1,4-bis[(2-methylphenyl)amino]anthraquinone

Endpoint summary

Description of key information

The skin sensitization potential of target chemical 1,4-bis[(2-methylphenyl)amino]anthraquinone (CAS No: 6737-68-4) was assessedin various experimental studies which were conducted on guinea for target chemical1,4-bis[(2-methylphenyl)amino]anthraquinone (CAS No: 6737-68-4) andits structurally similar read across substancesDisperse violet 4 (CAS No:1220-94-6)andSudan III (CAS No: 85-86-9). The predicted data usingQSAR toolboxhas also been compared with the experimental data.Based on the available data for the target and read across substances and applying the weight of evidence approach, it can be concluded that chemical 1,4-bis[(2-methylphenyl)amino]anthraquinone (CAS No: 6737-68-4) is unable to cause skin sensitization and thus can be considered as not sensitizing. Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Not Classified”.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Endpoint:

skin sensitisation: in vivo (non-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 3.4 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 3.4

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: 1,4-bis[(2-methylphenyl)amino]anthraquinone
- Molecular formula: C28H22N2O2
- Molecular weight: 418.494 g/mol
- Smiles notation : c1cc2C(=O)c3c(C(=O)c2cc1)c(Nc1ccccc1C)ccc3Nc1c(cccc1)C
- InChl : 1S/C28H22N2O2/c1-17-9-3-7-13-21(17)29-23-15-16-24(30-22-14-8-4-10-18(22)2)26-25(23)27(31)19-11-5-6-12-20(19)28(26)32/h3-16,29-30H,1-2H3
- Substance type: Organic
- Physical state: Solid

Species:

guinea pig

Strain:

Dunkin-Hartley

Sex:

male/female

Details on test animals and environmental conditions:

No data available

Route:

intradermal and epicutaneous

Vehicle:

not specified

Concentration / amount:

No data available

Day(s)/duration:

No data available

Adequacy of induction:

not specified

No.:

#1

Route:

epicutaneous, occlusive

Vehicle:

not specified

Concentration / amount:

No data available

Day(s)/duration:

72 hours

Adequacy of challenge:

not specified

No. of animals per dose:

20

Details on study design:

No data available

Reading:

1st reading

Hours after challenge:

72

Group:

test chemical

Dose level:

No data available

No. with + reactions:

0

Total no. in group:

20

Clinical observations:

No skin sensitization was observed in treated guinea pigs.

Remarks on result:

no indication of skin sensitisation

Cellular proliferation data / Observations:

No skin sensitization was observed in treated guinea pigs.

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

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

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 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: "c"

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

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Direct Addition of an Acyl Halide OR Acylation >> Direct Addition of an Acyl Halide >> Alkyl carbamyl halides OR Acylation >> P450 Mediated Activation to Isocyanates or Isothiocyanates OR Acylation >> P450 Mediated Activation to Isocyanates or Isothiocyanates >> Thioureas OR 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 >> Hydroquinones OR SN1 OR SN1 >> Iminium Ion Formation OR SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines OR SN1 >> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Aromatic azo OR SN1 >> Nitrenium Ion formation >> Aromatic nitro OR SN1 >> Nitrenium Ion formation >> Aromatic phenylureas OR SN1 >> Nitrenium Ion formation >> Primary aromatic amine OR SN1 >> Nitrenium Ion formation >> Secondary aromatic amine OR SN1 >> Nitrenium Ion formation >> Tertiary aromatic amine OR SN2 OR SN2 >> P450 Mediated Sulfoxidation OR SN2 >> P450 Mediated Sulfoxidation >> Thioureas-SN2 by DNA binding by OECD

Domain logical expression index: "e"

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

Domain logical expression index: "f"

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 Michael addition OR Michael addition >> Acid imides OR Michael addition >> Acid imides >> Acid imides-MA by Protein binding by OECD

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Alkyl arenes AND Anthracenone/ Antracendione AND Aromatic amine AND Aryl AND Cycloketone AND Diketone AND Fused carbocyclic aromatic by Organic Functional groups

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Alcohol by Organic Functional groups

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Alkyl arenes AND Anthracenone/ Antracendione AND Aromatic amine AND Aryl AND Cycloketone AND Diketone AND Fused carbocyclic aromatic by Organic Functional groups

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Sulfonic acid by Organic Functional groups

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Alkyl arenes AND Anthracenone/ Antracendione AND Aromatic amine AND Aryl AND Cycloketone AND Diketone AND Fused carbocyclic aromatic by Organic Functional groups

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Ether by Organic Functional groups

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Not categorized by Repeated dose (HESS)

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as 3-Methylcholantrene (Hepatotoxicity) Alert by Repeated dose (HESS)

Domain logical expression index: "o"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.561

Domain logical expression index: "p"

Parametric boundary:The target chemical should have a value of log Kow which is <= 9.91

Interpretation of results:

other: Not sensitizing

Conclusions:

