Registration Dossier

Administrative data

Description of key information

Oral:
There is no reliable data available for acute oral toxicity for the target substance. This value comes from the analogue category member. Both the analogue substance (tetra-n-butyl titanate, polymer with water) and the target substance hydrolyze rapidly in aqueous solutions releasing n-butanol.
The oral LD50 (rat; female) is greater than 2 000 mg/kg bw
Inhalation:
There is no reliable data available for acute inhalation toxicity for the target substance.
The LC50 (rat; male) for n-butanol, the degradation product, is > 20 100 mg/m3
Dermal:
There is no valid data available for acute dermal toxicity for the target substance.
The dermal LD50 (rat; male, female) for the n-butanol, the degradation product, is 5 300 mg/kg bw

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Study period:
12 July 2012 to 31 July 2012
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The study was conducted in accordance with OECD No. 423 guideline and in compliance with 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 the particular alcohol and hydrated titanium dioxide. This rapid hydrolysis (hydrolysis half-life < 3 minutes to < 2 hours) is the driving force for toxicokinetics of the target substance. Because of the rapid hydrolysis the influence of the mode of administration through inhalation, dermal and/or oral is related to the most hazardous degradation product (alcohol) released from the substance. The testing conducted with analogue substances of the category proves that the toxicity is similar to the toxicity of alcohol released from the target substance in contact with moisture. 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 toxicity of the target substance compared to the toxicity of the pure alcohol. The read-across approach from analogue category members are used to justify that the mode of administration through oral, inhalation and/or dermal is similar to the adverse effects of the degradation products. In addition, the test results of analogue category members releasing same alcohols are used to evaluate the short term and long-term toxicity, skin and eye irritation and sensitization, and mutagenic properties of the target substance.
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Qualifier:
according to
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Qualifier:
according to
Guideline:
other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 12 Nohsan, Notification No. 8147, April 2011; including the most recent partial revisions.
Qualifier:
according to
Guideline:
other: As required by the Dutch Act on Animal Experimentation (February 1997), this type of protocol was reviewed and agreed by the Laboratory Animal Welfare Officer and the Ethical Committee (DEC 03-42)
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany.
- Age at study initiation: Young adult animals (approx. 11-12 weeks old)
- Weight at study initiation: Body weight variation did not exceed +/- 20% of the sex mean
- Fasting period before study: Animals were deprived of food overnight prior to dosing and until 3-4 hours after administration of the test substance.
- Housing: Group housing of 3 animals per cage in labeled Makrolon cages (MIV type; height 18 cm.) containing sterilized sawdust as bedding material (Litalabo, S.P.P.S., Argenteuil, France) and paper as cage-enrichment.
- Diet (e.g. ad libitum): Free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany).
- Water (e.g. ad libitum): Free access to tap water
- Acclimation period: Acclimatization period was at least 5 days before start of treatment under laboratory conditions

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 to 24 degrees C
- Humidity (%): 40 to 70
- Air changes (per hr): 15 room air changes/hour
- Photoperiod (hrs dark / hrs light): 12-hour light/12-hours dark cycle
Route of administration:
oral: gavage
Vehicle:
other: Kaydoll mineral oil
Details on oral exposure:
VEHICLE
- Amount of vehicle (if gavage): Homogeneity was accomplished to a visually acceptable level. Adjustment was made for specific gravity of the vehicle
- Justification for choice of vehicle: The vehicle was selected based on trial formulations performed at WIL Research Europe and on test substance.

MAXIMUM DOSE VOLUME APPLIED: 2000mg/kg BW
Doses:
2000 mg/kg body weight
No. of animals per sex per dose:
3
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Day 1 (pre-administration), 8 and 15
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology.
Statistics:
No data
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occured
Clinical signs:
Lethargy, hunched/flat posture, slow breathing and/or uncoordinated movements were noted among the animals on Day 1.
Body weight:
The body weight gain shown by the animals over the study period was considered to be similar to that expected of normal untreated animals of the same age and strain
Gross pathology:
No abnormalities were found at macroscopic post mortem examination of the animals

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: expert judgment
Conclusions:
The oral LD50 value of tetra-n-butyl titanate in Wistar rats was established to exceed 2000 mg/kg body weight.

