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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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1990
Report date:
1990

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
GLP compliance:
yes
Type of study:
guinea pig maximisation test

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of substance: Tetrahydrothiopyran-3-aldehyd
- Substance number: 89/713
- Batch No.: "Aus Fass 72"
- Date of manufacturing: Nov. 1, 1988
- Degree of purity/composition: about 93%
- Physical state/appearance: liquid, achromatic
- Homogeneity of the test substance: the sample appeared to be homogeneous
- Storage stability of the test substance at about 8° C:
- Stability of the test substance preparation(s): the stability of the test substance in olive oil DAB 9 was confirmed by analysis
On completion of all tests the stability of the substance will be verified by a repeated analysis. The result can be obtained from the sponsor (BASF AG)

In vivo test system

Test animals

Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
female
Details on test animals and environmental conditions:
- Strain/quality: Pirbright White, Dunkin Hartley HOE DHPK [SPF-LAC] BÖ
- Origin: Lippische Versuchstierzucht, Hagemann GmbH & Co. KG, 0-49 23 Extertal 1, FRG
- Sex: Female
- Body weight at the beginning of the study: 293 - 348 g
- Housing: individual
- Diet: Kliba 341.4 mm (Kaninchen-Meerschweinchen-Haltungsdiät) ad libitum
- Supplier: Firma Klingentalmuehle AG, CH-4303 Kaiseraugst, Switzerland
- Water: Water ad libitum (tap water; about.2 g of ascorbic acid per 10 1 water was added to the drinking water twice a week)
- Acclimatization period: At least 7 days before the beginning of the study in the laboratory for dermal toxicity

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12/12


Feed analysis:
The feed used in the study was assayed for contaminants. In view of the aim and duration of the study the contaminants occurring in commercial feed ought not to influence the results.

Drinking water analysis:
The drinking water is regularly assayed for contaminants by the municipal authorities of Frankenthal and the Technical Services of BASF AG. In view of
the aim and duration of the study there are no special requirements exceeding the specifications of the drinking water.

Analysis of the bedding:
The bedding is regularly assayed for contaminants (chlorinated hydrocarbons, heavy metals) . In view of the aim and duration of the study there are no special requirements exceeding the specification of a commercial grade monitored by the manufacturer.

Study design: in vivo (non-LLNA)

Inductionopen allclose all
Route:
intradermal and epicutaneous
Vehicle:
olive oil
Concentration / amount:
Intradermal induction: 5 % in olive oil DAB 9 resp. in Freund’s adjuvant/0.9 % aqueous NaCl solution (1:1) resp. olive oil DAB 9
Percutaneous induction: 75 % in olive oil. DAB 9 resp. olive oil DAB 9
1st challenge: 50 % in olive oil DAB 9 resp. olive oil DAB 9
2nd challenge 50 % in olive oil DAB 9 resp. olive oil DAB 9
Challengeopen allclose all
Route:
epicutaneous, occlusive
Vehicle:
olive oil
Concentration / amount:
Intradermal induction: 5 % in olive oil DAB 9 resp. in Freund’s adjuvant/0.9 % aqueous NaCl solution (1:1) resp. olive oil DAB 9
Percutaneous induction: 75 % in olive oil. DAB 9 resp. olive oil DAB 9
1st challenge: 50 % in olive oil DAB 9 resp. olive oil DAB 9
2nd challenge 50 % in olive oil DAB 9 resp. olive oil DAB 9
No. of animals per dose:
10 animals per control group (1 and 2)
20 animals in the test group
Details on study design:
Conduct and aim of the study
Based on the method of Magnusson, 8. and Kligman. A.M.: The Identification of Contact Allergens by Animal Assay. The Guinea Pig Maximization Test. J. Invest. Dermatol. 52, 268 - 276 (1969).
The maximization test was carried out to assess whether the test substance has a sensitizing potential.

General
Weight check of the individual animals:
before intradermal induction and before the end of the study.

Clipping of the test animals:
if required, about 3 to 5 hours before each reading and before each test substance application
at the appropriate application sites.

Clinical examinations:
no detailed examinations; check
for sick animals and for those showing a deteriorated general state each workday.

Form of application:
- intradermal and percutaneous occlusive
For a detailed assessment of a sensitizing potential the percutaneous application which corresponds to the everyday possibility of exposure was preceded by an intradermal
application so that the skin barrier was perforated and thus a possible intensified uptake via injured skin areas was taken into account.

