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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:
key study
Study period:
from 15-DEC-1999 to 15-MAY-2000
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: guidance test with GLP compliance

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2000
Report date:
2000

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
other: Directive 96/54/EEC, B.6. "Acute Toxicity - Skin Sensitization", July 30, 1996.
Deviations:
no
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

Test material

Constituent 1
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Details on test material:
Identification: FAT41'029/A
Batch number: ARL 123/PP 1/99 UL
Purity: approx. 98 %
Color / Physical form: orange red to brown powder
Stability of test article: Stable under storage conditions
Expiry date: 04-NOV-2005
Storage conditions: In the original container, at room temperature (range of 20 ± 3 °C), away from direct sunlight
Safety precautions: Routine hygienic procedures were used to ensure the health and safety of the personnel

In vivo test system

Test animals

Species:
guinea pig
Strain:
other: Ibm: GOHI; SPF-quality
Sex:
female
Details on test animals and environmental conditions:
TEST SYSTEM
Test system: Ibm: GOHI; SPF-quality guinea pigs (synonym: Himalayan spotted)
Source: RCC Ltd Biotechnology & Animal Breeding Division CH-4414 Füllinsdorf / Switzerland
Number of animals for main study / pretest: 15 female / 3 female animals
Age at delivery: 4-6 weeks
Body weight at beginning of acclimatization period: 359 - 406 g
Acclimatization: One week for the control and test group under test conditions after health examination. No acclimatization for the animals of the pretest. Only animals without any visible signs of illness were used for the study.

HUSBANDRY
Conditions
Standard Laboratory Conditions:
Air-conditioned with 10-15 air changes per hour and continuously monitored environment with a range for room temperature of 22±3 °C, and for relative humidity between 40-70 %. The animals were provided with a 12-hour light, 12-hour dark cycle. Music was played during the light period.
Accommodation: Individually in Makrolon type-4 cages with standard softwood bedding
Diet: Pelleted standard Nafag Ecosan 845 25W4, batch nos. 85/99 and 96/99, guinea pig breeding / maintenance diet, containing Vitamin C, ad libitum.
Water: Community tap-water.

Study design: in vivo (non-LLNA)

