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Administrative data

Description of key information

The skin sensitization potential of target chemical 4-[(E)-2-(2,4-dimethylphenyl)diazen-1-yl]-3-methyl-1-phenyl-4,5-dihydro-1H-pyrazol-5-one (CAS No: 6407-78-9) was assessedin various experimental studies which were conducted on guinea pigs and humans for target chemical4-[(E)-2-(2,4-dimethylphenyl)diazen-1-yl]-3-methyl-1-phenyl-4,5-dihydro-1H-pyrazol-5-one (CAS No: 6407-78-9) and its structurally similar read across substance Edaravone(CAS No:-89-25-8) and functionally similar read across substance C.I. Pigment Red 3(CAS No: 2425-85-6). 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 4-[(E)-2-(2,4-dimethylphenyl)diazen-1-yl]-3-methyl-1-phenyl-4,5-dihydro-1H-pyrazol-5-one (CAS No: 6407-78-9) 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 3.3 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:
Buehler test
Justification for non-LLNA method:
not specified
Specific details on test material used for the study:
- Name of test material (IUPAC name): 4-[(E)-2-(2,4-dimethylphenyl)diazen-1-yl]-3-methyl-1-phenyl-4,5-dihydro-1H-pyrazol-5-one
- Common name: Solvent Yellow 18
- Molecular formula: C18H18N4O
- Molecular weight: 306.367 g/mol
- Smiles notation: O=C1N(N=C(C)[C@@H]1\N=N\c1c(cc(cc1)C)C)c1ccccc1
- InChl: 1S/C18H18N4O/c1-12-9-10-16(13(2)11-12)19-20-17-14(3)21-22(18(17)23)15-7-5-4-6-8-15/h4-11,17H,1-3H3/b20-19+
- Substance type: Organic
- Physical state: Solid
Species:
guinea pig
Strain:
other: Pirbright White
Sex:
not specified
Details on test animals and environmental conditions:
No data available
Route:
epicutaneous, occlusive
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:
48 hours
Adequacy of challenge:
not specified
No. of animals per dose:
10
Details on study design:
No data available
Reading:
1st reading
Hours after challenge:
48
Group:
test chemical
Dose level:
No data available
No. with + reactions:
0
Total no. in group:
10
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 9 nearest neighbours
Domain  logical expression:Result: Out of Domain

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

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 >> Aromatic azo AND SN1 >> Nitrenium Ion formation >> Unsaturated heterocyclic azo by DNA binding by OECD

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Schiff base formation AND Schiff base formation >> Pyrazolones and Pyrazolidinones derivatives AND Schiff base formation >> Pyrazolones and Pyrazolidinones derivatives >> Pyrazolones and Pyrazolidinones  by Protein binding by OASIS v1.3

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Acylation AND Acylation >> Direct Acylation Involving a Leaving group AND Acylation >> Direct Acylation Involving a Leaving group >> Acetates AND SN2 AND SN2 >> SN2 reaction at sp3 carbon atom AND SN2 >> SN2 reaction at sp3 carbon atom >> Alkyl diazo by Protein binding by OECD

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Amides AND Hydrazines by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Amides OR Hydrazines by Aquatic toxicity classification by ECOSAR ONLY

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Acylation AND Acylation >> Direct Acylation Involving a Leaving group AND Acylation >> Direct Acylation Involving a Leaving group >> Acetates AND SN2 AND SN2 >> SN2 reaction at sp3 carbon atom AND SN2 >> SN2 reaction at sp3 carbon atom >> Alkyl diazo by Protein binding by OECD

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Amides AND Hydrazines by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "h"

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

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> DNA Intercalators with Carboxamide Side Chain OR Non-specific OR Non-specific >> Incorporation into DNA/RNA, due to structural analogy with  nucleoside bases    OR Non-specific >> Incorporation into DNA/RNA, due to structural analogy with  nucleoside bases    >> Specific Imine and Thione Derivatives OR Radical OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Hydrazine Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitroarenes with Other Active Groups OR Radical >> Radical mechanism via ROS formation (indirect) >> Specific Imine and Thione Derivatives OR SN1 OR SN1 >> Nucleophilic attack after diazonium or carbenium ion formation OR SN1 >> Nucleophilic attack after diazonium or carbenium ion formation >> Nitroarenes with Other Active Groups OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitroarenes with Other Active Groups OR SN1 >> Nucleophilic substitution on diazonium ions OR SN1 >> Nucleophilic substitution on diazonium ions >> Specific Imine and Thione Derivatives OR SN2 OR SN2 >> SN2 attack on activated carbon Csp3 or Csp2 OR SN2 >> SN2 attack on activated carbon Csp3 or Csp2 >> Nitroarenes with Other Active Groups by DNA binding by OASIS v.1.3

