Titanium(4+) ethanolate

Endpoint summary

Description of key information

Skin irritation:
Not irritating (rabbits)
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:

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

Adequacy of study:

weight of evidence

Study period:

1986

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

not specified

GLP compliance:

not specified

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

no data

Type of coverage:

occlusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

undiluted

Duration of treatment / exposure:

4 hour(s)

Observation period:

72 hours

Number of animals:

6

Details on study design:

TEST SITE
- Area of exposure: not specified
- % coverage: 6cm2
- Type of wrap if used: under an exposure chamber.

REMOVAL OF TEST SUBSTANCE: no data

SCORING SYSTEM: Draize method

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

erythema score

Basis:

mean

Time point:

other: 1 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 48 hours

Irritation parameter:

erythema score

Basis:

mean

Time point:

24 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 48 hours

Irritation parameter:

erythema score

Basis:

mean

Time point:

48 h

Remarks on result:

not determinable

Irritation parameter:

erythema score

Basis:

mean

Time point:

72 h

Remarks on result:

not determinable

Irritant / corrosive response data:

Scores for oedema were 0.0 at all time points. (1, 24, 48, 72 hours)

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

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

In a guideline skin irritation study using rabbits, ethanol caused mild transient irritation (very slight, barely perceptible erythema) which disappeared within 48 hours of application.

Executive summary:

The degree of response was insufficient to warrant labelling as a skin irritant either under directive 67/548 or the EU GHS regulation.

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:

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

Adequacy of study:

weight of evidence

Study period:

before 1998

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Remarks:

The source is a published peer-reviewed tabulation of detailed results from in-house eye irritation studies performed according to a guideline that is intended as a reference work for the development of in vitro studies. The work is published by a reputable organization and is therefore considered reliable.

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

not specified

GLP compliance:

not specified

Remarks:

Study indicated to be to GLP but no test laboratory named.

Species:

rabbit

Strain:

not specified

Details on test animals or tissues and environmental conditions:

no data

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

Concentration: 100 % active substance
- instillation of 0.1 ml

Duration of treatment / exposure:

single instillation

Observation period (in vivo):

Up to 21 days unless symptoms disappeared first.

Number of animals or in vitro replicates:

3

Details on study design:

SCORING SYSTEM: Standard Draize grading scale for lesions.

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Score:

1.1

Max. score:

4

Reversibility:

fully reversible within: 4 days

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Score:

0.44

Max. score:

2

Reversibility:

fully reversible within: 4 days

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

24/48/72 h

Score:

2.1

Max. score:

3

Reversibility:

fully reversible within: 14 days

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Score:

1.3

Max. score:

4

Reversibility:

fully reversible within: 14 days

Irritation parameter:

other: MMAS

Basis:

mean

Time point:

24 h

Score:

24

Max. score:

110

Irritant / corrosive response data:

Individual animal observations reported. Full reversal of all symptoms in animals occurred within 14 days. Most persistent effect was conjunctival redness, still present, grade 1, at 7 daysin 2 animals (last observation time before 14 day observation). One animal showed full recovery of all symptoms by day 4.

Other effects:

none reported.

The MMAS (modified maximum average score is calculated per animal from the 24 hour observations based corneal effects (capacity x area x 5), iris effects (x5) and conjunctival effects (redness + chemosis + discharge scores). The total possible is 80 (cornea) + iris (10) plus conjunctivae (20), ie a maximum of 110.

Average scores (all animals)

	Day 1	Day 2	Day 3
Corneal opacity	1.33	1.33	0.66
Iritis	0.33	0.66	0.33
Conjunctival redness	2.66	2.00	1.66
Chemosis	1.66	1.66	0.66

Average scores (worst two animals)

	ANIMAL #1 (average days 1,2,3)	ANIMAL #2 (average days 1,2,3)
Corneal opacity	1.33	1.66
Iritis	1	0.33
Conjunctival redness	2.66	2.33
Chemosis	2	1.66

Based on the criteria for classification, only the conjunctival redness in animal one is meets the criteria for the definition of a significant occular lesions would be regarded as significant but such a response in only one animal is not regarded as sufficient for classification as an eye irritant under directive 67/548. The average results across all 3 animals are not sufficient either. However, the criteria for classification under GHS are more stringent and a positive response is seen under these criteria for corneal opacity (2 animals >1) and conjunctival redness (2 animals >2), hence classification as an eye irritant (category 2) is required.

The peer review process used in this publication ensured that only high quality data was included. Checks included purity of substance, guideline and GLP compliance, amount of substance and a minimum of 3 animals used.

This is a preferred result for this end point as it is a recent study carried out to a recognized protocol that is reported in detail.

Interpretation of results:

irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

In a guideline eye irritation study in rabbits, ethanol clearly shows reversible eye irritant properties.

