Methyl isonicotinate

Endpoint summary

Description of key information

Acute oral toxicity: 

Based on the prediction done by SSS (2017) on Methyl isonicotinate, LD50 was estimated to be 3906 mg/kg bw, when Sprague-Dawley male and female rats were treated with Methyl isonicotinate by oral gavage route. Thus, comparing this value with the criteria of CLP regulation, Methyl isonicotinate can be classified as category V for acute oral toxicity.

Acute Dermal toxicity: 

Based on the prediction done by SSS (2017) on Methyl isonicotinate, LD50 was estimated to be 3828 mg/kg bw, when rabbits were treated with Methyl isonicotinate by dermal application occlusively. Thus, comparing this value with the criteria of CLP regulation, Methyl isonicotinate can be classified as category V for acute dermal toxicity.

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:

Data is predicted using OECD QSAR toolbox version 3.3 and the supporting QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: estimated

Principles of method if other than guideline:

Prediction is done using QSAR Toolbox version 3.3

GLP compliance:

not specified

Test type:

other: not specified

Limit test:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report): Methyl isonicotinate
- Molecular formula (if other than submission substance): C7H7NO2
- Molecular weight (if other than submission substance): 137.1373 g/mole
- Substance type: Organic
- SMILES:COC(=O)c1ccncc1
- InChI: 1S/C7H7NO2/c1-10-7(9)6-2-4-8-5-3-6/h2-5H,1H3

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

not specified

Route of administration:

oral: gavage

Vehicle:

not specified

Details on oral exposure:

not specified

Doses:

3906 mg/kg

No. of animals per sex per dose:

not specified

Control animals:

not specified

Details on study design:

not specified

Statistics:

not specified

Preliminary study:

not specified

Sex:

male/female

Dose descriptor:

LD50

Effect level:

3 906 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 50% mortality observed

Mortality:

not specified

Clinical signs:

other: not specified

Gross pathology:

not specified

Other findings:

not specified

The prediction was based on dataset comprised from the following descriptors: LD50
Estimation method: Takes average value from the 6 nearest neighbours
Domain  logical expression:Result: In Domain

((((((((((((("a" or "b" or "c" )  and ("d" and ( not "e") )  )  and ("f" and ( not "g") )  )  and ("h" and ( not "i") )  )  and "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 ( not "u") )  )  and ("v" and ( not "w") )  )  and ("x" and "y" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Esters (Acute toxicity) by US-EPA New Chemical Categories

Domain logical expression index: "b"

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

Domain logical expression index: "c"

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

Domain logical expression index: "d"

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

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Isocyanates and Isothiocyanates OR Acylation >> Isocyanates and Isothiocyanates >> Isocyanates 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 of Heterocyclic Ring Systems OR Michael addition >> P450 Mediated Activation of Heterocyclic Ring Systems >> Thiophenes-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 >> 5-alkoxyindoles 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 >> Methylenedioxyphenyl OR Michael addition >> Polarised Alkenes-Michael addition OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated aldehydes OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated esters OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated ketones OR Schiff base formers OR Schiff base formers >> Direct Acting Schiff Base Formers OR Schiff base formers >> Direct Acting Schiff Base Formers >> Mono aldehydes OR SN1 OR SN1 >> Carbenium Ion Formation OR SN1 >> Carbenium Ion Formation >> Alpha halo ethers (including alpha halo thioethers) 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 (unsaturated) heterocyclic amine OR SN1 >> Nitrenium Ion formation >> Primary aromatic amine OR SN1 >> Nitrenium Ion formation >> Tertiary (unsaturated) heterocyclic amine  OR SN1 >> Nitrenium Ion formation >> Tertiary aromatic amine OR SN2 OR SN2 >> Direct Acting Epoxides and related OR SN2 >> Direct Acting Epoxides and related >> Epoxides OR SN2 >> Episulfonium Ion Formation OR SN2 >> Episulfonium Ion Formation >> 1,2-Dihaloalkanes OR SN2 >> Episulfonium Ion Formation >> Mustards OR SN2 >> P450 Mediated Epoxidation OR SN2 >> P450 Mediated Epoxidation >> Coumarins OR SN2 >> P450 Mediated Epoxidation >> Thiophenes-SN2 OR SN2 >> Ring opening SN2 Reaction OR SN2 >> Ring opening SN2 Reaction >> Sultones OR SN2 >> SN2 at an sp3 Carbon atom OR SN2 >> SN2 at an sp3 Carbon atom >> Aliphatic halides OR SN2 >> SN2 at an sp3 Carbon atom >> Phosphates OR SN2 >> SN2 at an sp3 Carbon atom >> Phosphonic esters OR SN2 >> SN2 at an sp3 Carbon atom >> Sulfonates by DNA binding by OECD

