Registration Dossier
Registration Dossier
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EC number: 203-321-6 | CAS number: 105-67-9
Endpoint summary
Administrative data
Description of key information
Based on the results of the Guinea pig maximization test, the test substance is considered to moderately sensitising to skin.
Key value for chemical safety assessment
Skin sensitisation
Link to relevant study records
- Endpoint:
- skin sensitisation: in vitro
- Data waiving:
- study scientifically not necessary / other information available
- Justification for data waiving:
- the study does not need to be conducted because the substance is classified as skin corrosion (Category 1, 1A, 1B or 1C)
- Reason / purpose for cross-reference:
- data waiving: supporting information
- Endpoint:
- skin sensitisation: in vivo (non-LLNA)
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- From 4 September 1997 to 14 September 1998
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- 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
- Type of study:
- guinea pig maximisation test
- Justification for non-LLNA method:
- A LLNA was not conducted with the test substance as a Guinea pig maximisation test was already available allowing assessment of the skin sensitisation potential of the substance. Moreover, the test substance is corrosive hence any additional testing is not required as per Annex VII column 2 of REACH Regulation (1907/2006).
- Species:
- guinea pig
- Strain:
- Dunkin-Hartley
- Sex:
- female
- Details on test animals and environmental conditions:
- Strain/quality: Pirbright White, Dunkin Hartley Crl:(HA)BR [SPF]
Origin: Charles River GmbH - Wiga,Kisslegg, FRG
Age of the animals: Young adult animals
Body weight range at the beginning of the study: 322 - 399 g
Acclimatization period: 7 days before the beginning of the study in the laboratory for dermal toxicity
Housing conditions:
The animals were housed in fully air-conditioned rooms in which a central air-conditioning system ensured a temperature in the range of 21 - 25°C and a relative humidity in the range of 30 - 70%.
Illumination period:
12 h light (6.00 a.m. - 6.00 p.m.) 12 h darkness (6.00 p.m. -6.00 a.m.)
No. of animals per cage: 5
Type of diet: Kliba Labordiat(Kanin chen-Meerschweinchen Haltungsdiat) ad libitum
Watering: Tap water ad libitum
Bedding: Granulat Type 3/4 (staubfrei); SNIFF - Route:
- intradermal
- Vehicle:
- other: Lutrol E 400 DAB
- Concentration / amount:
- 0.5% / 0.1 mL
- Day(s)/duration:
- Reading: 24 h after the beginning of application
- Route:
- epicutaneous, occlusive
- Vehicle:
- other: Lutrol E 400 DAB
- Concentration / amount:
- 25% / 1 mL
- Day(s)/duration:
- 48 h
- No.:
- #1
- Route:
- epicutaneous, occlusive
- Vehicle:
- other: Lutrol E 400 DAB
- Concentration / amount:
- 5% / 0.5 mL
- Day(s)/duration:
- 24 h
- No.:
- #2
- Route:
- epicutaneous, occlusive
- Vehicle:
- other: Lutrol E 400 DAB
- Concentration / amount:
- 5% / 0.5 mL
- Day(s)/duration:
- 24 h
- No. of animals per dose:
- Number of animals per control group: 10
Number of animals of the test group: 20 - Details on study design:
- Pretest
Intradermal Pretest:
Amount applied: 6 intradermal injections in groups of two per animal were applied to each animal
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.
Site of application: shoulder
No. of animals:
- 2 per test substance concentration
Reading:
24 h after the beginning of application
Percutaneous Pretest:
Amount applied:
2 x 2 cm filter paper strips containing the test substance formulation were applied to the skin of the flanks under an occlusive dressing. In the case of liquid test substance formulations the filter paper strip was soaked in the test substance formulation.
The dressing consisted of rubberized linen patches (4 x 4 cm from Russka), patches of Idealbinde (5 x 5 cm from Pfalzische Verbandstoff-Fabrik) and Fixomull® Stretch (adhesive fleece) from Beiersdorf AG.
Exposure period:
The test substance was applied 2 times for 24 hours within a period of 96 hours in order to detect non specific phenomena that are not caused by a sensiti zation reaction but could possibly be attributed to a shift in the irritation threshold.
