reaction mass of cerium(IV)oxide, praseodymium(III,IV)oxide and zirconium (IV)oxide

Endpoint summary

Description of key information

Skin irritation

Based on the results of the available in vivo skin irritation studies for praseodymium(III,IV) oxide (Shapiro, 1991a), zirconium dioxide (BIBRA, 1986) and the reaction mass of cerium dioxide and zirconium dioxide (Harlan, 2009; De Jouffrey, 1996b), it could be concluded that the reaction mass of cerium dioxide, praseodymium(III,IV) oxide and zirconium dioxide is not a skin irritant and does not need to be classified for skin irritation under the CLP Regulation.

Eye irritation

Based on the results of the available in vivo skin irritation studies for praseodymium(III,IV) oxide (Shapiro, 1991b), yttrium zirconium oxide (Japanese Chemical Evaluation and Research Institute, 2000) and the reaction mass of cerium dioxide and zirconium (De Jouffrey, 1996c), it could be concluded that the reaction mass of cerium dioxide, praseodymium(III,IV) oxide and zirconium dioxide does not need to be classified for eye irritation under the CLP Regulation.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Reference 1

Endpoint:

skin irritation: in vitro / ex vivo

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

an in vitro skin irritation study does not need to be conducted because adequate data from an in vivo skin irritation study are available

Justification for type of information:

Note that no justification was given by the laboratory why an in vivo study was performed with the reaction mass of cerium dioxide and zirconium dioxide (Harlan, 2009) instead of first performing an in vitro test.

Reference 2

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

from 16-OCT-1995 to 08-MAR-1996

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Elevage Cunicole de Val de Selle, 80160 Prouzel, France
- Age at study initiation: no data
- Weight at study initiation: 2.4 +/- 0.2 kg
- Housing: individually in polystyrene cages (35x55x32 cm or 48.2x58x36.5 cm)
- Diet (e.g. ad libitum): free access to 112 pelleted diet (U.A.R., 91360 Villemoisson-sur-Orge, France)
- Water (e.g. ad libitum): drinking water filtered by a Millipore membrane (0.22 micron), ad libitum
- Acclimation period: at least 5 days before the start of the study

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 +/- 3°C
- Humidity (%): 30 to 70% relative humidity
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12h / 12h

IN-LIFE DATES: From: 15 nov 1995 To: 18 nov 1995

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

other: control on the other untreated flank

Amount / concentration applied:

500 mg

Duration of treatment / exposure:

4 hours

Observation period:

72 hours

Number of animals:

3

Details on study design:

TEST SITE
- Area of exposure: 500 mg of the substance was applied to a 6 cm2 moistened gauze pad which was thus applied to the right flank of the animals.
- Type of wrap if used: The test item and the gauze pad were held in contact with the skin by means of an adhesive hypoallergenic aerated semi-occlusive dressing and a restraining bandage.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Any residual test item was wiped off by means of a moistened gauze pad.

SCORING SYSTEM: according to EEC Criteria

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Interpretation of results:

GHS criteria not met

Conclusions:

Not irritating to skin.

The reaction mass of cerium dioxide and zirconium dioxide is not classified according to the criteria of the EU-CLP Regulation 1272/2008.

Executive summary:

In a primary dermal irritation study (CIT, 1996), New Zealand White rabbits (3 males) were dermally exposed to 500 mg of the reaction mass of cerium dioxide and zirconium dioxide onto one flank.

Test sites were covered with semi-occlusive dressing for 4 hours. The cutaneous examinations were performed 1, 24, 48 and 72 hours after removal of the dressing. The mean score values for erythema and oedema were calculated for 24, 48 and 72 hours.

No cutaneous reactions were observed during the study.

In this study, the reaction mass of cerium dioxide and zirconium dioxide is not classified according to the EU classification criteria.

Reference 3

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

2008-12-02 to 2009-01-14

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

yes

Remarks:

No information was provided on the initial test or weight of evidence to waive the need for an initial test.

