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Diss Factsheets

Administrative data

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2008-02-11 to 2008-04-05
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2008
Report date:
2008

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.6 (Skin Sensitisation)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Type of study:
guinea pig maximisation test

Test material

Constituent 1
Chemical structure
Reference substance name:
Slags, ilmenite electrothermal smelting
EC Number:
293-671-6
EC Name:
Slags, ilmenite electrothermal smelting
Cas Number:
91081-64-0
Molecular formula:
M3O5
IUPAC Name:
Slags, ilmenite electrothermal smelting
Details on test material:
- Name of test material (as cited in study report): Titanium Slag „Exxaro Sulphate Slag“
- Substance type: technical product
- Physical state: solid, black brown granular
- Composition of test material, percentage of components: 100 % UGI
- Purity test date: 14 December 2006
- Lot/batch No.: MKT_SUL_061207_0000
- Receipt no. 38606
- Date of receipt December 19, 2007
- Expiration date of the lot/batch: December 2026
- Storage condition of test material: at room temperature
No further details are given.

In vivo test system

Test animals

Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland GmbH
- Age at study initiation: 32 days
- Weight at study initiation: 291-363 g (positive control group: 289-349 g)
- Housing: The animals were kept in pairs in MAKROLON cages (type III plus).
- Diet: Commercial diet, ssniff® Ms-H V2233 served as food. This food was offered ad libitum.
- Water: ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3
- Humidity (%): 55 +/- 15
- Photoperiod: 12 hours dark/light

No further details are given.

Study design: in vivo (non-LLNA)

Inductionopen allclose all
Route:
intradermal
Vehicle:
other: The test item was suspended in aqua ad iniectabilia (Batch nos. 30704631 and 21706) to the appropriate concentrations for all stages.
Concentration / amount:
see details on study design
Challengeopen allclose all
Route:
epicutaneous, occlusive
Vehicle:
other: The test item was suspended in aqua ad iniectabilia (Batch nos. 30704631 and 21706) to the appropriate concentrations for all stages.
Concentration / amount:
see details on study design
No. of animals per dose:
15 guinea pigs: 10 treated titanium slag exposed animals and 5 vehicle controls
8 further guine pigs for a preliminary test
Details on study design:
RANGE FINDING TESTS:
Eight animals were used for the preliminary test: 6 animals for the topical administration and 2 animals for the intracutaneous administration. The allocation of different test sites of the animals was alternated in order to minimise site-to-site variations in response. The shoulder and the flank region of the animals were shaved or shaved and depilated (approx. 5 x 5 cm). Animals, even if only slightly injured, were replaced.
(a) intracutaneous: 0.1 ml of the prepared test item was administered intracutaneously (shoulder region). Three concentrations of the test item were injected intradermally into one, 3 further concentrations into a second animal.
(b) topical: The test area of 3 animals each was shaved or depilated. 2 ml of the test preparation was spread over a filter paper (2 x 4 cm) and applied to the test area and held in contact by an occlusive dressing. Two concentrations each were applied to the shaved or shaved and depilated flanks of 3 animals each. The occlusive dressing and the filter paper containing the test item were removed after 24 or 48 hours and the application sites were assessed immediately, 24 and 48 (depilated) or immediately and 24 hours (non-depilated) after removal of the filter paper for erythema and oedema.
Six concentrations were tested by intracutaneous injection: 0.01, 0.1, 0.5, 1, 5 or 10 % suspensions.
Six concentrations were tested by topical application: 0.5, 1, 5, 10, 25 and 50% suspensions.

MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: 3 pairs of intradermal injections of 0.1 ml were given in the shoulder region which was cleared of hair so that one of each pair lay on each side of midline:
(1) Freund's complete adjuvant (Batch no. 067K8614) (diluted 1:1 with 0.9% NaCl (Batch no. 05712201)),
(2) the test item,
(3) the test item in a 1:1 mixture (v/v) FCA/aqua ad iniectabilia.
In injection 3, the final concentration of the test item was equal to that in injection 2. Injections (1) and (2) were given close to each other and nearest the head, while (3) was given towards the caudal part of the test area. 7 days after the intracutaneous injection, the shoulder region of the same animals was shaved again. A filter paper (2x4 cm) was fully-loaded with the test item and was applied to the test area and held in contact by an occlusive dressing (exposure time: 48 hours). No cleaning of the skin was necessary.
- Duration: from day 0 to day 7
- Concentrations: Stage 1: intracutaneous: 0.5% suspension of Titanium Slag „Exxaro Sulphate Slag“ in aqua ad iniectabilia and Stage 2: topical: 50% suspension of Titanium Slag „Exxaro Sulphate Slag“ in aqua ad iniectabilia