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as SN1 AND SN1 >> Nitrenium Ion formation AND SN1 >> Nitrenium Ion formation >> Aromatic azo AND SN1 >> Nitrenium Ion formation >> Unsaturated heterocyclic azo by DNA binding by OECD

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> P450 Mediated Activation to Isocyanates or Isothiocyanates OR Acylation >> P450 Mediated Activation to Isocyanates or Isothiocyanates >> Formamides 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 >> Alkyl phenols OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Arenes OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Hydroquinones OR No alert found OR SN1 >> Iminium Ion Formation OR SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines OR SN1 >> Nitrenium Ion formation >> Aromatic nitro OR SN1 >> Nitrenium Ion formation >> Unsaturated heterocyclic nitro by DNA binding by OECD

Domain logical expression index: "l"

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

Domain logical expression index: "m"

Similarity boundary:Target: Cc1ccc(N=NC2C(C)=NN(c3ccccc3)C2=O)c(C)c1
Threshold=50%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "n"

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

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Carboxylic acid derivative by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Alkyl arenes AND Aryl AND Azo AND Pyrazolone AND Unsaturated heterocyclic amine AND Unsaturated heterocyclic fragment by Organic Functional groups

Domain logical expression index: "q"

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

Domain logical expression index: "r"

Parametric boundary:The target chemical should have a value of log Kow which is >= 4.84

Domain logical expression index: "s"

Parametric boundary:The target chemical should have a value of log Kow which is <= 9.4

Interpretation of results:
other: Not sensitizing
Conclusions:
The chemical 4-[(E)-2-(2,4-dimethylphenyl)diazen-1-yl]-3-methyl-1-phenyl-4,5-dihydro-1H-pyrazol-5-one (CAS No: 6407-78-9) was estimated to be not sensitizing to the skin of Pirbright White guinea pigs. Based on the estimated result 4-[(E)-2-(2,4-dimethylphenyl)diazen-1-yl]-3-methyl-1-phenyl-4,5-dihydro-1H-pyrazol-5-one (CAS No: 6407-78-9) failed to induce skin sanitization effects and hence is considered to be not sensitizing to Pirbright White guinea pigs.
Executive summary:

The skin sensitization potential of 4-[(E)-2-(2,4-dimethylphenyl)diazen-1-yl]-3-methyl-1-phenyl-4,5-dihydro-1H-pyrazol-5-one (CAS No: 6407-78-9) was estimated using OECD QSAR toolbox version 3.3 with log Pow as the primary descriptor. The chemical 4-[(E)-2-(2,4-dimethylphenyl)diazen-1-yl]-3-methyl-1-phenyl-4,5-dihydro-1H-pyrazol-5-one (CAS No: 6407-78-9) was estimated to be not sensitizing to the skin of Pirbright White guinea pigs. Based on the estimated result 4-[(E)-2-(2,4-dimethylphenyl)diazen-1-yl]-3-methyl-1-phenyl-4,5-dihydro-1H-pyrazol-5-one (CAS No: 6407-78-9) failed to induce skin sanitization effects and hence is considered to be not sensitizing to Pirbright White 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 chemical 4-[(E)-2-(2,4-dimethylphenyl)diazen-1-yl]-3-methyl-1-phenyl-4,5-dihydro-1H-pyrazol-5-one (CAS No: 6407-78-9) 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 chemical4-[(E)-2-(2,4-dimethylphenyl)diazen-1-yl]-3-methyl-1-phenyl-4,5-dihydro-1H-pyrazol-5-one (CAS No: 6407-78-9) and its structurally similar read across substanceEdaravone (CAS No:-89-25-8) and functionally similar read across substance C.I. Pigment Red 3(CAS No: 2425-85-6).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 4-[(E)-2-(2,4-dimethylphenyl)diazen-1-yl]-3-methyl-1-phenyl-4,5-dihydro-1H-pyrazol-5-one (CAS No: 6407-78-9)was estimated using OECD QSAR toolbox version 3.3 with log Pow as the primary descriptor. The chemical 4-[(E)-2-(2,4-dimethylphenyl)diazen-1-yl]-3-methyl-1-phenyl-4,5-dihydro-1H-pyrazol-5-one (CAS No: 6407-78-9)was estimated to be not sensitizing to the skin of Pirbright White guinea pigs. Based on the estimated result 4-[(E)-2-(2,4-dimethylphenyl)diazen-1-yl]-3-methyl-1-phenyl-4,5-dihydro-1H-pyrazol-5-one (CAS No: 6407-78-9) failed to induce skin sanitization effects and hence is considered to be not sensitizing to Pirbright White guinea pigs.

