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Diss Factsheets

Administrative data

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
30 August 1999 - 8 October 1999
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study has been performed according to OECD and EC guidelines and according to GLP principles.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1999
Report date:
1999

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.6 (Skin Sensitisation)
Deviations:
no
GLP compliance:
yes
Type of study:
guinea pig maximisation test

Test material

Constituent 1
Reference substance name:
STI571 Y5A
IUPAC Name:
STI571 Y5A
Details on test material:
- Physical state: Brown solid
- Analytical purity: 98.6%
- Lot/batch No.: 992301
- Expiration date of the lot/batch: 01 July 2001
- Storage condition of test material: In refrigerator in the dark

In vivo test system

Test animals

Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Kisslegg, Germany.
- Number of animals: 15 females (females were nulliparous and non-pregnant), 10 females in experimental group and 5 females in the control group.
- Age at study initiation: Young adult animals (approx. 5 weeks old)
- Weight at study initiation: < 500 grams
- Housing: Group housing of 5 animals per labelled metal cage with wire-mesh floors and equipped with an automatic drinking system (ITL, Bergen, The Netherlands).
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: The acclimatisation period was at least 5 days before the start of treatment under laboratory conditions.

ENVIRONMENTAL CONDITIONS
A controlled environment was maintained in the room with optimal conditions considered as being approximately 15 air changes per hour, a temperature of 21°C, a relative humidity of 30-70% and 12 hours artificial fluorescent light and 12 hours dark per day.

IN-LIFE DATES: From: 30 August 1999 To: 8 October 1999

Study design: in vivo (non-LLNA)

Inductionopen allclose all
Route:
intradermal
Vehicle:
propylene glycol
Concentration / amount:
induction intradermal 20%
induction epidermal 50%
challenge: 0 and 50%
Challengeopen allclose all
Route:
epicutaneous, occlusive
Vehicle:
propylene glycol
Concentration / amount:
induction intradermal 20%
induction epidermal 50%
challenge: 0 and 50%
No. of animals per dose:
Experimental group: 10 females.
Control group : 5 females.
Details on study design:
RANGE FINDING TESTS:

MAIN STUDY

Day 1 The scapular region was clipped and three pairs of intradermal injections (0.1 ml/site) were made in this area as follows:
A) A 1:1 w/w mixture of Freunds' Complete Adjuvant (Difco, Detroit, U.S.A.) with water for injection (Fresenius AG, Bad Homburg, Germany).
B) The test substance at a 20% concentration.
C} A 1:1 w/w mixture of the test substance, at twice the concentration used in (B) and Freunds' Complete Adjuvant.
Note: One of each pair was on each side of the midline and from cranial A) to caudal C).

Day 3 The dermal reactions caused by the intradermal injections were assessed for irritation.

Day 7 The scapular area between the injection sites was clipped and subsequently rubbed with 10% sodium-dodecyl-sulfate (SDS, Boom, Meppel, The Netherlands) in vaseline using a spatula. This concentration of SDS provokes a mild inflammatory reaction.

Day 8 The 10% SDS treated area between the injection sites was treated with 0.5 ml of a 50% test substance concentration using a Metalline patch (2x3 cm) mounted on Medical tape, which was held in place with Micropore tape and subsequently Coban elastic bandage.
The dressing was removed after 48 hours exposure, the skin cleaned of residual test substance and the dermal reactions caused by the epidermal exposure were assessed for irritation.

The control animals were treated as described for the experimental animals except that, instead of the test substance, vehicle alone was administered.

B. CHALLENGE EXPOSURE
Day 22 One flank of all animals (including control) was clipped and treated by epidermal application of a 50% test substance concentration and the vehicle (0.15 ml each), using Patch Test Plasters (Leukoteste , Beiersdorf Medical, Almere, The Netherlands). The patches were held in place with Micropore tape and subsequently Coban elastic bandage. The dressing was removed after 24 hours exposure and the skin cleaned of residual test substance and vehicle. The treated sites were assessed for challenge reactions 24 and 48 hours after removal of the dressing.

Challenge controls:
not applicable (same treatment as experimental animals).
Positive control substance(s):
yes
Remarks:
ALPHA-HEXYLCINNAMICALDEHYDE, TECH. 85%.

Results and discussion

In vivo (non-LLNA)

Resultsopen allclose all
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
50%
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
no
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. Dose level: 50%. No with. + reactions: 0.0. Total no. in groups: 5.0. Clinical observations: no.
Reading:
2nd reading
Hours after challenge:
24
Group:
negative control
Dose level:
0%
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
no
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 24.0. Group: negative control. Dose level: 0%. No with. + reactions: 0.0. Total no. in groups: 5.0. Clinical observations: no.
Reading:
1st reading
Hours after challenge:
48
Group:
negative control
Dose level:
50%
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
no
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 50%. No with. + reactions: 0.0. Total no. in groups: 5.0. 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
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 0%. No with. + reactions: 0.0. Total no. in groups: 5.0. Clinical observations: no.
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
50%
No. with + reactions:
10
Total no. in group:
10
Clinical observations:
no
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 50%. No with. + reactions: 10.0. Total no. in groups: 10.0. Clinical observations: no.
Reading:
2nd reading
Hours after challenge:
24
Group:
test chemical
Dose level:
0%
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
no
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 24.0. Group: test group. Dose level: 0%. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: no.
Reading:
1st reading
Hours after challenge:
48
Group:
test chemical
Dose level:
50%
No. with + reactions:
10
Total no. in group:
10
Clinical observations:
no
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: test group. Dose level: 50%. No with. + reactions: 10.0. Total no. in groups: 10.0. Clinical observations: no.
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
0%
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
no
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 0%. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: no.

Any other information on results incl. tables

Induction phase

Since a 50% concentration, selected in the preliminary irritation study, could not be injected, a 20% concentration was used instead. The signs of necrosis seen in the control animals after the intradermal injection with vehicle only were in consistency with the results in the preliminary irritation study after injection of propylene glycol. The reactions noted in the experimental and control animals after the epidermal induction exposure were considered to be enhanced by the SDS treatment.

Challenge phase

Skin reactions varying between grades 2 and 3 were observed in all experimental animals in response to the 50% test substance concentration. No skin reactions were evident in the control animals. Eschar formation and fissuring of the skin was seen in some treated skin sites among the experimental animals.

No mortality occurred 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

Applicant's summary and conclusion

Interpretation of results:
sensitising
Remarks:
Migrated information
Conclusions:
The skin reactions observed in response to a 50% test substance concentration in ten (of the ten) experimental animals in the challenge phase were considered indicative of sensitisation, based on the absence of any response in the control animals.
These results indicate a sensitisation rate of 100 per cent.
Based on these results and according to the EC criteria for classification and labelling requirements for dangerous substances and preparations (Guidelines in Commission Directive 93/21/EEC), STI571 Y5A should be labelled as: may cause sensitisation by skin contact (R 43).