rats showed normal bodyweight development.
Gross pathology:
Gross pathology findings are presented in Table 3, which is attached as background material.
Premature decedents: red patches or stripes on the mucous glands of the stomach, haemorrhaging of the glandular stomach (in one rat), dark red to brownish discoloration of the lungs.
Rats killed at the end of the observation period: one rat showed red focal atelectasis on the left lobe of the lung. There were no findings in the remaining rats.
Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: expert judgment
Conclusions:
Acute oral toxicity of titanium tetraisopropanolate was evaluated using a LD50 test. The LD50 value was 7 500 mg/kg of body weight measured by administering test substance as a single oral dose to male rats.
Executive summary:

This study was regarded reliable with restrictions since only male rats were studied. However, the study provides adequate information on acute oral toxicity for regulatory/classification purposes.

Titanium tetraisopropanolate was administered as a single oral dose by intragastric gavage to male rats. Deaths were observed in dose level 5 620mg/kg and higher and signs of toxicity were observed at the lowest tested dose 4 640mg/kg bw. By the study report the test substance is considered to be practically nontoxic.

The result of this study would lead to no classifiction for acute oral toxicity according to EU regulation No. 1272/2008 (CLP).

This information is used as a weight of evidence in CSA.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
7 500 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:
weight of evidence
Study period:
no study period reported
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Non GLP, method deviates from current guideline. However, study report contains necessary information for assessment.
Qualifier:
no guideline followed
Principles of method if other than guideline:
Groups of 6 male rats were exposed to the test item aerosol in a 40-l glass chamber at 26°C for a single 4-hour period. Following exposure the rats were observed for clinical signs and weighed daily throughout a 14 day period or until death.
GLP compliance:
not specified
Test type:
fixed concentration procedure
Limit test:
no
Species:
rat
Strain:
other: ChR-CD
Sex:
male
Details on test animals and environmental conditions:
The rats were sourced from Charles River Breeding Laboratories Inc, North Wilmington, Massachusetts, USA. and were in the initial weight range of 230-298g and approximately 60 days old. They were quarantined for 1 week prior to use.
Following exposure the animals were returned to their cages (suspended stainless steel, wire mesh cages), housed in pairs and provided food (Purine Rat Chow, Purina Company, St. Louis, Missouri, USA) and water ad libitum.
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
whole body
Vehicle:
air
Details on inhalation exposure:
A dynamic air flow system was employed to produce constant and uniform atmospheric concentrations. A syringe driver (Harvard Apparatus Compact Infusion Pump) supplied a continuous amount of the test item into a spraying systems nebuliser, incorporated with a diluent air supply (anhydrous, 20 p.s.i.g.) creating an aerosol atmosphere.
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
0.04 mg/l, 3.23 mg/l, 4.56 mg/l, 6.71 mg/l, 7.78 mg/l, 10.26 mg/l
concentrations were reported as time weighted averages
No. of animals per sex per dose:
6 males
Control animals:
no
Details on study design:
Groups of 6 male ChR-CD albino rats, initially in the weight range 230-298g and approximately 60 days old, were exposed to the test item aerosols in a 40-l glass chamber at 26°C, for a single 4 hour period. Following exposure the rats were returned to their cages, housed in pairs and provided food and water ad libitum. The rats were observed for clinical signs and weighed daily (excluding week-ends) throughout a 14-day recovery period or until death.

Analytical verification of the test item aerosols was performed by spectrophotometric analysis employing a Beckman Scanning Spectrophotometer (Model number 25) measuring absorbance at 230 nm. Samples of test item atmospheres were collected at approximately 30-minute intervals by drawing a known volume through 100% ethanol contained in 2 midget impingers, connected in series. A time weighted average (T.W.A.) concentration was calculated.
Chamber atmospheric concentrations determined as above were supported with gravimetric analyses (6 samples per exposure).
Statistics:
The LC50 was calculated using Probit analysis (D.J. Finney, Probit Analysis, 2nd Ed., 1952, Cambridge University Press)
Sex:
male
Dose descriptor:
LC50
Effect level:
7 780 mg/m³ air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Mortality:
0.04 mg/l - 0/6
3.23 mg/l - 0/6
4.56 mg/l - 0/6
6.71 mg/l - 0/6
7.78 mg/l - 3/6
10.26 mg/l - 6/6
Clinical signs:
other: Due to high concentrations involved, a dense aerosol cloud formed in the chamber and made clinical observation difficult. Immediately after exposure, animals in 3.23 mg/l or greater exposure groups were fully covered with white dust and were completely in
Body weight:
Surviving animals in the 3.23 mg/l or greater exposure groups exhibited a mild to moderate weight loss 24 hours post exposure followed by normal weight gain throughout the 14-day recovery.
Gross pathology:
No gross pathology reported.
Other findings:
The LC50 value of 7.78 mg/l (=7780mg/m3) was considered to be slightly to moderately toxic on an acute inhalation basis.
Interpretation of results:
moderately toxic
Remarks:
Migrated information Criteria used for interpretation of results: expert judgment
Conclusions:
Acute inhalation toxicity of Titanium tetraisopropanolate was evaluated using a LC50 test. The LC50 value calculated after single 4-hour exposure was 7 780 mg/m3.
Executive summary:

Male rats were exposed to aerosol atmospheres of titanium tetraisopropanolate. By the study report, titanium tetraisopropanolate is considered slightly to moderately toxic by inhalation.

