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Diss Factsheets

Administrative data

Description of key information

1. Information on zirconium dioxide (CAS# 1314-23-4)
In a traditional skin sensitisation test in guinea pigs (Hartley strain) zirconium dioxide (stabilised with yttrium oxide, a similar non-hazardous metal oxide) was observed to be not sensitising to the skin.

2. Information on erbium oxide (CAS# 12061-16-4)
Erbium oxide was considered to be a non-sensitiser under the conditions of a skin sensitisation study run in accordance with EU criteria.

3. Conclusion on erbium zirconium oxide
Based on the available data on the individual components in the 'solid solution', erbium zirconium oxide is not expected to cause sensitising effects in skin.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Referenceopen allclose all

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
Endpoint:
skin sensitisation, other
Remarks:
LLNA and GPMT
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
Read across based on the study from the Chemicals Inspection and Testing Institute (1999) with yttrium zirconium dioxide (GPMT) and a study from Henzell (2012) with dierbium trioxide (LLNA). The read across justification document is attached in IUCLID Section 13.
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Key result
Reading:
other: read across conclusion
Remarks on result:
other: Erbium zirconium oxide is not expected to cause sensitising effects in skin based on the studies from Henzell (2012) and the Chemicals Inspection and Testing Institute (1999) performed with the read across substances Er2O3 and YZrO, respectively.
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
weight of evidence
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

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 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 vivo (LLNA)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
18 September 2012 - 9 October 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
Study conducted to GLP 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.
Qualifier:
according to guideline
Guideline:
OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.42 (Skin Sensitisation: Local Lymph Node Assay)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Type of study:
mouse local lymph node assay (LLNA)
Species:
mouse
Strain:
other: CBA/Ca
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Strain: CBA/Ca (CBA/CaOlaHsd)
- Age at study initiation: 8 - 12 weeks
- Weight at study initiation: 17 - 21 g
- Housing: the animals were individually housed in suspended solid-floor polypropylene cages furnished with softwood woodflakes
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum access to mains tap water
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 25 °C
- Humidity (%): 30 - 70 %
- Air changes (per hr): approximately 15
- Photoperiod (hrs dark / hrs light): lighting was controlled by a time switch to give twelve hours continuous light (0600 to 1800) and twelve hours darkness.

IN-LIFE DATES: From: 18 September 2012 To: 9 October 2012
Vehicle:
propylene glycol
Concentration:
50, 25 and 10 % w/w
No. of animals per dose:
4 animals per group (main test)
Details on study design:
PRELIMINARY SCREENING TEST
A preliminary screening test was performed using one mouse. The mouse was treated by daily application of 25 µL at a concentration of 50 % w/w in propylene glycol, to the dorsal surface of each ear for three consecutive days (Days 1, 2, 3). The mouse was observed twice daily on Days 1, 2 and 3 and once daily on Days 4, 5 and 6. Local skin irritation was scored daily. Any clinical signs of toxicity, if present, were also recorded. The bodyweight was recorded on Day 1 (prior to dosing) and on Day 6.
The thickness of each ear was measured using an Oditest micrometer (Dyer, PA), pre-dose on Day 1, post dose on Day 3 and on Day 6. Any changes in the ear thickness were noted. Mean ear thickness changes were calculated between time periods Days 1 and 3 and Days 1 and 6. A mean ear thickness increase of equal to or greater than 25 % was considered to indicate excessive irritation and limited biological relevance to the endpoint of sensitisation.
No signs of toxicity, visual local skin irritation or irritation indicated by an equal to or greater than 25 % increase in mean ear thickness were noted. Based on this information the dose levels selected for the main test were 50, 25 and 10 % w/w in propylene glycol.

MAIN TEST
-Test Material Administration
The mice were treated by daily application of 25 µL of the appropriate concentration of the test material to the dorsal surface of each ear for three consecutive days (Days 1, 2, 3). The test material formulation was administered using an automatic micropipette and spread over the dorsal surface of the ear using the tip of the pipette.
A further group of four mice received the vehicle alone in the same manner.

