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Diss Factsheets

Toxicological information

Skin sensitisation

Currently viewing:

Administrative data

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
20 August 1984 to 20 September 1984
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1987
Report date:
1987

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Version / remarks:
12 May 1981
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
GLP statement dates to Dec 18, 1987
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
The test was performed before the OECD guideline 429 (LLNA) entered into force. The Guinea Pig Maximization Test (GPMT) has been carried out as an animal test to predict human sensitization for over a decade and is recommended by international test guidelines such as OECD.

Test material

Constituent 1
Chemical structure
Reference substance name:
1-(3,5-dichloro-2,4-difluorophenyl)-3-(2,6-difluorobenzoyl)urea
EC Number:
617-441-5
Cas Number:
83121-18-0
Molecular formula:
C14 H6 Cl2 F4 N2 O2
IUPAC Name:
1-(3,5-dichloro-2,4-difluorophenyl)-3-(2,6-difluorobenzoyl)urea
Test material form:
solid: crystalline

In vivo test system

Test animals

Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Kleintierfarm Madoerin AG, CH 4414 Fuellinsdorf / Switzerland
- Age at study initiation: 8-9 weeks
- Weight at study initiation: males: 430 - 507 g, females: 423 - 520 g
- Housing: Individually in Makrolon type-3 cages
- Diet: ad libitum, pelleted standard Kliba 342, guinea pig breeding/maintenance diet
- Water: ad libitum, tap water
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 45-65
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12

Study design: in vivo (non-LLNA)

Inductionopen allclose all
Route:
intradermal
Vehicle:
other: physiological saline/ polypropylene glycol (1:1)
Concentration / amount:
2.5%
Day(s)/duration:
single application
Route:
epicutaneous, occlusive
Vehicle:
other: physiological saline/polypropylene glycol (1:1)
Concentration / amount:
25%
Day(s)/duration:
Day 7/2 days
Challengeopen allclose all
No.:
#1
Route:
epicutaneous, occlusive
Vehicle:
other: physiological saline/polypropylene glycol (1:1)
Concentration / amount:
25%
Day(s)/duration:
Day 21/24 h
No.:
#2
Route:
epicutaneous, occlusive
Vehicle:
other: physiological saline/polypropylene glycol (1:1)
Concentration / amount:
25%
Day(s)/duration:
Day 28/24 h
No. of animals per dose:
5 males and 5 females for the vehicle control group;
10 males and 10 females for the test substance group.
Details on study design:
RANGE FINDING TESTS:
The objective of this investigation was to identify irritant test substance concentrations suitable for the induction phase of the main study. In addition, a suitable non-irritant concentration of the test substance, by the topical route of administration, was identified for the Challenge application.
Intradermal injections (0.1 mL/site) were made into the clipped flank of 4 guinea-pigs, using concentrations of 2.5 and 5% of the test substance in physiological saline/polypropylene glycol (1:1). The resulting dermal reactions (erythema and edema) were assessed 24 hours later.
Topical applications: Patches of filter paper (2 x 2 cm) were saturated with concentrations of 25% of the test substance in physiological saline/polypropylene glycol (1:1) and applied to the clipped and shaved flanks of each of 4 guinea-pigs. The patches were covered by a strip of aluminium foil and firmly secured by elastic plaster wrapped around the trunk and covered with impervious adhesive tape. The dressings were removed after an exposure period of 24 hours and the reaction sites were assessed for erythema and edema, on a numerical basis scale (0 to 4 numerical score). Further examination of the sites were performed 24 and 48 hours after removal of the dressings.

MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: 2
- Exposure period: 7 days (intradermal), 2 days (topical)
- Test groups:

Intradermal: single application
Anterior sites: 0.1 mL Freund‘s complete adjuvant 50:50 with physiological saline/polypropylene glycol (1:1) for injection.
Middle sites: 0.1 mL of the test substance, diluted to 2.5% with physiological saline/polypropylene glycol (1:1).
Posterior sites: 0.1 mL of the test substance at the concentration of 2.5%, emulsified in a 50:50 mixture of Freunds’ complete adjuvant, and the vehicle used.

