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Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

Based on the prediction done using the OECD QSAR toolbox version 3.4 with log kow as the primary descriptor and considering the five closest read across substances, gene mutation was predicted for 1,5-bis(cyclohexylamino)-9,10-anthraquinone ( 15958-68-6). 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. 1,5-bis(cyclohexylamino)-9,10-anthraquinone  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 3.4 and the supporting QMRF report has been attached.
Reference:
Composition 1
Qualifier:
according to
Guideline:
other: As mention below
Principles of method if other than guideline:
Prediction is done using OECD QSAR Toolbox version 3.4, 2017
GLP compliance:
not specified
Type of assay:
bacterial reverse mutation assay
Test material information:
Composition 1
Specific details on test material used for the study:
- Name of test material: 1,5-bis(cyclohexylamino)-9,10-dihydroanthracene-9,10-dione
- Molecular formula: C26H30N2O2
- Molecular weight: 402.535 g/mol
- Smiles notation: O=C1c2c(c(NC3CCCCC3)ccc2)C(=O)c2cccc(NC3CCCCC3)c12
- InChl: 1S/C26H30N2O2/c29-25-20-14-8-16-22(28-18-11-5-2-6-12-18)24(20)26(30)19-13-7-15-21(23(19)25)27-17-9-3-1-4-10-17/h7-8,13-18,27-28H,1-6,9-12H2
- Substance type: Organic
- Physical state: Solid
Target gene:
Histidine
Species / strain:
S. typhimurium TA 1535, TA 1537, TA 98, TA 100 and TA 102
Details on mammalian cell lines (if applicable):
Not applicable.
Additional strain 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:
not specified
Negative controls:
not specified
Solvent controls:
not specified
True negative controls:
not specified
Positive controls:
not specified
Details on test system and 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:
other: TA 1535, TA 1537, TA 98, TA 100 and TA 102
Metabolic activation:
with
Genotoxicity:
negative
Cytotoxicity:
not specified
Vehicle controls valid:
not specified
Negative controls valid:
not specified
Positive controls valid:
not specified
Remarks on result:
other: No mutagenic effect were observed.
Additional information on results:
not specified

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 ("k" and ( not "l") )  )  and ("m" and ( not "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 AN2 AND AN2 >>  Michael-type addition, quinoid structures AND AN2 >>  Michael-type addition, quinoid structures >> Quinones and Trihydroxybenzenes AND Non-covalent interaction AND Non-covalent interaction >> DNA intercalation AND Non-covalent interaction >> DNA intercalation >> Quinones and Trihydroxybenzenes AND Radical AND Radical >> Radical mechanism via ROS formation (indirect) AND Radical >> Radical mechanism via ROS formation (indirect) >> Quinones and Trihydroxybenzenes by DNA binding by OASIS v.1.4

Domain logical expression index: "b"

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

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as AN2 AND AN2 >> Michael-type addition to quinoid structures  AND AN2 >> Michael-type addition to quinoid structures  >> N-Substituted Aromatic Amines by Protein binding by OASIS v1.4

Domain logical expression index: "d"

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

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Moderate binder, NH2 group OR Moderate binder, OH grooup OR Non binder, impaired OH or NH2 group OR Non binder, MW>500 OR Non binder, non cyclic structure OR Strong binder, NH2 group OR Strong binder, OH group OR Very strong binder, OH group OR Weak binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as No alert found by Protein binding by OECD

Domain logical expression index: "g"

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 >> Acetates OR Acylation >> Isocyanates and Related Chemicals OR Acylation >> Isocyanates and Related Chemicals >> Isocyanates OR Acylation >> Isocyanates and Related Chemicals >> Isothiocyanates OR Michael addition OR Michael addition >> Acid imides OR Michael addition >> Acid imides >> Acid imides-MA OR Michael addition >> Polarised Alkenes OR Michael addition >> Polarised Alkenes >> Polarised alkene - amides OR Michael addition >> Polarised Alkenes >> Polarised alkene - ketones OR Michael addition >> Quinones and Quinone-type Chemicals OR Michael addition >> Quinones and Quinone-type Chemicals >> Benzoquinones OR Michael addition >> Quinones and Quinone-type Chemicals >> Quinone-imine OR Schiff Base Formers OR Schiff Base Formers >> Direct Acting Schiff Base Formers OR Schiff Base Formers >> Direct Acting Schiff Base Formers >> 1-2-Dicarbonyls by Protein binding by OECD

