Ethyl N-hydroxyacetimidate

Endpoint summary

Description of key information

Skin Sensitization:

The skin sensitization potential of (E)-(ethyl N-hydroxyethenecarboximidate)was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor.(E)-(ethyl N-hydroxyethenecarboximidate)was predicted to be not sensitizing to the skin of guinea pigs.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Remarks:

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

Type of study:

other: Estimated data

Justification for non-LLNA method:

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:

guinea pig

Strain:

Dunkin-Hartley

Sex:

male

Details on test animals and environmental conditions:

no data available

Route:

epicutaneous, occlusive

Vehicle:

not specified

Adequacy of induction:

not specified

No.:

#1

Route:

epicutaneous, occlusive

Vehicle:

not specified

Adequacy of challenge:

not specified

No. of animals per dose:

10

Details on study design:

no data available

Challenge controls:

no data available

Positive control substance(s):

not specified

Positive control results:

no data available

Other effects / acceptance of results:

no data available

Reading:

1st reading

Group:

test chemical

Clinical observations:

no dermal reactions observed

Remarks on result:

no indication of skin sensitisation

The prediction was based on dataset comprised from the following descriptors: "Skin Sensitisation"
Estimation method: Takes highest 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 ("j" and ( not "k") )  )  and ("l" and ( not "m") )  )  and ("n" and ( not "o") )  )  and ("p" and ( not "q") )  )  and "r" )  and "s" )  and ("t" and "u" )  )

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 OECD

Domain logical expression index: "f"

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 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 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 >> Direct Acting Epoxides and related OR SN2 >> Direct Acting Epoxides and related >> Epoxides OR SN2 >> Epoxidation of Aliphatic Alkenes OR SN2 >> Epoxidation of Aliphatic Alkenes >> Halogenated polarised alkenes 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: "g"

Referential boundary: The target chemical should be classified as Non binder, non cyclic structure 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, 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: "i"

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

Domain logical expression index: "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 Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as (!Undefined)Group C Surface Tension > 62 mN/m OR (!Undefined)Group CNS Surface Tension > 62 mN/m OR Exclusion rules not met OR Group All log Kow < -3.1 OR Group All Melting Point > 200 C OR Group C Aqueous Solubility < 0.0001 g/L OR Group CN Aqueous Solubility < 0.1 g/L OR Group CN Melting Point > 180 C OR Group CN Vapour Pressure < 0.001 Pa OR Group CNS log Kow < 0.5 OR Group CNS log Kow < -2 OR Group CNS Melting Point > 120 C OR Group CNS Melting Point > 50 C by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "l"

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: "m"

Referential boundary: The target chemical should be classified as SN2 OR SN2 >> Nucleophilic substitution at sp3 carbon atom OR SN2 >> Nucleophilic substitution at sp3 carbon atom >> (Thio)Phosphates  by Protein binding alerts for skin sensitization by OASIS v1.3

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as H-acceptor-path3-H-acceptor by in vivo mutagenicity (Micronucleus) alerts by ISS

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as alpha,beta-unsaturated aliphatic alkoxy group OR No alert found by in vivo mutagenicity (Micronucleus) alerts by ISS

Domain logical expression index: "p"

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: "q"

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

Domain logical expression index: "r"

Similarity boundary:Target: CCOC(C)=NO
Threshold=10%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "s"

Similarity boundary:Target: CCOC(C)=NO
Threshold=80%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "t"

Parametric boundary:The target chemical should have a value of log Kow which is >= -0.211

Domain logical expression index: "u"

Parametric boundary:The target chemical should have a value of log Kow which is <= 1.19

Interpretation of results:

other: Not sensitizing

Conclusions:

The skin sensitization potential of (E)-(ethyl N-hydroxyethenecarboximidate) was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor. (E)-(ethyl N-hydroxyethenecarboximidate) was predicted to be not sensitizing to the skin of male guinea pigs.

