2-chloro-4-nitrophenol

Endpoint summary

Description of key information

The skin sensitization potential of 2-chloro- 4-nitrophenol (CAS No: 619-08-9) was estimated using OECD QSAR toolbox version 3.3 with log Pow as the primary descriptor. The substance 2-chloro- 4-nitrophenol (CAS No: 619-08-9) was estimated to be not sensitizing to the skin of Dunkin-Hartley guinea pigs. Based on the estimated result 2-chloro- 4-nitrophenol (CAS No: 619-08-9) 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)

Remarks:

in vivo

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:

- IUPAC Name: 2-chloro-4-nitrophenol
- Common Name: Nitrofungin
- Mol. formula: C6H4ClNO3
- Molecular Weight: 173.555 g/mol
- Smiles: c1(cc(c(O)cc1)Cl)[N+](=O)[O-]
- InChI: 1S/C6H4ClNO3/c7-5-3-4(8(10)11)1-2-6(5)9/h1-3,9H

Species:

guinea pig

Strain:

Dunkin-Hartley

Sex:

not specified

Details on test animals and environmental conditions:

not specified

Route:

other:

Vehicle:

not specified

Concentration / amount:

not specified

Day(s)/duration:

not specified

Adequacy of induction:

not specified

No.:

#1

Route:

epicutaneous, occlusive

Vehicle:

not specified

Concentration / amount:

not specified

Day(s)/duration:

72 hours

Adequacy of challenge:

not specified

No. of animals per dose:

20

Details on study design:

not specified

Reading:

1st reading

Hours after challenge:

72

Group:

test chemical

Dose level:

not specified

No. with + reactions:

0

Total no. in group:

20

Clinical observations:

No skin sensitization was observed.

Remarks on result:

no indication of skin sensitisation

Cellular proliferation data / Observations:

No skin sensitization was observed.

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" or "e" or "f" )  and ("g" and ( not "h") )  )  and "i" )  and ("j" and ( not "k") )  )  and ("l" and ( not "m") )  )  and ("n" and ( not "o") )  )  and ("p" and "q" )  )

Domain logical expression index: "a"

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

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Radical AND Radical >> Radical mechanism via ROS formation (indirect) AND Radical >> Radical mechanism via ROS formation (indirect) >> Nitroarenes with Other Active Groups AND Radical >> Radical mechanism via ROS formation (indirect) >> Nitrophenols, Nitrophenyl Ethers and Nitrobenzoic Acids AND SN1 AND SN1 >> Nucleophilic attack after diazonium or carbenium ion formation AND SN1 >> Nucleophilic attack after diazonium or carbenium ion formation >> Nitroarenes with Other Active Groups AND SN1 >> Nucleophilic attack after reduction and nitrenium ion formation AND SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitroarenes with Other Active Groups AND SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitrophenols, Nitrophenyl Ethers and Nitrobenzoic Acids AND SN2 AND SN2 >> SN2 attack on activated carbon Csp3 or Csp2 AND 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: "c"

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

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Moderate binder, OH grooup by Estrogen Receptor Binding

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Phenols and Anilines by Acute aquatic toxicity MOA by OASIS

Domain logical expression index: "f"

