Calcium zirconium oxide

Endpoint summary

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1999-03-08 to 1999-05-24

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well-documented non GLP study similar to OECD guideline 406.

Qualifier:

according to guideline

Guideline:

other: Maximization Test of the Guideline for Toxicity Studies of Drugs (Notification No. 1-24 of Pharmaceuticals and Cosmetics Division dated September 11, 1989)

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 406 (Skin Sensitisation)

GLP compliance:

not specified

Type of study:

guinea pig maximisation test

Justification for non-LLNA method:

Study was performed before the LLNA method became the preferred method for skin sensitisation testing. Moreover, the GPMT test is preferred specifically for zirconium compounds.

Species:

guinea pig

Strain:

Hartley

Sex:

female

Details on test animals and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories Japan, Inc.
- Age at study initiation: 4 weeks old
- Weight at study initiation: 272 g - 302 g
- Housing: Five guinea pigs were kept together in each aluminum bracket cage (360 W x 520 D x 330 H mm, Bottom: 320 W x 480 D mm) until the elicitation treatment, then were kept individually in aluminum bracket cages (220 W x 380 D x 250 H mm) after the elicitation treatment. The cages were changed once a week.
- Diet: Solid feed (RC4, Oriental Yeast Col, Ltd)
- Water: Hita municipal water supply was used for water, which was provided freely by automatic water-supply equipments.
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23+/- 2 degrees C
- Humidity (%): 55 +/- 15%
- Air changes (per hr): 10 ~ 15 ventilation per hour
- Photoperiod (hrs dark / hrs light): 12 hour light and dark period ( light on at 7 am- off at 7 pm)

IN-LIFE DATES: From: 1999-02-23 To: 1999-05-24

Route:

intradermal and epicutaneous

Vehicle:

physiological saline

Concentration / amount:

Intradermal sensitization
1) Test agent group

- E-FCA (equal volume (v/v) of "distilled injection water" and Freund's complete adjuvant (FCA) were mixed and emulsified in water-in-oil style)
- 2.5% test agent
- 2.5% test agent/FCA emulsion

2) Control group

- E-FCA

3) Positive control group

- E-FCA
- 0.1% DNCB/olive oil
- 0.1% DNCB/FCA emulsion

Patch sensitization
1) Test agent group
- 25% test agent
2) Control group
- distilled injection water
3) Positive control group
- 0.5% DNCB
Elicitation Treatment
1) Test group and control group
- 25% test agent
- 2.5% test agent
2) Positive control group
- 0.1% DNCB

Route:

epicutaneous, occlusive

Vehicle:

physiological saline

Concentration / amount:

Intradermal sensitization
1) Test agent group

- E-FCA (equal volume (v/v) of "distilled injection water" and Freund's complete adjuvant (FCA) were mixed and emulsified in water-in-oil style)
- 2.5% test agent
- 2.5% test agent/FCA emulsion

2) Control group

- E-FCA

3) Positive control group

- E-FCA
- 0.1% DNCB/olive oil
- 0.1% DNCB/FCA emulsion

Patch sensitization
1) Test agent group
- 25% test agent
2) Control group
- distilled injection water
3) Positive control group
- 0.5% DNCB
Elicitation Treatment
1) Test group and control group
- 25% test agent
- 2.5% test agent
2) Positive control group
- 0.1% DNCB

No. of animals per dose:

Control group: 5 animals
Test agent group: 10 animals
Positive conrol group: 5 animals

Details on study design:

Intradermal Sensitization:
Supra scapular fur was shaved by an electric clipper in order to establish 24 cm sensitization regions, and with the midline as the axis of symmetry, 0.1 ml of below preparations were injected per region of each left-right pair.
1) Test agent group
E-FCA
2.5% test agent
2.5% test agent/FCA emulsion
2) Control group
E-FCA (2 pairs in total)
3) Positive control group
E-FCA
0.1% DNCB/olive oil
0.1% DNCB/FCA emulsion

Patch Sensitization:
Six days after the intradermal sensitization, the fur in the sensitization regions of the animals in the control groups and the test agent group were shaved by an electric clipper and an electric shaver, then sodium lauryl sulfate (contains 10% petrolatum) was applied. Seven days after the intradermal sensitization, the control group animals were applied with distilled injection water, the test agent group with 25 % test agent, and the positive control group with 0.5 % DNCB, by placing 24 cm lints (Nankai Sangyou Co.) moistened with 0.2 ml each of the preparation on the shaved sensitization regions and by covering them with rubber dam sheets (Nihon Rikagaku Industry Co., Ltd.), then the trunks were wrapped with Dermicel (Johnson & Johnson K.K.) for 48 hours for occlusive dressing.

Elicitation Treatment (challenge):
Fourteen days after the start of the patch sensitization, the flank fur of the animals were shaved by an electric clipper and an electric shaver, and for the control group and the test agent group, the areas were applied with 25% test agent and 2.5% test agent to each group, respectively, by placing 22 cm lints moistened with 0.1 ml of the preparation, and by covering them with oilpaper and rubber dam sheets, then the trunks were wrapped with Dermicel (Johnson & Johnson K.K.) for 24 hours for occlusive dressing. For the positive control group, 0.1% DNCB was applied by placing 22 cm lints moistened with 0.1 ml of the preparation and by covering them with rubber dam sheets, then the trunks were wrapped with Dermicel (Johnson & Johnson K.K.) for 24 hours for occlusive dressing.

Challenge controls:

25% test agent
- 2.5 g of the test agent was suspended in distilled injection water to make 10 ml.
2.5% test agent
- 0.25 g of the test agent was suspended in distilled injection water to make 10 ml.
0.1% DNCB
- 0.01 g of DNCB was dissolved in ethanol to make 10 ml.

