Dipotassium 4,4'-bis[6-anilino-4-[bis(2-hydroxyethyl)amino-1,3,5-triazin-2-yl]amino]stilbene-2,2'-disulphonate

Endpoint summary

Description of key information

The skin sensitization potential of Dipotassium 4,4’-bis[6-anilino-4-[bis(2-hydroxyethyl)amino-1,3,5-triazin-2-yl]amino]stilbene-2,2’-disulphonate (CAS No: 71230-67-6)was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor. The substance Dipotassium 4,4’-bis[6-anilino-4-[bis(2-hydroxyethyl)amino-1,3,5-triazin-2-yl]amino]stilbene-2,2’-disulphonate (CAS No: 71230-67-6)failed to induce skin sensitization effects on Hartley guinea pig skin and hence considered to be not sensitizing to the skin.

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 v3.3 and the QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: estimated data

Principles of method if other than guideline:

Prediction was done using OECD QSAR toolbox v3.3

GLP compliance:

not specified

Type of study:

other: Estimated data

Specific details on test material used for the study:

- Name of test material: Dipotassium 4,4'-bis[6-anilino-4-[bis(2-hydroxyethyl)amino-1,3,5-triazin-2-yl]amino]stilbene-2,2'-disulphonate
- Molecular formula: C40H42K2N12O10S2
- Molecular weight: 993.174 g/mol
- Smiles notation: [K+].[K+].C(=C\c1c(cc(cc1)Nc1nc(nc(n1)N(CCO)CCO)Nc1ccccc1)S(=O)(=O)[O-])\c1c(cc(cc1)Nc1nc(nc(n1)N(CCO)CCO)Nc1ccccc1)S(=O)(=O)[O-]
- InChl: 1S/C40H44N12O10S2.2K/c53-21-17-51(18-22-54)39-47-35(41-29-7-3-1-4-8-29)45-37(49-39)43-31-15-13-27(33(25-31)63(57,58)59)11-12-28-14-16-32(26-34(28)64(60,61)62)44-38-46-36(42-30-9-5-2-6-10-30)48-40(50-38)52(19-23-55)20-24-56;;/h1-16,25-26,53-56H,17-24H2,(H,57,58,59)(H,60,61,62)(H2,41,43,45,47,49)(H2,42,44,46,48,50);;/q;2*+1/p-2/b12-11+;;
- Substance type: Organic
- Physical state: Solid

Details on the study design:

no data available

Details on the study design:

no data available

Species:

guinea pig

Strain:

Hartley

Sex:

male

Details on test animals and environmental conditions:

No data available

Route:

intradermal and epicutaneous

Vehicle:

unchanged (no vehicle)

Concentration / amount:

5%

Adequacy of induction:

not specified

No.:

#1

Route:

epicutaneous, occlusive

Vehicle:

unchanged (no vehicle)

Adequacy of challenge:

not specified

No. of animals per dose:

15

Details on study design:

no data available

Challenge controls:

no data available

Positive control substance(s):

not specified

Vehicle:

not specified

Concentration:

no data available

No. of animals per dose:

no data available

Details on study design:

no data available

Positive control substance(s):

not specified

Statistics:

no data available

Positive control results:

no data available

Other effects / acceptance of results:

no data available

Reading:

1st reading

Group:

test chemical

Dose level:

no data available

Clinical observations:

no data available

Remarks on result:

no indication of skin sensitisation

Cellular proliferation data / Observations:

no data available

The prediction was based on dataset comprised from the following descriptors: "Skin Sensitisation"
Estimation method: Takes highest mode value from the 7 nearest neighbours
Domain  logical expression:Result: In Domain

(((((((("a" or "b" or "c" or "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" and "q" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as C.I. Fluorescent Brightener 28 113 by OECD HPV Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Substituted Triazines (Acute toxicity) by US-EPA New Chemical Categories

Domain logical expression index: "c"

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: "d"

Referential boundary: The target chemical should be classified as Acid moiety OR Salt OR Triazines, Aromatic by Aquatic toxicity classification by ECOSAR ONLY

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OASIS v.1.3

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> Fused-Ring Primary Aromatic Amines OR Radical OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Fused-Ring Primary Aromatic Amines OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitro Azoarenes OR SN1 OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> Fused-Ring Primary Aromatic Amines OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitro Azoarenes OR SN2 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 Mustards by DNA binding by OASIS v.1.3

Domain logical expression index: "g"

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: "h"

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: "i"

Referential boundary: The target chemical should be classified as Non binder, MW>500 by Estrogen Receptor Binding

