Tetra-n-butyl titanate, polymer with water

Endpoint summary

Description of key information

Skin irritation:
Data is from the analogue category member of the target substance, titanium tetrabutanolate
Irritating (rabbits)
Eye irritation:
Data is from the analogue category member of the target substance, titanium tetrabutanolate
Serious eye damage due to irreversible effects (rabbits)
Respiratory irritation:
The following result is from n-butanol, the degradation product of the target substance.
Irritating due to the decrease in the respiration rate (mice)

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Study period:

October 23, 1978 - January 12, 1979

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: Study pre-dates GLP and performed according to a non-guideline method. Insufficient data is provided on study methods and results.

Justification for type of information:

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:

no guideline followed

Principles of method if other than guideline:

One drop (~0,05ml) 5% and 50% solution (vol/vol) of the test material in acetone was applied on shaved, shoulder intact skin of 10 guinea pigs. Skin reaction was observed and recorded at 24h and at 48h after test material application.

GLP compliance:

no

Species:

guinea pig

Strain:

other: albino

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 480g

Type of coverage:

not specified

Preparation of test site:

shaved

Vehicle:

other: acetone

Controls:

no

Amount / concentration applied:

TEST MATERIAL
- Amount applied: One drop (~0,05ml)
- Concentration (if solution): 5% and 50% (vol/vol)

VEHICLE
- Amount(s) applied (volume or weight with unit):
- Concentration (if solution):
- Lot/batch no. (if required):
- Purity:

Duration of treatment / exposure:

24 hours and 48 hours

Observation period:

At 24 hours and 48 hours after test material application skin reactions were recorded

Number of animals:

10 animals

Details on study design:

TEST SITE
-shoulder skin of the animal

REMOVAL OF TEST SUBSTANCE
-washing of the test substance was not done

SCORING SYSTEM:
+ mild erythema
++ moderate erythema
+++ strong erythema
++++ erythema plus edema
+++++ necrosis

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not determinable

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not determinable

Irritation parameter:

other:

Basis:

animal #1

Time point:

48 h

Score:

1

Max. score:

6

Reversibility:

not specified

Remarks on result:

probability of weak irritation

Irritation parameter:

other:

Basis:

animal #2

Time point:

48 h

Score:

1

Max. score:

6

Reversibility:

not specified

Remarks on result:

probability of weak irritation

Irritant / corrosive response data:

Titanic acid, tetrabutyl ester caused moderate to no irritation when tested as a 50% suspension in acetone on the shaved, intact skin of guinea pigs and mild to no irritation when tested as a 5% suspension.

Reactions on intact guinea pig skin

	Test group (10 animals)	Test group (10 animals)
Concentration in acetone	50%	5%
Primary irritation test - 24 hours	1+, 9 negative	1+, 9 negative
Primary irritation test - 48 hours	1 +, 9 negative	1+, 9 negative

Reaction codes are as follows: + mild erythema ++moderate erythema +++ strong erythema ++++ erythema plus oedema +++++necrosis

Interpretation of results:

slightly irritating

Remarks:

Migrated information Criteria used for interpretation of results: expert judgment

Conclusions:

The primary dermal irritation potential of titanium tetrabutanolate was evaluated when applied to the skin of guinea pigs for 24 hour and for 48 hour. The test substance is considered to be mild skin irritant according to this study.

Executive summary:

Titanium tetrabutanolate was applied in two concentrations (5% and 50% vol/vol in acetone) to two separate test areas on the intact skin on each animal´s back. By the study report the test material is considered to be mild irritant to the skin of guinea pigs.

 

This study was regarded not reliable since the study pre-dates GLP and it is non-guideline study. Furthermore, the study report includes insufficient details on study methods and results. This study does not satisfy the guideline requirements for the skin irritation study.

 

This toxicity study from this analogue category member (Titanium tetrabutanolate) is used for the weight of evidence to justify that the skin irritation of Tetra-n-butyl titanate, polymer with water. Skin irritation result from organometallic category member Titanium tetrabutanolate is justified.

The result of this study is used as a weight of evidence in hazard assessment.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation: in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Study period:

October 23, 1978 - December 22, 1978

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: This study predates current guideline and the study report does not include details on test substance, test animals and test procedure.