GLP compliance:

yes (incl. QA statement)

Remarks:

The Department of Health of the Government of the United Kingdom

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan UK Limited, Bicester, Oxon, UK
- Age at study initiation: 12-20 weeks
- Weight at study initiation: 2.0 to 3.5 kg
- Housing: individually in suspended cages
- Diet (e.g. ad libitum): ad libitum, 2030 Taklad Global Rabbit diet
- Water (e.g. ad libitum): mains drinking water
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17-23
- Humidity (%): 30-70
- Air changes (per hr): 15/hour
- Photoperiod (hrs dark / hrs light): 12/12 (06:00 - 18:00 light)


IN-LIFE DATES: From: no data To: no data

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

water

Controls:

not required

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 g

VEHICLE
- Amount(s) applied (volume or weight with unit): 0.5 mL

Duration of treatment / exposure:

4 hours

Observation period:

1, 24, 48 and 72 hours

Number of animals:

3

Details on study design:

TEST SITE
- Area of exposure: dorsal/flank
- Type of wrap if used: Cotton gauze patch was used to apply test substances to shorn skin. The patch was secured in position with a strip of surgical adhesive tape. The trunk of each test animal was wrapped in an elasticated corset and the animals were returned to their cages for the duration of the exposure period.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): water soaked cotton wool cloth
- Time after start of exposure: 4 hours

SCORING SYSTEM: Draize (1959) - The scores for erythema and oedema at the 24 and 72-hour readings were totalled for the three test rabbits and this total was divided by six to give the primary irritation index of the test substance.

Irritation parameter:

primary dermal irritation index (PDII)

Basis:

mean

Time point:

other: 24 and 72-hour readings

Score:

0

Max. score:

8

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

No evidence of skin irritation was reported under the test conditions.

Other effects:

All test animals showed expected gain in body weight during the study.

Interpretation of results:

GHS criteria not met

Conclusions:

Under the conditions of the test, the test substance failed to produce an irritation to the skin of the test animals. Under these test conditions it can be stated that the test substance can be classified as not irritating to rabbit skin according to the Draize classification scheme. No corrosive effects were reported.

Reference 4

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

26 December 1990 - 5 February 1991

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results. No irritation scores recorded for the 48 hour time point.

Qualifier:

according to guideline

Guideline:

other: FHSA 16 CFR 1500.41

Deviations:

no

GLP compliance:

not specified

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Housing: Individually housed in suspended stainless steel caging with mesh floors.
- Diet (e.g. ad libitum): ad libitum; pelleted Purina Rabbit Chow
- Water (e.g. ad libitum): Tap water supplied by automatic watering system supplied ad libitum.
- Acclimation period: 20 days
- Source: Davidson’s Mill Farm, S. Brunswick, New Jersey

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 72 - 75 °F

IN-LIFE DATES: From: 26 December 1990 To: 29 December 1990

Type of coverage:

occlusive

Preparation of test site:

other: shaved test sites with both intact and abraded skin

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

0.5 g undiluted

Duration of treatment / exposure:

24 hours

Observation period:

72 hours

Number of animals:

3 males and 3 females

Details on study design:

- The rabbits were prepared by clipping the skin free of hair over approximately 10% of the body surface (dorsal and ventral surfaces from scapular to pelvic area). Two test application sites, each approximately 2.5 cm² were delineated. One site was left intact while the other was abraded with a needle, taking special precaution not to penetrate the stratum corneum and not to cause bleeding.
- 0.5 g test material was placed on each site and was immediately covered with a 2 x 2.25 inch adhesive-backed gauze patch. The patches and entire trunk of each rabbit were then wrapped with an elastic cloth to aid in maintaining test-patch position and to minimise evaporation.
- The patches were removed after 24 hours of exposure at which time the test sites were gently wiped clean of any residual test material.

Skin sites were evaluated at approximately 24 and 72 hours after initial exposure and scored as follows:

Erythema and eschar formation:

No erythema: 0
Very slight erythema (barely perceptible): 1
Well-defined erythema: 2
Moderate to severe erythema: 3
Severe erythema (beet redness) or eschar formation (injuries in depth) preventing erythema reading: 4

Oedema formation:

No oedema: 0
Very slight oedema (barely perceptible): 1
Slight oedema (edges of area well-defined by definite raising): 2
Moderate oedema (edges raised approximately 1 millimeter): 3
Severe oedema (raised more than 1 millimeter and extending beyond the area of exposure): 4

Irritation parameter:

primary dermal irritation index (PDII)

Score:

0.09

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Remarks on result:

no indication of irritation

Remarks:

measured at 24 h and 72 h

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Remarks on result:

no indication of irritation

Remarks:

measured at 24 h and 72 h

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Remarks on result:

no indication of irritation

Remarks:

measured at 24 h and 72 h

Irritation parameter:

erythema score

Basis:

animal #4

Time point:

24/48/72 h

Score:

0

Remarks on result:

no indication of irritation

Remarks:

measured at 24 h and 72 h

Irritation parameter:

erythema score

Basis:

animal #5

Time point:

24/48/72 h

Score:

0

Remarks on result:

no indication of irritation

Remarks:

measured at 24 h and 72 h

Irritation parameter:

erythema score

Basis:

animal #6

Time point:

24 h

Score:

