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Toxicological information

Skin sensitisation

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Administrative data

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Study period:
02-NOV-2005 to 31-JAN-2006
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study was performed according to the EU guideline B.6 and in compliance with GLP. However, as the data are used in a read-across approach, the maximal reliability score was decreased from 1 to 2, according to Practical Guide n°6.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2006
Report date:
2006

Materials and methods

Test guideline
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

Test material

Constituent 1
Reference substance name:
Dicerium tricarbonate
EC Number:
208-655-6
EC Name:
Dicerium tricarbonate
Cas Number:
537-01-9
IUPAC Name:
dicerium tricarbonate
Test material form:
solid - liquid: suspension
Remarks:
migrated information: dispersion

In vivo test system

Test animals

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: 5-6 weeks
- Weight at study initiation: 316-382 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: 13 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 02-NOV-2005 To 09-DEC-2005

Study design: in vivo (non-LLNA)

Inductionopen allclose all
Route:
intradermal and epicutaneous
Vehicle:
water
Concentration / amount:
1st application: Induction 25% intracutaneous
2nd application: Induction 50% occlusive epicutaneous
3rd application: Challenge 25% occlusive epicutaneous
Challengeopen allclose all
Route:
epicutaneous, occlusive
Vehicle:
water
Concentration / amount:
1st application: Induction 25% intracutaneous
2nd application: Induction 50% occlusive epicutaneous
3rd application: Challenge 25% occlusive epicutaneous
No. of animals per dose:
1 (intradermal pre-test), 2 (epidermal pre-test), 5 (control group), 10 (test group)
Details on study design:
* RANGE FINDING TESTS:
>>> INTRADERMAL INJECTION:
4 intradermal injections of a 1:1 (v/v) mixture of Freund's Complete Adjuvant/physiological saline were made into the shaved neck of one guinea pig. Six days later intradermal injections were made into the clipped flank of the same guinea pig at concentrations of B = 25% and C = 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 A = 50% (w/w) into the intra-cellular space.
Dermal reactions were assessed 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 APPLICATION:
4 intradermal injections of a 1:1 (v/v) mixture of Freund's Complete Adjuvant/physiological saline were made into the shaved neck of two guinea pigs. 4 patches of filter paper were saturated with the test item at D = 50% (technically the highest possible concentration to be applied sufficiently), E = 25%, F = 15% and G = 10% (w/w) in purified water and applied to the clipped and shaved flanks. The dressings were removed after an exposure period of 24 hours.
Approximately 21 hours after removal of the dressing the application site was depilated.
Approximately 3 hours later (48 hours from the epidermal application) the skin reaction was observed and recorded. After this observation a second observation (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 % and 25 % (w/w), respectively.

* MAIN STUDY:
A. INDUCTION EXPOSURE
- No. of exposures: 2
- Exposure period: On D1 and D8
- Site: Dorsal skin of the scapular region
- Concentrations: 25% (intradermal), 50% (epidermal)

> INTRADERMAL INJECTION / DAY 1
3 pairs of intradermal injections (0.1 mL/site) were made at the border of a 4 x 6 cm area in the clipped region as follows:
1) 1:1 (v/v) mixture of Freund's Complete Adjuvant and physiological saline (test and control groups).
2) The test item at 25% (w/w) in purified water, or purified water alone for control group.
3) The test item at 25% (w/w) in a 1:1 (v/v) mixture of Freund's Complete Adjuvant and physiological saline, or 1:1 (w/w) mixture of purified water in a 1:1 (v/v) mixture of Freund's Complete Adjuvant and physiological saline for control group.

> EPIDERMAL APPLICATIONS / DAY 8
On test day 8, a 2 x 4 cm patch of filter paper was saturated with the test item at 50% (w/w) in purified water (0.3 mL) and placed over the injection sites of the test animals. The control group was treated as described above with purified water only. The patch was covered with aluminum foil and firmly secured by an elastic plaster wrapped around the trunk of the animal and secured with impervious adhesive tape. The occlusive dressings were left in place for 48 hours.

B. CHALLENGE EXPOSURE
- No. of exposures: 1
- Day(s) of challenge: Day 22
- Exposure period: 24 hours
- Test groups and control: 2 patches (3 x 3 cm) of filter paper were saturated with the test item at the highest tested non-irritating concentration of 25% (w/w) and the vehicle only (volume: 0.2 mL).
- Site: Left flank (test item), right flank (control).
- Concentrations: 25%
- Evaluation: 48 and 72 hours after challenge
Positive control substance(s):
yes
Remarks:
hexyl cinnamic aldehyde (CAS No 101-86-0)

Results and discussion

Positive control results:
Hexyl cinnamic aldehyde was test 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 another report (joined in appendix), as regularly control.

