Yttrium 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:

from 02-NOV-2005 to 31-JAN-2005

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study was performed according to EU guidelines and GLP

Qualifier:

according to guideline

Guideline:

EU Method B.6 (Skin Sensitisation)

Version / remarks:

Cited as Directive 96/54/EC, B.6

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Type of study:

guinea pig maximisation test

Species:

guinea pig

Strain:

Dunkin-Hartley

Sex:

female

Details on test animals and environmental conditions:

TEST ANIMALS:
- Source: Charles River Deutschland GmbH
- Age at study initiation: 4 - 6 weeks
- Weight at study initiation: 321 - 393 g
- Housing: individually in Makrolon type-4 cages with standard softwood bedding
- Diet: pelleted standard Provimi Kliba 3418, ad libitum
- Water: community tap water from Füllinsdorf, ad libitum
- Acclimation period: 12 days

ENVIRONMENTAL CONDITIONS
- Temperature: 22 +/- 3 °C
- Humidity: 30 - 70 %
- Air changes: 10 - 15 per hr
- Photoperiod: 12 hrs dark / 12 hrs light

IN-LIFE DATES: from 14-NOV-2005 to 08-DEC-2005

Route:

intradermal and epicutaneous

Vehicle:

water

Concentration / amount:

25% w/w (intradermal induction), 50 % w/w (epidermal induction and challenge)
1st application: Induction 25 % intracutaneous
2nd application: Induction 50 % occlusive epicutaneous
3rd application: Challenge 50 % occlusive epicutaneous

Route:

epicutaneous, occlusive

Vehicle:

water

Concentration / amount:

25% w/w (intradermal induction), 50 % w/w (epidermal induction and challenge)
1st application: Induction 25 % intracutaneous
2nd application: Induction 50 % occlusive epicutaneous
3rd application: Challenge 50 % occlusive epicutaneous

No. of animals per dose:

15 (main study: 5 in control group, 10 in test group), 3 (pretest)

Details on study design:

* RANGE FINDING TEST:
>>> INTRADERMAL INJECTIONS:
One guinea pig was intradermally injected into the clipped flank at concentrations of 25 % and 15 % (w/w) of the test item in purified water. Due to the high viscosity of the application dilution and the obstacle caused by the tissues, it was not technically possible to inject the liquid dilution at the concentration of 50 % (w/w) into the intra-cellular space.
Dermal reactions were assessed approximately 24 hours later.
Based on the results, the test item concentration of 25 % (w/w) was selected for intradermal induction in the main study.

>>> EPIDERMAL APPLICATIONS:
4 patches of filter paper were saturated with the test item at 50 % (technically the highest possible concentration to be applied sufficiently), 25 %, 15 % and 10 % (w/w) in purified water and applied to the clipped and shaved flanks of 2 guinea pigs. The patches were covered by a strip of aluminum foil and firmly secured by elastic plaster wrapped around the trunk and covered with impervious adhesive tape. The dressings were removed after an exposure period of 24 hours.
21 hours after removal of the dressing the application site was depilated in order to visualize any resulting erythema.
3 hours later (48 hours from the epidermal application) the skin reaction was observed and recorded. After this observation a second observation (approximately 72 hours from the epidermal application) was made and once again recorded.
Based on the results obtained the concentration selected for induction and challenge in the main study was 50 % (w/w).


* MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: 2 (intradermal injections + topical application)
- Type of epicutaneous induction: occlusive
- SLS application: yes (0.5 mL at 10% w/w in paraffinum perliquidum)
- Exposure period: on D1 (intradermal) and D8 (epidermal, 48-hr exposure)
- Test groups:
>>> Intradermal induction:
1) 1:1 (v/v) mixture of Freund's Complete Adjuvant and physiological saline
2) The test item at 25 % (w/w) in purified water
3) The test item at 25 % (w/w) in a 1:1 (v/v) mixture of Freund's Complete Adjuvant and physiological saline
>>> Epidermal application: test item at 50 % (w/w) in purified water
- Control group:
>>> Intradermal induction:
1) 1:1 (v/v) mixture of Freund's Complete Adjuvant and physiological saline
2) Purified water
3) 1:1 (w/w) mixture of purified water in a 1:1 (v/v) mixture of Freund's Complete Adjuvant and physiological saline
>>> Epidermal application: purified water only
- Site: dorsal skin of the scapular region
- Frequency of applications: not applicable
- Duration: 8 days (total duration of induction period)
- Concentrations: 25 % (w/w) by intradermal injection, 50 % (w/w) by epidermal application

