Methyl N-(2,6-dimethylphenyl)-DL-alaninate

Endpoint summary

Description of key information

Acute oral toxicity: 

Acute oral toxicity dose (LD50) of 2-(2,6-dimethyl-phenylamino)-propionic acid methyl ester (CAS no: 52888-49-0) was predicted based on OECD QSAR toolbox 3419 mg/kg bw and different studies available on structurally similar read across substance 2,6-xylidinium chloride (21436-98-6) 2042 mg/kg bw and for the functionally similar read across substance Methyl-N-methyl anthranilite (CAS No. 85-91-6) >2000 mg/kg body weight. All these studies concluded that the LD50 value is >2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, 2-(2,6-dimethyl-phenylamino)-propionic acid methyl ester cannot be classified for acute oral toxicity.

Acute Dermal toxicity: 

Acute Dermal toxicity dose (LD50) for 2-(2,6-dimethyl-phenylamino)-propionic acid methyl ester (CAS no: 52888-49-0) was predicted based on OECD QSAR toolbox 3604 mg/kg bwand differentstudies available for the structurally similar read across substance Methyl N-(2,6-dimethylphenyl)-N-(methoxyacetyl)-DL-alaninate (57837-19-1) >3100 mg/kg bw and for the functionally similar read across substance Methyl-N-methyl anthranilite (CAS No. 85-91-6) >2000 mg/kg body weight. All these studies concluded that the LD50 value is>2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, 2-(2,6-dimethyl-phenylamino)-propionic acid methyl ester cannot be classified 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 data

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: 2-(2,6-dimethyl-phenylamino)-propionic acid methyl ester
SMILES:CC(C(=O)OC)Nc1c(C)cccc1C
InChI:1S/C12H17NO2/c1-8-6-5-7-9(2)11(8)13-10(3)12(14)15-4/h5-7,10,13H,1-4H3
Molecular Formula:C12H17NO2
Molecular Weight:207.271 g/mole

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:

unchanged (no vehicle)

Details on oral exposure:

not specified

Doses:

3419 mg/kg

No. of animals per sex per dose:

10

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:

3 419 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 50% mortality was 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 8 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 ( not "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" )  and ("y" and "z" )  )