In vivo (non-LLNA)

Resultsopen allclose all
Reading:
1st reading
Hours after challenge:
48
Group:
test chemical
Dose level:
25% 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: 25% 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:
test chemical
Dose level:
0 (vehicle alone)
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: 0 (vehicle alone). No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: none.
Reading:
1st reading
Hours after challenge:
48
Group:
negative control
Dose level:
25% 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: 25% 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:
negative control
Dose level:
0 (vehicle alone)
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: 0 (vehicle alone). No with. + reactions: 0.0. Total no. in groups: 5.0. Clinical observations: none.
Reading:
1st reading
Hours after challenge:
48
Group:
positive control
Dose level:
1% alpha-hexylcinnamaldehyde (w/w) in PEG300
No. with + reactions:
4
Total no. in group:
10
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: positive control. Dose level: 1% alpha-hexylcinnamaldehyde (w/w) in PEG300. No with. + reactions: 4.0. Total no. in groups: 10.0.
Reading:
1st reading
Hours after challenge:
48
Group:
positive control
Dose level:
0.1% alpha-hexylcinnamaldehyde (w/w) in PEG300
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: positive control. Dose level: 0.1% alpha-hexylcinnamaldehyde (w/w) in PEG300. No with. + reactions: 0.0. Total no. in groups: 10.0.
Reading:
1st reading
Hours after challenge:
48
Group:
positive control
Dose level:
0 (vehicle only)
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: positive control. Dose level: 0 (vehicle only). No with. + reactions: 0.0. Total no. in groups: 10.0.
Reading:
2nd reading
Hours after challenge:
72
Group:
test chemical
Dose level:
25% w/w/ 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: 25% w/w/ purified water. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: none.
Reading:
2nd reading
Hours after challenge:
72
Group:
test chemical
Dose level:
0 (vehicle control)
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: 0 (vehicle control). No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: none.
Reading:
2nd reading
Hours after challenge:
72
Group:
negative control
Dose level:
25% w/w 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: 25% w/w purified water. No with. + reactions: 0.0. Total no. in groups: 5.0. Clinical observations: none.
Reading:
2nd reading
Hours after challenge:
72
Group:
negative control
Dose level:
0 (vehicle only)
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: 0 (vehicle only). No with. + reactions: 0.0. Total no. in groups: 5.0. Clinical observations: none.
Reading:
2nd reading
Hours after challenge:
72
Group:
positive control
Dose level:
1% alpha-hexylcinnamaldehyde (w/w) in PEG300
No. with + reactions:
1
Total no. in group:
10
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 72.0. Group: positive control. Dose level: 1% alpha-hexylcinnamaldehyde (w/w) in PEG300. No with. + reactions: 1.0. Total no. in groups: 10.0.
Reading:
2nd reading
Hours after challenge:
72
Group:
positive control
Dose level:
0.1% alpha-hexylcinnamaldehyde (w/w) in PEG300
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 72.0. Group: positive control. Dose level: 0.1% alpha-hexylcinnamaldehyde (w/w) in PEG300. No with. + reactions: 0.0. Total no. in groups: 10.0.
Reading:
2nd reading
Hours after challenge:
72
Group:
positive control
Dose level:
0 (vehicle only)
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 72.0. Group: positive control. Dose level: 0 (vehicle only). No with. + reactions: 0.0. Total no. in groups: 10.0.
Reading:
rechallenge
Hours after challenge:
48
Group:
positive control
Dose level:
1% alpha-hexylcinnamaldehyde (w/w) in PEG300
No. with + reactions:
7
Total no. in group:
10
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 48.0. Group: positive control. Dose level: 1% alpha-hexylcinnamaldehyde (w/w) in PEG300. No with. + reactions: 7.0. Total no. in groups: 10.0.
Reading:
rechallenge
Hours after challenge:
48
Group:
positive control
Dose level:
0.1% alpha-hexylcinnamaldehyde (w/w) in PEG300
No. with + reactions:
4
Total no. in group:
10
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 48.0. Group: positive control. Dose level: 0.1% alpha-hexylcinnamaldehyde (w/w) in PEG300. No with. + reactions: 4.0. Total no. in groups: 10.0.
Reading:
rechallenge
Hours after challenge:
72
Group:
positive control
Dose level:
1% alpha-hexylcinnamaldehyde (w/w) in PEG300
No. with + reactions:
4
Total no. in group:
10
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 72.0. Group: positive control. Dose level: 1% alpha-hexylcinnamaldehyde (w/w) in PEG300. No with. + reactions: 4.0. Total no. in groups: 10.0.
Reading:
rechallenge
Hours after challenge:
72
Group:
positive control
Dose level:
0.1% alpha-hexylcinnamaldehyde (w/w) in PEG300
No. with + reactions:
1
Total no. in group:
10
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 72.0. Group: positive control. Dose level: 0.1% alpha-hexylcinnamaldehyde (w/w) in PEG300. No with. + reactions: 1.0. Total no. in groups: 10.0.

Applicant's summary and conclusion

Interpretation of results:
not sensitising
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Dicerium tricarbonate is not classified as skin sensitising according to Annex VI of the Directive 67/548/EEC.
Executive summary:

The test of skin sensitisation in guinea pigs was performed according to OECD guideline No. 406, Directive 67/548/EEC, Annex V, test method B.6 and in compliance with Good Laboratory Practices.

 

Fifteen female Dukin/Hartley guinea-pigs were included in this study. Ten animals were used for the test article and 5 for the control, respectively. Induction was carried out in 2 phases:

- Phase 1: Day 1, animals were injected by the intradermal route with dicerium tricarbonate (25 % w/w in purified water) ± Freund Complete Adjuvant or with the vehicle;

- Phase 2: 48-hour topical occlusive application was performed Day 8 with dicerium tricarbonate at 25 % w/w in purified water or the vehicle.

The control and test animals were challenged topically 2 weeks after the topical induction application with dicerium tricarbonate at 25 % w/w in purified water for 24 hours. The challenge sites were evaluated 24 and 48 hours after removal of the patches. The reaction was graded for erythema and oedema according to a numerical scale.

 

No clinical signs and no deaths, related to treatment, were noted during the study. No cutaneous reactions were observed after challenge application.

 

From the results obtained, dicerium tricarbonate is not classified as skin sensitizer according to Annex VI of the Directive 67/548/EEC.