B. CHALLENGE EXPOSURE
Two weeks after the topical application (corresponds to a monitoring period of 21 days) the flanks of the same animals were shaved and depilated for a further topical application using the patch-test technique. The filter paper containing the test item was applied to the left flank, the filter paper with the vehicle to the right flank of the animal (exposure time: 24 hours). 21 hours after the filter paper had been removed no cleaning of the skin was necessary.
- Concentrations: Stage 3: topical: 50% suspension of Titanium Slag „Exxaro Sulphate Slag“ in aqua ad iniectabilia
- Evaluation: 21 hours after removing the filter paper the challenge area was cleaned and cleared of hair if necessary. 3 hours later (at 48 hours from the start of challenge application) the skin reaction was observed and recorded. 24 hours after this observation a second observation (72 hours) was made and recorded.
- Scoring system: see attached table

C. VEHICLE CONTROL (Aqua ad iniectabilia)
The vehicle control animals were treated in the same way as the animals of the test group (2), but received aqua ad iniectabilia instead of the test item.
However, in stage 3 the left flank was treated with the test item, the right flank with the vehicle i.e. in the same way as the test group (2).
Challenge controls:
no data
Positive control substance(s):
yes
Remarks:
Benzocaine

Study design: in vivo (LLNA)

Statistics:
The body weight was analysed statistically using STUDENT's t-test (p ≤ 0.01).

Results and discussion

Positive control results:
Animals of the same strain treated with benzocaine in 40% ethanolic 0.9% NaCl solution exhibited a sensitising reaction in all animals in form of a discrete or patchy erythema (grade 1).

In vivo (non-LLNA)

