Pyrazine-2-carboxylic acid

Endpoint summary

Description of key information

Acute toxicity: oral

The acute toxicity study was predicted using OECD QSAR toolbox version 3.3 (2017); to evaluate the toxic effects of administration of pyrazine-2-carboxylic acid (CAS No. 98-97-5) in rat by the oral route. 50% mortality observed at 2538.02 mg/kg bw in treated rats. Therefore, the acute oral median lethal dose (LD50) of pyrazine-2-carboxylic acid in rat was estimated to be 2538.02 mg/kg b.wt.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

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:

Prediction is done using OECD QSAR toolbox version 3.3 and the supporting QMRF report has been attached.

Qualifier:

according to guideline

Guideline:

other: refer below

Principles of method if other than guideline:

Prediction is done using OECD QSAR Toolbox version 3.3

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report): 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:

rat

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

No data available

Route of administration:

oral: unspecified

Vehicle:

not specified

Details on oral exposure:

No data available

Doses:

No data available

No. of animals per sex per dose:

No data available

Control animals:

not specified

Details on study design:

No data available

Statistics:

No data available

Sex:

not specified

Dose descriptor:

LD50

Effect level:

2 538.02 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 50% mortality observed.

Mortality:

50% mortality observed at 2538.02 mg/kg bw in treated rats.

Clinical signs:

other: No data available

Gross pathology:

No data available

Other findings:

No data available

The prediction was based on dataset comprised from the following descriptors: LD50
Estimation method: Takes average value from the 5 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 ( not "m") )  )  and ("n" and ( not "o") )  )  and ("p" and ( not "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 AND Carboxylic acid AND Pyrazine by Organic Functional groups

Domain logical expression index: "b"

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

Domain logical expression index: "c"

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: "d"

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: "e"

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: "f"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OASIS v.1.4

Domain logical expression index: "g"

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 reaction with cycloisomerization OR AN2 >> Nucleophilic addition reaction with cycloisomerization >> Hydrazine Derivatives 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 Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> Polycyclic Aromatic Hydrocarbon and Naphthalenediimide Derivatives OR Radical OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Hydrazine Derivatives 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 and Naphthalenediimide 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 and Naphthalenediimide Derivatives OR SN2 >> Direct nucleophilic attack on diazonium cation OR SN2 >> Direct nucleophilic attack on diazonium cation >> Hydrazine Derivatives by DNA binding by OASIS v.1.4

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 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: "j"

Referential boundary: The target chemical should be classified as Non binder, without OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "k"

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: "l"

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

Domain logical expression index: "m"

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 >> Acetates OR Michael addition OR Michael addition >> Polarised Alkenes OR Michael addition >> Polarised Alkenes >> Polarised alkene - esters OR Michael addition >> Polarised Alkenes >> Polarised alkene - ketones OR Michael addition >> Polarised Alkenes >> Polarised alkene - pyridines OR Schiff Base Formers OR Schiff Base Formers >> Direct Acting Schiff Base Formers OR Schiff Base Formers >> Direct Acting Schiff Base Formers >> Mono-carbonyls by Protein binding by OECD

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Not classified by Oncologic Primary Classification

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Acrylate Reactive Functional Groups OR Acyl and Benzoyl Type Compounds OR Aldehyde Type Compounds OR Alpha- and beta-Haloether Reactive Functional Groups OR Aromatic Amine Type Compounds OR Organophosphorus Type Compounds OR Silicone and Siloxane Type Compounds by Oncologic Primary Classification

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as No alert found by Respiratory sensitisation

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as Pro-SN2 OR Pro-SN2 >> Pro-ring opening SN2 OR Pro-SN2 >> Pro-ring opening SN2 >> Vinyl benzenes OR SN2 OR SN2 >> SN2 at chlorine OR SN2 >> SN2 at chlorine >> Chloro nitrogen by Respiratory sensitisation

Domain logical expression index: "r"

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 by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as (!Undefined)Group C Surface Tension > 62 mN/m OR (N/A) OR Group All log Kow < -3.1 OR Group All Melting Point > 200 C 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 CN Melting Point > 180 C by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "t"

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: "u"

Referential boundary: The target chemical should be classified as Group 14 - Metals Sn,Pb OR Group 15 - Phosphorus P OR Group 17 - Halogens Cl OR Group 17 - Halogens F,Cl,Br,I,At by Chemical elements

Domain logical expression index: "v"

Similarity boundary:Target: OC(=O)c1cnccn1
Threshold=10%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "w"

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

Domain logical expression index: "x"

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

Interpretation of results:

other: not classified based on CLP criteria

Conclusions:

The acute toxicity study was predicted using OECD QSAR toolbox version 3.3 (2017); to evaluate the toxic effects of administration of pyrazine-2-carboxylic acid (CAS No. 98-97-5) in rat by the oral route. 50% mortality observed at 2538.02 mg/kg bw in treated rats. Therefore, the acute oral median lethal dose (LD50) of pyrazine-2-carboxylic acid in rat was estimated to be 2538.02 mg/kg b.wt.

