2-[(4-chloro-2-nitrophenyl)azo]-N-(4-ethoxyphenyl)-3-oxobutyramide

Endpoint summary

Description of key information

The skin sensitization potential of target chemical 2-[(E)-2-(4-chloro-2-nitrophenyl)diazen-1-yl]-N-(4-ethoxyphenyl)-3-oxobutanamide (CAS No: 52320-66-8) was assessedin various experimental studies which were conducted on guinea pigs and humans for target chemical2-[(E)-2-(4-chloro-2-nitrophenyl)diazen-1-yl]-N-(4-ethoxyphenyl)-3-oxobutanamide (CAS No: 52320-66-8) andits structurally similar read across substancesC. I. Pigment Yellow 12 (CAS no: 6358-85-6) and C. I. Pigment Yellow 13 (CAS no: 5102-83-0). 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 2-[(E)-2-(4-chloro-2-nitrophenyl)diazen-1-yl]-N-(4-ethoxyphenyl)-3-oxobutanamide (CAS No: 52320-66-8) 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:

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): 2-[(E)-2-(4-chloro-2-nitrophenyl)diazen-1-yl]-N-(4-ethoxyphenyl)-3-oxobutanamide
- Molecular formula: C18H17ClN4O5
- Molecular weight: 404.808 g/mol
- Smiles notation: O=C(Nc1ccc(OCC)cc1)[C@@H](\N=N\c1c([N+](=O)[O-])cc(cc1)Cl)C(=O)C
- InChl: 1S/C18H17ClN4O5/c1-3-28-14-7-5-13(6-8-14)20-18(25)17(11(2)24)22-21-15-9-4-12(19)10-16(15)23(26)27/h4-10,17H,3H2,1-2H3,(H,20,25)/b22-21+
- Substance type: Organic
- Physical state: Solid

Species:

guinea pig

Strain:

Dunkin-Hartley

Sex:

not specified

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:

48 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:

48

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 9 nearest neighbours
Domain  logical expression:Result: In Domain

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

Domain logical expression index: "a"

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

Domain logical expression index: "b"

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 >> Aromatic nitro by DNA binding by OECD

Domain logical expression index: "c"

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 >> Acyl halide 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 Michael addition >> Polarised Alkenes-Michael addition OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated esters OR No alert found OR Schiff base formers OR Schiff base formers >> Chemicals Activated by P450 to Glyoxal  OR Schiff base formers >> Chemicals Activated by P450 to Glyoxal  >> Ethylenediamines (including piperazine) OR SN1 >> Carbenium Ion Formation OR SN1 >> Carbenium Ion Formation >> Hydrazine OR SN1 >> Iminium Ion Formation OR SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines OR SN1 >> Nitrenium Ion formation >> Aromatic phenylureas OR SN1 >> Nitrenium Ion formation >> Primary (unsaturated) heterocyclic amine OR SN1 >> Nitrenium Ion formation >> Primary aromatic amine OR SN1 >> Nitrenium Ion formation >> Tertiary aromatic amine OR SN1 >> Nitrenium Ion formation >> Unsaturated heterocyclic azo OR SN2 OR SN2 >> SN2 at an sp3 Carbon atom OR SN2 >> SN2 at an sp3 Carbon atom >> Phosphates by DNA binding by OECD

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Acylation AND Acylation >> Ester aminolysis AND Acylation >> Ester aminolysis >> Amides by Protein binding by OASIS v1.3

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Nucleophilic addition OR Nucleophilic addition >> Addition to carbon-hetero double bonds OR Nucleophilic addition >> Addition to carbon-hetero double bonds >> Ketones by Protein binding by OASIS v1.3

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Has superfragment AND O=C(R{*})C(C(=O)NR{*})N=NR{*} by Superfragments ONLY

