3,3,5-trimethylcyclohexyl acrylate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Remarks:

in silico

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 adequate and reliable documentation / justification

Justification for type of information:

See enclosed files

Data source

Reference

Reference 1

Reference Type:

publication

Title:

pkCSM: predicting small-molecule pharmacokinetic properties using graph-based signatures

Author:

Pires DEV, Blundell TL and Ascher DB

Year:

2015

Bibliographic source:

Journal of Medicinal Chemistry, 58 (9):4066–4072

Reference 2

Reference Type:

other: web site

Title:

Unnamed

Year:

2018

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

other: REACH Guidance on QSARs R.6

Test guideline 2

Qualifier:

according to guideline

Guideline:

other: REACH Guidance on IR&CSA, Chapter R.14, Occupational exposure assessment Update to change the scope of the guidance from exposure estimation to exposure assessment

Version / remarks:

August 2016

Principles of method if other than guideline:

pkCSM uses graph-based signatures to develop predictive models of central ADME properties. pkCSM performs as well or better than current methods.

Test material

Test material information

Constituent 1

Reference substance name:

3,3,5-trimethylcyclohexyl acrylate

EC Number:

289-200-9

EC Name:

3,3,5-trimethylcyclohexyl acrylate

Cas Number:

86178-38-3

Molecular formula:

C12H20O2

IUPAC Name:

3,3,5-trimethylcyclohexyl prop-2-enoate

Specific details on test material used for the study:

SMILES:C=CC(=O)OC1CC(CC(C1)C)(C)C

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

Intestinal absorption (human): 96.281%

Main ADME results 2

Type:

distribution

Results:

VDss (human) (log L/kg): 0.165

Main ADME results 3

Type:

distribution

Results:

Fraction unbound (human) : 0.482

Main ADME results 4

Type:

distribution

Results:

BBB permeability (log BB): 0.523

Main ADME results 5

Type:

distribution

Results:

CNS permeability (log PS): -2.686

Main ADME results 6

Type:

excretion

Results:

Renal OCT2 substrate: no

Main ADME results 7

Type:

excretion

Results:

Total Clearance (log ml/min/kg): 1.191

Toxicokinetic / pharmacokinetic studies

Details on absorption:

According to the model "Intestinal absorption (human)", 96.281% of the substance is absorbed after oral exposure.

Details on distribution in tissues:

According to the model "VDss (human)", the volume of distribution (VD, i.e. theoritical volume that the total dose of a drug would need to be uniformly distributed to give the same concentration as in blood plasma) is moderate (Log between -0.15 and 0.45).
According to the model "Fraction unbound (human)", 48.2% of the absorbed dose is unbound in the plasma.
According to the model "BBB permeability", the substance is readily cross the blood-brain barrier (Log BB > 0.3).
According to the model "CNS permeability", it is not possible to predict if the substance is unable or not to penetrate the CNS (-3

Details on excretion:

According to the model "Renal OCT2 substrate", the substance is not a OCT2 substrate. The substance is not transported by this renal transporter.
According to the model "Total clearance" , the predicted total clearance (hepatic & renal clearance) is of 15 ml/min/kg (log(ml/min/kg) 1.191) corresponding to the high clearance (between 14 and 30 ml/min/kg).

Metabolite characterisation studies

Metabolites identified:

no

Any other information on results incl. tables

Property	Model Name	Predicted Value	Unit
Absorption	Water solubility	-2.73	Numeric (log mol/L)
Absorption	Caco2 permeability	1.657	Numeric (log Papp in 10^-6cm/s)
Absorption	Intestinal absorption (human)	96.281	Numeric (% Absorbed)
Absorption	Skin Permeability	-2.313	Numeric (log Kp)
Absorption	P-glycoprotein substrate	No	Categorical (Yes/No)
Absorption	P-glycoprotein I inhibitor	No	Categorical (Yes/No)
Absorption	P-glycoprotein II inhibitor	No	Categorical (Yes/No)
Distribution	VDss (human)	0.165	Numeric (log L/kg)
Distribution	Fraction unbound (human)	0.482	Numeric (Fu)
Distribution	BBB permeability	0.523	Numeric (log BB)
Distribution	CNS permeability	-2.686	Numeric (log PS)
Metabolism	CYP2D6 substrate	No	Categorical (Yes/No)
Metabolism	CYP3A4 substrate	No	Categorical (Yes/No)
Metabolism	CYP1A2 inhibitior	No	Categorical (Yes/No)
Metabolism	CYP2C19 inhibitior	No	Categorical (Yes/No)
Metabolism	CYP2C9 inhibitior	No	Categorical (Yes/No)
Metabolism	CYP2D6 inhibitior	No	Categorical (Yes/No)
Metabolism	CYP3A4 inhibitior	No	Categorical (Yes/No)
Excretion	Total Clearance	1.191	Numeric (log ml/min/kg)
Excretion	Renal OCT2 substrate	No	Categorical (Yes/No)

Applicant's summary and conclusion

Conclusions:

According to the QSAR pkCSM, the substance is well absorbed by oral route, and well distributed into the body including in the CNS. Moreover, a high total clearance is expected.