1,5-bis(cyclohexylamino)anthraquinone

Endpoint summary

Description of key information

The skin sensitization potential of 1,5-bis(cyclohexylamino)-9,10-anthraquinone (CAS No: 15958-68-6)was estimated using OECD QSAR toolbox version 3.3 with log Pow as the primary descriptor. The substance 1,5-bis(cyclohexylamino)-9,10-anthraquinone (CAS No: 15958-68-6)was estimated to be not sensitising to the skin of Dunkin-Hartley guinea pigs. Based on the estimated result 1,5-bis(cyclohexylamino)-9,10-anthraquinone (CAS No: 15958-68-6)failed to induce skin sanitization effects and hence is considered to be not sensitizing to Dunkin-Hartley guinea pigs.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Endpoint:

skin sensitisation: in vivo (LLNA)

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 QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: estimated data

Principles of method if other than guideline:

Prediction is done using QSAR Toolbox version 3.3

GLP compliance:

not specified

Type of study:

guinea pig maximisation test

Justification for non-LLNA method:

not specified

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

Details on the study design:

No data available

Species:

guinea pig

Strain:

Dunkin-Hartley

Sex:

not specified

Details on test animals and environmental conditions:

No data available

Route:

intradermal and epicutaneous

Adequacy of induction:

not specified

No.:

#1

Route:

epicutaneous, occlusive

Adequacy of challenge:

not specified

No. of animals per dose:

No data available

Details on study design:

No data available

Challenge controls:

No data available

Reading:

1st reading

Group:

test chemical

Dose level:

no data available

No. with + reactions:

0

Clinical observations:

no skin sensitization reactions were observed.

Remarks on result:

no indication of skin sensitisation

Cellular proliferation data / Observations:

no skin sensitization reactions were observed.

The prediction was based on dataset comprised from the following descriptors: "Skin Sensitisation"
Estimation method: Takes 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 ("i" and "j" )  )

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 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 Weak binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as (!Undefined)Group All Lipid Solubility < 0.01 g/kg AND (!Undefined)Group CN Lipid Solubility < 0.4 g/kg AND Group All log Kow > 9 AND Group All Melting Point > 200 C AND Group CN Aqueous Solubility < 0.0001 g/L AND Group CN Aqueous Solubility < 0.1 g/L AND Group CN log Kow > 4.5 AND Group CN log Kow > 5.5 AND Group CN Melting Point > 180 C AND Group CN Molecular Weight > 290 g/mol AND Group CN Vapour Pressure < 0.001 Pa by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as (!Undefined)Group C Surface Tension > 62 mN/m OR (!Undefined)Group CNHal Lipid Solubility < 4 g/kg OR (!Undefined)Group CNHal Lipid Solubility < 400 g/kg OR Group C Melting Point > 55 C OR Group C Vapour Pressure < 0.0001 Pa OR Group CHal Melting Point > 65 C OR Group CNHal Aqueous Solubility < 0.001 g/L OR Group CNHal Aqueous Solubility < 0.1 g/L OR Group CNHal log Kow > 3.8 OR Group CNHal Molecular Weight > 370 g/mol OR Group CNHal Molecular Weight > 380 g/mol by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "h"

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

Domain logical expression index: "i"

Parametric boundary:The target chemical should have a value of log Kow which is >= 5.56

Domain logical expression index: "j"

Parametric boundary:The target chemical should have a value of log Kow which is <= 11.9

Interpretation of results:

other: not sensitising

Conclusions:

The substance 1,5-bis(cyclohexylamino)-9,10-anthraquinone (CAS No: 15958-68-6)was estimated to be not sensitising to the skin of Dunkin-Hartley guinea pigs. Based on the estimated result 1,5-bis(cyclohexylamino)-9,10-anthraquinone (CAS No: 15958-68-6)failed to induce skin sanitization effects and hence is considered to be not sensitizing to Dunkin-Hartley guinea pigs.

Executive summary:

The skin sensitization potential of 1,5-bis(cyclohexylamino)-9,10-anthraquinone (CAS No: 15958-68-6)was estimated using OECD QSAR toolbox version 3.3 with log Pow as the primary descriptor. The substance 1,5-bis(cyclohexylamino)-9,10-anthraquinone (CAS No: 15958-68-6)was estimated to be not sensitising to the skin of Dunkin-Hartley guinea pigs. Based on the estimated result 1,5-bis(cyclohexylamino)-9,10-anthraquinone (CAS No: 15958-68-6)failed to induce skin sanitization effects and hence is considered to be not sensitizing to Dunkin-Hartley guinea pigs and can be classified under the category ˋ Not Classified’ as per CLP regulation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

Various studieshas been investigated for the test chemical1,5-bis(cyclohexylamino)-9,10-anthraquinone (CAS No: 15958-68-6)to observe the potential for skin sensitization to a greater or lesser extent. The studies are based on in vivo experiments in guinea pigs and humans for target chemical1,5-bis(cyclohexylamino)-9,10-anthraquinone (CAS No: 15958-68-6)and its structurally similar read across substances2-methyl-9,10-anthraquinone (CAS No: 84-54-8) and C.I. Acid Blue 62 (CAS No: 4368-56-3).The predicted data using the OECD QSAR toolbox has also been compared with the experimental data and summarized as below;

