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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
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:
1,3-di-o-tolylguanidine
EC Number:
202-577-6
EC Name:
1,3-di-o-tolylguanidine
Cas Number:
97-39-2
Molecular formula:
C15H17N3
IUPAC Name:
1,3-di-o-tolylguanidine
Specific details on test material used for the study:
SMILES: N=C(Nc(c(ccc1)C)c1)Nc(c(ccc2)C)c2

Results and discussion

Main ADME resultsopen allclose all
Type:
absorption
Results:
Intestinal absorption (human): 84.7%
Type:
distribution
Results:
VDss (human) (log L/kg): 2.227
Type:
distribution
Results:
Fraction unbound (human) : 0.354
Type:
distribution
Results:
BBB permeability (log BB): 0.258
Type:
distribution
Results:
CNS permeability (log PS): -0.922
Type:
excretion
Results:
Renal OCT2 substrate: yes
Type:
excretion
Results:
Total Clearance (log ml/min/kg): 0.802

Toxicokinetic / pharmacokinetic studies

Details on absorption:
According to the model "Intestinal absorption (human)", 84.7% 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 high (Log >> 0.45).
According to the model "Fraction unbound (human)", 35.4% of the absorbed dose is unbound in the plasma.
According to the model "BBB permeability", the substance is able moderately to cross the blood-brain barrier (Log BB between -1 and 0.3).
According to the model "CNS permeability",the substance is able to penetrate the CNS (log PS > -2).
Details on excretion:
According to the model "Renal OCT2 substrate", the substance is a OCT2 substrate. The substance is transported by this renal transporter.
According to the model "Total clearance" , the predicted total clearance (hepatic & renal clearance) is of 6.34 ml/min/kg (log(ml/min/kg) 0.802) corresponding to a moderate clearance (between 6 and 14 ml/min/kg).

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 (84.7%), well distributed into the body including the the brain, and probably excreted in the urines.