Registration Dossier

Skin Irritation:

The dermal irritation potential of (E)-(ethyl N-hydroxyethenecarboximidate)was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor.

(E)-(ethyl N-hydroxyethenecarboximidate)was estimated to be corrosive to the skin of New Zealand White rabbits.

Based on the estimated result; (E)-(ethyl N-hydroxyethenecarboximidate) can be considered corrosive to skin and can be classified under the category “Category 1” as per CLP regulation.

Eye Irritation:

The ocular irritation potential of (E)-(ethyl N-hydroxyethenecarboximidate)was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor.

(E)-(ethyl N-hydroxyethenecarboximidate) was estimated to be corrosive to the eyes of New Zealand White rabbits.

Based on the estimated results,(E)-(ethyl N-hydroxyethenecarboximidate)can be considered corrosive to eyes and can be classified under the category “Category 1” as per CLP regulation.

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 v3.3 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 v3.3

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material (IUPAC name) : (E)-(ethyl N-hydroxyethenecarboximidate)
- Common name : Ethyl N-hydroxyacetimidate, Ethyl Acetohydroximate
- Molecular formula : C4H9NO2
- Molecular weight : 103.12 g/mol
- Smiles notation : C(=N/O)(\OCC)C
- InChl : 1S/C4H9NO2/c1-3-7-4(2)5-6/h6H,3H2,1-2H3
- Substance type : Organic
- Physical state : Liquid

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

no data available

Type of coverage:

occlusive

Preparation of test site:

not specified

Vehicle:

not specified

Controls:

not specified

Amount / concentration applied:

0.5g

Duration of treatment / exposure:

24 hours

Observation period:

24, 72 hours

Number of animals:

2

Details on study design:

no data available

Other effects / acceptance of results:

no data available

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

72 h

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Irritant / corrosive response data:

Positive indication of irritation 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 ("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 ( not "x") ) ) and ("y" and ( not "z") ) ) and ("aa" and ( not "ab") ) ) and ("ac" and ( not "ad") ) ) and ("ae" and ( not "af") ) ) and ("ag" and ( not "ah") ) ) and ("ai" and ( not "aj") ) ) and ("ak" and "al" ) )

Domain logical expression index: "a"

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

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Alkoxy AND Ether by Organic Functional groups

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Alkoxy AND Ether AND Overlapping groups by Organic Functional groups (nested)

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] AND Aliphatic Carbon [-CH2-] AND Aliphatic Carbon [-CH3] AND Azomethine, aliphatic attach [-N=C] AND Hydroxy, nitrogen attach [-OH] AND Olefinic carbon [=CH- or =C<] AND Oxime, aliphatic attach [-CH=N-OH] AND Oxygen, nitrogen attach [-O-] by Organic functional groups (US EPA)

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 >> Carbamoylation after isocyanate formation OR AN2 >> Carbamoylation after isocyanate formation >> N-Hydroxylamines OR AN2 >> Shiff base formation after aldehyde release OR AN2 >> Shiff base formation after aldehyde release >> Specific Acetate Esters OR Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> Acridone, Thioxanthone, Xanthone and Phenazine Derivatives 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 OR Radical >> Radical mechanism by ROS formation >> Acridone, Thioxanthone, Xanthone and Phenazine Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> N-Hydroxylamines 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 metabolic nitrenium ion formation OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> N-Hydroxylamines OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> Single-Ring Substituted Primary Aromatic Amines OR SN2 OR SN2 >> Acylation OR SN2 >> Acylation >> Specific Acetate Esters 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 >> Sulfonates and Sulfates 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 >> SN2 at sp3-carbon atom OR SN2 >> SN2 at sp3-carbon atom >> Alpha-Haloethers 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 Acylation OR Acylation >> P450 Mediated Activation to Isocyanates or Isothiocyanates OR Acylation >> P450 Mediated Activation to Isocyanates or Isothiocyanates >> Benzylamines-Acylation OR Acylation >> P450 Mediated Activation to Isocyanates or Isothiocyanates >> Formamides 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 >> 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 >> Hydroquinones 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 Schiff base formers OR Schiff base formers >> Chemicals Activated by P450 to Glyoxal OR Schiff base formers >> Chemicals Activated by P450 to Glyoxal >> Ethanolamines (including morpholine) OR Schiff base formers >> Chemicals Activated by P450 to Glyoxal >> Ethylenediamines (including piperazine) OR Schiff base formers >> Chemicals Activated by P450 to Mono-aldehydes OR Schiff base formers >> Chemicals Activated by P450 to Mono-aldehydes >> Benzylamines-Schiff base 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 OR SN2 >> SN2 at an sp3 Carbon atom OR SN2 >> SN2 at an sp3 Carbon atom >> Aliphatic halides by DNA binding by OECD

