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Diss Factsheets

Toxicological information

Skin sensitisation

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Administrative data

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study with GLP.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2003
Report date:
2003

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
EU Method B.6 (Skin Sensitisation)
Deviations:
yes
Remarks:
. modification according to Maurer and Hess
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Deviations:
yes
Remarks:
. modification according to Maurer and Hess
Principles of method if other than guideline:
The maximisation test of B. Magnusson and A. M. Kligman modified according to Maurer & Hess was performed [Th. Maurer and R. Hess (1989): The maximization test for skin sensitization potential-updating the standard protocol and validation of a modified protocol. Fd Chem. Toxic. Vol. 27, No. 12, p. 807-811].
The use of the maximisation test of B. Magnusson and A. M. Kligman modified according to Maurer & Hess is justified because the test substance is poorly soluble in the solvents, commonly used in the original GPMT.
GLP compliance:
yes
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
The LLNA-method was not available at the time of initiation the study.

Test material

Constituent 1
Chemical structure
Reference substance name:
-
EC Number:
457-660-1
EC Name:
-
Cas Number:
104797-47-9
Molecular formula:
C14H10N4O3S3 (Hill formula) C14H10N4O3S3 (CAS Formula)
IUPAC Name:
(Z)-[1-(2-amino-1,3-thiazol-4-yl)-2-(1,3-benzothiazol-2-ylsulfanyl)-2-oxoethylidene]amino acetate
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Details on test material:
Name: T15-AE
Chemical name: syn-2-(2-Aminothiazol-4-yl)-2-(methylcarbonyloximino) aceticacid-mercaptobenzthiazolylester.
Supplier: Sponsor.
Batch No.: PBi 5/184.
Molecular formula: C14 H10 N4 O3 S3.
Appearance: Yellow powder.
Purity: 96.8 % (HPLC)
Conditions of storage: In the deep freezer, in the dark; may be used under light.
Stability at conditions of storage: 12 months.
Stability at room temperature: Ca. 2 weeks.
Expiry date: October 2003
pH: 8.1 of a 1 % suspension in water.

In vivo test system

Test animals

Species:
guinea pig
Strain:
Hartley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Winkelmann, 33178 Borchen, Germany
- Age: Approx. 5 - 7 weeks at the first application
- Weight at the first application: 343 - 396 g.

- Housing: Group caging in plastic containers (48 cm x 105 cm x 36 cm), partly shaded, 6 (control group) or 11 (test substance group) animals per container.
- Diet (e.g. ad libitum): Altromin No. 3122, ad libitum.
- Water (e.g. ad libitum): Tap water offered in Makrolon bottles with stainless steel canules ad libitum.
- Acclimation period: 5 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Mean of 22.0.
- Humidity (%): Mean of 45.8.
- Air changes (per hr): Approx. 12/h
- Photoperiod (hrs dark / hrs light): Only artificial light from 6.00 a.m. to 6.00 p.m.

Study design: in vivo (non-LLNA)

Induction
Route:
intradermal and epicutaneous
Vehicle:
petrolatum
Concentration / amount:
50 % in white petrolatum for induction, based on preliminary experiments. 50 % test substance preparation was the highest technically feasible concentration and produced slight irritations.
25 % in white petrolatum for challenge.
Prepared immediately before administration.
Challenge
Route:
epicutaneous, occlusive
Vehicle:
petrolatum
Concentration / amount:
50 % in white petrolatum for induction, based on preliminary experiments. 50 % test substance preparation was the highest technically feasible concentration and produced slight irritations.
25 % in white petrolatum for challenge.
Prepared immediately before administration.
No. of animals per dose:
5 control and 10 test substance animals were used.
Details on study design:
Intradermal FCA-administration: The application site for all injections was an area of about 2 cm x 4 cm in the interscapular region. In two injection rows two intradermal injections were made side by side. A volume of 0.1 ml was applied for each injection site.

Induction exposures:
The test substance was incorporated in white petrolatum. Filter papers, about 2 cm x 4 cm, covered with the test substance formulation (test substance group) or with white petrolatum (control group), respectively, were applied to the area of the intradermal FCA-injections. They were fixed with a strip of non-irritating tape. The area of administration was then covered occlusively with aluminium foil and finally fixed with a self adhesive hypoallergenic non woven fabric.
Induction exposure on Day 0:
About 0.5 g of test substance formulation or about 0.4 of white petrolatum were applied to each animal. The exposure time was 24 hours.
Induction exposure on Day 7:
About 0.5 g of test substance formulation or of white petrolatum were applied to each animal. The exposure time was 48 hours.