Preparation of the test substance formulations:
-Formulations of the test substance were prepared gravimetrically;
all concentrations were determined in weight/weight.

Pretest
Amount applied:
2 x 2 cm filter paper strips were applied to the skin of the flanks under an occlusive dressing. In the case of liquids the test filter paper strip was soaked in the test substance resp. test substance formulation; thus, the animals were exposed to about 0.15 g of the test substance resp. test substance formulation.

Exposure period:
The test substance was applied 2 times for 24 hours within a period of 96 hours in order to detect non-specific phenomena that are not caused by a sensitization reaction but could possibly be attributed to a shift in the irritation threshold.

Site of application:
- flank, respective on the same area

Number of test animals:
- 4 per test concentration

Readings:
- about 24 and 48 h after the beginning of application

Assessment of skin findings:
1. Erythema and eschar formation
0) No erythema
1) Very slight erythema (barely perceptible)
2) Well-defined erythema
3) Moderate to severe erythema
4) Severe erythema (beet redness) to slight eschar formation (injuries in depth)

2. Edema formation
0) No edema
1) Very slight edema (barely perceptible)
2) Slight edema (edges of area well defined by definite raising)
3) Moderate edema (raised approximately 1 mm)
4) Severe edema (raised more than 1 mm and extending beyond the area of exposure)

Main test
Number of animals per control group 10
Number of animals per test group 20

Induction
Intradermal induction:
- 6 intradermal injections in groups of two per animal

Injections for the test group:
A) front row: 2 injections each of 0.1 ml Freund's adjuvant without test substance emulsified with 0.9% aqueous NaCl-solution in a ratio of 1 :1
B) middle row: 2 injections each of 0.1 ml of the test substance formulation
C) back row: 2 injections each of 0.1 ml Freund's adjuvant / 0.9% aqueous NaCl-solution (1 :1) with test substance

Injections for control groups 1 and 2:
- The animals were given the same injections (A, B, C) but without test substance, only with the formulating agent.

Site of application:
- shoulder

Readings:
-24 h after the beginning of application
Assessment of the skin findings:
- analogous to the pretest

Percutaneous induction:
- Percutaneous induction was carried out about one week after intradermal induction

Amount applied:
2 x 4 cm filter paper strips were applied to the skin of the shoulder under an occlusive dressing. In the case of liquids the filter paper strip was soaked in the test substance formulation; thus, the animals were exposed to about 0.3 g of the test substance formulation.
-The control groups were treated analogously to the test group but only with the solvent without the test substance.

Duration of exposure:
- 48 hours

Site of application:
- shoulder, same area as in the case of the previous intradermal application

Readings:
- 48 h after the beginning of application

Assessment of skin findings:
- analogous to the pretest

Challenge
Test concentration: non-irritant concentration
First challenge: 14 days after percutaneous application.
Second challenge: one week later

Amount applied:
2 x 2 cm filter paper strips were applied to the skin of the flank under an occlusive dressing. In the case of liquids the test filter paper strip was soaked in the test substance formulation; thus the animals were exposed to about 0.15 g of the test substance formulation.

1st challenge:
- treatment of the test group and of control group 1 with the test substance formulation. Additionally, olive oil DAB 9 was applied as a vehicle. Control group 2 only received olive oil DAB 9

2nd challenge:
- treatment of the test group and of control groups 1 and 2 with the test substance formulation. Analogous to the first challenge olive oil DAB 9 was applied as a vehicle

Duration of exposure:
- 24 hours

Site of application:
- intact clipped flank

Readings:
- 24, 48 and 72 h after the beginning of application

Assessments of skin findings:
- analogous to the pretest

EVALUATION
Based on the criteria of Annex VI/II D of the Council Directive of July 29, 1983 for the 5th Amendment of the Directive 67/548 EEC (= 83/467 EEC). The number of animals sensitized is primarily taken into account in the evaluation. The control animals are used to rule out a substance-induced primary skin irritation. The findings obtained 48 hours after the beginning of application are taken into account for the determination of the sensitization rate.
Challenge controls:
previously vehicle-treated animals were used as challenge controls
Positive control substance(s):
no

Results and discussion

In vivo (non-LLNA)

