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Registration Dossier
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EC number: 264-885-7 | CAS number: 64417-98-7
Endpoint summary
Administrative data
Description of key information
In a skin sensitisation test in guinea pigs (Hartley strain) zirconium
dioxide stabilised with yttrium oxide was observed to be not sensitising
to the skin (Chemical Inspection and Testing Institute, 1999). The study
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).
Key value for chemical safety assessment
Skin sensitisation
Link to relevant study records
- 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:
- guideline study with acceptable restrictions
- Remarks:
- Non-GLP study.
- 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.
- 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
- Vehicle:
- physiological saline
- Concentration / amount:
- 2.5% w/v in physiological saline
Amount applied: 0.1 mL per injection - Day(s)/duration:
- Day 1
- Adequacy of induction:
- not specified
- Route:
- epicutaneous, occlusive
- Vehicle:
- other: distilled injection water
- Concentration / amount:
- 25% w/v in distilled injection water
Amount applied: 0.2 mL - Day(s)/duration:
- Day 8, 48 h of exposure
- Adequacy of induction:
- non-irritant substance, but skin pre-treated with 10% SDS
- No.:
- #1
- Route:
- epicutaneous, occlusive
- Vehicle:
- other: distilled injection water
- Concentration / amount:
- 25% and 2.5% w/v in distilled injection water
Amount applied: 0.1 mL - Day(s)/duration:
- Day 22, 24 h of exposure
- Adequacy of challenge:
- not specified
- No. of animals per dose:
- Control group: 5 animals
Test agent group: 10 animals
Positive conrol group: 5 animals - Details on study design:
- Intradermal sensitisation:
Suprascapular fur was shaved by an electric clipper in order to establish 2x4 cm sensitisation 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 sensitisation:
Six days after the intradermal sensitisation, the fur in the sensitisation 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 sensitisation, the control group was applied with distilled injection water, the test agent group with 25% test agent, and the positive control group with 0.5% DNCB, by placing 2x4 cm lints (Nankai Sangyou Co.) moistened with 0.2 mL each of the preparation on the shaved sensitisation 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 sensitisation, the flank fur of the animals was 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 2x2 cm lints moistened with 0.1 mL of the preparation, and by covering them with oil paper 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 2x2 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 (2,4-dinitrochlorobenzene, positive control substance)
- 0.01 g of DNCB was dissolved in ethanol to make 10 mL. - Positive control substance(s):
- yes
- Remarks:
- DNCB (2,4-dinitrochlorobenzene)
- Positive control results:
- 0.1% DNCB elicited region: Diffuse moderate erythema or severe erythema and oedema 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 was 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:
- test chemical
- Dose level:
- 25% w/v in distilled injection water
- No. with + reactions:
- 0
- Total no. in group:
- 10
- Clinical observations:
- none
- Remarks on result:
- no indication of skin sensitisation
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- test chemical
- Dose level:
- 25% w/v in distilled injection water
- No. with + reactions:
- 0
- Total no. in group:
- 10
- Clinical observations:
- none
- Remarks on result:
- no indication of skin sensitisation
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- test chemical
- Dose level:
- 2.5% w/v in distilled injection water
- No. with + reactions:
- 0
- Total no. in group:
- 10
- Clinical observations:
- none
- Remarks on result:
- no indication of skin sensitisation
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- test chemical
- Dose level:
- 2.5% w/v in distilled injection water
- No. with + reactions:
- 0
- Total no. in group:
- 10
- Clinical observations:
- none
- Remarks on result:
- no indication of skin sensitisation
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- negative control
- Dose level:
- 25% w/v in distilled injection water
- No. with + reactions:
- 0
- Total no. in group:
- 5
- Clinical observations:
- none
- Remarks on result:
- no indication of skin sensitisation
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- negative control
- Dose level:
- 25% w/v in distilled injection water
- No. with + reactions:
- 0
- Total no. in group:
- 5
- Clinical observations:
- none
- Remarks on result:
- no indication of skin sensitisation
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- negative control
- Dose level:
- 2.5% w/v in distilled injection water
- No. with + reactions:
- 0
- Total no. in group:
- 5
- Clinical observations:
- none
- Remarks on result:
- no indication of skin sensitisation
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- negative control
- Dose level:
- 2.5% w/v in distilled injection water
- No. with + reactions:
- 0
- Total no. in group:
- 5
- Clinical observations:
- none
- Remarks on result:
- no indication of skin sensitisation
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- positive control
- Dose level:
- 0.1% w/v DNCB in ethanol
- No. with + reactions:
- 5
- Total no. in group:
- 5
- Clinical observations:
- Diffuse moderate erythema or severe erythema and oedema were acknowledged in every animal. Furthermore, scab formations were acknowledged in 4 out of 5 animals.
- Remarks on result:
- positive indication of skin sensitisation
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- positive control
- Dose level:
- 0.1% w/v DNCB in ethanol
- No. with + reactions:
- 5
- Total no. in group:
- 5
- Clinical observations:
- Diffuse moderate erythema or severe erythema and oedema were acknowledged in every animal. Furthermore, scab formations were acknowledged in 4 out of 5 animals, and desquamation was acknowledged in all cases.
- Remarks on result:
- positive indication of skin sensitisation
- 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 concluded that the test substance does not have skin sensitising potential under the conditions of this test. On the other hand, it was confirmed that 2,4-dinitrochlorobenzene, the positive control agent, has an extreme skin sensitising potential.
- Endpoint:
- skin sensitisation: in vitro
- Data waiving:
- study scientifically not necessary / other information available
- Justification for data waiving:
- an in vitro skin sensitisation study does not need to be conducted because adequate data from an in vivo skin sensitisation study are available
Referenceopen allclose all
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.
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed (not sensitising)
- Additional information:
One reliable (Klimisch 2) study is available and selected as the key study (Chemical Inspection and Testing Institute, 1999). The study was performed using yttrium stabilised zirconia. The skin sensitisation 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). Female Guinea pigs of the Hartley strain received following treatment:
Intradermal sensitisation
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 sensitisation
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
Yttrium stabilised zirconia was found to be not sensitising to the skin at a level up to 25% whilst the positive control substance, DNCB, was found to have an extreme skin sensitising potential.
Based on the available data, yttrium zirconium oxide is not expected to cause skin sensitising effects.
Respiratory sensitisation
Endpoint conclusion
- Endpoint conclusion:
- no study available
Justification for classification or non-classification
Based on the test results and according to the criteria of the CLP Regulation, yttrium zirconium oxide should not be classified as a skin sensitiser.
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