Challenge exposure on Day 20:
The test substance was incorporated in white petrolatum. Filter papers, about 2 cm x 2 cm, covered with the test substance formulation, were applied to the left flanks of all animals of both groups. Filter papers of the same size, covered with white petrolatum, were applied to the right flanks of all animals. Mode of fixation was the same as for the epicutaneous induction exposures. About 0.6 g of test substance formulation or of white petrolatum were applied to each animal. The exposure time was 24 hours.
Challenge controls:
The challenge exposure consisted of two separate epicutaneous applications, identically given to test substance and negative control group animals.
Positive control substance(s):
yes
Remarks:
hexyl cinnamic aldehyde, periodically

Results and discussion

Positive control results:
At the last check made, the net rate of animals with a positive skin reaction, regarded as sensitised by hexyl cinnamic aldehyde was 70 %.

In vivo (non-LLNA)

Resultsopen allclose all
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
0
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
no
Remarks on result:
no indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
0
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
no
Remarks on result:
no indication of skin sensitisation
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
25 %
No. with + reactions:
9
Total no. in group:
10
Clinical observations:
no
Remarks on result:
no indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
25 %
No. with + reactions:
8
Total no. in group:
10
Clinical observations:
no
Remarks on result:
no indication of skin sensitisation
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
0
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
no
Remarks on result:
other: negative group to the positive group
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
0
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
no
Remarks on result:
other: negative group to positive group
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
20
No. with + reactions:
7
Total no. in group:
10
Clinical observations:
very slight to severe erythema and/or oedema
Remarks on result:
positive indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Dose level:
20
No. with + reactions:
7
Total no. in group:
10
Clinical observations:
very slight to severe erythema and/or oedema
Remarks on result:
positive indication of skin sensitisation

Any other information on results incl. tables

All animals survived till the end of the study.

No relevant effects of the test substance on body weights was derived from the data.

Immediately after the beginning of all epicutaneous exposures (inductions, challenge) the motor activities of all animals were decreased. This is due to the dressings which restrict the freedom of movement. No other 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 interscapular region (score "3"), which were attributed to the effects of the adjuvant.

Skin reactions after the challenge exposure

Negative control group

Vehicle site: No positive skin reaction in any animal at any reading time.

Test substance site: No positive skin reaction in any animal at any reading time.

Test substance group:

Vehicle site: No positive skin reaction in any animal at any reading time.

Test substance site: 9/10 animals (90 %) had very slight to severe erythema and/or oedema 24 and/or 48 hours after the end of the challenge exposure.

Applicant's summary and conclusion

Interpretation of results:
sensitising
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The substance is considered to be a skin sensitizer.
Executive summary:

The "maximisation test" of B. Magnusson and A. M. Kligman modified according to Maurer & Hess was performed to reveal a possible sensitising potential of the test substance. Methods of the EC-directive 96/54, B.6. and the OECD-guideline 406 were applied. A test substance group with 10 female guinea pigs and a negative control group with 5 female guinea pigs were used. The administered test substance concentrations were derived from the results of a preliminary test.

Two induction exposures were performed with a one week interval. First induction exposure: Intracutaneous injection of Freund´s complete adjuvant and epicutaneous administration of the test substance (50 % in white petrolatum). Second induction exposure: Epicutaneous administration of the test substance (50 % in white petrolatum). Control animals were given plain white petrolatum at both inductions.

Challenge exposure: Two weeks after the second induction exposure. Epicutaneous administration of the test substance (25 % in white petrolatum) and the vehicle (white petrolatum), was identical for the test substance group and the negative control group. For the epicutaneous exposures occlusive dressings were used.

Results of the challenge exposure: The control sites of all animals of both groups were normal at each reading time. After the challenge exposures, 9/10 animals of the test substance group had positive skin reactions at the test substance treated sites. No adverse skin reactions were observed in the control animals. The substance is considered to be a skin sensitizer.