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

Endpoint summary

Description of key information

The skin sensitization potential of 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride(59703-00-3) was estimated by using OECD QSAR toolbox v3.3 with log kow as the primary descriptor and considering the six closest read across substances. 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride (59703-00-3) was predicted to be not sensitizing to the skin of female and male Hartley guinea pig.

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 version 3.3 and the QMRF report has been attached

Qualifier:

according to guideline

Guideline:

OECD Guideline 406 (Skin Sensitisation)

Principles of method if other than guideline:

Prediction is done by using OECD QSAR toolboxv.3.3

GLP compliance:

not specified

Type of study:

Buehler test

Justification for non-LLNA method:

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:

guinea pig

Strain:

Hartley

Sex:

male/female

Details on test animals and environmental conditions:

No data available

Route:

epicutaneous, occlusive

Vehicle:

other: Mineral oil

Concentration / amount:

75%

Day(s)/duration:

3week

Route:

epicutaneous, open

Vehicle:

other: Mineral oil

Concentration / amount:

75%

Day(s)/duration:

48 hour

No. of animals per dose:

10 animals

Details on study design:

MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: 3
- Exposure period: The test substance was applied once per week until a total of 3 induction applications had been made.
- Concentrations: 75%

B. CHALLENGE EXPOSURE
- No. of exposures: 1
- Day(s) of challenge: Challenge performed 13 days after last induction application
- Concentrations: 75%
- Evaluation (hr after challenge): 24 and 48

Challenge controls:

No data available.

Positive control substance(s):

yes

Remarks:

1-chloro-2, 4- dinitrobenzene (DNCB)

Statistics:

No data available.

Reading:

2nd reading

Hours after challenge:

48

Group:

test chemical

Dose level:

75%

No. with + reactions:

0

Total no. in group:

10

Clinical observations:

No skin sensitization reaction observed.

Remarks on result:

no indication of skin sensitisation

The prediction was based on dataset comprised from the following descriptors: "S M W N"
Estimation method: Takes highest mode value from the 6 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 ( not "m") )  )  and ("n" and ( not "o") )  )  and ("p" and "q" )  )

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 >> Coumarins 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) >> Coumarins OR SN1 OR SN1 >> Nucleophilic attack after carbenium ion formation OR SN1 >> Nucleophilic attack after carbenium ion formation >> Specific Acetate Esters OR SN2 OR SN2 >> Acylation OR SN2 >> Acylation >> Specific Acetate Esters 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 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Specific Acetate Esters 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 Not possible to classify according to these rules by DPRA Cysteine peptide depletion

Domain logical expression index: "h"

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

Domain logical expression index: "i"

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

Domain logical expression index: "j"

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

Domain logical expression index: "k"

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

Domain logical expression index: "l"

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

Domain logical expression index: "m"

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

Domain logical expression index: "n"

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: "o"

Referential boundary: The target chemical should be classified as Alkylalkanol-amines OR Quaternary organic ammonium compounds by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "p"

Parametric boundary:The target chemical should have a value of log Kow which is >= -3.02

Domain logical expression index: "q"

Parametric boundary:The target chemical should have a value of log Kow which is <= 2.33

Interpretation of results:

other: Negative

Conclusions:

The skin sensitization potential of 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride(59703-00-3) was estimated by using OECD QSAR toolbox v3.3 with log kow as the primary descriptor and considering the six closest read across substances. 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride (59703-00-3) was predicted to be not sensitizing to the skin of female and male Hartley guinea pig.

Executive summary:

The skin sensitization potential of 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride(59703-00-3) was estimated by using OECD QSAR toolbox v3.3 with log kow as the primary descriptor and considering the six closest read across substances. 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride (59703-00-3)  was predicted to be not sensitizing to the skin of female  and male Hartley guinea pig.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

Skin sensitization

In different studies, 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride(59703-00-3) has been investigated for potential for dermal sensitization to a greater or lesser extent. The prediction is based on in vivo experiments in guinea pig for target chemical 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride(59703-00-3) and in vivo experiments in human for its structurally similar read across substancesTriethanolamine (102 -17 -6). The predicted data using the OECD QSAR toolbox have also been compared with the experimental data of read across.

The skin sensitization potential of 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride(59703-00-3) was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor and considering the six closest read across substances. 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride (59703-00-3) was predicted to be not sensitizing to the skin of female and male Hartley guinea pig.

Further supported by experimental data conducted by SIDS Initial Assessment Report, SIAM 3 (SIDS Initial Assessment Report for SIAM 3, 1995) on structurally similar read across substance Triethanolamine (102 -17 -6)in humans. The read across substances share high similarity in structure and log kow .Therefore, it is acceptable to derive information on skin sensitization from the analogue substance. The skin sensitization study of Triethanolamine (102 -17 -6) was performed by repeated insult patch test in 64 human volunteers. By using 0.1% Triethanolamine. In induction phase, repeated patch applications was done using 0.1% test substance for 24hr per application at upper arm of the volunteers for 3 times per week for 3 weeks . After 14 days rest period, challenge application of 0.1% test substance was applied on opposite arm of the subject. Evaluation was performed after 48hr and 96hr.No evidence of sensitivity was noted. Hence it is considered that Triethanolamine(102 -17 -6) was not skin sensitizing in human .

Thus based on the above predictions on4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride(59703-00-3) as well as its read across substances and applying weight of evidence, it can be concluded that4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride(59703-00-3)  is not a skin sensitizer. Thus comparing the above annotations with the criteria of CLP regulation, 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride(59703-00-3)can be considered as not classified for skin sensitization effects.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Thus comparing the above annotations with the criteria of CLP regulation, 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride(59703-00-3)can be considered as not classified for skin sensitization effects.