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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:
January 1993 to August 1993
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1993
Report date:
1993

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Version / remarks:
17 July 1992
GLP compliance:
yes
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
The test was conducted prior to implementation of the updated guideline. Furthermore, the test item showed a clear sensitizing potential, thus, potency is not required.

Test material

Constituent 1
Chemical structure
Reference substance name:
trans-(5RS,6SR)-6-amino-2,2-dimethyl-1,3-dioxepan-5-ol
EC Number:
419-050-3
EC Name:
trans-(5RS,6SR)-6-amino-2,2-dimethyl-1,3-dioxepan-5-ol
Cas Number:
79944-37-9
Molecular formula:
C7H15NO3
IUPAC Name:
6-amino-2,2-dimethyl-1,3-dioxepan-5-ol

In vivo test system

Test animals

Species:
guinea pig
Strain:
Pirbright-Hartley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hagemann
- Weight at study initiation: 345-434 g males; 303-419 g females
- Housing: 1 or 2 in Makrolon® , type Ill cages; conventional
- Diet (e.g. ad libitum): ad libitum; pell. Altromin® MS, apple, hay
- Water (e.g. ad libitum): ad libitum; demineralized, acidified water (pH 2-3)
- Acclimation period: >18 days, maximization test; 7 days, local tolerance test
- Indication of any skin lesions: no

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-23
- Humidity (%): 54-70
- Photoperiod (hrs dark / hrs light): 12/12

Study design: in vivo (non-LLNA)

Inductionopen allclose all
Route:
epicutaneous, occlusive
Vehicle:
paraffin oil
Concentration / amount:
25%
Day(s)/duration:
24h occlusive, then further 23 days (2 weeks after epdermal administartion)
Adequacy of induction:
non-irritant substance, but skin pre-treated with 10% SDS
Route:
intradermal
Vehicle:
paraffin oil
Concentration / amount:
1.25%
Day(s)/duration:
8 days
Adequacy of induction:
highest technically applicable concentration used
Challenge
No.:
#1
Route:
epicutaneous, occlusive
Vehicle:
paraffin oil
Concentration / amount:
25%
Day(s)/duration:
24 h
Adequacy of challenge:
highest non-irritant concentration
No. of animals per dose:
10 males and 10 females
Details on study design:
RANGE FINDING TESTS:
intracutaneous tolerance
(The intracutaneous tolerance of the test item was tested at 3 different concentrations on 3 animals, each at different sites of the neck.
Concentrations:
A = 5.0% (w/v) test item
B = 2.5% (w/v) test item
C = 1.25% (w/v) test item
Epidermal tolerance
4 animals (2M, 2F) received two concentrations of ZK 38.199 under occlusive conditions
(24-hour exposure time) on the right and left side (one concentration/side) under the spine.

MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: Two:
1) lntradermal injections: ln the neck region (right to left side of the spine) of each animal an overall area of 4 x 6 cm was shorn (10M/10F). A total of 6 lntradermal injections, 3 on each side, were made according to the following scheme:
A. Test group
a) 0.1 mL FCA + vehicle (1+1)
b) 0.1 mL test item 1.25% (w/v)
c) 0.1 mL test item 2.5% (w/v) + FCA (1 +1) ≙ 1.25% (w/v) of the test item
Control group
a) 0.1 mL FCA + vehicle (1+1)
b) 0.1 mL vehicle
c) 0.1 mL FCA + vehicle (1+1)
- Exposure period: injected once and fiurther treatment after 8 days
- Site: back, beginning cranial and moving to caudal
- Frequency of applications: once
2) Epidermal application
In order to provoke the possible sensitizing effect of the test item the same area of skin (4x 6 cm) in which lntradermal injections were performed was reshaved on day 8 of the test and epidermally treated with approximately 1 mL sodium lauryl sulphate [10% (w/v)] in liquid paraffin. 24 hours later, on day 9, 0.2 ml of a 25% (w/v) suspension of the test item in liquid paraffin was spread over a 2 x 4 cm filter paper (Whatmann, no. SMM) for use in the test group, whereas for the control group only liquid paraffin was used. This filter paper was subsequently applied to the above-mentioned area pretreated with sodium lauryl sulphate. The patch was bandaged occlusively for 48 hours.

