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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:
weight of evidence
Study period:
December 1997 - July 1998
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
Planning and conduct of the study were based on the guidance provide by the following guidelines and directives: EEC Directive 96/54, L248, Annex IV C, Test B.6 (dated September 30, 1996) EEC Directive 93/21, L 110 A, Annex IV (dated May 04, 1993) OECD guidelines for the testing of chemicals (guideline 406 adopted July 17, 1992)

Data source

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

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
Study was already available.

Test material

Reference
Name:
Unnamed
Type:
Constituent

In vivo test system

Test animals

Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Wiga GmbH, Sulzfeld
- Age at study initiation: approx. 28 days
- Weight at study initiation: 287 +/-10 g (n=15)
- Housing: Altromin Type S8/15, granulated soft wood bedding (Altromin, 32791 Lage/Lippe, Germany) Batch No. 051297 until 17/12/97, thereafter 181297
- Diet (ad libitum): Altromin 1322, standard diet for guinea pigs, Batch No: 040398/0725
- Water (ad libitum): tap water (municipal supply Bitterfeld) in Makrolon bottles, daily change
- Acclimation period: 6 days before the start of the study

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-23°C
- Humidity (%): 30-60%
- Air changes (per hr): 10-15 air changes per hour
- Photoperiod (hrs dark / hrs light): artificial light is set to give a cycle of 12 hours light and 12 hours dark

Study design: in vivo (non-LLNA)

Induction
Route:
intradermal and epicutaneous
Vehicle:
water
Concentration / amount:
INDUCTION EXPOSURE:
Day 0: Induction by intradermal injection: Two pairs of intradermal injections of 0.1 ml each were administered to each animal.
Control group:
Injection 1: 50:50 mixture (v/v) of FCA and Aqua pro injectione
Injection 2: Aqua pro injectione
Injection 3: the third injection was not necessary because the chosen vehicle was Aqua pro injectione
Dose group:
Injection 1: 50:50 mixture (v/v) of FCA and Aqua pro injectione
Injection 2: 10% solution (w/v) of the test article in Aqua pro injectione
Injection 3: 10% emulsion (w/v) of the test article in 50:50 mixture (v/v) Aqua pro injectione and FCA

Day 7: Induction by dermal application
Control group: Filter papers (2x4 cm) were soaked in 0.1 g of white vaseline. One paper each was then placed on the skin on both sides of the body and covered with an occlusive dressing for 48 hours.
Dose group:
Filter papers (2x4 cm) were soaked in 0.1 g of the 75:25 mixture (w/w) of test article and white vaseline. One paper each was then placed on the skin on both sides of the body and covered with an occlusive dressing for 48 hours.
Adequacy of induction:
highest concentration used causing mild-to-moderate skin irritation and well-tolerated systemically
Challenge
No.:
#1
Route:
epicutaneous, occlusive
Vehicle:
water
Concentration / amount:
INDUCTION EXPOSURE:
Day 0: Induction by intradermal injection: Two pairs of intradermal injections of 0.1 ml each were administered to each animal.
Control group:
Injection 1: 50:50 mixture (v/v) of FCA and Aqua pro injectione
Injection 2: Aqua pro injectione
Injection 3: the third injection was not necessary because the chosen vehicle was Aqua pro injectione
Dose group:
Injection 1: 50:50 mixture (v/v) of FCA and Aqua pro injectione
Injection 2: 10% solution (w/v) of the test article in Aqua pro injectione
Injection 3: 10% emulsion (w/v) of the test article in 50:50 mixture (v/v) Aqua pro injectione and FCA

Day 7: Induction by dermal application
Control group: Filter papers (2x4 cm) were soaked in 0.1 g of white vaseline. One paper each was then placed on the skin on both sides of the body and covered with an occlusive dressing for 48 hours.
Dose group:
Filter papers (2x4 cm) were soaked in 0.1 g of the 75:25 mixture (w/w) of test article and white vaseline. One paper each was then placed on the skin on both sides of the body and covered with an occlusive dressing for 48 hours.

