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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:
25.10.1988 - 24.11.1988
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: study performed according to OECD guideline (406) and under GLP conditions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1989
Report date:
1989

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

Test material

Constituent 1
Chemical structure
Reference substance name:
Retinyl propionate
EC Number:
230-363-2
EC Name:
Retinyl propionate
Cas Number:
7069-42-3
Molecular formula:
C23H34O2
IUPAC Name:
retinyl propionate
Details on test material:
- Identification: Vitamin A-Propionate 2.5 mIU/g stab. with BHA / BHT
- Physical state: yellowish liquid
- Analytical purity: approx. 90%
- Lot/batch No.: Lot 808007
- Expiration date of the lot/batch: August 1990
- Storage condition of test material: stable

In vivo test system

Test animals

Species:
guinea pig
Strain:
other: Himalayan White spotted guinea pigs (outbred)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Institute of Biomedical Research
- Age at study initiation: males: 7 weeks; females: 8 weeks
- Weight at study initiation: males: 324 - 377 g; females: 318 - 347 g
- Housing: individually in Makrolon type-3 cages with standard softwood bedding ("Lignocel", Schill AG, 4132 Muttehnz, Switzerland)
- Diet (e.g. ad libitum): ad libitum (pelleted standard NAFAG)
- Water (e.g. ad libitum): community tap water, ad libitum
- Acclimation period: one week under test conditions after veterinary examination

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C +/- 3
- Humidity (%): 40 - 70 %
- Air changes (per hr): 10-15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours artificial fluorescent light / 12 hours dark, music/light period

Study design: in vivo (non-LLNA)

Inductionopen allclose all
Route:
intradermal and epicutaneous
Vehicle:
olive oil
Concentration / amount:
test article, diluted to 5% with olive oil
Challengeopen allclose all
Route:
epicutaneous, semiocclusive
Vehicle:
olive oil
Concentration / amount:
test article, diluted to 5% with olive oil
No. of animals per dose:
vehicle control: 5 males, 5 females
test article treated group: 10 males, 10 females
Details on study design:
RANGE FINDING TESTS: yes
Intradermal injections (0.1 ml / site) were made into the clipped flank of two guinea-pigs at concentrations of 5, 3, 1, 0.5, 0.3 and 0 . 1 % of the test
article in olive oil . The resulting dermal reactions were assessed 24 hours later.

MAIN STUDY
A. INDUCTION EXPOSURE
- Three pairs of intradermal injections (0.1 ml/site) were made at the border of a 4x6 cm area in the clipped region. Test article was diluted to 5% with
olive oil.
- one week after the injections, the scapular area was again clipped and shaved free of hair. A patch of filter paper was saturated with the undiluted test article and place over the injection sites of the test animals. The patch was covered by aluminum foil and firmly secured by an elastic paster wrapped around the trunk of the animal and secured with impervious adhesive tape. The dressing were left in place for approximately 48 hours. The epidermal
application procedure described ensured intesive contact of the test article to the skin.

Reaction sites were assessed for erythema and edema immediately, 24 and 48 hours after removal of the dressing, using the numerical grading system:

Erythema and edema were assessed using the following numerical grading system:

Erythema and eschar formation:

No erythema 0
Slight erythema (barely perceptible) 1
Well-defined erythema 2
Moderate erythema 3
Severe erythema (beet redness) to slight
eschar formation ( injuries in depth) 4

Edema formation:

No edema 0
Slight edema ( barely perceptible ) 1
Well-defined edema (edges of area
well-defined by definiteraising ) 2
Moderate edema (raised approximately
1 millimeter ) 3
Severe edema ( raised more than 1 milli -
meter and extending beyond the area of
exposure) 4


B. CHALLENGE EXPOSURE
Test and control guinea-pigs were challenged two weeks after the epidermal induction application.
- Exposure period: 24 hours
- Concentrations: test article diluted to 30% in olive oil
- Evaluation (hr after challenge): immediately, 24 and 48 hours

C. RE-CHALLENGE:
Due to the reactions observed after the first challenge application, no second challenge was performed.
Positive control substance(s):
yes
Remarks:
Dinitro-chloro-benzene

Results and discussion

Positive control results:
Clear positive testing results were observed in the DNCB treated animals after the epidermal challenge application (September 1988).
10 Dunkin-Hartley albino guinea-pigs (from DUHA Kleintierfarm Madoerin, Switzerland) were used, of which 6 reacted positive and 3 negative (1 diedspontaneously on day 11 of test). This results in a 67% positive reaction.
Induction by 0.5% DNCB in ethanol, challenge by 0.3% DNCB. Substance: DNCB (1-chloro-2,4-dinitro-benzol) from Fluka (Switzerland) frabricated under No. 24440 with a purity of 98%.
Substance possesses a strong skin sensitizing potential according to the test.

