2-hydroxypyridine 1-oxide

Endpoint summary

Description of key information

The skin sensitization potential of Pyridin-2-ol 1-oxide (CAS No: 13161-30-3) was estimated using OECD QSAR toolbox version 3.3 with log Pow as the primary descriptor. The substance Pyridin-2-ol 1-oxide (CAS No: 13161-30-3) was estimated to be not sensitizing to the skin of guinea pigs. Based on the estimated result Pyridin-2-ol 1-oxide (CAS No: 13161-30-3) failed to induce skin sanitization effects and hence is considered to be not sensitizing to guinea pigs.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Endpoint:

skin sensitisation

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:

- Name of test material (IUPAC name): 2-Hydroxypyridine 1-oxide
- Molecular formula: C5H5NO2
- Molecular weight: 111.1 g/mol
- Smiles notation: n1(c(O)cccc1)=O
- InChl: 1S/C5H5NO2/c7-5-3-1-2-4-6(5)8/h1-4,7H
- Substance type: Organic
- Physical state: Solid

Species:

guinea pig

Strain:

not specified

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:

other:

Concentration / amount:

No data available

Day(s)/duration:

72 hrs

Adequacy of challenge:

not specified

No. of animals per dose:

No data available

Details on study design:

No data available

Challenge controls:

No data available

Reading:

1st reading

Hours after challenge:

72

Group:

test chemical

Dose level:

No data available

No. with + reactions:

0

Clinical observations:

sensitization was not observed in treated animals.

Remarks on result:

no indication of skin sensitisation

Cellular proliferation data / Observations:

sensitization was not observed in treated animals.

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" or "e" )  and ("f" and ( not "g") )  )  and ("h" and ( not "i") )  )  and ("j" and ( not "k") )  )  and "l" )  and ("m" and ( not "n") )  )  and ("o" and ( not "p") )  )  and "q" )  and ("r" and ( not "s") )  )  and ("t" and ( not "u") )  )  and "v" )  and "w" )  and ("x" and ( not "y") )  )  and ("z" and "aa" )  )

Domain logical expression index: "a"

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

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Aryl OR Heterocyclic Phenol OR N-Oxide OR Pyridine by Organic Functional groups ONLY

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Heterocyclic Phenol OR N-Oxide OR Overlapping groups by Organic Functional groups (nested) ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Alcohol, olefinic attach [-OH] OR Aromatic Carbon [C] OR Aromatic Nitrogen OR Hydroxy, aromatic attach [-OH] OR Miscellaneous sulfide (=S) or oxide (=O) OR Nitrogen oxide, aromatic nitrogen [n=O] OR Nitrogen oxide, aromatic nitrogen [n=O] non fused  OR Olefinic carbon [=CH- or =C<] OR Oxygen, one aromatic attach [-O-] OR Pyridine, non fused rings  by Organic functional groups (US EPA) ONLY

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Aromatic compound OR N-oxide OR Phenol by Organic functional groups, Norbert Haider (checkmol) ONLY

Domain logical expression index: "f"

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

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as AN2 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 Michael addition OR Michael addition >> Quinone type compounds OR Michael addition >> Quinone type compounds >> Quinone methides 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 Primary Aromatic Amines OR Radical OR Radical >> Radical mechanism by ROS formation OR Radical >> Radical mechanism by ROS formation >> Polynitroarenes 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 Radical >> Radical mechanism via ROS formation (indirect) >> Nitroaniline Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitrophenols, Nitrophenyl Ethers and Nitrobenzoic Acids 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 >> Quinone methides OR SN1 OR SN1 >> Alkylation after metabolically formed carbenium ion species OR SN1 >> Alkylation after metabolically formed carbenium ion species >> Polycyclic Aromatic Hydrocarbon Derivatives 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 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 >> Nitrophenols, Nitrophenyl Ethers and Nitrobenzoic Acids OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Polynitroarenes OR SN2 OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation >> Polycyclic Aromatic Hydrocarbon Derivatives OR SN2 >> Direct acting epoxides formed after metabolic activation OR SN2 >> Direct acting epoxides formed after metabolic activation >> Quinoline Derivatives OR SN2 >> DNA alkylation OR SN2 >> DNA alkylation >> Alkylphosphates, Alkylthiophosphates and Alkylphosphonates OR SN2 >> SN2 at an activated carbon atom OR SN2 >> SN2 at an activated carbon atom >> Quinoline Derivatives by DNA binding by OASIS v.1.3

Domain logical expression index: "h"

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

Domain logical expression index: "i"

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 >> Benzylamines-Acylation 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 >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Polycyclic (PAHs) and heterocyclic (HACs) aromatic hydrocarbons-Michael addition OR Michael addition >> Polarised Alkenes-Michael addition OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated esters OR SN1 OR SN1 >> Carbenium Ion Formation OR SN1 >> Carbenium Ion Formation >> Allyl benzenes OR SN1 >> Iminium Ion Formation OR SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines OR SN1 >> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Aromatic azo OR SN1 >> Nitrenium Ion formation >> Aromatic nitro OR SN1 >> Nitrenium Ion formation >> Primary aromatic amine OR SN1 >> Nitrenium Ion formation >> Tertiary aromatic amine by DNA binding by OECD

