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Diss Factsheets

Administrative data

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2003
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Title:
Unnamed
Year:
2003
Report date:
2003

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Principles of method if other than guideline:
The "maximisation test" of B. Magnusson and A. M.Kligman modified according to Maurer & Hess al was performed to reveal a possible sensitising potential of "STl571 F8".
GLP compliance:
yes
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
LLNA method was not available yet at the time the study was conducted.

Test material

Constituent 1
Test material form:
solid: particulate/powder
Details on test material:
Batch number: 022401

In vivo test system

Test animals

Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
female
Details on test animals and environmental conditions:

Age of the animals: Approx. 5 - 7 weeks at the firs1 application.

Weight range of the animals at the first application: 281 g to 341 g.

Number of the animals in the main study: 10 animals for the test substance group 5 animals for the control group.

Hygiene:
Optimal hygienic conditions.

Room number:
EH1-21.

Room temperature:
Average of 21.9 °C (continuous control and recording).

Relative humidity: Average of 48.6 % (continuous control and recording).

Air exchange: Approx. 12/h.

Light: Only artificial light from 6.00 a.m. to 6.00 p.m.

Cages: Until Day 0: Makrolon cages type Ill (23 cm x 39 cm bottom area, 18 cm height) with wire mesh lids, single caging.
From Day O: group cagirg in plastic containers (46 cm x 105 cm x 36 cm), partly shaded, 6 (control group) or 11 (test substance group) animals per contcliner.

Feed: Altromin Maintenance Diet No. 3122, rich in crude fiber, ad libitum, offered in stainless steel containers. Analysis of the feed for ingredients and contclminants are performed randomly by
Altromin GmbH, D-32791 Lage.

Bedding material: Wood chips (aspen) from Fa. ABEDD Dominik Mayr KEG,
A-8580 Koflach. Reduction of microorganisms by autoclaving.

Water: Tap water offered in Makrolon bottles with stainless steel canules ad libitum.
Identification of the animals: Numbers tattooed in the pinna of the right ear.

Acclimatisation: 5 days.

Study design: in vivo (non-LLNA)

Inductionopen allclose all
Route:
epicutaneous, occlusive
Vehicle:
petrolatum
Concentration / amount:
50% (w/w)in white petrolatum for the second induction exposure)
About 0.5 g of test substance formulation or of white petrolatum were applied to each animal.
Day(s)/duration:
7-9
Route:
epicutaneous, occlusive
Vehicle:
petrolatum
Remarks:
50% (w/w) in white petrolatum
Concentration / amount:
intradermal injections of FCA (to e,nhance a possible sensitisation) and immediately afterwards epicutaneous application of the, test substance to the sites of the intradermal injections. Application site was an area of approx. 2 cm x 4 cm in the interscapular region.
Day(s)/duration:
0-1
Challenge
Route:
epicutaneous, occlusive
Vehicle:
petrolatum
Concentration / amount:
50 % in white petrolatum. About 0.5 g of test substance formulation or of white petrolatum were applied to each animal.
Day(s)/duration:
24
Adequacy of challenge:
not specified
No. of animals per dose:
Number of animals in test group: 10
Number of animals in negative control group: 5
Details on study design:
According to the Guidelines, the concentrations of the test substance used for each induction exposure should be well-tolerated systemically and should be the highest to cause mild-to­ moderate skin irritation. The concentration used for the challenge exposure should be the highest non irritant one. To obtain the appropriate concentrations of the test substance for the definitive study, a preliminary test was carried out with 3 female guinea pigs. FCA was administered intradermally and immediately afterwards the test substance (50 % in white petrolatum, w/w)
was applied epicutaneously to the sites of the intrade1-mal injections to examine possible systemic toxic effects.
8 days later 4 concentrations of the test substance wme administered epicutaneously to the flanks of the animals. The modes of application were the same as in the de-'initive study. The duration of the epicutaneous exposure was 24 hours. The test substance was incorporated in white petrolatum. A test substance concentration of 50 % (w/w) in white petrolatum was the highest technically feasible concentration.