Tetra-n-butyl titanate does not have to be classified and has no obligatory labelling requirement for acute oral toxicity according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2011) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures.
Executive summary:

Tetra-n-butyl titanate, polymer with water, analogue category member of titanium tetrabutanolate, was administered as an oral gavage in female rats to evaluate acute toxicity. This study result from analogue category member is used for the weight of evidence to evaluate the acute oral toxicity of titanium tetrabutanolate because both substances release butanol upon hydrolysis.

Tetra-n-butyl titanate, polymer with water did not cause any deaths during the study period and thus the LD50 value was concluded to be > 2 000mg/kg body weight. Based on this result, titanium tetrabutanolate is expected have low acute oral toxicity.

This study was regarded reliable since the study was conducted in accordance with OECD No. 423 guideline and in compliance with GLP.

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:
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:
The study intended to determine co-exposure effect of xylene and n-butanol, rotarod performance and respiratory depression measured according to standard protocol but guideline followed was not mentioned. 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:
no guideline followed
Principles of method if other than guideline:
Rotarod performance was tested according to the principle described by Kaplan and Murphy.
GLP compliance:
not specified
Test type:
other:
Species:
other: Rats and mice
Strain:
other: Wistar rats and balb/c mice
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: DAK Stock outbred
- Weight at study initiation: 250-300g for rats and 25-30 g mice

Route of administration:
inhalation: vapour
Type of inhalation exposure:
other:
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Dynamic inhalation chamber
- Exposure chamber volume: 1.3 M3


TEST ATMOSPHERE
- Brief description of analytical method used: The concentration of solvent vapours were measured every 30 min with a gas chromatograph with flame ionization detector using 1.5 m metal column with 10% OV on chromosorb WHP (80-100 mesh) as a stationary phase at column temprature of 100 C.



Analytical verification of test atmosphere concentrations:
yes
Remarks:
Gas chromatography
Duration of exposure:
4 h
Remarks on duration:
4hr exposure period was for rats and mice exposed for 6 min as to determine respiratory depression.
Concentrations:
Exposure concentration of n-butyl alcohol were expressed in ppm. 1 ppm of n-butanol = 3.08 mg/m3. Concentration range of n-butanol was 100 to 100 000 ppm.
No. of animals per sex per dose:
8-10 male mice per group for measuring respiratory rate
10 male rats per group for measuring rotarod performance
Control animals:
yes
Details on study design:
- Duration of observation period following administration: no data

- Other examinations performed: Rotarod performance was tested before exposure and immediately after exposure to several concentration of n-butyl alcohol and in control animal for 1 hour.

The respiratory pattern was recorded continuously before exposure, during 6 min exposure and after termination of exposure.

Spontaneous motor activity was measured by the use of UMA-2-10 actometer during one hour immediately after termination of 4 hour exposure to rats
Statistics:
Probit analysis was applied to determin the medial effective concentration (EC50 and RD50 value). Frequency data were also compared using the Chi-square test.
Sex:
male
Dose descriptor:
other: EC 50
Effect level:
6 531 ppm
Based on:
other: rotarod performance
95% CL:
4 950 - 10 370
Exp. duration:
4 h
Sex:
male
Dose descriptor:
other: RD50: concentration dependent decrease in respiratory rate to 50%
Effect level:
3 010 ppm
Based on:
other: plethysmographic method

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

Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: expert judgment
Conclusions:
In this study neurotoxicity of n-butanol was assessed based on the rotarod performance in rats and based on the measurement of respiratory rate in mice. For n-butanol EC50 ( effective concentration for disturbance in rotarod performance) and RD50 (concentration for 50% decrease in respiratory rate) were determined as 6530 ppm and 3010 ppm, respectively.
Executive summary:

This study is performed for -n-butanol, the decomposition product of the target substance. The study shows in 4 -hour exposures, an inhalation EC50 value of 6 530 ppm (20.1 mg/l) for disturbance of rotarod performance by male Wistar rats and an inhalation RD50 value (concentration to cause 50% decrease in respiratory rate) of 3 010 ppm (9.3 mg/l) for mice. The study result is used as a weight of evidence in the hazard assessment.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
20 100 mg/m³

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
5 300 mg/kg bw

Additional information

Acute toxicity oral

There are two low quality studies available for titanium tetrabutanolate to evaluate the acute oral toxicity. As the target substance is hydrolytically unstable having the half-life less than 5 minutes (Brekelmans, M. J. C., 2013), information from degradation products are also used to evaluate the lethality and non-lethality of the target substance after oral administration. Weight of evidence approach is used to assess the acute oral toxicity of the target substance based on the data from substance itself and from the hazardous degradation products.

The study by Warheit, D. B. (1985) is not reliable alone to be used for evaluation of acute oral toxicity since the tested substance contained only 25 % of titanium tetrabutanolate. The main component was kerosene (75 %). The oral toxicity of this mixture was studied in several rats, one animal per dose level. Following administration test animals were observed for clinical signs and mortality for 14 days. Clinical signs included lethargy, wet and/or yellow stained perineum, low posture, ataxia, limpness, clear discharge from the eyes, lung noise, salivation and dry red discharge from the nose and mouth. However, no mortalities were observed associated with any doses given. Thus, the approximate lethal dose (ALD) was concluded to be > 25 000 mg/kg bw.

In the other low quality study by Foulger, J.H. (1949) conducted for the target substance one rat per dose level was administered oral dose at 450, 1 000, 2 250, 3 375, 5 000 and 7 500 mg/kg bw. The rat that received highest dose died within 1 hour after treatment. Thus, the ALD based on this study was 7 500 mg/kg/day.

The additional data to evaluate acute oral toxicity of the target substance comes from the analogue category member, tetra-n-butyl titanate, polymer with water (Beerens-Heijnen, 2013). This analogue substance (tetra-n-butyl titanate, polymer with water) of the category of highly water reactive titanates hydrolyzed rapidly (half-life < 2h) in aqueous test media releasing n-butanol with the hydrated titanium oxide precipitating out of the test solution. Due to the rapid hydrolysis, it was considered that any toxicity would be due to the presence of n-butanol and not the parent test item. The category justification is presented in the Annex I of this CSR.

The acute oral toxicity of tetra-n-butyl titanate, polymer with water was conducted in accordance with OECD 423 guideline and in compliance with GLP (Beerens-Heijnen, 2013). Fasted adult rats received the unchanged test material by oral gavage. The oral LD50 value of tetra-n-butyl titanate, polymer with water was established to exceed 2 000 mg/kg body weight. Thus, it can be concluded that the analogue substance of titanium tetrabutanolate has low order of acute toxicity after oral route of exposure. Following clinical signs were noted among the animals on day 1; lethargy, hunched/flat posture, slow breathing and/or uncoordinated movements. No signs of toxicity were observed on Day 2.

CNS effects (lethargy, uncoordinated movements) are reported in the acute oral toxicity studies conducted for titanium tetrabutanolate (Warheit, 1985) and its analogue category substance (Beerens-Heijnen, 2013). Because of rapid hydrolysis of these substances the intrinsic properties are related to the most hazardous decomposition product, n-butanol. As this alcohol causes effects indicative for CNS depression, and has been proposed the classification to hazard class STOT SE 3 H336, titanium tetrabutanolate will be classified accordingly.

For n-butanol, the decomposition product of the target substance, the most relevant exposure route for humans is inhalation. However, several oral toxicity studies are summarized in UNEP, 2004 showing very low oral toxicity for n-butanol.