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Non binder, non cyclic structure by Estrogen Receptor Binding

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Moderate binder, NH2 group OR Non binder, impaired OH or NH2 group OR Non binder, MW>500 OR Non binder, without OH or NH2 group OR Strong binder, NH2 group OR Strong binder, OH group OR Weak binder, NH2 group OR Weak binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as No superfragment by Superfragments 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 by Eye irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Exclusion rules not met OR Group All Aqueous Solubility < 0.000005 g/L OR Group All Aqueous Solubility < 0.00002 g/L OR Group All log Kow < -3.1 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 OR Group CN Aqueous Solubility < 0.1 g/L OR Group CN log Kow > 4.5 OR Group CN Molecular Weight > 290 g/mol OR Group CNS log Kow < -2 OR Group CNS Melting Point > 50 C by Eye irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "n"

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: "o"

Referential boundary: The target chemical should be classified as (!Undefined)Group C Surface Tension > 62 mN/m OR Group CN Melting Point > 180 C OR Group CN Vapour Pressure < 0.001 Pa by Skin irritation/corrosion Exclusion rules by BfR

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 Primary and secondary aliphatic amines by Skin irritation/corrosion Inclusion rules by BfR

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 Metalloids 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 15 - Phosphorus P by Chemical elements

Domain logical expression index: "v"

Similarity boundary:Target: CCOC(C)=NO
Threshold=60%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "w"

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

Domain logical expression index: "x"

Referential boundary: The target chemical should be classified as Oximes (Hemolytic anemia with methemoglobinemia) Rank B by Repeated dose (HESS)

Domain logical expression index: "y"

Referential boundary: The target chemical should be classified as No alert found by Carcinogenicity (genotox and nongenotox) alerts by ISS

Domain logical expression index: "z"

Referential boundary: The target chemical should be classified as Structural alert for nongenotoxic carcinogenicity OR Substituted n-alkylcarboxylic acids (Nongenotox) by Carcinogenicity (genotox and nongenotox) alerts by ISS

Domain logical expression index: "aa"

Referential boundary: The target chemical should be classified as -CH2- [linear] AND Methyl [-CH3] by Biodegradation fragments (BioWIN MITI)

Domain logical expression index: "ab"

Referential boundary: The target chemical should be classified as Aliphatic alcohol [-OH] by Biodegradation fragments (BioWIN MITI)

Domain logical expression index: "ac"

Referential boundary: The target chemical should be classified as -CH2- [linear] AND Methyl [-CH3] by Biodegradation fragments (BioWIN MITI)

Domain logical expression index: "ad"

Referential boundary: The target chemical should be classified as -CH- [linear] by Biodegradation fragments (BioWIN MITI)

Domain logical expression index: "ae"

Referential boundary: The target chemical should be classified as -CH2- [linear] AND Methyl [-CH3] by Biodegradation fragments (BioWIN MITI)

Domain logical expression index: "af"

Referential boundary: The target chemical should be classified as Not calculated by Biodegradation fragments (BioWIN MITI)

Domain logical expression index: "ag"

Referential boundary: The target chemical should be classified as Not categorized by OECD HPV Chemical Categories

Domain logical expression index: "ah"

Referential boundary: The target chemical should be classified as Secondary amines by OECD HPV Chemical Categories

Domain logical expression index: "ai"

Referential boundary: The target chemical should be classified as ECHA PR AND EINECS AND REACH ECB AND TSCA by Inventory Affiliation

Domain logical expression index: "aj"

Referential boundary: The target chemical should be classified as (N/A) by Inventory Affiliation

Domain logical expression index: "ak"

Parametric boundary:The target chemical should have a value of log Kow which is >= -0.642

Domain logical expression index: "al"

Parametric boundary:The target chemical should have a value of log Kow which is <= 1.33

Interpretation of results:

Category 1 (corrosive) based on GHS criteria

Conclusions:

(E)-(ethyl N-hydroxyethenecarboximidate) was estimated to be corrosive to the skin of New Zealand White rabbits.

