[S(R*,R*)]-2,3-bis[(4-methylbenzoyl)oxy]succinic acid

Skin sensitisation

Administrative data

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

data is from peer reviewed journals

Data source

Reference

Reference Type:

publication

Title:

Allergic Contact Dermatitis to the test chemical

Author:

Edward Emmett et.al

Year:

1973

Bibliographic source:

Journal of Investigative Dermatology, 1973

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: Modification of the Draize method

Principles of method if other than guideline:

The procedure used for sensitization was a modification of the method proposed by Draize.

GLP compliance:

not specified

Type of study:

other: Modification of the Draize method

Justification for non-LLNA method:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

p-toluic acid

EC Number:

202-803-3

EC Name:

p-toluic acid

Cas Number:

99-94-5

Molecular formula:

C8H8O2

IUPAC Name:

4-methylbenzoic acid

Test material form:

solid

Details on test material:

- Name of test material (as cited in study report): 4-Methylbenzoic acid
- Molecular formula: C8H8O2
- Molecular weight : 136.1492 g/mol
- Substance type: Organic
- Physical state: Solid

In vivo test system

Test animals

Species:

other: humans

Strain:

not specified

Sex:

male/female

Details on test animals and environmental conditions:

TEST ANIMALS
- Source: Department of Environmental Health , Kettering Laboratory, University of Cincinnati
- Age: 19-49 years old

Study design: in vivo (non-LLNA)

Induction

Route:

epicutaneous, occlusive

Vehicle:

other: 50% polystyrene

Concentration / amount:

50% in polystyrene

Day(s)/duration:

24 hours

Adequacy of induction:

other: non irritating concentration

Challenge

No.:

#1

Route:

epicutaneous, occlusive

Vehicle:

other: 50% polystyrene

Concentration / amount:

50% in polystyrene

Day(s)/duration:

48 hours

Adequacy of challenge:

other: non irritating concentration

No. of animals per dose:

10 - test

Details on study design:

MAIN STUDY
Range finding study: A single 48 hour application of the test chemical in 50% polystyrene was made to the backs of atleast 10 normal subjects to ensure that concentrations used were non-irritating

A. INDUCTION EXPOSURE
- No. of exposures: 9 applications
- Exposure period: 24 hours
- Test groups: 5
- Control group: 10, vehicle control
- Site: non hairy region of the back
- Frequency of applications: Patches were applied to the same sites on Monday, Wednesday, and Friday for 3 weeks , a total of 9 applications.
- Duration: 3 weeks
- Concentrations: small amount in 50% polystyrene

B. CHALLENGE EXPOSURE
- No. of exposures: single
- Day(s) of challenge:
- Exposure period: 48 hours
- Test groups: 10
- Control group: 10, vehicle control
- Site: untested site on the back
- Concentrations: test chemical, 50% in polystyrene
- Evaluation (hr after challenge): 48 and 96 hours after removal of the patch

OTHER:
Grading of the reactions was performed using the scale recommended by the International Contact Dermatitis League. They are:
NT = not tested
- = Negative reaction
?+ = Doubtful reaction
+ = weak (nonvesicular) reaction
++ = strong (edematous and vesicular reaction)
+++ = extreme reactions

Challenge controls:

Also these 10 subjects were challenged with non irritating concentrations of undiluted polystyrene.

Positive control substance(s):

not specified

Results and discussion

In vivo (non-LLNA)

Results

Results 1

Reading:

1st reading

Hours after challenge:

48

Group:

test chemical

Dose level:

test chemical,50% in polystyrene

No. with + reactions:

5

Total no. in group:

10

Clinical observations:

Sensitization reactions were observed in 5 of the 10 patients

Remarks on result:

positive indication of skin sensitisation

Results 2

Reading:

1st reading

Hours after challenge:

48

Group:

other: vehicle control

Dose level:

polystyrene

No. with + reactions:

0

Total no. in group:

10

Clinical observations:

no reactions were observed

Remarks on result:

no indication of skin sensitisation

Results 3

Reading:

1st reading

Hours after challenge:

96

Group:

test chemical

Dose level:

50% in polystyrene

No. with + reactions:

5

Total no. in group:

10

Clinical observations:

sensitization was observed in 5 of the 10 patients

Remarks on result:

positive indication of skin sensitisation

Any other information on results incl. tables

Table: Simultaneous application of test chemical, 50% in polystyrene

Subject	*Reactions to the test chemical
	Third week of sensitizing application			Challenge application
	Mon	Wed	Fri	48 hours	96 hours
P.C	-	+	++	++	++
S.H	-	++	++	+++	+++
R.W	-	-	+	++	++
M.S	-	-	-	++	++
C.M	-	+	++	++	++

Grading of the reactions was performed using the scale recommended by the International Contact Dermatitis League. They are:

NT = not tested; - = Negative reaction; ?+ = Doubtful reaction; + = weak (nonvesicular) reaction; ++ = strong (edematous and vesicular reaction); +++ = extreme reactions

Applicant's summary and conclusion

Interpretation of results:

other: sensitizing

Conclusions:

Sensitization reactions were observed in 5 of the 10 patients. In some subjects, the challenge reactions were so reactive to necessitate removal of patches before the completion of 48 hour period.
Hence, the test chemical was considered to have potential to cause dermal sensitization.

Executive summary:

The procedure used for sensitization was a modification of the method proposed by Draize.

25 healthy human volunteers, 14 males, 11 females (23 Caucasians and 2 Negroes), aged 19-49 were used in the study. None of the subjects gave positive past history of atopy or contact sensitivity.

A single 48 hour application of the test chemical in 50% polystyrene was made to the backs of atleast 10 normal subjects to ensure that concentrations used were non-irritating.

In the induction exposure, a small quantity of test material 50% in polystyrene was placed on the wetted central gauze portion of 1.5 inch square J&J BANDAID before application to a non hairy region of the upper back. Dermicel hypoallergic tape was used to occlude, cover and secure the patches. Patches were applied to the same sites on alternate days for 3 weeks, a total of 9 applications. They were left in place for 24 hours and then removed. The subjects were told not to expose their backs to sunlight. Residual powder was gently removed from skin using soft pads wetted with water or 70% alcohol. Challenge exposure was performed on Monday of the 6^thweek following a rest period of 14 days.

Patches were applied to the untreated sites of the skin of back and were left in situ for 48 hours. Reactions were graded after removal of patches and again at 96 and 144 hours. Also these 10 subjects were challenged with non irritating concentrations of undiluted polystyrene. No significant reactions were observed to the vehicle.

Sensitization reactions were observed in 5 of the 10 patients. In some subjects, the challenge reactions were so reactive to necessitate removal of patches before the completion of 48 hour period.

Hence, the test chemical was considered to have potential to cause dermal sensitization.