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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics, other
Remarks:
in silico
Type of information:
(Q)SAR
Adequacy of study:
other information
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

Referenceopen allclose all

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 Type:
other: web site
Title:
Unnamed
Year:
2018

Materials and methods

Objective of study:
absorption
distribution
excretion
metabolism
Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
other: REACH Guidance on QSARs R.6
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

Constituent 1
Chemical structure
Reference substance name:
Dibenzylbenzene, ar-methyl derivative
EC Number:
258-649-2
EC Name:
Dibenzylbenzene, ar-methyl derivative
Cas Number:
53585-53-8
Molecular formula:
C21H20
IUPAC Name:
dibenzylbenzene, ar-methyl derivative
Test material form:
liquid
Specific details on test material used for the study:
SMILES:
Cc1cc(Cc2ccccc2)ccc1Cc1ccccc1 : 1,4-dibenzyl-2-methylbenzene
Cc1cccc(Cc2ccccc2)c1Cc1ccccc1 : 1,2-dibenzyl-3-methylbenzene
Cc1c(Cc2ccccc2)cccc1Cc1ccccc1 : 1,3-dibenzyl-2-methylbenzene
Cc1ccc(Cc2ccccc2)cc1Cc1ccccc1 : 1,3-dibenzyl-4-methylbenzene
Cc1ccc(Cc2ccccc2)c(Cc2ccccc2)c1 : 1,2-dibenzyl-4-methylbenzene
Cc1cc(Cc2ccccc2)cc(Cc2ccccc2)c1 : 1,3-dibenzyl-3-methylbenzene

Results and discussion

Main ADME resultsopen allclose all
Type:
absorption
Results:
Intestinal absorption (human): 97%
Type:
distribution
Results:
VDss (human) (log L/kg): 0.426
Type:
distribution
Results:
Fraction unbound (human) : 0.102
Type:
distribution
Results:
BBB permeability (log BB): 0.906
Type:
distribution
Results:
CNS permeability (log PS): -0.998
Type:
excretion
Results:
Total Clearance (log ml/min/kg): 0.176
Type:
excretion
Results:
Renal OCT2 substrate: no

Any other information on results incl. tables

 

1,4-dibenzyl-2-methylbenzene

1,2-dibenzyl-3-methylbenzene

1,3-dibenzyl-2-methylbenzene

1,3-dibenzyl-4-methylbenzene

1,2-dibenzyl-4-methylbenzene

1,3-dibenzyl-3-methylbenzene

Dibenzyl toluene

 

 

 

 

 

Cc1cc(Cc2ccccc2)ccc1Cc1ccccc1

Cc1cccc(Cc2ccccc2)c1Cc1ccccc1

Cc1c(Cc2ccccc2)cccc1Cc1ccccc1

Cc1ccc(Cc2ccccc2)cc1Cc1ccccc1

Cc1ccc(Cc2ccccc2)c(Cc2ccccc2)c1

Cc1cc(Cc2ccccc2)cc(Cc2ccccc2)c1

 

 

Model Name

Predicted Value

Predicted Value

Predicted Value

Predicted Value

Predicted Value

Predicted Value

Mean predicted value

Unit

Absorption

 

 

 

 

 

 

 

 

Water solubility

-6.817

-6.729

-6.773

-6.809

-6.73

-6.801

-6.777

Numeric (log mol/L)

Caco2 permeability

1.466

1.62

1.485

1.489

1.753

1.634

1.575

Numeric (log Papp in 10-6cm/s)

Intestinal absorption (human)

97.364

98.101

97.956

97.262

97.435

97.31

97.571

Numeric (% Absorbed)

Skin Permeability

-2.711

-2.718

-2.714

-2.712

-2.707

-2.706

-2.711

Numeric (log Kp)

P-glycoprotein substrate

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Categorical (Yes/No)

P-glycoprotein I inhibitor

No

No

No

No

No

No

No

Categorical (Yes/No)

P-glycoprotein II inhibitor

No

No

No

No

No

No

No

Categorical (Yes/No)

Distribution

 

 

 

 

 

 

 

 

VDss (human)

0.46

0.392

0.433

0.432

0.401

0.439

0.426

Numeric (log L/kg)

Fraction unbound (human)

0.106

0.112

0.113

0.103

0.088

0.089

0.102

Numeric (Fu)

BBB permeability

0.925

0.912

0.941

0.922

0.853

0.88

0.906

Numeric (log BB)

CNS permeability

-0.995

-1.032

-1.018

-0.985

-0.981

-0.977

-0.998

Numeric (log PS)

Metabolism

 

 

 

 

 

 

 

 

CYP2D6 substrate

No

No

No

No

No

No

No

Categorical (Yes/No)

CYP3A4 substrate

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Categorical (Yes/No)

CYP1A2 inhibitior

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Categorical (Yes/No)

CYP2C19 inhibitior

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Categorical (Yes/No)

CYP2C9 inhibitior

No

Yes

No

No

No

No

Inconclusive

Categorical (Yes/No)

CYP2D6 inhibitior

No

No

No

No

No

No

No

Categorical (Yes/No)

CYP3A4 inhibitior

No

No

No

No

No

No

No

Categorical (Yes/No)

Excretion

 

 

 

 

 

 

 

 

Total Clearance

0.175

0.19

0.168

0.179

0.185

0.16

0.176

Numeric (log ml/min/kg)

Renal OCT2 substrate

No

No

No

No

No

No

No

Categorical (Yes/No)

Applicant's summary and conclusion