3,7-bis(diethylamino)phenoxazin-5-ium tetrachlorozincate (2:1)

Endpoint summary

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

Prediction done using the OECD QSAR toolbox version 3.3 with log kow as the primary descriptor and considering the five closest read across substances, gene mutation was predicted for Bis[3,7-bis(diethylamino)phenoxazin-5-ium] tetrachlorozincate(2-) ( 63589-47-9). The study assumed the use of Salmonella typhimurium strains TA 1535, TA 1537, TA 98, TA 100 and TA 102 with and without S9 metabolic activation system. Bis[3,7-bis(diethylamino)phenoxazin-5-ium] tetrachlorozincate(2-)was predicted to not induce gene mutation in Salmonella typhimurium strains TA 1535, TA 1537, TA 98, TA 100 and TA 102 in the presence and absence of S9 metabolic activation system and hence, according to the prediction made, it is not likely to classify as a gene mutant in vitro. Based on the predicted result it can be concluded that the substance is considered to not toxic as per the criteria mentioned in CLP regulation.

Link to relevant study records

Reference

Endpoint:

in vitro gene mutation study in bacteria

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 the supporting QMRF report has been attached.

Qualifier:

according to guideline

Guideline:

other: As mention below

Principles of method if other than guideline:

Prediction is done using OECD QSAR Toolbox version 3.3, 2017

GLP compliance:

not specified

Type of assay:

bacterial reverse mutation assay

Specific details on test material used for the study:

Name - 3,7-bis(diethylamino)phenoxazin-5-ium tetrachlorozincate (2:1)
Molecular Weight - 324.445 g/mole
InChI - 1S/C20H26N3O/c1-5-22(6-2)15-9-11-17-19(13-15)24-20-14-16(23(7-3)8-4)10-12-18(20)21-17/h9-14H,5-8H2,1-4H3/q+1
Smiles - c1cc(cc2[o+]c3cc(ccc3nc12)N(CC)CC)N(CC)CC

Target gene:

Histidine

Species / strain / cell type:

S. typhimurium TA 1535, TA 1537, TA 98, TA 100 and TA 102

Details on mammalian cell type (if applicable):

Nopt applicable.

Additional strain / cell type characteristics:

not specified

Cytokinesis block (if used):

not specified

Metabolic activation:

with

Metabolic activation system:

S9 metabolic activation

Test concentrations with justification for top dose:

not specified

Vehicle / solvent:

not specified

Untreated negative controls:

not specified

Negative solvent / vehicle controls:

not specified

True negative controls:

not specified

Positive controls:

not specified

Details on test system and experimental conditions:

not specified

Rationale for test conditions:

not specified

Evaluation criteria:

Prediction was done considering a dose dependent increase in the number of revertants/plate.

Statistics:

not specified

Species / strain:

S. typhimurium, other: TA 1535, TA 1537, TA 98, TA 100 and TA 102

Metabolic activation:

with

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

not specified

Vehicle controls validity:

not specified

Untreated negative controls validity:

not specified

Positive controls validity:

not specified

Additional information on results:

not specified

Remarks on result:

other: No mutagenic effect were observed.

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

(((((((((("a" or "b" or "c" )  and ("d" and ( not "e") )  )  and ("f" and ( not "g") )  )  and ("h" and ( not "i") )  )  and ("j" and ( not "k") )  )  and ("l" and ( not "m") )  )  and ("n" and ( not "o") )  )  and "p" )  and "q" )  and ("r" and "s" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Zinc metal and salts by OECD HPV Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Soluble complexes of Zinc by US-EPA New Chemical Categories

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as SN1 AND SN1 >> Nitrenium Ion formation AND SN1 >> Nitrenium Ion formation >> Tertiary aromatic amine by DNA binding by OECD

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Non binder, MW>500 by Estrogen Receptor Binding

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Moderate binder, OH grooup OR Non binder, impaired OH or NH2 group OR Non binder, non cyclic structure OR Non binder, without OH or NH2 group OR Strong binder, NH2 group OR Strong binder, OH group OR Weak binder, NH2 group OR Weak binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Not possible to classify according to these rules (GSH) by Protein binding potency

