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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:
2003-03-04 to 2003-04-04
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions

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:
OECD Guideline 406 (Skin Sensitisation)
Version / remarks:
adopted 17 July 1992
Deviations:
yes
Remarks:
The concentration of the test substance used for epicutanous induction was not tested at levels >25 % in order to cause potential mild skin irritation.
Qualifier:
according to guideline
Guideline:
EU Method B.6 (Skin Sensitisation)
Deviations:
not specified
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.2600 (Skin Sensitisation)
Deviations:
not specified
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. In accordance with the same Regulation, the data was included to avoid unnecessary testing.

Test material

Constituent 1
Chemical structure
Reference substance name:
Methanone,(4-hydroxyphenyl)(2,3,4-trihydroxyphenyl)-
EC Number:
608-581-8
Cas Number:
31127-54-5
Molecular formula:
C13H10O5
IUPAC Name:
Methanone,(4-hydroxyphenyl)(2,3,4-trihydroxyphenyl)-
Test material form:
solid

In vivo test system

Test animals

Species:
guinea pig
Strain:
other: Mol:DH (Moellegaard)
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: M & B A/S, Ry, Denmark
- Weight at study initiation: 283 - 405 g (range)
- Housing: 5 animals per cage were housed in transparent macrolon cages (type V) on soft wood granulate.
- Diet: Sniff Ms-H (V 2233), ad libitum
- Water: Tap water, ad libitum
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 50 ± 20
- Air changes (per hr): Air-conditioned room
- Photoperiod (hrs dark / hrs light): 12/12
- IN-LIFE DATES: From: 04 Mar 2003 To: 04 Apr 2003

Study design: in vivo (non-LLNA)

Inductionopen allclose all
Route:
intradermal
Vehicle:
other: Sesame oil
Concentration / amount:
1%
Day(s)/duration:
Single injection on Day 1
Adequacy of induction:
highest concentration used causing mild-to-moderate skin irritation and well-tolerated systemically
Route:
epicutaneous, occlusive
Vehicle:
other: Sesame oil
Concentration / amount:
25%
Day(s)/duration:
Applied on Day 7, 48 h
Adequacy of induction:
other: non-irritating concentration
Challenge
No.:
#1
Route:
epicutaneous, occlusive
Vehicle:
other: Sesame oil
Concentration / amount:
25%
Day(s)/duration:
24 h
Adequacy of challenge:
highest non-irritant concentration
No. of animals per dose:
10 (in test groups), 5 (controls)
Details on study design:
RANGE FINDING TESTS: To determine a suitable concentration for the intradermal induction in the main study, 3 concentrations of the test substance (0.2, 1.0 and 5.0%) in sesame oil were selected. Each of the preparations was administered twice by intradermal injection of each 0.1 mL to 2 guinea pigs. The injection sites (sites 1, 2 and 3) were all within a dorsal area measuring 2 x 4 cm in the vicinity of the shoulders. The degree of erythema and edema at the injection sites was recorded approximately 24, 48, 72 h and 96 h after injection. A concentration of 5% in sesame oil could not be applied. A concentration of 1% in sesame oil induced clear erythema and edema (grade 1) on Days 1 - 4, therefore this concentration was selected for the intradermal induction stage of the main study. To determine a suitable concentration for the epicutaneous induction in the main study, 3 females each received 4 intradermal injections of a 50% Freund's Complete Adjuvant emulsion into the dorsal area, and then each female was treated by epicutaneous application with 1, 5 and 25% of the test substance in sesame oil. The test substance was applied to the clipped flanks of the animals under occlusive dressings for 24 hours, and the degree of erythema and edema was assessed approximately 24 h after patch removal. As no erythema and edema were observed after 24 h after administration of all test concentrations, 25% was selected for the main study for the topical induction and topical challenge.

MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: 2 (intradermal and epicutaneous)
- Exposure period: 2 injections (intradermal) and 48 h (epicutaneous)
- Test groups:
Intradermal (2 injections per injection site):
Site 1: 50% Freund`s Adjuvants
Site 2: 1% formulation of the test substance in sesame oil
Site 3: 1% formulation of the test substance in sesame oil in 50% Freund`s Adjuvants
Epicutaneous: 25% in sesame oil
- Control group:
Site 1: 50% Freund`s Adjuvants
Site 2: sesame oil
Site 3: sesame oil in 50% Freund`s Adjuvants
Epicutaneous: sesame oil
- Site: shoulder region (intradermal and epicutaneous)
- Frequency of applications: Day 1 (intradermal) and Day 8 (epicutaneous)
- Duration: 1 - 8 days

B. CHALLENGE EXPOSURE
- No. of exposures: 1 (challenge)
- Day of challenge: 22
- Exposure period: 24 h
- Test group: test substance in sesame oil
- Control group: test substance in sesame oil
- Site: Left flank (treatment and control)
- Concentrations: 25%
- Evaluation: Approximately 24 and 48 h after dermal challenge the degree of erythema and edema at the injection sites was evaluated.

OTHER: Any evidence of systemic toxicity was recorded between Days 2 - 7. The body weight of each animal was recorded at the start and end of the study.