1

Reversibility:

fully reversible within: 72 h

Remarks on result:

other: very slight erythema without oedema at both abraded and intact sites at 24 h

Irritation parameter:

erythema score

Basis:

animal #6

Time point:

72 h

Score:

0

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Remarks on result:

no indication of irritation

Remarks:

measured at 24 h and 72 h

Irritation parameter:

edema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Remarks on result:

no indication of irritation

Remarks:

measured at 24 h and 72 h

Irritation parameter:

edema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Remarks on result:

no indication of irritation

Remarks:

measured at 24 h and 72 h

Irritation parameter:

edema score

Basis:

animal #4

Time point:

24/48/72 h

Score:

0

Remarks on result:

no indication of irritation

Remarks:

measured at 24 h and 72 h

Irritation parameter:

edema score

Basis:

animal #5

Time point:

24/48/72 h

Score:

0

Remarks on result:

no indication of irritation

Remarks:

measured at 24 h and 72 h

Irritation parameter:

edema score

Basis:

animal #6

Time point:

24/48/72 h

Score:

0

Remarks on result:

no indication of irritation

Remarks:

measured at 24 h and 72 h

Irritant / corrosive response data:

Very slight erythema without oedema was observed at both abraded and intact sites of one rabbit only at 24 hours post-dosing. By 72 hours, no irritation was observed.

Other effects:

All animals appeared active and healthy. There were no signs of gross toxicity, adverse pharmacologic effects or abnormal behaviour.

Table 1 Primary Dermal Irritation (PDI) Scores - Individual Results

Rabbit	24 hours		72 hours
	Abraded	Intact	Abraded	Intact
8058 8059 8060 8061 8062 8063	0/0 0/0 0/0 0/0 0/0 1/0	0/0 0/0 0/0 0/0 0/0 1/0	0/0 0/0 0/0 0/0 0/0 0/0	0/0 0/0 0/0 0/0 0/0 0/0
Total	1/0	1/0	0/0	0/0
Mean	0.17/0	0.17/0	0/0	0/0

Key: erythema and eschar / oedema

Interpretation of results:

GHS criteria not met

Conclusions:

Under the conditions of this study, the test material is not irritating to skin and requires no classification in accordance with the CLP criteria.

Reference 5

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1986-03-04 to 1986-07-17

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

Well documented, scientifically sound GLP study that was based on the OECD Guideline 404 "Acute Dermal Irritation/Corrosion". The test substance was tested simultaneously on the same animals.

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

yes

Remarks:

substances were tested simultaneously on the same animals

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Regal Rabbits, Great Bookham, Surrey
- Housing: individually in metal grid-floored cages
- Diet: ad libitum, Grain Harvester's special rabbit diet 679
- Water: ad libitum tap water
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-23
- Humidity (%): 43-74

Type of coverage:

occlusive

Preparation of test site:

shaved

Vehicle:

water

Controls:

not required

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): spread on a patch previously moistened with 0.5 mL of water to ensure good contact with the skin

Duration of treatment / exposure:

4 hours

Observation period:

24, 48 and 72 hours

Number of animals:

4 male animals

Details on study design:

TEST SITE
- Area of exposure: dorsal
- Type of wrap if used: 2.5 cm square patches were applied to the skin on 6 cm square patches of polythene held in place by adhesive tape and elastic net bandages.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): tap water
- Time after start of exposure: 4 hours

SCORING SYSTEM: Draize (1959), indices of irritation were calculated for each animal by totalling the scores for oedema and erythema for each animal and dividing by two.

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

24 h

Score:

ca. 0

Max. score:

8

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

48 h

Score:

ca. 0

Max. score:

8

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

72 h

Score:

ca. 0

Max. score:

8

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

animal #4

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #4

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

No reaction to the test substances was reported in any of the test animals.

Interpretation of results:

GHS criteria not met

Conclusions:

The test substance was determined to be not irritating to the skin of rabbits.

Reference 6

Endpoint:

skin irritation: in vivo

Type of information:

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

Adequacy of study:

weight of evidence

Justification for type of information:

The in vivo skin irritation studies on praseodymium(III,IV) oxide, zirconium dioxide, and the reaction mass of cerium dioxide and zirconium dioxide are considered relevant for drawing conclusion on the reaction mass of cerium dioxide, praseodymium(III,IV) oxide and zirconium dioxide. The read across justification document is attached to IUCLID Section 13.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Remarks:

Based on the results of the in vivo studies performed with praseodymium(III,IV) oxide, zirconium dioxide, and the reaction mass of cerium dioxide and zirconium dioxide, it can be concluded that no erythema is to be expected in similar studies with the reaction mass of cerium dioxide, praseodymium(III,IV) oxide and zirconium dioxide. The reaction mass is not expected to cause skin irritation and therefore does not need to be classified for skin irritation or corrosion.