Executive summary:

In a reference handbook of peer reviewed, guideline GLP eye irritation study results in rabbits, ethanol was found to cause eye irritation. All symptoms reversed within 14 days. The response was not sufficiently severe to trigger classification under the criteria of directive 67/548 but was sufficient with respect to the corneal and conjunctival effects to trigger classification as a reversible eye irritant (category 2) under CLP Regulation 1272/2008.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin irritation

There are no studies available on titanium (4+) ethanolate itself to evaluate the skin irritation of the substance. The potential of this substance to cause skin irritation is evaluated based on the read-across data on skin irritation of the decomposition products, because the target substance is hydrolytically unstable having the half-life less than 5 minutes (Brekelmans, M.J.C., 2013). The weight of evidence approach is used to determine the skin irritation of this substance evaluating relevant data also from the decomposition products, ethanol and titanium dioxide (TiO₂).

There is little evidence of skin irritancy in animal studies. A study conducted to OECD 404 standards in rabbits showed ethanol to be not irritating (Jacobs, 1992). Ethanol caused mild transient irritation (very slight, barely perceptible erythema) which disappeared within 48 hours of application. In a study that was similar to the Draize protocol for skin irritancy testing, rabbits were exposed to liquid ethanol for a period of 24 hours under occlusive conditions. Ethanol caused only slight irritation which was similar to the observations made in the skin exposed to distilled water. As observations were only made for 24 hours, reversibility could not be assessed (Phillips, 1972).

In a study that was designed to be as similar as possible to the Draize protocol for skin irritancy testing, human male volunteers were exposed to liquid ethanol for a period of 24 hours under occlusive conditions, using the forearm as the site of exposure. No irritation was seen (Phillips, 1972).The result of other human study by Basketter, 2004, supports that ethanol does not warrant classification as a skin irritant.Overall, the results indicate that ethanol has a low potential to irritate the skin of humans under anything other than extreme and unrealistic exposure conditions.

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, the weight of evidence of the skin irritation on titanium (4+) ethanolate and on the decomposition products is considered reliable. These results do not indicate this substance to be classified as irritating to skin.

Eye irritation

There are no studies available on titanium (4+) ethanolate itself to evaluate the eye irritation of the substance. The assessment of this substance to cause eye irritation is evaluated based on the relevant read-across data of the decomposition products, because the target substance is hydrolytically unstable having the half-life less than 5 minutes (Brekelmans, M.J.C., 2013). The weight of evidence approach is used to determine the eye irritation of this substance evaluating relevant data also from the decomposition products, ethanol and titanium dioxide (TiO2).

In an OECD guideline study an eye irritation potential caused by 100% ethanol was investigated in rabbits (ECETOC, 1998). Ethanol was found to cause moderate eye irritation that fully reversed within 8 days. No interim washing stage done 24 hours from instillation. In another guideline eye irritation study in rabbits, for which only basic but key details are reported, 100% ethanol was also found to cause eye irritation (Jacobs, 1990). This study did not include sufficient observations to be able to judge reversibility. The level of response in both studies was sufficient to trigger classification as a category 2 irritant under regulation 1272/2008.

Based on the REACH registration data from 2010, ethanol is proposed to be classified as eye irritant 2 with SCL of 50%. Registration data contains several eye irritation studies performed using diluted ethanol solutions. Data analysis performed by registrants indicates that eye irritation effects to trigger classification are not reached until a concentration of around 70%. However, registrants have taken a conservative position to propose SCL of 50% for ethanol mixtures.

Another decomposition product of titanium (4+) ethanolate is non-hazardous titanium dioxide. Possible risk of eye irritation is related only to the titanium dioxide dust. After hydrolysis of titanium(4 +) ethanolate, TiO2 does not cause any relevant eye irritation hazard for humans as it exists hydrated solid precipitate.

In conclusion of the irritation properties, the known skin irritation properties of the main decomposition product of titanium (4+) ethanolate indicate this substance is not irritating to the skin. Based on the eye irritation data of decomposition products, the substance is irritating to the eyes if ethanol content in the target substance is 50% or higher.

Justification for selection of skin irritation / corrosion endpoint:
No studies available for the target substance which is highly reactive. Data is obtained from the reliable study performed according to OECD guideline for the main decomposition product, ethanol.

Justification for selection of eye irritation endpoint:
No studies available for the target substance which is highly reactive. Data is obtained from the reliable study performed according to OECD guideline for the main decomposition product, ethanol.

Effects on eye irritation: irritating

Justification for classification or non-classification

Based on the skin irritation information on the 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 the 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/ECC when the concentration of the decompostion product (ethanol) in the target substance exceeds specific concentration limit of 50 %.