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

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >> Michael-type addition on alpha, beta-unsaturated carbonyl compounds OR AN2 >> Michael-type addition on alpha, beta-unsaturated carbonyl compounds >> Four- and Five-Membered Lactones 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 AN2 >> Schiff base formation >> Dicarbonyl compounds OR AN2 >> Schiff base formation by aldehyde formed after metabolic activation OR AN2 >> Schiff base formation by aldehyde formed after metabolic activation >> Geminal Polyhaloalkane Derivatives OR AN2 >> Shiff base formation after aldehyde release OR AN2 >> Shiff base formation after aldehyde release >> Specific Acetate Esters OR AN2 >> Shiff base formation for aldehydes OR AN2 >> Shiff base formation for aldehydes >> Geminal Polyhaloalkane Derivatives OR AN2 >> Shiff base formation for aldehydes >> Haloalkane Derivatives with Labile Halogen OR Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> Coumarins OR Non-covalent interaction >> DNA intercalation >> DNA Intercalators with Carboxamide Side Chain OR Radical OR Radical >> Generation of reactive oxygen species OR Radical >> Generation of reactive oxygen species >> Thiols OR Radical >> Generation of ROS by glutathione depletion (indirect) OR Radical >> Generation of ROS by glutathione depletion (indirect) >> Haloalkanes Containing Heteroatom OR Radical >> Radical mechanism by ROS formation (indirect) or direct radical attack on DNA OR Radical >> Radical mechanism by ROS formation (indirect) or direct radical attack on DNA >> Organic Peroxy Compounds OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Coumarins OR Radical >> Radical mechanism via ROS formation (indirect) >> Geminal Polyhaloalkane Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitroarenes with Other Active Groups OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitrophenols, Nitrophenyl Ethers and Nitrobenzoic Acids OR Radical >> Radical mechanism via ROS formation (indirect) >> p-Substituted Mononitrobenzenes OR Radical >> Radical mechanism via ROS formation (indirect) >> Single-Ring Substituted Primary Aromatic Amines OR SN1 OR SN1 >> Carbenium ion formation OR SN1 >> Carbenium ion formation >> Alpha-Haloethers OR SN1 >> Nucleophilic attack after carbenium ion formation OR SN1 >> Nucleophilic attack after carbenium ion formation >> Specific Acetate Esters OR SN1 >> Nucleophilic attack after diazonium or carbenium ion formation OR SN1 >> Nucleophilic attack after diazonium or carbenium ion formation >> Nitroarenes with Other Active Groups OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> Single-Ring Substituted Primary Aromatic Amines OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitroarenes with Other Active Groups OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitrophenols, Nitrophenyl Ethers and Nitrobenzoic Acids OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> p-Substituted Mononitrobenzenes OR SN2 OR SN2 >> Acylation OR SN2 >> Acylation >> Specific Acetate Esters OR SN2 >> Acylation involving a leaving group  OR SN2 >> Acylation involving a leaving group  >> Geminal Polyhaloalkane Derivatives OR SN2 >> Acylation involving a leaving group  >> Haloalkane Derivatives with Labile Halogen OR SN2 >> Acylation involving a leaving group after metabolic activation OR SN2 >> Acylation involving a leaving group after metabolic activation >> Geminal Polyhaloalkane Derivatives 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 cyclization OR SN2 >> Alkylation, direct acting epoxides and related after cyclization >> Nitrogen Mustards OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom >> Haloalkane Derivatives with Labile Halogen OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom >> Sulfonates and Sulfates OR SN2 >> Alkylation, ring opening SN2 reaction OR SN2 >> Alkylation, ring opening SN2 reaction >> Four- and Five-Membered Lactones OR SN2 >> Direct acting epoxides formed after metabolic activation OR SN2 >> Direct acting epoxides formed after metabolic activation >> Coumarins OR SN2 >> Direct acting epoxides formed after metabolic activation >> Quinoline Derivatives OR SN2 >> DNA alkylation OR SN2 >> DNA alkylation >> Alkylphosphates, Alkylthiophosphates and Alkylphosphonates OR SN2 >> DNA alkylation >> Vicinal Dihaloalkanes OR SN2 >> Internal SN2 reaction with aziridinium and/or cyclic sulfonium ion formation (enzymatic) OR SN2 >> Internal SN2 reaction with aziridinium and/or cyclic sulfonium ion formation (enzymatic) >> Vicinal Dihaloalkanes OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Haloalkanes Containing Heteroatom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Specific Acetate Esters OR SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation OR SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation >> Geminal Polyhaloalkane Derivatives OR SN2 >> Ring opening SN2 reaction OR SN2 >> Ring opening SN2 reaction >> Sultones OR SN2 >> SN2 at an activated carbon atom OR SN2 >> SN2 at an activated carbon atom >> Quinoline Derivatives OR SN2 >> SN2 at sp3-carbon atom OR SN2 >> SN2 at sp3-carbon atom >> Alpha-Haloethers OR SN2 >> SN2 attack on activated carbon Csp3 or Csp2 OR SN2 >> SN2 attack on activated carbon Csp3 or Csp2 >> Nitroarenes with Other Active Groups by DNA binding by OASIS v.1.3

Domain logical expression index: "f"

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

Domain logical expression index: "g"

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 >> Polarised Alkenes-Michael addition OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated esters 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 >> 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 >> P450 Mediated Epoxidation OR SN2 >> P450 Mediated Epoxidation >> Thiophenes-SN2 by DNA binding by OECD

Domain logical expression index: "h"

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: "i"

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 Low reactive OR Low reactive >> Saturated acid anhydrides by DPRA Cysteine peptide depletion

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 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: "l"

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

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 >> 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 Acylation >> Ester aminolysis OR Acylation >> Ester aminolysis >> Amides OR Acylation >> Ester aminolysis or thiolysis OR Acylation >> Ester aminolysis or thiolysis >> Activated aryl esters  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 Michael Addition >> Michael addition on conjugated systems with electron withdrawing group >> Cyanoalkenes OR Nucleophilic addition OR Nucleophilic addition >> Addition to carbon-hetero double bonds OR Nucleophilic addition >> Addition to carbon-hetero double bonds >> Ketones OR Schiff base formation OR Schiff base formation >> Schiff base formation with carbonyl compounds OR Schiff base formation >> Schiff base formation with carbonyl compounds >> Aldehydes OR SN2 OR SN2 >> Nucleophilic substitution on benzilyc carbon atom OR SN2 >> Nucleophilic substitution on benzilyc carbon atom >> alpha-Activated benzyls  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: "n"

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

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 >> Acetates OR SN2 OR SN2 >> SN2 reaction at sp3 carbon atom OR SN2 >> SN2 reaction at sp3 carbon atom >> Allyl acetates and related chemicals by Protein binding by OECD