Topical:
One week after the injections, the scapular area was again clipped and shaved free of hair. A 4 x 4 cm patch of filter paper was saturated with the test article (25%) and placed over the injection sites of the test animals. The patch was covered by aluminum foil and firmly secured by an elastic plaster wrapped around the trunk of the animal and secured with impervious adhesive tape. The dressings were left in place for approximately 48 hours.


- Control group: The guinea-pigs of the control group received identical
treatment without the test article.



B. CHALLENGE EXPOSURE
- No. of exposures: 2
- Day(s) of challenge: 21 and 28 (second Challenge was performed one week after the first challenge)
- Exposure period: 24 hours for each challenge
- Test groups: 2 x 2 cm patch of filter paper, saturated with 25% test article in vehicle
- Control group: vehicle only
- Site: left flank
- Evaluation (hr after challenge): just after application, 24 and 48 hours after removal of the patch (for challenge and re-challenge).

OTHER:
Statistics: Mean values with standard deviations where applicable.
Fischer-Test (The Exact Fischer Test for comparison of the basic probability of two binominal distributions, 1971)

INTERPRETATION:
The results evident in test animals at the challenge applications were compared with the results evident in control animals.

An allergic reaction was defined by visible reddening of the challenge site. The significance of difference in the number of animals with positive reactions between the treated group and the control group was assessed by the Fisher Test.
If the dermal reactions of a test animal at challenge were more persistent or marked than those of the control animals, the animal was considered to show evidence of delayed contact hypersensitivity.
If the dermal reactions of a test animal at challenge was not clearly different from the reactions in control group animals, the results for the test animal were considered inconclusive.
If the dermal reactions to the challenge application was identical to or less persistent/marked than the dermal reactions in control animals, the animal was considered to show no evidence of delayed contact hypersensitivity.
Challenge controls:
The control animals were treated with the test substance in the same concentration as the animals of the test group to avoid wrong positive results (challenge and re-challenge).
Positive control substance(s):
no

Results and discussion

Positive control results:
No data.

In vivo (non-LLNA)

Resultsopen allclose all
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
25%
No. with + reactions:
5
Total no. in group:
20
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
25%
No. with + reactions:
1
Total no. in group:
20
Key result
Reading:
rechallenge
Hours after challenge:
24
Group:
test chemical
Dose level:
25%
No. with + reactions:
0
Total no. in group:
20
Key result
Reading:
rechallenge
Hours after challenge:
48
Group:
test chemical
Dose level:
25%
No. with + reactions:
0
Total no. in group:
20
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
0%
No. with + reactions:
3
Total no. in group:
10
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
0%
No. with + reactions:
0
Total no. in group:
10
Key result
Reading:
rechallenge
Hours after challenge:
24
Group:
negative control
Dose level:
0%
No. with + reactions:
0
Total no. in group:
10
Key result
Reading:
rechallenge
Hours after challenge:
48
Group:
negative control
Dose level:
0%
No. with + reactions:
0
Total no. in group:
10
Reading:
1st reading
Group:
positive control
Remarks on result:
not measured/tested

Any other information on results incl. tables

No mortality was observed.


The body weight gain of the test animals was not affected by the test procedure.


Clinical signs:


Local: Erythema and edema was observed in the control as well as in the test article treated animals after intracutaneous injections.


Systemic: Two control animals and 6 test substance-treated animals showed a decrease in water consumption, slight sedation, ruffled fur, curved body position and enophthalmus at day 4 of the test, whereas at day 5 the same animals showed decrease in water consumption, ruffled fur and slight enophthalmos. They had recovered at day 6 of the test period.


 


Regarding the dermal reaction to the challenge, there was no significant (p < 0.01) difference between the results of the animals of the test article treated and vehicle control group.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met