Executive summary:

The acute toxicity study was predicted using OECD QSAR toolbox version 3.3 (2017); to evaluate the toxic effects of administration of pyrazine-2-carboxylic acid (CAS No. 98-97-5) in rat by the oral route. 50% mortality observed at 2538.02 mg/kg bw in treated rats. Therefore, the acute oral median lethal dose (LD50) of pyrazine-2-carboxylic acid in rat was estimated to be 2538.02 mg/kg b.wt. Thus, according to CLP criteria for acute toxicity rating for the chemicals, it infers that pyrazine-2-carboxylic acid (CAS No.98-97-5) does not exhibit acute toxicity via the oral route.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 538.02 mg/kg bw

Quality of whole database:

The data is Klimicsh 2 and from OECD QSAR toolbox version 3.3 (2017).

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Various studies including predicted results from the validated model and experimental study has been investigated for acute oral toxicity to a greater or lesser extent for the test chemical Pyrazine-2-carboxylic acid (CAS No. 98-97-5) along with its structurally similar read across substances pyrazinamide (CAS No.98 -96 -4), Acipimox (CAS No.51037 -30 -0) and Nicotinic acid (CAS No. 59-67-6). The predicted data for target chemical Pyrazine-2-carboxylic acid (CAS No. 98-97-5) has been compared with experimental data (in vivo experiments in rodents i.e. most commonly in rats) for read across substance. The studies are summarized as below:

 

The acute toxicity study was predicted using OECD QSAR toolbox version 3.3 (2017); to evaluate the toxic effects of administration of pyrazine-2-carboxylic acid (CAS No. 98-97-5) in rat by the oral route. 50% mortality observed at 2538.02 mg/kg bw in treated rats. Therefore, the acute oral median lethal dose (LD50) of pyrazine-2-carboxylic acid in rat was estimated to be 2538.02 mg/kg b.wt.

The above study is supported by the experimental study published in a peer-reviewed journal (American Review of Tuberculosis. Vol. 70, Pg. 423, 1954.), in which the acute toxicity study was conducted to evaluate the toxic effects of administration of pyrazinamide (CAS No. 98 -96 -4) in rat by the oral route. The acute oral lowest published lethal dose (LDLo) of pyrazinamide in rat was observed to be 3000.0 mg/kg b.wt. 

 

This is further supported by the study published in a journal (European Journal of Medicinal Chemistry--Chimie Therapeutique. Vol. 15, Pg. 157, 1980), in which the acute toxicity study was conducted to evaluate the toxic effects of administration of Acipimox (CAS No. 51037 -30 -0) in mouse by the oral route. 50% mortality observed at 3500.0 mg/kg bw in treated mouse. Therefore, the acute oral median lethal dose (LD50) of Acipimox in mouse was observed to be 3500.0 mg/kg b.wt. 

 

Moreover, in a screening information data set (SIDS) of OECD high production volume chemicals programme, 7, (1993); the acute oral toxicity of Nicotinic acid (CAS No. 59-67-6) was determined in Wistar rats according to OECD guideline 401. There was no mortality at all doses and no substance related symptoms. LD50 was determined as higher than 5000mg/kg/body weight (>5000 mg/kg bw) - which was the highest dose tested.

 

So, based on the above mentioned studies for target substance pyrazine-2-carboxylic acid (CAS No.98-97-5) and to its read across substance, the median lethal dose (LD50) value was found to be in the range of 2538.02 mg/kg bw to >5000 mg/kg bw and LDLo value to be 3000 mg/kg bw. Thus, based on these LD50 and LDLo value and by comparing these with the criteria of CLP regulation, it infers that the test substance pyrazine-2-carboxylic acid (CAS No.98-97-5) does not classify as an acute oral toxicant.

Justification for classification or non-classification

Based on the above mentioned studies for target substance pyrazine-2-carboxylic acid (CAS No.98-97-5) and to its read across substance, it can be found that LD50 oral value is greater than 2000 mg/kg b.wt. Thus, according to CLP criteria for acute toxicity rating for the chemicals, it infers that the test substance pyra zine-2-carboxylic acid (CAS No.98-97-5) does not classify as an acute oral toxicant.