In vivo (non-LLNA)

Resultsopen allclose all
Reading:
2nd reading
Hours after challenge:
0
Group:
negative control
Dose level:
vehicle (olive oil)
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
none
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 0.0. Group: negative control. Dose level: vehicle (olive oil). No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: none.
Reading:
2nd reading
Hours after challenge:
24
Group:
negative control
Dose level:
vehicle (olive oil)
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
none
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 24.0. Group: negative control. Dose level: vehicle (olive oil). No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: none.
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
vehicle (olive oil)
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
none
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: vehicle (olive oil). No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: none.
Reading:
2nd reading
Hours after challenge:
0
Group:
negative control
Dose level:
30% Vitamin A propionate in olive oil
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
none
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 0.0. Group: negative control. Dose level: 30% Vitamin A propionate in olive oil. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: none.
Reading:
2nd reading
Hours after challenge:
24
Group:
negative control
Dose level:
30% Vitamin A propionate in olive oil
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
none
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 24.0. Group: negative control. Dose level: 30% Vitamin A propionate in olive oil. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: none.
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
30% Vitamin A propionate in olive oil
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
none
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 30% Vitamin A propionate in olive oil. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: none.
Reading:
2nd reading
Hours after challenge:
24
Group:
test chemical
Dose level:
30% Vitamin A propionate in olive oil
No. with + reactions:
1
Total no. in group:
19
Clinical observations:
erythema
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 24.0. Group: test group. Dose level: 30% Vitamin A propionate in olive oil. No with. + reactions: 1.0. Total no. in groups: 19.0. Clinical observations: erythema.
Reading:
2nd reading
Hours after challenge:
0
Group:
test chemical
Dose level:
vehicle (olive oil)
No. with + reactions:
0
Total no. in group:
19
Clinical observations:
none
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 0.0. Group: test group. Dose level: vehicle (olive oil). No with. + reactions: 0.0. Total no. in groups: 19.0. Clinical observations: none.
Reading:
2nd reading
Hours after challenge:
24
Group:
test chemical
Dose level:
vehicle (olive oil)
No. with + reactions:
0
Total no. in group:
19
Clinical observations:
none
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 24.0. Group: test group. Dose level: vehicle (olive oil). No with. + reactions: 0.0. Total no. in groups: 19.0. Clinical observations: none.
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
vehicle (olive oil)
No. with + reactions:
0
Total no. in group:
19
Clinical observations:
none
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: vehicle (olive oil). No with. + reactions: 0.0. Total no. in groups: 19.0. Clinical observations: none.
Reading:
2nd reading
Hours after challenge:
0
Group:
test chemical
Dose level:
30% Vitamin A propionate in olive oil
No. with + reactions:
0
Total no. in group:
19
Clinical observations:
none
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 0.0. Group: test group. Dose level: 30% Vitamin A propionate in olive oil. No with. + reactions: 0.0. Total no. in groups: 19.0. Clinical observations: none.
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
30% Vitamin A propionate in olive oil
No. with + reactions:
0
Total no. in group:
19
Clinical observations:
none
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 30% Vitamin A propionate in olive oil. No with. + reactions: 0.0. Total no. in groups: 19.0. Clinical observations: none.

Any other information on results incl. tables

SENSITIZING EFFECTS:

Vehicle Control: No positive reactions were evident after the first challenge application.

Test article: One animal out of nineteen showed positive reactions after the first challenge application.

VIABILITY/MORTALITY:

One Female animal (test article - treated group) died spontaneously on day 21 of test. This animal showed following macroscopical findings: lungs: discoloration, dark red

SYMPTOMS, LOCAL:

Vehicle control: Application area around the injection sites 1 to 3 were found to show slight edema and erythema from day 2 to 6 of test. Starting from day 7 to 8 and 10 to 13, crusts were observed and exfoliation from day 14 to 31 (termination). Discoloration was observed on day 24 of test.

Test article: The animals of the test article-treated group showed the same reactions as described above. No discoloration of the treated skin area was observed. At day 9 of test no observation could be performed because of the application area the animals were treated semi-occlusively.

SYMPTOMS, SYSTEMIC:

No systemic symptoms were observed.

BODY WEIGHTS:

The body weight gain of all animals was not affected during the test procedure.

Applicant's summary and conclusion

Interpretation of results:
not sensitising
Remarks:
Migrated information
Conclusions:
Based on the data reported it can be concluded that Vitamin-A-propionate shows no allergenicity for guinea pigs. The probability that it might cause skin complaints of allergic origin in man seems low, if any.
Executive summary:

In this allergenicity study Vitamin A propionate was used at concentrations of 5 and 30% in olive oil for epicutaneous and intradermal induction. After challenging with 30% Vitamin A propionate in olive oil all controls and 18 of 19 experimental animals stayed negative. One experimental animal showed slight short-lasting skin responses. Due to its intensity and duration these skin reactions were classified as of primary irritant origin. One experimental animal died spontaneously. Based on the data reported Vitamin A propionate shows no allergenicity for guinea pigs.