Registration Dossier

Administrative data

Description of key information

Irritancy in the skin and eye are assessed

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1976
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study not conducted in compliance with GLP and test standard not referenced within the report, however data included for OECD SIDS dossier. Read across to supporting substance, CAS No. 68442-68-2, by structural analogue. Approach considered valid as an in vitro skin irritation test did not demonstrate the potential for the substance to be a skin irritant.
Justification for type of information:
Please refer to IUCLID Section 13 for the read-across justification.
Reason / purpose:
read-across source
Qualifier:
no guideline available
Principles of method if other than guideline:
The guideline followed is not specified within the SIDS dossier; only the end result.
GLP compliance:
no
Species:
rabbit
Strain:
not specified
Details on test animals and environmental conditions:
Not specified
Type of coverage:
not specified
Preparation of test site:
not specified
Vehicle:
not specified
Controls:
not specified
Amount / concentration applied:
Not specified
Duration of treatment / exposure:
Not specified
Observation period:
Not specified
Number of animals:
Unknown
Details on study design:
Not specified
Irritation parameter:
other: Not specified
Basis:
other: Not specified
Time point:
other: unknown
Score:
0.46
Irritant / corrosive response data:
Primary Skin Irritation. Was originally classified as non-irritating; however, according to current classifications, it would be a mild irritant. The result
was 0.46.
Interpretation of results:
GHS criteria not met
Conclusions:
The study was originally classified as non-irritating; however, according to current classifications, it would be a mild irritant. The result was 0.46. However, this does not result in classification under the current EU CLP scheme. Read across to supporting substance, CAS No. 68442 -68 -2, by structural analogue. This approach considered valid as an in vitro skin irritation test did not demonstrate the potential for the substance to be a skin irritant.
Executive summary:

Study not conducted in compliance with GLP and test standard not referenced within the report, however data included for OECD SIDS dossier. Was originally classified as non-irritating; however, according to current classifications, it would be a mild irritant. The result was 0.46. Does not result in classification under the current EU CLP scheme. Read across to supporting substance, CAS No. 68442 -68 -2, by structural analogue.

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.

 

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.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1976
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study not conducted in compliance with GLP and test standard not referenced within the report, however data included for OECD SIDS dossier.
Qualifier:
no guideline available
Principles of method if other than guideline:
The guideline followed is not specified within the SIDS dossier; only the end result.
GLP compliance:
no
Species:
rabbit
Strain:
other: albino
Details on test animals or tissues and environmental conditions:
Young adult rabbits. Not further data specified within the report.
Vehicle:
not specified
Remarks:
presumably as is.
Controls:
not specified
Amount / concentration applied:
Not specified
Duration of treatment / exposure:
Not specified
Observation period (in vivo):
Observations were made at 24, 48, and 72 hours and at 7 days.
Number of animals or in vitro replicates:
Six young adult albino rabbits.
Details on study design:
Standard protocol of the times for eye irritation. Six young adult albino rabbits, three with and three without a wash.
Irritation parameter:
other: Not specified
Basis:
other: Not specified
Reversibility:
not specified
Remarks on result:
other: Mild irritant when not followed by wash.

Mild irritant when not followed by wash.

Interpretation of results:
GHS criteria not met
Conclusions:
Slightly irritating, does not result in classification.
Executive summary:

Study not conducted in compliance with GLP and test standard not referenced within the study report, however data included for OECD SIDS dossier. Result: slightly irritating, does not result in classification. Mild irritant when not followed by wash. Read across to supporting substance, CAS No. 68442 -68 -2, by structural analogue.

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.

 

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.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Results are available in vivo for read across purposes from an equivalent substance. In the interests of animal welfare it was deemed appropriate to assess the effects of the substance in vitro, and apply read across for in vivo results. Results indicate that this category of substances are not irritant.

 

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.

 

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.

  

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.

 


Justification for selection of skin irritation / corrosion endpoint:
Results are available in vivo for read across purposes from an equivalent substance. In the interests of animal welfare it was deemed appropriate to assess the effects of the substance in vitro, and apply read across for in vivo results. Results indicate that this category of substances are not irritant.

Justification for selection of eye irritation endpoint:
Results are available in vivo for read across purposes from an equivalent substance. In the interests of animal welfare it was deemed appropriate to assess the effects of the substance in vitro, and apply read across for in vivo results. Results indicate that this category of substances are not irritant.

Justification for classification or non-classification

The above studies have all been ranked reliability 1 or 2 according to the Klimisch et al system. This ranking was deemed appropriate because the animal studies were not conducted to GLP but are in compliance with agreed "older" protocols. The in vitro studies were conducted to GLP. Sufficient dose ranges and numbers are detailed; hence it is appropriate for use based on reliability and animal welfare grounds.

The above results triggered no classification under the CLP Regulation (EC No 1272/2008). No classification for irritation effects is therefore required.