Registration Dossier

Skin Irritation:

The dermal irritation potential of 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride (CAS No: 59703-00-3) was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor. 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride (CAS No: 59703-00-3) was estimated to be not irritating to the skin of Vienna White rabbits.

Based on the estimated result, 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride (CAS No: 59703-00-3) can be considered to be not irritating to skin and can be classified under the category "Not Classified" as per CLP regulation.

Eye Irritation:

The ocular irritation potential of 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride (CAS No: 59703-00-3) was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor.4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride (CAS No: 59703-00-3) was estimated to be not irritating to the eyes of Vienna White rabbits.

Based on the estimated result, 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride (CAS No: 59703-00-3) can be considered to be not irritating to eye and can be classified under the category "Not Classified"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 version 3.3 and the 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

Specific details on test material used for the study:

- Name of test material (as cited in study report): 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride
- Molecular formula: C7H9ClN2O3
- Molecular weight: 204.612 g/mol
- Substance type: Organic
- Physical state: Solid

Species:

rabbit

Strain:

Vienna 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:

unchanged (no vehicle)

Controls:

not specified

Amount / concentration applied:

No data available

Duration of treatment / exposure:

1, 5, 15 min20 h

Observation period:

8 days

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:

other: 8 days

Reversibility:

not specified

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

No irritation was observed.

Estimation method: Takes mode value from the 5 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 ( not "n") ) ) and ("o" and ( not "p") ) ) and ("q" and ( not "r") ) ) and ("s" and ( not "t") ) ) and ("u" and ( not "v") ) ) and "w" ) and "x" ) and "y" ) and "z" ) and ("aa" and ( not "ab") ) ) and "ac" ) and ("ad" and "ae" ) )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Direct Addition of an Acyl Halide OR Acylation >> Direct Addition of an Acyl Halide >> Alkyl carbamyl halides OR SN1 OR SN1 >> Iminium Ion Formation OR SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines by DNA binding by OECD ONLY

Domain logical expression index: "b"

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 >> (Thio)Acyl and (thio)carbamoyl halides and cyanides OR Nucleophilic addition OR Nucleophilic addition >> Addition to carbon-hetero double bonds OR Nucleophilic addition >> Addition to carbon-hetero double bonds >> Ketones by Protein binding by OASIS v1.3 ONLY

Domain logical expression index: "c"

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 Acylation >> Direct Acylation Involving a Leaving group >> Acyl halides (including benzyl and carbamoyl deriv.) OR Acylation >> Direct Acylation Involving a Leaving group >> Dialkyl carbamoylhalides by Protein binding by OECD ONLY

Domain logical expression index: "d"

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

Domain logical expression index: "e"

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

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Alkali Earth OR Alkaline Earth OR Metalloids OR Transition Metals by Groups of elements

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Group 14 - Carbon C AND Group 15 - Nitrogen N AND Group 16 - Oxygen O AND Group 17 - Halogens Cl AND Group 17 - Halogens F,Cl,Br,I,At by Chemical elements

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Group 15 - Phosphorus P OR Group 16 - Sulfur S OR Group 17 - Halogens Br OR Group 17 - Halogens F OR Group 17 - Halogens I by Chemical elements

Domain logical expression index: "i"

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

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as 3-Methylcholantrene (Hepatotoxicity) Alert OR Aliphatic amines (Mucous membrane irritation) Rank C OR Aliphatic nitriles (Hepatotoxicity) Rank B OR Allyl esters (Hepatotoxicity) Rank A OR Chlorphentermine (Hepatotoxicity) Alert OR Dantrolene (Hepatotoxicity) Alert OR Fialuridine (Hepatotoxicity) Alert OR Oxyphenistain (Hepatotoxicity) Alert OR Perhexiline (Hepatotoxicity) Alert OR Valproic acid (Hepatotoxicity) Alert by Repeated dose (HESS)

Domain logical expression index: "k"

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: "l"

