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Administrative data

Description of key information

Oral:
The oral ALD (rat; male) 5 000 mg/kg bw
Inhalation:
There is no valid data available for acute inhalation toxicity for the substance. LC50 for the organic degradation product ( Exxal 8), is greater than 24 mg/m3.
Dermal:
Not relevant route of exposure. There is no valid data available for acute dermal toxicity for the substance. Supporting information for the organic degradation product (Exxal 8), LD50 is greater than 2632 mg/kg.

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:
June 7, 1993 - December 1, 1993
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study was conducted in compliance with EPA TSCA Good Laboratory Paractice Standards (40 CFR 792) and the method is comparable to OECD guideline 401. However, only one animal per dose rate was used and only one sex (males) were studied.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
Only one animal per dose rate was used and only one sex (males) were studied.
Principles of method if other than guideline:
LD50 test; 6 groups of one male rat received a single oral gavage dose of the test substance; 14 day post administration observation period.
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: Crl:CD BR
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Kingston, New York
- Age at study initiation: approximately 7 weeks old
- Weight at study initiation: 261, 254, 256, 258, 253, 231 g
- Fasting period before study: not mentioned
- Housing: singly in suspended, stainless steel, wire-mesh cages
- Diet (e.g. ad libitum): Purina Certified Rodent Chow #5002
- Water (e.g. ad libitum): ad libitum
- Acclimation period: one week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23°C +/- 2°C
- Humidity (%): 50% +/- 10%
- Photoperiod (hrs dark / hrs light): 12-hour light / 12-hour dark cycle
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
Dosage (mg/kg) Dose Volume (ml) Mixture Concentration (mg/ml) Initial Body Weight (g)
670 1.2 150 261
2300 3.9 150 254
3400 2.9 300 256
5000 4.3 300 258
7500 6.3* 300 253
11000 8.5* 300 231

* administered in 2 portions approximately 15minutes apart

Doses:
670, 2300, 3400, 5000, 7500, 11 000 mg/bw
No. of animals per sex per dose:
1 male / dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Daily until signs of toxicity subsided, and then at least 3 times per week throughout the 14-day recovery period
- Necropsy of survivors performed: no
- Other examinations performed: clinical signs and body weight
Sex:
male
Dose descriptor:
LD100
Effect level:
5 000 mg/kg bw
Based on:
test mat.
Mortality:
Dosage (mg/kg) Mortality
670 No
2300 No
3400 No
5000 Yes
7500 Yes
11 000 Yes

Clinical signs:
Dosage(mg/kg) Clinical signs
670 no clinical signs
2300 low carriage and ruffled fur at 1.5h. Diarrhea, brown-stained perineum, ruffled fur or hunched posture up to 2days after dosing
3400 yellow-stained perineum up to 4 days after dosing
5000 slight salivation at 1 hour after dosing. Dead one day after dosing.
7500 profuse salivation and hunched posture at 1 hour after dosing. Lethargic behavior, low posture, low carriage, or yelow-stained perineum up to two days after dosing. Found dead at day 3.
11 000 lethargic behavior, limpness, no righting reflex at 1 hour after dosing. Found dead 1 day after dosing
Body weight:
Surviving rats: Weight losses up to 4% of initial body weight were observed in some rats by 1 day after dosing. The rat dosed at 7500mg/kg had weight loss of 14% of initial body weight by 2 days after dosing.
Gross pathology:
not done
Interpretation of results:
practically nontoxic
Remarks:
Migrated information The test substance was concluded to be slightly toxic by the study report Criteria used for interpretation of results: expert judgment
Conclusions:
An approximate lethal dose (ALD) of Titanium tetra(octanolate), branched and linear was determined by using test method equal to OECD401. The ALD value was 5000mg/kg of body weight determined from mortality of test animals after test substanc administration. According to this result substance is considered to be slightly toxic (given the study report) or nontoxic (concluded by the submitter).
Executive summary:

This study was regarded reliable with restrictions since only male rats were studied and there was used only 1 animal / dose level. However, the study was performed according to EPA TSCA Good Laboratory Paractice Standards (40 CFR 792) and the method is comparable to OECD guideline 401.