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Class 3 (unspecific reactivity) by Acute aquatic toxicity classification by Verhaar (Modified) ONLY

Domain logical expression index: "q"

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

Domain logical expression index: "r"

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

Domain logical expression index: "s"

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

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 16 - Sulfur S by Chemical elements

Domain logical expression index: "v"

Similarity boundary:Target: CC(C(=O)OC)Nc1c(C)cccc1C
Threshold=10%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "w"

Similarity boundary:Target: CC(C(=O)OC)Nc1c(C)cccc1C
Threshold=20%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "x"

Similarity boundary:Target: CC(C(=O)OC)Nc1c(C)cccc1C
Threshold=40%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "y"

Parametric boundary:The target chemical should have a value of log Kow which is >= 1.66

Domain logical expression index: "z"

Parametric boundary:The target chemical should have a value of log Kow which is <= 4.04

Interpretation of results:

other: Not classified

Conclusions:

LD50 was estimated to be 3419 mg/kg bw, when 10 male and female Sprague-Dawley rats were treated with 2-(2,6-dimethyl-phenylamino)-propionic acid methyl ester (CAS no: 52888-49-0) via 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

2-(2,6-dimethyl-phenylamino)-propionic acid methyl ester (CAS no: 52888-49-0). The LD50 was estimated to be 3419 mg/kg bw, when 10 male and female Sprague-Dawley rats were treated with 2-(2,6-dimethyl-phenylamino)-propionic acid methyl ester via oral route.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

3 419 mg/kg bw

Quality of whole database:

Data is Klimisch 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 data

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: 2-(2,6-dimethyl-phenylamino)-propionic acid methyl ester
SMILES:CC(C(=O)OC)Nc1c(C)cccc1C
InChI:1S/C12H17NO2/c1-8-6-5-7-9(2)11(8)13-10(3)12(14)15-4/h5-7,10,13H,1-4H3
Molecular Formula:C12H17NO2
Molecular Weight:207.271 g/mole

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

not specified

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

not specified

Duration of exposure:

24 hours

Doses:

3604 mg/kg

No. of animals per sex per dose:

10

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:

3 604 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 50% mortality was 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 7 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 ( not "p") )  )  and "q" )  and ("r" and ( not "s") )  )  and ("t" and ( not "u") )  )  and ("v" and "w" )  )

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

Domain logical expression index: "e"

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 AN2 >> Schiff base formation by aldehyde formed after metabolic activation OR AN2 >> Schiff base formation by aldehyde formed after metabolic activation >> Geminal Polyhaloalkane Derivatives OR AN2 >> Shiff base formation after aldehyde release OR AN2 >> Shiff base formation after aldehyde release >> Specific Acetate Esters OR AN2 >> Shiff base formation for aldehydes OR AN2 >> Shiff base formation for aldehydes >> Geminal Polyhaloalkane Derivatives OR AN2 >> Shiff base formation for aldehydes >> Haloalkane Derivatives with Labile Halogen OR Radical OR Radical >> Generation of reactive oxygen species OR Radical >> Generation of reactive oxygen species >> Thiols OR Radical >> Generation of ROS by glutathione depletion (indirect) OR Radical >> Generation of ROS by glutathione depletion (indirect) >> Haloalkanes Containing Heteroatom OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Geminal Polyhaloalkane Derivatives OR SN1 OR SN1 >> Nucleophilic attack after carbenium ion formation OR SN1 >> Nucleophilic attack after carbenium ion formation >> Specific Acetate Esters OR SN2 OR SN2 >> Acylation OR SN2 >> Acylation >> Specific Acetate Esters OR SN2 >> Acylation involving a leaving group  OR SN2 >> Acylation involving a leaving group  >> Geminal Polyhaloalkane Derivatives OR SN2 >> Acylation involving a leaving group  >> Haloalkane Derivatives with Labile Halogen OR SN2 >> Acylation involving a leaving group after metabolic activation OR SN2 >> Acylation involving a leaving group after metabolic activation >> Geminal Polyhaloalkane Derivatives OR SN2 >> Alkylation, direct acting epoxides and related OR SN2 >> Alkylation, direct acting epoxides and related >> Epoxides and Aziridines OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom >> Haloalkane Derivatives with Labile Halogen OR SN2 >> DNA alkylation OR SN2 >> DNA alkylation >> Alkylphosphates, Alkylthiophosphates and Alkylphosphonates OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Haloalkanes Containing Heteroatom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Specific Acetate Esters OR SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation OR SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation >> Geminal Polyhaloalkane Derivatives by DNA binding by OASIS v.1.3

