Pyrazine-2-carboxylic acid

Endpoint summary

Description of key information

The skin sensitization potential of Pyrazine-2-carboxylic acid (CAS No: 98 -97 -5) was estimated using OECD QSAR toolbox version 3.3 with log Pow as the primary descriptor. Pyrazine-2-carboxylic acid (CAS No: 98 -97 -5) was estimated to be not sensitising to the skin of Pirbright White guinea pigs. Based on the estimated result Pyrazine-2-carboxylic acid (CAS No: 98 -97 -5) 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.

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 3.3 and the QMRF report has been attached.

Qualifier:

according to guideline

Guideline:

other: Prediction

Principles of method if other than guideline:

Prediction was done using OECD QSAR Toolbox version 3.3.

GLP compliance:

not specified

Type of study:

other: estimated data

Justification for non-LLNA method:

No data

Specific details on test material used for the study:

- Name of test material: Pyrazine-2-carboxylic acid
- Molecular formula: C5H4N2O2
- Molecular weight: 124.099 g/mol
- Substance type: organic
- Physical state: solid
- Smiles: c1ncc(C(=O)O)nc1
- InChI: 1S/C5H4N2O2/c8-5(9)4-3-6-1-2-7-4/h1-3H,(H,8,9)

Species:

guinea pig

Strain:

Pirbright-Hartley

Sex:

male/female

Details on test animals and environmental conditions:

No data

Route:

epicutaneous, occlusive

Vehicle:

physiological saline

Concentration / amount:

50 % of a 0.5 % aqueous solution

Day(s)/duration:

6 hours

Adequacy of induction:

not specified

No.:

#1

Route:

epicutaneous, occlusive

Vehicle:

physiological saline

Concentration / amount:

50 %

Day(s)/duration:

on day 30

Adequacy of challenge:

not specified

No. of animals per dose:

5 animals in treatment group. 10 animals in a control group.

Details on study design:

No data

Challenge controls:

No data

Reading:

2nd reading

Hours after challenge:

48

Group:

test chemical

Dose level:

50%

No. with + reactions:

0

Total no. in group:

10

Clinical observations:

none

Remarks on result:

no indication of skin sensitisation

Cellular proliferation data / Observations:

No skin reaction were detectable at 24 and 48 hours after epidermal challenge. No systemic toxicity was observed.

The prediction was based on dataset comprised from the following descriptors: "Skin Sensitisation"
Estimation method: Takes mode value from the 6 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 ( not "l") )  )  and ("m" and ( not "n") )  )  and "o" )  and ("p" and ( not "q") )  )  and ("r" and ( not "s") )  )  and "t" )  and ("u" and "v" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Aryl OR Carboxylic acid OR Pyrazine by Organic Functional groups ONLY

Domain logical expression index: "b"

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

Domain logical expression index: "c"

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<] by Organic functional groups (US EPA) ONLY

Domain logical expression index: "d"

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: "e"

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

Domain logical expression index: "f"

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 Radical 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 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 >> 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: "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 >> 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 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 Non binder, without OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Non binder, impaired OH or NH2 group OR Non binder, MW>500 OR Non binder, non cyclic structure by Estrogen Receptor Binding

Domain logical expression index: "k"

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

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Ester aminolysis OR Acylation >> Ester aminolysis >> Amides 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 >> Polarised Alkenes OR Michael Addition >> Polarised Alkenes >> Polarised Alkene - alkenyl pyridines, pyrazines, pyrimidines or triazines  OR 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: "m"

Referential boundary: The target chemical should be classified as (!Undefined)Group All Lipid Solubility < 0.01 g/kg AND (!Undefined)Group CN Lipid Solubility < 0.4 g/kg AND Group All Melting Point > 200 C AND Group CN Melting Point > 180 C by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as (!Undefined)Group C Surface Tension > 62 mN/m OR (!Undefined)Group CNS Surface Tension > 62 mN/m OR Group All log Kow < -3.1 OR Group All log Kow > 9 OR Group C Aqueous Solubility < 0.0001 g/L OR Group C Melting Point > 55 C OR Group C Vapour Pressure < 0.0001 Pa OR Group CN Aqueous Solubility < 0.1 g/L OR Group CN log Kow > 4.5 OR Group CNS Melting Point > 50 C by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "o"

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

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Non-Metals by Groups of elements

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as Alkali Earth OR Metalloids by Groups of elements

Domain logical expression index: "r"

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: "s"

Referential boundary: The target chemical should be classified as Group 15 - Phosphorus P by Chemical elements

Domain logical expression index: "t"

Referential boundary: The target chemical should be classified as Reactive unspecified by Acute aquatic toxicity MOA by OASIS ONLY

Domain logical expression index: "u"

Parametric boundary:The target chemical should have a value of log Kow which is >= -0.452

Domain logical expression index: "v"

Parametric boundary:The target chemical should have a value of log Kow which is <= 1.15

Interpretation of results:

not sensitising

Remarks:

Migrated information

Conclusions:

Pyrazine-2-carboxylic acid (CAS No: 98 -97 -5) was estimated to be not sensitising to the skin of Pirbright White guinea pigs.