Resultsopen allclose all
Reading:
1st reading
Hours after challenge:
48
Group:
test chemical
Dose level:
50 %
No. with + reactions:
4
Total no. in group:
20
Clinical observations:
erythema in one animal, edema in 3 animals
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: test group. Dose level: 50 %. No with. + reactions: 4.0. Total no. in groups: 20.0. Clinical observations: erythema in one animal, edema in 3 animals.
Reading:
1st reading
Hours after challenge:
48
Group:
negative control
Dose level:
50 %
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 50 %. No with. + reactions: 0.0. Total no. in groups: 10.0.
Reading:
2nd reading
Hours after challenge:
72
Group:
negative control
Dose level:
50 %
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 72.0. Group: negative control. Dose level: 50 %. No with. + reactions: 0.0. Total no. in groups: 10.0.
Reading:
rechallenge
Hours after challenge:
48
Group:
test chemical
Dose level:
50 %
No. with + reactions:
4
Total no. in group:
20
Clinical observations:
erythema in one animal, edema in 3 animals
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 48.0. Group: test group. Dose level: 50 %. No with. + reactions: 4.0. Total no. in groups: 20.0. Clinical observations: erythema in one animal, edema in 3 animals.
Reading:
rechallenge
Hours after challenge:
48
Group:
negative control
Dose level:
50 %
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 48.0. Group: negative control. Dose level: 50 %. No with. + reactions: 0.0. Total no. in groups: 10.0.
Reading:
rechallenge
Hours after challenge:
72
Group:
negative control
Dose level:
50 %
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 72.0. Group: negative control. Dose level: 50 %. No with. + reactions: 0.0. Total no. in groups: 10.0.

Any other information on results incl. tables

SUMMARY

The substance Tetrahydrothiopyran-3-aldehyd was tested for its sensitizing effect on the skin of the guinea pig in the maximization test based on the method of Magnusson and Kligman.

After intradermal induction distinct erythema and edema were observed at the injection sites of the control animals and the test animals, at which only Freund's adjuvant/0.9% aqueous NaCl solution (1:1) was applied. Injection of the test substance preparation in olive oil DAB 9 also caused distinct erythema and edema in the test animals. After the application of the test substance preparation in Freund's adjuvant/0.9% aqueous NaCl-solution (1 :1) necrotic skin changes in addition to distinct edema could be observed in the test animals. The control animals injected with olive oil DAB 9 (vehicle) showed distinct erythema. After the percutaneous induction necrotic skin changes (caused by the intradermal induction) in addition to distinct edema were observed in the test animals. The animals of control group 1 and 2 which were applied with olive oil DAB 9 (vehicle) exhibited incrustation, partially open (caused by the intradermal induction) in

addition to distinct erythema and edema. The number of animals with skin findings after the 1stchallenge (20 days after intradermal induction) and after the 2ndchallenge (27 days after intradermal induction) is summarized in the following table:

 

 

1st challenge

2nd challenge

50% in olive oil DAB 9

olive oil DAB 9

50% in olive oil DAB 9

olive oil DAB 9

Control group 1

0/10

0/10

0/10

0/10

Control group 2

no application of test substance

0/10

0/10

0/10

Test group

4/20

2/20

4/20

0/20

x/y: number of positive reactions/number of animals readings 48 h after the beginning of application

 

After the first challenge with the 50 % test substance preparation in olive oil DAB 9 (48 hours after the beginning of application) distinct erythema in addition to slight edema could be observed in one out of 20 test animals. 3 out of 20 test animals showed slight erythema. The animals of control group one did not show any skin reactions at the 48- and 72 hour - readings. After the second challenge with the 50 % test substance preparation in olive oil DAB 9 (48 hours after the beginning of application) in one out of 20 test animals distinct erythema was observed. 3 out of 20 test animals showed slight erythema. The animals of control group one and two did not show any skin reactions at the 48- and 72 hour - readings.

Olive oil DAB 9 applied as a vehicle caused distinct erythema in one animal and slight erythema in another animal of the test group 48 hours after the first challenge. The control animals did not show any skin reaction neither after the first, nor after the second challenge (48- and 72 hour - readings).

Under these test conditions and following the results described above Tetrahydrothiopyran-3-aldehyd does not have a sensitizing effect on the skin of the guinea pig.

Applicant's summary and conclusion

Interpretation of results:
not sensitising
Remarks:
Migrated information