[4-[4,4'-bis(dimethylamino)benzhydrylidene]cyclohexa-2,5-dien-1-ylidene]dimethylammonium chloride

Endpoint summary

Description of key information

The skin sensitization potential of N-(4-{bis[4-(dimethylamino)phenyl]methylene}cyclohexa-2,5-dien-1-ylidene)-N-methylmethanaminium chloride (548-62-9)was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor and considering the six closest read across substances ofN-(4-{bis[4-(dimethylamino)phenyl]methylene}cyclohexa-2,5-dien-1-ylidene)-N-methylmethanaminium chloride (548-62-9) was predicted to be not sensitizing to the skin of male and female Dunkin-Hartley guinea pig .

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 v3.3 and the QMRF report has been attached.

Qualifier:

equivalent or similar to guideline

Guideline:

other: As mentioned below

Principles of method if other than guideline:

Prediction was done using OECD QSAR toolbox v3.3, 2017

GLP compliance:

not specified

Type of study:

guinea pig maximisation test

Justification for non-LLNA method:

No data available

Specific details on test material used for the study:

Name of test material (as cited in study report): Crystal violet
- IUPAC name: N-(4-{bis[4-(dimethylamino)phenyl]methylene}cyclohexa-2,5-dien-1-ylidene)-N-methylmethanaminium chloride
- Molecular formula : C25H30N3.Cl
Molecular weight : 407.986 g/mol
- Smiles notation: C(\c1ccc(N(C)C)cc1)(c1ccc(N(C)C)cc1)=C1\C=C\C(=[N+](/C)C)C=C1.[ClH-]
- InChl:1S/C25H30N3.ClH/c1-26(2)22-13-7-19(8-14-22)25(20-9-15-23(16-10-20)27(3)4)21-11-17-24(18-12-21)28(5)6;/h7-18H,1-6H3;1H/q+1;/p-1
- Substance type: Organic
- Physical state: Solid

Species:

guinea pig

Strain:

Dunkin-Hartley

Sex:

male/female

Details on test animals and environmental conditions:

No data available

No. of animals per dose:

Total :30
Test group: 10 males and 10females
Control group: 5 males and 5females

Details on study design:

No data available

Challenge controls:

No data available

Positive control substance(s):

not specified

Statistics:

No data available

Positive control results:

No data available

Reading:

1st reading

Group:

test chemical

Dose level:

2.5%

No. with + reactions:

0

Total no. in group:

20

Clinical observations:

No skin sensitization reaction was observed

Remarks on result:

no indication of skin sensitisation

The prediction was based on dataset comprised from the following descriptors: "Skin Sensitisation"
Estimation method: Takes highest mode value from the 9 nearest neighbours
Domain  logical expression:Result: In Domain

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

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Alkene OR Ammonium salt OR Aromatic amine OR Aryl by Organic Functional groups ONLY

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Alkene OR Ammonium salt OR Aromatic amine OR Overlapping groups by Organic Functional groups (nested) ONLY

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] OR Aliphatic Carbon [-CH2-] OR Aliphatic Carbon [-CH3] OR Aliphatic Nitrogen, one aromatic attach [-N] OR Amino, aliphatic attach [-N<] OR Aromatic Carbon [C] OR Olefinic carbon [=CH- or =C<] by Organic functional groups (US EPA) ONLY

Domain logical expression index: "d"

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

Domain logical expression index: "e"

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

Domain logical expression index: "f"

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 >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Single-Ring Substituted Primary Aromatic Amines 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 SN1 >> Nucleophilic attack after metabolic nitrenium ion formation OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> Single-Ring Substituted Primary Aromatic Amines 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: "g"

Referential boundary: The target chemical should be classified as Bioavailable by Lipinski Rule Oasis ONLY

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Group 14 - Carbon C AND Group 15 - Nitrogen N AND Group 17 - Halogens Cl AND Group 17 - Halogens F,Cl,Br,I,At by Chemical elements

