Pyrazine-2-carboxylic acid

Endpoint summary

Description of key information

Skin irritation:

The dermal irritation 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 irritating to the skin of New Zealand White rabbits. Based on the estimated result Pyrazine-2-carboxylic acid (CAS No: 98 -97 -5) can be considered to be not irritating to skin and can be classified under the category ˋ Not Classified’ as per CLP regulation.

Eye irritation:

The ocular irritation 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 irritating into the eyes of New Zealand White rabbits. Based on the estimated result Pyrazine-2-carboxylic acid (CAS No: 98 -97 -5) can be considered to be not irritating to eye and can be classified under the category ˋ Not Classified’ as per CLP regulation.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: 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: estimated data

Principles of method if other than guideline:

Prediction was done using OECD QSAR Toolbox version 3.3

GLP compliance:

not specified

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:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

No data

Type of coverage:

occlusive

Preparation of test site:

clipped

Vehicle:

water

Amount / concentration applied:

No data available

Duration of treatment / exposure:

4 hour exposure

Observation period:

Approximately one hour following the removal of the patches at 4, 24 and 48 hours.

Number of animals:

1 Male, 2 Females

Details on study design:

No data

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

other: at 4, 24 and 48 hours

Score:

0

Max. score:

0

Reversibility:

not specified

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

Skin irritation was not observed.

Estimation method: Takes mode value from the 5 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 ("n" and ( not "o") )  )  and ("p" and "q" )  )

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 OR SN1 >> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Primary (unsaturated) heterocyclic amine 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 (!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: "l"

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 < 0.0001 g/L OR Group CN Aqueous Solubility < 0.1 g/L OR Group CN log Kow > 4.5 OR Group CN log Kow > 5.5 OR Group CN Molecular Weight > 290 g/mol OR Group CN Vapour Pressure < 0.001 Pa OR Group CNS Melting Point > 50 C by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "m"

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

Domain logical expression index: "n"

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

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Aliphatic amines (Mucous membrane irritation) Rank C OR Tamoxifen (Hepatotoxicity) Alert by Repeated dose (HESS)

Domain logical expression index: "p"

Parametric boundary:The target chemical should have a value of log Kow which is >= -0.451

Domain logical expression index: "q"

Parametric boundary:The target chemical should have a value of log Kow which is <= 0.801

Interpretation of results:

other: not irritating

Conclusions:

Pyrazine-2-carboxylic acid (CAS No: 98 -97 -5) is estimated to be not irritating when applied to the skin of New Zealand White rabbits.

Executive summary:

The skin irritation 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 irritating to the skin of New Zealand White rabbits. Based on the estimated result Pyrazine-2-carboxylic acid (CAS No: 98 -97 -5) can be considered to be not irritating to skin and can be classified under the category ˋ Not Classified’ as per CLP regulation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation: 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:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Principles of method if other than guideline:

Prediction was done using OECD QSAR Toolbox version 3.3

GLP compliance:

not specified

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:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

No data

Vehicle:

not specified

Controls:

not specified

Amount / concentration applied:

No data available

Duration of treatment / exposure:

7 days

Observation period (in vivo):

Reading time points: 24, 48, 72h and on days 4 and 7.

Number of animals or in vitro replicates:

9 rabbits

Details on study design:

No data available

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

other: 24, 48 and 72 h

Score:

0

Reversibility:

not specified

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

No corneal opacity, iritis, conjuctival redness, chemosis, or discharge was noted in the washed or unwashed treated eyes of any of the animals.

Estimation method: Takes mode value from the 5 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 ( not "o") )  )  and "p" )  and "q" )  and ("r" and ( not "s") )  )  and ("t" and ( not "u") )  )  and "v" )  and ("w" and "x" )  )

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 OR SN2 >> Alkylation, direct acting epoxides and related >> Epoxides and Aziridines 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 OR SN1 >> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Primary (unsaturated) heterocyclic amine 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 High (Class III) by Toxic hazard classification by Cramer (original) ONLY

Domain logical expression index: "l"

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: "m"

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 < 0.0001 g/L OR Group CN Aqueous Solubility < 0.1 g/L OR Group CN log Kow > 4.5 OR Group CN log Kow > 5.5 OR Group CN Molecular Weight > 290 g/mol OR Group CN Vapour Pressure < 0.001 Pa OR Group CNS Melting Point > 50 C by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "n"

