2-hydroxypropyl [(1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl] carbonate

Sensitisation data (human)

Administrative data

Endpoint:

sensitisation data (humans)

Type of information:

other: human data

Adequacy of study:

supporting study

Study period:

1997-12-01 to 1998-01-09

Reliability:

other: not rated acc. to Klimisch

Rationale for reliability incl. deficiencies:

other: relevant

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1998

Report date:

1998

Materials and methods

Type of sensitisation studied:

skin

Study type:

study with volunteers

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

To determine the irritant effect on the skin of the test product in a forced repetitive cutaneous test under occlusive conditions in a patch test.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]propan-2-ol

EC Number:

607-858-0

Cas Number:

260781-16-6

Molecular formula:

C14H26O4

IUPAC Name:

1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]propan-2-ol

Method

Type of population:

general

Ethical approval:

confirmed and informed consent free of coercion received

Subjects:

- Number of subjects exposed: 50 volunteers
- Sex: 14 males / 36 females
- Age: 23 to 68 years
- Race: Caucasian
The selection of volunteers is done in regard to special criteria.
A) Criteria for inclusion:
1. have healthy skin on the test areas
2. are not taking long-term medica mentation which could influence the test results
3. lead one to expect low, normal or average skin sensitivity
B) Criteria for exclusion.
1. persons younger than 18 years
2. persons of the negroid race
3. persons taking medica mentation that raise the sensibility of the organism and especially of the skin

Clinical history:

- History of allergy or casuistics for study subject or populations:
At the beginning of the test the skin history of each volunteer was recorded, which lead to the following information:
1) allergic rhinitis: 10/50 volunteers
2) contact allergy: 10/50 volunteers
3) allergy to drugs: 3/50 volunteers
4) atopic eczema: 2/50 volunteers
5) allergic asthma: 2/50 volunteers
6) food allergy: 1/50 volunteer

Eleven (22%) of the 50 volunteers are atopics and can be characterized with a sensitive skin (identified by means of cradle cap, allergic rhinitis, allergic asthma or an allergic eczema).
In addition, the atopic score is ascertained according to Diepgen (1989)* in order to characterize the group of volunteers better. The probability of an atopic diathesis can be estimated by means of the atopic score. Five of the volunteers who take part in the study reach an atopic score by means they can be characterized with a sensitive skin, too.

*Reference:
- Diepgen et al, Acta Derm. Venereol. (Stockh.), 1989, Suppl. 144, 50 - 54

Controls:

To standardize the test a blank plaster without a test product and two well tolerated standard products are included in the study. Standard L is an oil in water emulsion, the other standard, N, is a water in oil emulsion. Following our experiences with these products and according to our grading system both standards get an overall rating of very well tolerated. Very well tolerated test products should not show more reactions than these standard products.

In addition a positive control, sodiumdodecylsulfate solution (03% aqueous solution), and a negative control, deionized water, are included in this study.

Route of administration:

dermal

Details on study design:

TYPE OF TEST(S) USED: patch test (epicutaneous test)

ADMINISTRATION
- Type of application: occlusive
- Description of patch: an occlusive cutaneous test plaster (HAL, Allergy test chambers)
- Concentrations: 3 % of the test item
- Volume applied: about 50 µL of test product
- Testing/scoring schedule and removal of test substance: the test product was applied to the back of each volunteer under the test plaster. After 48 hours respectively 72 hours at the weekend after test item application, the plasters are removed from the marked test areas. Any residues of the adhesives are cleaned with medical spirit. Six hours after the removal of the test plasters the reactions of each volunteer are assessed. Then the products are applied again on the same test areas under an occlusive cutaneous test plaster. This repetitive process lasts three weeks. At the end of the third week a 14-day-break is done. In the following challenge phase the products are applied on contralaterally skin areas on the back not used until now. After 48 hours the test plasters are removed and the final checks are made 48, 72 and 96 hours after the product application of the challenge phase.

EXAMINATIONS
- Grading/Scoring system: grading system of Shelanski* (PI grading system)
Please also refer to table 1 in the field "Any other information on materials and methods incl. tables" below.
- Statistical analysis: in order to estimate how many percent of the population will tolerate the test product with a 95 % certainty, the confidence limits of the binomial distribution** are given for 0 to 4 reactions.
Please also refer to table 2 in the field "Any other information on materials and methods incl. tables" below.

References:
* PI Grading System for Shelanski Repeated Insult Patch Test Product Investigations Inc./151 East Tenth Avenue/Conshohocken
** Tables V and IX, "Binominal Confidence Limits, Tables for Use with Binominal Samples" by Donald Mainland et al., Department of Medical statistics, New York University, College of Medicine, 1956

Results and discussion

Results of examinations:

Note: Please refer for grading to the field "Any other information on materials and methods incl. tables" above.

