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Toxicological information

Skin sensitisation

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Administrative data

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Not specified
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Cross-reference
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
other: SIDS Dossier Data
Title:
Unnamed
Year:
1996
Report Date:
1997

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.6 (Skin Sensitisation)
Deviations:
no
GLP compliance:
yes
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
Study was conducted in 1997 - 19 years ago

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid: viscous
Details on test material:
CAS number 184378-08-3
CAS Descriptor Benzenamine, N-phenyl-, reaction products with isobutylene and 2, 4, 4-trimethylpentene
EINECS-Number 270-128-1
Molecular Weight 225-393

In vivo test system

Test animals

Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
not specified
Details on test animals and environmental conditions:
No data

Study design: in vivo (non-LLNA)

Inductionopen allclose all
Route:
intradermal and epicutaneous
Vehicle:
arachis oil
Concentration / amount:
Intradermal induction – A row of three injections (0.1 ml each): a)Freund’s Complete Adjuvant/ water (1:1), b)25% in arachis oil BP, and c) 25% in arachis oil BP in a 1:1 preparation of Freund’s Complete Adjuvant in water; Control animals received a)Freund’s Complete Adjuvant/ water (1:1), b)arachis oil BP, and c) a 50% formulation of arachis oil BP in Freund’s Complete Adjuvant/ water 1:1
Topical induction –undiluted as supplied.
Topical Challenge –undiluted as supplied and 75% in arachis oil BP
Challengeopen allclose all
Route:
epicutaneous, occlusive
Vehicle:
arachis oil
Concentration / amount:
Intradermal induction – A row of three injections (0.1 ml each): a)Freund’s Complete Adjuvant/ water (1:1), b)25% in arachis oil BP, and c) 25% in arachis oil BP in a 1:1 preparation of Freund’s Complete Adjuvant in water; Control animals received a)Freund’s Complete Adjuvant/ water (1:1), b)arachis oil BP, and c) a 50% formulation of arachis oil BP in Freund’s Complete Adjuvant/ water 1:1
Topical induction –undiluted as supplied.
Topical Challenge –undiluted as supplied and 75% in arachis oil BP
No. of animals per dose:
Twenty test and ten control animals were used in this study.
Details on study design:
Intradermal induction – A row of three injections (0.1 ml each): a)Freund’s Complete Adjuvant/ water (1:1), b)25% in arachis oil BP, and c) 25% in arachis oil BP in a 1:1 preparation of Freund’s Complete Adjuvant in water; sites were evaluated at 24 and 48 hrs. Control animals received a)Freund’s Complete Adjuvant/ water (1:1), b)arachis oil BP, and c) a 50% formulation of arachis oil BP in Freund’s Complete Adjuvant/ water 1:1 and evaluated as the same as the test material.
Topical induction –7days after the injections undiluted as supplied was applied to the same area on the clipped shoulder region and covered by an occlusive patch. After 48 hrs the patch was removed and the site was evaluated.
Topical Challenge – On Day 21 undiluted as supplied and 75% in arachis oil BP was applied to a clipped area and covered with an occlusive patch. After 24 hrs the patch was removed; skin reactions were evaluated at 24 and 48 hours.
The intradermal and topical induction doses were based on the highest concentration that caused only mild to moderate irritation and was well tolerated systemically. The highest non-irritating concentration and one lower concentration were selected for the topical challenge.
Challenge controls:
Not specified
Positive control substance(s):
yes
Remarks:
Freund’s Complete Adjuvant

Results and discussion

Positive control results:
Not specified

In vivo (non-LLNA)

Results
Reading:
2nd reading
Hours after challenge:
48
Group:
test group
Dose level:
Not specified
No. with + reactions:
0
Total no. in group:
20
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: Not specified. No with. + reactions: 0.0. Total no. in groups: 20.0.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
The test material produced 0% (0/20) sensitization rate and was classified as a non-sensitizer to the guinea pig skin.
Executive summary:

Study conducted to OECD and EU test guidelines in compliance with GLP. The test material produced 0% (0/20) sensitisation rate and was classified as a non-sensitiser to the guinea pig. Read across to supporting substance, CAS No. 184378 -08 -3, by structural analogue. This approach is deemed appropriate as it supports the human study conducted on the actual substance itself.