Executive summary:

The dermal irritation potential of (E)-(ethyl N-hydroxyethenecarboximidate)was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor.

(E)-(ethyl N-hydroxyethenecarboximidate)was estimated to be corrosive to the skin of New Zealand White rabbits.

Based on the estimated result; (E)-(ethyl N-hydroxyethenecarboximidate) can be considered corrosive to skin and can be classified under the category “Category 1” as per CLP regulation.

Endpoint conclusion:

adverse effect observed (corrosive)

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 v3.3 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 v3.3

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material (IUPAC name) : (E)-(ethyl N-hydroxyethenecarboximidate)
- Common name : Ethyl N-hydroxyacetimidate, Ethyl Acetohydroximate
- Molecular formula : C4H9NO2
- Molecular weight : 103.12 g/mol
- Smiles notation : C(=N/O)(\OCC)C
- InChl : 1S/C4H9NO2/c1-3-7-4(2)5-6/h6H,3H2,1-2H3
- Substance type : Organic
- Physical state : Liquid

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

no data available

Vehicle:

not specified

Controls:

not specified

Amount / concentration applied:

0.1g

Duration of treatment / exposure:

4 hours

Observation period (in vivo):

72 hours

Duration of post- treatment incubation (in vitro):

no data available

Number of animals or in vitro replicates:

4

Details on study design:

no data available

Other effects / acceptance of results:

no data available

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

72 h

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Irritant / corrosive response data:

Positive indication of irritation

Estimation method: Takes mode value from the 8 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 ("j" and ( not "k") ) ) and ("l" and ( not "m") ) ) and ("n" and ( not "o") ) ) and "p" ) and ("q" and ( not "r") ) ) and ("s" and ( not "t") ) ) and ("u" and ( not "v") ) ) and ("w" and ( not "x") ) ) and ("y" and ( not "z") ) ) and ("aa" and ( not "ab") ) ) and ("ac" and ( not "ad") ) ) and ("ae" and ( not "af") ) ) and ("ag" and ( not "ah") ) ) and ("ai" and ( not "aj") ) ) and ("ak" and ( not "al") ) ) and ("am" and "an" ) )

Domain logical expression index: "a"

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

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Alkoxy AND Ether by Organic Functional groups

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Alkoxy AND Ether AND Overlapping groups by Organic Functional groups (nested)

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] AND Aliphatic Carbon [-CH2-] AND Aliphatic Carbon [-CH3] AND Azomethine, aliphatic attach [-N=C] AND Hydroxy, nitrogen attach [-OH] AND Olefinic carbon [=CH- or =C<] AND Oxime, aliphatic attach [-CH=N-OH] AND Oxygen, nitrogen attach [-O-] by Organic functional groups (US EPA)

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Non binder, non cyclic structure by Estrogen Receptor Binding

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Moderate binder, NH2 group OR Moderate binder, OH grooup OR Non binder, impaired OH or NH2 group OR Non binder, MW>500 OR Non binder, without OH or NH2 group OR Strong binder, NH2 group OR Strong binder, OH group OR Weak binder, NH2 group OR Weak binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "g"

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

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Ester aminolysis OR Acylation >> Ester aminolysis >> Amides OR Michael Addition OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group >> alpha,beta-Carbonyl compounds with polarized double bonds OR Nucleophilic addition OR Nucleophilic addition >> Addition to carbon-hetero double bonds OR Nucleophilic addition >> Addition to carbon-hetero double bonds >> Azomethyme type compounds OR SN2 OR SN2 >> Interchange reaction with sulphur containing compounds OR SN2 >> Interchange reaction with sulphur containing compounds >> Thiols and disulfide compounds OR SN2 >> Nucleophilic substitution at sp3 carbon atom OR SN2 >> Nucleophilic substitution at sp3 carbon atom >> (Thio)Phosphates OR SN2 >> Nucleophilic substitution at sp3 carbon atom >> Alkyl halides by Protein binding by OASIS v1.3