Justification for type of information:

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:

no guideline followed

Principles of method if other than guideline:

0,1 ml of the undiluted test substance was placed into the right conjunctival sac of two albino rabbit. After 20 seconds treated eye was washed with tap water for one minute. The treated eye of the other rabbit was not washed. Observations of the cornea, iris and conjunctiva were made at one and four hours, and at one, two, three, seven, fourteen and twenty-one days.

GLP compliance:

no

Species:

rabbit

Strain:

not specified

Details on test animals or tissues and environmental conditions:

Rabbits were described albino rabbits. There were no details on environmental conditions.

Vehicle:

unchanged (no vehicle)

Controls:

not required

Amount / concentration applied:

0.1 ml

Duration of treatment / exposure:

Test substance was placed into the right conjunctival sac. Observations were made at 1, 4, 24, 48, 72 hours, and at days 7, 14, and/or 21.

Observation period (in vivo):

21 days

Number of animals or in vitro replicates:

2

Details on study design:

0.1 ml test substance was placed into the right conjunctival sac. Total of 2 animals were treated. After 20 seconds treated eye of the one rabbit was washed with tap water for one minute. The treated eye of the other rabbit was not washed. Observations of the cornea, iris and conjunctiva were made with hand-slit lamp at 1, 4, 24, 48, 72 hours, and at days 7, 14, and 21. Fluor-i-strip stain and a biomicroscope were used at examinations after the day of treatment.

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not determinable

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not determinable

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not determinable

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not determinable

Animal/treatment	Cornea	Iris	Conjunctiva
0.1 ml undiluted liquid, Eye not washed	Cornea not seen 1 -4 hrs. due to conjunctival swelling. Generalized moderate opacity with severe corneal swelling 1 -14 days. Moderate area of moderate opacity with moderate to severe swelling at 21 days.	Iris not seen 1 -4 hrs. due to conjunctival swelling. Moderate to severe irritis with a flare 1 -3 days; moderate at 7 days; slight injection at 14 days.	Redness: Severe 1 hr.-7 days with blanching at 1 hr. - 1 day; moderate at 14 days. Swelling:. Severe 1 - 4hrs.; moderate 1 -4 days; mild at 7 days; slight at 14 days Discharge: Copious Hemastix -Positive 1hr-2 days; moderate Hemastix-Positive at 3 days; mild at 7 days
0.1 ml undiluted liquid, Eye washed after 20 seconds	Generalized mild opacity 1 hr.-3 days with severe corneal swelling 1 -2 days and moderate to severe swelling at 3 days; Moderate area of slight opacity with mild to moderate swelling at 7 days; Small area of slight opacity with mild corneal swelling 14 -21 days	Moderate iritis 1hr.-3 days with a flare 1 -2 days	Redness: Severe 1 hr-3 days with blanching at 1 hr-1 day. Swelling: Moderate at 1 hr.; moderate to severe at 4hrs.; moderate 1 -2 days; mild at 3 days Discharge: Copious Hemastix-Positive 1 hr.-1 day; moderate at 2 days; mild at 3 days

Interpretation of results:

Category 1 (irreversible effects on the eye)

Remarks:

Migrated information Criteria used for interpretation of results: expert judgment

Conclusions:

The eye irritation potential of Titanium tetrabutanolate was evaluated when introduced to the eyes of rabbits. The test material caused persistent lesions which were not fully reversible within an observation period of 21 days and is thus classified in Category 1 eye irritant by the applicant.

Executive summary:

Titanium tetrabutanolate was applied undiluted into the eyes of two rabbits. After 20 seconds, treated eye of one rabbit was washed with water. The treated eye of the other rabbit was not washed. Observations were made at 1 and 4 hours, and at 1, 2, 3, 7, 14, and 21 days for the treated eyes. Titanium tetrabutanolate severely irritated the cornea and conjunctiva and moderately to severily irritated the iris of both the washed and unwashed rabbit eyes. At 21 days, the unwashed eye had moderate to severe corneal irritation and the washed eye had mild corneal irritation.

This study was regarded as non reliable, since the study report does not include details on test material and test procedure. Furthermore, tabulation of irritant/corrosive response data for each animal at each observation time point is missing.

