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

Toxicity to aquatic algae and cyanobacteria

Link to relevant study record(s)

Reference

Endpoint:

toxicity to aquatic algae and cyanobacteria

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:

The supporting QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: as mentioned below

Principles of method if other than guideline:

The data is predicted using the OECD QSAR toolbox version 3.3 with logKow as the primary descriptor.

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 (if other than submission substance): C7H9ClN2O3
- Molecular weight (if other than submission substance): 204.612 g/mol
- Smiles notation (if other than submission substance): N1(C(C(=O)N(CC1)CC)=O)C(=O)Cl
- InChI: 1S/C7H9ClN2O3/c1-2-9-3-4-10(7(8)13)6(12)5(9)11/h2-4H2,1H3
- Substance type: Organic
- Physical state: Solid

Analytical monitoring:

not specified

Vehicle:

not specified

Test organisms (species):

Raphidocelis subcapitata (previous names: Pseudokirchneriella subcapitata, Selenastrum capricornutum)

Test type:

static

Water media type:

freshwater

Total exposure duration:

72 h

Key result

Duration:

72 h

Dose descriptor:

EC50

Effect conc.:

260.183 mg/L

Nominal / measured:

estimated

Conc. based on:

test mat.

Basis for effect:

growth rate

The prediction was based on dataset comprised from the following descriptors: EC50
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 "h" )  and ("i" and ( not "j") )  )  and "k" )  and "l" )  and ("m" and ( not "n") )  )  and ("o" and ( not "p") )  )  and "q" )  and ("r" and "s" )  )

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 >> 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 >> DNA Intercalators with Carboxamide Side Chain OR Radical OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitroarenes with Other Active Groups 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 reduction and nitrenium ion formation OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitroarenes with Other Active Groups OR SN2 OR SN2 >> Acylation OR SN2 >> Acylation >> Specific Acetate Esters 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 acting epoxides formed after metabolic activation 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 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Specific Acetate Esters 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 Class 5 (Not possible to classify according to these rules) by Acute aquatic toxicity classification by Verhaar (Modified) ONLY

Domain logical expression index: "h"

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

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Not possible to classify according to these rules (GSH) by Protein binding potency

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Moderately reactive (GSH) OR Moderately reactive (GSH) >> 2-Vinyl carboxamides (MA) by Protein binding potency

Domain logical expression index: "k"

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

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 Halogens AND Non-Metals by Groups of elements

Domain logical expression index: "n"

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

Domain logical expression index: "o"

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: "p"

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

Domain logical expression index: "q"

Similarity boundary:Target: CCN1CCN(C(=O)Cl)C(=O)C1=O
Threshold=20%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "r"

Parametric boundary:The target chemical should have a value of log Kow which is >= -2.98

Domain logical expression index: "s"

Parametric boundary:The target chemical should have a value of log Kow which is <= 0.183

Validity criteria fulfilled:

not specified

Conclusions:

The median Effective concentration (EC50) value for 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride on Pseudokirchneriella subcapitata in a 72 hour study was estimated to be 260 mg/L on the basis of effects on growth rate.

Executive summary:

Based on the prediction done using the OECD QSAR toolbox version 3.3 with log kow as the primary descriptor and considering the five closest read across substances, the short term toxicity on aquatic algae and cyanobacteria was predicted for target substance 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride (CAS no. 59703 -00 -3). EC50 value was estimated to be 260 mg/l for Pseudokirchneriella subcapitata for 72 h duration. Based on this value it can be concluded that the substance 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride is considered to be non-toxic to aquatic environment and can be considered to be not classified as per the CLP classification criteria.

Description of key information

Based on the prediction done using the OECD QSAR toolbox version 3.3 with log kow as the primary descriptor and considering the five closest read across substances, the short term toxicity on aquatic algae and cyanobacteria was predicted for target substance 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride (CAS no. 59703 -00 -3) (2017). EC50 value was estimated to be 260 mg/l for Pseudokirchneriella subcapitata for 72 h duration. Based on this value it can be concluded that the substance 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride is considered to be non-toxic to aquatic environment and can be considered to be not classified as per the CLP classification criteria.

