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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:
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

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:
other: REACH Guidance on QSARs R.6
Qualifier:
according to
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

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid
Specific details on test material used for the study:
SMILES:
Cc1ccccc1Cc1ccccc1 : Benzene, 1-methyl-2-(phenylmethyl)-
Cc1ccc(Cc2ccccc2)cc1 : Benzene, 1-methyl-4-(phenylmethyl)-
Cc1cccc(Cc2ccccc2)c1 : Benzene, 1-methyl-3-(phenylmethyl)-

Results and discussion

Main ADME resultsopen allclose all
Type:
absorption
Results:
Intestinal absorption (human): 96%
Type:
distribution
Results:
VDss (human) (log L/kg): 0.714
Type:
distribution
Results:
Fraction unbound (human) : 0.042
Type:
distribution
Results:
BBB permeability (log BB): 0.642
Type:
distribution
Results:
CNS permeability (log PS): -1.258
Type:
excretion
Results:
Total Clearance (log ml/min/kg): 0.197
Type:
excretion
Results:
Renal OCT2 substrate: no

Any other information on results incl. tables

 

Benzene, 1-methyl-2-(phenylmethyl)-

Benzene, 1-methyl-4-(phenylmethyl)-

Benzene, 1-methyl-3-(phenylmethyl)-

Benzyl toluene

 

 

 

 

 

Cc1ccccc1Cc1ccccc1

Cc1ccc(Cc2ccccc2)cc1

Cc1cccc(Cc2ccccc2)c1

 

 

Model Name

Predicted Value

Predicted Value

Predicted Value

Mean predicted value

Unit

Absorption

 

 

 

 

 

Water solubility

-4.774

-4.695

-4.695

-4.721

Numeric (log mol/L)

Caco2 permeability

1.503

1.51

1.646

1.553

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

Intestinal absorption (human)

96.25

96.078

96.33

96.219

Numeric (% Absorbed)

Skin Permeability

-1.995

-1.959

-1.947

-1.967

Numeric (log Kp)

P-glycoprotein substrate

Yes

No

Yes

Inconclusive

Categorical (Yes/No)

P-glycoprotein I inhibitor

No

No

No

No

Categorical (Yes/No)

P-glycoprotein II inhibitor

No

No

No

No

Categorical (Yes/No)

Distribution

 

 

 

 

 

VDss (human)

0.756

0.692

0.695

0.714

Numeric (log L/kg)

Fraction unbound (human)

0.042

0.048

0.035

0.042

Numeric (Fu)

BBB permeability

0.657

0.649

0.621

0.642

Numeric (log BB)

CNS permeability

-1.267

-1.246

-1.261

-1.258

Numeric (log PS)

Metabolism

 

 

 

 

 

CYP2D6 substrate

No

No

No

No

Categorical (Yes/No)

CYP3A4 substrate

Yes

Yes

Yes

Yes

Categorical (Yes/No)

CYP1A2 inhibitior

Yes

Yes

Yes

Yes

Categorical (Yes/No)

CYP2C19 inhibitior

Yes

Yes

Yes

Yes

Categorical (Yes/No)

CYP2C9 inhibitior

Yes

Yes

Yes

Yes

Categorical (Yes/No)

CYP2D6 inhibitior

No

No

No

No

Categorical (Yes/No)

CYP3A4 inhibitior

No

No

No

No

Categorical (Yes/No)

Excretion

 

 

 

 

 

Total Clearance

0.204

0.19

0.198

0.197

Numeric (log ml/min/kg)

Renal OCT2 substrate

No

No

No

No

Categorical (Yes/No)

Applicant's summary and conclusion