Domain logical expression index: "h"

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: "i"

Referential boundary: The target chemical should be classified as Extremely reactive (GSH) OR Extremely reactive (GSH) >> Benzoquinones (MA) OR Extremely reactive (GSH) >> Fumaronitriles (MA) OR Extremely reactive (GSH) >> Naphthoquinones (MA) by Protein binding potency

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as No superfragment by Superfragments ONLY

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as No alert found by DNA alerts for CA and MNT by OASIS v.1.1

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >>  Michael-type addition, quinoid structures OR AN2 >>  Michael-type addition, quinoid structures >> Quinoneimines OR AN2 >>  Michael-type addition, quinoid structures >> Quinones and Trihydroxybenzenes OR AN2 >> Carbamoylation after isocyanate formation OR AN2 >> Carbamoylation after isocyanate formation >> N-Hydroxylamines OR AN2 >> Nucleophilic addition reaction with cycloisomerization OR AN2 >> Nucleophilic addition reaction with cycloisomerization >> Hydrazine Derivatives OR Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> Acridone, Thioxanthone, Xanthone and Phenazine Derivatives OR Non-covalent interaction >> DNA intercalation >> DNA Intercalators with Carboxamide and Aminoalkylamine Side Chain OR Non-covalent interaction >> DNA intercalation >> Fused-Ring Nitroaromatics OR Non-covalent interaction >> DNA intercalation >> Quinones and Trihydroxybenzenes OR 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 attack after one-electron reduction of diazonium cation OR Radical >> Radical attack after one-electron reduction of diazonium cation >> Arenediazonium Salts OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Acridone, Thioxanthone, Xanthone and Phenazine Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> Fused-Ring Nitroaromatics OR Radical >> Radical mechanism via ROS formation (indirect) >> Hydrazine Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> N-Hydroxylamines OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitroaniline Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitroarenes with Other Active Groups OR Radical >> Radical mechanism via ROS formation (indirect) >> Quinones and Trihydroxybenzenes OR Radical >> Radical mechanism via ROS formation (indirect) >> Specific Imine and Thione Derivatives OR Radical >> ROS formation after GSH depletion (indirect) OR Radical >> ROS formation after GSH depletion (indirect) >> Quinoneimines OR SN1 OR SN1 >> Nucleophilic attack after diazonium or carbenium ion formation OR SN1 >> Nucleophilic attack after diazonium or carbenium ion formation >> Nitroarenes with Other Active Groups OR SN1 >> Nucleophilic attack after nitrenium ion formation OR SN1 >> Nucleophilic attack after nitrenium ion formation >> N-Hydroxylamines OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Fused-Ring Nitroaromatics OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitroaniline Derivatives OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitroarenes with Other Active Groups OR SN1 >> Nucleophilic substitution on diazonium ion OR SN1 >> Nucleophilic substitution on diazonium ion >> Specific Imine and Thione Derivatives OR SN2 OR SN2 >> Acylation OR SN2 >> Acylation >> N-Hydroxylamines OR SN2 >> Direct nucleophilic attack on diazonium cation OR SN2 >> Direct nucleophilic attack on diazonium cation >> Arenediazonium Salts OR SN2 >> Direct nucleophilic attack on diazonium cation >> Hydrazine Derivatives OR SN2 >> SN2 attack on activated carbon Csp3 or Csp2 OR SN2 >> SN2 attack on activated carbon Csp3 or Csp2 >> Nitroarenes with Other Active Groups by DNA alerts for CA and MNT by OASIS v.1.1

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as No alert found by Protein binding alerts for skin sensitization by OASIS v1.4

Domain logical expression index: "n"