Titanium tetra(octanolate), branched and linear was administered as a single oral dose by intragastric intubation to male rats. Deaths occurred up to 3 days after dosing. Clinical signs of toxicity were observed in lethally and nonlethally dosed animals. Under the conditions of this test, the ALD was 5000mg/kg of body weight. By the study report Titanium tetra(octanolate), branched and linear is considered to be slightly toxic (ALD 500 - 5000 mg/kg) when administered as a single oral dose.

However, based on the results presented in study report this substance is considered to be nontoxic according to EU Regulation No. 1272/2008 (CLP).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
5 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Acceptable, well-documented study report equivalent or similar to OECD guideline 403: pre-GLP. Read-across justification: The substance is hydrolytically unstable. When it comes in contact with water or moisture complete hydrolysis will take place with no significant reaction products other than alcohol and hydrated titanium dioxide. This rapid hydrolysis (hydrolysis half-life < 3 minutes to < 2 hours) is the driving force for the toxicokinetics of target substance. Because of the rapid hydrolysis, the influence of the mode of administration through inhalation, dermal and oral is related to the hazardous degradation product (alcohol) released from the target substance. The identification of degradation products from the hydrolysis study conducted for the target substance verifies that there are no impurities in the alcohol released from the target substance, which might change the hazardous properties of the target substance compared to the properties of the pure alcohol. As there is a mechanistic reasoning to the read-across, the unnecessary animal testing is avoided by using the read-across data from the degradation product (relevant alcohol) to evaluate irritation, sensitization and the short term and long-term toxicological effects and mutagenicity of the target substance.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
GLP compliance:
not specified
Test type:
fixed concentration procedure
Limit test:
no
Species:
other: mouse, rat and guinea pig were tested
Strain:
other: Swiss-Webster mice, Sprague Dawley rats, and Hartley guinea pigs
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Housing: 5 per cage
- Diet (e.g. ad libitum): Purina cubed diet ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 7 days

Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: closed chamber
- Exposure chamber volume: 100 l
- Method of holding animals in test chamber: Plexiglass chamber
- Source and rate of air: 30 l/min
- Method of conditioning air: Dried, filtered and preheated
- System of generating particulates/aerosols: three-necked flask immersed in a heated water bath and bubbled with air
- Treatment of exhaust air: Fume hood
- Temperature, humidity, pressure in air chamber: room temp
Analytical verification of test atmosphere concentrations:
no
Duration of exposure:
ca. 6 h
Concentrations:
Exposure concentration was determined on a nominal basis only and was calculated by dividing the net weight of compound used during the 6 h experiment by the total air flow through the chamber during the exposure. The nominal concentration was computed to be 24 ug/l.
No. of animals per sex per dose:
10
Control animals:
yes
Details on study design:
- Duration of observation period following administration: daily for 14 days
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights
Statistics:
No data was analyzed
Sex:
male
Dose descriptor:
LC50
Effect level:
> 0.024 mg/L air (nominal)
Exp. duration:
6 h
Remarks on result:
other: For mice, rats, and guinea pigs
Mortality:
0%
Body weight:
The exposed animals appeared to gain weight normally during the observation period.
Gross pathology:
Lungs were observed to be grayish or marked by gray and red foci. There were moderate incidences of mottled livers and kidneys.
Other findings:
As the experiment progressed, most mice became quiet, went to sleep or were mildly sedated. Respiration in some of the rats and guinea pigs appeared to be slightly labored. All signs of depressed physiological function were resolved upon moving the animals to fresh air.

Read-across justifications and data matrices are presented in IUCLID section 13.

Interpretation of results:
other: not classifiable
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
This data can not be used for classification purposes.
Executive summary:

