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Toxicological information

Skin sensitisation

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Administrative data

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Remarks:
in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Remarks:
Non-GLP, published literature based data. Reference states a recognised scientific method and observations. Deemed appropriate for use based on animal welfare grounds.

Data source

Reference
Reference Type:
publication
Title:
A Collection of Guinea Pig Sensitization Test Results — Grouped by Chemical Class
Author:
Rao, K. S. et al. (1981)
Year:
1981
Bibliographic source:
Rao, K. S., Betso, J. E. and Olson, K. J.(1981)'A Collection of Guinea Pig Sensitization Test Results — Grouped by Chemical Class',Drug and Chemical Toxicology,4:4,331 — 351

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: Maguire, H. C. The bioassay of contact allergens in the guinea pig. J. Soc. Cosmet. Chem., 24, 151, 1973.
Principles of method if other than guideline:
The modification of the Maguire method is designed to detect weaker allergens. The method derives from the "split-adjuvant" technique, in which chemical allergen and Freund's adjuvant are administered separately to the skin rather than as an emulsion. A topical application of a 0.1 mL aliquot of the test substance was applied to the clipped and depilated backs of 10 male guinea pigs (approximately 300 g) 4 times in 10 days. At the time of the third application, 0.2 mL of Freund’s adjuvant was injected intradermally at one point adjacent to the insult site. After a 2-week rest period, the guinea pigs were challenged on the clipped flanks with the test material on 1 flank of each animal. The challenge site was evaluated for erythema and edema at 24 and 48 hours. A moderate erythema and/or edema in 2 or more guinea pigs was considered sufficient to classify the test material as a potential human skin sensitizer. Ten additional guinea pigs were treated with the diglycidyl ether of 2,2-di-(p,p’-hydroxyphenyl)propane, which served as a positive control.
GLP compliance:
no
Type of study:
other: Dermal Sensitization (Modified Maguire Method)
Justification for non-LLNA method:
This study preceeds the OECD LLNA guideline requirements

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
not specified
Details on test material:
- Name of test material: p,p'-oxydianiline or 4,4'-diaminodiphenyl ether or 4,4'-oxidianilline
- Molecular weight (if other than submission substance): Not specified.
- Smiles notation (if other than submission substance): Not specified.
- InChl (if other than submission substance): Not specified.
- Structural formula attached as image file (if other than submission substance): Included within the literature report; confirms the identity.
- Substance type: Not specified.
- Physical state: Not specified.
- Analytical purity: Not specified.
- Impurities (identity and concentrations): Not specified.
- Composition of test material, percentage of components: Not specified.
- Isomers composition: Not specified.
- Purity test date: Not specified.
- Lot/batch No.: Not specified.
- Expiration date of the lot/batch: Not specified.
- Radiochemical purity (if radiolabelling): Not applicable
- Specific activity (if radiolabelling): Not applicable
- Locations of the label (if radiolabelling): Not applicable
- Expiration date of radiochemical substance (if radiolabelling): Not applicable
- Stability under test conditions: Not applicable
- Storage condition of test material: Not applicable
Specific details on test material used for the study:
4,4'-oxydianiline
4,4'-diaminodiphenyl ether
CAS 101-80-4

In vivo test system

Test animals

Species:
guinea pig
Strain:
Hartley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Random
- Age at study initiation: Not specified
- Weight at study initiation: ca. 300 g
- Housing: Random (full details not specified)
- Diet (e.g. ad libitum): Purina guinea pig chow supplemented with green vegetables ad libitum
- Water (e.g. ad libitum): Source unspecified, ad libitum
- Acclimation period: Not specified


ENVIRONMENTAL CONDITIONS
- Temperature (°C): Not specified
- Humidity (%): Not specified
- Air changes (per hr): Not specified
- Photoperiod (hrs dark / hrs light): Not specified

All animals were maintained in rooms designed to control temperature, humidity and light cycle; specific details were not detailed within the literature report.