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Moderately reactive (GSH) OR Moderately reactive (GSH) >> Alkyl 2-alkenoates (MA) by Protein binding potency

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as No Data by Ultimate biodeg

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as > 100 days by Ultimate biodeg

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Not known precedent reproductive and developmental toxic potential by DART scheme v.1.0

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Alpha aryloxy substituted acetic acid (9c) OR Aromatic di-amine derived diazo dyes (12b) OR Known precedent reproductive and developmental toxic potential OR NO2-alkyl/NO2-benzene derivatives (8b) OR Toluene and small alkyl toluene derivatives (8a) by DART scheme v.1.0

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as No alert found by DNA alerts for AMES, MN and CA by OASIS v.1.3

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Non-specific OR Non-specific >> Incorporation into DNA/RNA, due to structural analogy with  nucleoside bases    OR Non-specific >> Incorporation into DNA/RNA, due to structural analogy with  nucleoside bases    >> Specific Imine and Thione Derivatives OR Radical OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Specific Imine and Thione Derivatives OR SN1 OR SN1 >> Nucleophilic substitution on diazonium ion OR SN1 >> Nucleophilic substitution on diazonium ion >> Specific Imine and Thione Derivatives by DNA alerts for AMES, MN and CA by OASIS v.1.3

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Halogens AND Non-Metals AND Transition Metals by Groups of elements

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Alkali Earth by Groups of elements

Domain logical expression index: "p"

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

Domain logical expression index: "q"

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

Domain logical expression index: "r"

Parametric boundary:The target chemical should have a value of log Kow which is >= 2.67

Domain logical expression index: "s"

Parametric boundary:The target chemical should have a value of log Kow which is <= 16.4

Conclusions:

Bis[3,7-bis(diethylamino)phenoxazin-5-ium] tetrachlorozincate(2-) ( 63589-47-9) was predicted to not induce gene mutation in Salmonella typhimurium strains TA 1535, TA 1537, TA 98, TA 100 and TA 102 in the presence of S9 metabolic activation system and hence, according to the prediction made, it is not likely to classify as a gene mutant in vitro.

Executive summary:

Based on the prediction done using the OECD QSAR toolbox version 3.3 with log kow as the primary descriptor and considering the five closest read across substances, gene mutation was predicted for Bis[3,7-bis(diethylamino)phenoxazin-5-ium] tetrachlorozincate(2-) ( 63589-47-9). The study assumed the use of Salmonella typhimurium strains TA 1535, TA 1537, TA 98, TA 100 and TA 102 with S9 metabolic activation system. Bis[3,7-bis(diethylamino)phenoxazin-5-ium] tetrachlorozincate(2-)was predicted to not induce gene mutation in Salmonella typhimurium strains TA 1535, TA 1537, TA 98, TA 100 and TA 102 in the presence of S9 metabolic activation system and hence, according to the prediction made, it is not likely to classify as a gene mutant in vitro.

Based on the predicted result it can be concluded that the substance is considered to not toxic as per the criteria mentioned in CLP regulation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (negative)

Genetic toxicity in vivo

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Genetoxicity in vitro

Prediction model based estimation and data from read across chemical have been reviewed to determine the mutagenic nature of Bis[3,7-bis(diethylamino)phenoxazin-5-ium] tetrachlorozincate(2-) ( 63589-47-9). The studies are as mentioned below

Based on the prediction done using the OECD QSAR toolbox version 3.3 with log kow as the primary descriptor and considering the five closest read across substances, gene mutation was predicted for Bis[3,7-bis(diethylamino)phenoxazin-5-ium] tetrachlorozincate(2-) ( 63589-47-9). The study assumed the use of Salmonella typhimurium strains TA 1535, TA 1537, TA 98, TA 100 and TA 102 with and without S9 metabolic activation system. Bis[3,7-bis(diethylamino)phenoxazin-5-ium] tetrachlorozincate(2-)was predicted to not induce gene mutation in Salmonella typhimurium strains TA 1535, TA 1537, TA 98, TA 100 and TA 102 in the presence and absence of S9 metabolic activation system and hence, according to the prediction made, it is not likely to classify as a gene mutant in vitro. Based on the predicted result it can be concluded that the substance is considered to not toxic as per the criteria mentioned in CLP regulation.

