2-methylcyclohexanone

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Study period:

13/04/2021

Reliability:

1 (reliable without restriction)

Data source

Reference

Reference Type:

other company data

Title:

Unnamed

Year:

2021

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: RAAF framework (ECHA, 2017)

Version / remarks:

Final

Deviations:

no

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

2-methylcyclohexanone

EC Number:

209-513-6

EC Name:

2-methylcyclohexanone

Cas Number:

583-60-8

Molecular formula:

C7H12O

IUPAC Name:

2-methylcyclohexan-1-one

Test material form:

liquid

Details on test material:

As received, undiluted, the sample was observed to be a free-flowing
clear liquid.

Results and discussion

Main ADME results

Type:

absorption

Results:

High GI absorption

Toxicokinetic / pharmacokinetic studies

Details on absorption:

High

Details on distribution in tissues:

Can permeate the blood-brain barrier (BBB).

Metabolite characterisation studies

Metabolites identified:

yes

Remarks:

Three metabolites identified: 5‐hydroxy‐2‐methylcyclohexan‐1‐one, 2‐hydroxy‐2‐methylcyclohexan‐1‐one, 2‐methylcyclohexan‐1‐ol.

Details on metabolites:

All three metabolites do not fire any alert for DNA binding nor for protein binding, meaning that they are not likely to interact with DNA nor with proteins.
All three metabolites are not categorized by the Repeated Dose Toxicity HESS Profiler, meaning that they do not belong to any category expected to induce toxicological effects in repeated dose oral toxicity.

Enzymatic activity

Enzymatic activity measured:

Does not interact with cytochromes P450 (CYP), meaning that they are not likely to cause significant drug interactions through inhibition of CYPs.

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:

0.55

Applicant's summary and conclusion

Conclusions:

Both the target 2-methylcyclohexanone and the source cyclohexanone have a high gastrointestinal absorption, meaning that they are readily absorbed following oral exposure.
Both the target 2-methylcyclohexanone and the source cyclohexanone can permeate the blood-brain barrier (BBB).
Both the target 2-methylcyclohexanone and the source cyclohexanone are not substrate of the
permeability glycoprotein.
Both the target 2-methylcyclohexanone and the source cyclohexanone do not interact with
cytochromes P450 (CYP), meaning that they are not likely to cause significant drug interactions through inhibition of CYPs.
Both the target 2-methylcyclohexanone and the source cyclohexanone meet the Lipinski rule-of-five.
Both the target 2-methylcyclohexanone and the source cyclohexanone have similar bioavailability
scores.

Executive summary:

A read-across study was performed for the target substance 2-methylcyclohexanone where the ADME data was assessed as a part of it. For this read-across study, initially, the search for suitable analogues with experimental data on repeated dose toxicity was conducted. One substance (cyclohexanone) was selected as source chemical for the target, 2-methylcyclohexanone (one-to-one read-across). The target and the source compounds are mono-constituent substances. The read-across hypothesis was sustained by the assessment of similarity in terms of structural, mechanistic (toxicophore), physico-chemical, pharmacokinetics/ADME, metabolic similarity. Such assessment showed that the cyclohexanone (source compound) is appropriately structurally similar to the 2-methylcyclohexanone (target) to justify a read-across approach. The identified structural difference, i.e. methyl group in the target, is not expected to significantly impact the toxicity of the two chemicals. The target 2-methylcyclohexanone and the source cyclohexanone exhibit high mechanistic similarity: they do not fire any alert for DNA binding nor for protein binding, meaning that they are not likely to interact with DNA nor with proteins; they are both assigned to Cramer class II, and they are both not categorized by the Repeated Dose Toxicity HESS Profiler, meaning that they do not belong to any category expected to induce toxicological effects in repeated dose oral toxicity. From the physicochemical and reactivity perspective, only minimal variations are observed not expected to affect their toxicity.

 

The target and the source show very similar pharmacokinetic and ADME (absorption, distribution, metabolism, and excretion) profiles: they have a high gastrointestinal absorption; they can permeate the blood-brain barrier (BBB); they are not substrate of the permeability glycoprotein and they do not interact with cytochromes P450 (CYP). In addition, the target and the source share
the same “drug-likeness” profile.

Finally, the two compounds are characterized by moderate similarity in terms of their potential metabolites: the predicted and experimentally identified metabolites do not raise elements of potential concern for their toxicity.Thus, the pharmacokinetics and ADME similarity analysis leads to the conclusion that target 2-methylcyclohexanone and the source cyclohexanone exhibit very similar pharmacokinetics and ADME profiles.

 

Two major conclusions are the following:

Thus, the pharmacokinetics and ADME similarity analysis leads to the conclusion that target 2-methylcyclohexanone and the source cyclohexanone exhibit very similar pharmacokinetics and ADME profiles.

Thus, the comparison of potential metabolic products highlights that the target 2-methylcyclohexanone and the source cyclohexanone exhibit moderate similarity in terms of their potential metabolites. In addition, the predicted and experimentally identified metabolites do not raise elements of potential concern.