Bis(ethyl acetoacetato-O1',O3)bis(propan-2-olato)titanium

Endpoint summary

Description of key information

Skin irritation: Not irritating (guinea pigs)
Eye irritation: Irritating (rabbits)

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

January 11, 1978 - April 14, 1978

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: Method is not validated and the documentation is insufficient for assessment

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 was applied on the 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: 541g
- Weight at study conclusion: 724g

Type of coverage:

not specified

Preparation of test site:

shaved

Vehicle:

other: dimethyl phthalate

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):
- 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:

erythema score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not determinable

Remarks:

Details on the results provided in the table.

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not determinable

Remarks:

Details on the results provided in the table.

Irritant / corrosive response data:

Bis(ethylacetoaceto-O1,O3)bis(propan-2-olato)titanium was applied in two concentrations (5% and 50% vol/vol in dimethyl phthalate) on the skin on ten animals. Mild irritation was observed in two animals after 24 hour exposure and in three animals after 48 hour exposure.

Reactions on intact guinea pig skin

	Test group (10 animals)	Test group (10 animals)
Concentration in DMP	50%	5%
Primary irritation test - 24 hours	2+, 8 negative	10 negative
Primary irritation test - 48 hours	3+, 7 negative	10 negative

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

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: expert judgment

Conclusions:

The primary dermal irritation potential of Bis(ethylacetoaceto-O1,O3)bis(propan-2-olato)titanium was evaluated when applied to the skin of guinea pigs for 24 hours and for 48 hours. The test material is considered to be slightly irritant to the skin of guinea pigs. No guideline was followed in this study.

Executive summary:

Bis(ethylacetoaceto-O1,O3)bis(propan-2-olato)titanium was applied in two concentrations (5% and 50% vol/vol in dimethyl phthalate) to two separate test areas on the intact shoulder skin on ten animals. Mild irritation was observed in two animals after 24 hour exposure and in three animals after 48 hour exposure. Clinical signs were not reported during the study nor were autopsy at the termination. By the study report the test material is considered to be slightly irritant to the skin of guinea pigs.

This study was regarded not reliable, since this study does not satisfy the guideline requirements for the skin irritation study. Thus the result is used as a weight of evidence for hazard assessment.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

January 11, 1978 - February 17, 1978

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: Method is not validated and the documentation is insufficient for assessment

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 and three days.

GLP compliance:

no

Species:

rabbit

Strain:

not specified

Vehicle:

unchanged (no vehicle)

Controls:

not required

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1ml
- Concentration (if solution): 100%

Duration of treatment / exposure:

Rabbit 1 : Exposure 20 seconds, then the eye was washed for 1min
Rabbit 2 : After test item application no washing was perfomed

Observation period (in vivo):

Three days

Number of animals or in vitro replicates:

2

Details on study design:

0,1ml of undiluted test material was placed into the right conjuctival sac of each of two albino rabbits. One treated eye was washed after 20 seconds, the treated eye of the other rabbit was not washed. Observations of the cornea, iris and conjunctiva were mafe with a hand-slit lamp at one and four hours, and at one, two, and three days.

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not determinable

Remarks:

Details on the results provided in the table.

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not determinable

Remarks:

Details on the results provided in the table.

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not determinable

Remarks:

Details on the results provided in the table.

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not determinable

Remarks:

Details on the results provided in the table.

Irritant / corrosive response data:

Bis(ethylacetoacetato-O1',O3") bis(propan-2-olato)titanium produced a small area of transient slight opacity and mild conjunctivitis with no iritic effect when tested in a rabbit eye. Ocular effects were reversible and both eyes were normal within 3 days

Animal/treatment	Cornea	Iris	Conjunctiva
0.1 ml undiluted liquid, Eye not washed	Localized slight opacity 1 -4 hrs, increasing to a small area of slight opacity at 1 day.	None	Redness: Mild 1 hour - 2 days. Swelling: Slight 1 hour - 2 days Discharge: Mild 1 -4 hours. Modearate 1 -2 days
0.1 ml undiluted liquid, Eye washed after 20 seconds	Localized slight dulling at 1 hour increasing to localized slight opacity at 4 hours.	None	Redness: Mild 4 hours - 2 days; Swelling: Slight 1 -4 hours. Mild at 1 day. Slight at 2 days Discharge: Mild at 1 hours. Moderate 4 hours - 1 day.

Interpretation of results:

slightly irritating

Remarks:

Migrated information Criteria used for interpretation of results: expert judgment

Conclusions:

The eye irritation potential of Bis(ethylacetoacetato-O1',O3") bis(propan-2-olato)titanium was evaluated when introduced to the eyes of rabbits. The test material is considered a slightly irritating according to the results of this study. The study predates current guideline study and is missing the details on test procedure and test substance.

Executive summary:

Bis(ethylacetoacetato-O1',O3") bis(propan-2-olato)titanium 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 days for the treated eyes. Bis(ethylacetoacetato-O1',O3") bis(propan-2-olato)titanium) slightly irritated the cornea and mildly irritated conjunctiva. At 3 days, the ocular effects were reversible and both eyes were normal.

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. Thus the result of this study is used as a weight of evidence for hazard assessment.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin irritation

Weight of evidence approach is used to evaluate the skin irritation of bis(ethylacetoacetato-O1’,O3”) bis(propan-2-olato)titanium. In addition of the skin irritation data from substance itself, also relevant read-across data from the decomposition products is used for hazard assessment. The target substance is hydrolytically unstable having the half-life less than 10 minutes (Brekelmans, M. J. C., 2013). Thus, the supporting irritation information for this endpoint was collected from the decomposition products, isopropyl alcohol (IPA), ethyl acetoacetate (EAA) and titanium dioxide (TiO2).

