Titanium dioxide

Endpoint summary

Description of key information

Titanium dioxide has been tested in various in vivo skin and eye irritation studies. All tests show a negative response, thus titanium dioxide does not require classification either as skin or as eye irritant.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Reference 1

Endpoint:

skin irritation / corrosion, other

Remarks:

in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2003-04-14 to 2003-05-15

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study OECD 404; no GLP compliance statement.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

GLP compliance:

no

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Covance Research Products, Denver, Pennsylvania
- Age at study initiation: young adult
- Housing: The rabbits were housed singly in stainless steel, wire-mesh cages suspended above cage boards.
- Diet: approximately 125 grams of PMI® Nutrition International, LLC Certified High Fiber Rabbit LabDiet® 5325 daily during the study
- Water: ad libitum
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 +/- 1
- Humidity (%): 50 +/- 10
- Photoperiod: 12-hour light/12-hour dark cycle

Type of coverage:

semiocclusive

Preparation of test site:

other: clipped skin on the back

Vehicle:

water

Controls:

not specified

Amount / concentration applied:

0.5g, moistened with deionised water

Duration of treatment / exposure:

4 hours

Observation period:

1, 24 and 48 hours after removal

Number of animals:

3 males

Details on study design:

Four separate, localised test sites (approximately 6 cm² each) were marked on each rabbit's back with a water-insoluble marker. Approximately 0.5 g of each test substance, moistened with approximately 0.2 or 0.3 mL of deionised water to form a thick paste, was applied to the designated test site and covered with a 2-ply, 1-inch square gauze pad. The pad was held in place with non-irritating tape. Removal of the test substance with warm water and soap. Observation of clinical signs. Measuring of body weight. Scoring after Draize.

Irritation parameter:

erythema score

Basis:

mean

Time point:

other: 1-48 hours

Score:

0

Max. score:

0

Reversibility:

fully reversible

Remarks on result:

other: all tested substances

Irritation parameter:

edema score

Basis:

mean

Time point:

other: 1-48 hours

Score:

0

Max. score:

0

Reversibility:

fully reversible

Remarks on result:

other: all tested substances

Irritant / corrosive response data:

No dermal irritation in any of the rabbits during the study. Test sites treated with test items 1, 2 and 3 were stained by the test substance.

Other effects:

No clinical signs, no body weight loss.

Interpretation of results:

GHS criteria not met

Conclusions:

According to the criteria specified by Directive 67/548/EC and subsequent regulations none of the four test items is a skin irritant and therefore no classification is required.

Reference 2

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1994-08-31 to 1994-09-27

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study OECD 404; no GLP compliance statement.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

GLP compliance:

no

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hare Marland, Hewitt, New Jersey
- Age at study initiation: young adult
- Housing: The rabbits were housed sigly in suspended, stainless steel, wire-mesh cages.
- Diet: approx. 125 g of Purina Certified High Fiber Rabbit Chow #5325 daily during the study
- Water: ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 +/- 2
- Humidity (%): 50 +/- 10
- Photoperiod: 12 hours dark/light

Type of coverage:

semiocclusive

Preparation of test site:

other: clipped skin on the back

Vehicle:

water

Controls:

not specified

Amount / concentration applied:

0.5g, moistened with deionised water

Duration of treatment / exposure:

4 hours

Observation period:

1, 24, 48 and 72 hours after removal

Number of animals:

3 males and 3 females

Details on study design:

An 0.5 g aliquot of the test substance was applied directly to a 2-inch gauze square that had been pre-moistened with deionised water. The gauze square was then placed on the test side and was held in place with non-irritating tape. Removal of the test substance with warm water and Ivory soap. Evaluation according to Draize.