Site of application:
-flank, on the same area respectively
Number of test animals:
-4 per test concentration
-Readings:
-24 hand 48 h after the beginning of application
Main test
Number of animals per control group: 10 Number of animals of the test group: 20
Induction
Intradermal induction
6 intradermal injections in groups of two per animal were given.
Injections for the control groups:
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)
Injections for the test group:
Analogous to the intradermal pretest see 3.3.3.1.
Site of application: shoulder
Reading:
24 h after the beginning of application
Percutaneous induction
Percutaneous induction was carried out one week after intradermal induction.
Amount applied:
4 x 2 cm gauze patches (6 layers surgical gauze
Ph. Eur. from Lohmann GmbH & Co. KG) containing the test substance formulation were applied to the skin of the shoulder under an occlusive dressing. The dressing consisted of rubberized linen patches
(6 x 4 cm from Russka) and Fixomull® Stretch (adhesive fleece) from Beiersdorf AG.
1 ml of the test substance formulation was applied to each animal.
The control groups were treated analogously to the test group but only with the vehicle without the test substance.
Duration of exposure:
48 h
Site of application:
shoulder, same area as in the case of the previous intradermal application
Readings:
48 h after the beginning of application
Challenge
The first challenge was performed 21 days after the intradermal induction. A second challenge was carried out one week after the first one.
Amount applied:
2x 2 cm gauze patches (6 layers surgical gauze Ph. Eur. from Lohmann GmbH & Co. KG) containing the test substance formulation were applied to the skin of the flank under an occlusive dressing. The dressing consisted of rubberized linen patches
(4 x 4 cm from Russka), patches of Idealbinde
(5 x 5 cm from Pfalzische Verbandstoff-Fabrik) and Fixomull® Stretch (adhesive fleece) from Beiers dorf AG.
0.5 ml of the test substance formulation was applied to each animal.
1st challenge:
The test group and control group 1 were treated with the test substance formulation. Additionally,
Lutrol E 400 DAB was applied as a vehicle control. Control group 2 only received Lutrol E 400 DAB.
2nd challenge:
The test group and control groups 1 and 2 were treated with the test substance formulation.
Analogous to the 1st challenge Lutrol E 400 DAB was applied as a vehicle control.
Duration of exposure:
24 h
Site of application: intact flank
Readings:
24 and 48 h after the removal of the patch
Positive control
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. The positive control with Alpha-Hexylcinnamaldehyde techn. 85% showed that the chosen guinea pig strain was able to detect sensitizing compounds under the laboratory conditions chosen. The results of the most recent study is included in Appendix 6.6. - Positive control substance(s):
- yes
- Remarks:
- Alpha-Hexylcinnamaldehyde techn
- Positive control results:
- The positive control with Alpha-Hexylcinnamaldehyde techn. 85% showed that the chosen guinea pig strain was able to detect sensitizing compounds under the laboratory conditions chosen.
The results of this study show, that a weak to moderate human sensitizer.
Refer any other information on result including table section for the details - Key result
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- test chemical
- Dose level:
- 0.1 mL of 0.5%
- No. with + reactions:
- 11
- Total no. in group:
- 20
- Clinical observations:
- erythema and swelling in 1, moderate and confluent erythema in 8 and discrete or patchy erythema in 2 animals
- Remarks on result:
- positive indication of skin sensitisation
- Remarks:
- 55% incidence
- Key result
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- test chemical
- Dose level:
- 0.1 mL of 0.5%
- No. with + reactions:
- 9
- Total no. in group:
- 20
- Clinical observations:
- moderate and confluent erythema in 4 , discrete or patchy erythema as well as scaling in 2 , discrete or patchy erythema in 3 animals
- Remarks on result:
- positive indication of skin sensitisation
- Remarks:
- 45% incidence
- Key result
- Reading:
- rechallenge
- Hours after challenge:
- 24
- Group:
- test chemical
- Dose level:
- 0.5 mL of 5%
- No. with + reactions:
- 7
- Total no. in group:
- 20
- Clinical observations:
- moderate and confluent erythema in 4, discrete or patchy erythema in 3 animals
- Remarks on result:
- positive indication of skin sensitisation
- Key result
- Reading:
- rechallenge
- Hours after challenge:
- 48
- Group:
- test chemical
- Dose level:
- 0.5 mL of 5%
- No. with + reactions:
- 6
- Total no. in group:
- 20