The chemical 1,4-bis[(2-methylphenyl)amino]anthraquinone (CAS No: 6737-68-4) was estimated to be not sensitizing to the skin of Dunkin-Hartley guinea pigs. Based on the estimated result 1,4-bis[(2-methylphenyl)amino]anthraquinone (CAS No: 6737-68-4) 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 1,4-bis[(2-methylphenyl)amino]anthraquinone (CAS No: 6737-68-4) was estimated using OECD QSAR toolbox version 3.4 with log Pow as the primary descriptor. The chemical 1,4-bis[(2-methylphenyl)amino]anthraquinone (CAS No: 6737-68-4) was estimated to be not sensitizing to the skin of Dunkin-Hartley guinea pigs. Based on the estimated result 1,4-bis[(2-methylphenyl)amino]anthraquinone (CAS No: 6737-68-4) 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:

Skin sensitization:

Various studieshas been investigated for the test chemical1,4-bis[(2-methylphenyl)amino]anthraquinone (CAS No: 6737-68-4) 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 chemical1,4-bis[(2-methylphenyl)amino]anthraquinone (CAS No: 6737-68-4) and its structurally similar read across substancesDisperse violet 4 (CAS No:1220-94-6) and Sudan III (CAS No: 85-86-9). 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 1,4-bis[(2-methylphenyl)amino]anthraquinone (CAS No: 6737-68-4) was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor. 1,4-bis[(2-methylphenyl)amino]anthraquinone (CAS No: 6737-68-4) was estimated to be not sensitizing to the skin of Dunkin-Hartley guinea pigs. Based on the estimated result 1,4-bis[(2-methylphenyl)amino]anthraquinone (CAS No: 6737-68-4) can be considered to be not sensitizing to Dunkin-Hartley guinea pigs.

 

The JOE DINARDO, Raleigh, NC and ZOE DIANA DRAELOS conducted skin sensitization study of read across chemical Disperse violet 4 (CAS No: 1220-94-6) {Journal of Cosmetic Science, 58, no. 3 (2007): 209-214} in guinea pig using modified Buehler and Klecak method. For the induction phase, the left flanks of 10 albino guinea pigs were shaved and the test material Disperse violet 4 was applied three times weekly (Monday, Wednesday Friday) for three consecutive weeks. Each animal received 0.1 ml of the material over a 1.8-cm circular area. Following the induction period, the guinea pigs entered the challenge phase. The challenge phase began after a two-week rest period when the right flank of each guinea pig was shaved and exposed to three different dye test material concentration (10.0%, 5.0%, and 2.50%of the induction concentration). Twenty-four hours after the last induction and challenge application, the animals were depilated to clearly observe dermal reactions. The test sites were graded for erythema and edema 24 and 48 hours post-application using a four-point ordinal scale (0 = no reaction, 1 -- slight reaction, 2 = moderate reaction, 3 = severe reaction. A positive reaction was defined as an erythema/edema value during the challenge phase of at least one skin grade higher than during the last induction phase. No erythema/edema was observed after 24 and 48 hours post-application. Hence the test substance Disperse violet 4 (CAS No: 1220-94-6) was considered as not sensitizing to the guinea pigs skin.

 

The above results were further supported by the skin sensitization study conducted by TAKEHITO KGZUKA et.al, {Contact Dermatitis; Volume 6; Pg. no. 330-336; 1980} in human patients suffering from pigmented contact dermatitis caused by the commercial Brilliant Lake Red R for read across chemical Sudan III (CAS No: 85-86-9) to detect its contact sensitivity. The patch of Sudan III was applied onto the back of each patient for24 hours by using Finn Chambers® on Scanpor® (Epitest, Ltd. Oy) at a dose of 1% in petrolatum. After removal of patch, skin reactions were assessed according to the ICDRG classification for 2 days. Twenty-eight healthy female volunteers, aged 20 and 21, were also tested with the sample as controls. None gave a positive reaction. The negative skin sensitizing effects were observed in all treated patients. Thus the test chemical Sudan III (CAS No: 85-86-9) was considered to be not sensitizing in human patients suffering from pigmented contact dermatitis caused by the commercial Brilliant Lake Red R.

 

Thus on the basis of available data for thetarget chemical1,4-bis[(2-methylphenyl)amino]anthraquinone (CAS No: 6737-68-4) and its structurally similar read across substancesDisperse violet 4 (CAS No:1220-94-6)andSudan III (CAS No: 85-86-9),it can be concluded thatchemical 1,4-bis[(2-methylphenyl)amino]anthraquinone (CAS No: 6737-68-4) 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 1,4-bis[(2-methylphenyl)amino]anthraquinone (CAS No: 6737-68-4)  and its structurally similar read across substances Disperse violet 4 (CAS No:1220-94-6)andSudan III (CAS No: 85-86-9) were observed in various studies. From the results obtained from these studies it is concluded that the chemical 1,4-bis[(2-methylphenyl)amino]anthraquinone (CAS No: 6737-68-4) is not likely to cause skin sensitization and hence can be classified as non-skin sensitizer.