 

The skin sensitization potential of 1,5-bis(cyclohexylamino)-9,10-anthraquinone (CAS No: 15958-68-6)was estimated using OECD QSAR toolbox version 3.3 with log Pow as the primary descriptor. The substance 1,5-bis(cyclohexylamino)-9,10-anthraquinone (CAS No: 15958-68-6)was estimated to be not sensitising to the skin of Dunkin-Hartley guinea pigs. Based on the estimated result 1,5-bis(cyclohexylamino)-9,10-anthraquinone (CAS No: 15958-68-6)failed to induce skin sanitization effects and hence is considered to be not sensitizing to Dunkin-Hartley guinea pigs.

 

The H. K. KROGH (1964) conducted sensitization study onstructurally similar read across substance2-methyl-9,10-anthraquinone(CAS No: 84-54-8) to assessed  its possible contact allergenic potential in wood factory workers by Patch test. A group of 72 furniture factory workers were investigated with the history of allergic contact eczema caused by true teak (Tectona grandis). All the 72 workers were interviewed and examined for skin lesions. For this purpose a Patch test was performed with native teak dust. The patch were applied for 24 hours on the volar side of the left forearm and read at the end of this period and read again after 48 and 72 hours. A challenge exposure was performed on the workers who showed allergic reactions. The patch was applied at the concentration of 0.1, 0.5, 1 and 2% tectoquinone. Acetone was used as vehicle. The interpretation of the patch tests was based on the usual criteria and was recorded as allergic, toxic, or negative. Identical Patch tests were applied on 10 controls. No skin sensitization effects were observed in test group or control group. Therefore2-methyl-9,10-anthraquinone (CAS No: 84-54-8) was considered to be non sensitizing in human by Patch test.

 

The above results were further supported by the Guinea pig maximisation test conducted by EUROPEAN COMMISSION HEALTH & CONSUMER PROTECTION DIRECTORATE-GENERAL (2005) forstructurally similar read across substance C.I. Acid Blue 62 (CAS No: 4368-56-3) on twenty (20) Hartley albino guinea pigs in order to determine its skin sensitization potential. Two preliminary studies were conducted to determine the challenge concentration of the test compound to be used in the principal study. The treatment region for each animal was clipped once a week. During induction, Ten male and ten female guinea pigs were administered a 0.1 ml intradermal injection of Freund’s Complete Adjuvant (FCA) diluted to 50% in sterile isotonic saline on days 1 and 10 of the study. Beginning on day 1 of the study, 0.5 ml of undiluted Acid Blue 62 was applied topically to the treatment site (which was just above the injection site) three times per week at 2-day intervals and once at the beginning of the fourth week. It was applied using a 2 cm² square of gauze that was moistened with water and kept in place by an occlusive patch. On day 36, animals were challenge with a 0.5 ml aqueous solution of Acid Blue 62 at a concentration of 25% (w/w) was administered on untreated skin on the clipped left flank of the animals for 48 hours under occlusion. The skin was evaluated for evidence of sensitization, e.g. erythema and oedema, at 1, 6, 24 and 48 hours after removal of the patch. Treatment sites were biopsied 6-7 hours after patch removal due to staining of the skin that prevented evaluation of erythema at the treatment site. The observation revealed no oedema and no abnormal histopathological findings. Four males and one female died during the course of the study but these deaths were not attributed to compound administration.Since there was no evidence of any contact sensitization, the chemicalC.I. Acid Blue 62 (CAS No: 4368-56-3)was considered to be not sensitizing on skin oftwenty (20) Hartley albino guinea pigs.

 

 

Thus on the basis of available data for thetarget chemical1,5-bis(cyclohexylamino)-9,10-anthraquinone (CAS No: 15958-68-6)and its structurally similar read across substances2-methyl-9,10-anthraquinone (CAS No: 84-54-8) and C.I. Acid Blue 62 (CAS No: 4368-56-3),it can be concluded thatchemical 1,5-bis(cyclohexylamino)-9,10-anthraquinone (CAS No: 15958-68-6)is unable to cause skin sensitization and considered as non skin sensitizer.Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Not Classified”.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

The skin sensitization potential of test substance 1,5-bis(cyclohexylamino)-9,10-anthraquinone (CAS No: 15958-68-6) and its structurally similar read across substances 2-methyl-9,10-anthraquinone (CAS No: 84-54-8) and C.I. Acid Blue 62 (CAS No: 4368-56-3) were observed in various studies. From the results obtained from these studies it is concluded that the chemical 1,5-bis(cyclohexylamino)-9,10-anthraquinone (CAS No: 15958-68-6)is not likely to cause skin sensitization and hence can be classified as non skin sensitizer.