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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:
weight of evidence
Study period:
30 Mar 1984
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1986
Report date:
1986

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Deviations:
yes
Remarks:
The challenge concentration was inadequate for elicitation of sensitisation and insufficient volume of the material was used on each test site during the irritancy and inductions phases so that the skin at the site was not entirely covered.
GLP compliance:
yes
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
Currently no LLNA study is available for assessment. The GPMT test has been carried out as an animal test to predict human sensitisation for over a decade and is recommended by international test guidelines such as OECD.

Test material

Constituent 1
Chemical structure
Reference substance name:
Chlorothalonil
EC Number:
217-588-1
EC Name:
Chlorothalonil
Cas Number:
1897-45-6
Molecular formula:
C8Cl4N2
IUPAC Name:
tetrachlorobenzene-1,3-dicarbonitrile

In vivo test system

Test animals

Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Females nulliparous and non-pregnant: yes
- Weight at study initiation: approximately 350 g
- Housing: housed individually in appropriately-sized cages
- Diet: guinea pig chow, ad libitum
- Water: ad libitum
- Acclimation period: 4 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16 - 23
- Humidity (%): 40 - 60
- Photoperiod (hrs dark / hrs light): 12/12

Study design: in vivo (non-LLNA)

Inductionopen allclose all
Route:
intradermal
Vehicle:
other: acetone
Concentration / amount:
Injection: 0.1 mL
Treatment: adjuvant (FCA) diluted equally with acetone
Day(s)/duration:
Day 0: First injection of the three pairs of intradermal injections
Route:
intradermal
Vehicle:
other: acetone
Concentration / amount:
Injection: 0.1 mL
Treatment: 0.5 % test substance (w/v) in a 50:50 mixture of FCA and acetone
Day(s)/duration:
Day 0: Second injection of three pairs of intradermal injections
Adequacy of induction:
highest concentration used causing mild-to-moderate skin irritation and well-tolerated systemically
Route:
intradermal
Vehicle:
other: acetone
Concentration / amount:
Injection: 0.1 mL
Treatment: 0.5 % test substance (w/v) in acetone
Day(s)/duration:
Day 0: Third injection of the three pairs of intradermal injections
Adequacy of induction:
highest concentration used causing mild-to-moderate skin irritation and well-tolerated systemically
Route:
intradermal
Vehicle:
other: acetone
Remarks:
control group
Concentration / amount:
Injection: 0.1 mL
Treatment: FCA diluted equally with acetone
Day(s)/duration:
Day 0: First control injection out of three pairs of injections
Route:
intradermal
Vehicle:
other: acetone
Remarks:
control group
Concentration / amount:
Injection: 0.1 mL
Treatment: FCA diluted equally with acetone
Day(s)/duration:
Day 0: Second control injection out of three pairs of injections
Route:
intradermal
Vehicle:
unchanged (no vehicle)
Remarks:
control group
Concentration / amount:
Injection: 0.1 mL
Treatment: Acetone
Day(s)/duration:
Day 0: Third control injection out of three pairs of intradermal injections
Route:
epicutaneous, occlusive
Vehicle:
other: acetone
Concentration / amount:
Volume/area: 0.1 mL/2 x 4 cm area over the site of injection
Treatment: 1 % test substance in acetone, occlusive
Day(s)/duration:
Day 7: all test animals for 48 h
Adequacy of induction:
highest technically applicable concentration used
Route:
epicutaneous, occlusive
Vehicle:
unchanged (no vehicle)
Concentration / amount:
Volume/area: 0.1 mL/2 x 4 cm area over the injection site
Treatment: Acetone; occlusive
Day(s)/duration:
Day 7: all control animals for 48 h
Challengeopen allclose all
No.:
#1
Route:
epicutaneous, occlusive
Vehicle:
other: acetone
Concentration / amount:
Volume/area: 0.05 mL/2 x 2 cm area on one flank of each guinea pig in the test and control groups
Treatment: 0.001 % test substance in acetone
Day(s)/duration:
Day 21: occlusive dressing for 24 h
Adequacy of challenge:
highest non-irritant concentration
No.:
#2
Route:
epicutaneous, occlusive
Vehicle:
other: acetone
Concentration / amount:
Volume: 0.75 mL
Treatment: 0.001 % test substance in acetone
Day(s)/duration:
48 h, occlusive
Adequacy of challenge:
other: Re-challenge done due to the wrong interpretation of irritation study
No. of animals per dose:
5 animals per sex per dose
Details on study design:
RANGE FINDING TEST/IRRITATION STUDY:
For irritation testing, four 2 x 2 cm sites (2 on each flank) were designated on each of 2 male and 2 female guinea pigs. A volume of 0.05 mL of each of 4 different concentrations of test substance in acetone (i.e. 0.5%, 0.01%, 0.005% and 0.001% (w/v) was applied to the 4 sites on each animal). The sequence of the 4 concentrations of test material was varied from animal to animal to minimize the bias associated with the location of application, e.g. skin thickness. After treatment, the application sites were covered with gauze, then with occlusive plastic dressings and, finally, elastoplast tape.
After 24 hours of occlusion, the coverings were removed and irritation at each application site was determined. The highest concentration of the test substance in acetone causing no erythema or oedema at the site of application on any of the 4 animals was considered to be the highest non-irritating concentration.
Challenge controls:
0.05 mL of acetone alone
Positive control substance(s):
no