Irritation parameter:

erythema score

Basis:

mean

Time point:

other: 1 hour

Score:

0.7

Max. score:

2

Reversibility:

fully reversible

Irritation parameter:

erythema score

Basis:

mean

Time point:

24 h

Score:

0.5

Max. score:

1

Reversibility:

fully reversible

Irritation parameter:

erythema score

Basis:

mean

Time point:

48 h

Score:

0.17

Max. score:

1

Reversibility:

fully reversible

Irritation parameter:

erythema score

Basis:

mean

Time point:

72 h

Score:

0.17

Max. score:

1

Reversibility:

fully reversible

Irritation parameter:

edema score

Basis:

mean

Time point:

other: 1 hour

Score:

0

Max. score:

0

Reversibility:

fully reversible

Irritation parameter:

edema score

Basis:

mean

Time point:

24 h

Score:

0

Max. score:

0

Reversibility:

fully reversible

Irritation parameter:

edema score

Basis:

mean

Time point:

48 h

Score:

0

Max. score:

0

Reversibility:

fully reversible

Irritation parameter:

edema score

Basis:

mean

Time point:

72 h

Score:

0

Max. score:

0

Reversibility:

fully reversible

Irritant / corrosive response data:

3/6 animals exhibited no dermal irritation during the study.
1 hour observation: slight erythema (2/6); mild erythema (1/6)
24 hours observation: slight erythema (3/6)
48 hours and 72 hours observation: slight erythema (1/6)
No oedema was observed during the study.

Interpretation of results:

GHS criteria not met

Conclusions:

According to the criteria specified by Directive 67/548/EC and subsequent regulations the test item is no skin irritant and requires no classification.

Reference 3

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2006-05-10 to 2006-07-27

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline study; no GLP compliance statement.

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Qualifier:

according to guideline

Guideline:

other: EEC 92/69/EEC (1992)

Qualifier:

according to guideline

Guideline:

other: EPA OPPTS 870.2500 (1998)

GLP compliance:

no

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Covance Research Products, Denver, Pennsylvania
- Weight at study initiation: 3290 - 3915 g
- Housing: All animals were housed singly in stainless steel, wire-mesh cages suspended above cage boards.
- Diet: approximately 125 grams of PMI® Nutrition International, LLC Certified Rabbit LabDiet® 5322 daily during the study
- Water: ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16-22
- Humidity (%): 30-70
- Photoperiod: 12-hour light/dark cycle
No further details are given.

Type of coverage:

semiocclusive

Preparation of test site:

other: clipped skin on the back

Vehicle:

water

Controls:

not specified

Amount / concentration applied:

0.5g, moistened with 0.25 ml deionised water

Duration of treatment / exposure:

4 hours

Observation period:

1, 24, 48 and 72 hours after removal

Number of animals:

3 male

Details on study design:

Removal of TiO2 with warm water. Scoring after Draize. Measurement of body weight and observation of clinical signs.

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

fully reversible

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

fully reversible

Irritant / corrosive response data:

The rabbits exhibited no dermal irritation during the study.

Other effects:

No clinical signs of toxicity were observed, and no body weight loss occurred.

Interpretation of results:

GHS criteria not met

Conclusions:

According to the criteria specified by Directive 67/548/EC and subsequent regulations the test item is no skin irritant and requires no classification.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation, other

Remarks:

in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2006-05-25 to 2006-07-27

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline study; self-certified statement of compliance is missing.

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Qualifier:

according to guideline

Guideline:

EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2400 (Acute Eye Irritation)

GLP compliance:

not specified

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Covance Research Products, Denver, Pennsylvania
- Age at study initiation: young adult
- Housing: All animals were housed singly in stainless steel, wire-mesh cages suspended above cage boards.
- Diet: approximately 125 grams of PMI® Nutrition International, LLC Certified Rabbit LabDiet® 5322 daily during the study
- Water: ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16-22
- Humidity (%): 30-70
- Air changes (per hr):
- Photoperiod: 12-hour light/dark cycle
No further details are given.

Vehicle:

water

Controls:

other: left eye of each rabbit served as control

Amount / concentration applied:

57 mg

Duration of treatment / exposure:

single administration

Observation period (in vivo):

1, 24, 48, and 72 hours following administration of the test substance

Number of animals or in vitro replicates:

3 rabbits

Details on study design:

Approximately 57 mg of H-27416 was introduced into the lower conjunctival sac of the right eye of each rabbit. The left eye of each rabbit was not treated with the test substance and served as a control. The eyes remained unwashed following treatment. Each rabbit was observed for approximately 30 to 60 seconds before being returned to its cage. One rabbit was initially treated. Since no severe irritation or corrosion was observed, 2 additional rabbits were treated to complete the test.
The conjunctiva, iris, and cornea of each treated eye were evaluated and scored according to the Draize Scale.