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Not possible to classify according to these rules by DPRA Cysteine peptide depletion

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as High reactive OR High reactive >> Activated haloarenes OR High reactive >> alpha,beta-carbonyl compounds with polarized multiple bonds OR High reactive >> Thiols OR Low reactive OR Low reactive >> N-substituted aromatic amides OR Low reactive >> Saturated acid anhydrides by DPRA Cysteine peptide depletion

Domain logical expression index: "h"

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

Domain logical expression index: "i"

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

Domain logical expression index: "j"

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

Domain logical expression index: "k"

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

Domain logical expression index: "l"

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

Domain logical expression index: "m"

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: "n"

Referential boundary: The target chemical should be classified as Group 15 - Phosphorus P OR Group 16 - Sulfur S by Chemical elements

Domain logical expression index: "o"

Similarity boundary:Target: COC(=O)c1ccncc1
Threshold=10%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "p"

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: "q"

Referential boundary: The target chemical should be classified as Esters including acrylic and methacrylic esters OR Ketones OR Lactones by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "r"

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: "s"

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 >> Azlactones and unsaturated lactone derivatives  OR Acylation >> Direct acylation involving a leaving group >> Carbamates  OR Acylation >> Direct acylation involving a leaving group >> N-Acylated heteroaromatic amines  OR SN2 OR SN2 >> SN2 Reaction at a sp3 carbon atom OR SN2 >> SN2 Reaction at a sp3 carbon atom >> Activated alkyl esters and thioesters  by Protein binding alerts for skin sensitization by OASIS v1.3

Domain logical expression index: "t"

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 Eye irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "u"

Referential boundary: The target chemical should be classified as Group C Melting Point > 55 C by Eye irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "v"

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

Domain logical expression index: "w"

Referential boundary: The target chemical should be classified as Vinyl/Allyl Esters by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "x"

Parametric boundary:The target chemical should have a value of log Kow which is >= -0.343

Domain logical expression index: "y"

Parametric boundary:The target chemical should have a value of log Kow which is <= 2.84

Interpretation of results:

Category 5 based on GHS criteria

Conclusions:

LD50 was estimated to be 3906 mg/kg bw when Sprague-Dawley male and female rats were treated with Methyl isonicotinate by oral gavage route.

Executive summary:

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute oral toxicity was estimated for Methyl isonicotinate (2459-09-8). The LD50 was estimated to be 3906 mg/kg bw when Sprague-Dawley male and female rats were treated with Methyl isonicotinate by oral gavage route.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

3 906 mg/kg bw

Quality of whole database:

Data is Klimicsh 2 and from QSAR toolbox 3.3

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

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 predicted using OECD QSAR toolbox version 3.3 and the supporting QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: estimated

Principles of method if other than guideline:

Prediction is done using QSAR Toolbox version 3.3

GLP compliance:

not specified

Test type:

other: not specified

Limit test:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report): Methyl isonicotinate
- Molecular formula (if other than submission substance): C7H7NO2
- Molecular weight (if other than submission substance): 137.1373 g/mole
- Substance type: Organic
- SMILES:COC(=O)c1ccncc1
- InChI: 1S/C7H7NO2/c1-10-7(9)6-2-4-8-5-3-6/h2-5H,1H3

Species:

rabbit

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

not specified

Type of coverage:

occlusive

Vehicle:

not specified

Details on dermal exposure:

not specified

Duration of exposure:

not specified

Doses:

3828 mg/kg

No. of animals per sex per dose:

not specified

Control animals:

not specified

Details on study design:

not specified

Statistics:

not specified

Preliminary study:

not specified

Sex:

not specified

Dose descriptor:

LD50

Effect level:

3 828 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 50% mortality observed

Mortality:

not specified

Clinical signs:

other: not specified

Gross pathology:

not specified

Other findings:

not specified

The prediction was based on dataset comprised from the following descriptors: LD50
Estimation method: Takes average value from the 6 nearest neighbours
Domain  logical expression:Result: In Domain

(((((((((("a" or "b" or "c" )  and "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" and "r" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Esters (Acute toxicity) by US-EPA New Chemical Categories

Domain logical expression index: "b"

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

Domain logical expression index: "c"

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

Domain logical expression index: "d"

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

Domain logical expression index: "e"

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

Domain logical expression index: "f"

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 >> Alkyl phenols 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 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: "g"

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

Domain logical expression index: "h"

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 OR Strong binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "i"

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

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Ring opening acylation OR Acylation >> Ring opening acylation >> Active cyclic agents  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 SN2 OR SN2 >> SN2 Reaction at a sp3 carbon atom OR SN2 >> SN2 Reaction at a sp3 carbon atom >> Activated alkyl esters and thioesters  by Protein binding by OASIS v1.3

Domain logical expression index: "k"

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

Domain logical expression index: "l"

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 by Protein binding by OECD

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 Group 14 - Carbon C AND Group 15 - Nitrogen N AND Group 16 - Oxygen O by Chemical elements

Domain logical expression index: "o"

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

Domain logical expression index: "p"

Similarity boundary:Target: COC(=O)c1ccncc1
Threshold=10%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "q"

Parametric boundary:The target chemical should have a value of log Kow which is >= -0.345

Domain logical expression index: "r"

Parametric boundary:The target chemical should have a value of log Kow which is <= 4.3

Interpretation of results:

Category 5 based on GHS criteria

Conclusions:

LD50 was estimated to be 3828 mg/kg bw when rabbits were treated with Methyl isonicotinate by dermal application occlusively.

Executive summary:

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute dermal toxicity was estimated for  Methyl isonicotinate (2459-09-8). The LD50 was estimated to be 3828 mg/kg bw when rabbits were treated with Methyl isonicotinate by dermal application occlusively.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

3 828 mg/kg bw

Quality of whole database:

Data is Klimicsh 2 and from QSAR toolbox 3.3

Additional information

Acute oral toxicity:

In different studies, Methyl isonicotinate (2459-09-8) has been investigated for acute oral toxicity to a greater or lesser extent. Often are the studies based on in vivo experiments in rodents, i.e. most commonly in rats and mice for Methyl isonicotinate along with the study available on structurally similar read across substance Isonicotinic acid (CAS no: 55-22-1) and Methyl nicotinate (93-60-7). The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies. The studies are summarized as below –

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute oral toxicity was estimated for Methyl isonicotinate (2459-09-8). The LD50 was estimated to be 3906 mg/kg bw when Sprague-Dawley male and female rats were treated with Methyl isonicotinate by oral gavage route.

In an experimental study based on the QSAR prediction done using the Danish (Q)SAR Database (2017), the acute oral toxicity was estimated for the Methyl isonicotinate (2459-09-8). The LD50 was estimated to be 3300 mg/kg bw with Reliability Index 0.66 (0.5-0.75 = moderate prediction quality), when rats were treated with Methyl isonicotinate via oral route.

The above study supported by Tsarichenko et al. (Pharmaceutical Chemistry Journal, Volume 11, Issue 4, pp 481–483, April 1977), U.S. National Library of Medicine (ChemIDplus, 2017) and GESTIS SUBSTANCE Database (2017), for the structurally similar read across substance Isonicotinic acid (CAS no: 55-22-1).The acute oral toxicity was tested in rats at the dose concentration of 5000 mg/kg bw. Animals were observed for clinical signs. 50% mortality was observed at 5000 mg/kg with clinical signs such as, suppression of the general motor activity, an impairment of motor coordination of the animal, and its assumption of a lateral position was observed. Therefore, LD50 was considered to be 5000 mg/kg bw, when white rats were treated with Isonicotinic acid via oral gavage route.