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Remarks:

Based on the results of the in vivo studies performed with praseodymium(III,IV) oxide, zirconium dioxide, and the reaction mass of cerium dioxide and zirconium dioxide, it can be concluded that no edema is to be expected in similar studies with the reaction mass of cerium dioxide, praseodymium(III,IV) oxide and zirconium dioxide. The reaction mass is not expected to cause skin irritation and therefore does not need to be classified for skin irritation or corrosion.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Reference 1

Endpoint:

eye irritation: in vitro / ex vivo

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

an in vitro eye irritation study does not need to be conducted because adequate data from an in vivo eye irritation study are available

Reference 2

Endpoint:

eye irritation: in vivo

Type of information:

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

Adequacy of study:

weight of evidence

Justification for type of information:

The in vivo eye irritation studies on praseodymium(III,IV) oxide, yttrium zirconium oxide (i.e. zirconium dioxide with a small amount of yttrium oxide added to its crystal lattice), and the reaction mass of cerium dioxide and zirconium dioxide are considered relevant for drawing a conclusion on the reaction mass of cerium dioxide, praseodymium(III,IV) oxide and zirconium dioxide. The read across justification document is attached to IUCLID Section 13.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Irritation parameter:

overall irritation score

Remarks:

read across conclusion

Remarks on result:

no indication of irritation

Remarks:

Based on the results of the in vivo studies performed with praseodymium(III,IV) oxide, yttrium zirconium oxide (i.e. zirconium dioxide with a small amount of yttrium oxide added to its crystal lattice), and the reaction mass of cerium dioxide and zirconium dioxide, it can be concluded that no eye irritation requiring classification would be observed in a similar study with the reaction mass of cerium dioxide, praseodymium(III,IV) oxide and zirconium dioxide.

Reference 3

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

from 16-OCT-1995 to 08-MAR-1996

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Elevage Cunicole de Val de Selle, 80160 Prouzel, France
- Age at study initiation: no data
- Weight at study initiation: 2.5 +/- 0.4 kg
- Housing: individually in polystyrene cages (35x55x32 cm or 48.2x58x36.5 cm)
- Diet (e.g. ad libitum): free access to 112 pelleted diet (U.A.R., 91360 Villemoisson-sur-Orge, France)
- Water (e.g. ad libitum): drinking water filtered by a Millipore membrane (0.22 micron), ad libitum
- Acclimation period: at least 5 days before the start of the study

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 +/- 3°C
- Humidity (%): 30 to 70% relative humidity
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12h / 12h

IN-LIFE DATES: From: 22 nov 1995 To: 29 nov 1995

Vehicle:

unchanged (no vehicle)

Controls:

other: the right eye served as control

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 100 mg

Observation period (in vivo):

One hour, 24, 48 and 72 hours after the administration and then daily for 4 days at the latest.
Reversibility of ocular lesions was observed on day 4 (two animals) or 8.

Number of animals or in vitro replicates:

3

Details on study design:

REMOVAL OF TEST SUBSTANCE: not rinsed
SCORING SYSTEM: according to EEC Criteria
TOOL USED TO ASSESS SCORE: fluorescein

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0.7

Max. score:

4

Reversibility:

fully reversible within: 5 days

Irritation parameter:

cornea opacity score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0.3

Max. score:

4

Reversibility:

fully reversible within: 5 days

Irritation parameter:

cornea opacity score

Basis:

animal #3

Time point:

24/48/72 h

Score:

1.3

Max. score:

4

Reversibility:

fully reversible within: 5 days

Irritation parameter:

iris score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

2

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

2

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0.7

Max. score:

2

Reversibility:

fully reversible within: 72 h

Irritation parameter:

conjunctivae score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0.3

Max. score:

3

Reversibility:

fully reversible within: 8 days

Irritation parameter:

conjunctivae score

Basis:

animal #2

Time point:

24/48/72 h

Score:

1

Max. score:

3

Reversibility:

fully reversible within: 8 days

Irritation parameter:

conjunctivae score

Basis:

animal #3

Time point:

24/48/72 h

Score:

2.3

Max. score:

3

Reversibility:

fully reversible within: 8 days

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 72 h

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 72 h

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

24/48/72 h

Score:

1.3

Max. score:

4

Reversibility:

fully reversible within: 72 h

Other effects:

Clear ocular discharge was observed in 2 rabbits for 24 or 48 hours after administration of the test substance.