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

24 h

Score:

0.3

Max. score:

1

Reversibility:

fully reversible

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

48 h

Score:

0

Max. score:

0

Reversibility:

fully reversible

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

72 h

Score:

0

Max. score:

0

Reversibility:

fully reversible

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

0

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

0

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

0

Irritant / corrosive response data:

The test substance produced conjunctival redness (score of 1 or 2) in the treated eye of all three rabbits. Fluorescein stain examinations were negative for corneal injury. The treated eyes of the rabbits were normal by 24 or 48 hours after instillation of the test substance.

Other effects:

No clinical signs were observed, and no body weight loss occurred.

Interpretation of results:

GHS criteria not met

Conclusions:

The test substance produced conjunctival redness (score of 1 or 2) in the treated eye of all three rabbits. Fluorescein stain examinations were negative for corneal injury. The treated eyes of the rabbits were normal by 24 or 48 hours after instillation of the test substance. Titanium dioxide is not irritating to the eye.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Additional information

Skin corrosion/ irritation

Skin corrosion/ irritation studies with pigment-grade titanium dioxide

Finlay, C. (2003) treated 3 male rabbits in a semi-occlusive patch test with titanium dioxide. Rabbits were treated with 0.5 g titanium dioxide moistened with deionised water for 4 hours. Observations were recorded 1, 24 and 48 hours after removal. No dermal irritation in any of the rabbits during the study or clinical signs or body weight loss were observed.

 

Four batches of titanium dioxide were tested by Doyle, C.E. (1996 a-d) in four semi-occlusive patch tests. Three rabbits per test were treated with 0.5 g titanium dioxide moistened with deionised water or corn/olive oil for 4 hours. Observations were recorded 30-60min, 24, 48 and 72 hours after removal. No dermal irritation was observed in any of the rabbits during any of the four studies.

 

Durando, J. (2004) treated 3 female rabbits in a semi-occlusive patch test with silanised titanium dioxide. Rabbits were treated with 0.5 g titanium dioxide in mineral oil for 4 hours. Observations were recorded 1, 24, 48 and 72 hours after removal. All three animals exhibited slight erythema (score=1) 1 hour after patch removal and at the subsequent 24 and 48 hour observations. Treated skin sites appeared normal 72 hours after removal. The highest mean score (24, 48 and 72 h) for erythema calculated was 0.67. No oedema or other clinical signs of toxicity were observed during the study.

 

Edwards, D.F. (1975) treated 6 albino rabbits in a semi-occlusive patch test with titanium dioxide (98% purity). Rabbits were treated with 0.5 g titanium dioxide moistened with water for 24 hours. Observation was performed immediately after exposure and 24 hours later. Slight erythema (score = 1) were observed in 2 of 6 animals immediately after exposure, but no erythema were noted 24 hours after removal. No oedema or other clinical signs of toxicity were observed during the study.

 

Ferenz, R.L. (1978) treated 6 albino rabbits in a semi-occlusive patch test with titanium dioxide. Rabbits were treated with 0.5 g titanium dioxide in physiol. saline for 24 hours. Observations were performed immediately after exposure and 24 hours later. No skin irritation was observed when titanium dioxide was tested on the shaved, intact skin of six rabbits.

 

A patch test according to OECD 404 using titanium dioxide based slurry (purity 73%) was performed by Filliben, T.A. (1998). Three female rabbits were treated with 0.5 g titanium dioxide for 4 hours in a semi-occlusive patch test. Observations were recorded 1, 24, 48 and 72 hours after removal. One animal exhibited slight erythema (score=1) at 1 hour after removal, and another animal at the 24-hour observation. No other dermal or clinical signs of toxicity were observed during the study. The highest mean score (24, 48 and 72 h) for erythema calculated was 0.3.

Raw titanium dioxide was tested by Lees, D. (1996) in a semi-occlusive patch tests. Three male rabbits were treated with 0.5 g titanium dioxide moistened with deionised water or corn/olive oil for 4 hours. Observations were recorded 30-60 min, 24, 48 and 72 hours after removal. No dermal irritation was observed in any of the rabbits during the study.

