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

Endpoint summary

Description of key information

The skin sensitization potential of 3,7-bis(diethylamino)phenoxazin-5-ium acetate (CAS No: 79916-07-7) was estimated using OECD QSAR toolbox version 3.3 with log Pow as the primary descriptor. The chemical 3,7-bis(diethylamino)phenoxazin-5-ium acetate (CAS No: 79916-07-7) was estimated to be not sensitizing to the skin of Dunkin-Hartley guinea pigs. Based on the estimated result 3,7-bis(diethylamino)phenoxazin-5-ium acetate (CAS No: 79916-07-7) 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   “Not Classified” as per CLP regulation.

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 3.3 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 (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

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 5 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 ("i" and "j" )  )

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 to Quinones and Quinone-type Chemicals OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Arenes OR No alert found OR SN1 >> Iminium Ion Formation OR SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines OR SN1 >> Nitrenium Ion formation >> Aromatic azo by DNA binding by OECD

Domain logical expression index: "f"

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

Domain logical expression index: "g"

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

Domain logical expression index: "h"

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: "i"

Parametric boundary:The target chemical should have a value of log Kow which is >= 2.01

Domain logical expression index: "j"

Parametric boundary:The target chemical should have a value of log Kow which is <= 6.97

Interpretation of results:

other: Not sensitizing

Conclusions:

The chemical 3,7-bis(diethylamino)phenoxazin-5-ium acetate (CAS No: 79916-07-7) was estimated to be not sensitizing to the skin of Dunkin-Hartley guinea pigs. Based on the estimated result 3,7-bis(diethylamino)phenoxazin-5-ium acetate (CAS No: 79916-07-7) 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 3,7-bis(diethylamino)phenoxazin-5-ium acetate (CAS No: 79916-07-7) was estimated using OECD QSAR toolbox version 3.3 with log Pow as the primary descriptor. The chemical 3,7-bis(diethylamino)phenoxazin-5-ium acetate (CAS No: 79916-07-7) was estimated to be not sensitizing to the skin of Dunkin-Hartley guinea pigs. Based on the estimated result 3,7-bis(diethylamino)phenoxazin-5-ium acetate (CAS No: 79916-07-7) 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   “Not Classified” as per CLP regulation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information:

Skin sensitization:

Various studieshas been investigated for the test chemical3,7-bis(diethylamino)phenoxazin-5-ium acetate (CAS No: 79916-07-7) 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 chemical3,7-bis(diethylamino)phenoxazin-5-ium acetate (CAS No: 79916-07-7) and its structurally similar read across substances7-Diethylamino-4-methylcoumarin (CAS No: 91-44-1), 2,2'-ethene-1,2-diylbis{5-[(4-anilino-6-morpholin-4-yl-1,3,5-triazin-2-yl)amino]benzenesulfonate}) (CAS No: 16090-02-1) and N, N-Diethylaniline (CAS No: 91-66-7).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 3,7-bis(diethylamino)phenoxazin-5-ium acetate (CAS No: 79916-07-7) was estimated using OECD QSAR toolbox version 3.3 with log Pow as the primary descriptor. The chemical 3,7-bis(diethylamino)phenoxazin-5-ium acetate (CAS No: 79916-07-7) was estimated to be not sensitizing to the skin of Dunkin-Hartley guinea pigs. Based on the estimated result 3,7-bis(diethylamino)phenoxazin-5-ium acetate (CAS No: 79916-07-7) failed to induce skin sanitization effects and hence is considered to be not sensitizing to Dunkin-Hartley guinea pigs

 