- Clinical observations:
- moderate and confluent erythema in 1, discrete or patchy erythema in 5 animals
- Remarks on result:
- positive indication of skin sensitisation
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- negative control
- Dose level:
- 0.5 mL
- No. with + reactions:
- 0
- Total no. in group:
- 20
- Remarks on result:
- no indication of skin sensitisation
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- negative control
- Dose level:
- 0.5 mL
- No. with + reactions:
- 0
- Total no. in group:
- 20
- Remarks on result:
- no indication of skin sensitisation
- Reading:
- rechallenge
- Hours after challenge:
- 24
- Group:
- negative control
- Dose level:
- 0.5 mL
- No. with + reactions:
- 0
- Total no. in group:
- 20
- Remarks on result:
- no indication of skin sensitisation
- Reading:
- rechallenge
- Hours after challenge:
- 48
- Group:
- negative control
- Dose level:
- 0.5 mL
- No. with + reactions:
- 0
- Total no. in group:
- 20
- Remarks on result:
- no indication of skin sensitisation
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- positive control
- Dose level:
- 5%
- No. with + reactions:
- 11
- Total no. in group:
- 18
- Remarks on result:
- positive indication of skin sensitisation
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- positive control
- Dose level:
- 5%
- No. with + reactions:
- 5
- Total no. in group:
- 18
- Remarks on result:
- positive indication of skin sensitisation
- Reading:
- 2nd reading
- Hours after challenge:
- 24
- Group:
- positive control
- Dose level:
- 5%
- No. with + reactions:
- 8
- Total no. in group:
- 18
- Remarks on result:
- positive indication of skin sensitisation
- Interpretation of results:
- other: Category 1B (indication of skin sensitising potential) based on CLP
- Remarks:
- ≥ 30 % to < 60 % responding at > 0,1 % to ≤ 1 % intradermal induction dose criteria (i.e., 45-55% responding at 0.5% intradermal induction dose)
- Conclusions:
- Under the study conditions, the test substance was determined to be sensitising in a Guinea pig maximisation test.
- Executive summary:
A guinea pig maximisation test (GPMT) was conducted to determine the sensitising potential of test substance in guinea-pigs according to OECD Guideline 406, in compliance with GLP. The pretest was performed to determine the well tolerated local and systemic concentrations to use in the main study. During the pre-test, the highest concentration of the test substance (i.e., 25%) that caused slight to moderate irritation was chosen for the induction treatment, and the maximum non-irritant concentration (i.e., 5%) was determined for the challenge applications. Lutrol E 400 DAB was used as vehicle because of good solubility. During the induction phase, the animals were treated with intradermal injections of 0.1 mL of 0.5% test substance in Lutrol E 400 DAB or Freund’s adjuvant or 0.9% aqueous NaCl-solution (1:1). The treated skin was observed approximately 24 h after treatment. One week after intradermal induction, the animals were induced with percutaneous patches containing 1 mL of the 25% test substance in Lutrol E 400 DAB, under occlusive dressing for 48 h, The treated skin was observed approximately 48 h after the beginning of the application. Two challenges were performed after 14 and 21 days of the percutaneous induction, where the treated animals were challenged with 0.5 mL of the 5% test substance in Lutrol E 400 DAB under an occlusive dressing for 24 h. The treated skin was observed approximately 24 and 48 h after the removal of the patch. The intradermal induction with 0.5% test substance caused necrotic skin changes and swelling or moderate and confluent erythema and swelling in all test group animals. After the percutaneous induction with a 25% test substance, necrotic skin changes, partially open (caused by the intradermal induction) was observed in addition to swelling in all test group animals. After the challenges with a 5% test substance discrete or patchy, moderate and confluent or intense erythema and swelling were observed in test group animals. There were no other signs of toxicity and body weight gain of the test animals was comparable to that of the controls. Under the study conditions, the test substance was considered to be sensitising (Wiemann,1998). Based on the positive incidence percentage ranging from 45-55% at 0.5% intradermal induction concentration, the test substance is considered to be moderately sensitising to the skin.
Referenceopen allclose all
Pretest:
Intradermal Pretest: A concentration of the test substance that is welltolerated locally and systemically should be chosen for the intradermal induction treatment in the maintest.
