2-ethylhexyl 4-(dimethylamino)benzoate

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:

2-ethylhexyl 4-(dimethylamino)benzoate

EC Number:

244-289-3

EC Name:

2-ethylhexyl 4-(dimethylamino)benzoate

Cas Number:

21245-02-3

Molecular formula:

C17H27NO2

IUPAC Name:

2-ethylhexyl 4-(dimethylamino)benzoate

Specific details on test material used for the study:

SMILE : O=C(OCC(CCCC)CC)c(ccc(N(C)C)c1)c1

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

Intestinal absorption (human): 96.46 %

Main ADME results 2

Type:

distribution

Results:

VDss (human) (log L/kg): 0.341

Main ADME results 3

Type:

distribution

Results:

Fraction unbound (human) : 0.097

Main ADME results 4

Type:

distribution

Results:

BBB permeability (log BB): 0.512

Main ADME results 5

Type:

distribution

Results:

CNS permeability (log PS): -2.022

Main ADME results 6

Type:

excretion

Results:

Renal OCT2 substrate: no

Main ADME results 7

Type:

excretion

Results:

Total Clearance (log ml/min/kg): 0.97

Toxicokinetic / pharmacokinetic studies

Details on absorption:

According to the model "Intestinal absorption (human)", 96 % 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)", 9.7% of the absorbed dose is unbound in the plasma.
According to the model "BBB permeability", the substance is cross readily 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 9.3 ml/min/kg (log(ml/min/kg) 0.97) corresponding to a low clearance.

Metabolite characterisation studies

Metabolites identified:

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. Moreover, a low total clearance is expected.