This study does not satisfy the guideline requirements for the eye irritation study and thus the result of this study is used as a supporting evidence for hazard assessment

This toxicity study from this analogue category member (Titanium tetrabutanolate) is used for the weight of evidence to justify that the eye irritation of Tetra-n-butyl titanate, polymer with water. Eye irritation result from organometallic member Titanium tetrabutanolate is justified.

The result of this study is used as a weight of evidence in hazard assessment.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Additional information

Skin irritation

There is no skin irritation data available for tetra-n-butyl titanate, polymer with water. The weight of evidence approach is used to determine the skin irritation potential of this substance evaluating relevant data from the analogue substance and from the decomposition products.

The analogue substance (titanium tetrabutanolate) of category ofhighly reactive titanateshydrolyses 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 are two low quality skin irritation studies available for titanium tetrabutanolate, the analogue substance of tetra-n-butyl titanate, polymer with water. A skin irritation study by Ferenz, R. L. (1978) was conducted for 5 % and 50 % solution of titanium tetrabutanolate in acetone. The test substance was applied on the skin of six rabbits for 24 hours. Skin reactions were observed at 24 and 48 hours following application. Based on the study report, the test material in 50 % suspension was considered moderately irritating and in 5 % suspension mildly irritating to the skin of guinea pigs.

In the other study by Cargus, J. L. (1984) mixture of titanium tetrabutanolate was investigated. Because the tested item contained 25 % of titanium tetrabutanolate and 75 % kerosene the study result cannot be used for evaluation of skin irritation caused by the target substance. In the study six rabbits were exposed to test item for 24 hours and skin responses were recorded at 24, 48, 72 and 96 hours and 7 days after test item application. The test substance is considered to be severely irritating.

Further evidence on the potential of this substance to cause skin irritation is evaluated based on the read-across data from the decomposition products. The target substance is hydrolytically unstable having the half-life less than 2 hours (Brekelmans, M. J. C., 2013). Skin irritation of n-butanol has been studied in experimental animals. The results from most of the experiments indicate that n-butanol was irritating to skin (UNEP, 2004). n-Butanol has also the harmonized classification to Skin Irrit. 2.

The read-across data from the other decomposition product, TiO2, indicates that the substance is shown to lack irritation properties. Titanium dioxide has been used in various dermatological and cosmetic formulations, without any known adverse effects (WHO, 1982). Overall, the results indicate that titanium dioxide has a low potential to irritate the skin of humans under anything other than extreme and unrealistic exposure conditions.

As a conclusion of the skin irritation, the data from the analogue substance of tetra-n-butyl titanate, polymer with water and from the decomposition products is considered reliable. These results indicate this substance to be classified as irritating to skin.

Eye irritation

There is no skin irritation data available for tetra-n-butyl titanate, polymer with water. The weight of evidence approach is used to determine the eye irritation hazard of tetra-n-butyl titanate, polymer with water evaluating relevant data from the analogue substance but also from the decomposition products.

In an eye irritation study by Ferenz, R. L. (1978), 0.1 ml of the undiluted titanium tetrabutanolate, the analogue substance, was placed into the right conjunctival sac of two albino rabbit. After 20 seconds treated eye was washed with tap water for one minute. The treated eye of the other rabbit was not washed. Observations of the cornea, iris and conjunctiva were made at one and four hours, and at one, two, three, seven, fourteen and twenty-one days. Titanium tetrabutanolate severely irritated the cornea and conjunctiva and moderately to severely irritated the iris of both the washed and unwashed rabbit eyes. At 21 days, the unwashed eye had moderate to severe corneal irritation and the washed eye had mild corneal irritation. Results of this study indicate the irreversible effects on cornea in rabbits.

In the other study by Cargus, J. L (1984), mixture titanium tetrabutanolate was investigated. Because the tested item contained 25 % of titanium tetrabutanolate and 75 % kerosene the study result cannot be used for evaluation of eye irritation caused by the target substance. 0.01 ml of the undiluted test substance was placed into the right conjunctival sac of two albino rabbit. After 20 seconds treated eye was washed with 25 % propylene glycol in distilled water for one minute. The treated eye of the other rabbit was not washed. Observations of the cornea, iris and conjunctiva were made at one and four hours, and at one, two and three days. The test material caused conjunctival irritation (redness, grade 2) in the washed eye at 1 and 4 hours but subsided to grade 1 at 24 and 48 hours. Chemosis (grade 1) was noted in the unwashed and washed eyes at 1 and 4 hours. A discharge (grade 1) was observed in both the unwashed and washed eye at 1 and 4 hours only. No opacity or iritis was observed in either eye at any observation interval throughout the study. All observed effects were reversible within 72 hours.