Referential boundary: The target chemical should be classified as Acid anhydrides OR Acyl halides OR Alkylalkanol-amines OR Aromatic amines OR Esters including acrylic and methacrylic esters OR Ethylenglycolethers OR Ketones OR Lactones OR Phenols OR Substituted benzoic acid halogenides by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "m"

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

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Direct acylation at a carbonyl with a leaving group OR Acylation >> Direct acylation at a carbonyl with a leaving group >> Acyl chlorides OR Acylation >> Direct acylation at a carbonyl with a leaving group >> Phenyl acetates by Respiratory sensitisation

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 AN2 OR AN2 >> Michael addition to activated double bonds in heterocyclic ring systems OR AN2 >> Michael addition to activated double bonds in heterocyclic ring systems >> Pyrazolone and Pyrazolidine Derivatives OR AN2 >> Michael type addition to activated double bond of pyrimidine bases OR AN2 >> Michael type addition to activated double bond of pyrimidine bases >> Pyrimidines and Purines OR AN2 >> Shiff base formation with carbonyl compounds OR AN2 >> Shiff base formation with carbonyl compounds >> Pyrazolone and Pyrazolidine Derivatives OR AN2 >> Shiff base formation with carbonyl group of pyrimidine or purine bases OR AN2 >> Shiff base formation with carbonyl group of pyrimidine or purine bases >> Pyrimidines and Purines OR SN2 OR SN2 >> Alkylation, nucleophilic subsitution at sp3-Carbon atom OR SN2 >> Alkylation, nucleophilic subsitution at sp3-Carbon atom >> Alpha-Activated Haloalkanes 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 Acyl halides AND H-acceptor-path3-H-acceptor by in vivo mutagenicity (Micronucleus) alerts by ISS

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as Aliphatic halogen OR Aliphatic N-nitro group OR Alkyl carbamate and thiocarbamate OR alpha,beta-unsaturated aliphatic alkoxy group OR alpha,beta-unsaturated carbonyls OR Aromatic N-acyl amine OR Hydrazine OR Nitro-aromatic OR N-methylol derivatives OR No alert found OR Polycyclic Aromatic Hydrocarbons by in vivo mutagenicity (Micronucleus) alerts by ISS

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as Inclusion rules not met by Eye irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "t"

Referential boundary: The target chemical should be classified as Aliphatic esters of chloro formic acid OR Pyrrolidones by Eye irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "u"

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: "v"

Referential boundary: The target chemical should be classified as Alkyl amide, urea, thiourea, nitroso urea, carbonate, guanidine and carbamate derivatives (21b1) OR Alkyl amide, urea, thiourea, nitroso urea, carbonate, guanidine and carbamate derivatives (21b1) >> Alkyl formamide analogs OR Alkyl amide, urea, thiourea, nitroso urea, carbonate, guanidine and carbamate derivatives (21b1) >> Alkylamide or thioamide analogs OR Allantoin and dimethadione-like derivatives (17b) OR Barbital and ETU, PLTU-like derivatives (17a) OR Di-substituted hydrocarbons (24a) OR Known precedent reproductive and developmental toxic potential OR Metal chelators 24 (d, e, f) OR Miscellaneous cyclic chemicals (18) OR Purine and pyrimidine-like derivatives (7b) OR Toluene and small alkyl toluene derivatives (8a) by DART scheme v.1.0

Domain logical expression index: "w"

Referential boundary: The target chemical should be classified as Very fast by Bioaccumulation - metabolism half-lives ONLY

Domain logical expression index: "x"

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: "y"

Referential boundary: The target chemical should be classified as High (Class III) by Toxic hazard classification by Cramer (with extensions) ONLY

Domain logical expression index: "z"

Referential boundary: The target chemical should be classified as Not calculated by Hydrolysis half-life (pH 6.5-7.4) ONLY

Domain logical expression index: "aa"

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

Domain logical expression index: "ab"

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

Domain logical expression index: "ac"

Referential boundary: The target chemical should be classified as weeks - months by Biodeg ultimate (Biowin 3) ONLY

Domain logical expression index: "ad"

Parametric boundary:The target chemical should have a value of log Kow which is >= -1.91

Domain logical expression index: "ae"

Parametric boundary:The target chemical should have a value of log Kow which is <= -1.1

Interpretation of results:

other: not irritating

Conclusions:

4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride (CAS No: 59703-00-3) was estimated to be not irritating to the skin of Vienna White rabbits.