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

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Direct acylation involving a leaving group OR Acylation >> Direct acylation involving a leaving group >> (Thio)Acyl and (thio)carbamoyl halides and cyanides  OR Michael Addition OR Michael Addition >> Polarised Alkenes OR Michael Addition >> Polarised Alkenes >> Polarised Alkene - alkenyl pyridines, pyrazines, pyrimidines or triazines  by Protein binding alerts for skin sensitization by OASIS v1.3

Domain logical expression index: "p"

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

Domain logical expression index: "q"

Similarity boundary:Target: OC(=O)c1cnccn1
Threshold=30%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "r"

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: "s"

Referential boundary: The target chemical should be classified as AN2 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: "t"

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

Domain logical expression index: "u"

Referential boundary: The target chemical should be classified as Aliphatic amines (Mucous membrane irritation) Rank C OR Tamoxifen (Hepatotoxicity) Alert by Repeated dose (HESS)

Domain logical expression index: "v"

Referential boundary: The target chemical should be classified as Class 5 (Not possible to classify according to these rules) by Acute aquatic toxicity classification by Verhaar (Modified) ONLY

Domain logical expression index: "w"

Parametric boundary:The target chemical should have a value of log Kow which is >= -2.28

Domain logical expression index: "x"

Parametric boundary:The target chemical should have a value of log Kow which is <= 4.03

Interpretation of results:

other: not irritating

Conclusions:

Pyrazine-2-carboxylic acid (CAS No: 98 -97 -5) was estimated to be not irritating into the eyes of New Zealand White rabbits.

Executive summary:

The eye irritation 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 irritating into the eyes of New Zealand White rabbits. Based on the estimated result Pyrazine-2-carboxylic acid (CAS No: 98 -97 -5) can be considered to be not irritating to eye and can be classified under the category ˋ Not Classified’ as per CLP regulation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin irritation:

Various studieshas been investigated for the test chemicalPyrazine-2-carboxylic acid (CAS No: 98 -97 -5)to observe the potential for dermal irritation to a greater or lesser extent. The studies are based on in vivo experiments in rabbits, 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), Nicotinic acid (CAS no: 59-67-6)and Sodium Benzoate (CAS No: 532-32-1).The predicted data using the OECD QSAR toolbox has also been compared with the experimental data and summarized as below;

 

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the skin irritation potential was estimated for test chemicalPyrazine-2-carboxylic acid (CAS No: 98 -97 -5) .The chemical Pyrazine-2-carboxylic acid (CAS No: 98 -97 -5) is estimated to be not irritating to skin of New Zealand White rabbits.

 

The Cosmetic Ingredients Review (CIR, 2005) conductedPreliminary irritation test for structurally similar read across substance Niacinamide(CAS No: -98-92-0) in guinea pigs to determine the concentration suitable for the sensitization study [injection challenge concentration (ICC) and application challenge concentration(ACC)]. In the preliminary test, the guinea pigs were treated intradermally and dermally.8 previously untreated guinea pigs were (4/SEX) were injected intradermally in the clipped and shaved flanks with 0.1ml aliquots of a range of concentration of test substance in physiological saline. 24 hours later, the skin was examined for erythema and edema.The concentration giving slight but perceptible irritation with no oedema was selected as the injection challenge concentration (ICC). Aliquots of 0.1ml using a range of concentration of the test substance in distilled water were applied in small circular areas to the shaved flanks of 4 previously untreated guinea pigs.24 hours later, the skin was examined for erythema and the highest concentration which caused no irritation was selected as the application challenge concentration (ACC). As a result of preliminary studies, the concentration of Niacinamide at which no irritation was observed were 5% for the ICC and 20% for ACC. Since the test chemical did not induce any cutaneous effects at these concentrations, Niacinamide(CAS No: -98-92-0) was considered to be not irritating to the skin of guinea 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) in 3 (1male and 2 female) White Russian rabbits in accordance with OECD Guide-line 404 "Acute Dermal Irritation/Corrosion". About 500mg of the chemical was applied to the 6.25 cm2 of clipped dorsal skin of each rabbit under occlusion. S kin observations were made at 1 h and daily thereafter for 9 days. No significant signs of irritation were observed during 9 days observation period. The overall scores for erythema and edema after 1 and 24 hours were 0.0. Based on the scores, Niacinamide(CAS No: -98-92-0)was considered to be not-irritating to skin of White Russian rabbits.

