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EC number: 443-870-0 | CAS number: 163520-33-0
Skin sensitisation
Administrative data
- Endpoint:
- skin sensitisation: in vivo (non-LLNA)
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Study period:
- 24 Sep - 1 Nov 1996
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 997
- Report date:
- 1997
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 406 (Skin Sensitisation)
- Version / remarks:
- Adopted in 1992
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OPP 81-6 (Skin Sensitisation)
- Version / remarks:
- Adopted in 1984
- Deviations:
- no
- GLP compliance:
- yes
- Type of study:
- guinea pig maximisation test
- Justification for non-LLNA method:
- A non-LLNA test is available that was performed prior to the current data requirements, stipulated in Regulation (EC) No 1907/2006, and before the LLNA test method was available. In accordance with the same Regulation, the data was included to avoid unnecessary testing.
Test material
- Reference substance name:
- -
- EC Number:
- 443-870-0
- EC Name:
- -
- Cas Number:
- 163520-33-0
- Molecular formula:
- C18H17NO3
- IUPAC Name:
- ethyl 5,5-diphenyl-4,5-dihydro-1,2-oxazole-3-carboxylate
Constituent 1
In vivo test system
Test animals
- Species:
- guinea pig
- Strain:
- Dunkin-Hartley
- Sex:
- male
- Details on test animals and environmental conditions:
- TEST ANIMALS
- Source: D. Hall, Newchurch, UK
- Age at study initiation: 7 - 8 weeks
- Body weight at study initiation: 343 - 416 g
- Housing: group housed, five animals per cage, in suspended metal cages with wire mesh floors
- Diet: vitamin C enriched guinea-pig diet FD2, ad libitum, hay was given weekly
- Water: drinking water, ad libitum
- Acclimation period: 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 - 21
- Humidity (%): 45 - 54
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
- IN-LIFE DATES: From: 24 Sep 1996 To: 01 Nov 1996
Study design: in vivo (non-LLNA)
Induction
- Route:
- intradermal and epicutaneous
- Vehicle:
- other: intradermal injection: 5% acetone in Alembicol D (coconut oil, Alembic Products, Saltney, UK) for injection site 2 and 1:1 mixture of Freund's complete adjuvant and 5% acetone in Alembicol D for injection site 3; topical application: acetone
- Concentration / amount:
- intradermal injection: 7.5% (w/v); topical application: 70% (w/v)
- Day(s)/duration:
- At study initiation, animals received 3 pairs of intradermal injections. 6 days thereafter, the injection sites were pre-treated with 10% SDS. 24 h later, a patch soaked with the test substance was placed on the pre-treated skin and fixed for 48 h.
- Adequacy of induction:
- other: non-irritant substance after topical application, skin pre-treated with 10% SDS
Challenge
- No.:
- #1
- Route:
- epicutaneous, occlusive
- Vehicle:
- other: acetone
- Concentration / amount:
- 70% (w/v) in acetone (anterior site), 35% (w/v) in acetone (posterior site), 0.2 mL
- Day(s)/duration:
- 1 day
- Adequacy of challenge:
- other: Preliminary investigations indicated that the administration of the maximum technially achievable concentration of the test substance (i.e. 70% w/v) did not give rise to irritating effects.
- No. of animals per dose:
- 5 (control group), 10 (treatment group)
- Details on study design:
- RANGE FINDING TEST
In a preliminary study, animals were pre-treated with an intradermal injection of Freud's complete adjuvant (FCA), 1:1 with water, approx. 1 week prior to the start of the preliminary investigations.
The preliminary investigations indicated that the highest concentration tested, i.e. 7.5% (w/v) in 5% acetone in Alembicol D, induced erythema and oedema formation without affecting the animal adversely after intradermal injection. After topical application of the test substance, no skin irritation (erythema or oedema formation) was observed up to a concentration of 70% (w/v) in acetone. This concentration (i.e. 70%) was the maximum technically achievable concentration.
MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: 2 (intradermal and epicutaneous, respectively)
- Exposure period: single injection (intradermal) and 48 h (epicutaneous)
- Test groups:
Intradermal (3 pairs of injections):
Injection 1: a 1:1 mixture (v/v) FCA/water
Injection 2: 7.5% test substance in 5% acetone in Alembicol D
Injection 3: 7.5% test substance in a 1:1 mixture of FCA/5% acetone in Alembicol D
Epicutaneous: 70% test substance in acetone; pretreatment of application site with 10% (w/w) SDS in petrolatum 24 h prior to epicutaneous induction to produce irritation
- Control group:
Intradermal (3 pairs of injections):
Injection 1: a 1:1 mixture (v/v) FCA/water
Injection 2: 5% acetone in Alembicol D
Injection 3: a 1:1 mixture (v/v) of FCA/5% acetone in Alembicol D
Epicutaneous: acetone; pretreatment of application site with 10% (w/w) SDS in petrolatum 24 h prior to epicutaneous induction to produce irritation
- Site: interscapular area (intradermal and epicutaneous)
- Frequency of applications: topical application 7 days after intradermal injections
- Duration: Days 0 - 9, dressing was removed 48 h post topical application
- Concentrations: intradermal: 7.5%, epicutaneous: 70%
B. CHALLENGE EXPOSURE
- No. of exposures: 1
- Day(s) of challenge: Day 21 (14 days after epicutaneous induction)
- Exposure period: 24 h
- Test group: test substance
- Control group: test substance
- Site: left flank
- Concentrations: 35% posterior position, 70% anterior position
- Evaluation (h after challenge): 24 and 48 h after patch removal - Positive control substance(s):
- yes
- Remarks:
- Hexyl cinnamic aldehyde and mercaptobenzothiazole were used within 6 months prior to the conduct of the study to successfully verify the sensitivity of the test method.
Results and discussion
- Positive control results:
- The positive control substances (10% hexyl cinnamic aldehyde and 10% mercaptobenzothiazole) induced positive reactions in 10/10 animals (100%), thus meeting the reliability criteria for the guinea pig maximisation test (≥ 30% positive response).
In vivo (non-LLNA)
Resultsopen allclose all
- Key result
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- negative control
- Dose level:
- not induced
- No. with + reactions:
- 0
- Total no. in group:
- 5
- Remarks on result:
- no indication of skin sensitisation
- Key result
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- test chemical
- Dose level:
- induction: 7.5%, challenge: 35%
- No. with + reactions:
- 6
- Total no. in group:
- 10
- Remarks on result:
- positive indication of skin sensitisation
- Key result
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- test chemical
- Dose level:
- induction: 7.5%, challenge 70%
- No. with + reactions:
- 8
- Total no. in group:
- 10
- Remarks on result:
- positive indication of skin sensitisation
- Key result
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- positive control
- Dose level:
- induction: 10%, challenge: 40 and 83.33%
- No. with + reactions:
- 10
- Total no. in group:
- 10
- Remarks on result:
- positive indication of skin sensitisation
- Key result
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- negative control
- Dose level:
- not induced
- No. with + reactions:
- 0
- Total no. in group:
- 5
- Remarks on result:
- no indication of skin sensitisation
- Key result
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- test chemical
- Dose level:
- induction: 7.5%, challenge: 35%
- No. with + reactions:
- 6
- Total no. in group:
- 10
- Remarks on result:
- positive indication of skin sensitisation
- Key result
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- test chemical
- Dose level:
- induction: 7.5%, challenge: 70%
- No. with + reactions:
- 9
- Total no. in group:
- 10
- Remarks on result:
- positive indication of skin sensitisation
Any other information on results incl. tables
Induction
Intradermal injections: Necrosis was recorded at sites receiving Freund's Complete Adjuvant in test and control animals. Slight irritation was seen in test animals at sites receiving 7.5% (w/v) test substance in 5% acetone in Alembicol D and slight irritation was observed in control animals receiving 5% acetone in Alembicol D alone. Necrosis was observed in animals receiving 7.5% (w/v) test substance in a 1:1 mixture of FCA and 5% acetone in Alembicol D.