Domain logical expression index: "j"

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

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Ester aminolysis OR Acylation >> Ester aminolysis >> Amides OR Acylation >> Ester aminolysis or thiolysis OR Acylation >> Ester aminolysis or thiolysis >> Activated aryl esters  OR 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 >> alpha,beta-Carbonyl compounds with polarized double bonds  OR Michael Addition >> Polarised Alkenes OR Michael Addition >> Polarised Alkenes >> Polarised Alkene - alkenyl pyridines, pyrazines, pyrimidines or triazines  OR SNAr OR SNAr >> Nucleophilic aromatic substitution on activated aryl and heteroaryl compounds OR SNAr >> Nucleophilic aromatic substitution on activated aryl and heteroaryl compounds >> Activated aryl and heteroaryl compounds by Protein binding by OASIS v1.3

Domain logical expression index: "l"

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

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Inclusion rules not met by Eye irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Subststituted pyrazoles by Eye irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as No alert found by Protein binding alerts for Chromosomal aberration by OASIS v1.1

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Ac-SN2 OR Ac-SN2 >> Acylation involving an activated (glucuronidated) ester group OR Ac-SN2 >> Acylation involving an activated (glucuronidated) ester group >> Arenecarboxylic Acid Esters OR AN2 OR AN2 >> Michael-type addition to quinoid structures OR AN2 >> Michael-type addition to quinoid structures >> Phenols OR AN2 >> Nucleophilic addition to pyridonimine tautomer of aminopyridoindoles or aminopyridoimidazoles OR AN2 >> Nucleophilic addition to pyridonimine tautomer of aminopyridoindoles or aminopyridoimidazoles >> Heterocyclic Aromatic Amines OR Radical mechanism OR Radical mechanism >> ROS generation and direct attack of hydroxyl radical to the C8 position of nucleoside base OR Radical mechanism >> ROS generation and direct attack of hydroxyl radical to the C8 position of nucleoside base >> Heterocyclic Aromatic Amines OR SE reaction (CYP450-activated heterocyclic amines) OR SE reaction (CYP450-activated heterocyclic amines) >> Direct attack of arylnitrenium cation to the C8 position of nucleoside base OR SE reaction (CYP450-activated heterocyclic amines) >> Direct attack of arylnitrenium cation to the C8 position of nucleoside base >> Heterocyclic Aromatic Amines OR SR reaction (peroxidase-activated heterocyclic amines) OR SR reaction (peroxidase-activated heterocyclic amines) >> Direct attack of arylnitrenium radical to the C8 position of nucleoside base OR SR reaction (peroxidase-activated heterocyclic amines) >> Direct attack of arylnitrenium radical to the C8 position of nucleoside base >> Heterocyclic Aromatic Amines by Protein binding alerts for Chromosomal aberration by OASIS v1.1

Domain logical expression index: "q"

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

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as Not categorized by Repeated dose (HESS)

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as 3-Methylcholantrene (Hepatotoxicity) Alert OR Aromatic hydrocarbons (Liver enzyme induction) Rank C OR Benzene/ Naphthalene sulfonic acids (Less susceptible) Rank C OR Carboxylic acids (Hepatotoxicity) No rank OR Chlorphentermine (Hepatotoxicity) Alert OR Nitrophenols/ Halophenols (Energy metabolism dysfuntion) Rank B OR Phenols (Mucous membrane irritation) Rank C OR Tamoxifen (Hepatotoxicity) Alert OR Thiocarbamates/Sulfides (Hepatotoxicity) No rank by Repeated dose (HESS)

Domain logical expression index: "t"

Referential boundary: The target chemical should be classified as Inclusion rules not met by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "u"

Referential boundary: The target chemical should be classified as Aldehydes OR Ketones OR Phenols OR Sulfonic acids or their salts by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "v"

Referential boundary: The target chemical should be classified as Alcohol, olefinic attach [-OH] AND Aromatic Carbon [C] AND Aromatic Nitrogen AND Hydroxy, aromatic attach [-OH] AND Miscellaneous sulfide (=S) or oxide (=O) AND Nitrogen oxide, aromatic nitrogen [n=O] AND Nitrogen oxide, aromatic nitrogen [n=O] non fused  AND Olefinic carbon [=CH- or =C<] AND Oxygen, one aromatic attach [-O-] AND Pyridine, non fused rings  by Organic functional groups (US EPA) ONLY

Domain logical expression index: "w"

Referential boundary: The target chemical should be classified as Heterocyclic Phenol AND N-Oxide AND Overlapping groups by Organic Functional groups (nested) ONLY

Domain logical expression index: "x"

Referential boundary: The target chemical should be classified as Group 14 - Carbon C AND Group 15 - Nitrogen N AND Group 16 - Oxygen O by Chemical elements