Inductionopen allclose all
Route:
intradermal and epicutaneous
Vehicle:
other: PEG 300
Concentration / amount:
MAIN STUDY
INTRADERMAL INJECTIONS / PERFORMED ON TEST DAY 1
An area of dorsal skin from the scapular region (approximately 6x8 cm) was clipped free of hair. Three pairs of intradermal injections (0.1 ml/site) were made at the border of a 4 x 6 cm area in the clipped region.
EPIDERMAL APPLICATIONS / PERFORMED ON TEST DAY 8
On test day 8, a 2 x 4 cm patch of filter paper was saturated with the test article (50 % in PEG 300) and placed over the injection sites of the test animals. The amount of test article preparation applied was approximately 0.3 g. The patch was covered with aluminum foil and firmly secured by an elastic plaster wrapped around the trunk of the animal and secured with impervious adhesive tape. The occlusive dressings were left in place for 48 hours. The epidermal application procedure described ensures intensive contact of the test article. The guinea pigs of the control group were treated as described above with PEG 300 only, applied at a volume of approximately 0.3 ml.
CHALLENGE / PERFORMED ON TEST DAY 22
The test and control guinea pigs were challenged two weeks after the epidermal induction application and were treated in the same way.
Hair was clipped and shaved from a 5 x 5 cm area on the left and right flank of each guinea pig just prior to the application. Two patches (3x3 cm) of filter paper were saturated with the test article at the highest non-irritating concentration of 25 % (left flank) and the vehicle only (PEG 300 applied to the right flank) using the same method as for the epidermal application. The volume of test article preparation and vehicle applied was approximately 0.2 ml. The dressings were left in place for 24 hours.
Twenty-one hours after removal of the dressing the test sites treated with the test article were depilated as described in the epidermal pretest. The reaction sites were assessed 24 and 48 hours after removal of the bandage for erythema and oedema according to the method of Magnusson and Kligman.
Challengeopen allclose all
Route:
epicutaneous, occlusive
Vehicle:
other: PEG 300
Concentration / amount:
MAIN STUDY
INTRADERMAL INJECTIONS / PERFORMED ON TEST DAY 1
An area of dorsal skin from the scapular region (approximately 6x8 cm) was clipped free of hair. Three pairs of intradermal injections (0.1 ml/site) were made at the border of a 4 x 6 cm area in the clipped region.
EPIDERMAL APPLICATIONS / PERFORMED ON TEST DAY 8
On test day 8, a 2 x 4 cm patch of filter paper was saturated with the test article (50 % in PEG 300) and placed over the injection sites of the test animals. The amount of test article preparation applied was approximately 0.3 g. The patch was covered with aluminum foil and firmly secured by an elastic plaster wrapped around the trunk of the animal and secured with impervious adhesive tape. The occlusive dressings were left in place for 48 hours. The epidermal application procedure described ensures intensive contact of the test article. The guinea pigs of the control group were treated as described above with PEG 300 only, applied at a volume of approximately 0.3 ml.
CHALLENGE / PERFORMED ON TEST DAY 22
The test and control guinea pigs were challenged two weeks after the epidermal induction application and were treated in the same way.
Hair was clipped and shaved from a 5 x 5 cm area on the left and right flank of each guinea pig just prior to the application. Two patches (3x3 cm) of filter paper were saturated with the test article at the highest non-irritating concentration of 25 % (left flank) and the vehicle only (PEG 300 applied to the right flank) using the same method as for the epidermal application. The volume of test article preparation and vehicle applied was approximately 0.2 ml. The dressings were left in place for 24 hours.
Twenty-one hours after removal of the dressing the test sites treated with the test article were depilated as described in the epidermal pretest. The reaction sites were assessed 24 and 48 hours after removal of the bandage for erythema and oedema according to the method of Magnusson and Kligman.
No. of animals per dose:
10 animals for test group and 5 animals for control group
Details on study design:
OBSERVATIONS
Viability / Mortality: Daily from delivery of the animals to the termination of the test.
Clinical signs (local / systemic): Daily from delivery of the animals to the termination of the test.
Skin reactions: At the times specified during the pretest, induction and challenge periods.
Body weights: At pretest and acclimatization start, day 1 and termination of the test.

PATHOLOGY
NECROPSY
No necropsies were performed in the animals of the control and test group sacrificed at termination of the observation period nor in the animals of the intradermal and epidermal pretest sacrificed on test day 1 of the main study. The animals were sacrificed by intraperitoneal injection of NARCOREN at a dose of at least 2.0 ml/kg body weight and discarded.
Challenge controls:
vehicle: PEG 300
Positive control substance(s):
yes
Remarks:
ALPHA-HEXYLCINNAMALDEHYDE

Results and discussion

Positive control results:
ALPHA-HEXYLCINNAMALDEHYDE applied at a concentration of 1 % in PEG 300 has to be classified and labelled as a skin sensitizer.

In vivo (non-LLNA)

Resultsopen allclose all
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
25 % in PEG 300
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
No signs of systemic toxicity were observed in the animals.
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. Dose level: 25 % in PEG 300. No with. + reactions: 0.0. Total no. in groups: 5.0. Clinical observations: No signs of systemic toxicity were observed in the animals..
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
PEG 300 only
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
No signs of systemic toxicity were observed in the animals.
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. Dose level: PEG 300 only. No with. + reactions: 0.0. Total no. in groups: 5.0. Clinical observations: No signs of systemic toxicity were observed in the animals..
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
25 % in PEG 300
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
No signs of systemic toxicity were observed in the animals.
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 25 % in PEG 300. No with. + reactions: 0.0. Total no. in groups: 5.0. Clinical observations: No signs of systemic toxicity were observed in the animals..
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
PEG 300 only
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
No signs of systemic toxicity were observed in the animals.
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: PEG 300 only. No with. + reactions: 0.0. Total no. in groups: 5.0. Clinical observations: No signs of systemic toxicity were observed in the animals..
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
25 % in PEG 300
No. with + reactions:
6
Total no. in group:
10
Clinical observations:
No signs of systemic toxicity were observed in the animals.
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 25 % in PEG 300. No with. + reactions: 6.0. Total no. in groups: 10.0. Clinical observations: No signs of systemic toxicity were observed in the animals..
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
PEG 300 only
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
No signs of systemic toxicity were observed in the animals.
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: PEG 300 only. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: No signs of systemic toxicity were observed in the animals..
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
25 % in PEG 300
No. with + reactions:
5
Total no. in group:
10
Clinical observations:
No signs of systemic toxicity were observed in the animals.
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 25 % in PEG 300. No with. + reactions: 5.0. Total no. in groups: 10.0. Clinical observations: No signs of systemic toxicity were observed in the animals..
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
PEG 300 only
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
No signs of systemic toxicity were observed in the animals.
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: PEG 300 only. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: No signs of systemic toxicity were observed in the animals..