Interpretation of results:

GHS criteria not met

Conclusions:

The reaction mass of cerium dioxide and zirconium dioxide was found to be slightly irritating to rabbit eyes, however, the observed effects did not reach the classification limits under the CLP Regulation and therefore the reaction mass is not classified for eye irritation under the CLP Regulation.

Executive summary:

In a primary eye irritation study (CIT, 1996), 100 mg of the reaction mass of cerium dioxide and zirconium dioxide was instilled into the conjunctival sac of the left eye of New Zealand White rabbits (3 animals). Eyes were not rinsed and the right eye served as control. The ocular examinations were performed 1, 24, 48 and 72 hours after instillation.

Mean scores calculated for each animal over 24, 48 and 72 hours were 1.0, 1.0 and 1.3 for chemosis, 0.3, 1.0 and 2.3 for redness of the conjunctivae, 0.0, 0.0 and 0.7 for iris lesions and 0.7, 0.3 and 1.3 for corneal opacity. Total reversibility was observed by day 4 (2 animals) or day 8.

In this study, the reaction mass of cerium dioxide and zirconium dioxide is not classified as eye irritant based on the EU classification criteria.

Reference 4

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

31 December 1990 - 4 February 1991

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

Study conducted in accordance with generally accepted scientific principles, possibly with incomplete reporting or methodological deficiencies, which do not affect the quality of the relevant results. Irritation effects in animals only observed for 72 hours.

Qualifier:

according to guideline

Guideline:

other: FHSA 16 CFR 1500.42

Deviations:

no

GLP compliance:

not specified

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Housing: Individually housed in suspended stainless steel caging with mesh floors.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum tap water supplied by automatic watering system
- Acclimation period: 25 days

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 71 - 73 °F

IN-LIFE DATES: From: 31 December 1990 To: 3 January 1991

Vehicle:

unchanged (no vehicle)

Controls:

other: the right eye of each animal remained untreated and served as control

Amount / concentration applied:

Undiluted.
Amount applied: 0.1 g into the conjuctival sac of the left eye

Duration of treatment / exposure:

30 seconds for 3 of the treated eyes (washed eyes) and up to 72 hours for the 3 others (the upper and lower lids were gently held together for about 1 second to prevent loss of the test material).

Observation period (in vivo):

72 hours

Number of animals or in vitro replicates:

3 males and 3 females

Details on study design:

REMOVAL OF TEST SUBSTANCE
Three of the treated eyes were rinsed with 30 cc of saline 30 seconds post-instillation. The remaining three eyes were not irrigated.

SCORING SYSTEM: Draize Scale for Ocular Irritation
After instillation of the test material, ocular lesions were evaluated in accordance with Draize et al. at 24, 48 and 72 hours.
Special care was taken to look for and notate any unusual effects, such as pannus, blistering of the conjunctivae, ulceration and other indicators of corrosive action.

Draize Scale for Scoring Ocular Irritation:

1. CONJUNCTIVAE

(A) Redness (refers to palpebral and bulbar conjunctivae excluding cornea and iris)
Vessels normal............................................................................................................................................0
Vessels definitely injected above normal................................................................................................1
More diffuse, deeper crimson red, individual vessels not easily discernible....................................2
Diffuse beefy red.........................................................................................................................................3

(B) Chemosis
No swelling..................................................................................................................................................0
Any swelling above normal (includes nictitating membrane).............................................................1
Obvious swelling with partial eversion of lids.......................................................................................2
Swelling with lids about half closed.........................................................................................................3
Swelling with lids half closed to completely closed...............................................................................4

(C) Discharge
No discharge...............................................................................................................................................0
Any amount different from normal (does not include small amounts observed in inner
canthus of normal animals)......................................................................................................................1
Discharge with moistening of the lids and hairs just adjacent to lids...............................................2
Discharge with moistening of the lids and hairs a considerable area around the eye...................3

THE TOTAL SCORE = (A + B + C) x 2 MAXIMUM TOTAL = 20

2. IRIS

(D) Values
Normal.........................................................................................................................................................0
Folds above normal, congestion, swelling, circumcorneal injection (any or all
of these or combination of any thereof) iris still reacting to light
(sluggish reaction is positive).................................................................................................................1
No reaction to light, haemorrhage, gross destruction (any or all of these)....................................2

THE TOTAL SCORE = D x 5 MAXIMUM TOTAL = 10

3. CORNEA

(E) Degree of Opacity (most dense area used)
No opacity...................................................................................................................................................0
Scattered or diffuse areas, details of iris clearly visible......................................................................1
Easily discernible translucent areas, details of iris slightly obscured..............................................2
Opalescent areas, no details of iris visible, size of pupil barely discernible....................................3
Opaque, iris not discernible through the opacity................................................................................4