 

The OECD SIDS(1993) carried out Skin irritation study in 6New Zealand White rabbitsfor anotherstructurally similar read across substanceNicotinic acid (CAS no: 59-67-6) which supports the above results.In this study, the chemicalNicotinic acidwas applied to braded and intact skin of each rabbits for the exposure period of 4 hours under occlusive condition.No known signs of irritation were observed. Hence the chemicalNicotinic acid (CAS no: 59-67-6)was considered to be not irritating to theNew Zealand Whiterabbit’s skin.

 

The above results were further supported by experimental study performed byOECD SIDS (2001)onstructurally similar read across substanceSodium Benzoate (CAS No: 532-32-1) in rabbits.  Each rabbit received about 500 mg of Sodium Benzoate topically for 24 hours and skin reactions were scored after 48 hours. No signs of irritation were observed during 48 hours observation period. Hence the chemical Sodium Benzoate (CAS No: 532-32-1) was considered to be not irritating to the rabbit’s skin.

 

 

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), Nicotinic acid (CAS no: 59-67-6)and Sodium Benzoate (CAS No: 532-32-1),it can be concluded thatchemical Pyrazine-2-carboxylic acid (CAS No: 98 -97 -5) is unable to cause skin irritation and considered as not irritating.Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Not Classified”.

 

 

Eye irritation:

In different studies,the test chemicalPyrazine-2-carboxylic acid (CAS No: 98 -97 -5) has been investigated for potential for ocular irritationto a greater or lesser extent. The studies are based on in vivo experiments in rabbits for target chemicalPyrazine-2-carboxylic acid (CAS No: 98 -97 -5)its structurally similar read across substances Niacinamide(CAS No: -98-92-0)and Sodium Benzoate (CAS No: 532-32-1),The predicted data using the OECD QSAR toolbox has also been compared with the experimental data and summarized as below;

 

 

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the eye irritation potential was estimated for test chemicalPyrazine-2-carboxylic acid (CAS No: 98 -97 -5) .The chemical Pyrazine-2-carboxylic acid (CAS No: 98 -97 -5) is estimated to be not irritating to eye of New Zealand White rabbits.

 

 

The Cosmetic Ingredients Review (CIR, 2005) conducted Low volume eye testfor structurally similar read across substance Niacinamide(CAS No: -98-92-0)in New Zealand White Rabbits to determine the degree of eye irritancy caused by the chemical. During the test, 16% and 25% of Niacinamide dissolved in water was placed into the eye of each rabbits. The maximum average score (MAS) observed was 0.67 and the effects observed were cleared within 10 days. Since the chemical did not produce any acute ocular hazards, the chemical Niacinamide(CAS No: -98-92-0)was considered to be non-irritatingto the eye ofNew Zealand White Rabbits.

 

 

The above results were further supported by experimental study performed byOECD SIDS (2001)onstructurally similar read across substanceSodium Benzoate (CAS No: 532-32-1) in rabbits.Each rabbit received about 500 mg ofSodium Benzoate for 24 hours and skin reactions were scored at24 h, 48 h and 72 hours and day 7.No signs of irritation were observed during 7 day postexposure period. Hence the chemicalSodium Benzoate (CAS No: 532-32-1)was considered to be not irritating to the rabbit’s eye.

 

 

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)andSodium Benzoate (CAS No: 532-32-1),it can be concluded thatchemical Pyrazine-2-carboxylic acid (CAS No: 98 -97 -5) is unable to cause eye irritation and considered as not irritating.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 and eye irritation potential of test chemicalPyrazine-2-carboxylic acid (CAS No: 98 -97 -5) and its structurally similar read across substanceswere observed in various studies. The results obtained from these studies indicate that the chemicalPyrazine-2-carboxylic acidis unlikely to cause skin and eye irritation. HencePyrazine-2-carboxylic acid (CAS No: 98 -97 -5)can be classified under the category “Not Classified” for skin and eye as per CLP.