Executive summary:

The dermal irritation potential of 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride (CAS No: 59703-00-3) was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor. 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride (CAS No: 59703-00-3) was estimated to be not irritating to the skin of Vienna White rabbits.

Based on the estimated result, 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride (CAS No: 59703-00-3) can be considered to be not irritating to skin and can be classified under the category "Not Classified" as per CLP regulation.

Endpoint conclusion:

no adverse effect observed (not irritating)

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 version 3.3 and the 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

Specific details on test material used for the study:

- Name of test material (as cited in study report): 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride
- Molecular formula: C7H9ClN2O3
- Molecular weight: 204.612 g/mol
- Substance type: Organic
- Physical state: Solid

Species:

rabbit

Strain:

Vienna White

Details on test animals or tissues and environmental conditions:

no data available

Vehicle:

unchanged (no vehicle)

Controls:

not specified

Amount / concentration applied:

0.05 mL

Duration of treatment / exposure:

24 hours

Observation period (in vivo):

8 days

Duration of post- treatment incubation (in vitro):

no data available

Number of animals or in vitro replicates:

2 rabbits

Details on study design:

no data available

Other effects / acceptance of results:

no data available

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

other: 8 days

Reversibility:

not specified

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

no irritation was observed.

Estimation method: Takes mode value from the 5 nearest neighbours
Domain logical expression:Result: In Domain

(((((((((("a" or "b" or "c" ) and ("d" and ( not "e") ) ) and "f" ) and ("g" and ( not "h") ) ) and "i" ) and ("j" and ( not "k") ) ) and "l" ) and ("m" and ( not "n") ) ) and ("o" and ( not "p") ) ) and ("q" and "r" ) )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Direct Addition of an Acyl Halide OR Acylation >> Direct Addition of an Acyl Halide >> Alkyl carbamyl halides OR SN1 OR SN1 >> Iminium Ion Formation OR SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines by DNA binding by OECD ONLY

Domain logical expression index: "b"

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 >> (Thio)Acyl and (thio)carbamoyl halides and cyanides OR Nucleophilic addition OR Nucleophilic addition >> Addition to carbon-hetero double bonds OR Nucleophilic addition >> Addition to carbon-hetero double bonds >> Ketones by Protein binding by OASIS v1.3 ONLY

Domain logical expression index: "c"

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 Acylation >> Direct Acylation Involving a Leaving group >> Acyl halides (including benzyl and carbamoyl deriv.) OR Acylation >> Direct Acylation Involving a Leaving group >> Dialkyl carbamoylhalides by Protein binding by OECD ONLY

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 >> 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 Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> DNA Intercalators with Carboxamide Side Chain OR Non-specific OR Non-specific >> Incorporation into DNA/RNA, due to structural analogy with nucleoside bases OR Non-specific >> Incorporation into DNA/RNA, due to structural analogy with nucleoside bases >> Specific Imine and Thione Derivatives OR Radical OR Radical >> Generation of reactive oxygen species OR Radical >> Generation of reactive oxygen species >> N,N-Dialkyldithiocarbamate Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Geminal Polyhaloalkane Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitro Azoarenes OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitroarenes with Other Active Groups 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 Radical >> Radical mechanism via ROS formation (indirect) >> Specific Imine and Thione Derivatives OR SN1 OR SN1 >> Alkylation after metabolically formed carbenium ion species OR SN1 >> Alkylation after metabolically formed carbenium ion species >> Polycyclic Aromatic Hydrocarbon Derivatives 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 >> Nitro Azoarenes 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 >> p-Substituted Mononitrobenzenes OR SN1 >> Nucleophilic substitution on diazonium ions OR SN1 >> Nucleophilic substitution on diazonium ions >> Specific Imine and Thione Derivatives 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 after metabolic activation OR SN2 >> Acylation involving a leaving group after metabolic activation >> Geminal Polyhaloalkane Derivatives OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation >> Polycyclic Aromatic Hydrocarbon Derivatives OR SN2 >> Alkylation, ring opening SN2 reaction OR SN2 >> Alkylation, ring opening SN2 reaction >> Four- and Five-Membered Lactones OR SN2 >> Direct acylation involving a leaving group OR SN2 >> Direct acylation involving a leaving group >> Acyl Halides OR SN2 >> DNA alkylation 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 >> 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 >> 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 Acylation AND Acylation >> Direct Addition of an Acyl Halide AND Acylation >> Direct Addition of an Acyl Halide >> Alkyl carbamyl halides AND SN1 AND SN1 >> Iminium Ion Formation AND SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines by DNA binding by OECD ONLY

