Registration Dossier
Registration Dossier
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Skin sensitisation
Administrative data
- Endpoint:
- skin sensitisation: in vivo (non-LLNA)
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1996
- Reliability:
- 1 (reliable without restriction)
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Report date:
- 1996
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
- Type of study:
- guinea pig maximisation test
- Justification for non-LLNA method:
- According to the Reach Annex VIII, 8.3.2 column 2 the in vivo studies carried out before 10 May 2017 and that meet the requirements set out in Article 13(3), first subparagraph, and Article 13(4) shall be considered appropriate to address this standard information requirement. The non-LLNA study was conducted in 1996, according to GLP, and based on the performance and results it is considered suitable to cover the sensitisation endpoint.
Test material
- Reference substance name:
- bis[2-hydroxy-N,N-bis(2-hydroxyethyl)ethanaminium] 7-{[4-(4-{[2-(cyanoamino)-4-hydroxy-6-oxo-1,6-dihydropyrimidin-5-yl]diazenyl}benzamido)-3-methoxyphenyl]diazenyl}naphthalene-1,3-disulfonate
- Cas Number:
- 115811-45-5
- Molecular formula:
- C29H19N9O10S2.2C6H16NO3
- IUPAC Name:
- bis[2-hydroxy-N,N-bis(2-hydroxyethyl)ethanaminium] 7-{[4-(4-{[2-(cyanoamino)-4-hydroxy-6-oxo-1,6-dihydropyrimidin-5-yl]diazenyl}benzamido)-3-methoxyphenyl]diazenyl}naphthalene-1,3-disulfonate
- Test material form:
- solid
1
In vivo test system
Test animals
- Species:
- guinea pig
- Strain:
- Himalayan
- Sex:
- male
- Details on test animals and environmental conditions:
- TEST ANIMALS
- Source: BRL, Biological Research Laboratories Ltd., Wolferstrasse 4, 4414 Füllinsdorf / Switzerland
- Age at study initiation: 6-8 weeks
- Weight at study initiation: 296 - 397 g
- Housing: Individually in Makrolon type-3 cages with standard softwood bedding
- Diet (e.g. ad libitum): Pelleted standard Nafag Ecosan 845 25W4 guinea pig breeding/maintenance diet, ad libitum
- Water (e.g. ad libitum): Community tap water from Itingen, ad libitum.
- Acclimation period: Control and test group: 1 week; pretest animals: no acclimatation
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3°C
- Humidity (%): 40-70
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: To:
Study design: in vivo (non-LLNA)
Inductionopen allclose all
- Route:
- intradermal and epicutaneous
- Vehicle:
- water
- Concentration / amount:
- Concentration of test material and vehicle used at induction: - intradermal: 0.1 ml
/site
A) 1:1 (v/v) mixture of Freund's Complete Adjuvant and physiological saline B) test substance diluted to 5 % (w/w) in bidistilled water C) test substance diluted to 5 % (w/w) by emulsion in a 1:1 (v/v) mixture of Freund's Complete Adjuvant and physiological saline - epidermal: 0.3 ml test substance 50 % (w/w) in bi-distilled water
Concentration of test material and vehicle used for each challenge: - epidermal: 25 % (w/w) in bi-distilled water
Challengeopen allclose all
- Route:
- epicutaneous, semiocclusive
- Vehicle:
- water
- Concentration / amount:
- Concentration of test material and vehicle used at induction: - intradermal: 0.1 ml
/site
A) 1:1 (v/v) mixture of Freund's Complete Adjuvant and physiological saline B) test substance diluted to 5 % (w/w) in bidistilled water C) test substance diluted to 5 % (w/w) by emulsion in a 1:1 (v/v) mixture of Freund's Complete Adjuvant and physiological saline - epidermal: 0.3 ml test substance 50 % (w/w) in bi-distilled water
Concentration of test material and vehicle used for each challenge: - epidermal: 25 % (w/w) in bi-distilled water
- No. of animals per dose:
- Number of animals in test group: 20 Number of animals in negative control group: 10
- Details on study design:
- RANGE FINDING TESTS:
A pretest with 6 animals (intradermal: 2 animals, epidermal: 4 animals) was conducted to identify a maximally tolerated concentration of the test article suitable for the induction phase of the main study. In addition, a suitable non-irritant concentration of the test article, by the topical route of administration, was identified for the challenge application.
All animals were sensitized with intradermal application of a 1:1 suspension of FCA/physiological saline one week before the treatments.
