Bis[[4-[[4-(diethylamino)phenyl][4-(ethylamino)-1-naphthyl]methylene]cyclohexa-2,5-dien-1-ylidene]diethylammonium] dicopper(1+) hexa(cyano-C)ferrate(4-)

Endpoint summary

Description of key information

The skin sensitization potential of target chemical bis[[4-[[4-(diethylamino)phenyl][4-(ethylamino)-1-naphthyl]methylene]cyclohexa-2,5-dien-1-ylidene]diethylammonium] dicopper(1+) hexa(cyano-C)ferrate(4-) (CAS No.: 82338-76-9) was assessed in various experimental studies which were conducted on guinea and humans for target chemicalbis[[4-[[4-(diethylamino)phenyl][4-(ethylamino)-1-naphthyl]methylene]cyclohexa-2,5-dien-1-ylidene]diethylammonium] dicopper(1+) hexa(cyano-C)ferrate(4-) (CAS No.: 82338-76-9) and itsstructurally similar read across substance Basic violet 1 (CAS No: 8007 -87 -3) and its closest read across chemical with log Pow as the primary descriptor N, N-Diethylaniline (CAS No: 91-66-7). The predicted data usingQSAR toolboxhas also been compared with the experimental data.Based on the available data for the target and read across substances and applying the weight of evidence approach, it can be concluded that chemical bis[[4-[[4-(diethylamino)phenyl][4-(ethylamino)-1-naphthyl]methylene]cyclohexa-2,5-dien-1-ylidene]diethylammonium] dicopper(1+) hexa(cyano-C)ferrate(4-) (CAS No.: 82338-76-9) is unable to cause skin sensitization and thus can be considered as not sensitizing. Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Not Classified”.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Endpoint:

skin sensitisation

Remarks:

in vivo

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with limited documentation / justification

Justification for type of information:

Data is from OECD QSAR toolbox version 3.3 and QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: estimated data

Principles of method if other than guideline:

Prediction is done using QSAR Toolbox version 3.3

GLP compliance:

not specified

Type of study:

guinea pig maximisation test

Justification for non-LLNA method:

not specified

Specific details on test material used for the study:

- Name of test material : bis[[4-[[4-(diethylamino)phenyl][4-(ethylamino)-1-naphthyl]methylene]cyclohexa-2,5-dien-1-ylidene]diethylammonium] dicopper(1+) hexa(cyano-C)ferrate(4-)
- Molecular formula : C33H40N3.1/2C6FeN6.Cu
- Molecular weight : 1296.445 g/mol
- Smiles notation : CCNc1ccc(c2c1cccc2)C(=C3C=CC(=[N+](CC)CC)C=C3)c4ccc(cc4)N(CC)CC.CCNc1ccc(c2c1cccc2)C(=C3C=CC(=[N+](CC)CC)C=C3)c4ccc(cc4)N(CC)CC.C(#N)[Fe-4](C#N)(C#N)(C#N)(C#N)C#N.[Cu+].[Cu+]
- InChl : 1S/2C33H39N3.6CN.2Cu.Fe/c2*1-6-34-32-24-23-31(29-13-11-12-14-30(29)32)33(25-15-19-27(20-16-25)35(7-2)8-3)26-17-21-28(22-18-26)36(9-4)10-5;6*1-2;;;/h2*11-24H,6-10H2,1-5H3;;;;;;;;;/q;;;;;;;;2*+1;-4/p+2
- Substance type: Organic
- Physical state: Solid

Species:

guinea pig

Strain:

other: Pirbright White

Sex:

male/female

Details on test animals and environmental conditions:

No data available

Route:

intradermal and epicutaneous

Vehicle:

not specified

Concentration / amount:

No data available

Day(s)/duration:

No data available

Adequacy of induction:

not specified

No.:

#1

Route:

epicutaneous, occlusive

Vehicle:

not specified

Concentration / amount:

No data available

Day(s)/duration:

72 hours

Adequacy of challenge:

not specified

No. of animals per dose:

20

Details on study design:

No data available

Reading:

1st reading

Hours after challenge:

72

Group:

test chemical

Dose level:

No data available

No. with + reactions:

0

Total no. in group:

20

Clinical observations:

No skin sensitization was observed in treated guinea pigs.

Remarks on result:

no indication of skin sensitisation

Cellular proliferation data / Observations:

No skin sensitization was observed in treated guinea pigs.