Domain logical expression index: "f"

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

Domain logical expression index: "g"

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: "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 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: "j"

Referential boundary: The target chemical should be classified as No superfragment by Superfragments ONLY

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 by Eye irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Group All Aqueous Solubility < 0.000005 g/L OR Group All Aqueous Solubility < 0.00002 g/L OR Group All log Kow > 9 OR Group All Melting Point > 200 C OR Group C Aqueous Solubility < 0.0001 g/L OR Group C Aqueous Solubility < 0.0005 g/L OR Group C Melting Point > 55 C OR Group C Molecular Weight > 380 g/mol by Eye irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "m"

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: "n"

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: "o"

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: "p"

Referential boundary: The target chemical should be classified as Ac-SN2 OR Ac-SN2 >> Acylation involving an activated (glucuronidated) ester group OR Ac-SN2 >> Acylation involving an activated (glucuronidated) ester group >> Arenecarboxylic Acid Esters by Protein binding alerts for Chromosomal aberration by OASIS v1.1

Domain logical expression index: "q"

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

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 Amine AND Aromatic compound AND Carbonic acid derivative AND Carboxylic acid derivative AND Carboxylic acid ester AND Secondary amine AND Secondary mixed amine (aryl, alkyl) by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "u"

Referential boundary: The target chemical should be classified as CO2 derivative (general) OR Heterocyclic compound OR Lactone by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "v"

Parametric boundary:The target chemical should have a value of log Kow which is >= 1.66

Domain logical expression index: "w"

Parametric boundary:The target chemical should have a value of log Kow which is <= 4.47

Interpretation of results:

other: Not classified

Conclusions:

LD50 was estimated to be 3604 mg/kg bw, when 10 male and female New Zealand White rabbits were treated with 2-(2,6-dimethyl-phenylamino)-propionic acid methyl ester (CAS no: 52888-49-0) for 24 hours 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 2-(2,6-dimethyl-phenylamino)-propionic acid methyl ester (CAS no: 52888-49-0). The LD50 was estimated to be 3604 mg/kg bw, when 10 male and female New Zealand White rabbits were treated with 2-(2,6-dimethyl-phenylamino)-propionic acid methyl ester for 24 hours by dermal application occlusively.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

3 604 mg/kg bw

Quality of whole database:

Data is Klimisch 2 and from QSAR toolbox 3.3.

Additional information

Acute oral toxicity:

In different studies, 2-(2,6-dimethyl-phenylamino)-propionic acid methyl ester (CAS no: 52888-49-0) 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 for 2-(2,6-dimethyl-phenylamino)-propionic acid methyl ester along with the study available on structurally similar read across substance 2,6-xylidinium chloride (21436-98-6) and on functionally similar read across substanceMethyl-N-methyl anthranilite (CAS No. 85-91-6). 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  2-(2,6-dimethyl-phenylamino)-propionic acid methyl ester (CAS no: 52888-49-0). The LD50 was estimated to be 3419 mg/kg bw, when 10 male and female Sprague-Dawley rats were treated with 2-(2,6-dimethyl-phenylamino)-propionic acid methyl ester via oral gavage route.

The above study is supported by U.S. National Library of Medicine (ChemIDplus, 2017), for the structurally similar read across substance 2,6-xylidinium chloride (21436-98-6). Acute oral toxicity study was conducted in rats at the concentration of 2042 mg/kg bw. 50% Mortality was observed at dose 2042 mg/kg bw. Hence, LD50 value was considered to be2042 mg/kg bw, when rats were treated with2,6-xylidinium chloride via oral route.

This study is further supported by Sustainability Support Services (Europe) AB (study no.16160, 2017) was designed and conducted for the functionally similar read across substance Methyl-N-methyl anthranilite (CAS No. 85-91-6) in Sprague Dawley rats. Initially, three female animals were treated at the dose level of 300 mg/kg body weight of the test item (Step - I). Administration of the test item at 300 mg/kg did not result in any signs of toxicity and mortality at 24 hours after the dosing. As no mortality was observed at 24 hours after the dosing, three female animals were added to the study and treated with the same dose of 300 mg/kg of the test item (Step - II). Administration of the test item at 300 mg/kg did not result in any signs of toxicity and mortality after the dosing. No mortality was observed at 300 mg/kg dose group, hence additional three female animals were treated with the higher dose of 2000 mg/kg of the test item (Step - I). Administration of the test item at 2000 mg/kg did not result in any signs of toxicity and mortality after the dosing. As no mortality were observed at 24 hours after the dosing, additional three female animals were treated with the higher dose of  2000 mg/kg of the test item (Step - II). Administration of the test item at 2000 mg/kg did not result in any signs of toxicity and mortality after the dosing. Gross pathological examination did not reveal any abnormalities in animals from 300 mg/kg and 2000 mg/kg dose groups. The acute oral LD50 of Methyl-N-methyl anthranilite (CAS No. 85-91-6) was >2000 mg/kg body weight. Thus, it was concluded that the acute toxicity study of Methyl-N-methyl anthranilite (CAS No. 85-91-6), when administered via oral route in Sprague Dawley rats falls into the “Category Unclassified” criteria of CLP.

