3,7-bis(diethylamino)phenoxazin-5-ium acetate

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 3,7-bis(diethylamino)phenoxazin-5-ium acetate (79916-07-7).The study assumed the use of Salmonella typhimurium strains TA 1535, TA 1537, TA 98 TA100 and TA 102  with and without S9 metabolic activation system. 3,7-bis(diethylamino)phenoxazin-5-ium acetate was predicted to not induce gene mutation in Salmonella typhimurium strains TA 1535, TA 1537, TA 98 , TA 100and TA102 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 of test material (IUPAC name): 3,7-bis(diethylamino)phenoxazin-5-ium acetate
- Molecular formula: C22H29N3O3
- Molecular weight: 383.489 g/mol
- Smiles notation: c1c2nc3ccc(cc3[o+]c2cc(N(CC)CC)c1)N(CC)CC.C(C)(=O)[O-]
-InChl:1S/C20H26N3O.C2H4O2/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;1-2(3)4/h9-14H,5-8H2,1-4H3;1H3,(H,3,4)/q+1;/p-1
- Substance type: Organic

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):

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

Domain logical expression index: "a"

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: "b"

Referential boundary: The target chemical should be classified as Peroxy Acids by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "c"

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

Domain logical expression index: "d"

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: "e"

Referential boundary: The target chemical should be classified as Michael addition OR Michael addition >> P450 Mediated Activation of Heterocyclic Ring Systems OR Michael addition >> P450 Mediated Activation of Heterocyclic Ring Systems >> Thiophenes-Michael addition OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Arenes OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Hydroquinones OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Polycyclic (PAHs) and heterocyclic (HACs) aromatic hydrocarbons-Michael addition OR Michael addition >> Polarised Alkenes-Michael addition OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated amides OR No alert found OR SN1 >> Iminium Ion Formation OR SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines OR SN1 >> Nitrenium Ion formation >> Aromatic azo OR SN1 >> Nitrenium Ion formation >> Aromatic nitro OR SN1 >> Nitrenium Ion formation >> Primary aromatic amine OR SN1 >> Nitrenium Ion formation >> Secondary aromatic amine OR SN2 OR SN2 >> P450 Mediated Epoxidation OR SN2 >> P450 Mediated Epoxidation >> Thiophenes-SN2 by DNA binding by OECD

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Non binder, without OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Non binder, impaired OH or NH2 group OR Non binder, MW>500 OR Weak binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as No alert found by Protein binding by OASIS v1.3

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Direct acylation involving a leaving group OR Acylation >> Direct acylation involving a leaving group >> Carbamates  OR Michael Addition OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group >> alpha,beta-Carbonyl compounds with polarized double bonds  OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group >> Cyanoalkenes OR Michael Addition >> Quinoide type compounds OR Michael Addition >> Quinoide type compounds >> Quinone methide(s)/imines; Quinoide oxime structure; Nitroquinones, Naphthoquinone(s)/imines  OR SN1 OR SN1 >> Carbenium ion formation (enzymatic) OR SN1 >> Carbenium ion formation (enzymatic) >> Carbenium ion by Protein binding by OASIS v1.3

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 Aromatic di-amine derived diazo dyes (12b) OR Bicyclic compounds with aryl fused N containing heterocycle (14 b) OR Bicyclic compounds with aryl fused N containing heterocycle (14 b) >> Quinolones (14b-2) OR Known precedent reproductive and developmental toxic potential OR Toluene and small alkyl toluene derivatives (8a) OR Triarylmethane dyes (12c) by DART scheme v.1.0

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Acetoxy AND Aromatic amine AND Fused carbocyclic aromatic AND Fused heterocyclic aromatic AND Overlapping groups by Organic Functional groups (nested) ONLY

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Acetoxy AND Aromatic amine AND Fused carbocyclic aromatic AND Fused heterocyclic aromatic AND Overlapping groups by Organic Functional groups (nested) ONLY

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Acetoxy AND Aromatic amine AND Fused carbocyclic aromatic AND Fused heterocyclic aromatic AND Overlapping groups by Organic Functional groups (nested) ONLY

