di-tert-butyl (2S,3E)-3-[(dimethylamino)methylene]-4-oxopyrrolidine-1,2-dicarboxylate

Genetic toxicity: in vivo

Administrative data

Endpoint:

in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus

Remarks:

Type of genotoxicity: chromosome aberration

Type of information:

(Q)SAR

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Justification for type of information:

QSAR prediction: migrated from IUCLID 5.6

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Report date:

2015

Materials and methods

Principles of method if other than guideline:

Genotoxicity as micronucleus in vivo on rodent predictions were generated employing three predictors: ACD/Percepta, Leadscope Model Applier and Toxtree decision rule system.

GLP compliance:

no

Type of assay:

micronucleus assay

Test material

Test material information

Constituent 1

Reference substance name:

di-tert-butyl (2S,3E)-3-[(dimethylamino)methylene]-4-oxopyrrolidine-1,2-dicarboxylate

EC Number:

942-146-6

Cas Number:

166410-06-6

Molecular formula:

C17H28N2O5

IUPAC Name:

di-tert-butyl (2S,3E)-3-[(dimethylamino)methylene]-4-oxopyrrolidine-1,2-dicarboxylate

Test animals

Species:

other: rodent

Results and discussion

Any other information on results incl. tables

 

Name	ACD/Percepta	Leadscope	Toxtree	Consensus prediction
di-tert-butyl (2S,3E)-3-[(dimethylamino)methylidene]-4-oxopyrrolidine-1,2-dicarboxylate	OUT OF THE DOMAIN	NEGATIVE (Borderline reliable)	POSITIVE (Borderline reliable )	POSITIVE (Borderline reliable)

             

Leadscope FDA Model Applier prediction for micronucleus in vivo on rodent resulted to be NEGATIVE, since the positive prediction probability was equal to 0.13. Since 22 features were found, it was concluded that di-tert-butyl (2S,3E)-3-[(dimethylamino)methylidene]-4-oxopyrrolidine-1,2-dicarboxylate is represented by the model. Additionally, the identified features are mainly represented in negative training compounds. The robustness of the prediction was further evaluated by examining compounds similar to the di-tert-butyl (2S,3E)-3-[(dimethylamino)methylidene]-4-oxopyrrolidine-1,2-dicarboxylate from the training set. Only one compound was identified in the training set as analogues to di-tert-butyl (2S,3E)-3-[(dimethylamino)methylidene]-4-oxopyrrolidine-1,2-dicarboxylate (similarity > 30%), but characterized by little similarity (similarity = 0.32). Based on that, Leadscope prediction was assessed as borderline reliable.

Toxtree identified in the target di-tert-butyl (2S,3E)-3-[(dimethylamino)methylidene]-4-oxopyrrolidine-1,2-dicarboxylate three structural alerts: the α,β unsaturated carbonyl alert, the alkyl carbamate and thiocarbamate alert and the H-acceptor-path3-H-acceptor structural alert. Compounds with an α,β -unsaturated carbonyl are bis-electrophiles reactive molecules that may interact with electron-rich biological macromolecules. Because of conjugation with the carbonyl group, the B-carbon is positively polarized and becomes the preferred site of nucleophilic attack, as is in a classic Michael type addition. In spite of a common structural feature, alpha,beta-unsaturated carbonyl compounds can undergo different interactions with DNA, which lead to different genotoxic and mutagenic responses. Among the class of alkyl carbamate and thiocarbamate compounds, the most studied and representative molecule is urethane (ethyl carbamate). It has been accepted that urethane metabolism occurs via two major pathways, one being a detoxification pathway, the second being a bioactivation pathway, entails oxidative metabolism of urethane catalyzed by cytochromes P450, leading to the formation of vinyl carbamate and subsequently vinyl carbamate epoxide. Concerning the H-acceptorpath3- H-acceptor alert, it explores the possibility that a chemical interacts with DNA and/or proteins via non-covalent binding, such as DNA intercalation or groove-binding. Among the descriptors potentially accounting for non-covalent interactions, the molecular framework representing two bonded atoms connecting two H bond acceptors (calculated with software Leadscope Enteprise 2.4.15-6) resulted in an increased sensitivity/specificity for what concerns the Micronucleus training set.

However, it has to be highlighted that the three identified alerts are characterized by little percentage of true positive. Based on that the prediction was assessed as borderline reliable.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): positive borderline reliability
ACD/Percepta prediction resulted to be out of the domain. The borderline reliable Leadscope and Toxtree predictions were not in agreement: based on a precautionary approach, it was concluded that the target di-tert-butyl (2S,3E)-3-[(dimethylamino)methylidene]-4-oxopyrrolidine-1,2-dicarboxylate is predicted as POSITIVE for micronucleus in vivo on rodent. The prediction was considered of borderline reliability.