This study was regarded as reliable with restrictions since the study report is missing details on test conditions and test results. The result of this study is used as a weight of evidence in hazard assessment.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
Value:
7 780 mg/m³

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:
other:
Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Acute toxicity oral

There are two studies available on titanium tetraisopropanolate to evaluate the acute oral toxicity. The potential of this substance to cause lethality is also evaluated based on the read-across data on acute toxicity of the decomposition products, because the target substance is hydrolytically unstable having the half-life less than 3 minutes (Scholz, T. 2010). The weight of evidence approach is used to determine the lethality and non-lethality of this substance as the studies on the substance itself are unreliable and lacking some important information on non-lethality effects of the decomposition products. The information on lethality from the target substance and from the decomposition products together is considered as reliable to evaluate the acute oral toxicity of the target substance.

In a study report by Billmeier, J. (1978) male rats were gavaged using undiluted test substance at concentrations 4 640, 5 620, 6 810, 8 250 and 10 000 mg/kg bw. Following administration test animals were observed for clinical signs and mortality for 14 days. Clinical signs occurred in all groups including reduced or no spontaneous activity or reaction to external stimuli, ataxia, decreased or no upright reflex response, decreased muscle tone; decreased or no pain reflex; reduced or no corneal or pinna reflexes. The calculated LD50 value for test substance was 7 500 mg/kg bw. In other study of Hood, D. B. (1960) approximate lethal dose was determined using male rats. In this study, there was used only one animal per dose level and very limited amount of data is recorded. Animals were administered orally at doses 25 000, 17 000, 11 000, 7 500, 5 000, 3 400, 2 250 mg/kg bw and mortality and clinical signs were recorded. The estimated oral LD50 value for male rats was 11 000 mg/kg bw.

Based on these two studies, there is no evidence of acute oral toxicity. The supporting read-across data on acute toxicity of isopropyl alcohol (IPA) and titanium dioxide (TiO2) also proves that after the hydrolysis the decomposition products released from the substance do not cause evident lethality.

The LD50 values of the decomposition product, IPA, varies between 4475 mg/kg bw – 7990 mg/kg bw (OECD, 2004). This data proves that IPA has no acute lethality. However, IPA has non-lethal effects causing drowsiness or dizziness, and has the harmonized classification entry as STOT SE 3 H336 according to CLP Regulation No. 1272/2008. IPA is also classified as R67 according to EU Directive 67/548/EEC.

Based on the read-across data on the other decomposition product, TiO2, the lowest dose reported to produce any toxic effect in rats by oral route is determined to be 60 g/kg (US EPA, 1994). In other study, a group of 10 male and 10 female rats was given titanium dioxide in the diet at 100 g/kg, for 30-34 days. All animals remained healthy and behaved normally. Weight gain and food intake were comparable for the control group. No relevant gross pathology was observed at autopsy (WHO, 1982).

Lethality:

As a conclusion, the weight of evidence of the LD50-values on titanium tetraisopropanolate and the LD50-values on the decomposition products (IPA and hydrated titanium dioxide) are considered reliable. These results do not indicate this substance to be classified as causing evident acute oral toxicity in accordance with the criteria set out in the CLP Regulation 1272/2008 and Directive 67/548/EC. The key value for CSA was selected based on the study of Billmeier J (1978) as this LD50-value (7500 mg/kg) is presenting the lowest acute toxicity measured from titanium tetraisopropanolate.

Non-lethality:

Because of rapid hydrolysis (half-life < 3 minutes) the intrinsic properties of the target substance are related to the main decomposition product IPA. A number of poisoning cases has been reported due to the intentional ingestion of isopropanol, particularly among alcoholics or suicide victims. Ingestion of IPA typically results in a comatose condition. Pulmonary difficulty, nausea, vomiting, and headache accompanied by various degrees of central nervous system depression is typical (OECD, 2004). As there is evidence of neurotoxicity caused by IPA after single oral and also after inhalation exposure, this substance has been classified to hazard class STOT SE 3H336. The weight of evidence approach indicates titanium tetraisopropanolate to have similar properties than IPA. Thus, this leads to the classification of this substance for hazard class STOT SE 3 H336.