Results and discussion

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:
10
Remarks on result:
no indication of skin sensitisation
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
0.001 %
No. with + reactions:
1
Total no. in group:
10
Clinical observations:
Grade 2
Remarks on result:
positive 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:
other: 2nd challenge
Remarks:
no indication of skin sensitisation
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
0.001%
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
None
Remarks on result:
other: 2nd challenge
Remarks:
no indication of skin sensitisation
Group:
positive control
Remarks on result:
not measured/tested

Any other information on results incl. tables

The irritancy phase was repeated on all 24 guinea pigs. This testing was performed to give a guide in subsequent studies for determining irritancy levels. The following concentrations of the test substance were applied: 0.5%; 0.01%; 0.005%; and 0.001%. The volume was changed from 0.05 mL to 0.075 mL. An occlusive bandage covered the sites for 24 hours. The sites were graded 24 and 48 hours after the bandages were removed.

The 0.001% concentration of the test substance in acetone was the only concentration not to cause irritation on the test and control groups of animals. However, these animals had previously been exposed to acetone, test substance and FCA, which would tend to make them more reactive. Various difficulties encountered during the study made the results impossible to definitively interpret. The major problems were that 0.001% test substance was too low a concentration to have been applied in the challenge phase; the highest non-irritating concentration was probably nearer 0.005% or higher. The volume applied was also too low, and therefore the site was not adequately covered with solution. The volume which will cover the site is 0.075 mL.

Applicant's summary and conclusion

Interpretation of results:
study cannot be used for classification
Conclusions:
The first challenge with 0.001% test substance yielded a skin reaction in one animal, however due to technical problems encountered during the study, the results are inconclusive.
Executive summary:

The objective of the Guinea Pig Maximization Test (OECD 406, under GLP) was to evaluate the sensitisation potential of the test substance under exaggerated exposure conditions. In order to determine the lowest non-irritant concentration, 4 animals were exposed to 0.5%, 0.01%, 0.005%, and 0.001% (w/v) test substance in acetone. After 24 hours of occlusion, the coverings were removed and irritation at each application site was determined. The highest concentration of the test substance in acetone causing no erythema or oedema at the site of application on any of the 4 animals was considered to be the highest non-irritating concentration. Next, 20 animals (2 groups of 5 females and 5 males) were injected intradermally with 0.5% test substance in acetone with or without FCA (test group), FCA in acetone (test group and control group) or acetone alone (control group). After 7 days both groups were re-induced with topical, occlusive administration of 1% test substance in acetone or acetone alone (control group). Next, the animals were challenged (day 21) with 0.001% test substance.

The results were inconclusive, due to problems which occurred in this study. There were two major problems which occurred during the study. The primary difficulty was a challenge concentration of the test substance that was inadequate for elicitation of sensitisation. The second problem was that insufficient volume of the material was used on each test site during the irritancy and inductions phases of testing, so that the skin at the site was not entirely covered. This led to uneven concentrations in the patch test area and spurious results. A further study is needed to evaluate the sensitisation potential of this compound using the Guinea Pig Maximization test method.