-3H-Methyl Thymidine Administration
Five days following the first topical application of the test material or vehicle (Day 6) all mice were injected via the tail vein with 250 µL of phosphate buffered saline (PBS) containing 3H-methyl thymidine (3HTdR: 80 µCi/mL, specific activity 2.0 Ci/mmol) giving a total of 20 µCi to each mouse.

-Observations
Clinical Observations: All animals were observed twice daily on Days 1, 2 and 3 and on a daily basis on Days 4, 5 and 6. Any signs of toxicity or signs of ill health during the test were recorded.
Bodyweights: The bodyweight of each mouse was recorded on Day 1 (prior to dosing) and Day 6 (prior to termination).

-Terminal Procedures
Termination: Five hours following the administration of 3HTdR all mice were killed by carbon dioxide asphyxiation. The draining auricular lymph nodes from the four mice were excised and pooled for each experimental group. For each group 1 mL of PBS was added to the pooled lymph nodes.

Preparation of Single Cell Suspension: A single cell suspension of pooled lymph node cells was prepared by gentle mechanical disaggregation through a 200-mesh stainless steel gauze. The lymph node cells were rinsed through the gauze with 4 mL of PBS into a petri dish. The lymph node cell suspension was transferred to a centrifuge tube. The petri dish was washed with an additional 5 mL of PBS to remove all remaining lymph node cells and these were added to the centrifuge tube. The pooled lymph node cells were pelleted at 1400 rpm (approximately 190 x gravity) for ten minutes. The pellet was resuspended in 10 mL of PBS and re-pelleted. To precipitate out the radioactive material, the pellet was resuspended in 3 mL of 5 % trichloroacetic acid (TCA).

Determination of 3HTdR Incorporation: After approximately eighteen hours incubation at approximately 4 °C, the precipitates were recovered by centrifugation at 2100 rpm (approximately 450 x gravity) for ten minutes, resuspended in 1 mL of TCA and transferred to 10 mL of scintillation fluid (Optiphase 'Trisafe'). 3HTdR incorporation was measured by β-scintillation counting. The "Poly Q" vials containing the samples and scintillation fluid were placed in the sample changer of the scintillator and left for approximately twenty minutes. The purpose of this period of time in darkness was to reduce the risk of luminescence, which has been shown to affect the reliability of the results. After approximately twenty minutes, the vials were shaken vigorously. The number of radioactive disintegrations per minute was then measured using the Beckman LS6500 scintillation system (Beckman Instruments Inc., Fullerton, CA, USA).

INTERPRETATION OF RESULTS
The proliferation response of lymph node cells was expressed as the number of radioactive disintegrations per minute per lymph node (disintegrations per minute/node) and as the ratio of 3HTdR incorporation into lymph node cells of test nodes relative to that recorded for the control nodes (Stimulation Index).
A test material is regarded as a sensitiser if at least one concentration of the test material results in a threefold or greater increase in 3HTdR incorporation compared to control values. Any test material failing to produce a threefold or greater increase in 3HTdR incorporation is classified as a "non-sensitiser".
Positive control substance(s):
other: Phenylacetaldehyde at 2.5 % v/v in propylene glycol.
Positive control results:
The positive control was administered at 2.5 % v/v in propylene glycol and produced a stimulation index of 10.92. This corresponds to a positive result.
Therefore, the positive control was found to be a sensitiser under the conditions of the test.
Parameter:
SI
Value:
1.57
Test group / Remarks:
10 % w/w
Parameter:
SI
Value:
1.19
Test group / Remarks:
25 % w/w
Parameter:
SI
Value:
1.36
Test group / Remarks:
50 % w/w
Parameter:
other: disintegrations per minute (DPM)
Remarks on result:
other: Disintegrations per minute and disintegration per minute per node are displayed in Table 1. The highest dpm was found in the 10 % w/w group, which had a dpm of 17091.75 (dpm/Node: 2136.47)

