Titanium(4+) ethanolate

Endpoint summary

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Endpoint:

skin sensitisation: in vivo (LLNA)

Type of information:

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

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay)

Deviations:

yes

Remarks:

. OECD Guideline 429 recommends that animals are housed individually, and that females are used.

Principles of method if other than guideline:

The study was designed to evaluate the effect of vehicles (ethanol or diethyl phthalate) for use in the mouse local lymph node assay.

GLP compliance:

not specified

Type of study:

mouse local lymph node assay (LLNA)

Species:

mouse

Strain:

CBA

Sex:

male

Details on test animals and environmental conditions:

TEST ANIMALS
- Source: Harlan Interfauna UK, Shaw's Farm, Blackthorne, Bicester, Oxon, UK
- Age at study initiation: 8 - 12 wk
- Weight at study initiation: not stated
- Housing: Groups of four animals per cage under standard conditions
- Diet (e.g. ad libitum): Pelleted diet ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: not stated


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 25
- Humidity (%): 30 - 70
- Air changes (per hr): not stated
- Photoperiod (hrs dark / hrs light): Fluorescent light - 12-hr dark/12-hr light cycle

Vehicle:

unchanged (no vehicle)

No. of animals per dose:

4

Details on study design:

Four alternative vehicles (ethanol; 3:1 ethanol:diethyl phthalate; 1:3 ethanol:diethyl phthalate; and diethyl phthalate) were evaluated for their utility in the LLNA, and their influence on the skin sensitization potential of four test fragrance materials (p-t-butyl-alpha-methylhydrocinnamic aldehyde; geraniol; eugenol; and hydroxycitronellal). Groups of four male mice were treated with each test fragrance, at one of five concentrations, in one of the four vehicles or to the same volume of the vehicle (ethanol or diethyl phthalate) alone (see Table 1 for further details). Stimulation Index (SI), as a measure of T-lymphocyte proliferation, was calculated for each concentration of test fragrance relative to the concurrent vehicle-treated animals.

Positive control substance(s):

other: The test fragrances used in the study (p-t-butyl-alpha-methylhydrocinnamic aldehyde; geraniol; eugenol; and hydroxycitronellal) effectively acted as positive controls; they are all known to be mild to moderate sensitizers.

Statistics:

SI values for the test fragrances were compared using an analysis of variance. Estimated concentrations of test fragrances required to elicit as SI of 3 or more (EC3 value) were also calculated using dose-response data. As ethanol was tested as a vehicle control in this study, there was no appropriate comparison with untreated animals (or with the alternative vehicle used, diethyl phthalate).

Positive control results:

Although not true positive controls, the test fragrances clearly induced dose-related stimulation of T-lymphocyte proliferation (see Table 1).

Parameter:

other: disintegrations per minute (DPM)

Value:

>= 133 - <= 175

Test group / Remarks:

Ethanol

Parameter:

other: disintegrations per minute (DPM)

Value:

>= 185 - <= 267

Test group / Remarks:

diethyl phthalate

Although the study was not specifically designed to assess the sensitizing potential of ethanol, it is clear from the results (Table 1) that the level of induced T-lymphocyte proliferation (a necessary component of contact sensitization) in the lymph node draining the site of topical chemical application was low (as measured by the incorporation of radiolabelled thymidine into the dividing cells) for ethanol when compared with that for fragrance materials known to be mild to moderate skin sensitizers, and comparable to that for the other (negative) control vehicle tested, diethyl phthalate. In addition, there was no discernable induction (increase in cpm/node) across the four test fragrance control series when the ethanol concentration (in diethyl phthalate) was 0% [100% diethyl phthalate], 33% [1:3 ethanol:diethyl phthalate], 67% [3:1 ethanol:diethyl phthalate], and 100%, which would be expected were ethanol a significant skin sensitizer.

Interpretation of results:

not sensitising

Remarks:

Migrated information

Conclusions:

A study was carried out to evaluate the effect of vehicles (ethanol or diethyl phthalate) for use in the mouse local lymph node assay (LLNA). Based on the study results it was concluded that ethanol is not sensitising.

Executive summary:

A study was carried out to evaluate the effect of vehicles (ethanol or diethyl phthalate) for use in the mouse local lymph node assay (LLNA), and their influence on the skin sensitization potential of four test fragrance materials (p-t-butyl-alpha-methylhydrocinnamic aldehyde; geraniol; eugenol; and hydroxycitronellal). Groups of 4 mice were treated with each test fragrance, at one of five concentrations, either in ethanol or diethyl phthalate (and 1:3 or 3:1 mixtures of the two), or with ethanol (or diethyl phthalate) alone. Although there were no true control data for comparison with the ethanol-alone treated animals, the level of induced T-lymphocyte proliferation was low for ethanol when compared with that for fragrance materials known to be mild to moderate skin sensitizers, and comparable to that for the other (negative) control vehicle tested, diethyl phthalate. The investigators concluded that ethanol is an appropriate vehicle for use in the LLNA and is a suitable alternative to the current guideline recommended vehicles. A prerequisite for use as a vehicle would be a lack of sensitizing potential itself.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

Skin sensitisation

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

 

An ear swelling study was used to examine the skin sensitising potential of ethanol (Descotes, J., 1988). Ethanol was applied twice on the right ear after an induction procedure involving two scapular subcutaneous injection of adjuvant and multiple topical ethanol applications to the abdomen over a period of 14 days. The degree of contact hypersensitivity is deduced from ear swelling measured 24 and 48 hours after application. Ethanol was found not to cause any statistical increase in ear swelling, in contrast to 3 positive controls which all caused a statistically significant increase.

 

Data is also available from studies using ethanol as a vehicle (Lalko, 2004). It can be concluded that ethanol cannot have any significant skin sensitising properties since it was used as a solvent in this study at levels of up to 75%. A study was carried out to evaluate the effect of vehicles (e.g. ethanol) for use in the mouse local lymph node assay (LLNA), and their influence on the skin sensitization potential of fragrance materials. Groups of mice were treated with each test fragrance in ethanol (1:3 or 3:1 mixtures of the two), or with ethanol alone. Although there were no true control data for comparison with the ethanol-alone treated animals, the level of induced T-lymphocyte proliferation was low for ethanol when compared with that for fragrance materials known to be mild to moderate skin sensitizers, and comparable to other inert vehicles tested.

Published information on titanium and TiO₂confirmed that there was no human evidence of skin sensitization, contact dermatitis or appreciable dermal absorption (Clayton & Clayton (eds.), 1981). There is also evidence of a lack of titanium compound toxicity to the skin demonstrated by its use in the therapy of skin disorders and as a biocompatible implant material (West & Wyzan, 1963 cited in WHO, 1982)

As a conclusion on skin sensitisation,there is available enough reliable information to support the conclusion that titanium (4 +) ethanolate is not skin sensitizer. Decomposition products of titanium(4 +) ethanolate are not classified as skin sensitisers according to EU regulation No. 1272/2008 (CLP) Annex VI Table 3.1.

Migrated from Short description of key information:
Titanium(4+) ethanolate is not a skin sensitiser based on the results of the decomposition product (ethanol):
Mouse swelling study: negative
LLNA: negative

Justification for selection of skin sensitisation endpoint:
No studies available for the target substance which is highly reactive. Data is obtained from the most reliable study performed for the main decomposition product, ethanol.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Titanium (4+) ethanolate is not classified for skin sensitisation in accordance to the CLP Regulation No. 1272/2008 and EU Directive 67/548/EEC.