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Group  3 - Lanthanoids OR Group 1 - Alkali Earth Li,Na,K,Rb,Cs,Fr OR Group 10 - Trans.Metals Ni,Pd,Pt OR Group 11 - Trans.Metals Cu,Ag,Au OR Group 12 - Trans.Metals Zn,Cd,Hg OR Group 13 - Metalloids B OR Group 13 - Metals Al,Ga,In,Tl OR Group 14 - Metalloids Si,Ge OR Group 14 - Metals Sn,Pb OR Group 15 - Phosphorus P OR Group 16 - Oxygen O OR Group 16 - Selennm Se OR Group 16 - Sulfur S OR Group 17 - Halogens Br OR Group 17 - Halogens F OR Group 17 - Halogens I OR Group 2 - Alkaline Earth Be,Mg,Ca,Sr,Ba,Ra OR Group 3 - Trans.Metals Sc,Y OR Group 4 - Trans.Metals Ti,Zr,Hf OR Group 5 - Trans.Metals V,Nb,Ta OR Group 6 - Trans.Metals Cr,Mo,W OR Group 7 - Trans.Metals Mn,Tc,Re OR Group 8 - Trans.Metals Fe,Ru,Os OR Group 9 - Trans.Metals Co,Rh,Ir by Chemical elements

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] AND Aliphatic Carbon [-CH2-] AND Aliphatic Carbon [-CH3] AND Aliphatic Nitrogen, one aromatic attach [-N] AND Amino, aliphatic attach [-N<] AND Aromatic Carbon [C] AND Olefinic carbon [=CH- or =C<] by Organic functional groups (US EPA) ONLY

Domain logical expression index: "k"

Similarity boundary:Target: CN(C)c1ccc(C(=C2C=CC(=N{+}(C)(C).Cl{-})C=C2)c2ccc(N(C)C)cc2)cc1
Threshold=10%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "l"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.228

Domain logical expression index: "m"

Parametric boundary:The target chemical should have a value of log Kow which is <= 1.75

Interpretation of results:

other: not sensitizing

Conclusions:

The skin sensitization potential of N-(4-{bis[4-(dimethylamino)phenyl]methylene}cyclohexa-2,5-dien-1-ylidene)-N-methylmethanaminium chloride (548-62-9) was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor and considering the six closest read across substances of N-(4-{bis[4-(dimethylamino)phenyl]methylene}cyclohexa-2,5-dien-1-ylidene)-N-methylmethanaminium chloride (548-62-9) was predicted to be not sensitizing to the skin of male and female Dunkin-Hartley guinea pig .

Executive summary:

The skin sensitization potential of N-(4-{bis[4-(dimethylamino)phenyl]methylene}cyclohexa-2,5-dien-1-ylidene)-N-methylmethanaminium chloride (548-62-9)was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor and considering the six closest read across substances of N-(4-{bis[4-(dimethylamino)phenyl]methylene}cyclohexa-2,5-dien-1-ylidene)-N-methylmethanaminium chloride (548-62-9) was predicted to be not sensitizing to the skin of male and female Dunkin-Hartley guinea pig .

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

Skin sensitization 

In different studies, N-(4-{bis[4-(dimethylamino)phenyl]methylene}cyclohexa-2,5-dien-1-ylidene)-N-methylmethanaminium chloride (548-62-9)has been investigated for potential of skin sensitization to a greater or lesser extent. The studies are based on in vivo experiments in guinea pig and human for target chemical N-(4-{bis[4-(dimethylamino)phenyl]methylene}cyclohexa-2,5-dien-1-ylidene)-N-methylmethanaminium chloride (548-62-9) and its structurally similar read across substancesBasic Violet 1(8004 -87-3),the predicted data using the OECD QSAR toolbox has also been compared with the experimental data of read across.

 

The skin sensitization potential of N-(4-{bis[4-(dimethylamino)phenyl]methylene}cyclohexa-2,5-dien-1-ylidene)-N-methylmethanaminium chloride (548-62-9)was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor and considering the six closest read across substances of N-(4-{bis[4-(dimethylamino)phenyl]methylene}cyclohexa-2,5-dien-1-ylidene)-N-methylmethanaminium chloride (548-62-9) was predicted to be not sensitizing to the skin of male and female Dunkin-Hartley guinea pig .