The B.M. Hausen and M. Berger {Contact Dermatitis1989: 21: 141-147} conducted skin sensitization study of read across substance7-Diethylamino-4-methylcoumarin (CAS No: 91-44-1)in 10 female guinea pigs by using modified FCA and guinea pig maximization test.In the induction phase, the test compound was dissolved in FCA, 15 mg in 4 ml. Then physiological saline was added and an emulsion was prepared by mixing the material by mean of a 5ml syringe, until emulsification was completed.The intradermal injections of 6 X 0.10-0.15 ml of this emulsion was applied in a semi-circle arc on clipped and shaved shoulder from left to right in such a way that whole quantity of emulsion was used up for 10 animals. This procedure was repeated on 5^thand 9^thday. , leaving a gap of 2-3 cm between the rows of injection.After induction phase of 11 days, animals were challenged by applying 0.05ml of test chemical in a subirritant concentration, with further dilution to the clipped and shaved skin of the right flank of the treated animals, allowing 5 mins for drying. Control animals were also used.Mean Observations were made after 24, 48 and 72 hours. As no sensitization effects were observed, the test material 7-Diethylamino-4-methylcoumarin (CAS No: 91-44-1) can be concluded as non-sensitizing to the female guinea pigs.

 

The above results were supported by the human repeated insult patch test carried out by M.L.Keplinger {Toxicology and Applied Pharmacology; Volume 27, Issue 3, March 1974, Pages 494-506} on 200 subjects to assess the contact sensitization caused by the read across chemical 2,2'-ethene-1,2-diylbis{5-[(4-anilino-6-morpholin-4-yl-1,3,5-triazin-2-yl)amino]benzenesulfonate}) (CAS No: 16090-02-1) under occlusive condition.Induction was carried out on at a dose of 1 and 5% on petrolatum Mondays, Wednesdays and Fridays, total 10 applications were made. After 24 hours patches were removed and skin sits were scored for primary irritation.After a rest period of 10-14 days, a challenge patch was applied (to the same site, an adjacent site or both). After 24 hours the patches were removed and the sites were examined for reactions immediately and 24 and 48 hours later.Since there was no evidence of any contact sensitization, the chemicaldisodium 2,2'-ethene-1,2-diylbis{5-[(4-anilino-6-morpholin-4-yl-1,3,5-triazin-2-yl)amino]benzenesulfonate}) (CAS No: 16090-02-1) was considered to be notsensitizingon skin of human subjects.

 

The above results were further supported by the skin sensitization study reported by U.S. Environmental Protection Agency Hazard Characterization Document {U.S. Environmental Protection Agency Hazard Characterization Document. September, 2009}for read across chemicalN, N-Diethylaniline (CAS No: 91-66-7)in guinea pigs. In this study, the test animals were treated dermally with 10% solution of N, N-diethylaniline during induction. After induction, treated animals were dermally exposed to challenge concentration of 1 or 2% solutions of N, N-diethylaniline. Since the test animals failed to induce any cutaneous reaction at challenge concentrations, the test chemical N, N-Diethylaniline (CAS No: 91-66-7) was considered as not sensitizing to guinea pigs.

 

Thus on the basis of available data for thetarget chemical3,7-bis(diethylamino)phenoxazin-5-ium acetate (CAS No: 79916-07-7) and its structurally similar read across substances7-Diethylamino-4-methylcoumarin (CAS No: 91-44-1), 2,2'-ethene-1,2-diylbis{5-[(4-anilino-6-morpholin-4-yl-1,3,5-triazin-2-yl)amino]benzenesulfonate}) (CAS No: 16090-02-1) and N, N-Diethylaniline (CAS No: 91-66-7),it can be concluded thatchemical 3,7-bis(diethylamino)phenoxazin-5-ium acetate (CAS No: 79916-07-7) 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”.

Justification for classification or non-classification

The skin sensitization potential of test substance 3,7-bis(diethylamino)phenoxazin-5-ium acetate (CAS No: 79916-07-7)  and its structurally similar read across substances 7-Diethylamino-4-methylcoumarin (CAS No: 91-44-1), 2,2'-ethene-1,2-diylbis{5-[(4-anilino-6-morpholin-4-yl-1,3,5-triazin-2-yl)amino]benzenesulfonate}) (CAS No: 16090-02-1) and N, N-Diethylaniline (CAS No: 91-66-7) were observed in various studies. From the results obtained from these studies it is concluded that the chemical 3,7-bis(diethylamino)phenoxazin-5-ium acetate (CAS No: 79916-07-7) is not likely to cause skin sensitization and hence can be classified as non-skin sensitizer.