Domain logical expression index: "j"

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

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as No alert found by Protein binding by OASIS v1.3

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Michael Addition OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group >> Cyanoalkenes OR SN1 OR SN1 >> Carbenium ion formation (enzymatic) OR SN1 >> Carbenium ion formation (enzymatic) >> Carbenium ion by Protein binding by OASIS v1.3

Domain logical expression index: "m"

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

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 >> Acetates by Protein binding by OECD

Domain logical expression index: "o"

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

Domain logical expression index: "p"

Parametric boundary:The target chemical should have a value of log Kow which is >= -1.35

Domain logical expression index: "q"

Parametric boundary:The target chemical should have a value of log Kow which is <= 3.23

Interpretation of results:

other: Negative

Conclusions:

Dipotassium 4,4'-bis[6-anilino-4-[bis(2-hydroxyethyl)amino-1,3,5-triazin-2-yl]amino]stilbene-2,2'-disulphonate was predicted to be non sensitizing to the skin of male Hartley guinea pigs.

Executive summary:

The skin sensitization potential of Dipotassium 4,4'-bis[6-anilino-4-[bis(2-hydroxyethyl)amino-1,3,5-triazin-2-yl]amino]stilbene-2,2'-disulphonate was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor. Dipotassium 4,4'-bis[6-anilino-4-[bis(2-hydroxyethyl)amino-1,3,5-triazin-2-yl]amino]stilbene-2,2'-disulphonate was predicted to be non sensitizing to the skin of male Hartley guinea pigs.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

Skin sensitization:

Various studieshas been investigated for the test chemicalDipotassium 4,4’-bis[6-anilino-4-[bis(2-hydroxyethyl)amino-1,3,5-triazin-2-yl]amino]stilbene-2,2’-disulphonate (CAS No: 71230-67-6)to observe the potential for skin sensitization to a greater or lesser extent. The studies are based on in vivo experiments in guinea pigs for target chemicalDipotassium 4,4’-bis[6-anilino-4-[bis(2-hydroxyethyl)amino-1,3,5-triazin-2-yl]amino]stilbene-2,2’-disulphonate (CAS No: 71230-67-6)and its structurally similar read across substancesdisodium 4,4'-bis[6-anilino-[4-[bis(2-hydroxyethyl)amino]-1,3,5-triazin-2-yl]amino]stilbene-2,2'-disulphonate (Blankophor BA) (CAS No: 4193-55-9)and disodium 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).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 Dipotassium 4,4’-bis[6-anilino-4-[bis(2-hydroxyethyl)amino-1,3,5-triazin-2-yl]amino]stilbene-2,2’-disulphonate (CAS No: 71230-67-6)was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor. The substance Dipotassium 4,4’-bis[6-anilino-4-[bis(2-hydroxyethyl)amino-1,3,5-triazin-2-yl]amino]stilbene-2,2’-disulphonate (CAS No: 71230-67-6)failed to induce skin sensitization effects on Hartley guinea pig skin and hence considered to be not sensitizing to the skin.

 

 

The U.S. Environmental Protection Agency (2012) and Ciba Specialty Chemicals Inc (1989) reported a Maximization test ofsimilar read acrosschemical disodium 4,4'-bis[6-anilino-[4-[bis(2-hydroxyethyl)amino]-1,3,5-triazin-2-yl]amino]stilbene-2,2'-disulphonate (CAS No: 4193-55-9) in Dunkin-Hartley guinea pigs(male and female) in accordance with Directive 84/449/EEC, B.6 "Acute toxicity (skin sensitization)". Induction was performed by intradermal injections and later by topical application in the scapular area region. Intradermal induction was performed by 3 pairs of intradermal injections consist of a) Freund complete adjuvant mixed 50:50 with water, b) test item 1% in bi-destilled water, c) 50:50 mixture of a) and b). A control group was treated accordingly without the test item. Epicutaneous induction was made one week after the induction with 15 % chemical in petrolatum oil or vehicle only. The dressings were left in place for 48 hours. Skin reactions (edema, erythema) were read immediately following removal of bandages and 24 and 48 hours later. Challenge was made two weeks after the epidermal induction for test item (10 % in petrolatum oil) and vehicle controls. The dressings were removed after 24 hours and oedema and erythema assessed immediately as well as 24 and 48 hours later. Rechallenge was performed as for the first challenge two weeks after the first challenge. The flanks of the animals were changed .Controls were treated with vehicle only on the left flank. The formaldehyde was used as positive control in a separate experiment using the same guinea pig strain with 10 % dilution of HCHO in bi-distilled water for induction period a, and a 5 % dilution of HCHO for the challenge procedure which possessed a strong skin sensitizing (contact allergenic) potential in Dunkin-Hartley albino guinea pigs. The reactions were scored according to the Draize score system. Allergenicity was evaluated from the 24 hours readings and the percentage of animals’ sensitized. Mean values with standard deviation. Exact Fischer-test p-values were calculated from 24 hours values of treatment.  After the first challenge application with 10 % test chemical in petrolatum oil a mild allergenic potency was concluded. After a second challenge application no allergenic potency of the test article diluted to 10 % in petrolatum oil was observed. No death occurred during the test period. Therefore the chemical disodium 4,4'-bis[6-anilino-[4-[bis(2-hydroxyethyl)amino]-1,3,5-triazin-2-yl]amino]stilbene-2,2'-disulphonate (CAS No: 4193-55-9)was considered to be not sensitizing in Dunkin-Hartley guinea pigs.