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 by Estrogen Receptor Binding

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Acylation AND Acylation >> Direct Acylation Involving a Leaving group AND Acylation >> Direct Acylation Involving a Leaving group >> Acetates AND Acylation >> Direct Acylation Involving a Leaving group >> Acyl halides (including benzyl and carbamoyl deriv.) AND Acylation >> Direct Acylation Involving a Leaving group >> Dialkyl carbamoylhalides by Protein binding by OECD ONLY

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Inclusion rules not met by Eye irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Pyrrolidones by Eye irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "l"

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

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Stable form by Tautomers unstable

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Conjugated ketoamine(scy) - 1,5-H shift by Tautomers unstable

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Not categorized by US-EPA New Chemical Categories

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Aliphatic Amines OR Hindered Amines OR Imides (Acute toxicity) by US-EPA New Chemical Categories

Domain logical expression index: "q"

Parametric boundary:The target chemical should have a value of log Kow which is >= -2.37

Domain logical expression index: "r"

Parametric boundary:The target chemical should have a value of log Kow which is <= -0.388

Interpretation of results:

other: not irritating

Conclusions:

4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride (CAS No: 59703-00-3) was estimated to be not irritating to the eyes of Vienna White rabbits.

Executive summary:

The ocular irritation potential of 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride (CAS No: 59703-00-3) was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor.

4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride (CAS No: 59703-00-3) was estimated to be not irritating to the eyes of Vienna White rabbits.

Based on the estimated result, 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride (CAS No: 59703-00-3) can be considered to be not irritating to eye and can be classified under the category "Not Classified" as per CLP regulation.

Endpoint conclusion:

no adverse effect observed (not irritating)

Endpoint conclusion:

no study available

Skin Irritation:

In different studies, 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride has been investigated for potential for dermal irritation to a greater or lesser extent. The studies are based on in vivo experiments in rabbits along with predicted data for target chemical and its functionally similar read across substances 1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (CAS: 58-55-9) and 1,3 -bis(hydroxymethyl)-5,5-dimethylimidazolidine-2,4-dione (CAS: 6440-58-0). The predicted 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 for4-ethyl-2,3 -dioxopiperazine-1-carbonyl chloride. 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride was not irritating to Vienna White rabbit skin.

This result was supported by the study summarized in IUCLID Dataset,2000 for thefunctionally similar read across substance 1,3-dimethyl-3,7-dihydro-1H-purine-2,6 -dione (CAS: 58-55-9).The study was performed in accordance with OECD Guideline 404 "Acute Dermal Irritation/Corrosion". the rabbits were exposed to 500mg of 50% test chemical for 4 hours exposure period under semi-occlusive condition.

After 4 h, the application patches were removed, and the application sites were washed. Scoring was made at 4, 24, 48, and 72 hours after beginning of the study. Very slight reddening was observed in the 2 females at 4 hours. No other signs of irritation were noted. As the mean irritation index was 0.0, the test chemical Theophylline(CAS No:-58-55-9) was considered to be not irritating to the skin of White Vienna rabbits.