STANDARD PRODUCTS:
- empty test plaster: seven slight reactions, two moderate reactions and one intense reaction
- standard product L: two slight reactions of erythema.
- standard porduct N: six slight reactions and one moderate reaction of erythema

It can be inferred from the results of the standard product, which causes the highest amount of reaction points (standard N) that seven reactions can be expected in this study with products, which are very well tolerated by the skin. But most of the reactions should be slight and only be seen by single volunteers.

- positive control (SDS (0.05% in water)):
week 1: ten slight reactions of erythema of the grade 1.
week 2: 50 slight and 24 moderate reactions of erythema.
week 3: 65 slight reactions, eight moderate reactions and one intense reaction of erythema of the grade 1.
challenge phase: 25 slight and seven moderate reactions of erythema with an inflammatory grade of 1

TEST PRODUCT:
week 1: one slight, one moderate and one strong reaction of erythema
week 2: six slight reactions and five moderate reactions of erythema.
week 3: nine slight reactions, one moderate reaction and two intense reactions of erythema
challenge phase: four slight reactions and one intense reaction of erythema with an inflammatory grade of 1. Five erythema with elevation on the contact areas are assessed.

The application of the test product causes irritations of the skin with 13/50 volunteers (26%) who take part in this study.

A gradually increasing reaction pattern which possibly hints to a sensitization is recorded for one volunteer. The sensitization is confirmed by an increasing reaction pattern with reactions of an inflammatory grade of 2 in the challenge phase.

Reactions of the same intensity are recorded for another volunteer, which also hints to a sensitization.

Due to the observation that two volunteers, who are not conspicious in regard to their skin sensitivity, show reactions of an inflammatory grade of 2 in the challenge phase, the product has to be characterized as not tolerated by the skin in this study.

Applicant's summary and conclusion

Conclusions:

In conclusion, due to the observation that two volunteers, who are not conspicious in regard to their skin sensitivity, show moderate inflammatory reactions in the challenge phase, the product has to be characterized as not tolerated by the skin in this study.

Executive summary:

In this study the irritant effect on the skin of the test product in a forced repetitive cutaneous test under occlusive conditions in a patch test was determined. Fifty volunteers (14 males / 36 females) ranging in age from 23 to 68 years were selected for this study.

The test product (concentration: 3 %) was evaluated by administration to the skin of the back. About 50 µLof the test product was applied to the treatment area under an occlusive cutaneous test plaster. After 48 hours respectively 72 hours at the weekend after test item application, the plasters are removed and any residues of the adhesives are cleaned with medical spirit. Six hours after the removal of the test plasters the reactions of each volunteer are assessed. Then the products are applied again on the same test areas under an occlusive cutaneous test plaster. This repetitive process lasts three weeks. At the end of the third week a 14-day-break is done. In the following challenge phase the products are applied on contralaterally skin areas on the back not used until now. After 48 hours the test plasters are removed and the final checks are made 48, 72 and 96 hours after the product application of the challenge phase. In addition to the test product two standard products (standard L and standard N), an untreated control, a negative control (deionized water) and a positive control ( sodiumdodecylsulfate solution) were run concurrently. The test sites were graded according to a grading system of Shelanski (PI grading system) and analysed using statistics (binomial distribution).

The following results were obtained:

- untreated control: seven slight reactions, two moderate reactions and one intense reaction

- standard product L: two slight reactions of erythema.

- standard porduct N: six slight reactions and one moderate reaction of erythema

- positive control (SDS (0.05% in water)):

week 1: ten slight reactions of erythema of the grade 1.

week 2: 50 slight and 24 moderate reactions of erythema.

week 3: 65 slight reactions, eight moderate reactions and one intense reaction of erythema of the grade 1.

challenge phase: 25 slight and seven moderate reactions of erythema with an inflammatory grade of 1

- test product:

week 1: one slight, one moderate and one strong reaction of erythema

week 2: six slight reactions and five moderate reactions of erythema.

week 3: nine slight reactions, one moderate reaction and two intense reactions of erythema

challenge phase: four slight reactions and one intense reaction of erythema with an inflammatory grade of 1. Five erythema with elevation on the contact areas are assessed.

The application of the test product causes irritations of the skin with 13/50 volunteers (26%) who take part in this study.

A gradually increasing reaction pattern which possibly hints to a sensitization is recorded for one volunteer. The sensitization is confirmed by an increasing reaction pattern with reactions of an inflammatory grade of 2 in the challenge phase.

Reactions of the same intensity are recorded for another volunteer, which also hints to a sensitization.

In conclusion, due to the observation that two volunteers, who are not conspicious in regard to their skin sensitivity, show moderate inflammatory reactions in the challenge phase, the product has to be characterized as not tolerated by the skin in this study.