Tetra-n-butyl titanate, polymer with water

Endpoint summary

Description of key information

Oral:
There is reliable, guideline compliant study available for tetra-n-butyl titanate, polymer with water. 
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 oral 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:

experimental study

Adequacy of study:

key study

Study period:

July 4, 2012 - January 24, 2013

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study was conducted in accordance with OECD No. 423 guideline and in compliance with GLP.

Qualifier:

according to guideline

Guideline:

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

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Qualifier:

according to guideline

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

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 or test system 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:

Total 6 animals and per group 3 animals

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 (Table 1 in attached background material)

Clinical signs:

other: Lethargy, hunched/flat posture, slow breathing and/or uncoordinated movements were noted among the animals on Day 1. (Table 2 in attached background material)

Gross pathology:

No abnormalities were found at macroscopic post mortem examination of the animals (Table 4 in attached background material)

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, polymer with water in Wistar rats was established to exceed 2000 mg/kg body weight.

The substance does not have to be classified and has no obligatory labelling requirement for acute oral toxicity regulation No 1272/2008 on classification, labelling and packaging of substances and mixtures.

Executive summary:

Tetra-n-butyl titanate, polymer with water was administered as an oral gavage in female rats to evaluate acute toxicity. The test substance did not cause any deaths during the study period and thus the LD50 value was concluded to be > 2 000 mg/kg body weight under the conditions of this study.

Based on these results, Tetra-n-butyl titanate, polymer with water 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.

This study was regarded reliable without restrictions 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

Study period:

1993

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-butyl alcohol, rotarod performance and respiratory depression measured according to standard protocol but guideline followed was not mention. 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 or test system 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 M^3


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 -17 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 and 1 ppm of n-butyl alcohal = 3.08 mg/m3. and for n- butyl alcohol exposed concentration range was 100 to 100000 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 the exposure solvents, during 6 min of exposure and 6 min 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:

3 008 ppm

Based on:

other: plethysmographic method

Mortality:

no data

Clinical signs:

other: 1) Depression of central nervous system 2) irritation of eyes and upper respiratory tract

Body weight:

no data

Gross pathology:

no data

Other findings:

- Potential target organs: Central nervous system

All rats exposued for 4 hours to the tested concentrations of n-butyl alcohol and mixture survived the exposure, both solvents and thair mixture caused concentration dependent disturbances in rotarod performance of rats (refer the attached background material).

Both m-xylene and n-butyl alcohol caused a concentration dependent decrease in respiratory rate in mice (refer the attached background materia).

N-butyl alcohol and mixture solvents changed the spontaneous motor activity in the rat (refer the attached background materia).

Interpretation of results:

harmful

Remarks:

Migrated information Criteria used for interpretation of results: OECD GHS

Conclusions:

In this study neurotoxicity of n-butanol assessed on the basis of rotarod performance and spontaneous motor activity and the irritation effect was quantified by measurement of respiratory rate in mice. For n-butanol EC50 ( medial effective concentration) and RD50 (concentration dependent decrease in respiratory rate to 50%) were determined as 6531 ppm and 3008 ppm respectively.

Executive summary:

As the target substance hydrolyses immediately (half-life <2 hours) the intrinsic properties are related to this main organic degradation product (butanol) of the target substance. This information is used as a weight of evidence in CSA.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

20 100 mg/m³ air

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 is available a guideline compliant acute oral toxicity study conducted for tetra-n-butyl titanate, polymer with water. This study is considered reliable without restrictions and used as a key study in hazard assessment. As the target substance is hydrolytically unstable having the half-life less than 2 hours (Brekelmans, M. J. C., 2013), relevant data from the degradation products are also used as supporting information to evaluate the lethality and non-lethality of the target substance.

In a study by Beerens-Heijnen, C. G. M. (2013) the toxicity of the tetra-n-butyl titanate was assessed in a limit test by treatment of six females at a dose level of 2000 mg/kg body weight. Following administration test animals were observed for clinical signs and mortality for 14 days. No mortality occurred and no other clinical signs were observed than lethargy, hunched/flat posture, slow breathing and/or uncoordinated movements were noted among the animals on Day 1. Body weight gain was normal and no abnormalities were found post mortem examination of animals. The oral LD50 value of tetra-n-butyl titanate, polymer with water in Wistar rats was established to exceed 2000 mg/kg body weight.

The supporting read-across data on acute oral toxicity of n-butanol, the hazardous degradation product of the target substance proves that n-butanol is practically nontoxic (O’Neil, M.J. et al. 2006). Theoral toxicity study in rats shows LD50 value of > 5000 mg/kg bw 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, these results from tetra-n-butyl titanate, polymer with water and from the decomposition products (n-butanol and hydrated titanium dioxide) 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

There is no acute inhalation study available for the target substance. Weight of evidence approach is used to assess the acute inhalation toxicity of tetra-n-butyl titanate, polymer with water based on the data from titanium tetrabutanolate, the category member of the target substance and from n-butanol, the hazardous degradation product.

The analogue substance (titanium tetrabutanolate) of category of highly reactive titanates hydrolyses rapidly (half-life < 5 min) 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.

There is one low quality study conducted using titanium tetrabutanolate (Kinney, 1985). 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, tetra-n-butyl titanate, polymer with water 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 target substance because of adequate RMMs in use (see sections 9&10 of CSR). Furthermore, this substance decomposes very rapidly (half-life < 2 hours) 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
Klimisch score 1 study conducted for the substance itself

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 < 2 hours (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 < 2 hours (Brekelmans, M. J. C, 2013).

Justification for classification or non-classification

Lethality:

The available data for tetra-n-butyl titanate, polymer with water 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:

Tetra-n-butyl titanate, polymer with water and its analogue substance, titanium tetrabutanolate decompose rapidly to n-butanol. n-Butanol has been shown to cause transient sedation of the central nervous system after inhalation exposure. Uncoordinated movements were seen after oral administration of tetra-n-butyl titanate, polymer with water. Based on these observations, tetra-n-butyl titanate, polymer with water 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.