The above studies are also supported by the experimental study summarized in REPORTS of the Scientific Committee on Cosmetology (sixth series)- Commission of the European Communities ,Luxembourg; 1987, forthefunctionally similar read across substance 1,3-bis(hydroxymethyl)-5,5-dimethylimidazolidine-2,4-dione (CAS: 6440-58-0). 0.5 ml of test chemical was applied in to the intact or abraded skin of rabbits and later observed for any skin reactions. No known skin irritating effects were observed at this concentration. Hence the test chemical, 1,3 -Dimethylol-5,5-dimethylhydantoin(CAS No:-6440-58-0) was considered to be not irritating to the rabbits’ skin.

Based on the available data for the target and read across substances and applying the weight of evidence approach, 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride can be considered to be not irritating to skin.Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Not Classified”.

Eye Irritation:

In different studies, 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride has been investigated for potential for dermal irritation to a greater or lesser extent. The studies are based on in vivo experiments in rabbits along with predicted data for target chemical and its functionally similar read across substances 1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (CAS: 58-55-9); 1,3-bis(hydroxymethyl)-5,5-dimethylimidazolidine-2,4-dione (CAS: 6440-58-0) and structurally similar substance Diethylcarbamoyl chloride (CAS: 88-10-8). The predicted 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 4-ethyl-2,3 -dioxopiperazine-1-carbonyl chloride. 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride was not irritating to Vienna White rabbit eyes.

This result was supported by the study summarized in IUCLID Dataset,2000 for thefunctionally similar read across substance 1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (CAS: 58-55-9). The study was performed in accordance with OECD Guideline 405 "Acute Eye Irritation/Corrosion". The test substance was placed into the right conjunctival sac of each of 3 male White Vienna rabbits. The eyes were not rinsed. Scoring was made at 1, 24, 48, and 72 hours and at 8 days after instillation. Very slight corneal opacity was observed in 1-2 rabbits up to day 8. Slight to well-defined conjunctival redness and conjunctival swellings were observed in all 3 rabbits up to 72h and 48h, respectively. Mean irritation indices were 0.6 (corneal opacity), 0.0 (iritis), 1.8 (conjunctival redness), and 0.6 (conjunctival swelling).On day 8 one animal showed conjuctiva redness (grad 2) and slight cornea opacity (grad 1) and keratitis. The effects could possibly be due to mechanical irritation by the crystalline test substance. The iris was unaffected in each animal at each time. The findings were reversible in 2 of the 3 animals. The findings were reversible in 2 of the 3 animals. Hence the test chemical, Theophylline (CAS No:-58-55-9) was considered to be not irritating to the eyes of White Vienna rabbits.

The above are also supported by the experimental study summarized in GESTIS SUBSTANCE Database (information system in hazardous substance of the Berufsgenossenscheftn), 2017, for the structurally similar substance Diethylcarbamoyl chloride (CAS: 88-10-8). 0.5 ml of the test sample was installed into rabbits’ eyes caused severe irritation to the conjunctiva after 1 hour with formation of slight edema and delayed development of corneal opacity which was later reversible. As all the observed effects were reversible after 1 hour, the test chemical Diethylcarbamoyl chloride (CAS No:- 88-10-8 ) was considered to be not irritating to the rabbits’ eye.

These results are further supported by the experimental study summarized in REPORTS of the Scientific Committee on Cosmetology (sixth series)- Commission of the European Communities ,Luxembourg; 1987, forthefunctionally similar read across substance 1,3-bis(hydroxymethyl)-5,5-dimethylimidazolidine-2,4-dione (CAS: 6440-58-0). 1% of 1,3-bis(hydroxymethyl)-5,5-dimethylimidazolidine-2,4-dione was instilled in to rabbit eyes and observed for any ocular changes. Since the chemical did not induce any adverse effects at 1% concentration, the test chemical1,3-Dimethylol-5,5-dimethylhydantoin(CAS No:-6440-58-0) was considered to be not irritating to the rabbits’ eye.

Based on the available data for the target and read across substances and applying the weight of evidence approach, 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride can be considered to be not irritating to eyes.Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Not Classified”.

Available studies for4-ethyl-2,3-dioxopiperazine-1-carbonyl chloridesuggest that it is not irritating to eyes and skin. Hence,4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride can be classified under the category “Not Classified” as per CLP regulation.