Resultsopen allclose all
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
vehicle control
No. with + reactions:
0
Total no. in group:
0
Clinical observations:
No clinical signs were observed.
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. Dose level: vehicle control. No with. + reactions: 0.0. Total no. in groups: 0.0. Clinical observations: No clinical signs were observed..
Reading:
1st reading
Hours after challenge:
48
Group:
negative control
Dose level:
vehicle control
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
No clinical signs were observed.
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: negative control. Dose level: vehicle control. No with. + reactions: 0.0. Total no. in groups: 5.0. Clinical observations: No clinical signs were observed..
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
vehicle control
No. with + reactions:
5
Total no. in group:
5
Clinical observations:
No clinical signs were observed.
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: vehicle control. No with. + reactions: 5.0. Total no. in groups: 5.0. Clinical observations: No clinical signs were observed..
Reading:
2nd reading
Hours after challenge:
72
Group:
negative control
Dose level:
vehicle control
No. with + reactions:
5
Total no. in group:
5
Clinical observations:
No clinical signs were observed.
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 72.0. Group: negative control. Dose level: vehicle control. No with. + reactions: 5.0. Total no. in groups: 5.0. Clinical observations: No clinical signs were observed..
Reading:
rechallenge
Hours after challenge:
48
Group:
negative control
Dose level:
vehicle control
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
No clinical signs were observed. Left side of the animal was treated with test substance, right side served as untreated control.
Remarks on result:
other: see Remark
Remarks:
Reading: rechallenge. . Hours after challenge: 48.0. Group: negative control. Dose level: vehicle control. No with. + reactions: 0.0. Total no. in groups: 5.0. Clinical observations: No clinical signs were observed. Left side of the animal was treated with test substance, right side served as untreated control..
Reading:
rechallenge
Hours after challenge:
72
Group:
negative control
Dose level:
vehicle control
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
No clinical signs were observed. Left side of the animal was treated with test substance, right side served as untreated control.
Remarks on result:
other: see Remark
Remarks:
Reading: rechallenge. . Hours after challenge: 72.0. Group: negative control. Dose level: vehicle control. No with. + reactions: 0.0. Total no. in groups: 5.0. Clinical observations: No clinical signs were observed. Left side of the animal was treated with test substance, right side served as untreated control..
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
0.5% suspension
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
No clinical signs were observed.
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 0.5% suspension. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: No clinical signs were observed. .
Reading:
1st reading
Hours after challenge:
48
Group:
test chemical
Dose level:
0.5% suspension
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
No clinical signs were observed.
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: test group. Dose level: 0.5% suspension. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: No clinical signs were observed. .
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
50% suspension
No. with + reactions:
10
Total no. in group:
10
Clinical observations:
No clinical signs were observed.
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 50% suspension. No with. + reactions: 10.0. Total no. in groups: 10.0. Clinical observations: No clinical signs were observed. .
Reading:
2nd reading
Hours after challenge:
72
Group:
test chemical
Dose level:
50% suspension
No. with + reactions:
10
Total no. in group:
10
Clinical observations:
No clinical signs were observed.
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 72.0. Group: test group. Dose level: 50% suspension. No with. + reactions: 10.0. Total no. in groups: 10.0. Clinical observations: No clinical signs were observed..
Reading:
rechallenge
Hours after challenge:
48
Group:
test chemical
Dose level:
50% suspension
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
No clinical signs were observed. Left side of the animal was treated with test substance, right side served as untreated control.
Remarks on result:
other: see Remark
Remarks:
Reading: rechallenge. . Hours after challenge: 48.0. Group: test group. Dose level: 50% suspension. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: No clinical signs were observed. Left side of the animal was treated with test substance, right side served as untreated control..
Reading:
rechallenge
Hours after challenge:
72
Group:
test chemical
Dose level:
50% suspension
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
No clinical signs were observed. Left side of the animal was treated with test substance, right side served as untreated control.
Remarks on result:
other: see Remark
Remarks:
Reading: rechallenge. . Hours after challenge: 72.0. Group: test group. Dose level: 50% suspension. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: No clinical signs were observed. Left side of the animal was treated with test substance, right side served as untreated control..
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
2% (w/v) solution
No. with + reactions:
20
Total no. in group:
20
Clinical observations:
No clinical signs were observed.
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: positive control. Dose level: 2% (w/v) solution. No with. + reactions: 20.0. Total no. in groups: 20.0. Clinical observations: No clinical signs were observed. .
Reading:
1st reading
Hours after challenge:
48
Group:
positive control
Dose level:
2% (w/v) solution
No. with + reactions:
20
Total no. in group:
20
Clinical observations:
No clinical signs were observed.
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: positive control. Dose level: 2% (w/v) solution. No with. + reactions: 20.0. Total no. in groups: 20.0. Clinical observations: No clinical signs were observed. .
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Dose level:
5% (w/v) solution
No. with + reactions:
20
Total no. in group:
20
Clinical observations:
No clinical signs were observed.
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: positive control. Dose level: 5% (w/v) solution. No with. + reactions: 20.0. Total no. in groups: 20.0. Clinical observations: No clinical signs were observed. .
Reading:
2nd reading
Hours after challenge:
72
Group:
positive control
Dose level:
5% (w/v) solution
No. with + reactions:
20
Total no. in group:
20
Clinical observations:
No clinical signs were observed.
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 72.0. Group: positive control. Dose level: 5% (w/v) solution. No with. + reactions: 20.0. Total no. in groups: 20.0. Clinical observations: No clinical signs were observed. .
Reading:
rechallenge
Hours after challenge:
48
Group:
positive control
Dose level:
5% (w/v) solution
No. with + reactions:
20
Total no. in group:
20
Clinical observations:
No clinical signs were observed. Left side of the animal was treated with test substance, right side served as untreated control.
Remarks on result:
other: see Remark
Remarks:
Reading: rechallenge. . Hours after challenge: 48.0. Group: positive control. Dose level: 5% (w/v) solution. No with. + reactions: 20.0. Total no. in groups: 20.0. Clinical observations: No clinical signs were observed. Left side of the animal was treated with test substance, right side served as untreated control..
Reading:
rechallenge
Hours after challenge:
72
Group:
positive control
Dose level:
5% (w/v) solution
No. with + reactions:
20
Total no. in group:
20
Clinical observations:
No clinical signs were observed. Left side of the animal was treated with test substance, right side served as untreated control.
Remarks on result:
other: see Remark
Remarks:
Reading: rechallenge. . Hours after challenge: 72.0. Group: positive control. Dose level: 5% (w/v) solution. No with. + reactions: 20.0. Total no. in groups: 20.0. Clinical observations: No clinical signs were observed. Left side of the animal was treated with test substance, right side served as untreated control..

Any other information on results incl. tables

The challenge with 2 mL of a 50% suspension the test item in aqua ad iniectabilia/animal revealed no skin irritation in any animal and, thus, the test item had no sensitising properties. The vehicle control revealed no skin reactions. The body weight gain of the animals treated with the test item was within the range of the vehicle control during the experiment. Behaviour of the animals remained unchanged. Given the negative response in all treated animals further testing was not

considered necessary in order to reduce animal experiments for animal welfare reasons.

Applicant's summary and conclusion

Interpretation of results:
not sensitising
Remarks:
Migrated information
Conclusions:
Under the present test conditions the test item revealed no sensitising properties in guinea pigs in a test model according to Magnusson and Kligman.