B. CHALLENGE EXPOSURE
- No. of exposures: 1 (epidermal application)
- Day of challenge: day 22
- Exposure period: 24 hours
- Test groups: test item in the vehicle only (+ vehicle only on the other flank)
- Control group: test item in the vehicle only (+ vehicle only on the other flank)
- Site: left (test item) and right (vehicle) flanks
- Concentrations: 50% (w/w)
- Evaluation: 48 and 72 hr after beginning of the challenge

- Statistics: descriptive statistics were calculated for body weights. No inferential statistics were used.

Positive control substance(s):

yes

Remarks:

hexyl cinnamic aldehyde (CAS No 101-86-0) (regularly controlled)

Positive control results:

Hexyl cinnamic aldehyde was tested in the same conditions as described above. Based on the findings, hexyl cinnamic aldehyde at 1% in PEG 300 was considered as a skin sensitizer.
The positive control was not included in the study, but put in an other report as regular control.

Reading:

1st reading

Hours after challenge:

48

Group:

negative control

Dose level:

50 % yttrium oxide (W/W) in purified water

No. with + reactions:

0

Total no. in group:

5

Clinical observations:

none

Remarks on result:

other: Reading: 1st reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 50 % yttrium oxide (W/W) in purified water. No with. + reactions: 0.0. Total no. in groups: 5.0. Clinical observations: none.

Reading:

1st reading

Hours after challenge:

48

Group:

test chemical

Dose level:

50 % yttrium oxide (W/W) in purified water

No. with + reactions:

0

Total no. in group:

10

Clinical observations:

none

Remarks on result:

other: Reading: 1st reading. . Hours after challenge: 48.0. Group: test group. Dose level: 50 % yttrium oxide (W/W) in purified water. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: none.

Reading:

1st reading

Hours after challenge:

48

Group:

other: positive control (first challenge)

Dose level:

1 % (W/W) alpha-hexylcinnamaldehyde in PEG 300

No. with + reactions:

4

Total no. in group:

10

Clinical observations:

no data

Remarks on result:

other: Reading: 1st reading. . Hours after challenge: 48.0. Group: other: positive control (first challenge). Dose level: 1 % (W/W) alpha-hexylcinnamaldehyde in PEG 300. No with. + reactions: 4.0. Total no. in groups: 10.0. Clinical observations: no data.

Reading:

1st reading

Hours after challenge:

48

Group:

other: positive control (first challenge)

Dose level:

0.1 % (W/W) alpha-hexylcinnamaldehyde in PEG 300

No. with + reactions:

0

Total no. in group:

10

Clinical observations:

no data

Remarks on result:

other: see Remark

Remarks:

Reading: 1st reading. . Hours after challenge: 48.0. Group: other: positive control (first challenge). Dose level: 0.1 % (W/W) alpha-hexylcinnamaldehyde in PEG 300. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: no data.

Reading:

rechallenge

Hours after challenge:

48

Group:

other: positive control (second challenge)

Dose level:

1 % (W/W) alpha-hexylcinnamaldehyde in PEG 300

No. with + reactions:

7

Total no. in group:

10

Clinical observations:

no data

Remarks on result:

other: Reading: rechallenge. . Hours after challenge: 48.0. Group: other: positive control (second challenge). Dose level: 1 % (W/W) alpha-hexylcinnamaldehyde in PEG 300. No with. + reactions: 7.0. Total no. in groups: 10.0. Clinical observations: no data.

Reading:

rechallenge

Hours after challenge:

48

Group:

other: Positive control (second challenge)

Dose level:

0.1 % (W/W) alpha-hexylcinnamaldehyde in PEG 300

No. with + reactions:

1

Total no. in group:

10

Clinical observations:

no data

Remarks on result:

other: see Remark

Remarks:

Reading: rechallenge. . Hours after challenge: 48.0. Group: other: Positive control (second challenge). Dose level: 0.1 % (W/W) alpha-hexylcinnamaldehyde in PEG 300. No with. + reactions: 1.0. Total no. in groups: 10.0. Clinical observations: no data.

