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Skin sensitisation

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Administrative data

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
2002-07-22 to 2002-11-14
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
Well documented, scientifically sound study that was conducted in accordance to GLP, OECD guideline 406 and Directive 96/54/EC, B.6, "Skin Sensitisation."
Justification for type of information:
REPORTING FORMAT FOR THE CATEGORY APPROACH
1. HYPOTHESIS FOR THE ANALOGUE APPROACH: The hypothesis is that properties are likely to be similar or follow a similar pattern because of the presence of a common metal ion, in this case tungstate.
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES):
Source: Tungsten Trioxide
Target: Tungsten Dioxide
3. CATEGORY APPROACH JUSTIFICATION: See Annex 1 in CSR
4. DATA MATRIX: See Annex 1 in CSR
Cross-referenceopen allclose all
Reason / purpose:
reference to other study
Reason / purpose:
read-across: supporting information

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2002
Report Date:
2002

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Qualifier:
according to
Guideline:
EU Method B.6 (Skin Sensitisation)
GLP compliance:
yes
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
A 2002 guinea pig sensitisation study was available of good quality. Therefore, there is no need to conduct a LLNA study as the guinea pig sensitisation study scientifically fulfills the endpoint. The OECD 406 method provides sensitisation information likely to arise from exposure to test substance via intradermical injection and/or epidermical application to guinea pigs. The guinea pig sensitisation test detects chemicals with moderate to strong sensitisation potential, as well as those with relatively weak sensitisation potential. In such methods activity is measured as a function of challenge-induced dermal hypersensitivity reactions elicited in test animals compared with controls. In addition, guinea pigs have been the animal of choice for predictive sensitisation tests for several decades (way before the LLNA became the test of choice).
The existing guinea pig data submitted here is of good quality as clear results are presented in this robust summary and test methodology followed OECD 406 guidelines, and conducted under GLP. This study it is considered acceptable according to page 266 in ECHA's Chapter r7a on Guidance on Information Requirements and Chemical Safety Assessment.

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Tungsten Oxide (WO3)
- Supplier: Sponsor
- Physical state: Yellow to greenish powder
- Analytical purity: 99.88%
- Purity test date: 2002-05-28
- Stability under test conditions: 5 years
- Storage condition of test material: Room temperature
- Solubility in water: < 10 mg/L at 20 degrees C
- pH: 6.1 (aqueous solution)
- Melting point: Appox. 1473 degrees C

In vivo test system

Test animals

Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Winkelmann, Gartenstrasse 27, D-33178 Borchen
- Age at study initiation: Approximately 5-7 weeks
- Weight at study initiation: 316-404 g
- Housing: Until day 0- housed singly in Makrolon cages type III; From day 0- group caging in plastic containers (6 control or 11 test substance animals per container)
- Diet (e.g. ad libitum): Altromin Maintenance Diet No. 3122- ad libitum
- Water (e.g. ad libitum): Tap water offered in Makrolon bottles with stainless steel canules- ad libitum
- Acclimation period: 4 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Average 22.0 (step one), Average 21.9 (step two)
- Humidity(%): Average 59.9% (step one), Average 56.4% (step two)
- Air changes (per hr): 12/hr
- Photoperiod (hrs dark / hrs light): 12 dark/12 light (6 am to 6 pm)

Study design: in vivo (non-LLNA)

Induction
Route:
intradermal and epicutaneous
Vehicle:
petrolatum
Concentration / amount:
50% (w/w)
Challenge
Route:
epicutaneous, occlusive
Vehicle:
petrolatum
Concentration / amount:
50% (w/w)
No. of animals per dose:
2 x 10 animals for the substance group
2 x 5 animals for the control group
Details on study design:
RANGE FINDING TESTS: Preliminary test with 2 female guinea pigs. FCA was administered intradermally and immediately after, the test substance was administered (50% in white petrolatum, w/w) epicutaneously to the sites of the intradermal injections to examine possible systemic effects. 7 days later 4 concentrations of the test substance were administered epicutaneously for 24 hours.

MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: 2
- Exposure period: 24 hours (exposure 1), 48 hours (exposure 2)
- Test groups: 2 groups both dosed at 50% w/w
- Control group: Dosed with white petrolatum only
- Site: Shaved, 2 cm x 4 cm filter papers with test substance applied and fixed with non-irritating tape (interscapular region)
- Frequency of applications: Day 0 and day 8
- Duration: 25 days
- Concentrations: 50% w/w or 0% w/w

B. CHALLENGE EXPOSURE
- No. of exposures: 1
- Day(s) of challenge: day 22
- Exposure period: 24 hours
- Test groups: 2 groups both dosed at 50% w/w
- Control group: dosed with white petrolatum only
- Site: Shaved, 2 cm x 2 cm filter papers with test substance applied and fixed with non-irritating tape to the left flanks and vehicle to the right flanks.
- Concentrations:50% w/w
- Evaluation (hr after challenge): 3 hours after end of challenge exposure

OTHER: Intradermal injections of FCA were administered directly before epicutaneous exposures. Also, before the second induction exposure, the animals were pretreated with n-dodecylsulfate, sodium salt (10% in white petrolatum, w/w).