Results and discussion

Positive control results:
Reliability checks were performed from Dec 2002 to Jan 2003 at the testing laboratory to show the sensitivity and reliability of the study results. A summary of the study under same experimental conditions was included in the report. The animals were administered 25% α-hexylcinnamaldehyde in polyethylene glycole 400. 90% of the treatment group showed after the challenge treatment a positive reaction during the observation period. Therefore the positive control is considered to be valid.

In vivo (non-LLNA)

Resultsopen allclose all
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
Induction: 1% in sesame oil, 1% in 50% Freund`s Adjuvants and 50% Freund`s Adjuvant, repectively (intradermal), 25% in sesame oil (epicutaneous); challenge: 25% in sesame oil
No. with + reactions:
6
Total no. in group:
10
Clinical observations:
No signs of systemic toxicity were observed. Discrete or patchy erythema (5/10) and moderate to confluent erythema (1/10) were noted.
Remarks on result:
positive indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
Induction: 1% in sesame oil, 1% in 50% Freund`s Adjuvants and 50% Freund`s Adjuvant, repectively (intradermal), 25% in sesame oil (epicutaneous); challenge: 25% in sesame oil
No. with + reactions:
10
Total no. in group:
10
Clinical observations:
No signs of systemic toxicity occured. Discrete to patchy erythema (1/10), moderate to confluent erythema (6/10) and intense erythema and swelling (3/10) were observed. Dry, rough and scaly skin (10/10) and skin induration (9/10) were noted.
Remarks on result:
positive indication of skin sensitisation
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
Induction: sesame oil, 50% Freund`s Adjuvants and sesame oil in 50% Freund`s Adjuvant, repectively (intradermal), sesame oil (epicutaneous); challenge: 25% in sesame oil
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
No skin reactions and signs of systemic toxicity were observed
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
Induction: sesame oil, 50% Freund`s Adjuvants and sesame oil in 50% Freund`s Adjuvant, repectively (intradermal), sesame oil (epicutaneous); challenge: 25% in sesame oil
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
No skin reactions and signs of systemic toxicity were observed
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
Challenge: 25% α-hexylcinnamaldehyde in polyethylene glycole 400
No. with + reactions:
8
Total no. in group:
10
Clinical observations:
Discrete to patchy erythema (1/10), moderate to confluent erythema (2/10) and intense erythema and swelling (5/10) were observed.
Remarks on result:
positive indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Dose level:
Challenge: 25% α-hexylcinnamaldehyde in polyethylene glycole 400
No. with + reactions:
9
Total no. in group:
10
Clinical observations:
Discrete to patchy erythema (1/10), moderate to confluent erythema (2/10) and intense erythema and swelling (6/10) were observed.
Remarks on result:
positive indication of skin sensitisation

Any other information on results incl. tables

Observations

The administration of the 25% (w/v) solution of the test item in vehicle caused skin irritation signs in the animals of the treatment group following challenge treatment. No systemic toxicity was observed during the course of investigation and the mean value for body weight and the body weight gain were comparable between the treatment group and control group.

The intradermal injections with Freund`s Adjuvant with and without test substance caused severe erythema and edema as well as indurations and encrustations. The administration sites treated with the test substance in sesame oil showed slight erythema and edema. Intradermal injections of the sesame oil exhibited no signs of irritation. After the removal of the patches on Day 10, severe erythema and edema, indurated, scabbed and encrusted skin as well as necrosis were observed at the sites previously treated with Freund's Adjuvant. The administration sites treated with the test substance or the sesame oil alone showed no signs of irritation.

Applicant's summary and conclusion

Interpretation of results:
Category 1A (indication of significant skin sensitising potential) based on GHS criteria
Conclusions:
Based on the results of the present study, the substance is considered to be a potentially strong skin sensitizer.
Executive summary:

A study according to OECD TG 406 was conducted to evaluate the skin sensitization potential of the test material. Female guinea pigs received intradermal induction with 1 % test item in sesame oil, while dermal induction and challenge treatment was carried out with 25 % test item in sesame oil. No systemic toxicity was observed and the mean value for body weight and the body weight gain were comparable between the treatment group and control group. Intradermal injections with Freund's Adjuvant (with and without test substance) caused severe erythema and edema as well as indurations and encrustations. The administration sites treated with the test substance in sesame oil showed slight erythema and edema. Intradermal injections of the sesame oil alone exhibited no signs of irritation. Due to these strong irritation reactions of the skin, 10 % sodium dodecylsulfate was not administered at day 7. Severe erythema and edema, indurated, scabbed and encrusted skin as well as necrosis were observed after dermal induction treatment at the sites previously treated with Freund's Adjuvant after the removal of the patches on day 10. The administration sites treated with the test substance or the sesame oil alone showed no signs of irritation. After the dermal challenge no skin reactions were observed in the control group 24 and 48 hours after removal of the occlusive bandage. Six animals in the main test group showed very slight up to slight erythema 24 hours after removal of the occlusive bandage. 48 hours after removal of the occlusive bandage all animals showed positive skin reactions ranging from slight erythema to intense erythema and swelling. Additionally, induration, dry, rough and scally skin were observed. Under the conditions of the present study, all of ten animals of the treatment group showed a positive skin response after the challenge procedure. Based on the results of this study the test item may cause sensitization by skin contact.