For the main study the following concentrations of "STl571 F8" were therefore selected:
50 % (w/w) in white petrolatum for the first and the se,cond epicutaneous induction and 25 % (w/w) in white petrolatum for the ctlallenge exposure.
As the highest technically feasible test substance concentration of 50 % in white petrolatum did not cause markable skin irritations it was also decided to pretreat all animals of both groups with a formulation of n-dodecylsulfate, sodium salt, in white petrolatum, one day before the second epicutaneous induction exposure.
Day 0 was 11 February 2003.
Day O: removal of hair, recording of body weight, intradermal FCA administration and epicutaneous administration of the test substancH.
Day 1: end of epicutaneous induction exposure.
Day 2: skin examination.
Day 6: removal of hair, treatment with n-dodecylsulfate, sodium salt.
Day 7: epicutaneous induction exposure.
Day 9: end of the epicutaneous induction exposure.
Day 1O: skin examination.
Day 21: removal of hair, epicutaneous challenge exposure
Day 21: end of the epicutaneous challenge period.
Day 23: approximately 21 hours after removing the patch cleaning of the challenge area,
approximately 3 hours later skin examination.
Day 24: skin examination, recording of body weight, sacrifice of animals, end of test.

All animals were observed once daily for behavioural channes or signs of toxicity.
The body weight of each animal was recorded on Days 0 and 24.
The application sites were examined 24 hours after the encl of the first epicutaneous induction exposure, 24 hours after the end of the second epicutaneous induction exposure and 24 and 48 hours after the end of the epicutaneous challenge exposure (blind reading of test and control animals).

A skin reaction after the challenge exposure was regarded as positive when the site, where test substance formulation was applied, was more irritated than the area of the site, where the vehicle was applied. The rate of these positively reactir g animals in the test substance group minus the rate of positively reacting animals in the negative control group gave the net percentage of sensitised animals.
The t-test was used to evaluate differences of the mean body weights between the test substance group and the control group on Days O and 24 ( p= 0.05).
Challenge controls:
The application sites were examined 24 hours after the encl of the first epicutaneous induction exposure, 24 hours after the end of the second epicutaneous induction exposure and 24 and 48 hours after the end of the epicutaneous challenge exposure (blind reading of test and control animals).
Positive control substance(s):
yes
Remarks:
HEXYL CINNAMIC ALDEHYDE" (HCA)

Results and discussion

Positive control results:
Vehicle site: no positive skin reaction in any anima at any reading time.
Substance site: very slight to severe erythema and/or oedema in 7/1O animals 24 and/or 48 hours after the challenge exposure.
7/1O animals had a "positive skin reaction".

In vivo (non-LLNA)

Resultsopen allclose all
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
50% in white petrolatum
No. with + reactions:
10
Total no. in group:
10
Clinical observations:
All animals of both groups had severe erythema and edema in the interscapular region (score "3"), which were attributed to the effects of the adjuvant.
Remarks on result:
positive indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
50% in white petrolatum
No. with + reactions:
10
Total no. in group:
10
Clinical observations:
24 and/or 48 hours after the end of the challenge exposure 10/1O test substance group animals had very slight to severe erythema and/or oedema at the test substance treated sites, attended by eschars in 3/10 animals.
Remarks on result:
positive indication of skin sensitisation
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
50% in white petrolatum
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
no positive skin reaction in any anima at any reading time. No animal had a "positive skin reaction".
Remarks on result:
no indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Dose level:
50% in white petrolatum
No. with + reactions:
7
Total no. in group:
10
Clinical observations:
very slight to severe erythema and/or oedema in 7/1O animals 24 and/or 48 hours after the challenge exposure.
Remarks on result:
positive indication of skin sensitisation

Any other information on results incl. tables

Maximum concentration not causing irritating effects in preliminary test: 50 %

Signs of irritation during induction:
Severe erythema and oedema were observed at the induction
site.

Evidence of sensitisation of each challenge concentration:
Test substance group: 10/10 animals (100 %) had very slight
to severe erythema and/or oedema 24 and 48 hours after   the
end of the challenge exposure, attended by eschars in
3/10 animals.

Negative control group: No positive skin reaction in any
animal at any reading time.

Other observations:
No relevant toxic signs other than local effects were
observed.

Applicant's summary and conclusion

Interpretation of results:
Category 1B (indication of skin sensitising potential) based on GHS criteria
Conclusions:
STI571 F8 is a skin sensitizer: Cat.1