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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
Study period:
1999-09-13 to 1999-11-05
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP and guideline compliant study.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2000
Report date:
2000

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Version / remarks:
(1992)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.6 (Skin Sensitisation)
Version / remarks:
(1996)
Deviations:
no
GLP compliance:
yes
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
in vivo skin sensitisation study with gunea pig was already available.

Test material

Constituent 1
Chemical structure
Reference substance name:
3-(amidinothio)propionic acid
EC Number:
226-430-0
EC Name:
3-(amidinothio)propionic acid
Cas Number:
5398-29-8
Molecular formula:
C4H8N2O2S
IUPAC Name:
3-(carbamimidoylsulfanyl)propanoic acid
Details on test material:
- Substance type: organic
- Physical state: white powder
- Purity: as specified in section 1.1 and 1.2
- Storage condition of test material: at room temperature

In vivo test system

Test animals

Species:
guinea pig
Strain:
other: Hsd Poc: DH (SPF)
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Winkelmann GmbH, Borchen, Germany
- Age at study initiation: young adult
- Weight at study initiation: 341 - 400 g
- Housing: in groups of 5 animals (stainless steel wire mesh cages with plastic-coated grating, floor area: 3000 cm²)
- Diet: ad libitum, standard laboratory diet (Provimi Kliba SA, Kaiseraugst, Switzerland)
- Water: ad libitum, tap water
- Acclimation period: 6 days before the beginning of the study in the laboratory for dermal toxicity

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 - 25
- Humidity (%): 30 - 70
- Photoperiod (hrs dark / hrs light): 12-12

Study design: in vivo (non-LLNA)

Inductionopen allclose all
Route:
intradermal and epicutaneous
Vehicle:
other: Tylose CB 30.000 in water
Concentration / amount:
Intradermal induction: 5 %
Epicutaneous induction: 25 %
Challenge: 10 %
Challengeopen allclose all
Route:
epicutaneous, occlusive
Vehicle:
other: Tylose CB 30.000 in water
Concentration / amount:
Intradermal induction: 5 %
Epicutaneous induction: 25 %
Challenge: 10 %
No. of animals per dose:
5 per control group; 10 per test group
Details on study design:
RANGE FINDING TESTS: Intradermal and epicutaneous range finding study
Two 24-hour epicutaneous occlusive applications within 96 hours were performed. The minimum irritant concentration was found to be a 25 % test substance preparation in 1 % Tylose CB 30.000 in aqua bidest. The maximum non-irritant concentration was found to be a 10 % test substance preparation in 1 % Tylose CB 30.000 in aqua bidest.
Applicability: It was possible to inject a 5 % test substance preparation in 1 % Tylose CB 30.000 in aqua bidest. or in Freund's adjuvant /0.9 % aqueous NaCl-solution (1 : 1) with a syringe. The concentration was well-tolerated locally and systemically.

MAIN STUDY
A. INDUCTION EXPOSURE (INTRADERMAL)
- No. of exposures: 6
- Test groups: 3 different injections were given
A) front row: 2 injections each of 0.1 mL Freund's adjuvant without test substance emulsified with 0.9 % aqueous NaCl-solution in a ratio of 1: 1
B) middle row: 2 injections each of 0.1 mL of a test substance formulation in an appropriate vehicle at the selected concentration
C) back row: 2 injections each of 0.1 mL Freund's adjuvant /0.9 % aqueous NaCl-solution (1: 1) with test substance at the selected concentration.
- Control group: 3 different injections were given
A) front row: 2 injections each of 0.1 mL Freund's adjuvant without test substance emulsified with 0.9 % aqueous NaCl-solution in a ratio of 1: 1
B) middle row: 2 injections each of 0.1 mL of the undiluted vehicle
C) back row: 2 injections each of 0.1 mL of a 50 % formulation of the vehicle without test substance emulsified with Freund's adjuvant* /0.9 % aqueous NaCl-solution (1:1)
- Site: Shoulder
- Frequency of applications: once
- Duration: 7 days
- Concentrations: 5 % of test substance in 1 % Tylose CB 30.000 in aqua bidest.