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 Nucleophilic addition OR Nucleophilic addition >> Nucleophilic addition reaction at polarized N-functional double bond OR Nucleophilic addition >> Nucleophilic addition reaction at polarized N-functional double bond >> C-Nitroso compounds  OR SN1 OR SN1 >> Carbenium ion formation (enzymatic) OR SN1 >> Carbenium ion formation (enzymatic) >> Carbenium ion by Protein binding alerts for skin sensitization by OASIS v1.4

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Not bioavailable by Lipinski Rule Oasis ONLY

Domain logical expression index: "p"

Similarity boundary:Target: O=C1c2cccc(NC3CCCCC3)c2C(=O)c2cccc(NC3CCCCC3)c12
Threshold=20%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "q"

Similarity boundary:Target: O=C1c2cccc(NC3CCCCC3)c2C(=O)c2cccc(NC3CCCCC3)c12
Threshold=60%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "r"

Parametric boundary:The target chemical should have a value of log Kow which is >= 6.3

Domain logical expression index: "s"

Parametric boundary:The target chemical should have a value of log Kow which is <= 11.3

Conclusions:
1,5-bis(cyclohexylamino)-9,10-anthraquinone ( 15958-68-6) 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 3.4 with log kow as the primary descriptor and considering the five closest read across substances, gene mutation was predicted for 1,5-bis(cyclohexylamino)-9,10-anthraquinone ( 15958-68-6). 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. 1,5-bis(cyclohexylamino)-9,10-anthraquinone  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

Prediction model based estimation and data from read across chemical have been reviewed to determine the mutagenic nature of 1,5-bis(cyclohexylamino)-9,10-anthraquinone ( 15958-68-6).The studies are as mentioned below

Based on the prediction done using the OECD QSAR toolbox version 3.4 with log kow as the primary descriptor and considering the five closest read across substances, gene mutation was predicted for 1,5-bis(cyclohexylamino)-9,10-anthraquinone ( 15958-68-6). 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. 1,5-bis(cyclohexylamino)-9,10-anthraquinone  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 Patrudu S. Makenaet al.( Food and Chemical Toxicology,2007)to determine the mutagenic nature of (-)-Epigallocatechin , Regulatory name; 2H-1-Benzopyran-3,5,7-triol, 3,4-dihydro-2-(3,4,5-trihydroxyphenyl)-, (2R,3R). 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. (-)-Epigallocatechin was assessed for its possible mutagenic potential .For this purpose Ames Salmonella/microsomal mutagenicity inhibition test was performed on Salmonella typhimurium TA102. The test material was exposed at the concentration of 0 and 50 µg/plate in the presence and absence of mutagenic potential. No mutagenic effects were observed in the presence and absence of S9. Therefore (-)-Epigallocatechin was considered to be non mutagenic for Salmonella typhimurium TA102. Hence the test substance cannot be classified as genetox in vitro.

In a study for structurally and functionally similar read across chemical, Gene mutation toxicity study was performed by Errol Zeiger et.al. (Environmental and Molecular Mutagenesis, 1992) to determine the mutagenic nature of 4,4'-Dioctyldiphenylamine (101-67-7). 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. 4,4'-Dioctyldiphenylaminewas assessed for its mutagenic potential .For this purpose bacterial reverse mutation assay was performed on Salmonella typhimurium strains TA97, TA98, TA100, TA1535 and TA1537. The test material was used at the concentration of 100-10000 µg/PLATE in the presence and absence of metabolic activation. No mutagenic effects were observed in any strain. Therefore 4,4'-Dioctyldiphenylamine was considered to be non mutagenic in Salmonella typhimurium strains TA97, TA98, TA100, TA1535 and TA1537 in the presence and absence of metabolic activation. Hence the test 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 1,5-bis(cyclohexylamino)-9,10-anthraquinone ( 15958-68-6)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 . 1,5-bis(cyclohexylamino)-9,10-anthraquinone ( 15958-68-6)does not exhibit gene mutation in vitro. Hence the test chemical is not likely to classify as a gene mutant in vitro.