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

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Radical AND Radical >> Radical mechanism via ROS formation (indirect) AND Radical >> Radical mechanism via ROS formation (indirect) >> Nitroarenes with Other Active Groups AND Radical >> Radical mechanism via ROS formation (indirect) >> Nitrophenols, Nitrophenyl Ethers and Nitrobenzoic Acids AND SN1 AND SN1 >> Nucleophilic attack after diazonium or carbenium ion formation AND SN1 >> Nucleophilic attack after diazonium or carbenium ion formation >> Nitroarenes with Other Active Groups AND SN1 >> Nucleophilic attack after reduction and nitrenium ion formation AND SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitroarenes with Other Active Groups AND SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitrophenols, Nitrophenyl Ethers and Nitrobenzoic Acids AND SN2 AND SN2 >> SN2 attack on activated carbon Csp3 or Csp2 AND 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: "h"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >> Shiff base formation after aldehyde release OR AN2 >> Shiff base formation after aldehyde release >> Specific Acetate Esters OR No alert found OR Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> DNA Intercalators with Carboxamide Side Chain OR Non-covalent interaction >> DNA intercalation >> Fused-Ring Nitroaromatics OR Non-covalent interaction >> DNA intercalation >> Fused-Ring Primary Aromatic Amines OR Radical >> Generation of ROS by glutathione depletion (indirect) OR Radical >> Generation of ROS by glutathione depletion (indirect) >> Haloalkanes Containing Heteroatom OR Radical >> Radical mechanism by ROS formation OR Radical >> Radical mechanism by ROS formation >> Polynitroarenes OR Radical >> Radical mechanism via ROS formation (indirect) >> Fused-Ring Nitroaromatics OR Radical >> Radical mechanism via ROS formation (indirect) >> Fused-Ring Primary Aromatic Amines OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitro Azoarenes OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitroaniline Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> p-Substituted Mononitrobenzenes OR Radical >> Radical mechanism via ROS formation (indirect) >> Single-Ring Substituted Primary Aromatic Amines OR SN1 >> Carbenium ion formation OR SN1 >> Carbenium ion formation >> Alpha-Haloethers OR SN1 >> Nucleophilic attack after carbenium ion formation OR SN1 >> Nucleophilic attack after carbenium ion formation >> Specific Acetate Esters 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 metabolic nitrenium ion formation >> Single-Ring Substituted Primary Aromatic Amines OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Fused-Ring Nitroaromatics OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitro Azoarenes OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitroaniline Derivatives OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Polynitroarenes OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> p-Substituted Mononitrobenzenes OR SN2 >> Acylation OR SN2 >> Acylation >> Specific Acetate Esters OR SN2 >> Alkylation, direct acting epoxides and related OR SN2 >> Alkylation, direct acting epoxides and related >> Epoxides and Aziridines OR SN2 >> DNA alkylation OR SN2 >> DNA alkylation >> Alkylphosphates, Alkylthiophosphates and Alkylphosphonates OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Haloalkanes Containing Heteroatom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Specific Acetate Esters OR SN2 >> SN2 at sp3-carbon atom OR SN2 >> SN2 at sp3-carbon atom >> Alpha-Haloethers by DNA binding by OASIS v.1.3

Domain logical expression index: "i"

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

Domain logical expression index: "j"

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: "k"

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

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Aromatic compound AND Aryl chloride AND Aryl halide AND Halogen derivative AND Hydroxy compound AND Nitro compound AND Phenol by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "m"

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

Domain logical expression index: "n"

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 by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as (!Undefined)Group CN Lipid Solubility < 0.4 g/kg by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "p"

Parametric boundary:The target chemical should have a value of log Kow which is >= 2.46

Domain logical expression index: "q"

Parametric boundary:The target chemical should have a value of log Kow which is <= 4.12

Interpretation of results:

other: not sensitizing

Conclusions:

 The substance 2-chloro- 4-nitrophenol (CAS No: 619-08-9) was estimated to be not sensitizing to the skin of Dunkin-Hartley guinea pigs. Based on the estimated result 2-chloro- 4-nitrophenol (CAS No: 619-08-9) 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-chloro- 4-nitrophenol (CAS No: 619-08-9) was estimated using OECD QSAR toolbox version 3.3 with log Pow as the primary descriptor. The substance 2-chloro- 4-nitrophenol (CAS No: 619-08-9) was estimated to be not sensitizing to the skin of Dunkin-Hartley guinea pigs. Based on the estimated result 2-chloro- 4-nitrophenol (CAS No: 619-08-9) failed to induce skin sanitization effects and hence is considered to be not sensitizing to Dunkin-Hartley guinea pigs.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