In this study, groups of male mice, rats and guinea pigs were subjected to a whole body exposure of a nominal concentration of 24 ug/l of isooctanol as a saturated vapor for 6 hours. All animals survived the study. There were indications of depressed physiological function in all animals; indicated by sedation and labored breathing. These observations were resolved once the animals were moved into fresh air. From this study, it is concluded that the LC50 is greater than 0.024 mg/l as a 6 hour exposure.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Acceptable, well-documented study report equivalent or similar to OECD guideline 402: pre-GLP. Read-across justification: The substance is hydrolytically unstable. When it comes in contact with water or moisture complete hydrolysis will take place with no significant reaction products other than alcohol and hydrated titanium dioxide. This rapid hydrolysis (hydrolysis half-life < 3 minutes to < 2 hours) is the driving force for the toxicokinetics of target substance. Because of the rapid hydrolysis, the influence of the mode of administration through inhalation, dermal and oral is related to the hazardous degradation product (alcohol) released from the target substance. The identification of degradation products from the hydrolysis study conducted for the target substance verifies that there are no impurities in the alcohol released from the target substance, which might change the hazardous properties of the target substance compared to the properties of the pure alcohol. As there is a mechanistic reasoning to the read-across, the unnecessary animal testing is avoided by using the read-across data from the degradation product (relevant alcohol) to evaluate irritation, sensitization and the short term and long-term toxicological effects and mutagenicity of the target substance.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
GLP compliance:
no
Test type:
standard acute method
Species:
rabbit
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Housing: by exposure group
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: intact abdominal skin
- Type of wrap if used: gauze covered with a plastic sleeve


REMOVAL OF TEST SUBSTANCE
- Washing (if done): Sponged with Fuller's earth
- Time after start of exposure: 24 h
Duration of exposure:
24 H
Doses:
100, 316, 1000, 3160 ul/kg (83.2, 262, 832, 2629 mg/kg based on a density of 0.832 mg/cm3)
No. of animals per sex per dose:
4
Control animals:
no
Details on study design:
- Duration of observation period following administration: 1, 4, and 24 hours and daily thereafter for a total of 7 days
Statistics:
No data analyzed.
Dose descriptor:
LD50
Effect level:
> 2 632 mg/kg bw
Mortality:
1 animal in the 3160 ul/kg exposure group died within 24 hours post patch removal. All other animals survived until the end of the observation period.
Clinical signs:
Within 4 hours of application, animals in the 3160 ul/kg exposure group exhibited signs of depressed physiologic function. All adverse observations were resolved within 2 days post exposure.
Gross pathology:
Gross autopsy performed in the animal which succumbed revealed congested kidneys and lungs. All other animals had unremarkable findings.

Read-across justifications and data matrices are presented in IUCLID section 13.

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute dermal LD50 of isooctanol is >2632 mg/kg.
Executive summary:

In this study, rabbits were exposed to varying concentrations (100, 316, 1000, or 3160 ul/kg) of isooctanol via an occluded dermal patch for 24 hours. Observations were made at 1, 4, and 24 hours and daily thereafter for a total of 7 days. One animal in the highest dose group died within 24 hours of patch removal. All other animals survived. Within 4 hours of application, animals in the 3160 ul/kg exposure group exhibited signs of depressed physiologic function. All adverse observations were resolved within 2 days post exposure. It is concluded that the LD50 is greater than 3160 ul/kg (2632 mg/kg).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 632 mg/kg bw

Additional information

Oral

There is one key study available on titanium tetra(octanolate), branched and linear to evaluate the acute oral toxicity. As the target substance is hydrolytically unstable having the half-life less than 10 minutes (Brekelmans, M.J.C., 2013), supporting information from degradation products is also used to evaluate the lethality and non-lethality of this substance after oral administration.

In the study report by Sarwer (1993), titanium tetra(octanolate), branched and linear was administered orally to male rats. The LD50 value was not calculated since only one animal per dose rate was used. Instead, based on the study results approximate lethal dose (ALD) was established to be 5 000 mg/kg of body weight. The study was regarded reliable since the test was conducted using method comparable to OECD 401 guideline and in compliance with EPA TSCA Good Laboratory Practice Standards (40 CFR 792).

Supporting evidence on acute toxicity comes from two studies performed using Exxal 8, the degradation product of the target substance. In the study conducted by ExxonMobil (1988), male and female rats were administered a single oral exposure of 2 000 mg/kg and monitored for signs of acute toxicity daily for 15 days. This dose did not produce any mortality or any other adverse clinical signs of toxicity. It is concluded that the LD50 is greater than 2 000 mg/kg.

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/bw 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).

As a conclusion, the oral LD50-value for titanium tetra(octanolate), branched and linear and the LD50-values for the decomposition products (Exxal 8 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/EEC.