Positive Control: Concentrations of HCA
10 females for the positive control substance group and 5 females for the negative control group.
70% in acetone (v/v) for the 1st epicutaneous induction
70% in acetone (v/v) for the 2nd epicutaneous induction
20% in acetone (v/v) for the challenge exposure
Challenge controls:
Blind reading of test and control animals. All animals administered 50% in white petrolatum, w/w epicutaneously.
Positive control substance(s):
yes
Remarks:
hexyl cinnamic aldehyde (HCA)

Results and discussion

Positive control results:
7/10 animals (70%) represented also the net rate of animals sensitised by HCA.

In vivo (non-LLNA)

Resultsopen allclose all
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test group
Dose level:
50 % w/w
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
No positive skin reaction in any animal at any reading time
Remarks on result:
no indication of skin sensitisation
Remarks:
Reading: 1st reading. . Hours after challenge: 24. Group: test group. Dose level: 50 % w/w. No with. + reactions: 0.0. Total no. in groups: 20.0. Clinical observations: No positive skin reaction in any animal at any reading time .
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test group
Dose level:
50% w/w
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
No positive skin reaction in any animal at any reading time
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
Vehicle
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
No positive skin reaction in any animal at any reading time
Remarks on result:
no indication of skin sensitisation
Remarks:
Hours after challenge: 24 Group: negative control. Dose level: 0 % w/w. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: No positive skin reaction in any animal at any reading time.
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
Vehicle
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
No positive skin reaction in any animal at any reading time
Remarks on result:
no indication of skin sensitisation
Remarks:
Hours after challenge: 48 Group: negative control. Dose level: 0 % w/w. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: No positive skin reaction in any animal at any reading time.
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
70% in actone
No. with + reactions:
7
Total no. in group:
10
Clinical observations:
Very slight to severe erythema and/or oedema in 7/10 animals 24 and/or 48 hours after challenge exposure
Remarks on result:
positive indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Dose level:
70% HCA for induction and 20% HCA for challenge
No. with + reactions:
7
Total no. in group:
10
Clinical observations:
Very slight to severe erythema and/or oedema in 7/10 animals 24 and/or 48 hours after challenge exposure
Remarks on result:
positive indication of skin sensitisation

Any other information on results incl. tables

Mortality

All animals survived till the end of the study.

Body weight

- Step 1: There were no significant differences in the mean body weights between the animals of the test substance group and those of the control group on Days 0 and 25.

- Step 2: There were no significant differences in the mean body weights between the test substance group and the control group on Day 0. On Day 25 the mean body weight of the test substance group animals was slightly, but statistically, higher than that of the control animals. This was of no biological significance and was regarded as a random event.

General observations

Immediately after the beginning of all epicutaneous exposures (inductions, challenge) the motor activities of all animals were increased. This is due to the dressings which restrict the freedom of movement. Soon afterwards the behaviour was regular again. Except of the observations described above no abnormal behaviour or clinical signs were detected during the experiment in the animals.

Skin reactions after the intradermal FCA administration

Cranial and caudal injection sites: Local irritations were observed in all animals beginning on the day after the injections. The irritations started with local erythema, which became more severe and led to ulcerations. Lesions did not heal until the end of the study. These local alterations are known effects of Freund's adjuvant.

Skin reactions after the first and the second induction exposure

All animals of both groups had severe erythema and oedema in the interscapula region which were attributed to the effects of the adjuvant.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
None of the animals in the test substance group were regarded as sensitised.
Executive summary:

No skin sensitisation data of sufficient quality are available for tungsten dioxide (target substance).  However, skin sensitiationtoxicity data are available for tungsten trioxide (source substance), which will be used for read across. Due to similar water solubility, in vitro bioaccessibility in synthetic alveolar, lysosomal, and interstitial fluids simulating inhalation exposure, and available toxicity data for the target and source substances, the resulting toxicity potential would also be expected to be similar, so read-across is appropriate between these substances. In addition, read-across is appropriate for this endpoint because the classification and labeling is the same for the source and target substances, the PBT/vPvB profile is the same, and the dose descriptors are, or are expected to be, sufficiently similar. For more details, refer to the read-across category approach included in the Category section of this IUCLID submission and/or as an Annex in the CSR.