Positive control substance(s):

yes

Remarks:

DNCB

Positive control results:

0.1% DNCB elicited region: Diffused moderate erythema or severe erythema and edema were acknowledged in every sample 24 and 48 hours after the elicitation patch removal. Furthermore, scab formations were acknowledged in 4/5 cases after both 24 and 48 hours, and desquamation were acknowledged in all cases after 48 hours. The average scores 24 and 48 hours after the elicitation patch removal were 3.0 and 2.8, respectively.

Reading:

1st reading

Hours after challenge:

24

Group:

negative control

Dose level:

25%

No. with + reactions:

0

Total no. in group:

5

Clinical observations:

none

Reading:

2nd reading

Hours after challenge:

48

Group:

negative control

Dose level:

25%

No. with + reactions:

0

Total no. in group:

5

Clinical observations:

none

Reading:

1st reading

Hours after challenge:

24

Group:

negative control

Dose level:

2.5%

No. with + reactions:

0

Total no. in group:

5

Clinical observations:

none

Reading:

2nd reading

Hours after challenge:

48

Group:

negative control

Dose level:

2.5%

No. with + reactions:

0

Total no. in group:

5

Clinical observations:

none

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

25%

No. with + reactions:

0

Total no. in group:

10

Clinical observations:

none

Reading:

2nd reading

Hours after challenge:

48

Group:

test chemical

Dose level:

25%

No. with + reactions:

0

Total no. in group:

10

Clinical observations:

none

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

2.5%

No. with + reactions:

0

Total no. in group:

10

Clinical observations:

none

Reading:

2nd reading

Hours after challenge:

48

Group:

test chemical

Dose level:

2.5%

No. with + reactions:

0

Total no. in group:

10

Clinical observations:

none

Skin Reaction

2.1 Test Agent Group

1) 25% test agent elicited region.

No skin reaction was acknowledged 24 and 48 hours after the elicitation patch removal.

The average scores 24 and 48 hours after the elicitation patch removal were both 0.

2) 2.5% test agent elicited region

No skin reaction was acknowledged 24 and 48 hours after the elicitation patch removal.

The average scores 24 and 48 hours after the elicitation patch removal were both 0.

2.2 Control Group

1) 25% test agent elicited region.

No skin reaction was acknowledged 24 and 48 hours after the elicitation patch removal.

The average scores 24 and 48 hours after the elicitation patch removal were both 0.

2) 2.5% test agent elicited region

No skin reaction was acknowledged 24 and 48 hours after the elicitation patch removal.

The average scores 24 and 48 hours after the elicitation patch removal were both 0.

Interpretation of results:

GHS criteria not met

Conclusions:

Since no skin reaction was acknowledged in the elicited region of either the test agent group or the control group, it was surmised that TZ-3Y does not have skin sensitizing potential under the conditions of this test. On the other hand, it was confirmed that DNCB, the positive control agent, has an extreme skin sensitizing potential.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

1. Information on zirconium dioxide

One reliable (Klimisch 2) study was available for the skin sensitisation endpoint (Chemicals Inspection and Testing Institute, 1999). The test was performed according to OECD guideline 406 and the Maximization Test of the Guideline for Toxicity Studies of Drugs (Notification No. 1-24 of Pharmaceuticals and Cosmetics Division dated September 11, 1989). This study was performed with yttrium zirconium oxide, i.e. zirconia stabilised with a small amount of yttrium, and was considered relevant for zirconium dioxide as yttrium was demonstrated not to affect the non-hazardous toxicological profile of zirconium dioxide. The test substance was not found to be sensitising to the skin, and consequently, pure zirconium dioxide was also concluded not to be sensitising to skin.

2. Information on calcium oxide

Testing for this endpoint has been waived in the dossier for calcium oxide. There is no evidence of any sensitising potential for calcium oxide. Calcium is abundantly available in the environment, in food, and extensively distributed throughout the human body. Sensitisation by or intolerance to an abundantly available essential element such as calcium would be grossly implausible and can therefore safely be excluded.

3. Conclusion on calcium zirconium oxide

It is expected that the substance has a similar toxicological profile as zirconium dioxide, which is the main constituent in the crystal lattice of calcium zirconium oxide. Therefore, calcium zirconium oxide is concluded not to be sensitising to skin. The presence of calcium (oxide) in the crystal lattice is not expected to affect the non-hazardous character of zirconium dioxide, since no sensitising effects are expected for calcium either, which is an abundantly available essential element that is is extensively distributed throughout the human body. The read across justification is included in IUCLID Section 13.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

1. Information on zirconium dioxide

Based on the test results for the read across substance yttrium zirconium oxide and according to the criteria of the CLP Regulation, zirconium dioxide should not be classified as a skin sensitiser.

No reliable data are available for respiratory sensitisation, therefore no conclusion can be made on the classification of this endpoint.

2. Information on calcium oxide

Testing for this endpoint has been waived in the dossier for calcium oxide. There is no evidence of any sensitising potential for calcium oxide. Calcium is abundantly available in the environment, in food, and extensively distributed throughout the human body. Sensitisation by or intolerance to an abundantly available essential element such as calcium would be grossly implausible and can therefore safely be excluded. Calcium oxide is therefore considered not to be classified for any sensitising effects.

3. Conclusion on calcium zirconium oxide

Based on the available information for zirconium dioxide and the reasoning behind the non-classification of calcium oxide for sensitising effects, it is concluded that calcium zirconium oxide does not have to be classified as a skin sensitizer either.

In the absence of experimental data that would allow to conclude on repiratory sensitisation, no conclusion can be drawn on the classification for this endpoint.