This study is further supported by Tsarichenko et al. (Pharmaceutical Chemistry Journal, Volume 11, Issue 4, pp 481–483, April 1977) and U.S. National Library of Medicine (ChemIDplus, 2017), for the structurally similar read across substance Isonicotinic acid (CAS no: 55-22-1).The acute oral toxicity was tested in mice at the dose concentration of 3123 mg/kg bw. Animals were observed for clinical signs. 50% mortality was observed at 3123 mg/kg with clinical signs such as, suppression of the general motor activity, an impairment of motor coordination of the animal, and its assumption of a lateral position was observed. Therefore, LD50 was considered to be 3123 mg/kg with confidential limit of 2504.4-4746.6 mg/kg with s = 2.2, when white mice were treated with Isonicotinic acid via oral gavage route.

In another study conducted by Zuleikha et al.(Acta Poloniae Pharmaceutica - Drug Research, Vol. 64 No. 2 pp. 179 - 182, 2007), for the structurally similar read across substance Methyl nicotinate (93-60-7). The acute oral toxicity study was conducted in male and female mice at the concentration of1000, 2000, 3000 and 5000 mg/kg orally by gavage. 50 % mortality was observed in treated mice at 5000 mg/kg bw. Therefore, LD50 was considered to be 5000 mg/kg bw when male and female mice were treated with Methyl nicotinate orally by gavage.

Thus, based on the above studies on Methyl isonicotinate (2459-09-8) and it’s read across substances, it can be concluded that LD50 value is greater than 2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, Methyl isonicotinate can be classified as category V of acute oral toxicity.

Acute Dermal toxicity:

In different studies, Methyl isonicotinate (2459-09-8) has been investigated for acute dermal toxicity to a greater or lesser extent. Often are the studies based on in vivo experiments in rodents, i.e. most commonly in rabbits for Methyl isonicotinate along with the study available on structurally similar read across substance 3-Pyridinecarboxamide (98-92-0) and closely related read across substance 1,3-Dioxolan-2-one (96-49-1). The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies. The studies are summarized as below –

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute dermal toxicity was estimated for Methyl isonicotinate (2459-09-8). The LD50 was estimated to be 3828 mg/kg bw when rabbits were treated with Methyl isonicotinate by dermal application occlusively.

This study is supported by Cosmetic Ingredient Review (International Journal of Toxicology, 24(Suppl. 5):1–31, 2005), for the structurally similar read across substance 3-Pyridinecarboxamide (98-92-0).Theacute Dermal toxicity study was conducted in rabbits at the concentration of 2000 mg/kg bw. No Mortality observed at 2000 mg/kg bw for 24 h exposure. Therefore, LD50 was considered to be >2000 mg/kg bw, when rabbits were treated with 3-Pyridinecarboxamide for 24 h exposure by dermal application occlusively.

The above study is further supported by U.S. National Library of Medicine (ChemIDplus, 2017), for the closely related read across substance 1,3-Dioxolan-2-one (96-49-1).Acute Dermal toxicity study was conducted in rabbits at the concentration of 3000 mg/kg bw. No Mortality observed at 3000 mg/kg bw. Therefore, LD50 was considered to be >3000 mg/kg bw, when rabbits were treated with 1,3-Dioxolan-2-one (96-49-1) by dermal application.

Thus, based on the above studies on Methyl isonicotinate (2459-09-8) and it’s read across substances, it can be concluded that LD50 value is greater than 2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, Methyl isonicotinate can be classified as category V of acute dermal toxicity.

Justification for classification or non-classification

Based on the above studies and prediction on Methyl isonicotinate (2459-09-8) and it’s read across substances, it can be concluded that LD50 value is greater than 2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, Methyl isonicotinate can be classified as category V for acute oral and dermal toxicity.