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Skin sensitisation

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Administrative data

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Start of the experimental phase December 13, 2013, Termination of the in-life phase February 22, 2014.
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2014

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 (incl. QA statement)
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
Study performed before the amendments to Annexes VII and VIII.

Test material

Constituent 1
Test material form:
other: liquid
Details on test material:
- Name of test material (as cited in study report): FlocrylTM MADAM/MECL 75%
- Substance type: Organic
- Physical state: Clear to slightly yellow liquid
- Analytical purity: Monomer concentration 74.9%, 25.1% water
- Impurities (identity and concentrations): Not identified
- Composition of test material, percentage of components: 74.9%
- Purity test date: 04.12.2013
- Lot/batch No.: MADC 1-43-13-03-E
- Expiration date of the lot/batch:
- Stability under test conditions: stable
- Storage condition of test material: At room temperature, not stored together with oxidizing and self-igniting products.

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 Laboratories, Research Models and Services, Germany GmbH, Sandhofer Weg 7, 97633 Sulzfeld, Germany
- Age at study initiation: 5 weeks
- Weight at study initiation: 286 – 315 g (excluding positive control group); Positive control group: 313 – 371 g
- Housing: The animals were kept in pairs in MAKROLON cages (MZK 80/25). Granulated textured wood (Granulat A2, J. BRANDENBURG, 49424 Goldenstedt, Germany) was used as bedding material in the cages. The cages were changed and cleaned twice a week.
- Diet (e.g. ad libitum): Food was offered ad libitum.
- Water (e.g. ad libitum): Tap water (in drinking bottles) was offered ad libitum.
- Acclimation period: At least 5 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20°C ± 3°C (maximum range).
- Humidity (%): relative humidity of 55% ± 15% (maximum range)
- Air changes (per hr): 15 to 20 times
- Photoperiod (hrs dark / hrs light): Rooms were lit (about 150 lux at approx. 1.50 m room height) on a 12-hour light/12-hour dark cycle.

IN-LIFE DATES: From: January 29, 2014 To: February 22, 2014

Study design: in vivo (non-LLNA)

Inductionopen allclose all
Route:
other: shoulder region, first by intracutaneous application (stage 1) and 7 days later by topical administration (stage 2, exposure time: 48 hours).
Vehicle:
other: The test item was diluted in aqua ad iniectabilia for the stage 1 and the challenge or used as supplied for stage 2. Aqua ad iniectabilia Batch nos. 131718161 and 134078161; B. Braun Melsungen, AG, 34212 Melsungen, Germany.
Concentration / amount:
stage 1:intracutaneous: 5% solution of FlocrylTM MADAM/MECL 75% in aqua ad iniectabilia
stage 2: topical: undiluted FlocrylTM MADAM/MECL 75%
stage 3: topical: 0.1% solution of FlocrylTM MADAM/MECL 75% in aqua ad iniectabilia
Challengeopen allclose all
Route:
other: topically to the flank region (exposure time: 24 hours).
Vehicle:
other: The test item was diluted in aqua ad iniectabilia for the stage 1 and the challenge or used as supplied for stage 2. Aqua ad iniectabilia Batch nos. 131718161 and 134078161; B. Braun Melsungen, AG, 34212 Melsungen, Germany.
Concentration / amount:
stage 1:intracutaneous: 5% solution of FlocrylTM MADAM/MECL 75% in aqua ad iniectabilia
stage 2: topical: undiluted FlocrylTM MADAM/MECL 75%
stage 3: topical: 0.1% solution of FlocrylTM MADAM/MECL 75% in aqua ad iniectabilia
No. of animals per dose:
Vehicle control (aqua ad iniectabilia): 5
FlocrylTM MADAM/MECL 75%: 10
Positive control: 20
Details on study design:
RANGE FINDING TESTS: Sixteen animals were used for the preliminary test: 11 animals for the topical administration and 5 animals for the intracutaneous administration. The allocation of different test sites of the animals was alternated in order to minimize site-to-site variations in response.
- Exposure period: 24 hours and 48 hours for the shaved skin, 24 hours for the shaved and depilated skin.
- Concentrations: intracutan: 0.01, 0.1, 0.5, 1, 5, 10% of FlocrylTM MADAM/MECL 75%; topical 100, 75, 50, 25, 10, 5, 1% of FlocrylTM MADAM/MECL 75% (shaved); 0.001, 0.005, 0.01, 0.1, 0.5, 1, 5, 10, 25, 50, 75, 100 % of FlocrylTM MADAM/MECL 75% (shaved and depilated)

MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: 2 (intracutaneous and topical)
- Exposure period: 24 hours and 48 hours
- Test groups: 1
- Control group: 1
- Site: shoulder region
- Frequency of applications: shoulder region, first by intracutaneous application (stage 1) and 7 days later by topical administration (stage 2, exposure time: 48 hours).
- Duration:20 days
- Concentrations: intracutaneous: 5% solution of FlocrylTM MADAM/MECL 75% in aqua ad iniectabilia; topical: undiluted FlocrylTM MADAM/MECL 75%

B. CHALLENGE EXPOSURE
- No. of exposures: 1
- Day(s) of challenge: day 21
- Exposure period: 24 hours
- Test groups: 1
- Control group: 1
- Site: flank region
- Concentrations: 0.1% solution of FlocrylTM MADAM/MECL 75% in aqua ad iniectabilia
- Evaluation (hr after challenge): 48 and 72 hours

OTHER: day 6: 0.5 mL sodium laurylsulphate 10% in Vaseline in order to induce a local irritation
Positive control substance(s):
yes
Remarks:
α-hexyl cinnamic aldehyde

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:
5
Clinical observations:
none
Remarks on result:
other: Reading: 1st 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: none.
Reading:
1st reading
Hours after challenge:
48
Group:
negative control
Dose level:
0
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
none
Remarks on result:
other: Reading: 1st 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: none.
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
0
No. with + reactions:
5
Total no. in group:
5
Clinical observations:
discrete or patchy erythema
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 0. No with. + reactions: 5.0. Total no. in groups: 5.0. Clinical observations: discrete or patchy erythema.
Reading:
2nd reading
Hours after challenge:
72
Group:
negative control
Dose level:
0
No. with + reactions:
5
Total no. in group:
5
Clinical observations:
discrete or patchy erythema
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 72.0. Group: negative control. Dose level: 0. No with. + reactions: 5.0. Total no. in groups: 5.0. Clinical observations: discrete or patchy erythema.
Reading:
rechallenge
Hours after challenge:
48
Group:
negative control
Dose level:
0
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
none
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 48.0. Group: negative control. Dose level: 0. No with. + reactions: 0.0. Total no. in groups: 5.0. Clinical observations: none.
Reading:
rechallenge
Hours after challenge:
72
Group:
negative control
Dose level:
0
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
none
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 72.0. Group: negative control. Dose level: 0. No with. + reactions: 0.0. Total no. in groups: 5.0. Clinical observations: none.
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
5%
No. with + reactions:
10
Total no. in group:
10
Clinical observations:
discrete or patchy erythema
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 5%. No with. + reactions: 10.0. Total no. in groups: 10.0. Clinical observations: discrete or patchy erythema.
Reading:
1st reading
Hours after challenge:
48
Group:
test chemical
Dose level:
5%
No. with + reactions:
10
Total no. in group:
10
Clinical observations:
discrete or patchy erythema
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: test group. Dose level: 5%. No with. + reactions: 10.0. Total no. in groups: 10.0. Clinical observations: discrete or patchy erythema.
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
undiluted
No. with + reactions:
10
Total no. in group:
10
Clinical observations:
moderate or confluent erythema or intense erythema and swelling
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: undiluted. No with. + reactions: 10.0. Total no. in groups: 10.0. Clinical observations: moderate or confluent erythema or intense erythema and swelling.
Reading:
2nd reading
Hours after challenge:
72
Group:
test chemical
Dose level:
undiluted
No. with + reactions:
10
Total no. in group:
10
Clinical observations:
a moderate and confluent erythema or intense erythema and swelling
