Registration Dossier

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
Test material form:
liquid
Specific details on test material used for the study:
SMILES:
C(C)N(O)CC

Results and discussion

Main ADME resultsopen allclose all
Type:
absorption
Results:
Intestinal absorption (human): 92.784%
Type:
distribution
Results:
VDss (human) (log L/kg): 0.242
Type:
distribution
Results:
Fraction unbound (human) : 0.382
Type:
distribution
Results:
BBB permeability (log BB): 0.571
Type:
distribution
Results:
CNS permeability (log PS): -3.485
Type:
excretion
Results:
Total Clearance (log ml/min/kg): 1.602
Type:
excretion
Results:
Renal OCT2 substrate: no

Any other information on results incl. tables

Property

Model Name

Predicted Value

Unit

Absorption

Water solubility

-0.005

Numeric (log mol/L)

Absorption

Caco2 permeability

1.469

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

Absorption

Intestinal absorption (human)

100

Numeric (% Absorbed)

Absorption

Skin Permeability

-2.866

Numeric (log Kp)

Absorption

P-glycoprotein substrate

Yes

Categorical (Yes/No)

Absorption

P-glycoprotein I inhibitor

No

Categorical (Yes/No)

Absorption

P-glycoprotein II inhibitor

No

Categorical (Yes/No)

Distribution

VDss (human)

-0.102

Numeric (log L/kg)

Distribution

Fraction unbound (human)

0.751

Numeric (Fu)

Distribution

BBB permeability

0.053

Numeric (log BB)

Distribution

CNS permeability

-2.859

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

0.522

Numeric (log ml/min/kg)

Excretion

Renal OCT2 substrate

No

Categorical (Yes/No)

Toxicity

AMES toxicity

No

Categorical (Yes/No)

Toxicity

Max. tolerated dose (human)

1.133

Numeric (log mg/kg/day)

Toxicity

hERG I inhibitor

No

Categorical (Yes/No)

Toxicity

hERG II inhibitor

No

Categorical (Yes/No)

Toxicity

Oral Rat Acute Toxicity (LD50)

2.384

Numeric (mol/kg)

Toxicity

Oral Rat Chronic Toxicity (LOAEL)

1.466

Numeric (log mg/kg_bw/day)

Toxicity

Hepatotoxicity

No

Categorical (Yes/No)

Toxicity

Skin Sensitisation

No

Categorical (Yes/No)

Toxicity

T.Pyriformistoxicity

-0.937

Numeric (log ug/L)

Toxicity

Minnow toxicity

2.611

Numeric (log mM)

 

Applicant's summary and conclusion