Executive summary:

The skin sensitization potential of Pyrazine-2-carboxylic acid (CAS No: 98 -97 -5) was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor.

Pyrazine-2-carboxylic acid (CAS No: 98 -97 -5) was estimated to be not sensitising to the skin of Pirbright White guinea pigs.

Based on the estimated result Pyrazine-2-carboxylic acid (CAS No: 98 -97 -5) can be considered to be not sensitizing to Pirbright White guinea pigs and can be classified under the category ˋ Not Classified’ as per CLP regulation.

Data is from OECD QSAR Toolbox 3.3 and the QMRF report has been attached.

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 chemicalPyrazine-2-carboxylic acid (CAS No: 98 -97 -5)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 chemicalPyrazine-2-carboxylic acid (CAS No: 98 -97 -5) and its structurally similar read across substancesNiacinamide (CAS No: -98-92-0) 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 Pyrazine-2-carboxylic acid (CAS No: 98 -97 -5) was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor. Pyrazine-2-carboxylic acid (CAS No: 98 -97 -5) was estimated to be not sensitising to the skin of Pirbright White guinea pigs. Based on the estimated result Pyrazine-2-carboxylic acid (CAS No: 98 -97 -5) can be considered to be not sensitizing to Pirbright White guinea pigs.

 

 

According to Danish QSAR database , the skin sensitization effects were estimated by using four different models i.e, Battery, Leadscope, SciQSAR and CASE Ultra for Pyrazine-2-carboxylic acid (CAS No: 98 -97 -5). Based on estimation, no skin sensitization reactions were observed in guinea pigs and humans. Therefore, Pyrazine-2-carboxylic acid (CAS No: 98 -97 -5) was considered to be not sensitizing.

 

 

The Cosmetic Ingredients Review (CIR, 2005) conductedskin sensitization study for structurally similar read across substance Niacinamide(CAS No: -98-92-0) in guinea pigsto determine its sensitization potential.The preliminary irritation tests were performed in 8 guinea pigs to determine concentrations suitable for sensitization test [injection challenge concentration (ICC) and application challenge concentration(ACC)]. The concentration giving slight but perceptible irritation with no oedema was selected as the injection challenge concentration (ICC) and the highest concentration which caused no irritation was selected as the application challenge concentration ( ACC).As a result of the preliminary studies, the concentration selected for skin sensitization test were 5% forICC and 20% for ACC.During the induction phase,the total dose was administered on one occasion as 4 intradermal injections, each 2.5 times the ICC (2.5X5%). Fourteen days later each animal was challenged intradermally in one flank and topically in the other with 0.1 ml aliquots of test substance at the respective ICC and ACC (5%and 20% respectively). Twenty-four hours later the reactions were observed.Reactions were examined under a constant and artificial day light.In the absence of sensitization reactions at first challenge the induction and challenge procedures were repeated, andapparent sensitization reactions confirmed 7 days later by a second and confirmatory challenge with controls included.At 24 hours after the first challenge(A1)and at the second(B1)and confirmatory challenge(B2)with 5% and 20% niacinamide none of the rabbits showed positive results. Thus, it can be concluded that theNiacinamide(CAS No: -98-92-0)was considered to be not sensitizing onguinea pigs.

 

 

The above results were supported by Skin irritation study reported by European Food Safety Authority (EFSA, 2012) and OECD (Organization for Economic Cooperation and Development, 2002) for same read across substance Niacinamide(CAS No: -98-92-0)according to the OECD Guideline 406 (Skin Sensitization). During induction test, 50% in saline (0.9% NaCl)was applied on day 1, 8 and 15. Following 15 days rest period, animals were challenged at concentration of 50% Nicotinamide in saline. Skin reactions were evaluated after 24 and 48 hours (day 31 and 32). Also clinical signs and body weights were observed on day 2 and weekly thereafter. None of the animals exposed to the Nicotinamide showed any clinical signs, change in body weight and cutaneous sensitizing properties. Therefore the chemicalNiacinamide (CAS no: 98-92-0)was to be non-sensitizing.

 

 

 The OECD SIDS(1993) carried outSkin sensitizationstudy inPirbright white guinea pigsfor anotherstructurally similar read across substanceNicotinic 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 chemicalPyrazine-2-carboxylic acid (CAS No: 98 -97 -5) and its structurally similar read across substancesNiacinamide (CAS No: -98-92-0)andNicotinic acid (CAS no: 59-67-6),it can be concluded thatchemical Pyrazine-2-carboxylic acid (CAS No: 98 -97 -5) 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 Pyrazine-2-carboxylic acid (CAS No: 98 -97 -5) and its structurally similar read across substances Niacinamide (CAS No: -98-92-0)andNicotinic acid (CAS no: 59-67-6) were observed in various studies. From the results obtained from these studies it is concluded that the chemical Pyrazine-2-carboxylic acid (CAS No: 98 -97 -5) is not likely to cause skin sensitization and hence can be classified as non skin sensitizer.