Pyridine-2,4-dicarboxylic acid

Endpoint summary

Description of key information

The skin sensitization potential of target chemical 2,4-Pyridinedicarboxylic acid (CAS No: 499-80-9) was assessedin various experimental studies which were conducted on guinea pigs for target chemical2,4-Pyridinedicarboxylic acid (CAS No: 499-80-9) andits structurally similar read across chemicalsisophthalic acid (CAS No:121-91-5)and Nicotinic acid (CAS no: 59-67-6). 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 2,4-Pyridinedicarboxylic acid (CAS No: 499-80-9) 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 3.4 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 3.4

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): 2,4-Pyridinedicarboxylic acid
- Common name: Pyridine-2,4-dicarboxylic acid
- Molecular formula: C7H5NO4
- Molecular weight: 167.12 g/mol
- Smiles notation: c1(cc(ncc1)C(O)=O)C(O)=O
- InChl: 1S/C7H5NO4/c9-6(10)4-1-2-8-5(3-4)7(11)12/h1-3H,(H,9,10)(H,11,12)
- Substance type: Organic
- Physical state: Solid

Species:

guinea pig

Strain:

not specified

Sex:

not specified

Details on test animals and environmental conditions:

not specified

Route:

intradermal and epicutaneous

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 reaction was observed in treated guinea pigs.

Remarks on result:

no indication of skin sensitisation

Cellular proliferation data / Observations:

No skin sensitization reaction 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 7 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 ( not "m") )  )  and "n" )  and "o" )  and ("p" and "q" )  )

Domain logical expression index: "a"

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

Domain logical expression index: "b"

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

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Aryl OR Carboxylic acid OR Overlapping groups OR Pyridine/ Pyridinium ion by Organic Functional groups (nested) ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Aryl OR Carboxylic acid OR Pyridine/ Pyridinium ion 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 conjugate addition to activated alkene derivatives OR AN2 >> Michael-type conjugate addition to activated alkene derivatives >> Alpha-Beta Conjugated Alkene Derivatives with Geminal Electron-Withdrawing Groups 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 >> ROS formation after GSH depletion OR Radical >> ROS formation after GSH depletion >> Quinone methides 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 to Quinones and Quinone-type Chemicals OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Arenes OR Michael addition >> Polarised Alkenes-Michael addition OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated amides OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated esters OR SN1 OR SN1 >> Iminium Ion Formation OR SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines 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) carboxamide group OR Acylation >> Acylation involving an activated (glucuronidated) carboxamide group >> Carboxylic Acid Amides OR Acylation >> Acylation involving an activated (glucuronidated) sulfonamide group OR Acylation >> Acylation involving an activated (glucuronidated) sulfonamide group >> Arenesulfonamides OR Acylation >> Direct acylation involving a leaving group OR Acylation >> Direct acylation involving a leaving group >> Carboxylic Acid Amides OR AN2 OR AN2 >> Michael addition to alpha, beta-unsaturated acids and esters OR AN2 >> Michael addition to alpha, beta-unsaturated acids and esters >> alpha,beta-Unsaturated Carboxylic Acids and Esters 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 >> Michael-type addition to quinoid structures  OR AN2 >> Michael-type addition to quinoid structures  >> Carboxylic Acid Amides 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 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 >> Michael addition on conjugated systems with electron withdrawing group >> Cyanoalkenes 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"

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: "m"

Referential boundary: The target chemical should be classified as Group  3 - Lanthanoids OR Group 1 - Alkali Earth Li,Na,K,Rb,Cs,Fr OR Group 12 - Trans.Metals Zn,Cd,Hg OR Group 15 - Phosphorus P OR Group 16 - Sulfur S OR Group 17 - Halogens Cl OR Group 17 - Halogens F,Cl,Br,I,At OR Group 5 - Trans.Metals V,Nb,Ta OR Group 6 - Trans.Metals Cr,Mo,W OR Group 7 - Trans.Metals Mn,Tc,Re by Chemical elements

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Aryl AND Carboxylic acid AND Pyridine/ Pyridinium ion by Organic Functional groups ONLY

Domain logical expression index: "o"

Similarity boundary:Target: OC(=O)c1ccnc(C(O)=O)c1
Threshold=30%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "p"

Parametric boundary:The target chemical should have a value of log Kow which is >= -0.753

Domain logical expression index: "q"

Parametric boundary:The target chemical should have a value of log Kow which is <= 1.87

Interpretation of results:

other: not sensitizing

Conclusions:

The chemical 2,4-Pyridinedicarboxylic acid (CAS No: 499-80-9)was estimated to be not sensitizing to the skin of Dunkin-Hartley guinea pigs. Based on the estimated result 2,4-Pyridinedicarboxylic acid (CAS No: 499-80-9) 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 2,4-Pyridinedicarboxylic acid (CAS No: 499-80-9) was estimated using OECD QSAR toolbox version 3.4 with log Pow as the primary descriptor. The chemical 2,4-Pyridinedicarboxylic acid (CAS No: 499-80-9)was estimated to be not sensitizing to the skin of guinea pigs. Based on the estimated result 2,4-Pyridinedicarboxylic acid (CAS No: 499-80-9) 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)

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information:

Skin sensitization:

Various studieshas been investigated for the test chemical2,4-Pyridinedicarboxylic acid (CAS No: 499-80-9) 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 chemical 2,4-Pyridinedicarboxylic acid (CAS No: 499-80-9)and its structurally similar read across substances isophthalic acid (CAS No:121-91-5)and Nicotinic acid (CAS no: 59-67-6).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 2,4-Pyridinedicarboxylic acid (CAS No: 499-80-9) was estimated using OECD QSAR toolbox version 3.3 with log Pow as the primary descriptor. The chemical 2,4-Pyridinedicarboxylic acid (CAS No: 499-80-9) was estimated to be not sensitizing to the skin of guinea pigs. Based on the estimated result 2,4-Pyridinedicarboxylic acid (CAS No: 499-80-9) failed to induce skin sanitization effects and hence is considered to be not sensitizing to guinea pigs.

 

The cosmetic ingredient review expert panel {Safety Assessment of Trimellitic Anhydride Copolymers as Used in Cosmeticscosmetic ingredient review expert panel; November 14, 2016} and EUROPEAN COMMISSION – European Chemicals Bureau {IUCLID Dataset;EUROPEAN COMMISSION – European Chemicals Bureau;18–FEB–2000} reporteda Buehler Test on ten male guinea pigs for read across chemicalisophthalic acid (CAS No:121-91-5). In this test,Isophthalic acid was applied once a week at a dose of 0.3ml of a 30% (w/w) solution in dimethylsulfoxide (DMSO) to the shaved backs of ten male guinea pigs during an induction period of three weeks. Another group of 10 male guinea pigs served as a vehicle control and was similarly dosed with 0.3ml of undiluted DMSO. A third group of ten sham control guinea pigs was handled in the same manner, but was not treated with test article or vehicle. Two weeks following application of the third induction dose, the treated andsham control guinea pigs each received a challenge dose of 0.3 ml of the 30% test article/DMSO solution; the vehicle control guinea pigs each received a challenge dose of 0.3 ml of a 70% (w/w) aqueous DMSO solution. All guinea pigs were scored for erythema approximately 24 and 48 hours following application of the first induction dose and the challenge dose. Positive erythema reactions (i.e., a score >= 2) were observed in only one test article–treated guinea pig, compared to no vehicle or sham control guinea pigs during the challenge phase. Since no sensitization reactions were observed in majority of treated animals, the chemical isophthalicacid (CAS No:121-91-5) was considered as not sensitizing to the skin of guinea pigs.

 

The above results were further supported by the experimental study reported byOECD SIDS {NICOTINIC ACID CAS N°: 59-67-6; OECD SIDS; 1993} on Pirbright white guinea pigs for read across chemical Nicotinic acid (CAS no: 59-67-6) according to OECD guideline 406.During this test, the guinea pigs were exposed to theNicotinic acid and were observed for skin reactions. As no skin sensitizing effects were observed in treated animals, the chemical Nicotinic acid (CAS no: 59-67-6)was considered to be not sensitizing to thePirbright white guineapigs in Guinea pig maximization test.

 

Thus on the basis of available data for thetarget chemical2,4-Pyridinedicarboxylic acid (CAS No: 499-80-9)and its structurally similar read across substancesisophthalic acid (CAS No:121-91-5)and Nicotinic acid (CAS no: 59-67-6),it can be concluded thatchemical 2,4-Pyridinedicarboxylic acid (CAS No: 499-80-9)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”.

 

Justification for classification or non-classification

The skin sensitization potential of test substance 2,4-Pyridinedicarboxylic acid (CAS No: 499-80-9) and itsstructurallysimilar read across substancesisophthalic acid (CAS No:121-91-5)and Nicotinic acid (CAS no: 59-67-6) were observed in various studies. From the results obtained from these studies it is concluded that the chemical 2,4-Pyridinedicarboxylic acid (CAS No: 499-80-9) is not likely to cause skin sensitization and hence can be classified as non-skin sensitizer.