1,5-bis(cyclohexylamino)anthraquinone

Endpoint summary

Description of key information

LD50 was estimated to be 4025 mg/kg bw when Fischer 344 rats were orally exposed with 1,5-bis(cyclohexylamino)-9,10-dihydroanthracene-9,10-dione.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

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 predicted using OECD QSAR toolbox version 3.4 and the supporting QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: estimation

Principles of method if other than guideline:

Prediction is done using QSAR Toolbox version 3.4

GLP compliance:

not specified

Test type:

fixed dose procedure

Limit test:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report): 1,5-bis(cyclohexylamino)-9,10-dihydroanthracene-9,10-dione
- Molecular formula (if other than submission substance): C26H30N2O2
- Molecular weight (if other than submission substance): 402.535 g/mole
- Substance type: Organic

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

No data

Route of administration:

other: Oral

Vehicle:

corn oil

Details on oral exposure:

No data

Doses:

4025 mg/kg bw

No. of animals per sex per dose:

5 males and 5 females

Control animals:

not specified

Details on study design:

not specified

Statistics:

not specified

Preliminary study:

not specified

Sex:

male/female

Dose descriptor:

LD50

Effect level:

4 025 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 50 % mortality observed

Mortality:

not specified

Clinical signs:

other: not specified

Gross pathology:

not specified

Other findings:

not specified

The prediction was based on dataset comprised from the following descriptors: LD50
Estimation method: Takes average value from the 8 nearest neighbours
Domain  logical expression:Result: In Domain

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

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 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: "e"

Referential boundary: The target chemical should be classified as AN2 >>  Michael-type addition, quinoid structures >> Flavonoids OR AN2 >>  Michael-type addition, quinoid structures >> Quinoneimines 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 AN2 >> Schiff base formation by aldehyde formed after metabolic activation OR AN2 >> Schiff base formation by aldehyde formed after metabolic activation >> Geminal Polyhaloalkane Derivatives OR AN2 >> Shiff base formation after aldehyde release OR AN2 >> Shiff base formation after aldehyde release >> Specific Acetate Esters OR AN2 >> Thioacylation via nucleophilic addition after cysteine-mediated thioketene formation OR AN2 >> Thioacylation via nucleophilic addition after cysteine-mediated thioketene formation >> Haloalkenes with Electron-Withdrawing Groups OR No alert found OR Non-covalent interaction >> DNA intercalation >> Acridone, Thioxanthone, Xanthone and Phenazine Derivatives OR Non-covalent interaction >> DNA intercalation >> Amino Anthraquinones 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-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 >> Generation of ROS by glutathione depletion (indirect) OR Radical >> Generation of ROS by glutathione depletion (indirect) >> Haloalkanes Containing Heteroatom OR Radical >> Radical mechanism via ROS formation (indirect) >> Acridone, Thioxanthone, Xanthone and Phenazine Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> Amino Anthraquinones OR Radical >> Radical mechanism via ROS formation (indirect) >> C-Nitroso Compounds OR Radical >> Radical mechanism via ROS formation (indirect) >> Flavonoids OR Radical >> Radical mechanism via ROS formation (indirect) >> Fused-Ring Nitroaromatics OR Radical >> Radical mechanism via ROS formation (indirect) >> Geminal Polyhaloalkane Derivatives 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) >> Nitrophenols, Nitrophenyl Ethers and Nitrobenzoic Acids OR Radical >> Radical mechanism via ROS formation (indirect) >> Polynitroarenes OR Radical >> Radical mechanism via ROS formation (indirect) >> Single-Ring Substituted Primary Aromatic Amines 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) >> Haloalcohols OR Radical >> ROS formation after GSH depletion (indirect) >> Quinoneimines OR SN1 OR SN1 >> Carbenium ion formation OR SN1 >> Carbenium ion formation >> Alpha-Haloethers OR SN1 >> Nucleophilic attack after carbenium ion formation OR SN1 >> Nucleophilic attack after carbenium ion formation >> Acyclic Triazenes OR SN1 >> Nucleophilic attack after carbenium ion formation >> Specific Acetate Esters 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 metabolic nitrenium ion formation OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> Amino Anthraquinones OR SN1 >> Nucleophilic attack after nitrenium ion formation OR SN1 >> Nucleophilic attack after nitrenium ion formation >> N-Hydroxylamines OR SN1 >> Nucleophilic attack after nitrenium ion formation >> Single-Ring Substituted Primary Aromatic Amines 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 attack after reduction and nitrenium ion formation >> Nitrophenols, Nitrophenyl Ethers and Nitrobenzoic Acids OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Polynitroarenes OR SN1 >> Nucleophilic substitution after glutathione-induced nitrenium ion formation OR SN1 >> Nucleophilic substitution after glutathione-induced nitrenium ion formation >> C-Nitroso Compounds 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 >> Acylation >> Specific Acetate Esters OR SN2 >> Acylation involving a leaving group after metabolic activation OR SN2 >> Acylation involving a leaving group after metabolic activation >> Geminal Polyhaloalkane Derivatives OR SN2 >> Alkylation by epoxide metabolically formed after E2 reaction OR SN2 >> Alkylation by epoxide metabolically formed after E2 reaction >> Haloalcohols 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 cyclization OR SN2 >> Alkylation, direct acting epoxides and related after cyclization >> Nitrogen and Sulfur Mustards 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 >> Haloalkenes with Electron-Withdrawing Groups OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom >> Haloalkanes Containing Heteroatom OR SN2 >> Direct acting epoxides formed after metabolic activation OR SN2 >> Direct acting epoxides formed after metabolic activation >> Quinoline Derivatives OR SN2 >> Direct nucleophilic attack on diazonium cation OR SN2 >> Direct nucleophilic attack on diazonium cation >> Hydrazine Derivatives OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Haloalkanes Containing Heteroatom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Specific Acetate Esters OR SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation OR SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation >> Geminal Polyhaloalkane Derivatives OR SN2 >> SN2 at an activated carbon atom OR SN2 >> SN2 at an activated carbon atom >> Quinoline Derivatives OR SN2 >> SN2 at sp3-carbon atom OR SN2 >> SN2 at sp3-carbon atom >> Alpha-Haloethers 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 binding by OASIS v.1.4