Domain logical expression index: "i"

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

Domain logical expression index: "j"

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: "k"

Referential boundary: The target chemical should be classified as Exclusion rules not met OR Group All Aqueous Solubility < 0.000005 g/L OR Group All Aqueous Solubility < 0.00002 g/L OR Group All log Kow < -3.1 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 OR Group CN Aqueous Solubility < 0.1 g/L OR Group CN log Kow > 4.5 OR Group CN Molecular Weight > 290 g/mol OR Group CNS log Kow < -2 OR Group CNS log Kow > 1.5 OR Group CNS Melting Point > 50 C by Eye irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as No alert found by DNA alerts for AMES, MN and CA by OASIS v.1.3

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >> Carbamoylation after isocyanate formation OR AN2 >> Carbamoylation after isocyanate formation >> N-Hydroxylamines OR AN2 >> Shiff base formation after aldehyde release OR AN2 >> Shiff base formation after aldehyde release >> Specific Acetate Esters OR Radical OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> N-Hydroxylamines OR SN1 OR SN1 >> Nucleophilic attack after carbenium ion formation OR SN1 >> Nucleophilic attack after carbenium ion formation >> Specific Acetate Esters OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> N-Hydroxylamines OR SN2 OR SN2 >> Acylation OR SN2 >> Acylation >> Specific Acetate Esters OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Specific Acetate Esters by DNA alerts for AMES, MN and CA by OASIS v.1.3

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Not known precedent reproductive and developmental toxic potential by DART scheme v.1.0

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Di-substituted hydrocarbons (24a) OR Di-substituted hydrocarbons (24b) OR Known precedent reproductive and developmental toxic potential OR Not covered by current version of the decision tree OR Organophosphorus compounds (1b) by DART scheme v.1.0

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"

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

Domain logical expression index: "r"

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

Domain logical expression index: "s"

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: "t"

Referential boundary: The target chemical should be classified as Alkylalkanol-amines OR Ethylenglycolethers OR Primary and secondary aliphatic amines OR Tertiary aliphatic amine by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "u"

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: "v"

Referential boundary: The target chemical should be classified as (!Undefined)Group C Surface Tension > 62 mN/m OR Group CN Melting Point > 180 C OR Group CN Vapour Pressure < 0.001 Pa by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "w"

Referential boundary: The target chemical should be classified as No alert found by Carcinogenicity (genotox and nongenotox) alerts by ISS

Domain logical expression index: "x"

Referential boundary: The target chemical should be classified as Structural alert for nongenotoxic carcinogenicity OR Substituted n-alkylcarboxylic acids (Nongenotox) by Carcinogenicity (genotox and nongenotox) alerts by ISS

Domain logical expression index: "y"

Referential boundary: The target chemical should be classified as Not categorized by OECD HPV Chemical Categories

Domain logical expression index: "z"

Referential boundary: The target chemical should be classified as Secondary amines by OECD HPV Chemical Categories

Domain logical expression index: "aa"

Referential boundary: The target chemical should be classified as Alkoxy AND Ether by Organic Functional groups

Domain logical expression index: "ab"

Referential boundary: The target chemical should be classified as Aliphatic Amine, tertiary by Organic Functional groups

Domain logical expression index: "ac"

Referential boundary: The target chemical should be classified as Alkoxy AND Ether by Organic Functional groups

Domain logical expression index: "ad"

Referential boundary: The target chemical should be classified as Guanidine by Organic Functional groups

Domain logical expression index: "ae"

Referential boundary: The target chemical should be classified as Alkoxy AND Ether by Organic Functional groups

Domain logical expression index: "af"

Referential boundary: The target chemical should be classified as Ketoxime derivatives by Organic Functional groups

Domain logical expression index: "ag"

Referential boundary: The target chemical should be classified as Alkoxy AND Ether by Organic Functional groups

Domain logical expression index: "ah"