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Acetoxy AND Aromatic amine AND Fused carbocyclic aromatic AND Fused heterocyclic aromatic AND Overlapping groups by Organic Functional groups (nested) ONLY

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Acetoxy AND Aromatic amine AND Fused carbocyclic aromatic AND Fused heterocyclic aromatic AND Overlapping groups by Organic Functional groups (nested) ONLY

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as Acetoxy AND Aromatic amine AND Fused carbocyclic aromatic AND Fused heterocyclic aromatic AND Overlapping groups by Organic Functional groups (nested) ONLY

Domain logical expression index: "r"

Parametric boundary:The target chemical should have a value of log Kow which is >= 2.17

Domain logical expression index: "s"

Parametric boundary:The target chemical should have a value of log Kow which is <= 5.12

Conclusions:

3,7-bis(diethylamino)phenoxazin-5-ium acetate (79916-07-7)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 3,7-bis(diethylamino)phenoxazin-5-ium acetate (79916-07-7).The study assumed the use of Salmonella typhimurium strains TA 1535, TA 1537, TA 98 TA100 and TA 102  with S9 metabolic activation system. 3,7-bis(diethylamino)phenoxazin-5-ium acetate was predicted to not induce gene mutation in Salmonella typhimurium strains TA 1535, TA 1537, TA 98 , TA 100and TA102 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

Genetic toxicity in vitro

Prediction model based estimation and data from read across chemical have been reviewed to determine the mutagenic nature of 3,7-bis(diethylamino)phenoxazin-5-ium acetate (79916-07-7). 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 3,7-bis(diethylamino)phenoxazin-5-ium acetate (79916-07-7).The study assumed the use of Salmonella typhimurium strains TA 1535, TA 1537, TA 98 TA100 and TA 102  with and without S9 metabolic activation system. 3,7-bis(diethylamino)phenoxazin-5-ium acetate was predicted to not induce gene mutation in Salmonella typhimurium strains TA 1535, TA 1537, TA 98 , TA 100and TA102 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 Mortelmans et al. (Environmental Mutagenesis, 1986 ) to determine the mutagenic nature of N,N-dimethylaniline (RA CAS No 121-69-7). 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. Gene mutation toxicity study was performed to evaluate the mutagenic nature of the test compound N,N-diethylaniline. Salmonella Ames assay was performed by the preincubation method using the Salmonella typhimurium strains TA98, TA100, TA37 and TA1535 with and without S9 metabolic activation system. The test compound gave negative result for genetic toxicity in Ames test conducted on to S. typhimurium TA98, TA100, TA37 and TA153 with and without metabolic activation by 10% HLI/RLI S9 system. Hence, N,N-diethylaniline (RA CAS no 121 -69 -7) is not likely to classify as gene mutant in vitro.

In a study for structurally and functionally similar read across chemical, Gene mutation toxicity study was performed by John Ashby et al. (Mutation Research, 1985) to determine the mutagenic nature of Altretamine (645-05-6); IUPAC name: 2-N,2-N,4-N,4-N,6-N,6-N-hexamethyl-1,3,5-triazine-2,4,6-triamine. 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 genetox study Altretamine (645-05-6) was assessed for its possible mutagenic potential. For this purpose In vitro gene mutation study in bacteria was conducted on S. typhimurium strain TA1535, 1537, 1538, 97, 98 and TA100 by plate-incorporation assay. DMSO was used as a solvent .The test material was used at concentration of 0, 100-5000 µg/Plate in the presence and absence of metabolic activation. No significant mutagenic effects were observed for Altretamine in the presence and absence of metabolic activator.Therefore Altretamine (645-05-6) was considered to be non mutagenic with and without metabolic activator in S. typhimurium strain TA1535, 1537, 1538, 97, 98 and TA100 by plate-incorporation assay.Therefore it is not likely to be classifying as gene mutant in vitro.

Based on the data available for the target chemical and its read across substance and applying weight of evidence 3,7-bis(diethylamino)phenoxazin-5-ium acetate (79916-07-7)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 the above annotation and CLP criteria for the target chemical .3,7-bis(diethylamino)phenoxazin-5-ium acetate (79916-07-7)does not exhibit gene mutation in vitro. Hence the test chemical is not likely to classify as a gene mutant in vitro.