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Diss Factsheets

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:
1998
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1998
Report date:
1998

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Version / remarks:
1993
Qualifier:
according to guideline
Guideline:
EU Method B.6 (Skin Sensitisation)
Version / remarks:
1996
GLP compliance:
yes (incl. QA statement)
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
The Guinea Pig Test (1998) met the previous requirements before the entry into force of REACH. The test is suitable and reliable to cover this endpoint. For this reason and for animal welfare reasons, no further in vivo study (LLNA test) needs to be performed.

Test material

Constituent 1
Chemical structure
Reference substance name:
5-[(4-carboxybutanoyl)peroxy]-5-oxopentanoic acid
EC Number:
600-254-8
Cas Number:
10195-54-7
Molecular formula:
C10H14O8
IUPAC Name:
5-[(4-carboxybutanoyl)peroxy]-5-oxopentanoic acid

In vivo test system

Test animals

Species:
guinea pig
Strain:
Himalayan
Remarks:
spotted
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: BRL, Biological Research Laboratories Ltd. Wolferstrasse 4, CH-4414 Fullinsdorf / Switzerland
- Females: nulliparous and non-pregnant
- Age at study initiation: 5 - 7 weeks
- Weight at study initiation: 341 -416 g
- Housing: Individually in Makrolon type-4 cages with standard softwood bedding ("Lignocel", Schill AG, CH-4132 Muttenz).
- Diet: Pelleted standard Nafag Ecosan 845 25W4, batch nos. 35/98 and 52/98 guinea pig breeding / maintenance diet ("Nafag", Nahr- und Futtermittel AG, CH-9202 Gossau), ad libitum.
- Water: Community tap water from Fiillinsdorf, ad libitum. Once weekly additional supply of ascorbic acid (approx. 1 g/1) via the drinking water was provided.
- Acclimation period: One week for the control and test group under test conditions after health examination. No acclimatization for the animals of the pretest. Only animals without any visible signs of illness were used.
- Indication of any skin lesions: no

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24 °C
- Humidity (%): 44 - 74 %
- Air changes (per hr): 10 - 15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12-hour light, 12-hour dark cycle. Music was played during the light period.

IN-LIFE DATES:
Delivery of the Animals: 28-JUL-1998 (pretest) 04-AUG-1998 (main study)
Pretest Start: 28-JUL-1998
Acclimatization: 04-AUG-1998 to 10-AUG-1998
Treatment / Observation:11-AUG-1998 to 04-SEP-1998
Termination: 04-SEP-1998

Study design: in vivo (non-LLNA)

Inductionopen allclose all
Route:
intradermal
Vehicle:
polyethylene glycol
Remarks:
PEG 400
Concentration / amount:
diluted to 5%
Day(s)/duration:
single exposure on day 1
Route:
intradermal
Vehicle:
other: 1:1 (v/v) mixture of Freund's Complete Adjuvant and physiological saline
Concentration / amount:
diluted to 5%
Day(s)/duration:
single exposure on day 1
Route:
epicutaneous, occlusive
Vehicle:
polyethylene glycol
Remarks:
PEG 400
Concentration / amount:
50%
Day(s)/duration:
48 h (on day 7)
Challenge
No.:
#1
Route:
epicutaneous, occlusive
Vehicle:
polyethylene glycol
Remarks:
PEG 400
Concentration / amount:
50 %
Day(s)/duration:
48 h (14 days after epidermal induction)
No. of animals per dose:
10
Details on study design:
RANGE FINDING TESTS:
In the pretest 2 male animals were tested with concentrations of 5, 3 and 1% for intradermal injection (after 24h: erythema and oedema 1) and 50, 25, 15 and 10 % for epidermal injection (after 48h: oedema 0, erythema 1 form 25 % upwards). According to Magnusson - Kligman and to the findings observed, the concentration selected for the main study for intadermal injection was 5 %. According to Magnusson - Kligman and to the findings observed, the test article at 50 % for epidermal injection was considered to be the maximally tolerated concentration to stimulate a state of immune hypersensitivity and 10 % as the highest non-irritating concentration to be used for the challenge.

