m-(4,5-dihydro-5-imino-3-methyl-1H-pyrazol-1-yl)benzenesulphonic acid

Endpoint summary

Description of key information

Skin Sensitization:

The skin sensitization potential of 3-(5-imino-3-methyl-4,5-dihydro-1H-pyrazol-1-yl)benzene-1-sulfonic acid was estimated by SSS (2017) using OECD QSAR toolbox v3.4 with log kow as the primary descriptor. 3-(5-imino-3-methyl-4,5-dihydro-1H-pyrazol-1-yl)benzene-1-sulfonic acid was predicted to be not sensitizing to the skin of female guinea pigs.

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 v3.4 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 v3.4

GLP compliance:

not specified

Type of study:

guinea pig maximisation test

Specific details on test material used for the study:

- Name of test material: m-(4,5-dihydro-5-imino-3-methyl-1H-pyrazol-1-yl)benzenesulphonic acid
- IUPAC name: 3-(5-imino-3-methyl-4,5-dihydro-1H-pyrazol-1-yl)benzene-1-sulfonic acid
- Molecular formula: C10H11N3O3S
- Molecular weight: 253.281 g/mole
- Smiles: O=S(=O)(O)c1cccc(N2N=C(CC2=N)C)c1
- Inchl: 1S/C10H11N3O3S/c1-7-5-10(11)13(12-7)8-3-2-4-9(6-8)17(14,15)16/h2-4,6,11H,5H2,1H3,(H,14,15,16)
- Substance type: Organic
- Physical state: Solid

Species:

guinea pig

Strain:

not specified

Sex:

female

Details on test animals and environmental conditions:

no data available

Route:

intradermal and epicutaneous

Vehicle:

not specified

Adequacy of induction:

not specified

No.:

#1

Route:

epicutaneous, occlusive

Vehicle:

not specified

Adequacy of challenge:

not specified

No. of animals per dose:

10

Details on study design:

no data available

Challenge controls:

no data available

Positive control substance(s):

not specified

Reading:

1st reading

Group:

test chemical

No. with + reactions:

0

Total no. in group:

10

Clinical observations:

no signs of dermal sensitization observed

Remarks on result:

no indication of skin sensitisation

The prediction was based on dataset comprised from the following descriptors: "Skin Sensitisation"
Estimation method: Takes highest mode value from the 8 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 "l" )  and ("m" and ( not "n") )  )  and ("o" and ( not "p") )  )  and ("q" and ( not "r") )  )  and ("s" and ( not "t") )  )  and ("u" and ( not "v") )  )  and ("w" and ( not "x") )  )  and ("y" and "z" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Aromatic compound OR Heterocyclic compound OR Sulfonic acid OR Sulfonic acid derivative by Organic functional groups, Norbert Haider (checkmol) ONLY

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] OR Aliphatic Carbon [-CH2-] OR Aliphatic Carbon [-CH3] OR Aliphatic Nitrogen, one aromatic attach [-N] OR Aromatic Carbon [C] OR Azomethine, aliphatic attach [-N=C] OR Hydrazine [>N-N<] OR Hydroxy, sulfur attach [-OH] OR Miscellaneous sulfide (=S) or oxide (=O) OR Nitrogen, two or tree olefinic attach [>N-] OR Olefinic carbon [=CH- or =C<] OR Suflur {v+4} or {v+6} OR Sulfinic acid [-S(=O)OH] OR Sulfonate, aromatic attach [-SO2-O] by Organic functional groups (US EPA) ONLY

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Amidine OR Aryl OR Overlapping groups OR Sulfonic acid OR Unsaturated heterocyclic amine OR Unsaturated heterocyclic fragment by Organic Functional groups (nested) ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Amidine OR Aryl OR Sulfonic acid OR Unsaturated heterocyclic amine OR Unsaturated heterocyclic fragment by Organic Functional groups ONLY