The prediction was based on dataset comprised from the following descriptors: "Skin Sensitisation"
Estimation method: Takes highest mode value from the 6 nearest neighbours
Domain  logical expression:Result: In Domain

(((((("a" and ("b" and ( not "c") )  )  and "d" )  and ("e" and ( not "f") )  )  and "g" )  and ("h" and ( not "i") )  )  and ("j" and "k" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Amine OR Aromatic compound OR Cation OR Secondary amine OR Secondary mixed amine (aryl, alkyl) OR Tertiary amine OR Tertiary mixed amine by Organic functional groups, Norbert Haider (checkmol) ONLY

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OASIS v.1.3

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >> Nucleophilic addition to alpha, beta-unsaturated carbonyl compounds OR AN2 >> Nucleophilic addition to alpha, beta-unsaturated carbonyl compounds >> alpha, beta-Unsaturated Aldehydes OR AN2 >> Schiff base formation OR AN2 >> Schiff base formation >> alpha, beta-Unsaturated Aldehydes OR Michael addition OR Michael addition >> Quinone type compounds OR Michael addition >> Quinone type compounds >> Quinone methides OR Radical OR Radical >> ROS formation after GSH depletion OR Radical >> ROS formation after GSH depletion >> Quinone methides OR SN1 OR SN1 >> Alkylation after metabolically formed carbenium ion species OR SN1 >> Alkylation after metabolically formed carbenium ion species >> Polycyclic Aromatic Hydrocarbon Derivatives OR SN2 OR SN2 >> Alkylation, direct acting epoxides and related OR SN2 >> Alkylation, direct acting epoxides and related >> Epoxides and Aziridines OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation >> Polycyclic Aromatic Hydrocarbon Derivatives OR SN2 >> Direct acting epoxides formed after metabolic activation OR SN2 >> Direct acting epoxides formed after metabolic activation >> Quinoline Derivatives OR SN2 >> SN2 at an activated carbon atom OR SN2 >> SN2 at an activated carbon atom >> Quinoline Derivatives by DNA binding by OASIS v.1.3

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Class 5 (Not possible to classify according to these rules) by Acute aquatic toxicity classification by Verhaar (Modified) ONLY

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Group 14 - Carbon C AND Group 15 - Nitrogen N by Chemical elements

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Group 14 - Metalloids Si,Ge OR Group 15 - Phosphorus P OR Group 16 - Oxygen O OR Group 16 - Sulfur S by Chemical elements

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Alkene AND Ammonium salt AND Aromatic amine AND Aryl AND Fused carbocyclic aromatic AND Naphtalene AND Overlapping groups by Organic Functional groups (nested) ONLY

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Not categorized by Repeated dose (HESS)

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Aromatic hydrocarbons (Liver enzyme induction) Rank C by Repeated dose (HESS)

Domain logical expression index: "j"

Parametric boundary:The target chemical should have a value of log Kow which is >= -0.387

Domain logical expression index: "k"

Parametric boundary:The target chemical should have a value of log Kow which is <= 6.43

Interpretation of results:

other: not sensitizing

Conclusions:

The chemical bis[[4-[[4-(diethylamino)phenyl][4-(ethylamino)-1-naphthyl]methylene]cyclohexa-2,5-dien-1-ylidene]diethylammonium] dicopper(1+) hexa(cyano-C)ferrate(4-) (CAS No.: 82338-76-9)was estimated to be not sensitizing to the skin of Pirbright White guinea pigs. Based on the estimated result bis[[4-[[4-(diethylamino)phenyl][4-(ethylamino)-1-naphthyl]methylene]cyclohexa-2,5-dien-1-ylidene]diethylammonium] dicopper(1+) hexa(cyano-C)ferrate(4-) (CAS No.: 82338-76-9) failed to induce skin sanitization effects and hence is considered to be not sensitizing to Pirbright White guinea pigs.

Executive summary:

The skin sensitization potential of bis[[4-[[4-(diethylamino)phenyl][4-(ethylamino)-1-naphthyl]methylene]cyclohexa-2,5-dien-1-ylidene]diethylammonium] dicopper(1+) hexa(cyano-C)ferrate(4-) (CAS No.: 82338-76-9)was estimated using OECD QSAR toolbox version 3.3 with log Pow as the primary descriptor. The chemical bis[[4-[[4-(diethylamino)phenyl][4-(ethylamino)-1-naphthyl]methylene]cyclohexa-2,5-dien-1-ylidene]diethylammonium] dicopper(1+) hexa(cyano-C)ferrate(4-) (CAS No.: 82338-76-9)was estimated to be not sensitizing to the skin of Pirbright White guinea pigs. Based on the estimated result bis[[4-[[4-(diethylamino)phenyl][4-(ethylamino)-1-naphthyl]methylene]cyclohexa-2,5-dien-1-ylidene]diethylammonium] dicopper(1+) hexa(cyano-C)ferrate(4-) (CAS No.: 82338-76-9) failed to induce skin sanitization effects and hence is considered to be not sensitizing to Pirbright White guinea pigs and can be classified under the category ˋ Not Classified’ as per CLP regulation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

Various studieshas been investigated for the test chemicalbis[[4-[[4-(diethylamino)phenyl][4-(ethylamino)-1-naphthyl]methylene]cyclohexa-2,5-dien-1-ylidene]diethylammonium] dicopper(1+) hexa(cyano-C)ferrate(4-) (CAS No.: 82338-76-9)to observe the potential for skin sensitization to a greater or lesser extent. The studies are based on in vivo experiments in guinea pigs, mouse and humans for target chemicalbis[[4-[[4-(diethylamino)phenyl][4-(ethylamino)-1-naphthyl]methylene]cyclohexa-2,5-dien-1-ylidene]diethylammonium] dicopper(1+) hexa(cyano-C)ferrate(4-) (CAS No.: 82338-76-9) and itsstructurallysimilar read across substanceBasic violet 1 (CAS No: 8007 -87 -3) and its closest read across chemical with log Pow as the primary descriptor N, N-Diethylaniline (CAS No: 91-66-7).The predicted data using the OECD QSAR toolbox has also been compared with the experimental data and summarized as below;