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as (!Undefined)Group All Lipid Solubility < 0.01 g/kg AND (!Undefined)Group CNHal Lipid Solubility < 4 g/kg AND (!Undefined)Group CNHal Lipid Solubility < 400 g/kg AND Group All Melting Point > 200 C AND Group CNHal Aqueous Solubility < 0.001 g/L AND Group CNHal Aqueous Solubility < 0.1 g/L AND Group CNHal log Kow > 3.8 AND Group CNHal Molecular Weight > 370 g/mol AND Group CNHal Molecular Weight > 380 g/mol by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as (!Undefined)Group CN Lipid Solubility < 0.4 g/kg OR Group All log Kow > 9 OR Group CN Aqueous Solubility < 0.0001 g/L OR Group CN Aqueous Solubility < 0.1 g/L OR Group CN log Kow > 4.5 OR Group CN Melting Point > 180 C OR Group CN Molecular Weight > 290 g/mol OR Group CN Molecular Weight > 540 g/mol OR Group CN Vapour Pressure < 0.001 Pa by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Group 14 - Carbon C AND Group 15 - Nitrogen N AND Group 16 - Oxygen O AND Group 17 - Halogens Cl AND Group 17 - Halogens F,Cl,Br,I,At by Chemical elements

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Group 17 - Halogens F by Chemical elements

Domain logical expression index: "k"

Similarity boundary:Target: CCOc1ccc(NC(=O)C(C(C)=O)N=Nc2ccc(Cl)cc2N(=O)=O)cc1
Threshold=20%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "l"

Similarity boundary:Target: CCOc1ccc(NC(=O)C(C(C)=O)N=Nc2ccc(Cl)cc2N(=O)=O)cc1
Threshold=50%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Alkylarylether AND Aromatic compound AND Aryl chloride AND Aryl halide AND Carbonyl compound AND Carboxylic acid amide AND Carboxylic acid sec. amide AND Ether AND Halogen derivative AND Ketone AND Nitro compound by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Carbonic acid derivative OR CO2 derivative (general) OR Heterocyclic compound by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "o"

Parametric boundary:The target chemical should have a value of log Kow which is >= 3.55

Domain logical expression index: "p"

Parametric boundary:The target chemical should have a value of log Kow which is <= 8.15

Interpretation of results:

other: Not sensitizing

Conclusions:

The chemical 2-[(E)-2-(4-chloro-2-nitrophenyl)diazen-1-yl]-N-(4-ethoxyphenyl)-3-oxobutanamide (CAS No: 52320-66-8) was estimated to be not sensitizing to the skin of Dunkin-Hartley guinea pigs. Based on the estimated result 2-[(E)-2-(4-chloro-2-nitrophenyl)diazen-1-yl]-N-(4-ethoxyphenyl)-3-oxobutanamide (CAS No: 52320-66-8) 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 2-[(E)-2-(4-chloro-2-nitrophenyl)diazen-1-yl]-N-(4-ethoxyphenyl)-3-oxobutanamide (CAS No: 52320-66-8) was estimated using OECD QSAR toolbox version 3.4 with log Pow as the primary descriptor. The chemical 2-[(E)-2-(4-chloro-2-nitrophenyl)diazen-1-yl]-N-(4-ethoxyphenyl)-3-oxobutanamide (CAS No: 52320-66-8) was estimated to be not sensitizing to the skin of Dunkin-Hartley guinea pigs. Based on the estimated result 2-[(E)-2-(4-chloro-2-nitrophenyl)diazen-1-yl]-N-(4-ethoxyphenyl)-3-oxobutanamide (CAS No: 52320-66-8) 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)

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information:

Various studieshas been investigated for the test chemical2-[(E)-2-(4-chloro-2-nitrophenyl)diazen-1-yl]-N-(4-ethoxyphenyl)-3-oxobutanamide (CAS No: 52320-66-8)  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 chemical2-[(E)-2-(4-chloro-2-nitrophenyl)diazen-1-yl]-N-(4-ethoxyphenyl)-3-oxobutanamide (CAS No: 52320-66-8)  and its structurally similar read across substancesC. I. Pigment Yellow 12 (CAS no: 6358-85-6) and C. I. Pigment Yellow 13 (CAS no: 5102-83-0). 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 2-[(E)-2-(4-chloro-2-nitrophenyl)diazen-1-yl]-N-(4-ethoxyphenyl)-3-oxobutanamide (CAS No: 52320-66-8)  was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor. 2-[(E)-2-(4-chloro-2-nitrophenyl)diazen-1-yl]-N-(4-ethoxyphenyl)-3-oxobutanamide (CAS No: 52320-66-8)  was estimated to be not sensitizing to the skin of Dunkin-Hartley guinea pigs. Based on the estimated result 2-[(E)-2-(4-chloro-2-nitrophenyl)diazen-1-yl]-N-(4-ethoxyphenyl)-3-oxobutanamide (CAS No: 52320-66-8)  can be considered to be not sensitizing to Dunkin-Hartley guinea pigs.

 

The above result was further supported by the patch test studies conducted by Thierbach MA et.al., {Contact Dermatitis, 27, 22-26, (1992)} for two read across substances C. I. Pigment Yellow 12 (CAS no: 6358-85-6) and C. I. Pigment Yellow 13 (CAS no: 5102-83-0) as follow;

The patch test for both the chemical was performed in 32 patients with an established p-aminoazobenzene allergy (32 patients for each patch test). The test was conducted on a group of 32 patients with presumable allergic contact dermatitis and all with a positive patch teat reaction to p-aminoazobenzene (0.25% pet). The group consisted of 20 women (mean age 39.9 years) and men (mean age 46.6 years). 11 patients had previously also shown sensitization to PPD (Para-phenyldiamine). 30 patients with an allergic contact dermatitis but negative to p-aminoazobenzene and PPD were also tested with the same patch test series. A patch with test chemical was placed in small squares (about 1.0 cm2) and wetted with 1 drop of tap water, water was used to imitate the circumstances (wet hands or sweating of hands). By this procedure a slight but visible yellow stain on the skin was found at the test site after 2 days of application, indicating liberation of the dyes. The chemicals did not elicit a positive patch test reaction in any one of the 32 patients’ positive to p-aminoazobenzene nor in the 30 control subjects. Hence the chemicals C. I. Pigment Yellow 12 (CAS no: 6358-85-6) and C. I. Pigment Yellow 13 (CAS no: 5102-83-0) were considered to be not sensitizing.

 

Thus on the basis of available data for thetarget chemical2-[(E)-2-(4-chloro-2-nitrophenyl)diazen-1-yl]-N-(4-ethoxyphenyl)-3-oxobutanamide (CAS No: 52320-66-8)  and its structurally similar read across substancesC. I. Pigment Yellow 12 (CAS no: 6358-85-6) and C. I. Pigment Yellow 13 (CAS no: 5102-83-0),it can be concluded thatchemical 2-[(E)-2-(4-chloro-2-nitrophenyl)diazen-1-yl]-N-(4-ethoxyphenyl)-3-oxobutanamide (CAS No: 52320-66-8)  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 2-[(E)-2-(4-chloro-2-nitrophenyl)diazen-1-yl]-N-(4-ethoxyphenyl)-3-oxobutanamide (CAS No: 52320-66-8)   and its structurally similar read across substances C. I. Pigment Yellow 12 (CAS no: 6358-85-6) and C. I. Pigment Yellow 13 (CAS no: 5102-83-0) were observed in various studies. From the results obtained from these studies it is concluded that the chemical 2-[(E)-2-(4-chloro-2-nitrophenyl)diazen-1-yl]-N-(4-ethoxyphenyl)-3-oxobutanamide (CAS No: 52320-66-8)  is not likely to cause skin sensitization and hence can be classified as non-skin sensitizer.