Reading:

2nd reading

Hours after challenge:

72

Group:

negative control

Dose level:

50 % yttrium oxide (W/W) in purified water

No. with + reactions:

0

Total no. in group:

5

Clinical observations:

none

Remarks on result:

other: Reading: 2nd reading. . Hours after challenge: 72.0. Group: negative control. Dose level: 50 % yttrium oxide (W/W) in purified water. No with. + reactions: 0.0. Total no. in groups: 5.0. Clinical observations: none.

Reading:

2nd reading

Hours after challenge:

72

Group:

test chemical

Dose level:

50 % yttrium oxide (W/W) in purified water

No. with + reactions:

0

Total no. in group:

10

Clinical observations:

none

Remarks on result:

other: Reading: 2nd reading. . Hours after challenge: 72.0. Group: test group. Dose level: 50 % yttrium oxide (W/W) in purified water. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: none.

Reading:

2nd reading

Hours after challenge:

72

Group:

other: positive control (first challenge)

Dose level:

1 % (W/W) alpha-hexylcinnamaldehyde in PEG 300

No. with + reactions:

1

Total no. in group:

10

Clinical observations:

no data

Remarks on result:

other: Reading: 2nd reading. . Hours after challenge: 72.0. Group: other: positive control (first challenge). Dose level: 1 % (W/W) alpha-hexylcinnamaldehyde in PEG 300. No with. + reactions: 1.0. Total no. in groups: 10.0. Clinical observations: no data.

Reading:

2nd reading

Hours after challenge:

72

Group:

other: positive control (second challenge)

Dose level:

0.1 % (W/W) alpha-hexylcinnamaldehyde in PEG 300

No. with + reactions:

0

Total no. in group:

10

Clinical observations:

no data

Remarks on result:

other: see Remark

Remarks:

Reading: 2nd reading. . Hours after challenge: 72.0. Group: other: positive control (second challenge). Dose level: 0.1 % (W/W) alpha-hexylcinnamaldehyde in PEG 300. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: no data.

Reading:

rechallenge

Hours after challenge:

72

Group:

other: positive control (second challenge)

Dose level:

1 % (W/W) alpha-hexylcinnamaldehyde in PEG 300

No. with + reactions:

4

Total no. in group:

10

Clinical observations:

no data

Remarks on result:

other: see Remark

Remarks:

Reading: rechallenge. . Hours after challenge: 72.0. Group: other: positive control (second challenge). Dose level: 1 % (W/W) alpha-hexylcinnamaldehyde in PEG 300. No with. + reactions: 4.0. Total no. in groups: 10.0. Clinical observations: no data.

Reading:

rechallenge

Hours after challenge:

72

Group:

other: positive control (second challenge)

Dose level:

0.1 % (W/W) alpha-hexylcinnamaldehyde in PEG 300

No. with + reactions:

1

Total no. in group:

10

Clinical observations:

no data

Remarks on result:

other: see Remark

Remarks:

Reading: rechallenge. . Hours after challenge: 72.0. Group: other: positive control (second challenge). Dose level: 0.1 % (W/W) alpha-hexylcinnamaldehyde in PEG 300. No with. + reactions: 1.0. Total no. in groups: 10.0. Clinical observations: no data.

No mortality, no sign of systemic toxicity and no effect on body weight were observed during the study.

Detailed results on animals are shown in the following tables:

Table 1: Control group – skin response after the challenge application of purified water (right flank)

Animal No.	Sex	REACTION AFTER REMOVAL OF BANDAGE
		24 hours	48 hours
262	female	0	0
263	female	0	0
264	female	0	0
265	female	0	0
266	female	0	0

 

Table 2: Control group – skin response after challenge application of Yttrium oxyde, 50% (w/w) in purified water (left flank)

Animal No.	Sex	REACTION AFTER REMOVAL OF BANDAGE
		24 hours	48 hours
262	female	0	0
263	female	0	0
264	female	0	0
265	female	0	0
266	female	0	0

Approximately 3 hours prior to the 24-hour reading of the challenge the test sites were depilated.

