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Toxicological information

Skin sensitisation

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Administrative data

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Although the study was conducted according to GLP and well documented methods, " Practical guide 10: How to avoid unnecessary testing on animals", Section 3.3.2 states it is important that the reliability indicator (Klimisch score) reflects the assumptions of similarity. Thus, a score of 1 (reliable without restrictions) should normally not be used for results derived from read-across.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1990
Report Date:
1991

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
other: Guinea Pig Maximizatoin Test described by Magnusson B. and Kligman A.M, 1969
Principles of method if other than guideline:
Doses: concentrations of 5% intradermally (Day 1) and 10% epicutaneously (Day 8)

On day 32, all animals were sacrificed by overdose of barbiturate. Skin samples restricted to flank application sites (ie-sites given rechallenge doses) were taken and fixed in 10% neutral buffered formalin.

Hematoxylin and eosin-stained sections from all sampled sites of all animals were evaluated microscopically.
GLP compliance:
yes
Type of study:
guinea pig maximisation test

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report):L-158,086-005H salt
- Analytical purity: 98% (HPLC)
- Lot/batch No.: 10
- Stability under test conditions: stable

In vivo test system

Test animals

Species:
guinea pig
Strain:
Hartley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River, France
- Age at study initiation: 6 weeks
- Weight at study initiation: 290-320g
- Housing: Animals distributed in individual cages in an air-conditioned room
- Diet (e.g. ad libitum): UAR 114C Lab Chow
- Water (e.g. ad libitum):ad libitum
- Acclimation period:

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 deg C
- Humidity (%): 30-70%
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12/12

Study design: in vivo (non-LLNA)

Inductionopen allclose all
Route:
intradermal and epicutaneous
Vehicle:
petrolatum
Concentration / amount:
5% -intradermal; 10%-epicutaneous
Challengeopen allclose all
Route:
epicutaneous, occlusive
Vehicle:
petrolatum
Concentration / amount:
5% -intradermal; 10%-epicutaneous
No. of animals per dose:
10-control, 11-treatment
Details on study design:
MAIN STUDY.
A. INDUCTION EXPOSURE
- No. of exposures: 2 exposures (Day one-intradermal, Day 8-epicutaneous) Two 0.1 ml intradermal injections were given to each animal, one on each side of the dorsal midline.
- Exposure period:
- Test groups:
- Control group: Freund’s Complete Adjuvant diluted with an equal volume of distilled water.
- Site:
- Frequency of applications: weekly
- Duration:(injection)
- Concentrations: 5% in an emulsion formed by the mixing of the oil phase of Freund’s Complete Adjuvant with an equal volume of distilled water.

B. CHALLENGE EXPOSURE
- No. of exposures: 2
- Day(s) of challenge: Days 22, 29
- Exposure period:24 h
- Test groups:
- Control group:
- Site: 2x2 cm patch on right (negative control) and left flank (treatment)
- Concentrations: 10% in petrolatum. A factor of 1.09 was used in preparing doses.
- Evaluation (hr after challenge): 24 and 48h


OTHER:
On day 32, all animals were sacrificed by overdose of barbiturate. Skin samples restricted to flank application sites (ie-sites given rechallenge doses) were taken and fixed in 10% neutral buffered formalin.

Hematoxylin and eosin-stained sections from all sampled sites of all animals were evaluated microscopically.
Positive control substance(s):
not specified

Results and discussion

In vivo (non-LLNA)

Resultsopen allclose all
Reading:
1st reading
Hours after challenge:
24
Group:
test group
Dose level:
10%
No. with + reactions:
0
Total no. in group:
11
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 10%. No with. + reactions: 0.0. Total no. in groups: 11.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
test group
Dose level:
10%
No. with + reactions:
1
Total no. in group:
11
Clinical observations:
scattered redness and no swelling
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 10%. No with. + reactions: 1.0. Total no. in groups: 11.0. Clinical observations: scattered redness and no swelling.
Reading:
rechallenge
Hours after challenge:
24
Group:
test group
Dose level:
10%
No. with + reactions:
1
Total no. in group:
11
Clinical observations:
scattered redness and no swelling
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 24.0. Group: test group. Dose level: 10%. No with. + reactions: 1.0. Total no. in groups: 11.0. Clinical observations: scattered redness and no swelling.
Reading:
other: rechallenge-second reading
Hours after challenge:
48
Group:
negative control
Dose level:
0
No. with + reactions:
1
Total no. in group:
10
Clinical observations:
scattered redness and no swelling
Remarks on result:
other: Reading:
Reading:
rechallenge
Hours after challenge:
48
Group:
test group
Dose level:
10%
No. with + reactions:
3
Total no. in group:
11
Clinical observations:
2@scattered redness, no swelling. 1@ diffuse redness, no swelling
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 48.0. Group: test group. Dose level: 10%. No with. + reactions: 3.0. Total no. in groups: 11.0. Clinical observations: 2@scattered redness, no swelling. 1@ diffuse redness, no swelling.

Any other information on results incl. tables

Post-mortem evaluation: epidermal and dermal changes typifying a contact dermatisis (slight acanthosis with very slight diffuse mononuclear cell infiltration of the upper dermis were seen in the left application sites of three animals from the treatment group. In two animals, it was associated with intraepithelial vesicle formation and positive skin reactions were recorded grossly for these two animals.

Very slight acanthosis was occasionally noted in other animals of this group as well as animals from the control group. Very slight acanthosis was judged as the result of non-specific irritation due to occlusive applications of petrolatum (vehicle).

Applicant's summary and conclusion

Interpretation of results:
sensitising
Remarks:
Migrated information Criteria used for interpretation of results: expert judgment
Conclusions:
Losartan potassium and therefore, losartan free acid by read-across, is considered as a mild sensitiser.
Executive summary:

L-158, 086 (losartan potassium), and therefore, losartan free acid by read-across, is a considered a mild sensitizer at the concentrations tested in this study.