Calcium zirconium oxide

Endpoint summary

Description of key information

1. Information on zirconium dioxide
Skin irritation / corrosion:
Zirconium dioxide was observed not to be irritating to the skin of New Zealand White rabbit in an in vivo skin irritation study performed according to OECD guideline 404 (BIBRA, 1986).
Eye irritation:
Yttrium zirconium oxide was observed to be slightly irritating to New Zealand rabbit eyes in an in vivo eye irritation study performed according to a method equivalent to OECD Guideline 405 (Chemical Evaluation and Research Institute, 2000), however, the substance does not need to be classified (DSD, CLP) for eye irritation.
2. Information on calcium oxide 
Calcium oxide is considered to be irritating to skin and entails a risk of serious damage to the eye (data not included). These local effects are related to the alkaline reserve of the substance. The substance is classified as Skin irritant Category 2 and Eye damage Category 1 under the CLP Regulation.
3. Conclusion on calcium zirconium oxide 
No reliable studies are available for calcium zirconium oxide. Following the read across approach (see IUCLID Section 13) it is assumed that calcium zirconium oxide does not need to be classified for skin or eye irritation, similar to what is the case for zirconium dioxide. The underlying argumentation is based on the fact that only limited amounts of calcium are released from calcium zirconium oxide in water (as demonstrated by Eidam, 2014, 2015). Consequently, no adverse local effects are expected in skin and eye, such as those observed upon dissolution of calcium oxide (which dissolves very well in water, contrary to calcium zirconium oxide).

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1986-03-04 to 1986-07-17

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: 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:

mean

Time point:

other: average of 24, 48, and 72 hours

Score:

0

Max. score:

4

Irritation parameter:

edema score

Basis:

mean

Time point:

other: average of 24, 48, and 72 hous

Score:

0

Max. score:

4

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.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2000-02-08 to 2000-03-23

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well documented, scientifically sound study with methods similar to OECD guideline 405 with a few deviations.

Remarks:

Not GLP, no information on environmental conditions, individual eye endpoints (cornea, iris, conjunctiva) were 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

Time point:

other: 1 hour

Score:

4.7

Max. score:

110

Reversibility:

fully reversible within: 72 hours

Irritation parameter:

other: MOI

Basis:

mean

Time point:

other: 24 hours

Score:

6

Max. score:

110

Reversibility:

fully reversible

Remarks:

72 hours

Irritation parameter:

other: MOI

Basis:

mean

Time point:

other: 48 hours

Score:

2

Max. score:

110

Reversibility:

fully reversible within: 72 hours

Irritation parameter:

other: MOI

Basis:

mean

Time point:

other: 72 hours

Score:

0

Max. score:

110

Irritation parameter:

other: AOI

Basis:

mean

Time point:

other: 24 hours

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 rules in the DSD and CLP.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

1. Information on zirconium dioxide

Skin irritation / corrosion:

One reliable study was identified (BIBRA, 1986). This GLP study was performed according to the OECD Guideline 404 with minor deviations. The substance was determined not to be irritating to New Zealand White rabbit skin after 4 hours of exposure.

Eye irritation:

A reliable study is available for the read across substance yttrium zirconium oxide (Chemical Evaluation and Research Institute, 2000), i.e. zirconia stabilised with a small amount of yttria. The study was performed in New Zealand White rabbit according to a method equivalent to OECD Guideline 405 with some minor deviations. The test substance was determined to be slightly irritating based on the AFNOR criteria. Observed effects were fully reversible within 72 hours. However, the substance does not need to be classified for eye irritation according to the rules of the DSD and CLP Regulation.

2. Information on calcium oxide

Skin irritation / corrosion:

No data are included in this dossier on the irritating effects of calcium oxide in skin. Calcium oxide is classified as Skin irritant Category 2 (under the CLP Regulation) and is considered as irritating to skin under wet conditions due to its transformation to calcium hydroxide and dissociation of the latter compound, resulting in release of hydroxyl ions and a sharp increase of pH. Because dissolution of calcium (oxide) from calcium zirconium oxide in water has been demonstrated to be limited (Eidam, 2014, 2015), the data on calcium oxide as such are not considered relevant for inclusion in this dossier.

 

Eye irritation:

No data are included in this dossier on the local effects of calcium oxide in eyes. Calcium oxide is classified as Eye damage Category 1 (under the CLP Regulation) and its adverse effects (irreversible lesions) in eyes are related to the substance's dissolution, resulting in transformation to calcium hydroxide, which releases hydroxyl ions and causes a substantial increase of pH. Here too, because dissolution of calcium (oxide) from calcium zirconium oxide in water has been demonstrated to be limited (Eidam, 2014, 2015), the data on calcium oxide as such are not considered relevant for inclusion in this dossier.