 

The skin sensitization potential of bis[[4-[[4-(diethylamino)phenyl][4-(ethylamino)-1-naphthyl]methylene]cyclohexa-2,5-dien-1-ylidene]diethylammonium] dicopper(1+) hexa(cyano-C)ferrate(4-) (CAS No.: 82338-76-9) was estimated using OECD QSAR toolbox version 3.4 with log Pow as the primary descriptor. The chemical bis[[4-[[4-(diethylamino)phenyl][4-(ethylamino)-1-naphthyl]methylene]cyclohexa-2,5-dien-1-ylidene]diethylammonium] dicopper(1+) hexa(cyano-C)ferrate(4-) (CAS No.: 82338-76-9) was estimated to be not sensitizing to the skin of Dunkin-Hartley guinea pigs. Based on the estimated result bis[[4-[[4-(diethylamino)phenyl][4-(ethylamino)-1-naphthyl]methylene]cyclohexa-2,5-dien-1-ylidene]diethylammonium] dicopper(1+) hexa(cyano-C)ferrate(4-) (CAS No.: 82338-76-9) failed to induce skin sanitization effects and hence is considered to be not sensitizing to Dunkin-Hartley guinea pigs.

 

The JOE DINARDO at el., (Journal of Cosmetic Science, 58, no. 3 (2007): 209-214) conducted skin sensitization study for read across chemical Basic violet 1 (CAS No: 8007 -87 -3) in guinea pig using modified Buehler and Klecak method for open Epicutaneous testing. For the induction phase, the left flanks of 10 albino guinea pigs were shaved and the dye test material applied three times weekly (Monday, Wednesday Friday) for three consecutive weeks. Each animal received 0.1 ml of the test material over a 1.8-cm circular area. Following the induction period, the guinea pigs entered the challenge phase. The challenge phase began after a two-week rest period when the right flank of each guinea pig was shaved and exposed to three different test material concentration (10.0%, 5.0%, and 2.5%of the induction concentration). Twenty-four hours after the last induction and challenge application, the animals were depilated to clearly observe dermal reactions. The test sites were graded for erythema and edema 24 and 48 hours post-application using a four-point ordinal scale (0 = no reaction, 1 -- slight reaction, 2 = moderate reaction, 3 = severe reaction. A positive reaction was defined as an erythema/edema value during the challenge phase of at least one skin grade higher than during the last induction phase.  No erythema/edema was observed after 24 and 48 hours post-application. Hence the test substance Basic violet 1 (8007 -87 -3) was considered as not sensitizing to the guinea pigs skin.

 

The above results were further supported by the experimental study conducted by U.S. Environmental Protection Agency Hazard Characterization Document {U.S. Environmental Protection Agency Hazard Characterization Document. September,2009} in guinea pigs for read across chemical N, N-Diethylaniline (CAS No: 91-66-7).In this study, the test animals were treated dermally with 10% solution of N, N-diethylaniline during induction. After induction, treated animals were dermally exposed to challenge concentration of 1 or 2% solutions of N, N-diethylaniline. Since the chemical did not produce any cutaneous reaction at challenge concentrations, the test chemical N, N-Diethylaniline (CAS No: 91-66-7) was considered as not sensitizing to guinea pigs.

 

Based on the available data for the target chemical and read across substance,it can be concluded thatchemical bis[[4-[[4-(diethylamino)phenyl][4-(ethylamino)-1-naphthyl]methylene]cyclohexa-2,5-dien-1-ylidene]diethylammonium] dicopper(1+) hexa(cyano-C)ferrate(4-) (CAS No.: 82338-76-9) is unable to cause skin sensitization and considered as not sensitizing. Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Not Classified”.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

The skin sensitization potential of test substance bis[[4-[[4-(diethylamino)phenyl][4-(ethylamino)-1-naphthyl]methylene]cyclohexa-2,5-dien-1-ylidene]diethylammonium] dicopper(1+) hexa(cyano-C)ferrate(4-) (CAS No.: 82338-76-9) and itsstructurallysimilar read across substanceBasic violet 1 (CAS No: 8007 -87 -3) and its closest read across chemical with log Pow as the primary descriptor N, N-Diethylaniline (CAS No: 91-66-7) were observed in various studies. From the results obtained from these studies it is concluded that the chemical bis[[4-[[4-(diethylamino)phenyl][4-(ethylamino)-1-naphthyl]methylene]cyclohexa-2,5-dien-1-ylidene]diethylammonium] dicopper(1+) hexa(cyano-C)ferrate(4-) (CAS No.: 82338-76-9) is not likely to cause skin sensitization and hence can be classified as non-skin sensitizer.