 

Frank et al. (1969) performed a study on the primary irritation of titanium dioxide in 12 male albino guinea pigs as a 28% paste in saline solution. Applications of 0.5 g of powder and 0.1 g of paste were lightly rubbed into the intact shaved skin of the backs, which were subsequently covered with impervious film. The treatment area was covered with gauze and elastic bandage and removed 24 hours after application. Titanium dioxide (rutile form) either a powder or as a paste in saline solution produced no irritation on the intact skin of guinea pigs. The study is however not considered reliable, since the documentation is insufficient for assessment, i.e it is not clear which scoring system was used for skin irritation, and the results were not clearly stated. Apparently 12 animals were tested but only 10 are stated in the result section. The study is nevertheless used as supporting evidence, clearly showing that titanium dioxide does not show skin irritating properties.

 

Sanders, A. (1996), performed a semi-occlusive patch test according to OECD 404 using titanium dioxide. Three male rabbits were treated with 0.5 g titanium dioxide moistened with 0.5 mL distilled water for 4 hours. Observations were recorded 1, 24, 48 and 72 hours after removal. All three animals exhibited slight erythema (score=1) 1 hour after patch removal and at the subsequent 24 and 48 hour observations. Treated skin sites appeared normal 72 hours after removal. The highest mean score (24, 48 and 72 h) for erythema calculated was 0.67. No oedema or other clinical signs of toxicity were observed during the study.

 

Sarver, J.W. (1992) treated 2 male and 3 female rabbits in a semi-occlusive patch test with titanium dioxide (98.4% purity). Rabbits were treated with 0.5 g titanium dioxide moistened with deionised water for 24 hours. Observations were performed immediately after exposure and 48 and 72 hours after application. Slight erythema (score = 1) and mild erythema (score = 2) were observed in 2 animals each 24 hours after application. 48 hours after application mild erythema (score = 2) were noted in one animal and slight erythema (score = 1) in three animals. Slight erythema (score = 1) were still observed 72 hours after application in one animal. The mean scores (24, 48 and 72 h) for erythema calculated were 0, 0.67, 0.67, 1, and 1.67. No oedema were observed during the study. One rabbit was found dead during the exposure period. Examination found haemorrhaging of the neck area. As no other rabbits exhibited clinical signs of toxicity, the rabbit was considered to have died due to trauma associated with the method of restraint.

Miyani et al. (2017) conducted an in vitro skin irritation/corrosion assay using the EpiDerm system using two different pigmentary titanium dioxide samples, with none of the two TiO2 test items showing any signs of toxicity. However, the test material is insufficiently characterised. Due to an absence of a clear designation, purity or impurity information, it remains unclear whether the test item was in fact of industrial origin and therefore of relevance for the hazard and risk assessment of titanium dioxide. The study is in accordance with the generally accepted guideline for skin irritation testing (OECD 439) and is described in sufficient detail. Due to the poor test item characterisation, the study is used as supporting information only.

 

 

Skin corrosion/ irritation studies with ultrafine titanium dioxide

Finlay, C. (2006) treated 3 male rabbits in a semi-occlusive patch test with ultrafine titanium dioxide (100% purity: 79% rutile, 21% anatase) according to OECD 404. Rabbits were treated with 0.5 g titanium dioxide moistened with 0.25 mL deionised water for 4 hours. Observations were recorded 1, 24 and 48 hours after removal. No dermal irritation in any of the rabbits during the study or clinical signs or body weight loss were observed.

 

Filliben, T.A. (1994) treated 3 male and 3 female rabbits in a semi-occlusive patch test with ultrafine titanium dioxide (95.4% purity). Rabbits were treated with 0.5 g titanium dioxide moistened with deionised water for 4 hours. Observations were recorded 1, 24, 48 and 72 hours after removal. 1 hour after patch removal slight erythema (score = 1) was observed in 2 animals and mild erythema (score = 2) in 1 animal. Slight erythema (score = 1) was still observed 24 hours after application in three animal. 48 and 72 hours after application slight erythema (score = 1) was only noted in one animal. The highest mean score (24, 48 and 72 h) for erythema calculated was 1. No oedema or other clinical signs were observed during the study.