Referential boundary: The target chemical should be classified as Alkane branched with quaternary carbon by Organic Functional groups

Domain logical expression index: "ai"

Referential boundary: The target chemical should be classified as Alkoxy AND Ether by Organic Functional groups

Domain logical expression index: "aj"

Referential boundary: The target chemical should be classified as Aldoxime derivatives by Organic Functional groups

Domain logical expression index: "ak"

Referential boundary: The target chemical should be classified as Alkoxy AND Ether by Organic Functional groups

Domain logical expression index: "al"

Referential boundary: The target chemical should be classified as Alcohol by Organic Functional groups

Domain logical expression index: "am"

Parametric boundary:The target chemical should have a value of log Kow which is >= -1.89

Domain logical expression index: "an"

Parametric boundary:The target chemical should have a value of log Kow which is <= 1.33

Interpretation of results:

Category 1 (irreversible effects on the eye) based on GHS criteria

Conclusions:

(E)-(ethyl N-hydroxyethenecarboximidate) was estimated to be corrosive to the eyes of New Zealand White rabbits.

Executive summary:

The ocular irritation potential of (E)-(ethyl N-hydroxyethenecarboximidate)was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor.

(E)-(ethyl N-hydroxyethenecarboximidate) was estimated to be corrosive to the eyes of New Zealand White rabbits.

Based on the estimated results,(E)-(ethyl N-hydroxyethenecarboximidate)can be considered corrosive to eyes and can be classified under the category “Category 1” as per CLP regulation.

Endpoint conclusion:

adverse effect observed (irreversible damage)

Endpoint conclusion:

no study available

Skin Irritation:

Several studies were performed to ascertain the degree of dermal irritation caused by(E)-(ethyl N-hydroxyethenecarboximidate) in living organisms. These studies include in vivo studies in rabbits as well as predicted data for the target chemical as well as its closely related substance, Hexamethylenediamine[CAS: 124-09-4] and functionally similar read across substances, Diethylene Glycol Bis(3-aminopropyl) Ether[CAS: 4246 -51-9] and 3-Methoxypropylamine[CAS: 5332-73-0]. Thepredicted data using the OECD QSAR toolbox has also been compared with the experimental data.

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(E)-(ethyl N-hydroxyethenecarboximidate).(E)-(ethyl N-hydroxyethenecarboximidate)was corrosive to New Zealand White rabbit skin.

This result is supported by the experimental study summarized in American Industrial Hygiene Association Journal, Volume 30, 1969 - Issue 5, Pages 470-476; for thefunctionally similar read across substance, Diethylene Glycol Bis(3-aminopropyl) Ether[CAS: 4246-51-9]. Primary skin irritation on rabbits was recorded in a 10-grade ordinal series and was based upon the severest reaction that develops on the clipped abdominal skin of each of five albino rabbits within 24 hours of the uncovered application of 0.01 ml of undiluted sample or of solutions in water, propylene glycol, or acetone.

Grade 1 indicates no irritation and Grade 2 the least visible capillary injection from the undiluted chemical. Grade 6 indicates necrosis when undiluted and Grade 10 indicates necrosis from a 0.01% solution. Primary Irritation score after 24 hours for Diethylene Glycol Bis(3-aminopropyl) Ether was Grade 6.

Based on this grade, Diethylene Glycol Bis(3-aminopropyl) Ether can be considered moderately irritating to rabbit skin.

The above results are supported by the experimental study for the closely related read across substance,1,6-Diaminohexane[CAS: 124-09-4] summarized in Drug and Chemical Toxicology, 1:15–33, 2005. Undiluted 50µl of hexamethylenediamine was applied to the intact shaven skin of 10 guinea pigs and observed for signs of irritation (exact duration of exposure and observation period not specified).Severe necrosis was observed within 1 hour of exposure to undilutedhexamethylenediamine. Hence, hexamethylenediamine can be considered to be corrosive to guinea pig skin.