Form of application:
A) Freund'sadjuvant/0.9% aqueous NaCl-solution(11)
B) Substance1% in Lutrol E400DAB
C) Substance1% in A)
Animal No.: |
78 |
79 |
|||
Weight (g): |
587 |
598 |
|||
|
Left |
Right |
Left |
Right |
|
Findings after 24 h
|
A |
2/2 |
2/2 |
2/2 |
2/2 |
B |
N/2 |
N/2 |
N/2 |
N/2 |
|
C |
N/2 |
N/2 |
N/2 |
N/2 |
|
x/y;erythema/edema; N;necrotic skin changes
Form of application:
A) Freund'sadjuvant/0.9%aqueousNaCl-solution(11)
B) Substance 0.5% in Lutrol E400 DAB
Substance 0.5% in A)
Animal No.: |
80 |
81 |
|||
Weight (g): |
438 |
437 |
|||
|
Left |
Right |
Left |
Right |
|
Findings after 24 h
|
A |
2/2 |
2/2 |
2/2 |
2/2 |
B |
N/2 |
N/2 |
N/2 |
N/2 |
|
C |
2/2 |
2/2 |
2/2 |
2/2 |
|
x/y=erythema/edema; N =necrotic skin changes
Percutaneous Pretest:
For the dermal in duction treatment the highest concentration of the test substance that causes slight to moderate irritation and for the challenge themaximum non-irritant concentration was determined with the pretest.For detecting a possible influence on irritating effects of previous intradermal treatment withFreund'sadjuvant,animals pretreated with Freund's adjuvant/0.9%aqueousNaCl-solution(1:1)each,in the same manner as intradermal pretestreferring front row(A)and back row(C)without test substance(cf.page17)about 4weeks prior to the application of the test substance were used. The test substance was applied to the skin of the flanks for 2x24h under occlusive drressing.
Main Test
Induction
After the intradermal induction moderate and confluent 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. The injection sites of all control group animals at which Lutrol E 400 DAB or a 50% preparation of Lutrol E 400 DAB with Freund's adjuvant / 0.9% aqueous NaCl-solu tion (1 : 1) was applied, showed necrotic skin changes and swelling. Injections of a 0.5% test sub stance preparation in Lutrol E 400 DAB also caused necrotic skin changes and swelling in all test group animals. Moderate and confluent erythema and swelling were observed at the injection sites of all test group animals which were applied with a 0.5% test substance preparation in Freund's adjuvant / 0.9% aqueous NaCl-solution (1 : 1).
After the percutaneous induction with a 25% test substance preparation in Lutrol E 400 DAB necrotic skin changes, partially open (caused by the intra dermal induction), could be observed in addition to swelling in all test group animals.
The animals of control group 1 and 2, which were applied with Lutrol E 400 DAB exhibited the same skin reactions as the animals of the test group.
1st challenge
The 1st challenge with a 5% test substance preparation caused the following skin reactions.
Reading at 24 h after removal of the test patches:
no skin findings in all animals of control group 1
intense erythema and swelling in 1 out of 20 test group animals
moderate and confluent erythema in 8 out of 20 test group animals
discrete or patchy erythema in 2 out of 20 test group animals
Reading at 48 h after removal of the test patches:
no skin findings in all animals of control group 1
moderate and confluent erythema in 4 out of 20 test group animals
discrete or patchy erythema as well as scaling in 2 out of 20 test group animals
discrete or patchy erythema in 3 out of 20 test group animals
Lutrol E 400 DAB, which was applied as a vehicle control to all animals did not cause any skin reactions
2nd challenge
After the 2nd challenge with a 5% test substance preparation the following skin reactions could be observed.
Reading at 24 h after removal of the test patches:
no skin findings in all animals of control groups 1 and 2
moderate and confluent erythema in 4 out of 20 test group animals
discrete or patchy erythema in 3 out of 20 test group animals
Reading at 48 h after removal of the test patches:
no skin findings in all animals of control groups 1 and 2
moderate and confluent erythema in 1 out of 20 test group animals
discrete or patchy erythema in 5 out of 20 test group animals
Lutrol E 400 DAB, which was applied as a vehicle control to all animals, did not cause any skin reactions.