(F) Area of Cornea Involved
One quarter (or less) but not zero..........................................................................................................1
Greater than one quarter but less than half...........................................................................................2
Greater than half but less than three quarters......................................................................................3
Greater than three quarters, up to whole area.......................................................................................4

THE TOTAL SCORE = (E x F) x 5 MAXIMUM TOTAL = 80

MAXIMUM TOTAL SCORE POSSIBLE = 110

Irritation parameter:

cornea opacity score

Basis:

mean

Remarks:

of 3 animals

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Remarks on result:

other: Unwashed

Irritation parameter:

cornea opacity score

Basis:

mean

Remarks:

of 3 animals

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Remarks on result:

other: Washed

Irritation parameter:

iris score

Basis:

mean

Remarks:

of 3 animals

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

other: not applicable

Remarks on result:

other: Unwashed

Irritation parameter:

iris score

Basis:

mean

Remarks:

of 3 animals

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

other: not applicable

Remarks on result:

other: Washed

Irritation parameter:

conjunctivae score

Basis:

mean

Remarks:

of 3 animals

Time point:

24/48/72 h

Score:

1.11

Max. score:

3

Reversibility:

other: 1 animal still exhibited a hyperaemia score of 1 after 72 hours

Remarks on result:

other: Unwashed

Irritation parameter:

conjunctivae score

Basis:

mean

Remarks:

of 3 animals

Time point:

24/48/72 h

Score:

1.11

Max. score:

3

Reversibility:

other: 1 animal still exhibited a hyperaemia score of 1 after 72 hours

Remarks on result:

other: Washed

Irritation parameter:

chemosis score

Basis:

mean

Remarks:

of 3 animals

Time point:

24/48/72 h

Score:

0.33

Max. score:

4

Reversibility:

fully reversible within: 72 hours

Remarks on result:

other: Unwashed

Irritation parameter:

chemosis score

Basis:

mean

Remarks:

of 3 animals

Time point:

24/48/72 h

Score:

0.11

Max. score:

4

Reversibility:

fully reversible within: 48 hours

Remarks on result:

other: Washed

Irritation parameter:

other: discharge

Basis:

mean

Remarks:

of 3 animals

Time point:

24/48/72 h

Score:

0.11

Max. score:

3

Reversibility:

fully reversible within: 48 hours

Remarks on result:

other: Unwashed

Irritation parameter:

other: discharge

Basis:

mean

Remarks:

of 3 animals

Time point:

24/48/72 h

Score:

0.11

Max. score:

3

Reversibility:

fully reversible within: 48 hours

Remarks on result:

other: Washed

Irritant / corrosive response data:

- Conjunctival irritation was observed in all treated eyes, unwashed and washed, at 24 hours post-dosing. By 72 hours, this was observed in only one washed and one unwashed treated eye.
- No corneal opacity or iritis was noted during the test period.

Other effects:

All animals appeared active and healthy. There were no signs of gross toxicity, adverse pharmacologic effects or abnormal behaviour.

Table 1: Individual Results

Time Point (hours)	Rabbit Number	Cornea	Iris	Conjunctivae	Chemosis	Discharge
24	8087 8088 8089 8090 8091 8092	0 0 0 0 0 0	0 0 0 0 0 0	3 2 1 2 2 1	1 1 0 0 1 0	1 0 0 0 0 1
48	8087 8088 8089 8090 8091 8092	0 0 0 0 0 0	0 0 0 0 0 0	2 2 0 2 1 1	1 0 0 0 0 0	0 0 0 0 0 0
72	8087 8088 8089 8090 8091 8092	0 0 0 0 0 0	0 0 0 0 0 0	1 0 0 1 0 0	0 0 0 0 0 0	0 0 0 0 0 0

Rabbits 8090, 8091 and 8092 had the treated eye rinsed with 30 cc of saline solution 30 seconds post-installation

Interpretation of results:

GHS criteria not met

Conclusions:

The test material produced minimal irritation to both the unwashed and washed eyes; no classification is required.