 

 

 

The above results were further supported by experimental study conducted by OECD SIDS (2005) forstructurally similar read across substancedisodium 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) performed on female Himalayan spotted albino Guinea pigs to assess the degree of skin sensitization caused by the chemical in accordance with OECD TG 406 .in this study, induction was performed by intradermal injections and later by topical application in the interscapular region. Intradermal induction was performed by 3 pairs of intradermal injections in the interscapular region of the animals (0.1 ml/site): 1) a 1 : 1 mixture of Freund’s Complete adjuvant (FCA) with physiological saline, 2) a 1 % dilution of the test item in physiological saline and 3) a 1 % dilution of the test item in an 1 : 1 mixture of FCA and physiological saline. A control group was treated accordingly without the test item. On day 7, test sites were pretreated with 10 % sodium lauryl sulfate (SLS) to enhance sensitization by provoking a mild inflammatory reaction. On day 8, epidermal induction was performed by topical application of the chemical at 25 % in vaseline (nonirritating concentration of test item) for 48 hours under occlusive dressing. After a resting period of 2 weeks, the challenge was performed by epidermal application of the chemical at 25 % in vaseline under occlusive dressing for 18 hours. Cutaneous reactions, e.g. erythema and eschar as well as edema formation, were evaluated at 24 and 48 hours after the removal of the dressing. No clinical signs of systemic toxicity or dermal effects were noted in the treated animals and no deaths occurred. Both, 24 and 48 hours after challenge application, all skin reaction scores for erythema and edema were zero in each of the control and treated animals. Therefore the chemical disodium 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 not sensitizing on female Himalayan spotted albino Guinea pigs.

 

 

Thus on the basis of available data for thetarget chemicalDipotassium 4,4’-bis[6-anilino-4-[bis(2-hydroxyethyl)amino-1,3,5-triazin-2-yl]amino]stilbene-2,2’-disulphonate (CAS No: 71230-67-6)and its structurally similar read across substancesdisodium 4,4'-bis[6-anilino-[4-[bis(2-hydroxyethyl)amino]-1,3,5-triazin-2-yl]amino]stilbene-2,2'-disulphonate (Blankophor BA) (CAS No: 4193-55-9)and disodium 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),it can be concluded thatchemical Dipotassium 4,4’-bis[6-anilino-4-[bis(2-hydroxyethyl)amino-1,3,5-triazin-2-yl]amino]stilbene-2,2’-disulphonate (CAS No: 71230-67-6)is unable to cause skin sensitization and considered as non skin sensitizer.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

The skin sensitization potential of test substance Dipotassium 4,4’-bis[6-anilino-4-[bis(2-hydroxyethyl)amino-1,3,5-triazin-2-yl]amino]stilbene-2,2’-disulphonate (CAS No: 71230-67-6)and its structurally similar read across substancesdisodium 4,4'-bis[6-anilino-[4-[bis(2-hydroxyethyl)amino]-1,3,5-triazin-2-yl]amino]stilbene-2,2'-disulphonate (Blankophor BA) (CAS No: 4193-55-9)and disodium 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) were observed in various studies. From the results obtained from these studies it is concluded that the chemical Dipotassium 4,4’-bis[6-anilino-4-[bis(2-hydroxyethyl)amino-1,3,5-triazin-2-yl]amino]stilbene-2,2’-disulphonate (CAS No: 71230-67-6)is not likely to cause skin sensitization and hence can be classified as non skin sensitizer.