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OASIS v.1.4

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >>  Michael-type addition, quinoid structures OR AN2 >>  Michael-type addition, quinoid structures >> Quinone methides OR AN2 >>  Michael-type addition, quinoid structures >> Quinoneimines OR AN2 >> Nucleophilic addition to alpha, beta-unsaturated carbonyl compounds OR AN2 >> Nucleophilic addition to alpha, beta-unsaturated carbonyl compounds >> Alpha, Beta-Unsaturated Aldehydes OR AN2 >> Schiff base formation OR AN2 >> Schiff base formation >> Alpha, Beta-Unsaturated Aldehydes OR Radical OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Single-Ring Substituted Primary Aromatic Amines OR Radical >> ROS formation after GSH depletion OR Radical >> ROS formation after GSH depletion (indirect) OR Radical >> ROS formation after GSH depletion (indirect) >> Quinoneimines OR Radical >> ROS formation after GSH depletion >> Quinone methides OR SN1 OR SN1 >> Nucleophilic attack after nitrenium ion formation OR SN1 >> Nucleophilic attack after nitrenium ion formation >> Single-Ring Substituted Primary Aromatic Amines by DNA binding by OASIS v.1.4

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as No alert found 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 of Heterocyclic Ring Systems OR Michael addition >> P450 Mediated Activation of Heterocyclic Ring Systems >> Furans 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 SN1 OR SN1 >> Nitrenium Ion formation 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 No alert found by Protein binding by OASIS v1.4

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Acylation involving an activated (glucuronidated) sulfonamide group OR Acylation >> Acylation involving an activated (glucuronidated) sulfonamide group >> Arenesulfonamides OR AN2 OR AN2 >> Michael-type addition to activated double bonds in vinyl pyridines OR AN2 >> Michael-type addition to activated double bonds in vinyl pyridines >> Ethenyl Pyridines OR AN2 >> Nucleophilic addition at polarized N-functional double bond OR AN2 >> Nucleophilic addition at polarized N-functional double bond >> Arenesulfonamides OR Michael addition OR Michael addition >> Michael addition on polarised Alkenes OR Michael addition >> Michael addition on polarised Alkenes >> Polarised Alkene - alkenyl pyridines, pyrazines, pyrimidines or triazines  by Protein binding by OASIS v1.4

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Bioavailable by Lipinski Rule Oasis ONLY

Domain logical expression index: "l"

Similarity boundary:Target: CC1CC(=N)N(c2cccc(S(O)(=O)=O)c2)N=1
Threshold=40%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Benzene/ Naphthalene sulfonic acids (Less susceptible) Rank C by Repeated dose (HESS)

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Aliphatic amines (Mucous membrane irritation) Rank C OR Amine oxides (Less susceptible) No Rank by Repeated dose (HESS)

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Benzene/ Naphthalene sulfonic acids (Less susceptible) Rank C by Repeated dose (HESS)

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Thiocarbamates/Sulfides (Hepatotoxicity) No rank by Repeated dose (HESS)

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as Amidine AND Aryl AND Sulfonic acid AND Unsaturated heterocyclic amine AND Unsaturated heterocyclic fragment by Organic Functional groups

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as Alkene OR Alkyl by Organic Functional groups

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as Amidine AND Aryl AND Sulfonic acid AND Unsaturated heterocyclic amine AND Unsaturated heterocyclic fragment by Organic Functional groups

Domain logical expression index: "t"

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

Domain logical expression index: "u"

Referential boundary: The target chemical should be classified as Amidine AND Aryl AND Sulfonic acid AND Unsaturated heterocyclic amine AND Unsaturated heterocyclic fragment by Organic Functional groups

Domain logical expression index: "v"

Referential boundary: The target chemical should be classified as Saturated heterocyclic amine by Organic Functional groups

Domain logical expression index: "w"

Referential boundary: The target chemical should be classified as Not known precedent reproductive and developmental toxic potential by DART scheme v.1.0

Domain logical expression index: "x"

Referential boundary: The target chemical should be classified as Metals (1a) by DART scheme v.1.0

Domain logical expression index: "y"

Parametric boundary:The target chemical should have a value of log Kow which is >= -4.33

Domain logical expression index: "z"

Parametric boundary:The target chemical should have a value of log Kow which is <= -0.156

Interpretation of results:

other: not sensitizing

Conclusions:

3-(5-imino-3-methyl-4,5-dihydro-1H-pyrazol-1-yl)benzene-1-sulfonic acid was predicted to be not sensitizing to the skin of female guinea pigs.