These studies are supported by the experimental study for the functionally similar read across substance,3-Methoxypropylamine[CAS: 5332-73-0]summarized in ECETOC- TR-066- Skin Irritation -109; ECETOC; 1995. Undiluted 0.5ml of 3-Methoxypropylamine was applied to directly to the skin of 6 rabbits for 4 hours and observed for signs of irritation. The treated sites were observed and scored for erythema and edema formation at 1,24,48,72 hours, 7, 14, 15 days. The grading scale for irritant effects on rabbit skin, originally proposed by Draize and adopted by OECD 404 Guidelines, US and EC regulatory agencies was used. The “Primary Irritation Index (PII)” was calculated from erythema and edema grades.

Edema and erythema were observed in all the rabbits till 14 days of observation. Also the effects were irreversible even after 15 days. The PII was calculated to be 6.67.

Based on the observations and scores, 3-Methoxypropylamine can be considered to be corrosive to rabbit skin.

Even though the results for one of the read across substance was moderately irritating to skin, but the predicted data for the target and remaining functionally/structurally related read across substances indicate a very strong possibility of(E)-(ethyl N-hydroxyethenecarboximidate being corrosive to skin. Hence, by applying the weight of evidence approach, (E)-(ethyl N-hydroxyethenecarboximidate can be considered to be corrosive to skin.Comparing the above annotations with the criteria of CLP regulation,(E)-(ethyl N-hydroxyethenecarboximidatecan be classified under the category “Category 1”.

Eye irritation:

Several studies were performed to ascertain the degree of ocular irritation caused by(E)-(ethyl N-hydroxyethenecarboximidate) in living organisms. These studies include in vivo studies in rabbits as well as predicted data for the target chemical and functionally similar read across substances, Diethylene Glycol Bis(3-aminopropyl) Ether[CAS: 4246-51-9] and 3 -Methoxypropylamine[CAS: 5332-73-0]. Thepredicted data using the OECD QSAR toolbox has also been compared with the experimental data.

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the ocular irritation potential was estimated for(E)-(ethyl N-hydroxyethenecarboximidate).(E)-(ethyl N-hydroxyethenecarboximidate)was corrosive to New Zealand White rabbit skin.

This result is supported by the experimental study summarized in American Industrial Hygiene Association Journal, Volume 30, 1969 - Issue 5, Pages 470-476; for thefunctionally similar read across substance, Diethylene Glycol Bis(3-aminopropyl) Ether[CAS: 4246-51-9].Eye injury in rabbits is recorded in a 10- grade ordinal series and is based upon the degree of corneal necrosis that results from instillation of various volumes and concentrations of chemical.

Grade 1 indicates at most a very small area of necrosis resulting from 0.5 ml of undiluted chemical in the eye. Grade 5 indicates a so-called severe burn from 0.005 ml, and Grade 10 indicates a severe burn from 0.5 ml of a 1% solution in water or propylene glycol.

Primary Irritation score after 24 hours for Diethylene Glycol Bis(3-aminopropyl) Ether was Grade 8.

In the acute eye irritation study conducted in albino rabbits, Diethylene Glycol Bis(3-aminopropyl) Ether was considered to be moderately irritating to rabbit eyes.

The above results are also supported by the experimental study forthe functionally similar read across substance,3-Methoxypropylamine[CAS: 5332-73-0] summarized inDrug and Chemical Toxicology, 1:15–33, 2005. 85% solution of hexamethylenediamine was instilled in the eyes of rabbits and observed for signs of irritation till 6 hours.Severe initial reaction with extensive lacrimation was noted in all the rabbits. Six hours later, the irritation had progressed to severe conjunctivitis. These effects were reversible in 5 to 10 days post-treatment.

Based on these observations, Hexamethylenediamine can be considered to be a severe eye irritant.

Based on the available data for the target as well as read across chemicals and applying the weight of evidence approach,(E)-(ethyl N-hydroxyethenecarboximidatecan be considered to be irritating to eyes. Comparing the above annotations with the criteria of CLP regulation, test chemical can be classified under the category “Category 2”.

Available data for (E)-(ethyl N-hydroxyethenecarboximidate) indicates that it is likely to cause severe irritation (corrosion) to skin and eyes.

Hence, (E)-(ethyl N-hydroxyethenecarboximidate)can be classified under the category “Category 1” for skin irritation and AS" Category 2" for eye irritation as per CLP regulation.