Domain logical expression index: "y"

Referential boundary: The target chemical should be classified as Group 6 - Trans.Metals Cr,Mo,W by Chemical elements

Domain logical expression index: "z"

Parametric boundary:The target chemical should have a value of log Kow which is >= -1.73

Domain logical expression index: "aa"

Parametric boundary:The target chemical should have a value of log Kow which is <= 1.72

Interpretation of results:

other: not sensitizing

Conclusions:

The substance 4-Ethoxybenzoic acid (CAS No: 619-86-3) was estimated to be not sensitizing to the skin of guinea pigs. Based on the estimated result 4-Ethoxybenzoic acid (CAS No: 619-86-3) failed to induce skin sanitization effects and hence is considered to be not sensitizing to guinea pigs.

Executive summary:

The skin sensitization potential of 4-Ethoxybenzoic acid (CAS No: 619-86-3) was estimated using OECD QSAR toolbox version 3.3 with log Pow as the primary descriptor. The substance 4-Ethoxybenzoic acid (CAS No: 619-86-3) was estimated to be not sensitizing to the skin of guinea pigs. Based on the estimated result 4-Ethoxybenzoic acid (CAS No: 619-86-3) failed to induce skin sanitization effects and hence is considered to be not sensitizing to 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 chemicalPyridin-2-ol 1-oxide (CAS No: 13161-30-3)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 mouse for target chemicalPyridin-2-ol 1-oxide (CAS No: 13161-30-3) and its structurally similar read across substances2-amino-3-hydroxypyridine (CAS No: 16867-03-1) and Pyridine (CAS NO: 110-86-1). 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 Pyridin-2-ol 1-oxide (CAS No: 13161-30-3) was estimated using OECD QSAR toolbox version 3.3 with log Pow as the primary descriptor. The substance Pyridin-2-ol 1-oxide (CAS No: 13161-30-3) was estimated to be not sensitizing to the skin of guinea pigs. Based on the estimated result Pyridin-2-ol 1-oxide (CAS No: 13161-30-3) failed to induce skin sanitization effects and hence is considered to be not sensitizing to guinea pigs.

 

The Cosmetic Ingredient Review Expert Panel (2014) assessed the contact hypersensitivity ofstructurally similar read across substance2-amino-3-hydroxypyridine (CAS No: 16867-03-1) in a local lymph node assay (LLNA)in CBA female mice which supports the above mentioned result.CBA female mice were divided into groups of 5 and received 0%, 5%, 25%, or 50% of the test material in ethanol:water (7:3, v/v) on the ear surface (25 μl/ear) once daily for 3 consecutive days. Clinical signs of toxicity were assessed daily, body weights were measured on days 1 and 6, and on day 3, skin reactions were assessed. On day 6, all animals were injected intravenous-ly with 20μCi [3H] methyl thymidine and the proliferation of lymphocytes in the draining lymph nodes was measured andThe stimulation indices (SI) were calculated. The mean disintegrations per minute (DMP)/animal values for the each test group were 113, 332, 192, and 220 for the 0%, 5%, 25%, and 50% dose groups, respectively. The SI were 2.9, 1.7, and 1.9 for the 5%, 25%, and 50% dose groups, respectively.No clinical signs of toxicity, deaths, or skin reactions occurred during the treatment period in any dose group. Visual observations found the lymph nodes were all of equal size.Sincethere was no indication that 2-amino-3-hydroxypyridine(CAS No: 16867-03-1)could elicit an SI greater than 3, it was considered that 2-amino-3-hydroxypyridine(CAS No: 16867-03-1)was not a skin sensitizer in this LLNA.

 

The above results were further supported by the experimental study conducted by the MAK Collection for Occupational Health and Safety (2012) forstructurally similar read across substance Pyridine (CAS NO: 110-86-1) on guinea pigs to determine its skin sensitizing potential. No Skin sensitization reactions were observed in treated animals when exposed to the chemical Pyridine (CAS NO: 110-86-1). Hence Pyridine (CAS NO: 110-86-1)was considered to be not sensitizing to the skin ofguinea pigs.

 

Thus on the basis of available data for thetargetPyridin-2-ol 1-oxide (CAS No: 13161-30-3) and its structurally similar read across substances2-amino-3-hydroxypyridine (CAS No: 16867-03-1) and Pyridine (CAS NO: 110-86-1),it can be concluded thatchemical 4-Ethoxybenzoic acid (CAS No: 619-86-3) 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 Pyridin-2-ol 1-oxide (CAS No: 13161-30-3) and its structurally similar read across substances2-amino-3-hydroxypyridine (CAS No: 16867-03-1) and Pyridine (CAS NO: 110-86-1) were observed in various studies. From the results obtained from these studies it is concluded that the chemical Pyridin-2-ol 1-oxide (CAS No: 13161-30-3) is not likely to cause skin sensitization and hence can be classified as non skin sensitizer.