There is evidence of skin irritancy of this substance only in one animal study. A pre-guideline and pre-GLP study by Krivanek, 1978 was conducted using 10 guinea pigs. The target substance was applied on the skin of animals and the skin reactions were recorded at 24 and 48 hours following application. Mild irritation was reported in two animals after 24 hour exposure and in three animals after 48 hour exposure.

Publication by Nixon G. et al. (1975) evaluated the dermal irritation/corrosion potential of IPA by administering the substance on the intact and abrated skin of rabbits for 4 hours. Based on skin reactions recorded for 48 hours IPA was concluded to be non-irritant. Equally, IPA has no harmonized classification entry as Skin Irritant/Corrosive in the Annex VI of CLP regulation 1272/2008 and EU Directive 67/548/EEC.

Further information on skin irritation of the target substance comes from two studies conducted for EAA, another decomposition product of the target substance. Though very limited amount of information is available, the one study demonstrates that EAA has no irritating and the other study that EAA has mild irritating properties to skin (European Chemicals Bureau, 2002).

The read-across data from the third decomposition product, TiO2, indicates that the substance is shown to lack skin irritation properties. Titanium dioxide has been used in various dermatological and cosmetic formulations, without any known adverse effects (WHO, 1982).

Based on the weight of evidence approach, the data on the skin irritation properties of Bis(ethylacetoacetato-O1’,O3”) bis(propan-2-olato)titanium and on the decomposition products is considered reliable. It is concluded that these results do not indicate this substance to be classified as irritating to skin.

Eye irritation

Weight of evidence approach is used to evaluate the eye irritation of bis(ethylacetoacetato-O1’,O3”) bis(propan-2-olato)titanium. In addition to the eye irritation data from substance itself, also relevant read-across data from the decomposition products and from the analogue category member is used for hazard assessment. Since the target substance is hydrolytically unstable having the half-life less than 10 minutes (Brekelmans, M. J. C., 2013) it is justified to use the relevant irritation information from the decomposition products, isopropyl alcohol (IPA), ethyl acetoacetate (EAA) and titanium dioxide (TiO2).

There is evidence of eye irritancy of the target substance only in one animal study. In a pre-guideline and pre-GLP study by Edwards, 1978, undiluted bis(ethylacetoacetato-O1’,O3”) bis(propan-2-olato)titanium 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 and three days. Bis(ethylacetoacetato-O1',O3") bis(propan-2-olato)titanium) slightly irritated the cornea and mildly irritated conjunctiva. At 3 days, the ocular effects were reversible and both eyes were normal.

Further evidence on the eye irritation comes from the analogue category member of the target substance, titanium tetraisopropanolate. All these titanates in this category behave similar way when in contact with water. Furthermore, IPA is released from the target substance and from titanium tetraisopropanolate when the substances are in contact with water. The category justification and the read-across justifications are presented in the Annexes of the CSR.

The eye irritation potential of titanium tetraisopropanolate was investigated by Billmeier (1978). The study was broadly comparable to the current OECD 405 guideline and the study report contains sufficiently data for assessment. Therefore, the result of this study, irritating to eyes, is used as weight of evidence for hazard assessment.

The available eye irritation information for IPA, the degradation product of the target substance, is evaluated by OECD. They concluded IPA as eye irritant based on studies by Morgan, R. L. et al. (1987), Marzulli, F. N. et al. (1973) and Griffith, J. F. et al. (1980). IPA has also harmonized classification to eye irritation hazard (Eye Irrit. 2, H319) in the Annex VI of CLP regulation 1272/2008 and (Xi, R36) according to EU Directive 67/548/EEC.

Further information on eye irritation of the target substance comes from two studies conducted for EAA, the decomposition product of the target substance (European Chemicals Bureau, 2002). These studies demonstrated mild to moderate eye irritating effects that were fully reversible in three days.

TiO2 is non-hazardous decomposition product of Bis(ethylacetoacetato-O1’,O3”) bis(propan-2-olato)titanium. Possible risk of eye irritation caused by this substance is related only to the TiO2 dust. However, after hydrolysis of the target substance, TiO2 is not expected to cause any relevant eye irritation hazard for humans as it exists as a hydrated solid precipitate.

Although the eye irritation studies of the target substance and the decomposition products are not reported in great detail and are not performed in strict compliance with current guidelines, they indicate that the target substance is irritating to the eyes.

Justification for selection of skin irritation / corrosion endpoint:
This study predates current guideline. The study is performed using the target substance.

Justification for selection of eye irritation endpoint:
This study predates current guideline. The study is performed using the target substance.

Effects on eye irritation: irritating

Justification for classification or non-classification

Based on the skin irritation information on bis(ethylacetoacetato-O1’,O3”) bis(propan-2-olato)titanium and its decomposition products, the substance has not to be classified according to CLP Regulation 1272/2008 and Directive 67/548/EEC.

Based on the eye irritation information on bis(ethylacetoacetato-O1’,O3”) bis(propan-2-olato)titanium and its decomposition products, the substance has to be classified to hazard class Eye Irrit 2 according to CLP Regulation 1272/2008 and as Xi; R36 according to Directive 67/548/EEC.