 

TheCosmetic Ingredient Review, CIR Expert Panel {Journal Of The American College of Toxicology, Volume 11, Number 4, 1992; Mary Ann Liebert, Inc., Publishers} conducted skin sensitizationstudy on20 guinea pigsfor read across chemicalEdaravone(CAS No:-89-25-8).In induction phase, 0.5ml of a 0.5% aqueous 3-methyl-1-phenyl-5-pyrazolone solution was applied dermally onclipped skin of left scapular regionfor 1hr under occlusive condition. This procedure was repeated 3 times in week for total 10 applications. After removal of patch the test site was rinsed with water. During the study, the guinea pigs received 2 intradermal injections of 0.1ml3freund’s complete adjuvant diluted to 50% with sterile isotonic saline near the test site.After 12 days rest period, animals were challenged at concentration of 0.50ml on clipped skin of left flank of abdomen using occlusive patch for 1 hour. After removal of patch, skin site was rinsed and observations were made after 1, 6, 24, 48 hrs.None of the animal produced any ski reactions at challenge concentration .Hence3-Methyl-1-Phenyl-5-Pyrazolonewas (CAS No:-89-25-8) was considered to be not sensitizing to the skin of albino guinea pigs.

 

The above results were further supported by patch test study of read across chemical C.I. Pigment Red 3 (CAS No: 2425-85-6) conducted by TAKEHITO KGZUKA et.al., {Contact Dermatitis;Volume6; Pg. no.330-336; 1980}. This skin sensitization study was performed in human patients suffering from pigmented contact dermatitis caused by the commercial Brilliant Lake Red R.The patch of Toluidine Red was applied onto the back of each patient for24 hours by usingFinn Chambers® on Scanpor® (Epitest, Ltd. Oy) at a dose of 1% in petrolatum. After removal of patch, skin reactions were assessedaccording 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. Thusthe test chemicalToluidine Red(CAS No: 2425-85-6)was considered to be not sensitizingin human patients suffering from pigmented contact dermatitis caused by the commercial Brilliant Lake Red R.

 

Thus on the basis of available data for thetarget chemical 4-[(E)-2-(2,4-dimethylphenyl)diazen-1-yl]-3-methyl-1-phenyl-4,5-dihydro-1H-pyrazol-5-one (CAS No: 6407-78-9) and its structurally similar read across substance Edaravone(CAS No:-89-25-8) and functionally similar read across substance C.I. Pigment Red 3 (CAS No: 2425-85-6),it can be concluded that chemical 4-[(E)-2-(2,4-dimethylphenyl)diazen-1-yl]-3-methyl-1-phenyl-4,5-dihydro-1H-pyrazol-5-one (CAS No: 6407-78-9) 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 4-[(E)-2-(2,4-dimethylphenyl)diazen-1-yl]-3-methyl-1-phenyl-4,5-dihydro-1H-pyrazol-5-one (CAS No: 6407-78-9) and itsstructurallysimilar read across substanceEdaravone(CAS No:-89-25-8) and functionally similar read across substance C.I. Pigment Red 3 (CAS No: 2425-85-6) were observed in various studies. From the results obtained from these studies it is concluded that the chemical 4-[(E)-2-(2,4-dimethylphenyl)diazen-1-yl]-3-methyl-1-phenyl-4,5-dihydro-1H-pyrazol-5-one (CAS No: 6407-78-9) is not likely to cause skin sensitization and hence can be classified as non-skin sensitizer.