CHALLENGE EXPOSURE:
Day 21: Challenge by dermal application: each animal: 1.0 g sample of either vehicle or the 75:25 mixture (w/w) of test article and white vaseline
No. of animals per dose:
10 males (test group)
5 males (control group)
Details on study design:
RANGE FINDING TESTS:

MAIN STUDY
A. INDUCTION EXPOSURE
Induction by intradermal injection (Day 0)
- No. of exposures: 3
- Exposure period: -
- Test groups:
Injection 1: 50:50 mixture (v/v) of FCA and Aqua pro injectione
Injection 2: 10% solution (w/v) of the test article in Aqua pro injectione
Injection 3: 10% emulsion (w/v) of the test article in 50:50 mixture (v/v) Aqua pro injectione and FCA

- Control group:
Injection 1: 50:50 mixture (v/v) of FCA and Aqua pro injectione
Injection 2: Aqua pro injectione
Injection 3: the third injection was not necessary because the chosen vehicle was Aqua pro injectione
- Site: shoulder region, each side of the midline in cranial to caudal sequence
- Frequency of applications:
- Duration:
- Concentrations:

Induction by dermal application (Day 7)
Dose group:
Filter papers (2x4 cm) were soaked in 0.1 g of the 75:25 mixture (w/w) of test article and white vaseline. One paper each was then placed on the skin on both sides of the body and covered with an occlusive dressing for 48 hours.
Control group: Filter papers (2x4 cm) were soaked in 0.1 g of white vaseline. One paper each was then placed on the skin on both sides of the body and covered with an occlusive dressing for 48 hours.

B. CHALLENGE EXPOSURE
Challenge by dermal application (Day 21)
each animal: 1.0 g sample of either vehicle or the 75:25 mixture (w/w) of test article and white vaseline
- No. of exposures: each animal
- Day(s) of challenge: 21
- Exposure period: 24 hours
- Test groups: 1.0 g sample of either vehicle or the 75:25 mixture (w/w) of test article and white vaseline
- Control group: 1.0 g sample of either vehicle or the 75:25 mixture (w/w) of test article and white vaseline
- Site:dose group: right flank, controll group: left flank
- Concentrations: either vehicle or the 75:25 mixture (w/w) of test article and white vaseline
- Evaluation: 24 and 48 hours after patch removal (Days 23 and 24)
Challenge controls:
Guidelines recommend the use of guinea-pigs as the experimental rodent species for this type of study. The guinea-pig has been the mammal of choice for predictive sensitisation tests for several decades and a considerable data base is available from the literature.
Positive control substance(s):
yes
Remarks:
Freund's Complete Adjuvant (FCA)

Results and discussion

Positive control results:
80 % of the animals used reacted with skin sensitisation and the skin-fold thickness was significantly increased in the treated animals on days 23 and 24. The positive control results demonstrate that the laboratory has the capability to identify positive dermal sensitizers.

In vivo (non-LLNA)

Resultsopen allclose all
Key result
Reading:
2nd reading
Hours after challenge:
72
Group:
test chemical
Dose level:
75:25 (w/w) mixture of test article with white vaseline
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
no skin reaction
Key result
Reading:
1st reading
Hours after challenge:
48
Group:
test chemical
Dose level:
75:25 (w/w) mixture of test article with white vaseline
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
no skin reaction
Reading:
1st reading
Hours after challenge:
48
Group:
negative control
Dose level:
0
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
no skin reaction
Reading:
2nd reading
Hours after challenge:
72
Group:
negative control
Dose level:
0
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
no skin reaction
Reading:
1st reading
Hours after challenge:
48
Group:
positive control
Dose level:
10% solution in liquid paraffin
No. with + reactions:
8
Total no. in group:
10
Clinical observations:
increased skin-fold thickness
Reading:
2nd reading
Hours after challenge:
72
Group:
positive control
Dose level:
10% solution in liquid paraffin
No. with + reactions:
5
Total no. in group:
10
Clinical observations:
increased skin-fold thickness

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
Brüggolit FF6 has no skin sensitisation effect.
Executive summary:

The skin sensitisation potential of the test article was investigated in the Guinea-pig Maximisation Test with the Dunkin Hartley albino strain following OECD 406 and GLP criteria. The sensitivity of the test animals to benzocaine has been demonstrated. In the course of testing, no clinical signs were observed and the body weight gain of animals was not significantly influenced. The choice of doses was based on the results of the pilot study. The animals showed a very homogeneous reaction to the application of the test substance. The intradermal injection of the 10 % solution of the test article alone and in combination with sensitisation potentiating FCA lead to slight erythema and oedema. The same pattern was seen at injection site 1 (FCA/water mixture ) in the control animals. Topical induction was attempted with the 75:25 mixture of test article with white vaseline on day 7. After removal of the occlusive dressing on day 9 not any skin irritation was recorded in the animals.

After challenge with the 75:25 preparation in white vaseline neither the control nor the dose group animals showed any skin effects. Oedema formation was excluded by measurement of skin-fold thickness.