Benzeneacetic acid, 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-.alpha.,.alpha.-dimethyl-, ethyl ester

Skin sensitisation

Administrative data

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Sample reception: 31-10-1997 / Study completion date: 9-03-1998

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP study according to internetional guideline

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1998

Report date:

1998

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 406 (Skin Sensitisation)

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.6 (Skin Sensitisation)

GLP compliance:

yes

Type of study:

guinea pig maximisation test

Justification for non-LLNA method:

tudy was performed in 1998, which is before the OECD guideline for the LLNA method was adopted (2002).

Test material

Test material information

Constituent 1

Reference substance name:

4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethyl-ethyl ester benzeneacetic acid

EC Number:

616-391-1

Cas Number:

76812-02-7

Molecular formula:

C34 H41 N O4

IUPAC Name:

4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethyl-ethyl ester benzeneacetic acid

Constituent 2

Reference substance name:

4-(4-(4-Hydroxydiphenylmethyl)-1-piperidinyl)-1-oxobutyl- alpha,alphadimethylbenzeneacetic acid ethyl ester

IUPAC Name:

4-(4-(4-Hydroxydiphenylmethyl)-1-piperidinyl)-1-oxobutyl- alpha,alphadimethylbenzeneacetic acid ethyl ester

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

- Name of test material (as cited in study report): FEXOFENDONETHYLESTER
- Physical state: white powder
- Lot/batch No.: TAM 40/96/13
- Container: one plastic flask
- Date of receipt: 31 October 1997
- Storage condition of test material: at +4°C and protected from light

In vivo test system

Test animals

Species:

guinea pig

Strain:

Dunkin-Hartley

Sex:

female

Details on test animals and environmental conditions:

Breeder: Charles River France, 76410 Saint-Aubin-les-Elbeuf, France.
Allocation of the animals to the groups: on day 1, the animals were weighed and randomly allocated to two groups: a control group 1consisting of 5 females and a treated group 2 consisting of 10 females.
Age: 3 months old
Weight at initiation: 348 ± 21g.
Acclimatization: at least 5 days before the beginning of the study.
Identification of the animals: ear-tattoo.

Environmental conditions
The conditions in the animal room were set as follows:
- temperature: 21 ± 2°C
- relative humidity: 30 to 70%
- light/dark cycle: 12h/12h
- ventilation: approximately 12 cycles/hour of filtered, non-recycled air.
The temperature and relative humidity were under continuous control and recording. The records were checked daily and retained. During the acclimatization period and throughout the study, the animals were housed individually in polycarbonate cages (48cmx27cmx20cm) equipped with a polypropylene bottle.

Food and water
Food:  free access to "106 pelleted  diet" (U.A.R., 91360Villemoisson-sur-Orge,France).
Drinking water: filtered by a F.G.Millipore membrane (0.22 µ) was provided ad libitum.
No contaminants are known to be present in the diet, drinking water or bedding material at levels which may be expected to interfere with or prejudice the outcome of the study.

Study design: in vivo (non-LLNA)

Induction

Induction 1

Route:

intradermal and epicutaneous

Vehicle:

paraffin oil

Remarks:

The test substance was finely pulverised before being incorporated in the vehicle.

Induction 2

Concentration / amount:

Induction phase:
Intradermal:
Anterior site : FCA diluted at 50% (v/v) with 0.9% NaCl
Middle site: test substance at 0.1% (w/w) in parrafin oil
Posterior site: test substance at 0.1% (w/w) in a mixture FCA /0.9% NaCl 50/50 (v/v)

Cutaneous route:
application of 0.5 ml of the test substance at the concentration of 20% (w/w) under an occlusive dressing for 48h.

Challenge phase: application of 0.5 ml of the test substance at the concentration of 20% (w/w) under an occlusive dressing for 24h.

Challenge

Challenge 1

Route:

epicutaneous, occlusive

Vehicle:

paraffin oil

Remarks:

The test substance was finely pulverised before being incorporated in the vehicle.

Challenge 2

Concentration / amount:

Induction phase:
Intradermal:
Anterior site : FCA diluted at 50% (v/v) with 0.9% NaCl
Middle site: test substance at 0.1% (w/w) in parrafin oil
Posterior site: test substance at 0.1% (w/w) in a mixture FCA /0.9% NaCl 50/50 (v/v)

Cutaneous route:
application of 0.5 ml of the test substance at the concentration of 20% (w/w) under an occlusive dressing for 48h.

Challenge phase: application of 0.5 ml of the test substance at the concentration of 20% (w/w) under an occlusive dressing for 24h.

No. of animals per dose:

10 treated females
5 controls

Positive control substance(s):

yes

Remarks:

DNCB, Mercaptobenzothiazole

Results and discussion

In vivo (non-LLNA)

Results

Results 1

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

20 %

No. with + reactions:

0

Total no. in group:

10

Remarks on result:

other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 20 %. No with. + reactions: 0.0. Total no. in groups: 10.0.

Results 2

Reading:

2nd reading

Hours after challenge:

48

Group:

test chemical

Dose level:

20 %

No. with + reactions:

0

Total no. in group:

10

Remarks on result:

other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 20 %. No with. + reactions: 0.0. Total no. in groups: 10.0.

Applicant's summary and conclusion

Interpretation of results:

not sensitising

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Under our experimental conditions and according to the maximization method of Magnusson and Kligman, the test substance FEXOFENDONETHYLESTER does not induce delayed contact hypersensitivity in guinea-pigs.