Table 1 Disintegrations per Minute, Disintegrations per Minute/Node and Stimulation Index

Concentration (% w/w) in propylene glycol

dpm

dpm/Node*

Stimulation Index

Result

Vehicle

10884.85

1360.61

-

-

10

17091.75

2136.47

1.57

Negative

25

12956.87

1619.61

1.19

Negative

50

14789.84

1848.73

1.36

Negative

Positive Control

118861.70

14857.71

10.92

Positive

* Disintegrations per minute/node obtained by dividing the disintegrations per minute value by 8 (the total number of lymph nodes).

Clinical Observations and Mortality Data

There were no deaths. No signs of systemic toxicity were noted in the test or control animals during the study.

 

Bodyweight

Bodyweight changes of the test animals between Day 1 and Day 6 were comparable to those observed in the corresponding control group animals over the same period.

Interpretation of results:
other: Not classified according to EU criteria.
Conclusions:
The test material was considered to be a non-sensitiser under the conditions of this study in accordance with EU criteria.
Executive summary:

The potential of the test material to act as a sensitiser was investigated in accordance with the standardised guidelines OECD 429 and EU Method B.42.

The study assessed the skin sensitisation potential of the test material in female mice of the CBA/Ca strain following topical application to the dorsal surface of the ear. Three groups, each of four animals, were treated with 50 µL (25 µL per ear) of the test material as a suspension in propylene glycol at concentrations of 50, 25 and 10 % w/w. A further group of four animals was treated with propylene glycol alone. A concurrent positive control test, using a group of four animals, was performed with phenylacetaldehyde, at a concentration of 2.5 % v/v in propylene glycol.

The results for all three concentrations of the test material were negative, whilst the positive control material gave the expected result.

Therefore, the test material was considered to be a non-sensitiser under the conditions of this study in accordance with EU criteria.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

1. Information on zirconium dioxide (CAS# 1314-23-4)


One reliable (Klimisch 2) study was available for the skin sensitisation endpoint that is selected as the key study (TOSOH Corporation, 1999). The study was performed using yttrium stabilised zirconia (yttrium oxide being a similar non-hazardous metal oxide). The traditional 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


Zirconium dioxide was found to be not sensitising to the skin at level up to 25% whilst the positive control substance, DNCB, was found to have an extreme skin sensitising potential.


2. Information on erbium oxide (CAS# 12061-16-4)


One reliable (Klimisch 1) study was available for the skin sensitisation endpoint and selected as the key study (Henzell, 2013).


The study was run in accordance with the standardised guidelines OECD 429 and EU Method B.42.


The study assessed the skin sensitisation potential of the test material in female mice of the CBA/Ca strain following topical application to the dorsal surface of the ear. Three groups, each of four animals, were treated with 50 µL (25 µL per ear) of the test material as a suspension in propylene glycol at concentrations of 50, 25 and 10 % w/w. A further group of four animals was treated with propylene glycol alone. A concurrent positive control test, using a group of four animals, was performed with phenylacetaldehyde, at a concentration of 2.5 % v/v in propylene glycol.


The results for all three concentrations of the test material were negative, whilst the positive control material gave the expected result.


Therefore, erbium oxide was considered to be a non-sensitiser under the conditions of this study in accordance with EU criteria.


 


3. Conclusion on erbium zirconium oxide


Based on the available data on the individual components in the 'solid solution', erbium 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

1. Information on zirconium dioxide (CAS# 1314-23-4)

Based on the test results 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 for this endpoint.

2. Information on erbium oxide (CAS# 12061-16-4)

Based on the test results and according to the criteria of the CLP Regulation, erbium oxide 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 for this endpoint.

3. Conclusion on erbium zirconium oxide

Based on the classification of the individual components in the 'solid solution', it can be concluded that there is no need to classify erbium zirconium oxide for skin sensitising effects.

Due to the absence of data on respiratory sensitisation, no conclusion can be drawn on the classification for this endpoint.