B. CHALLENGE EXPOSURE
- No. of exposures: 1
- Day(s) of challenge: 24 h at days 23
- Exposure period: 24 h
- Test groups: Approximately 0.1 mL test item [25% (w/v)] in liquid paraffin, which previously proved to be locally tolerated, was spread over a 2 x 2 cm piece of filter paper. This patch was placed in the middle of the shorn area of skin and bandaged occlusively for 24 hours. Reactions were recorded 24 and 48 hours after removal of the bandage.
- Control group: On day 23 (two weeks after the epidermal administration) a skin area of 5 x 5 cm was shorn on the right flank of each animal in both groups.
- Evaluation (hr after challenge): 24 and 48h

Results and discussion

In vivo (non-LLNA)

Resultsopen allclose all
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Dose level:
not reported
Clinical observations:
not reported
Remarks on result:
other: results not reported
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
not reported
Clinical observations:
not reported
Remarks on result:
other: results not reported
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
0%
No. with + reactions:
0
Total no. in group:
9
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
0%
No. with + reactions:
0
Total no. in group:
9
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
25%
No. with + reactions:
4
Total no. in group:
10
Clinical observations:
One animal (no 8F) showed apathy, loss of body weight, prone position etc. after removal of the bandage after epidermal induction (day 11 of the test). The animal was sacrificed moribund on day 13 of the test.
Remarks on result:
positive indication of skin sensitisation
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
25%
No. with + reactions:
4
Total no. in group:
10
Clinical observations:
One animal (no 8F) showed apathy, loss of body weight, prone position etc. after removal of the bandage after epidermal induction (day 11 of the test). The animal was sacrificed moribund on day 13 of the test.
Remarks on result:
positive indication of skin sensitisation

Applicant's summary and conclusion

Interpretation of results:
Category 1 (skin sensitising) based on GHS criteria
Conclusions:
In the present GPMT some clinical signs were observed. One animal (no 8F) showed apathy, loss of body weight, prone position etc. after removal of the bandage after epidermal induction (day 11 of the test). The animal was sacrificed moribund on day 13 of the test. Macroscopic findings after post-mortem examination, raised suspicion of pneumonia.
On the basis of the local results after the epidermal challenge, Aminodioxepan proved to have a sensitizing potential in the guinea-pig.
Executive summary:

In a dermal sensitization study similar to OECD test guideline 406 (GPMT) with Aminodioxepan (100% a.i) in paraffin oil, young adult Pirbright White guinea-pigs (10/sex) were tested using the method of Magnusson and Kligman. In a pretest the maximum tolerable (epidermal and intradermal) concentration of the test item in paraffin oil was determined as 25% and 1.25 %, respectively. For the intradermal induction three different injections (1.25%) were made along the spine from cranial to caudal.


For the epidermal induction 25% of the test item were applied to the dorsal site of the guinea pigs for 48h after pretreatment with 10% SDS in paraffin oil for 24h. Two weeks after epidermal induction the challenge procedure was performed with 25% of the test item spread on a filter paper and applied to the site where the induction took place. The site was bandaged occlusively for 24 h and thereafter the reactions were recorded after 24 and 48 h.


One animal (no 8F) showed apathy, loss of body weight, prone position etc. after removal of the bandage after epidermal induction (day 11 of the test). The animal was sacrificed moribund on day 13 of the test. Macroscopic findings after post-mortem examination, raised suspicion of pneumonia.


On the basis of the local results after the epidermal challenge, Aminodioxepan proved to have a sensitizing potential in the guinea-pig.