 

 

Table 3: Test group – skin response after the challenge application of purified water (right flank)

Animal No.	Sex	REACTION AFTER REMOVAL OF BANDAGE
		24 hours	48 hours
267	female	0	0
268	female	0	0
269	female	0	0
270	female	0	0
271	female	0	0
272	female	0	0
273	female	0	0
274	female	0	0
275	female	0	0
276	female	0	0

  

Table 4: Test group – skin response after challenge application of Yttrium oxyde, 50% (w/w) in purified water (left flank)

Animal No.	Sex	REACTION AFTER REMOVAL OF BANDAGE
		24 hours	48 hours
267	female	0	0
268	female	0	0
269	female	0	0
270	female	0	0
271	female	0	0
272	female	0	0
273	female	0	0
274	female	0	0
275	female	0	0
276	female	0	0

 

Approximately 3 hours prior to the 24-hour reading of the challenge the test sites were depilated.

 

Interpretation of results:

not sensitising

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Classification: not sensitizing

Executive summary:

The sensitisation potential of Yttrium oxide was evaluated on Dunkin-Hartley guinea pigs according to the maximisation method of Magnusson and Kligman, described in Directive 67/548/EEC, method B.6, and in compliance with Good Laboratory Practice.

Ten test and five control guinea pigs were included in this study. Induction was carried as the following:

- on day one, animals were injected by the intracutaneous route with Yttrium oxide (25 % w/w in purified water) +/- Freund Complete Adjuvant (treated group) or with purified water +/- Freund Complete Adjuvant (control group) or with Freund Complete Adjuvant alone (both groups);

- on day 7, the same region received a topical application of sodium lauryl sulfate (10 % w/w in paraffinum perliquidum) in order to induce local irritation;

- on day 8, a 48-hour topical occlusive application was performed with Yttrium oxide at 50 % w/w in purified water (test animals) or the vehicle (controls).

- on day 22, the control and test animals were challenged by a cutaneous application of the test substance at 50 % w/w in purified water to the left flank. The right flank served as control and received the vehicle only. The test substance and the vehicle were maintained under an occlusive dressing for 24 hours.

Skin reactions (erythema and oedema) were evaluated approximately 24 and 48 hours after removal of the dressing.

No clinical signs and no deaths related to treatment were noted during the study.

After the challenge application, at the 24-hour and 48-hour readings, no cutaneous reactions were noted.

In this study, yttrium oxyde is not a dermal sensitizer.

This skin sensitisation study is classified as acceptable. It does satisfy the guideline requirement for a skin sensitisation study (EU Method B.6) in the guinea pigs.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

The sensitisation potential of Yttrium oxide was evaluated on Dunkin-Hartley guinea pigs according to the maximisation method of Magnusson and Kligman, described in Directive 67/548/EEC, method B.6, and in compliance with Good Laboratory Practice (Klimisch 1).

Ten test and five control guinea pigs were included in this study. Induction was carried as the following:

- On day 1, animals were injected by the intracutaneous route with Yttrium oxide (25 % w/w in purified water) +/- Freund Complete Adjuvant (treated group) or with purified water +/- Freund Complete Adjuvant (control group) or with Freund Complete Adjuvant alone (both groups);

- On day 7, the same region received a topical application of sodium lauryl sulfate (10 % w/w in paraffinum perliquidum) in order to induce local irritation;

- On day 8, a 48-hour topical occlusive application was performed with Yttrium oxide at 50 % w/w in purified water (test animals) or the vehicle (controls).

- On day 22, the control and test animals were challenged by a cutaneous application of the test substance at 50 % w/w in purified water to the left flank. The right flank served as control and received the vehicle only. The test substance and the vehicle were maintained under an occlusive dressing for 24 hours.

Skin reactions (erythema and oedema) were evaluated approximately 24 and 48 hours after removal of the dressing.

No clinical signs and no deaths related to treatment were noted during the study.

After the challenge application, at the 24-hour and 48-hour readings, no cutaneous reactions were noted.

According to the results of this study, yttrium oxide is not a dermal sensitizer.

Migrated from Short description of key information:
Based on the results of the only available (and reliable) study, the test substance is not considered as skin sensitiser.

Justification for selection of skin sensitisation endpoint:
Test was performed according to the GLP and international guideline.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

In accordance with the criteria for classification as defined in Annex I, Regulation 1272/2008, the test material does not require classification for skin sensitisation.