Domain logical expression index: "f"

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

Domain logical expression index: "g"

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

Domain logical expression index: "h"

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

Domain logical expression index: "i"

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

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Group 14 - Carbon C AND Group 15 - Nitrogen N AND Group 16 - Oxygen O by Chemical elements

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Group 16 - Sulfur S by Chemical elements

Domain logical expression index: "l"

Similarity boundary:Target: O=C1c2cccc(NC3CCCCC3)c2C(=O)c2cccc(NC3CCCCC3)c12
Threshold=10%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "m"

Similarity boundary:Target: O=C1c2cccc(NC3CCCCC3)c2C(=O)c2cccc(NC3CCCCC3)c12
Threshold=30%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "n"

Parametric boundary:The target chemical should have a value of log Kow which is >= 5.73

Domain logical expression index: "o"

Parametric boundary:The target chemical should have a value of log Kow which is <= 11.7

Interpretation of results:

Category 5 based on GHS criteria

Conclusions:

LD50 was estimated to be 4025 mg/kg bw when Fischer 344 rats were orally exposed with 1,5-bis(cyclohexylamino)-9,10-dihydroanthracene-9,10-dione.

Executive summary:

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute oral toxicity was estimated for 1,5-bis(cyclohexylamino)-9,10-dihydroanthracene-9,10-dione. The LD50 was estimated to be 4025 mg/kg bw when Fischer 344 rats were orally exposed with 1,5-bis(cyclohexylamino)-9,10-dihydroanthracene-9,10-dione.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

4 025 mg/kg bw

Quality of whole database:

Data is Klimisch 2 and from OECD QSAR toolbox

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Acute oral toxicity:

In different studies, 1,5-bis(cyclohexylamino)-9,10-dihydroanthracene-9,10-dione has been investigated for acute oral toxicity to a greater or lesser extent. Often are the studies based on in vivo experiments and estimated data in rodents, i.e. most commonly in rats for 1,5-bis(cyclohexylamino)-9,10-dihydroanthracene-9,10-dione along with the study available on structurally similar read across substance C.I. Solvent Green 3 (CAS no 128-80-3) and Seratrodast (CAS no 112665-43-7). The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies.

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute oral toxicity was estimated for 1,5-bis(cyclohexylamino)-9,10-dihydroanthracene-9,10-dione. The LD50 was estimated to be 4025 mg/kg bw when Fischer 344 rats were orally exposed with 1,5-bis(cyclohexylamino)-9,10-dihydroanthracene-9,10-dione.

In another prediction done by SSS (2017) using the by using Danish QSAR, 50 % mortality observed at 3900 mg/kg bw . Therefore, estimated LD50 was considered to be 3900 mg/kg bw when rat were treated with 1,5-bis(cyclohexylamino)-9,10-dihydroanthracene-9,10-dione orally.    

Further this is supported by experimental data given by U.S. National Library of Medicine (ChemIDplus, A Toxnet Database Lite-Browse-Advanced, 2017) on structurally similar read across substance C.I. Solvent Green 3 (CAS no 128-80-3), rat were treated with C.I. Solvent Green 3 orally. 50 % mortality observed at 3660 mg/kg bw . Therefore, LD50 was considered to be 3660 mg/kg bw when rat were treated with C.I. Solvent Green 3 orally.    

This further supported by by experimental data given by U.S. National Library of Medicine (ChemIDplus, A Toxnet Database Lite-Browse-Advanced, 2017) on structurally similar read across substance Seratrodast (CAS no 112665-43-7), rat were treated with Seratrodast orally. 50 % mortality observed at 3750 mg/kg bw. Therefore, LD50 was considered to be 3750 mg/kg bw when rat were treated with Seratrodast orally.    

Thus, based on the above studies and predictions on 1,5-bis(cyclohexylamino)-9,10-dihydroanthracene-9,10-dione and its read across substances, it can be concluded that LD50 value is greater than 2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, 1,5-bis(cyclohexylamino)-9,10-dihydroanthracene-9,10-dione can be classified as category V of acute oral toxicity.

Justification for classification or non-classification

Based on the above studies and predictions on 1,5-bis(cyclohexylamino)-9,10-dihydroanthracene-9,10-dione and its read across substances, it can be concluded that LD50 value is greater than 2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, 1,5-bis(cyclohexylamino)-9,10-dihydroanthracene-9,10-dione can be classified as category V of acute oral toxicity.