B. INDUCTION EXPOSURE (EPICUTANEOUS)
- No. of exposures: 1
- Exposure period: 48 hours
- Test groups: 1 mL of test substance formulation on gauze patches under an occlusive dressing
- Control group: treated analogously but with vehicle only
- Site: Shoulder
- Frequency of applications: once
- Duration: 14 days
- Concentrations: 25 %


C. CHALLENGE EXPOSURE
- No. of exposures: 3
- Day(s) of challenge: 14, 21 and 43 days after epicutaneous application
- Exposure period: 24 hours
- Test groups: 0.5 mL of test substance formulation on gauze patches under an occlusive dressing

1st challenge
The test group and control group 1 were treated with the test substance formulation. Additionally, 1 % Tylose in aqua bidest. was applied as a vehicle control. Control group 2 only received 1 % Tylose in aqua bidest.

2nd and 2rd challenge
Treatment of the test group and of control groups 1 and 2 with the test substance formulation. Analogous to the 1st challenge 1 % Tylose CB 30.000 in aqua bidest. was applied as a vehicle control.

- Site: left and right flank
- Concentrations: 10 %
- Evaluation (hr after challenge): 24 and 48 hours after removal of the patch.
Positive control substance(s):
no
Remarks:
A positive control (reliability check) with a known sensitizer is not included in this study. However, a separate study is performed twice a year in the laboratory to demonstrate sensitivity of the test system.

Results and discussion

Positive control results:
The positive controls with 2-Mercaptobenzothiazole and Formaldehyde solution (min. 36.5 % for Analysis Reag. ACS, stabilised by ca. 10 % methanol) showed that the test system was able to detect sensitizing compounds under the laboratory conditions chosen.

In vivo (non-LLNA)

Resultsopen allclose all
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
10 %
No. with + reactions:
8
Total no. in group:
10
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 10 %. No with. + reactions: 8.0. Total no. in groups: 10.0.
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
10 %
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. Dose level: 10 %. No with. + reactions: 0.0. Total no. in groups: 5.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
10 %
No. with + reactions:
8
Total no. in group:
10
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 10 %. No with. + reactions: 8.0. Total no. in groups: 10.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
10 %
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 10 %. No with. + reactions: 0.0. Total no. in groups: 5.0.
Reading:
other: 1st rechallenge
Hours after challenge:
24
Group:
test chemical
Dose level:
10 %
No. with + reactions:
8
Total no. in group:
10
Remarks on result:
other: Reading: other: 1st rechallenge. . Hours after challenge: 24.0. Group: test group. Dose level: 10 %. No with. + reactions: 8.0. Total no. in groups: 10.0.
Reading:
other: 1st rechallenge
Hours after challenge:
24
Group:
negative control
Dose level:
10 %
No. with + reactions:
1
Total no. in group:
5
Remarks on result:
other: Reading: other: 1st rechallenge. . Hours after challenge: 24.0. Group: negative control. Dose level: 10 %. No with. + reactions: 1.0. Total no. in groups: 5.0.
Reading:
other: 1st rechallenge
Hours after challenge:
48
Group:
test chemical
Dose level:
10 %
No. with + reactions:
4
Total no. in group:
10
Remarks on result:
other: Reading: other: 1st rechallenge. . Hours after challenge: 48.0. Group: test group. Dose level: 10 %. No with. + reactions: 4.0. Total no. in groups: 10.0.
Reading:
other: 1st rechallenge
Hours after challenge:
48
Group:
negative control
Dose level:
10 %
No. with + reactions:
1
Total no. in group:
5
Remarks on result:
other: Reading: other: 1st rechallenge. . Hours after challenge: 48.0. Group: negative control. Dose level: 10 %. No with. + reactions: 1.0. Total no. in groups: 5.0.
Reading:
other: 2nd rechallenge
Hours after challenge:
24
Group:
test chemical
Dose level:
10 %
No. with + reactions:
6
Total no. in group:
10
Remarks on result:
other: Reading: other: 2nd rechallenge. . Hours after challenge: 24.0. Group: test group. Dose level: 10 %. No with. + reactions: 6.0. Total no. in groups: 10.0.
Reading:
other: 2nd rechallenge
Hours after challenge:
24
Group:
negative control
Dose level:
10 %
No. with + reactions:
1
Total no. in group:
5
Remarks on result:
other: Reading: other: 2nd rechallenge. . Hours after challenge: 24.0. Group: negative control. Dose level: 10 %. No with. + reactions: 1.0. Total no. in groups: 5.0.
Reading:
other: 2nd rechallenge
Hours after challenge:
48
Group:
test chemical
Dose level:
10 %
No. with + reactions:
6
Total no. in group:
10
Remarks on result:
other: Reading: other: 2nd rechallenge. . Hours after challenge: 48.0. Group: test group. Dose level: 10 %. No with. + reactions: 6.0. Total no. in groups: 10.0.
Reading:
other: 2nd rechallenge
Hours after challenge:
48
Group:
negative control
Dose level:
10 %
No. with + reactions:
1
Total no. in group:
5
Remarks on result:
other: Reading: other: 2nd rechallenge. . Hours after challenge: 48.0. Group: negative control. Dose level: 10 %. No with. + reactions: 1.0. Total no. in groups: 5.0.