Executive summary:

The skin sensitization potential of (E)-(ethyl N-hydroxyethenecarboximidate)was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor.(E)-(ethyl N-hydroxyethenecarboximidate)was predicted to be not sensitizing to the skin of male guinea pigs.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

Various studieshas been investigated for the test chemical(E)-(ethyl N-hydroxyethenecarboximidate) (CAS No: 10576-12-2)to observe the potential for skin sensitization to a greater or lesser extent. The studies are based on in vivo experiments in guinea pigs for target chemical(E)-(ethyl N-hydroxyethenecarboximidate) (CAS No: 10576-12-2) and its closely related read across substanceswith logPow as the primary descriptor N,N-Diethylhydroxylamine (CAS no: 3710-84-7) and Dibutyl ether (CAS no: 142-96-1).The predicted data using the OECD QSAR toolbox has also been compared with the experimental data and summarized as below;

 

The skin sensitization potential of (E)-(ethyl N-hydroxyethenecarboximidate) (CAS No: 10576-12-2)was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor. The chemical (E)-(ethyl N-hydroxyethenecarboximidate) (CAS No: 10576-12-2)was estimated to be not sensitizing to the skin of Dunkin-Hartley guinea pigs. Based on the estimated result (E)-(ethyl N-hydroxyethenecarboximidate) (CAS No: 10576-12-2) can be considered to be not sensitizing to Dunkin-Hartley guinea pigs.

 

The HSDB {U.S. National Library of Medicine National Institutes of Health, Health & Human Services; 2017} and OECD SIDS {Robust Summary & Test Plans: Diethylhydroxylamine: Robust Summary; IUCLID Dataset-OECD SIDS; 2006 JANURY 13} conducted a Buehler test on male guinea pigs of read across chemical N,N-Diethylhydroxylamine (CAS no: 3710-84-7) . In this test,after establishing the highest non-irritating dose concentration, a 3 week induction period was initiated during which 10 young adult, male, guinea pigs were treated with the test material applied as a 30% w/w solution in deionized water and 10 were treated with 0.08% Dinitrochlorobenzene (DNCB) in 95% ethyl alcohol (positive controls). During the induction period the animals were dosed on alternate days until a total of nine dose applications were achieved. Seventeen days after the nine applications a challenge dose was applied to a naive site on each guinea pig and approximately 24 and 48 hours later the animals were scored for a sensitization response (erythema and edema). A naive control group of five animals was maintained under the same environmental conditions and was treated with thewith the test material at challenge only. All guinea pigs appeared active and healthy throughout the test period. There were no signs of gross toxicity, adverse pharmacologic effects or abnormal behavior. All animals gained weight. After 24 and 48 hours, all sites were erythemic, showing a faint to moderate response but no irritation was observed in test and naive groups after challenge. Hence thechemicalN,N-Diethylhydroxylamine (CAS no: 3710-84-7) was considered to be not-sensitizing to the skin of guinea pigs in a Buehler test.

 

 The above results were further supported by an open epicutaneous test of read across chemical Dibutyl ether (CAS no: 142-96-1) reported by OECD SIDS {SIDS Initial Assessment Report For SIAM 22 Paris, France, 18 - 21 April 2006} in Hartley guinea pigs. During the test, the hair on the dorsum was clipped 24 hours before exposure. For induction, the animals received a total application of 50 μl undiluted dibutyl ether with each animal received two 25 μl amounts on separate sites. Five days later, each guinea pig received on virgin sites six challenge applications of 25 μl undiluted aliquots. A rechallenge was performed 9 days after the first challenge. Skin reaction was scored by the method of Draize at 24 and 48 hours after application.The animals did not respond with dermal hypersensitivity reactions when challenged with dibutyl ether. The mean scores 24 hours after day 5 and day 14 challenge were 0.8 and 0.0, respectively. No individual scores were greater than 1.0 (maximum possible score of 8). According to these results, dibutyl ether has no sensitization potency.Thus on the basis of scores, the chemicalDibutyl ether (CAS no: 142-96-1) was considered to be not-sensitizing to the skin of Hartley guinea pigs in an open epicutaneous test.

 

 

 Thus on the basis of available data for thetarget chemical(E)-(ethyl N-hydroxyethenecarboximidate) (CAS No: 10576-12-2)and its closely related read across substanceswith logPow as the primary descriptor N,N-Diethylhydroxylamine (CAS no: 3710-84-7) and Dibutyl ether (CAS no: 142-96-1),it can be concluded thatchemical (E)-(ethyl N-hydroxyethenecarboximidate) (CAS No: 10576-12-2) is unable to cause skin sensitization and considered as non-skin sensitizer.Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Not Classified”.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

The skin sensitization potential of test substance (E)-(ethyl N-hydroxyethenecarboximidate) (CAS No: 10576-12-2) and its closely related read across substanceswith logPow as the primary descriptor N,N-Diethylhydroxylamine (CAS no: 3710-84-7) and Dibutyl ether (CAS no: 142-96-1)were observed in various studies. From the results obtained from these studies it is concluded that the chemical (E)-(ethyl N-hydroxyethenecarboximidate) (CAS No: 10576-12-2) is not likely to cause skin sensitization and hence can be classified as non-skin sensitizer.