Key value for chemical safety assessment

EC50 for freshwater algae:

260 mg/L

Additional information

2 predicted data for the target chemical 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride (CAS no. 59703-00-3) which is supported further by total 2 weight of evidence studies (from secondary source) for its closest read across substance with logKow as the primary descriptor were reviewed for the toxicity to aquatic algae and cyanobacteria end point which are summarized as below:

 

Short term toxicity on aquatic algae and cyanobacteria of target chemical 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride (CAS no. 59703-00-3), was predicted using the OECD QSAR toolbox version 3.3 with log kow as the primary descriptor and considering the five closest read across substances (2017). EC50 value was estimated to be 260 mg/l for Pseudokirchneriella subcapitata for 72 h duration. Based on this value it can be concluded that the substance 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride is considered to be non-toxic to aquatic environment and can be considered to be not classified as per the CLP classification criteria.

 

In another prediction done using the EPI Suite ECOSAR version 1.10 (2017), short term toxicity on green algae was predicted for test substance 4 -ethyl-2,3 -dioxopiperazine-1 -carbonyl chloride (CAS: 59703 -00 -3). On the basis of effects observed in a static freshwater system, the effect concentration EC50 value for the substance is estimated to be 18098.6 mg/l for green algae for 96 hr duration. Based on this value, it can be concluded that the test chemical 4 -ethyl-2,3 -dioxopiperazine-1 -carbonyl chloride can be considered as non-toxic to green algae at environmentally relevant concentrations and can be considered to be not classified as per the CLP classification criteria.

 

In a supporting weight of evidence study of read across chemical 2 -(2 -Dimethylaminoethoxy)ethanol (CAS no. 1704-62-7) from OECD SIDS (2014), short term toxicity to Pseudokirchnerella subcapitata (algae) study was carried out for 72 hrs. The study was based on the effects of the test compound 2 -(2 -Dimethylaminoethoxy)ethanol on Pseudokirchnerella subcapitata in a static fresh water system. The 72hr-EC50 and NOEC values of 2 -(2 -Dimethylaminoethoxy)ethanol to Pseudokirchnerella subcapitata was determined as 160 and 40 mg/L for growth rate and 72 hr EC50 value was determined to be 73 mg/L for area under growth curve, respectively. Thus, based on EC50 value (160 mg/l), it can be concluded that the substance 2 -(2 -Dimethylaminoethoxy)ethanol can be considered as non-toxic to aquatic organisms and thus cannot be classified as hazardous as per the CLP classification criteria.

 

Another short term toxicity study to Selenastrum capricornutum (algae) of read across substance N-phenylacetamide (CAS no. 103 -84 -4) was carried out for 72 hrs (OECD SIDS, 2001). The study was performed according to OECD TG 201 Guideline, “Alga, Growth Inhibition Test”. The study was based on the effects of the test compound N-phenylacetamide on Selenastrum capricornutum in a static fresh water system at a temperature of 22 -24°C. Stock solution was prepared with OECD medium and sterilized through 0.45 μm acrodisc filter. Test chemical conc. used for the study were 3, 6, 13, 25, 50, 100 mg/l (nominal conc.) and 4, 8, 18, 29, 58, 105 mg/l (measured conc.), respectively.Selenastrum capricornutumATCC 22662 was used as test organism obtained from American Type Culture Collection and subcutured at the testing facility. Test was carried out in an100 ml Erlenmeyer flask at a temperature range of 22 -24°C and light intensity of 8,220 - 8,312 Lux, continuous, respectively. Standard OECD medium was used as growth medium. Non-linear regression analysis was employed to determine EC50 by Comprehensive Toxicity Data Analysis and Database Software (Version 5.0). For the determination of NOEC, Dennett’s test was used (p < 0.05). Cell density in control increased by 120 times at the termination of experiment (72 hr). Based on the effect on biomass of test organismSelenastrum capricornutum, the 72 hr EC50 and NOEC value for chemical N-phenylacetamide was determined to be 13.5 and < 4 mg/l, respectively. Thus, based on EC50 value, it can be concluded that the substance N-phenylacetamide can be considered as toxic to aquatic organisms. Since the chemical is readily biodegradable in nature, chemical N-phenylacetamide can be considered as non-toxic to aquatic organisms and thus cannot be classified as hazardous as per the CLP classification criteria.

 

Thus, based on the overall reported results for target chemical 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride (from OECD QSAR toolbox 3.3 and EPI suite, 2017) and for its read across substance (from secondary source OECD SIDS), it can be concluded that the test substance 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride can be considered as non-toxic to aquatic environment and can be considered to be not classified as per the CLP classification criteria.