This substance has been supported under Environmental Protection Agency’s (EPA’s) High Production Volume (HPV) Challenge Program. The American Chemical Councils RAPA Panel, has derived a “Substituted Diphenylamines” category of chemicals for this substance, please refer to EPA reference 201-14700A located at

 

http://www.epa.gov/hpv/pubs/summaries/subdipha/c13378rt.pdf

 

Relying on several factors specified in EPA’s guidance document on “Development of Chemical Categories in the HPV Challenge Program,” in which use of chemical categories is encouraged, the following closely related chemicals constitute a chemical category:

 

Structural Similarity. A key factor supporting the classification of these chemicals as a category is their structural similarity (see Figure 1). All share a common starting material; Diphenylamine (Benzenamine, N-phenyl-, CAS# 122-39-4), a common synthetic pathway, and all compounds in this category are diamines with various substitutions.

 

Similarity of Physicochemical Properties. The similarity of the physicochemical properties of these materials parallels their structural similarity. All are off-white to light brown solids or viscous liquids intended for use as antioxidants in finished rubber articles or as antidegradant additives that extend the useful life of heavy-duty industrial functional fluids used in high-speed, high-temperature and/or high-load applications. As a class, these amine-based antidegradant compounds are less migratory (more polymer-bound) and less staining than the Substituted p-Phenylenediamine antidegradants. The use of these materials requires that they be stable under high temperatures. Their low volatility is due to their low vapor pressure, highly viscous or solid form. The existing information for these materials indicates that they have low water solubility and high flash points.

 

Fate and Transport Characteristics. Members of this category have been shown to be not readily biodegradable, so additional testing is not needed. The lack of water solubility of the members of this category makes hydrolysis testing unnecessary. These materials have been shown not to partition to water or air if released into the environment due to their low water solubility and low vapor pressure.

 

Toxicological Similarity. Review of existing published and unpublished test data for Substituted Diphenylamines shows the aquatic and mammalian toxicity among the materials within this category are similar.

 

Mammalian Toxicology - Acute. Data on acute mammalian toxicity were reviewed, and the findings indicate a low concern for acute toxicity for all materials. Data are available for most members of the category indicating that the category has been well tested for acute mammalian effects. Therefore, for the purposes of the HPV Program, no

additional acute mammalian toxicity testing is proposed.

 

Mammalian Toxicology - Mutagenicity. Data from bacterial reverse mutation assays, in vitro and in vivo chromosome aberration studies, as well as additional supporting in vitro and in vivo genetic toxicity studies were reviewed, and the findings indicate a low concern for mutagenicity either for aryl or alkyl substituted materials. Similarly, the data for a mixed aryl/alkyl substituted molecule also indicates a lack of mutagenicity. Data are available for several members of the category or close structural analogs, and these data can be bridged to the other members of the category. Therefore, for the purposes of the HPV Program, the category has been adequately tested for mutagenicity, and no additional mutagenicity testing is proposed.

 

Mammalian Toxicology – Repeated Dose Toxicity. Data from repeated-dose toxicity studies were reviewed. Sufficient data are not available to adequately represent the Substituted Diphenylamines for the purposes of the HPV Program, and additional testing is proposed on the smallest aryl- and akyl-substituted materials.

 

Mammalian Toxicology - Reproductive and Developmental Toxicity. Data from reproductive and developmental toxicity studies were reviewed. Sufficient data are not available to adequately represent the Substituted Diphenylamines for the purposes of the HPV Program, and additional testing is proposed, and additional testing is proposed. It is proposed to test the smallest aryl- and akyl-substituted materials.

 

Conclusion. Based upon the data reviewed in “Substituted Diphenylamines” category of chemicals, the physicochemical and toxicological properties of the Substituted Diphenylamine category members are similar and follow a regular pattern as a result of that structural similarity. Therefore, the definition of a chemical category has been met, and read across is considered appropriate for the category of chemical.