4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride

Endpoint summary

Description of key information

LD50 was estimated to be 3727 mg/kg bw when rats were orally exposed with 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride.

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: as below

Principles of method if other than guideline:

Prediction is done using QSAR Toolbox version 3.3

GLP compliance:

not specified

Test type:

other: No data

Limit test:

no

Specific details on test material used for the study:

- Name of the test material: 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride
- IUPAC name: 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride
- Molecular Formula: C7H9ClN2O3
- Molecular Weight: 204.612 g/mol
- Substance type: Organic
- Smiles: N1(C(C(=O)N(CC1)CC)=O)C(=O)Cl

Species:

rat

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

No data

Route of administration:

oral: unspecified

Vehicle:

not specified

Details on oral exposure:

No data

Doses:

3727 mg/kg bw

No. of animals per sex per dose:

No data

Control animals:

not specified

Details on study design:

No data

Statistics:

No data

Preliminary study:

No data

Sex:

not specified

Dose descriptor:

LD50

Effect level:

3 727 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 50 % mortality observed

Mortality:

No data

Clinical signs:

other: No data

Gross pathology:

No data

Other findings:

No data

The prediction was based on dataset comprised from the following descriptors: LD50
Estimation method: Takes average 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 ( not "j") )  )  and ("k" and ( not "l") )  )  and "m" )  and ("n" and ( not "o") )  )  and ("p" and ( not "q") )  )  and "r" )  and ("s" and ( not "t") )  )  and ("u" and ( not "v") )  )  and ("w" and ( not "x") )  )  and ("y" and "z" )  )

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 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 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 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) >> Coumarins 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, nucleophilic substitution at sp3-carbon atom 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 >> 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 at an activated carbon atom OR SN2 >> SN2 at an activated carbon atom >> Quinoline 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 Not known precedent reproductive and developmental toxic potential by DART scheme v.1.0

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as ARA inhibitors, Candesartan-like chemicals (5c-3) OR ARA inhibitors, Candesartan-like chemicals (5c-3) >> Candesartan-like ARA inhibitors OR Barbital and ETU, PLTU-like derivatives (17a) OR Imidazole derivatives (13a) OR Known precedent reproductive and developmental toxic potential OR Purine and pyrimidine-like derivatives (7b) by DART scheme v.1.0

Domain logical expression index: "k"

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: "l"

Referential boundary: The target chemical should be classified as Alkyl carbamate and thiocarbamate OR alpha,beta-unsaturated carbonyls OR Hydrazine OR N-methylol derivatives OR No alert found by in vivo mutagenicity (Micronucleus) alerts by ISS

Domain logical expression index: "m"

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

Domain logical expression index: "n"

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

Domain logical expression index: "o"

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

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 AND Group 17 - Halogens Cl AND Group 17 - Halogens F,Cl,Br,I,At by Chemical elements

Domain logical expression index: "q"

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

Domain logical expression index: "r"

Similarity boundary:Target: CCN1CCN(C(=O)Cl)C(=O)C1=O
Threshold=10%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "s"

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

Domain logical expression index: "t"

Referential boundary: The target chemical should be classified as Aliphatic amines (Mucous membrane irritation) Rank C by Repeated dose (HESS)

Domain logical expression index: "u"

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: "v"

Referential boundary: The target chemical should be classified as Low reactive OR Low reactive >> N-substituted aromatic amides by DPRA Cysteine peptide depletion

Domain logical expression index: "w"

Referential boundary: The target chemical should be classified as No Data by Ultimate biodeg

Domain logical expression index: "x"

Referential boundary: The target chemical should be classified as > 100 days OR 1 to 10 days OR 10 to 100 days by Ultimate biodeg

Domain logical expression index: "y"

Parametric boundary:The target chemical should have a value of log Kow which is >= -2.39

Domain logical expression index: "z"

Parametric boundary:The target chemical should have a value of log Kow which is <= -0.348

Interpretation of results:

Category 5 based on GHS criteria

Conclusions:

LD50 was estimated to be 3727 mg/kg bw when rats were orally exposed with 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloridehas.

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 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloridehas. The LD50 was estimated to be 3727 mg/kg bw when rats were orally exposed with 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloridehas.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

3 727 mg/kg bw

Quality of whole database:

Data is Kilmisch 2 and from OECD QSAR toolbox

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Acute oral toxicity:

In different studies, 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride as been investigated for acute oral toxicity to a greater or lesser extent. Often are the studies based on in vivo experiments and estimated data in rodents, i.e. most commonly in rats for 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride along with the study available on structurally similar read across 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 acute oral toxicity was estimated for 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride. The LD50 was estimated to be 3727 mg/kg bw when rats were orally exposed with 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride.

In another prediction done by using Danish QSAR (2017), the acute oral toxicity was estimated for 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride. The LD50 was estimated to be 2400 mg/kg bw when rats were orally exposed with 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride.

Also it is further supported experimental data conducted by Dupont chem (Scientific associates, OTS0571246, report number: 8EHQ-1092-11308, October 15. 1992) on 50-60% structurally similar read across substance Diethylcarbamoyl chloride (CAS: 88-10-8), Sprague Dawlay male and female rats were treated with Diethylcarbamoyl chloride undiluted in the concentration of 2000, 2350, 2600 and 2900 mg/kg bw orally by gavage. All the five female rats were died at 2900 mg/kg bw. Half of deaths occurred in 30 minutes to two hours while the other occurred in 24 to 72 hours. 1 male and 1 female rat died at 2600 mg/kg bw, 1 male rat died at 2350 mg/kg bw and No mortality were observed in treated male and female rats at 2000 mg/kg bw. Muscular in coordination, lethargy, convulsions and coma were observed in died rats. Moderately severe diarrhea was observed in all surviving rats. Decreased in 8 to 15 % body weight was observed in treated rats. In addition, Alteration In Gastric Secretion, severally irritant intestinal mucosa, abnormally dark liver and greenish colure spleen was observed in treated rats. Hemorrhogic area in Liver and congestion of tubule in kidney were observed in treated rats. Therefore, LD50 was estimated to 2700 mg/kg bw when Sprague Dawlay male and female rats were treated with Diethylcarbamoyl chloride orally by gavage.

Thus, based on the above studies and predictions on 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride and its read across substances, it can be concluded that LD50 value is greater than 2000 mg/kg bw. Thus comparing this value with the criteria of CLP regulation, 4-methylphenyl acetate can be ‘Not classified’ for acute oral toxicity.

Justification for classification or non-classification

Thus, based on the above studies and predictions on 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride and its read across substances, it can be concluded that LD50 value is greater than 2000 mg/kg bw. Thus comparing this value with the criteria of CLP regulation, 4-methylphenyl acetate can be ‘Not classified’ for acute oral toxicity.