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 72.0. Group: test group. Dose level: undiluted. No with. + reactions: 10.0. Total no. in groups: 10.0. Clinical observations: a moderate and confluent erythema or intense erythema and swelling.
Reading:
rechallenge
Hours after challenge:
48
Group:
test chemical
Dose level:
0.1%
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
none
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 48.0. Group: test group. Dose level: 0.1%. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: none.
Reading:
rechallenge
Hours after challenge:
72
Group:
test chemical
Dose level:
0.1%
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
none
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 72.0. Group: test group. Dose level: 0.1%. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: none.
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
10%
No. with + reactions:
20
Total no. in group:
20
Clinical observations:
discrete or patchy erythema
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: positive control. Dose level: 10%. No with. + reactions: 20.0. Total no. in groups: 20.0. Clinical observations: discrete or patchy erythema.
Reading:
1st reading
Hours after challenge:
48
Group:
positive control
Dose level:
10%
No. with + reactions:
20
Total no. in group:
20
Clinical observations:
discrete or patchy erythema
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: positive control. Dose level: 10%. No with. + reactions: 20.0. Total no. in groups: 20.0. Clinical observations: discrete or patchy erythema.
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Dose level:
100%
No. with + reactions:
20
Total no. in group:
20
Clinical observations:
moderate and confluent erythema
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: positive control. Dose level: 100%. No with. + reactions: 20.0. Total no. in groups: 20.0. Clinical observations: moderate and confluent erythema.
Reading:
2nd reading
Hours after challenge:
72
Group:
positive control
Dose level:
100%
No. with + reactions:
20
Total no. in group:
20
Clinical observations:
discrete or patchy erythema
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 72.0. Group: positive control. Dose level: 100%. No with. + reactions: 20.0. Total no. in groups: 20.0. Clinical observations: discrete or patchy erythema.
Reading:
rechallenge
Hours after challenge:
48
Group:
positive control
Dose level:
0.01%
No. with + reactions:
20
Total no. in group:
20
Clinical observations:
discrete or patchy erythema or moderate and confluent erythema
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 48.0. Group: positive control. Dose level: 0.01%. No with. + reactions: 20.0. Total no. in groups: 20.0. Clinical observations: discrete or patchy erythema or moderate and confluent erythema.
Reading:
rechallenge
Hours after challenge:
72
Group:
positive control
Dose level:
0.01%
No. with + reactions:
13
Total no. in group:
20
Clinical observations:
discrete or patchy erythema
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 72.0. Group: positive control. Dose level: 0.01%. No with. + reactions: 13.0. Total no. in groups: 20.0. Clinical observations: discrete or patchy erythema.

Any other information on results incl. tables

Behaviour of the animals remained unchanged.

Applicant's summary and conclusion

Interpretation of results:
not sensitising
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The challenge with 2 mL of a 1% solution of Flocryl MADAM / MEC 75% in aqua ad iniectabilia/animal revealed no skin irritation in any animal and, thus, the test item had no sensitising properties.

The vehicle control revealed no skin reactions.

Animals of the same strain treated with α-hexyl cinnamic aldehyde in sesame oil exhibited a sensitising reaction in all animals in form of a moderate and confluent erythema (grade 2).

Under the present test conditions, Flocryl MADAM / MEC 75% in aqua ad iniectabilia/animal revealed no skin irritation in any animal and, thus, the test item had no sensitising properties. was found to be not sensitising to guinea pigs in a test model according to MAGNUSSON and KLIGMAN.