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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics, other
Remarks:
Predicted metabolism
Type of information:
(Q)SAR
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a (Q)SAR model, with limited documentation / justification
Remarks:
Simulated metabolism data from ECETOC recommended Metaprint2D-React tool (ALL metabolite model: 2010.2).
Justification for type of information:
Refer to the section 13 for details on the read across justification. The metabolism study with the substance is considered sufficient to fulfil the information requirements as further explained in the provided endpoint summary.
QSAR prediction from an ECHA acknowledged metabolism model. Although no domain definition has been specified in the tool, only the most frequently reported site of metabolism (with 0.66 <= NOR <= 1.00) as per the metabolite database of MetaPrint2D tool has been considered. For more details refer to the attached background material (Type of transformation reactions + structure of metabolites).

Data source

Reference
Reference Type:
other: software
Title:
MetaPrint2D-React: Predict metabolic transformations, and likely metabolites formed (experimental)
Author:
MetaPrint2D-React
Year:
2013
Bibliographic source:
MetaPrint2D-React, metabolic product predictor, Unilever centre for molecular science informatics, University of Cambridge

Materials and methods

Objective of study:
metabolism
Test guideline
Qualifier:
no guideline required
Principles of method if other than guideline:
MetaPrint2D-React is a tool that predicts xenobiotic metabolism through data-mining and statistical analysis of known metabolic transformations reported in scientific literature. It can make predictions concerning a wider range of reactions, and is able to predict the types of transformation that can take place at ease site of metabolism, and the likely metabolite formed. The modelling was conducted for the test substance, quaternary ammonium compounds, (C16-18 and C18-unsatd. alkyl) trimethyl, chlorides (i.e., tallow alkyl trimethyl ammonium chloride) using the SMILES notation as the input parameter.

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Specific details on test material used for the study:
- Name of test material: Quaternary ammonium compounds, (C16-18 and C18-unsatd. alkyl) trimethyl, chlorides (i.e., tallow alkyl trimethyl ammonium chloride) (CAS 68002-61-9)
- Smiles notation: C(=CCCCCCCCCN(C)(C)(C)Cl)CCCCCCCC (i.e., corresponding to the C16-18 chain length of the test substance)

Results and discussion

Main ADME resultsopen allclose all
Type:
other: Simulated metabolism (phase-I metabolism with (0.66 <= NOR <= 1.00)
Results:
As per the MetaPrint2D tool the reactions occurring at the terminal two carbon atoms of the longer alkyl chain are: reduction (at single or double bond), epoxidation, epoxidation/hydrolysis, hydroxylation/tautomerization, tautomerization and hydration.
Type:
other: Simulated metabolism (phase-I metabolism with (0.33 <= NOR < 0.66)
Results:
As per the MetaPrint2D tool the reactions occurring at the two adjacent carbons on either side of the unsaturation are: oxidation (including oxidation at di ketone group), alkylation, methylation and demethylation.
Type:
other: Simulated metabolism common to both the above mentioned sites
Results:
As per the MetaPrint2D tool the common reactions occurring at the above mentioned sites are: hydroxylation, oxidation at (=O-OH), single and double bonds, at ketone) and dealkylation.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
The most frequently reported site of phase-I metabolism (with 0.66 <= NOR <= 1.00) for C16-18 and C18-unsatd. TMAC as per the metabolite database of MetaPrint2D tool at the terminal two carbon atoms of the longer alkyl chain were: reduction (at single or double bond), epoxidation, epoxidation/hydrolysis, hydroxylation/tautomerization, tautomerization and hydration reactions.

Metabolism transformation reactions with (0.33 <= NOR < 0.66) for C16-18 and C18-unsatd. TMAC as per the metabolite database of MetaPrint2D tool at the two adjacent carbons on either side of the unsaturation were: oxidation (including oxidation at di ketone group), alkylation, methylation and demethylation.

Metabolism transformation reactions occuring at both the above mentioned sites were: hydroxylation, oxidation at (=O-OH), single and double bonds, at ketone) and dealkylation.

Refer to attached background material for details (types of transformation reactions and metabolites).

Any other information on results incl. tables

Refer to the attached background material for details.

Applicant's summary and conclusion

Conclusions:
The most frequently reported site of metabolism for C16-18 and C18-unsatd. TMAC as per the metabolite database of MetaPrint2D tool is at the terminal two carbon atoms of the longer alkyl chain along with the two adjacent carbons on either side of the unsaturation are. The transformation reactions at these two sites include different types of phase-I metabolism reactions (including oxidation, hydroxylation, alkylation, methylation, demethylation, dealkylation, acylation), conjugation reactions (i.e., glutathionation), epoxidation, epoxidation/hydrolysis, hydroxylation/tautomerization, tautomerization and hydration reactions
Executive summary:

The most likely site of metabolism and the metabolites of the test substance, C16-C18 and C18-unsatd. TMAC, were predicted using ECETOC recommended Metaprint2D-React tool (ALL metabolite model: 2010.2). The SMILES were used as the input parameters. The most frequently reported site of phase-I metabolism occurs at the terminal two carbon atoms of the longer alkyl chain (reduction (at single or double bond), epoxidation, epoxidation/hydrolysis, hydroxylation/tautomerization, tautomerization and hydration reactions). Metabolism transformation reactions occur at the two adjacent carbons on either side of the unsaturation (oxidation including oxidation at di ketone group, alkylation, methylation, glutathionation and demethylation). Metabolism transformation reactions occuring at both the above mentioned sites were hydroxylation, oxidation (including carboxylation, ketonization, unsaturation) and dealkylation, alkylation, methylation, demethylation, dealkylation and conjugation i.e., glutathionation reactions.