Any other information on results incl. tables

SKIN EFFECTS AFTER INTRADERMAL INDUCTION - PERFORMED ON TEST DAY 1

The expected and common findings were observed in the control and test group after the different applications using FCA intradermally and consisted of erythema, oedema, necrotizing dermatitis, encrustation and exfoliation of encrustation. No description of the results is given in the report as these FCA effects are well-known.

SKIN EFFECTS AFTER EPIDERMAL INDUCTION-PERFORMED ON TEST DAY 8

CONTROL GROUP: No erythematous or oedematous reaction was observed in the animals treated with PEG 300 only.

TEST GROUP: As the test article at 50 % stained the skin red, it was not possible to determine whether erythema was present or not. However, no oedema was observed.

SKIN EFFECTS AFTER THE CHALLENGE - PERFORMEDON TEST DAY 22

CONTROL GROUP: No skin reactions were observed in the animals when treated with either PEG 300 only or when treated with the test article at 25 % in PEG 300. Red discoloration produced by the test article was noted directly after removal of the patch. To remove the discoloration all animals were depilated 3 hours prior to challenge reading.

TEST GROUP: Discrete/patchy to moderate/confluent erythema were observed in six (at the 24-hour reading) and discrete/patchy erythema in five (at the 48-hour reading) out of 10 animals after treatment with the test article at 25 % in PEG 300. No skin reactions were observed in the animals treated with PEG 300 only. Red discoloration produced by the test article was noted directly after removal of the patch. To remove the discoloration all animals were depilated 3 hours prior to challenge reading.

VIABILITY / MORTALITY / MACROSCOPIC FINDINGS

There were no deaths during the course of the study, hence no necropsies were performed.

CLINICAL SIGNS, SYSTEMIC

No signs of systemic toxicity were observed in the animals.

BODY WEIGHTS

The body weight of the animals was within the range commonly recorded for animals of this strain and age.

Applicant's summary and conclusion

Interpretation of results:
sensitising
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Test article is considered to possess skin sensitizing potential in albino guinea pigs.
Executive summary:

In order to assess the cutaneous allergenic potential of FAT41'029/A, the Maximization-Test was performed in 15 (10 test and 5 control) female albino guinea pigs, in accordance with OECD Guideline No. 406 and the Directive 96/54/EEC, B.6.

The intradermal induction of sensitization in the test group was performed in the nuchal region with a 10 % dilution of the test article in PEG 300 and in an emulsion of Freund's Complete Adjuvant (FCA) / physiological saline. The epidermal induction of sensitization was conducted for 48 hours under occlusion with the test article at 50 % in PEG 300 one week after the intradermal induction and following pretreatment of the test areas with 10 % Sodium-Lauryl-Sulfate (SLS) 23 hours prior to application of the test article. The animals of the control group were intradermally induced with PEG 300 and FCA/physiological saline and epidermally induced with PEG 300 under occlusion following pretreatment with 10 % SLS. Two weeks after epidermal induction the control and test animals were challenged by epidermal application of the test article at 25 % in PEG 300 and PEG 300 alone under occlusive dressing. Cutaneous reactions were evaluated at 24 and 48 hours after removal of the dressing.

No toxic symptoms were evident in the guinea pigs of the control or test group. No deaths occurred. Six out of 10 test animals showed discrete/patchy to moderate/confluent erythema at the 24-hour reading and five out of 10 test animals showed discrete/patchy erythema at the 48-hour reading after the challenge treatment with FAT41'029/A at 25 % (w/w) in PEG 300. No skin effect was observed in the control group.

Based on the above mentioned findings in an adjuvant sensitization test in guinea pigs, FAT41'029/A is classified as a skin sensitizer.