Intradermal injections: 1, 3, and 5% in bidistilled water
Epidermal application: 10, 15, 25, 50% in bidistilled water
Reactions were evaluated 24h (intradermal injection) and 24 and 48h (epidermal application) after beginning of the treatment.
MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: 3 pairs of intradermal application with FCA, test item, and test item + FCA; 1 epicutaneous application with test item
- Exposure period: epicutaneous application: 48h
- Site: scapular region
- Frequency of applications: day 1: intradermal application; day 8: epicutaneous application
- Test item concentration: intradermal application: 5%; epicutaneous application: 50%
B. CHALLENGE EXPOSURE
- No. of exposures:
- Day(s) of challenge: on day 22
- Exposure period: approximately 24h
- Site: left and right flank
- Concentration: 25% (highest non-irritating concentration)
- Evaluation (hr after challenge): 24 and 48h after chellenge
OTHER:
- The following observations and data were recorded during the test and observation period: Viability/Mortality, Clinical Signs (local/systemic), Skin reactions, Body Weights.
Records were maintained of all additional and standard observations. - Positive control substance(s):
- yes
- Remarks:
- alpha-hexylcinnamaldehyde, 2- mercaptobenzothiazole
Results and discussion
- Positive control results:
- ALPHA-HEXYLCINNAMALDEHYDE
In the positive control study 65% (at 24-hour reading) and 60% (at 48-hour reading) of the animals of the test group were observed with positive skin reactions after treatment with a non-irritant test substance concentration of 15% alpha-hexylcinnamaldehyde in PEG 400.
No skin reactions were observed in the control group.
2- MERCAPTOBENZOTHIAZOLE
In this positive control study 90% (at the 24-hour reading) and 100% (at the 48-hour reading) of the animals of the test group were observed with positive skin reactions after treatment with a non-irritant test substance concentration of 50% in mineral oil.
No skin reactions were observed in the control group.
In vivo (non-LLNA)
Resultsopen allclose all
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- positive control
- Dose level:
- 0%
- 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:
- 0%
- 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:
- positive control
- Dose level:
- 50%
- No. with + reactions:
- 20
- Total no. in group:
- 20
- Remarks on result:
- positive indication of skin sensitisation
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- positive control
- Dose level:
- 50%
- No. with + reactions:
- 18
- Total no. in group:
- 20
- Remarks on result:
- positive indication of skin sensitisation
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- test chemical
- Dose level:
- 0 %
- 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:
- test chemical
- Dose level:
- 25 %
- 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:
- test chemical
- Dose level:
- 0 %
- 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:
- test chemical
- Dose level:
- 25 %
- 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:
- negative control
- Dose level:
- 0 %
- No. with + reactions:
- 0
- Total no. in group:
- 10
- Remarks on result:
- no indication of skin sensitisation
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- negative control
- Dose level:
- 25 %
- No. with + reactions:
- 0
- Total no. in group:
- 10
- 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:
- 10
- Remarks on result:
- no indication of skin sensitisation
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- negative control
- Dose level:
- 25 %
- No. with + reactions:
- 0
- Total no. in group:
- 10
- Remarks on result:
- no indication of skin sensitisation
Applicant's summary and conclusion
- Interpretation of results:
- not sensitising
- Remarks:
- Migrated information
- Conclusions:
- The substance applied at a concentration of 25% in bi-distilled water is considered to be a non-sensitizer.
- Executive summary:
In order to assess the cutaneous allergenic potential of the substance, the Maximization-test in accordance with OECD Guideline No. 406 and the Directive 92/69 EEC B.6 was carried out in 30 (20 test and 10 control) male albino guinea pigs.
The intradermal induction of sensitization was carried out with a 5% dilution of the test article in bi-distilled water and in an emulsion with Freund's Complete Adjuvant (FCA)/physiological saline. The epicutaneous induction of sensitization was conducted under occlusion with the test article at 50% in bi-distilled water. Two weeks after the epicutaneous induction application the challenge was completed by epicutaneous application of the test article at 25% in bi-distilled water under occlusive dressing. The animals of the control group were induced with bi-distilled water and FCA/physiological and challenged similarly as those of the test group. Cutaneous reactions, i.e erythema and eschar, as well as oedema formation were evaluated at 24 and 48 hours after removal of the dressing.
No reactions were observed 24 and 48h after the challenge period.
In this study 0% of the animals of the test and control group were observed with positive skin reactions after treatment with a non-irritant test substance concentration of 25% in bi-distilled water.
Therefore, the substance applied at a concentration of 25% in bi-distilled water is considered to be a non-sensitizer when used under the described test conditions.
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