The experimental study conducted by Joe Dinardo, Raleigh, Nc and Zoe Diana Draelos (j. Cosmet, Sci 58, 209-214 (May/June2 007) ,The skin sensitization study of Basic Violet 3 (548-62-9) was performed by Buehler test and the Klecak method for open epicutaneous testing (OET) in 10 guinea pigs. In induction phase, induction given using0.1ml of 10% solution in polyethylene glycol (PG) on left flank (1.8-cm circular area) by topical application for three times weekly ( Monday, Wednesday Friday) for three consecutive weeks. 0.5% 2,4-dinitrochlorobenzene (DNCB) in ethanol used as positive control. In challenge phase, After 2 weeks rest period, challenge application given in doseconcentration0.1ml of10% , 5%, 2.5% in PG on right flank. Evaluation done 24hr and 48 hr after challenge application. No indication of skin sensitization was observed. Hence it is considered that Basic Violet 3(548-62-9) was not skin sensitizing in guinea pig by Buehler test and the Klecak method for open epicutaneous testing (OET).

Also it is further Supported by experimental study conducted byJA Torres, J Sastre, M De las Heras,L Requena, R del Haro, A Cazorla(J Investig Allergol Clin Immunol 2009; Vol. 19(1): 64-79)In skin sensitization study, 1 female volunteer was tested by maximization test at a concentration of 0.25%, 0.5%, and 2% in water by open and closed patch. No reaction was observed after 48 and 96 hr, therefore, the basic violet 3(548-62-9) was considered to be not sensitizing to human.

In another experimental study conducted by Catherine Diamante, et al.( International Journal of Toxicology 28(Suppl 3) 193S-204S, 2010) 11 volunteers were tested by maximization test using basic violet 3. Test material was applied for 20-24 hr and evaluated after 6 -7 days. Because the skin was colored by the tested dyes, it was not possible to evaluate the erythematous reaction. Clinical sings like itching+; isolated papules+; edema, confluent papules, and infiltration++; or vesicular reaction+++ were observed which showed positive reaction for test material in 8 volunteers. Therefore, basic violet 3(548-62-9) was considered to be sensitizing to humans.

The experimental study conducted by Joe Dinardo, Raleigh, Nc and Zoe Diana Draelos (j. Cosmet, Sci 58, 209-214 (May/June2 007) , to evaluate the skin sensitizing potential of read across substance Basic Violet 1(8004 -87-3) in guinea pig. The skin sensitization study of Basic Violet 1(8004 -87-3) was performed by Buehler test and the Klecak method for open epicutaneous testing (OET) in 10 guinea pigs. In induction phase, induction given using0.1ml of 10% solution in polyethylene glycol (PG) on left flank (1.8-cm circular area) by topical application for three times weekly ( Monday, Wednesday Friday) for three consecutive weeks. 0.5% 2,4-dinitrochlorobenzene (DNCB) in ethanol used as positive control. In challenge phase, After 2 weeks rest period, challenge application given in dose concentration0.1ml of10% , 5%, 2.5% in PG on right flank.Evaluation done 24hr and 48 hr after challenge application. No indication of skin sensitization was observed. Hence it is considered that Basic Violet 1 (8004 -87 -3)was not skin sensitizing in guinea pig by Buehler test and the Klecak method for open epicutaneous testing (OET).

Thus based on the above predictions on N-(4-{bis[4-(dimethylamino)phenyl]methylene}cyclohexa-2,5-dien-1-ylidene)-N-methylmethanaminium chloride (548-62-9)as well as its read across and applying weight of evidence, it can be concluded that N-(4-{bis[4-(dimethylamino)phenyl]methylene}cyclohexa-2,5-dien-1-ylidene)-N-methylmethanaminium chloride (548-62-9) is not a skin sensitizer. Expect report given by Catherine Diamante, et al.( International Journal of Toxicology 28(Suppl 3) 193S-204S, 2010) as this is not detailed study and also no of volunteers are not sufficient and it was not possible to evaluate the erythematous reaction because skin was colored by the tested dyes. Hence we cannot consider this study for assessment. Thus comparing the above studies with the criteria of CLP regulation, 4,7-Dichloroquinoline (86-98-6) can be considered as not classified for skin sensitization

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Thus comparing the above studies with the criteria of CLP regulation, 4,7-Dichloroquinoline (86-98-6) can be considered as not classified for skin sensitization