The key value for CSA was selected based on the study of Sarwer (1993) (ALD 5 000 mg/kg body weight) as it is presenting the acute toxicity value for the substance itself (titanium tetra(octanolate), branched and linear).

Inhalation

There is no studies available on titanium tetra(octanolate), branched and linear itself to evaluate the acute inhalation toxicity of the substance. The test substance is hydrolytically unstable. When it comes in contact with water or moisture, a complete hydrolysis will take place with no significant reaction products other than alcohol and hydrated titanium dioxide. Because of rapid hydrolysis, read-across data on the acute inhalation toxicity of Exxal 8; alcohols, C7 -C9 -iso, C8 -rich and TiO2 is used to evaluate the lethality and non-lethality of this substance.

Furthermore, when evaluating inhalation hazard of the target substance the volatility of the substance should be taken into account. Titanium tetra(octanolate), branched and linear decomposes during testing and the vapor pressure could not be determined. Thus, the volatility of the decomposition product, Exxal 8, is relevant to discuss here. Exxal 8 is not considered very volatile (the vapor pressure is 0.02 kPA) and therefore has low fugacity level according to ECHA guidance R14, page 28. Based on this conclusion inhalation is not considered as relevant exposure route of the target substance. The study results on the degradation products discussed below justify this conclusion.

Groups of male mice, rats and guinea pigs were subjected to a whole body exposure of a nominal concentration of 24 µg/l of Exxal 8 as a saturated vapor for 6 hours. All animals survived the study. There were indications of depressed physiological function in all animals; indicated by sedation and labored breathing. These observations were resolved once the animals were moved into fresh air. Based on the study results it was concluded that the LC50 is greater than 24 mg/m3.

In a second study, mice, rats, and guinea pigs were subjected to a 6 hour whole body exposure to 200 ppm isooctanol, the main component of Exxal 8 (see read-across justifications in Annexes of the CSR). All animals survived the exposure. There were no adverse clinical signs observed during exposure. In this study, the LC50 is greater than 200 ppm. The results of these both studies cannot be used for classification purposes.

Another decomposition product of titanium tetra(octanolate), branched and linear is TiO2. TiO2 does not cause any relevant exposure hazard for humans as it is non-volatile solid precipitate after hydrolysis of the target substance.

Based on the results, inhalation exposure poses little hazard at any feasible exposure concentration. 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/EEC.

Dermal

There is no valid data available for acute dermal toxicity. Furthermore, dermal route is not considered to be relevant exposure route as skin contact is not likely during the production and use of the substance since the adequate RMMs are in use (CSR sections 9 & 10). Furthermore, this substance decomposes very rapidly (half-life < 10 minutes) releasing Exxal 8 and non-hazardous titanium dioxide.

There is available one acute dermal toxicity study performed using Exxal 8 where rabbits were exposed to varying concentrations (100, 316, 1 000, or 3 160 µl/kg) of test substance via an occluded dermal patch for 24 hours. Observations were made at 1, 4, and 24 hours and daily thereafter for a total of 7 days. One animal in the highest dose group died within 24 hours of patch removal. All other animals survived. Within 4 hours of application, animals in the 3 160 ul/kg exposure group exhibited signs of depressed physiologic function. All adverse observations were resolved within 2 days post exposure. It is concluded that the LD50 is greater than 3 160 µl/kg (2 632 mg/kg).


Justification for selection of acute toxicity – oral endpoint
Reliable study with measured LD50 value for the target substance.

Justification for selection of acute toxicity – inhalation endpoint
Based on the read-across data from the main decomposition product as the target substance is highly reactive (hydrolytically unstable with half-life of < 10 minutes (Brekelmans, M.J.C, 2013). LC50 value was beyond the range tested (>24mg/m3).

Justification for selection of acute toxicity – dermal endpoint
Based on the read-across data from the main decomposition product as the target substance is highly reactive (hydrolytically unstable with half-life of < 10 minutes (Brekelmans, M.J.C, 2013).

Justification for classification or non-classification

The available data for titanium tetra(octanolate), branched and linear indicate low potential for acute toxicity. Based on the acute effects of titanium tetra(octanolate), branched and linear and the decomposition products, the substance has not to be classified according to CLP Regulation 1272/2008 and Directive 67/548/EEC.

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