 

A semi-occlusive patch test according to OECD 404 using ultrafine titanium dioxide was performed by Clouzeau, J. (1994). Three rabbits were treated with 0.5 g titanium dioxide moistened with water for 3 min and 1 hour (1 animal each) and 4 hours (3 animals). Observations were recorded 1, 24, 48 and 72 hours after removal and daily until day 9. The mean score (24, 48 and 72 h) for erythema after 3 min and 1 hour application was 0.7 each. One animal was free of dermal irritation after the application period of 4 hours. The other two animals showed slight to moderate erythema (score = 1 or 2) at 1, 24, 48 and 72 hours observations. The mean score (24, 48 and 72 h) for erythema was 0, 0.7 and 2, respectively. Only one animal showed slight oedema at 1 hour observation. The mean score (24, 48 and 72 h) for oedema was 0. On day 9 all skin reactions were reversible.

 

Miyani et al. (2017) conducted an in vitro skin irritation/corrosion assay using the EpiDerm system using four different nanoparticulate titanium dioxide samples, with none of the four TiO2 test items showing any signs of toxicity. However, the test material is insufficiently characterised. Due to an absence of a clear designation, purity or impurity information, it remains unclear whether the test item was in fact of industrial origin and therefore of relevance for the hazard and risk assessment of titanium dioxide. The study is in accordance with the generally accepted guideline for skin irritation testing (OECD 439) and is described in sufficient detail. Due to the poor test item characterisation, the study is used as supporting information only.

 

Conclusion

Based on the findings in all studies presented above, it is concluded that both pigment-grade and ultrafine titanium dioxide are not irritating to the skin.

 

Eye irritation

Eye irritation studies with pigment-grade titanium dioxide

Durando, J. (2004) treated 3 female rabbits in an acute eye irritation study with silanised titanium dioxide. 100 mg of the test material was placed into the conjunctival sac of the right eye. The left eye of each rabbit was not treated and served as a control. Observations were recorded 1, 24, 48 and 72 hours after administration. The test item produced conjunctival redness (Score =1 or 2) in the treated eye of all three rabbits 1 and 24 hours after administration. The treated eyes were normal 48 hours after instillation of the test item. Fluorescein stain examinations were negative for corneal injury. The mean score (24, 48 and 72 h) for conjunctival redness was 0.33 in all three animals. No corneal opacity, iritis or conjunctival chemosis were observed.

Sanders, A. (1996) treated 3 male rabbits in an acute eye irritation study with titanium dioxide according to OECD 405. A volume of 0.1ml of the test material, which was found to weigh approximately 98 mg was placed into the conjunctival sac of the right eye. The left eye of each rabbit was not treated and served as a control. The eyes remained unwashed following treatment. Observations were recorded 1, 24, 48 and 72 hours after administration. The test substance produced conjunctival redness and chemosis (score 1) in the treated eye of all three rabbits. Conjunctival redness (score = 1) was still observed after 24h in two rabbits. The treated eyes of the rabbits were normal by 48 hours after instillation of the test substance. No corneal opacity or iritis had been observed. The mean score (24, 48 and 72 h) for conjunctival redness for two animals was 0.33.

Three following studies were disregarded for hazard assessment purposes, mainly due to experimental deficiencies, such as testing only in one animal, test item rinse off after 20 sec exposure or using no grading scale for ocular lesions:

Filibien, 1994: The test item produced moderate conjunctival redness and slight chemosis in both the treated washed and unwashed rabbit eyes. The treated washed and unwashed eyes were normal by 1 and 3 days, respectively, following treatment. No clinical signs of toxicity were observed.

Edwards, 1978: Transient minimal iritis and very mild conjunctivitis when tested in a rabbit eye. The ocular effects were reversible and the eye was normal within 1-3 days. Study shows significant deficiencies, such as only one animal (unwashed) being tested instead of three, no usage of grading scale of ocular lesion, purity and stability data of the test item are missing, and exposure duration was not according to guideline.