Various studieshas been investigated for the test chemical2-chloro- 4-nitrophenol (CAS No: 619-08-9)to observe the potential for skin sensitization to a greater or lesser extent. The studies are based on in vivo experiments in guinea pigs for target chemical2-chloro- 4-nitrophenol (CAS No: 619-08-9) and its structurally similar read across substances1,2-Dichloro-4-nitrobenzene (CAS no: 99-54-7), 2-Chloro-4-nitroaniline(CAS No: 121-87-9)and2-nitroaniline(CAS No: 88-74-4).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-chloro- 4-nitrophenol (CAS No: 619-08-9) was estimated using OECD QSAR toolbox version 3.3 with log Pow as the primary descriptor. The substance 2-chloro- 4-nitrophenol (CAS No: 619-08-9) was estimated to be not sensitizing to the skin of Dunkin-Hartley guinea pigs. Based on the estimated result 2-chloro- 4-nitrophenol (CAS No: 619-08-9) failed to induce skin sanitization effects and hence is considered to be not sensitizing to Dunkin-Hartley guinea pigs.

 

The above results were supported by theGuinea pig maximization testof read across substance 1,2-Dichloro-4-nitrobenzene (CAS no: 99-54-7) conductedin accordance with OECD Test Guideline 406bythe MAK Collection for Occupational Health and Safety{1,2-Dichlor-4-nitrobenzol [MAK Value Documentation in German language, 2006]. The MAK Collection for Occupational Health and Safety. 1–14. 2012.}.The induction was carried out intracutaneously with 5 % 1,2-dichloro-4-nitrobenzene solution and topically with an occlusive 48-hour application of a 50 % 1,2-dichloro-4-nitrobenzene solution. To provoke the animals, a 50 % solution was applied occlusively to the skin for 24 hours. A second provocation reaction took place seven days later with 25- and 12% 1,2-dichloro-4-nitrobenzene. None of the animals showed a sensitization reaction. Hence the chemical1,2-Dichloro-4-nitrobenzene (CAS no: 99-54-7) was considered to be not sensitizing to the skin of guinea pigs.

 

 

The IFA GESTIS {GESTIS SUBSTANCE Database (information system in hazardous substance of the Berufsgenossenscheftn) 2017} and EUROPEAN COMMISSION – European Chemicals Bureau {IUCLID Dataset, 2000} reported skin sensitization study of read across substance 2-Chloro-4-nitroaniline(CAS No: 121-87-9) conducted by using Buehler test according to OECD guideline 406 on guinea pig. No skin sensitization was observed after the challenge application Hence2-Chloro-4-nitroaniline(CAS No:121-87-9) was considered as not skin sensitizing in guinea pig.

The above results further supported by the maximization test reported by IFA GESTIS {GESTIS SUBSTANCE Database (information system in hazardous substance of the Berufsgenossenscheftn) 2017} and OECD SIDS {SIDS Initial Assessment Report for SIAM 13, Bern, Switzerland, 6-9 November 2001} on read across substance 2-nitroaniline(CAS No: 88-74-4) by using OECD guideline 406 on guinea pig. The 30 animals were divided into two groups, test group 20 were as in control group 10 animals. In induction phase, first induction given by intracutaneous route in concentration 5 % while in 2nd Induction 50 % active substance as occlusive epicutaneous applied .Challenge given using 50% concentration of active substance by epicutaneous route as occlusive patch. No skin sensitization was observed after the challenge application Hence 2-nitroaniline (CAS No: 88-74-4) was considered as not skin sensitizing in guinea pig.

 

Based on the available data for the target chemical, supporting studies and read across substance,it can be concluded thatchemical 2-chloro- 4-nitrophenol (CAS No: 619-08-9) is unable to cause skin sensitization and considered as not sensitizing .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 2-chloro- 4-nitrophenol (CAS No: 619-08-9) and its structurally similar read across substances1,2-Dichloro-4-nitrobenzene (CAS no: 99-54-7), 2-Chloro-4-nitroaniline(CAS No: 121-87-9)and2-nitroaniline(CAS No: 88-74-4) were observed in various studies. From the results obtained from these studies it is concluded that the chemical 2-chloro- 4-nitrophenol (CAS No: 619-08-9) is not likely to cause skin sensitization and hence can be classified as non- skin sensitizer.