For TiO2, the other decomposition product, 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 and no relevant gross pathology was observed at autopsy (WHO, 1982).

As a conclusion, the LD50-values on titanium tetrabutanolate, the analogue category substance and on the decomposition products (n-butanol 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.

Acute toxicity inhalation

Weight of evidence approach is used to assess the acute inhalation toxicity of titanium tetrabutanolate based on the data from the substance itself and from the hazardous degradation product, n-butanol. There is one low quality study conducted using the target substance. However, this study result cannot be used for evaluation of acute inhalation toxicity since the tested substance contained only 25 % of titanium tetrabutanolate. The main component was kerosene (75 %). In the study 10 male rats / dose level were exposed for a single, 4-hour period to an aerosol atmosphere of the test substance in air. The rats were observed for clinical signs and weighed daily throughout a 14-day recovery period or until death. An approximate lethal concentration (ALC) was determined to be 11 mg/l under conditions of this study. During or immediately following exposure, some rats in all groups were lethargic, had no response when the chamber was tapped, wet perineum, diarrhea, decreased muscle tone and impaired breathing.

There is available a study for n-butanol, the decomposition product of the target substance, showing adverse effects on the function of central nervous system (CNS)(Korsak et al., 1993). The study shows in 4 -hour exposures, an inhalation EC50 value of 6 530 ppm (20.1 mg/l) for disturbance of rotarod performance by male Wistar rats and an inhalation RD50 value (concentration for 50% reduction in respiratory rate) of 3 010 ppm (9.3 mg/l) for mice. As available information suggest that n-butanol causes central nervous system effects, and has been proposed the classification to hazard class STOT SE 3 H336, titanium tetrabutanolate will be classified accordingly.

TiO2 is non-hazardous substance and has very low acute and long-term toxicity (US EPA, 1994; WHO, 1982). Furthermore, it is a solid precipitate of the target substance after hydrolysis, and present in hydrated form in the solution after the degradation. Thus, it is not relevant to be considered for this endpoint.

Acute toxicity dermal

There is no valid data available for acute dermal toxicity for the target substance. Furthermore, 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 < 5 minutes) releasing n-butanol and hydrated titanium dioxide (TiO2).

n- Butanol was only slowly absorbed through the skin (Boman and Maibach, 2000) and TiO2 has no adsorption potential through skin (US EPA, 1994; WHO, 1982). Furthermore, n-butanol has low dermal LD50 value of 5 300 mg/kg (Patty, 1982).

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
There is available one not reliable and one not assignable acute oral toxicity study for the target substance. This study was selected because it is reliable and conducted for the analogue category member. Both the analogue substance (tetra-n-butyl titanate, polymer with water) and the target substance hydrolyze rapidly in aqueous solutions releasing n-butanol.

Justification for selection of acute toxicity – inhalation endpoint
No study available for the substance itself. Based on the read-across data from the main decomposition product as the target substance is hydrolytically unstable with half-life of < 5 minutes (Brekelmans, M. J. C, 2013).

Justification for selection of acute toxicity – dermal endpoint
Dermal route is not considered to be relevant exposure route since skin contact in use and production of the test substance is not likely. Based on the read-across data from the main decomposition product as the target substance is hydrolytically unstable with half-life of < 5 minutes (Brekelmans, M. J. C, 2013).

Justification for classification or non-classification

Lethality:

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

Toxicity to a specific organ:

Titanium tetrabutanolate and its analogue substance, tetra-n-butyl titanate decompose rapidly to n-butanol. n-Butanol has been shown to cause transient sedation of the central nervous system after inhalation exposure. Similar effects were seen after oral administration of tetra-n-butyl titanate. Based on these observations, titanium tetrabutanolate has to be classified to hazard class STOT SE 3 H336 according to CLP Regulation 1272/2008 and as R 67 according to Directive 67/548/EEC.