Read-across data from the decomposition products is used for assessment, because the target substance is hydrolytically unstable having the half-life less than 2 hours (Brekelmans, M. J. C., 2013). Eye irritation of n-butanol, the decomposition product of the target substance, has been studied in experimental animals. The results from these studies indicate that n-butanol was severe irritant (UNEP, 2004). n-Butanol has also the harmonized classification to Eye Dam. 1.

Another decomposition product of tetra-n-butyl titanate, polymer with water is non-hazardous titanium dioxide. Possible risk of eye irritation is related only to the titanium dioxide dust. After hydrolysis of tetra-n-butyl titanate, polymer with water, TiO2 does not cause any relevant eye irritation hazard for humans as the substance exists as hydrated solid precipitate.

Respiratory irritation

There is no respiratory irritation data available for the target substance. Thus, read-across data from n-butanol, the most hazardous degradation product of the target substance, is evaluated here.

The effect of n-butanol on the respiratory rate in mice (six mice per dose level) was investigated by Ceaurriz et al. (1981). Animals were exposed for 2 hours and the RD 50 was determined to be 1268 ppm. The RD50 is the concentration of an irritant that causes a 50 % decrease in breathing rate. Based on the study results it was predicted that 40 mg/m³(13 ppm) in air would have a minimal or no effect on humans, 390.9 mg/m³(127 ppm) would be uncomfortable, and 3909 mg/m³(1268 ppm) would be intolerable.

Because of rapid hydrolysis of the target substance the intrinsic properties are related to the most hazardous decomposition product, n-butanol. As this alcohol causes irritation of the respiratory tract during 5 min exposure, and has the harmonized classification to hazard class STOT SE 3 H335, tetra-n-butyl titanate, polymer with water will be classified accordingly.

In conclusion, the known skin irritation properties of titanium tetrabutanolate, the analogue substance of tetra-n-butyl titanate and the properties of n-butanol, the hazardous decomposition product indicate this substance is irritating to the skin. Based on the eye irritation data from the analogue substance and from the decomposition product, this substance produces serious eye damage. Based on respiratory irritation data of n-butanol in experimental animals, tetra-n-butyl titanate, polymer with water has to be classified into specific target organ toxicity category 3 (STOT SE3, H335).

Justification for selection of skin irritation / corrosion endpoint:
There is no skin irritation study available for the target substance. This study was selected because it is the most reliable study conducted for the analogue category member. Both the analogue substance (titanium tetrabutanolate) and the target substance hydrolyse rapidly in aqueous solutions releasing n-butanol.

Justification for selection of eye irritation endpoint:
There is no eye irritation study available for the target substance. This study was selected because it is the most reliable study conducted for the analogue category member. Both the analogue substance (titanium tetrabutanolate) and the target substance hydrolyse rapidly in aqueous solutions releasing n-butanol.

Effects on skin irritation/corrosion: irritating

Effects on eye irritation: corrosive

Effects on respiratory irritation: irritating

Justification for classification or non-classification

Based on the skin irritation information on the analogue substance and on the hazardous decomposition product, the substance has to be classified to hazard class Skin Irrit. 2 according to CLP Regulation 1272/2008 and as Xi; R38 according to Directive 67/548/EEC.

Based on the eye irritation information on the analogue substance and on the hazardous decomposition product, the substance has to be classified to hazard class Eye Dam. 1 according to CLP Regulation 1272/2008 and as Xi; R41 according to Directive 67/548/EEC.

Tetra-n-butyl titanate, polymer with water decomposes rapidly to n-butanol. n-Butanol has been shown to cause irritation of the respiratory tract in the experimental animal studies. As the intrinsic properties of the target substance are related to the decomposition product, the target substance has to be classified to hazard class STOT SE 3H335 according to CLP Regulation 1272/2008 and as Xi; R37 according to Directive 67/548/EEC.