In a study for structurally and functionally similar read across chemical, Gene mutation toxicity study was performed by Lynnette R. Ferguson et al.( Mutation Research ,1995)to determine the mutagenic nature of (N-(2-CHLOROETHYL)-N-ETHYL-4-(5-(4-METHYL-1-PIPERAZINYL)(2,5'-BI-1H-BENZIMIDAZOL)-2'-YL)-BENZENAMINE(166546-18-5). The read across substances share high similarity in structure and log kow .Therefore, it is acceptable to derive information on mutation from the analogue substance. In Vitro Genetoxicity study for (N-(2-CHLOROETHYL)-N-ETHYL-4-(5-(4-METHYL-1-PIPERAZINYL)(2,5'-BI-1H-BENZIMIDAZOL)-2'-YL)-BENZENAMINE was assessed for its mutagenic potential. For this purpose are Bacterial Reverse mutation assay was performed in Salmonella strains TA98, TA100 and TA102. The test material was exposed at the concentration of 0,4,10,20,40,80 and 120µg/plate in the presence and absence of metabolic activation. No mutagenic effects were observed. Therefore (N-(2-CHLOROETHYL) -N-ETHYL -4-(5- (4-METHYL-1-PIPERAZINYL)(2,5'-BI-1H-BENZIMIDAZOL)-2'-YL)-BENZENAMINE was considered to be non mutagenic in Salmonella strains TA98, TA100 and TA102 by bacterial reverse mutation assay. Hence the substance cannot be classified as gene mutant in vitro.

In a study for structurally and functionally similar read across chemical, Gene mutation toxicity study was performed by Lynnette R. Ferguson et al.( Mutation Research ,1995)to determine the mutagenic nature ofN,N-BIS(2-CHLOROETHYL)-4-(5-((5-(4-METHYL-1-PIPERAZINYL)-1H-BENZIMIDAZOL-2-YL)METHYL)-1H-BENZIMIDAZO L-2-YL)-BENZENAMINE (166546-20-9 ). The read across substances share high similarity in structure and log kow .Therefore, it is acceptable to derive information on mutation from the analogue substance. In Vitro Genetoxicity study for N,N-BIS(2-CHLOROETHYL)-4-(5-((5-(4-METHYL-1-PIPERAZINYL)-1H-BENZIMIDAZOL-2-YL)METHYL)-1H-BENZIMIDAZO L-2-YL)-BENZENAMINE  was assessed for its mutagenic potential. For this purpose are Bacterial Reverse mutation assay was performed in Salmonella strains TA98, TA100 and TA102. The test material was exposed at the concentration of 0,4,10,20,40,80 and 120µg/plate in the presence and absence of metabolic activation. No mutagenic effects were observed. Therefore N,N-BIS(2-CHLOROETHYL)-4-(5-((5-(4-METHYL-1-PIPERAZINYL)-1H-BENZIMIDAZOL-2-YL)METHYL)-1H-BENZIMIDAZO L-2-YL)-BENZENAMINE was considered to be non mutagenic in Salmonella strains TA98, TA100 and TA102 by bacterial reverse mutation assay. Hence the substance cannot be classified as gene mutant in vitro.

 

Based on the data available for the target chemical and its read across substance and applying weight of evidence Bis[3,7-bis(diethylamino)phenoxazin-5-ium] tetrachlorozincate(2-) ( 63589-47-9) does not exhibit gene mutation in vitro. Hence the test chemical is not likely to classify as a gene mutant in vitro.

Justification for classification or non-classification

Thus based on theabove annotation and CLP criteria for the target chemical .Bis[3,7-bis(diethylamino)phenoxazin-5-ium] tetrachlorozincate(2-) ( 63589-47-9) does not exhibit gene mutation in vitro. Hence the test chemical is not likely to classify as a gene mutant in vitro.