Reference 5

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

2000-02-08 to 2000-03-23

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

Well documented, scientifically sound study according to a method similar to OECD guideline 405 with a few deviations. However, not GLP, no information on environmental conditions, individual eye endpoints (cornea, iris, conjunctiva) not reported in the results.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

yes

Remarks:

not GLP, no information on environmental conditions, individual eye endpoints (cornea, iris, conjunctiva) were not reported in the results

GLP compliance:

no

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Biotech Co., Ltd
- Age at study initiation: 4 months old
- Weight at study initiation: 3.22-3.59 kg
- Housing: no data
- Diet (e.g. ad libitum): no data
- Water (e.g. ad libitum): no data
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data

IN-LIFE DATES: From: no data To: no data

Vehicle:

unchanged (no vehicle)

Controls:

other: right eyes were kept as controls

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 g
- Concentration (if solution): not applicable

VEHICLE
- Amount(s) applied (volume or weight with unit): not applicable
- Concentration (if solution): not applicable
- Lot/batch no. (if required): not applicable
- Purity: not applicable

Duration of treatment / exposure:

single instillation

Observation period (in vivo):

1, 24, 48, and 72 hours

Number of animals or in vitro replicates:

3 animals (administered to the left eye of each animal)

Details on study design:

SCORING SYSTEM: According to Draize's standard (1959). Cornea, iris and conjunctiva were observed, and acknowledged damages were recorded. After calculating the total scores of each observation of each animal (Individual ocular irritation index, IOI) and the average score of each observation of each group (Mean ocular irritation index, MOI), the evaluation was made according to the AFNOR (1982) evaluation criteria. The acute ocular irritation index (AOI) was defined as the maximum of the MOI.

Accident Value Test of Corneal Epithelium: After the accident value test of anterior ocular segment done 24 hours after the application, corneal epithelium were dyed with fluorescein, and the stainability was evaluated.

TOOL USED TO ASSESS SCORE: hand-slit lamp

Irritation parameter:

other: MOI

Basis:

mean

Remarks:

of 3 animals

Time point:

other: 1 hour

Score:

4.7

Max. score:

110

Reversibility:

fully reversible within: 72 hours

Irritation parameter:

other: MOI

Basis:

mean

Remarks:

of 3 animals

Time point:

24 h

Score:

6

Max. score:

110

Reversibility:

fully reversible within: 72 hours

Irritation parameter:

other: MOI

Basis:

mean

Remarks:

of 3 animals

Time point:

48 h

Score:

2

Max. score:

110

Reversibility:

fully reversible within: 72 hours

Irritation parameter:

other: MOI

Basis:

mean

Remarks:

of 3 animals

Time point:

72 h

Score:

0

Max. score:

110

Reversibility:

other: not applicable

Irritation parameter:

other: AOI

Basis:

mean

Remarks:

of 3 animals

Time point:

24 h

Score:

6

Max. score:

110

Reversibility:

fully reversible within: 72 hours

Irritant / corrosive response data:

The AOI was determined to be 6.0 at 24 hours and the MOI after 48 hours was 2.0, therefore, this test agent was determined to be slightly irritating based on the AFNOR (1982) criteria. No irritation was observed after 72 hours.

The Accident Value Test of Corneal Epithelium 24 hours after application was zero in all three animals.

Other effects:

There were no abnormalities in the general condition or the weight changes to any of the 3 animals.

Interpretation of results:

GHS criteria not met

Conclusions:

The test agent was determined to be slightly irritating based on the AFNOR criteria. It does however not need to be classified for eye irritation according to the CLP criteria.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin irritation

1. Information on the reaction mass of cerium dioxide and zirconium dioxide

In a primary dermal irritation study (De Jouffrey, 1996b; Klimisch 1), 3 male New Zealand White rabbits were dermally exposed to 500 mg of the reaction mass of cerium dioxide and zirconium dioxide onto one flank. Test sites were covered with semi-occlusive dressing for 4 hours. The cutaneous examinations were performed 1, 24, 48 and 72 hours after removal of the dressing. The mean scores for erythema and edema were calculated for 24, 48 and 72 hours. No cutaneous reactions were observed during the study warranting classification.

In addition, a similar acute dermal irritation test in New Zealand White rabbits was performed by Harlan (2009; Klimisch 1). Three rabbits were dermally exposed to 500 mg of the reaction mass of cerium dioxide and zirconium dioxide onto a dorsal flank for 4 hours. Cotton gauze was used to apply the test substance to shorn skin. The cutaneous examinations were performed 1, 24, 48 and 72 hours after removal of the dressing. The mean scores for erythema and edema were calculated for 24, 48 and 72 hours. No evidence of skin irritation was reported under the conditions of the test.

Based on these studies the reaction mass of cerium dioxide and zirconium dioxide was concluded not to be irritating to skin and not classified for this endpoint under the CLP Regulation.

2. Information on praseodymium(III,IV) oxide

In the guideline study performed by Shapiro (1991a; Klimisch 2), 0.5 g of the test material was applied to both an intact and abraded site on each of six New Zealand White rabbits. The sites were occluded for 24 hours, after which the patches were removed and the test sites wiped to prevent further exposure. Evaluation occurred 24 and 72 hours after exposure. With the exception of one rabbit, which exhibited very slight erythema without oedema at both the intact and abraded site at 24 hours (reversible within 72 h), all sites were clear of irritation during the test period (PDII = 0.09). This study was considered reliable with restrictions because no observations were made at 48 hours after exposure. Based on the results of this study, praseodymium(III,IV) oxide is considered not be a dermal irritant and does not require classification.

