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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:
Bis(piperidinothiocarbonyl) hexasulphide
EC Number:
213-537-2
EC Name:
Bis(piperidinothiocarbonyl) hexasulphide
Cas Number:
971-15-3
Molecular formula:
C12H20N2S8
IUPAC Name:
1,1'-(hexasulfane-1,6-diyldicarbonothioyl)dipiperidine
Specific details on test material used for the study:
SMILES: N(C(=S)SSSSSSC(N(CCCC1)C1)=S)(CCCC2)C2

Results and discussion

Main ADME resultsopen allclose all
Type:
absorption
Results:
Intestinal absorption (human): 80.802%
Type:
distribution
Results:
VDss (human) (log L/kg): 0.372
Type:
distribution
Results:
Fraction unbound (human) : 0.313
Type:
distribution
Results:
BBB permeability (log BB): 1.138
Type:
distribution
Results:
CNS permeability (log PS): -4.105
Type:
excretion
Results:
Renal OCT2 substrate: no
Type:
excretion
Results:
Total Clearance (log ml/min/kg): -0.532

Toxicokinetic / pharmacokinetic studies

Details on absorption:
According to the model "Intestinal absorption (human)", 80.8% 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)", 31.3% of the absorbed dose is unbound in the plasma.
According to the model "BBB permeability", the substance is readily cross the blood-brain barrier (Log BB > 0.3).
According to the model "CNS permeability",the substance is unable to penetrate the CNS (log PS <-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 0.29 ml/min/kg (log(ml/min/kg) -0,532) corresponding to the very low clearance (below 6 ml/min/kg).

Metabolite characterisation studies

Metabolites identified:
no

Any other information on results incl. tables

Property

Model Name

Predicted Value

Unit

Absorption

Water solubility

-6.675

Numeric (log mol/L)

Absorption

Caco2 permeability

1.092

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

Absorption

Intestinal absorption (human)

80.802

Numeric (% Absorbed)

Absorption

Skin Permeability

-2.605

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)

0.372

Numeric (log L/kg)

Distribution

Fraction unbound (human)

0.313

Numeric (Fu)

Distribution

BBB permeability

1.138

Numeric (log BB)

Distribution

CNS permeability

-4.105

Numeric (log PS)

Metabolism

CYP2D6 substrate

No

Categorical (Yes/No)

Metabolism

CYP3A4 substrate

YES

Categorical (Yes/No)

Metabolism

CYP1A2 inhibitior

YES

Categorical (Yes/No)

Metabolism

CYP2C19 inhibitior

YES

Categorical (Yes/No)

Metabolism

CYP2C9 inhibitior

YES

Categorical (Yes/No)

Metabolism

CYP2D6 inhibitior

No

Categorical (Yes/No)

Metabolism

CYP3A4 inhibitior

No

Categorical (Yes/No)

Excretion

Total Clearance

-0.532

Numeric (log ml/min/kg)

Excretion

Renal OCT2 substrate

No

Categorical (Yes/No)

Applicant's summary and conclusion

Conclusions:
According to the QSAR pkCSM, the substance is well absorbed by oral route (80.8%), and well distributed into the body. Moreover, no hepatic and renal clearance is expected.