IN-LIFE DATES: Not specified

Study design: in vivo (non-LLNA)

Induction
Route:
epicutaneous, open
Vehicle:
not specified
Concentration / amount:
0.1 mL aliquot
Day(s)/duration:
4 times in 10 days
Challenge
No.:
#1
Route:
epicutaneous, open
Vehicle:
not specified
Concentration / amount:
0.1 mL aliquot
Day(s)/duration:
1 time
No. of animals per dose:
10
Details on study design:
The typical test procedure consisted of topical application of a 0.1 ml aliquot of the test material to the clipped and depilated backs of 10 guinea pigs per test material four times in 10 days. At the time of the third application, 0.2 ml of Freund's adjuvant (Bacto-Adjuvant Complete, H 37 Ra, DIFCO Laboratories, Detroit, Michigan) was injected intradermally at one point adjacent to the insult site. After a 2-week rest period, the guinea pigs were challenged on the clipped flanks with the test material on one flank and a solvent (if used) on the other flank. The challenge site was evaluated for erythema and edema at 24 and 48 hours. A moderate erythema and/or edema in two or more guinea pigs was considered sufficient to classify the test material as a potential human skin sensitizer.
Challenge controls:
Along with each test series, ten guinea pigs were routinely subjected to the same dosing regimen with the diglycidyl ether of 2,2-di-(p,p'-hydroxyphenyl)propane (DER 331 Epoxy Resin -- Dow Chemical U.S.A.)
Positive control substance(s):
yes
Remarks:
diglycidyl ether of 2,2-di-(p,p'-hydroxyphenyl)propane

Results and discussion

Positive control results:
The positive control sensitized at least 70 percent of the guinea pigs each time, producing slight to marked erythema and slight to moderate edema on the challenge application site and was positive in every instance that was tested in this laboratory. Thus, these results validate the repeated insult patch tests as performed by the laboratory cited in the report.

In vivo (non-LLNA)

Resultsopen allclose all
Key result
Reading:
1st reading
Hours after challenge:
48
Group:
test group
Dose level:
0.1 ml
No. with + reactions:
6
Total no. in group:
10
Clinical observations:
Reading:Unspecified timeframe (either 24 or 48 hours). Dose level: 0.1 ml.: No with. + reactions: 6.0. Total no. in groups: 10.0.
Remarks on result:
positive indication of skin sensitisation
Remarks:
A moderate erythema and/or edema in two or more guinea pigs was considered sufficient to classify the test material as a potential human skin sensitizer
Reading:
1st reading
Hours after challenge:
48
Group:
positive control
Dose level:
not specified
No. with + reactions:
7
Total no. in group:
10
Clinical observations:
slight to marked erythema and slight to moderate edema on the challenge application site
Remarks on result:
positive indication of skin sensitisation
Remarks:
routine positive control group in the laboratory showed at least 70% sensitised animals
Reading:
1st reading
Hours after challenge:
48
Group:
negative control
No. with + reactions:
0
Remarks on result:
not determinable
Remarks:
Results of he negative controls not reported in the publication.

Any other information on results incl. tables

Specific results for the negative control (concurrent solvent, if used) were not reported in the publication.

A positive control group was routinely tested in the laboratory and was found to sensitize at least 70% of the guinea pigs each time.

Applicant's summary and conclusion

Interpretation of results:
Category 1 (skin sensitising) based on GHS criteria
Conclusions:
Selected epoxy containing chemicals which may have a potential skin sensitization reaction based on chemical structure or past experience or on those chemicals which may be expected to have extensive skin contact such as consumer products were tested as part of this published study data. The tested materials have been grouped into chemical classes in an effort to point out those classes having sensitizing potential. It is scientifically understood that chemicals having an epoxide structure are potential skin allergens. The results of the work indicate that not all epoxy-containing chemicals are sensitizers, but the majority have some potential for causing skin sensitization.
A full copy of the literature report is attached within this robust summary.

On the basis of these results, the substance 4,4’-oxydianaline can be considered as a moderate to severe skin sensitiser, with a sensitisation rate of 60%. As such, the substance should be classified as a skin sensitiser.

Executive summary:

The test substance was assessed accoding to the Maguire method modified. The method derives from the "split-adjuvant" technique, in which chemical allergen andFreund's adjuvant are administered separately to the skin rather than as an emulsion.

A topical application of a 0.1 mL aliquot of the test substance was applied to the clipped and depilated backs of 10 male guinea pigs (approximately 300 g) 4 times in 10 days. At the time of the third application, 0.2 mL of Freund’s adjuvant was injected intradermally at one point adjacent to the insult site. After a 2-week rest period, the guinea pigs were challenged on the clipped flanks with the test material on 1 flank of each animal. The challenge site was evaluated for erythema and edema at 24 and 48 hours.

Positive reactions were observed in 6/10 animals treated with the substance.

The substance 4,4’-oxydianaline can be considered as a moderate to severe skin sensitiser, with a sensitisation rate of 60%. As such, the substance should be classified as a skin sensitiser.