3. Conclusion on calcium zirconium oxide

Calcium zirconium oxide is a stabilised zirconia with (according to the SIP) >= 90% w/w zirconium dioxide in the crystal lattice. Zirconium dioxide is not classified for local effects in skin and eye. On the other hand however, calcium oxide is classified as Skin irritant Category 2 and Eye damage Category 1 under the CLP Regulation. Calcium oxide, as an individual substance, is transformed to calcium hydroxide when dissolved in aqueous media. When applied on moist skin and in eyes, calcium oxide will be transformed to calcium hydroxide, and calcium hydroxide will dissociate, releasing hydroxyl ions. The pH increase due to the basic behaviour of the substance results in local adverse effects in both skin and eyes. In skin, no adverse effects were however observed when the test substance was not moistened. Nevertheless, a classification as Skin Irritant Category 2 and Eye damage Category 1 is assigned to calcium oxide under the CLP Regulation. The studies used for endpoint coverage in the calcium oxide dossier were not included in the dossier for calcium zirconium oxide, because they are considered less relevant due to the limited water solubility of calcium zirconium oxide. Indeed, only limited amounts of calcium (oxide) will be dissolved when calcium zirconium oxide comes into contact with moistened skin or with eyes. The limited release of calcium from the substance has been demonstrated in pure water by Eidam (2014, 2015), indicating that only 0.0145% w/w of the total amount of calcium zirconium oxide accounts for release of calcium to the test medium (results for a test sample containing 10% w/w CaO). Based on this limited dissolution of calcium from calcium zirconium oxide, no such pH effect as was observed with the individual substance calcium oxide should be expected when calcium zirconium oxide comes into contact with (moistened) skin and with eyes. In conclusion, the non-hazardous toxicological profile of zirconium dioxide is not affected by addition of calcium oxide to its crystal lattice, and calcium zirconium oxide can be considered as equally non-hazardous with regard to skin and eyes as pure zirconium dioxide.

Justification for classification or non-classification

1. Information on zirconium dioxide

Based on to the available data and according to the criteria of the DSD and CLP Regulation, this substance should not be classified for skin corrosion / irritation or for serious eye damage / irritation.

2. Information on calcium oxide

Calcium oxide is classified as irritating to the skin according to the DSD (R38) and Skin irritant Category 2 (H315) according to the CLP Regulation. In addition, the substance is classified for risk of serious damage to the eye (R41) according to the DSD and Eye damage Category 1 (H318) according to the CLP Regulation.

3. Conclusion on calcium zirconium oxide

Calcium zirconium oxide is a stabilised zirconia, whereby zirconium dioxide and calcium oxide are incorporated in a single crystal lattice. The main component (>= 90% w/w) is zirconium dioxide. Zirconium dioxide is not classified for local effects in skin and eyes. Calcium oxide on the other hand is classified as Skin irritant Category 2 (H315), and Eye damage Category 1 (H318) due to a pH increasing effect occurring when calcium oxide comes into contact with body fluids. When applying – as a worst case approach – the mixture rules for classification, and taking into account the fact that the current SIP supports calcium zirconium oxide with up to 10% w/w calcium oxide, calcium zirconium oxide with 10% w/w calcium oxide would be classified as Skin irritant Category 2 (H315) (total concentration of ingredients classified as Skin irritant Category 2 ≥ 10%) and Eye damage Category 1 (H318) (total concentration of ingredients classified for Eye damage Category 1 ≥ 3%), with gradually less stringent classifications with decreasing % w/w of calcium oxide. Even in case additivity would not apply, the substance should be classified as Skin irritant Category 2 (concentration of an ingredient classified as Skin irritant Category 2 ≥ 3%) and for Eye damage Category 1 (concentration of an ingredient classified for Eye damage Category 1 ≥ 1%).

However, the water solubility tests performed by Eidam (2014, 2015), in which the release of zirconium and calcium to the test medium (water) was quantified, indicated that maximally 0.0145% w/w calcium is released from calcium zirconium oxide (sample with 10% w/w calcium oxide). Assuming a hypothetical mixture of zirconium dioxide and calcium oxide in which all calcium oxide is dissolved in the aqueous medium, this would correspond to a mixture containing 0.02% w/w calcium oxide. Now, applying the generic cut-off values for substances in mixtures, calcium zirconium oxide should not be classified, as the % w/w calcium oxide is < 1%. Due to the limited release of calcium from calcium zirconium oxide, it is highly unlikely that a substantial pH increase and concurrent local effects would be observed in skin and eye due to dissolution of calcium (oxide). Therefore, the substance is considered as non-hazardous to skin and eyes.