Thus, based on the above studies on 2-(2,6-dimethyl-phenylamino)-propionic acid methyl ester (CAS no: 52888-49-0) and it’s read across substances, it can be concluded that LD50 value is >2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, 2-(2,6-dimethyl-phenylamino)-propionic acid methyl ester cannot be classified for acute oral toxicity.

Acute Dermal toxicity:

In different studies, 2-(2,6-dimethyl-phenylamino)-propionic acid methyl ester (CAS no: 52888-49-0) 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 and rats for 2-(2,6-dimethyl-phenylamino)-propionic acid methyl ester along with the study available on the structurally similar read across substance Methyl N-(2,6-dimethylphenyl)-N-(methoxyacetyl)-DL-alaninate (57837-19-1) and on functionally similar read across substance Methyl-N-methyl anthranilite (CAS No. 85-91-6). 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 2-(2,6-dimethyl-phenylamino)-propionic acid methyl ester (CAS no: 52888-49-0). The LD50 was estimated to be 3604 mg/kg bw, when 10 male and female New Zealand White rabbits were treated with 2-(2,6-dimethyl-phenylamino)-propionic acid methyl ester for 24 hours by dermal application occlusively.

This study is supported by U.S. National Library of Medicine (ChemIDplus, 2017) and IFA GESTIS (GESTIS SUBSTANCE Database, 2017), for the structurally similar read across substance Methyl N-(2,6-dimethylphenyl)-N-(methoxyacetyl)-DL-alaninate (57837-19-1). Acute Dermal toxicity study was conducted in rats at the concentration of 3100 mg/kg bw. No Mortality was observed at dose 3100 mg/kg bw. Hence, LD50 value was considered to be >3100 mg/kg bw, when rats were treated withMethyl N-(2,6-dimethylphenyl)-N-(methoxyacetyl)-DL-alaninate by dermal application to skin.

The above study is further supported by Sustainability Support Services (Europe) AB (study no.19161, 2017) was designed and conducted for the functionally similar read across substanceMethyl-N-methyl anthranilite (CAS No. 85-91-6) in Sprague Dawley rats. The test item was applied to shorn skin of 5 male and 5 female animals at 2000 mg/kg body weight. Administration of the test item at 2000 mg/kg did not result in any skin reaction at the site of application during the study period of 14 days. Administration of the test item did not result in any signs of toxicity and mortality during the study period of 14 days. Animals exhibited normal body weight gain through the study period of 14 days. Gross pathological examination did not reveal any abnormalities attributable to the treatment. It was concluded that the acute dermal median lethal dose (LD50) of Methyl-N-methyl anthranilite (CAS No. 85-91-6), when administered to male and female Sprague Dawley rats was found to be >2000 mg/kg body weight. Thus, according to CLP criteria for acute toxicity rating for the chemicals, it infers that Methyl-N-methyl anthranilite (CAS No. 85-91-6) does not classify as an acute dermal toxicant. CLP Classification: “Unclassified”.

Thus, based on the above studies 2-(2,6-dimethyl-phenylamino)-propionic acid methyl ester (CAS no: 52888-49-0) and it’s read across substances, it can be concluded that LD50 value is >2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, 2-(2,6-dimethyl-phenylamino)-propionic acid methyl ester cannot be classified for acute dermal toxicity.

Justification for classification or non-classification

Based on the above studies and prediction on 2-(2,6-dimethyl-phenylamino)-propionic acid methyl ester (CAS no: 52888-49-0) and it’s read across substances, it can be concluded that LD50 value is >2000 mg/kg bw for acute oral and dermal toxicity. Thus, comparing this value with the criteria of CLP regulation, 2-(2,6-dimethyl-phenylamino)-propionic acid methyl ester cannot be classified for acute oral and dermal toxicity.