3. Information on zirconium dioxide

In a guideline study performed by The British Industrial Biological Research Association (1986; Klimisch 2), zirconium dioxide was found not to be irritating to the skin of New Zealand White rabbits. The overall irritation score was calculated to be zero and hence, it can be concluded that zirconium dioxide does not need to be classified for skin irritation.

4. Conclusion on the reaction mass of cerium dioxide, praseodymium(III,IV) oxide and zirconium dioxide

Based on the studies available for praseodymium(III,IV) oxide, zirconium dioxide and the reaction mass of cerium dioxide and zirconium dioxide, it can safely be concluded that the reaction mass of cerium dioxide, praseodymium(III,IV) oxide and zirconium dioxide is not irritant to skin and does not need to be classified for skin irritation under the CLP Regulation.

Eye irritation

1. Information on the reaction mass of cerium dioxide and zirconium dioxide

In a primary eye irritation study (De Jouffrey, 1996c; Klimisch 1), 100 mg of the reaction mass of cerium dioxide and zirconium dioxide was instilled into the conjunctival sac of the left eye of New Zealand White rabbits (3 animals). Eyes were not rinsed and the right eye served as control. The ocular examinations were performed 1, 24, 48 and 72 hours after treatment. Mean scores calculated for each animal over 24, 48 and 72 hours were 1.0, 1.0 and 1.3 for chemosis, 0.3, 1.0 and 2.3 for redness of the conjunctivae, 0.0, 0.0 and 0.7 for iris lesions and 0.7, 0.3 and 1.3 for corneal opacity. Total reversibility was observed by day 4 (2 animals) or day 8. Based on these observations the reaction mass of cerium dioxide and zirconium dioxide is not classified as eye irritant under the CLP Regulation.

2. Information on praseodymium(III,IV) oxide

In the guideline study performed by Shapiro (1991b; Klimisch 2), 0.1 g of the test material was instilled into the left eye of six New Zealand white rabbits, with three of the treated eyes being rinsed after 30 seconds with saline. The animals were observed for 72 hours and the eyes examined at 24, 48 and 72 hours. Irritation was scored according to the method of Draize. In this study, the test item produced minimal irritation to both the unwashed and washed eyes but no classification is required under the conditions of this study in accordance with the CLP criteria.

3. Information on zirconium dioxide

In the guideline study performed by the Chemical Evaluation and Research Institute of Japan (2000; Klimisch 2), 0.1 g of yttrium zirconium oxide (test item with a low amount of yttrium oxide incorporated into the crystal lattice of zirconium dioxide) was instilled into the left eye of 3 New Zealand White rabbits. The results were calculated in terms of the Mean ocular irritation index (MOI). The test item was determined to be slightly irritating based on the AFNOR criteria, but the irritation was reversible at 72 h. It does not need to be classified for eye irritation according to the criteria of the CLP regulation. The results of this study were considered relevant for zirconium dioxide. The study was considered reliable with restrictions because no scores for each individual eye irritation endpoint for each individual animal were reported.

4. Conclusion on the reaction mass of cerium dioxide, praseodymium(III,IV) oxide and zirconium dioxide

Based on the studies available for praseodymium(III,IV) oxide, yttrium zirconium oxide (i.e. zirconium dioxide with a small amount of yttrium oxide added to its crystal lattice) and the reaction mass of cerium dioxide and zirconium dioxide, it can safely be concluded that the reaction mass of cerium dioxide, praseodymium(III,IV) oxide and zirconium dioxide does not need to be classified for eye irritation either under the CLP Regulation.

Justification for classification or non-classification

Based on the studies available for praseodymium(III,IV) oxide, zirconium dioxide and the reaction mass of cerium dioxide and zirconium dioxide, it can safely be concluded that the reaction mass of cerium dioxide, praseodymium(III,IV) oxide and zirconium dioxide is not irritant to skin and does not need to be classified for skin irritation under the CLP Regulation.

Based on the studies available for praseodymium(III,IV) oxide, yttrium zirconium oxide (i.e. zirconium dioxide with a small amount of yttrium oxide added to its crystal lattice) and the reaction mass of cerium dioxide and zirconium dioxide, it can be concluded that the reaction mass of cerium dioxide, praseodymium(III,IV) oxide and zirconium dioxide does not need to be classified for eye irritation either under the CLP Regulation.