Any other information on results incl. tables

Induction

After the intradermal induction intense erythema and swelling were observed at the injection sites of all control group animals and all test group animals at which only Freund's adjuvant / 0.9 % aqueous NaCl-solution (1:1) was applied. After the injection of a 5 % test substance preparation in 1 % Tylose GB 30.000 in aqua bidest. all test group animals exhibited moderate and confluent erythema. Injections of a 5 % test substance preparation in Freund's adjuvant / 0.9% aqueous NaCl-solution (1:1) caused intense erythema and swelling in all test group animals. The control group animals, injected with 1 % Tylose CB 30.000 in aqua bidest. (vehicle) did not show any skin reactions. A 50 % formulation of 1 % Tylose GB 30.000 in aqua bidest. with Freund's adjuvant / 0.9 % aqueous NaCl-solution (1:1) caused intense erythema and swelling in all control group animals. The epicutaneous induction with a 25 % test substance preparation in 1 %Tylose GB 30.000 in aqua bidest. led to incrustation, partially open (caused by the intradermal induction), intense erythema in addition to swelling in all test group animals. The control group animals, which were treated with 1 % Tylose GB 30.000 in aqua bidest. (vehicle) exhibited incrustation, partially open (caused by the intradermal induction) in addition to moderate and confluent erythema with swelling.

Challenge

A 10 % test substance preparation in 1 % Tylose CB 30.000 in aqua bidest. caused the following skin reactions:

Reading at 24 hours after removal of the patches:

- no skin findings in all animals of control group 1

- discrete or patchy erythema in 2 out of 10 test group animals

- moderate and confluent erythema in 1 out of 10 test group animals

- moderate and confluent erythema and swelling in 4 out of 10 test group animals

- intense erythema and swelling in 1 out of 10 test group animals

Reading at 48 hours after removal of the patches:

- no skin findings in all animals of control group 1

- discrete or patchy erythema in 1 out of 10 test group animals

- discrete or patchy erythema and scaling in 1 out of 10 test group animals

- moderate and confluent erythema and scaling in 3 out of 10 test group animals

- moderate and confluent erythema, swelling and scaling in 3 out of 10 test group animals

1 % Tylose CB 30.000, which was applied as a vehicle control to all animals, did not cause any skin reactions.

1st rechallenge

A 10 % test substance preparation in 1 % Tylose CB 30.000 in aqua bidest. the following skin reactions could be observed:

Reading at 24 hours after removal of the patches:

- no skin findings in all animals of control group 2

- discrete or patchy erythema in 1 out of 5 animals of control group 1

- discrete or patchy erythema in 5 out of 10 test group animals

- moderate and confluent erythema and swelling in 3 out of 10 test group animals

Reading at 48 hours after removal of the patches:

- no skin findings in all animals of control group 2

- discrete or patchy erythema in 1 out of 5 animals of control group 1

- discrete or patchy erythema in 3 out of 10 test group animals

- moderate and confluent erythema and scaling in 1 out of 10 test group animals

1 % Tylose CB 30.000, which was applied as a vehicle control to all animals, did not cause any skin reactions.

2nd rechallenge

A 10 % test substance preparation in 1 % Tylose CB 30.000 in aqua bidest. the following skin reactions could be observed:

Reading at 24 hours after removal of the patches:

- no skin findings in all animals of control group 2

- discrete or patchy erythema in 1 out of 5 animals of control group 1

- discrete or patchy erythema in 1 out of 10 test group animals

- moderate and confluent erythema in 4 out of 10 test group animals

- moderate and confluent erythema and swelling in 1 out of 10 test group animals

Reading at 48 hours after removal of the patches:

- no skin findings in all animals of control group 2

- discrete or patchy erythema in 1 out of 5 animals of control group 1

- discrete or patchy erythema in 1 out of 10 test group animals

- moderate and confluent erythema in 2 out of 10 test group animals

- intense erythema and swelling in 3 out of 10 test group animals

1 % Tylose CB 30.000, which was applied as a vehicle control to all animals, did not cause any skin reactions.

Applicant's summary and conclusion

Interpretation of results:
sensitising
Remarks:
Migrated information