Topical application: Slight erythema was observed in test animals following topical application of 70% (w/v) test substance in acetone. Slight erythema was also seen in the control guinea pigs.
Clinical signs
No signs of toxicity were recorded.
Body weight
No effect on body weight and body weight gain was observed.
Table 1: Dermal reactions observed after each induction
| Site | Intradermal injection | Topical application | ||
| Test animals | Control animals | Test animals | Control animals | |
| 1 | Necrosis | Necrosis | Slight erythema | Slight erythema |
| 2 | Slight irritiation | Slight irritiation | ||
| 3 | Necrosis | Necrosis | ||
Injection site 1: Freund's complete adjuvant : water, 1:1
Injection site 2: 7.5% test substance in 5% acetone in Alembicol D
Injection site 3: 7.5% test substance in a 1:1 mixture of Freund's complete adjuvant and 5% acetone in Alembicol D
Table 2: Dermal reactions observed after the challenge application with the test substance
| Animal number | Skin reaction | Score | Results Positive (+) Negative (-) |
|||
| 24 h | 48 h | |||||
| Anterior | Posterior | Anterior | Posterior | |||
| control - 1 | Erythema | 0 | 0 | 0 | 0 | - |
| Oedema | 0 | 0 | 0 | 0 | ||
| control - 2 | Erythema | 0 | 0 | 0 | 0 | - |
| Oedema | 0 | 0 | 0 | 0 | ||
| control - 3 | Erythema | 0 | 0 | 0 | 0 | - |
| Oedema | 0 | 0 | 0 | 0 | ||
| control - 4 | Erythema | 0 | 0 | 0 | 0 | - |
| Oedema | 0 | 0 | 0 | 0 | ||
| control - 5 | Erythema | 0 | 0 | 0 | 0 | - |
| Oedema | 0 | 0 | 0 | 0 | ||
| test animal - 1 | Erythema | 1 | 1 | NE 1 | # 1 | + |
| Oedema | 1 | 1 | # 2 | 2 | ||
| test animal - 2 | Erythema | # 1 | 2 | NP 3 | # 1 | + |
| Oedema | 2 | 1 | # 2 | 1 | ||
| test animal - 3 | Erythema | 2 | 1 | # 2 | # 1 | + |
| Oedema | 1 | 0 | 1 | 1 | ||
| test animal - 4 | Erythema | # 2 | 1 | # 2 | # 1 | + |
| Oedema | 2 | 1 | 2 | 1 | ||
| test animal - 5 | Erythema | 1 | 0 | 1 | 0 | + |
| Oedema | 0 | 0 | * 0 | 0 | ||
| test animal - 6 | Erythema | 2 | 0 | # 2 | 0 | + |
| Oedema | 1 | 0 | 2 | * 0 | ||
| test animal - 7 | Erythema | 0 | 0 | 0 | 0 | - |
| Oedema | 0 | 0 | 0 | 0 | ||
| test animal - 8 | Erythema | 0 | 1 | 1 | 1 | + |
| Oedema | 0 | * 0 | * 0 | * 0 | ||
| test animal - 9 | Erythema | # 2 | 1 | # 2 | # 2 | + |
| Oedema | 2 | 2 | 2 | 2 | ||
| test animal - 10 | Erythema | L 1 | 0 | # 1 | 0 | + |
| Oedema | * 0 | * 0 | 1 | * 0 | ||
Score: grading from 0 (no erythema/oedema) to maximum 4 (severe erythema/oedema)
Anterior: anterior site exposed to 70% test substance in acetone
Posterior: posterior site exposed to 35% test substance in acetone
Control: control animals were treated with Freund's complete adjuvant
NE: necrotic edge
NP: necrotic patch
#: thickening, dryness and sloughing of the epidermis
*: dryness and sloughing of the epidermis
L: localised dermal reaction
Applicant's summary and conclusion
- Interpretation of results:
- Category 1B (indication of skin sensitising potential) based on GHS criteria
- Conclusions:
- CLP: Skin sens Cat. 1B, H317
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