Acute toxicity inhalation

There is one study available on titanium tetraisopropanolate to evaluate the acute inhalation toxicity. The potential of this substance to cause toxicity is also evaluated based on the read-across data on acute toxicity of the decomposition products, because the target substance is hydrolytically unstable having the half-life less than 3 minutes (OECD 111). The weight of evidence approach is used to determine the lethality and non-lethality of this substance as there is only one study available on substance itself. The information on the lethality from the target substance and from the decomposition products, isopropyl alcohol (IPA) and titanium dioxide (TiO2) together is considered as reliable to evaluate the acute inhalation toxicity of the target substance.

In the study report by Gardner, R. J. (1979) male rats, 6 animals per dose level, was exposed to various concentrations of aerosol atmospheres of titanium tetraisopropanolate for 4 hours. The rats observed and weighed daily (excluding week-ends) throughout a 14-day recovery period or until death. The LC50 value was calculated to be 7,78mg/L (= 7780mg/m3).Based on this study, there is no evidence of acute inhalation toxicity.

The supporting read-across data on acute inhalation toxicity of IPA also proves that the substance do not cause evident lethality.In the publication by Gill, M. W. et al. (1995) neurotoxicity effects of IPA were investigated in rats after 6-hour exposure. During the study no mortalities were observed at the highest concentration tested. Thus, the LC50 value was concluded to be > 10 000 ppm (>24 600mg/m3). Behavioral observations were made prior to and 1, 6 and 24 h after exposure. Exposure to IPA caused spectrum of transient effects indicative of narcosis at 10 000 ppm and sedation at 5000 ppm.Prostration or severe anemia, decreased arousal, slowed or labored respiration, decreased neuromuscular function, hypothermia and loss of reflex function were observed 1 and 6 h after exposure to 10 000 ppm isopropanol vapor. Similar, but less severe alterations were observed in animals in the 5 000 ppm exposure group 1 h after exposure. Exposure concentration-related decreases in motor-activity were observed in males and females in the 5000 and 10 000 ppm groups and slight decrease in motor activity were observed in males in the 1500 ppm group. Animals in the 1500 and 5000 ppm exposure groups recovered from these motor activity effects within 5h.Based on this study, exposure of male and female rats to IPA vapor produced transient, concentration-related narcosis and/or sedation at concentration of 5000 and 10 000 ppm and minor decreases in motor activity in males at a concentration of 1500ppm.

Another decomposition product of titanium tetraisopropanolate is non-hazardous hydrated titanium dioxide.TiO2is not relevant as it is non-volatile solid precipitate after hydrolysis.

Lethality:

As a conclusion, the weight of evidence of the LD50-value on titanium tetraisopropanolate and the LC50-value on the decomposition product (IPA) is considered reliable. These results do not indicate this substance to be classified as causing evident acute inhalation toxicity in accordance with the criteria set out in the CLP Regulation 1272/2008 and Directive 67/548/EC. The key value for CSA was selected based on the study of Gardner, R. J. (1979) as this LC50-value (7780mg/m3) is presenting the acute toxicity measured from titanium tetraisopropanolate.

Non-lethality:

Because of rapid hydrolysis (half-life < 3 minutes) the intrinsic properties of the target substance are related to the main decomposition product IPA. As this alcohol causes defects indicative for CNS depression after single application, and has a harmonized classification to hazard class STOT SE 3H336, the weight of evidence approach indicates titanium tetraisopropanolate to have similar properties than IPA. Thus, this leads to the classification of this substance for hazard class STOT 3 H336.

 

Acute toxicity dermal

 

There is no valid data available for acute dermal toxicity. However, dermal route is not considered to be relevant exposure route, as skin contact is not likely during the production and use of the test substance because of adequate RMMs in use (see sections 9&10 of CSR). Furthermore, this substance decomposes very rapidly (half-life < 3 minutes) releasing isopropyl alcohol (IPA) and non-hazardous titanium dioxide. IPA can be considered practically non-toxic via dermal route, since dermal LD50value for IPA has been determined to be 12 870 mg/kg (Smyth, H.F., Carpenter, C.P., (1948) cited in OECD 2004).Thus the chemical safety assessment does not indicate the need to investigate further the acute dermal toxicity.


Justification for selection of acute toxicity – oral endpoint
The study was selected based on the lowest measured LD50 value for the substance.

Justification for selection of acute toxicity – inhalation endpoint
Only one study available where the target substance was investigated

Justification for selection of acute toxicity – dermal endpoint
Not relevant exposure route

Justification for classification or non-classification

Lethality:

The available data for titanium tetraisopropanolate indicate relatively low potential for acute toxicity.

Based on the lethal effects of titanium tetraisopropanolate and the decomposition products, the substance has not to be classified according to CLP Regulation 1272/2008 and Directive 67/548/EC.

Toxicity to a specific organ:

Titanium tetraisopropanolate decomposes rapidly to IPA. IPA has been shown to causes transient sedation of the central nervous system. As the intrinsic properties of the substance are related to the decomposition product, titanium tetraisopropanolate has to be classified to hazard class STOT SE 3H336 according to CLP Regulation 1272/2008 and as R 67 according to Directive 67/548/EC.