Executive summary:

The skin sensitization potential of 3-(5-imino-3-methyl-4,5-dihydro-1H-pyrazol-1-yl)benzene-1-sulfonic acid was estimated by SSS (2017) using OECD QSAR toolbox v3.4 with log kow as the primary descriptor. 3-(5-imino-3-methyl-4,5-dihydro-1H-pyrazol-1-yl)benzene-1-sulfonic acid was predicted to be not sensitizing to the skin of female guinea pigs.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

Skin Sensitization:         

In different studies,3-(5-imino-3-methyl-4,5-dihydro-1H-pyrazol-1-yl)benzene-1-sulfonic acidhas been investigated for potential for dermal sensitization to a greater or lesser extent. The studies are based on in vivo experiments in rabbits along with predicted data for target chemical and its structurally similar read across substances, 4­Aminobenzenesulfonic acid[CAS: 121-57-3] and Phenylbenzimidazole Sulfonic Acid[CAS: 27503-21-7].The predicted data using the OECD QSAR toolbox has also been compared with the experimental data.

 

The skin sensitization potential of 3-(5-imino-3-methyl-4,5-dihydro-1H-pyrazol-1-yl)benzene-1-sulfonic acid was estimated by SSS (2017) using OECD QSAR toolbox v3.4 with log kow as the primary descriptor. 3-(5-imino-3-methyl-4,5-dihydro-1H-pyrazol-1-yl)benzene-1-sulfonic acid was predicted to be not sensitizing to the skin of female guinea pigs.

This is supported by the experimental study performed by D. A. Basketter et.al (Contact Dermatitis, Volume 27, Issue 4, April 1992, Pages 209–213) for the structurally similar read across substance, 4­Aminobenzenesulfonic acid[CAS: 121-57-3].Preliminary irritation tests were carried out to determine concentrations of sulphanilic acid suitable for induction of sensitization and for sensitization challenge. Dunkin-Hartley Guinea pigs weighing approximately 350 grams, 10 in the test group and 4 in the control group were used for the assay. 25% Sulphanilic acid was applied twice weekly for 2 weeks using 24 hours occlusive patches to the shoulder area of test animals to induce dermal reactions. Immediately before the third application,

the test and 4 control guinea pigs were injected with Freund's complete adjuvant in the shoulder region at the site to be patched.Test and control animals were challenged after a 12 days rest period by open application at the maximum non-irritant concentration (25%). 25% in 0.9% NaCl/PEG400 (50/50, v/v) was applied to the shoulder region of the test animals and observed for erythema. Challenge sites were scored for erythema (scale 0-3) at 24 and 48 hours.

0% guinea pigs were sensitized when evaluated after the challenge exposure. Sulphanilic Acid failed to induce any evidence of sensitization at higher concentrations in the cumulative contact enhancement test (CCET). Therefore, Sulphanilic Acid (121 -57 -3) was considered to be not sensitizing.

The above results are further supported by the experimental study summarized in OPINION ON PHENYLBENZIMIDAZOLE SULFONIC ACID AND ITS SALTS- SCCP/1056/06; for the structurally similar read across substance, Phenylbenzimidazole Sulfonic Acid[CAS: 27503-21-7]. 20 Dunkin Hartley guinea pigs in test group and 10 Dunkin Hartley guinea pigs in negative controls were used. Guinea pigs were induced with intradermal injections of 0.1ml Freund’s complete adjuvant in water, Phenylbenzimidazole Sulfonic Acid 1% w/v in arachis oil, and Freund’s + Phenylbenzimidazole Sulfonic Acid 1% w/v in arachis oil (1:1) into three separate sites.After 1 week, a single topical application of0.2 – 0.3 ml Phenylbenzimidazole Sulfonic Acid 50% w/w in arachis oilunder occlusion for 48 hours was applied. On day 21 animals were challenged with 0.1-0.2 ml Phenylbenzimidazole Sulfonic Acid 25 and 10% w/w in arachis oil.

Since there was no evidence of any skin reaction, Ensulizole/Phenylbenzimidazole Sulfonic Acid (CAS No: -27503-81-7) can be concluded as not sensitizing to guinea pigs.

Based on the available data for the target as well as read across substances and applying the weight of evidence approach,3-(5-imino-3-methyl-4,5-dihydro-1H-pyrazol-1-yl)benzene-1-sulfonic acidwas not sensitizing to skin.Comparing the above annotations with the criteria of CLP regulation, test chemical can be classified under the category “Not Classified”.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Available data for 3-(5-imino-3-methyl-4,5-dihydro-1H-pyrazol-1-yl)benzene-1-sulfonic acid indicates that it is not likely to cause any dermal sensitization to skin.

3-(5-imino-3-methyl-4,5-dihydro-1H-pyrazol-1-yl)benzene-1-sulfonic acid can be considered to be not sensitizer to skin and can be classified under the category “Not Classified” as per CLP regulation.