MAIN STUDY
A. INDUCTION EXPOSURE
- Exposure period: single treatment
- Test groups:
1) 1:1 (v/v) mixture of Freund's Complete Adjuvant and physiological
saline.
2) The test article, diluted to 5 % with PEG 400.
3) The test article diluted to 5 % by emulsion in a 1:1 (v/v)
- Control group:
1) 1:1 (v/v) mixture of Freund's Complete Adjuvant and physiological
saline.
2) PEG 400
3) 1:1 (w/w) mixture of PEG 400 in a 1:1 (v/v) mixture of Freund's Complete Adjuvant and physiological saline.
- Site: dorsal skin from the scapular region (approximately 6x8 cm)
- Frequency of applications: 1
Epidermal application: after 7 days, concentration 50% in PEG 400, patch covered with aluminium foil for 48h. Reaction sites were assessed after 24 and 48h according to Draize

B. CHALLENGE EXPOSURE
- No. of exposures: 1
- Days after epidermal induction: 14
- Exposure period: 24 h
- Test groups: highest non-irritating concentration of 10 % (left flank)
- Control group: vehicle only (PEG 400 applied to the right flank)
- Evaluation: 24 and 48h
Challenge controls:
vehicle only (PEG 400)
Positive control substance(s):
yes
Remarks:
ALPHA-HEXYLCINNAMALDEHYDE

Results and discussion

Positive control results:
The study was performed with five males used as control group I, five males used as control group II and ten males used as test group.
Twenty percent of the test animals were observed with a very slight erythematous reaction at the 24-hour reading after treatment with ALPHA-HEXYLCINNAMALDEHYDE at 1 % in PEG 400. The same reactions still persisted at the 48-hour reading in two animals and were also observed in a third animal. No reaction was observed in the control group I. During the second challenge 90 % (at the 24-hour reading) and 80 % (at the 48-hour reading) of the test animals were observed with very slight to well-defined (in one animal only) erythema when treated with the test article at 5 % in PEG 400. The control group I, previously exposed to the test article during the first challenge, also reacted up to 60 %. Although erythematous reactions were observed in two animals used as pretest after epidermal application of the test article at 5 %, no skin reaction was observed in the 5 animals of the control group n (with FCA/physiological saline pretreatment), prepared in the same conditions as the animals of the epidermal pretest and also treated as the control group I and test group in the second challenge. After treatment with the test article at 3 % in PEG 400, 40 % (at the 24-hour reading) and 30 % (at the 48-hour reading) of the test animals were observed with very slight erythematous reactions while no skin reaction was observed in the control group I and II. Therefore, the test article ALPHA-HEXYLCINNAMALDEHYDE applied at a concentration of 1 %, 3 % and 5 % in PEG 400 is considered to be a sensitizer when used under the described test conditions.

In vivo (non-LLNA)

Resultsopen allclose all
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
0
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
no
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
0
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
no
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
10 %
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
no
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
10 %
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
no

Any other information on results incl. tables

As there were no deaths during the course of the treatment period no necropsies were performed. No symptoms of systemic toxicity were observed in the animals. The body weight of the animals was within the range commonly recorded for animals of this strain and age.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
A guinea pig maximization assay according to OECD 406 gave no evidence of contact sensitization after induction and challenge doses of 10%.
Executive summary:

The test substance (10% in GAP) was tested for contact hypersensitivity in the albino guinea pig according to the EU method B6, the OECD guideline 406 and based on the method described by Magnusson and Kligman. Test substance concentrations selected for the Main study were based on the results of a preliminary study. In the main study, 10 experimental animals were intradermally injected with 5% concentration and epidermally exposed to a 50% concentration. 5 control animals were similarly treated, but with the vehicle (GAP) only. Two weeks after the epidermal application all animals were challenged with a 10% test substance concentration and the vehicle.

No mortality occured and no symptoms of systemic toxicity were observed in the animals of the main study. Body weights and body weight gain of experimental animals remained in the same range as controls over the study period.

No skin reactions were observed in the test and control animals. Therefore, the test article applied at a concentration of 10 % in PEG 400 is considered not to be a sensitizer when used under the described test conditions.