Dion, 1971: Titanium dioxide treated with mono and and bis butyl phosphate mixture produced only temporary mild or minimal conjunctival irritation with no significant corneal or iritic effect when instilled as a solid or as a suspension in propylene glycol into the eyes of rabbits. The study shows relevant methodical deficiencies, such as only one animal (unwashed) being tested instead of three, no usage of a grading scale for ocular lesions, deficiencies in evaluation, data on purity and stability of the test item are missing, and the exposure duration was not according to guideline.

 

Eye irritation studies with ultrafine titanium dioxide

Finlay, C. (2006) treated 3 male rabbits in an acute eye irritation study with ultrafine titanium dioxide (100% purity: 79% rutile, 21% anatase) according to OECD 405. Approx. 57 mg titanium dioxide were introduced into the lower conjunctival sac of the right eye of each rabbit. The left eye of each rabbit was not treated and served as a control. The eyes remained unwashed following treatment. Observations were recorded 1, 24, 48 and 72 hours after administration. The test substance produced conjunctival redness (score of 1 or 2) in the treated eye of all three rabbits. Fluorescein stain examinations were negative for corneal injury. The treated eyes of the rabbits were normal by 24 or 48 hours after instillation of the test substance. No corneal opacity, iritis or conjunctival chemosis was observed. The mean score (24, 48 and 72 h) for conjunctival redness for one animal was 0.33.

Another acute eye irritation study according to OECD 405 with ultrafine titanium dioxide was reported by de Jouffrey (1995). A single introduction of about 100 mg titanium dioxide was placed into the conjunctival sac of the left eye of rabbits. The left eye of each rabbit was not treated and served as a control. The eyes were not rinsed after administration of the test substance. Observations were recorded 1, 24, 48 and 72 hours after administration. All three animal exhibited slight ocular reactions 1 to 24 hours after treatment. No effects were observed at 48 and 72 hours. The mean score (24, 48 and 72 h) for conjunctival redness for two animal was 0.33 and for conjunctival chemosis for one animal was 0.33. No corneal opacity or iritis had been observed

 

Conclusion

Based on the findings in all studies presented above, it is concluded that both pigment-grade and ultrafine titanium dioxide are not irritating to the eye.

Justification for classification or non-classification

Skin irritation

Finlay, C.(2003) is considered as the key studies for skin irritation and will be used for classification.

The overall irritation results are as follows:

erythema, 0-48h after application: mean score=0.0

oedema, 0-48h after application: mean score=0.0

The classification criteria acc. to regulation (EC) 1272/2008 as irritating to skin are not met since the

mean erythema score after 24h was 0.5, hence no classification required.

Supporting information (Finlay, C.(2006) and Filliben, T.A.(1994)) on uncoated nano-sized titanium dioxide indicate a lack of irritation potential to the skin. The results are as follows:

Finlay, C.(2006):

erythema, 0-72h after application: mean score=0.0

oedema, 0-72h after application: mean score=0.0

Filliben, T.A.(1994)

erythema, 1h after application: mean score=0.7 fully reversible

erythema, 24h after application: mean score=0.5 fully reversible

erythema, 48 and 72h after application: mean score=0.17 fully reversible

oedema, 0-72h after application: mean score=0.0

This finding is supported by additional studies with pigment grade and ultrafine titanium dioxide.

 

Eye irritation

Reference Finlay, C.(2006) is considered as the key study for eye irritation and will be used for

classification. The overall irritation results are as follows:

conjunctival redness, 1h after application: mean score=1.3

conjunctival redness, 24h after application: mean score=0.3

conjunctival redness, 48 and 72h after application: mean score=0.0

The classification criteria acc. to regulation (EC) 1272/2008 as irritating to eyes are not met since the mean score after 24h was 0.3, hence no classification required.

This study was conducted with uncoated nano-sized titanium dioxide, however, it is supported by additional studies with uncoated nano-sized and fine titanium dioxide.

 

Respiratory irritation

The classification as respiratory irritant is covered under the endpoint specific target organ toxicity- single exposure and repeated exposure. Please refer to the endpoint summaries on acute toxicity (IUCLID endpoint 7.2) and repeated dose toxicity (IUCLID endpoint 7.5) for further information.