The number of animals with skin findings after the 1st challenge and after the 2nd challenge is summarized in the following table
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
x/y: number of positive reactions/number of animals tested (reading at 24 hand/or 48 h after the removal of the patch)
Bodyweights:The expected body weight gain was generally observed in the course of the study.The individual body weights are shown in the respective tables in the Appendix6.5.
Positive control results:
Two challenges were preformed 14 and 21 days after the percutaneous induction.After the 1st challenge with a 5% test substance preparation in Lutrol E 400 DAB very slight erythema could be observed in 6 out of 18 test group animals24 hours after removal of the patches. 3 out of 18 test group animals exhibited well-defined erythema, whereas 1 out of these animals additionally showed very slight edema. In 2 test group animals moderate erythema and very slight edema were observed. 48 hours after removal of the patches very slight erythema was seen in 2 out of 18 test group animals, whereas 1 out of these animals additionally exhibited scaling. Well-defined erythema could be observed in 2 test group animals. 1 out of these animals additionally showed very slight edema and superficial scabbing. Moderate erythema, very slight edema and superficial scabbing was seen in 1 test group animal. 2 test group animals exhibited scaling.The animals of control group 1 did not show any skin reactions.
Lutrol E 400 DAB which was applied as a vehicle control to all animals did not cause any skin reactions.
The 2nd challenge with a 5% test substance preparation in Lutrol E 400 DAB caused very slight erythema in 4 out of 18 test group animals 24 hours after removal of.:;--the patches. Well-defined erythema could be observed in 4 out of 18 test group animals, whereas 1 out of these animals additionally showed scaling. 48 hours after removal of the patches very slight erythema was noted in 4 out of 18 test group animals, whereas 2 out of these animals additionally exhibited scaling. Well-defined erythema was noted in 1 test group animal. No skin reactions were observed in all animals of control groups 1 and 2.
Lutrol E 400 DAB which was applied as a vehcile control to all animals did not cause any skin reactions
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed (sensitising)
- Additional information:
A guinea pig maximisation test (GPMT) was conducted to determine the sensitising potential of test substance in guinea-pigs according to OECD Guideline 406, in compliance with GLP. The pretest was performed to determine the well tolerated local and systemic concentrations to use in the main study. During the pre-test, the highest concentration of the test substance (i.e., 25%) that caused slight to moderate irritation was chosen for the induction treatment, and the maximum non-irritant concentration (i.e., 5%) was determined for the challenge applications. Lutrol E 400 DAB was used as vehicle because of good solubility. During the induction phase, the animals were treated with intradermal injections of 0.1 mL of 0.5% test substance in Lutrol E 400 DAB or Freund’s adjuvant or 0.9% aqueous NaCl-solution (1:1). The treated skin was observed approximately 24 h after treatment. One week after intradermal induction, the animals were induced with percutaneous patches containing 1 mL of the 25% test substance in Lutrol E 400 DAB, under occlusive dressing for 48 h, The treated skin was observed approximately 48 h after the beginning of the application. Two challenges were performed after 14 and 21 days of the percutaneous induction, where the treated animals were challenged with 0.5 mL of the 5% test substance in Lutrol E 400 DAB under an occlusive dressing for 24 h. The treated skin was observed approximately 24 and 48 h after the removal of the patch. The intradermal induction with 0.5% test substance caused necrotic skin changes and swelling or moderate and confluent erythema and swelling in all test group animals. After the percutaneous induction with a 25% test substance, necrotic skin changes, partially open (caused by the intradermal induction) was observed in addition to swelling in all test group animals. After the challenges with a 5% test substance discrete or patchy, moderate and confluent or intense erythema and swelling were observed in test group animals. There were no other signs of toxicity and body weight gain of the test animals was comparable to that of the controls. Under the study conditions, the test substance was considered to be sensitising (Wiemann,1998). Based on the positive incidence percentage ranging from 45-55% at 0.5% intradermal induction concentration, the test substance is considered to be moderately sensitising to the skin.
Respiratory sensitisation
Endpoint conclusion
- Endpoint conclusion:
- no study available
Justification for classification or non-classification
Based on the skin sensitisation responses observed in the GPMT, the test substance warrant a ‘Skin Sens. 1B; H317: May cause an allergic skin reaction’ classification according to the EU CLP criteria (Regulation EC 1272/2008).
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
