Propane-2-thiol

Basic toxicokinetics

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

Data source

Reference

Reference 1

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 2

Reference Type:

other: web site

Title:

Unnamed

Year:

2018

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

other: REACH Guidance on QSARs R.6

Test guideline 2

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

Principles of method if other than guideline:

pkCSM uses graph-based signatures to develop predictive models of central ADMET properties. pkCSM performs as well or better than current methods.

Test material

Specific details on test material used for the study:

Propane-2-thiol: CC(S)C
Propane-1-thiol: CCCCS
Butane-1-thiol: CCCCS
Butane-2-thiol: C(C(C)S)C
2-Methylpropane-2-thiol: CC(C)(C)S

Results and discussion

Any other information on results incl. tables

Property	Model Name	Predicted Value					Unit
		propane-2-thiol	Propane-1-thiol	Butane-1-thiol	Butane-2-thiol	2-Methyl propane-2-thiol
Absorption	Water solubility	-1.105	-1.025	-1.618	-1.355	-1.659	Numeric (log mol/L)
Absorption	Caco2 permeability	1.401	1.385	1.384	1.393	1.406	Numeric (log Papp in 10^-6cm/s)
Absorption	Intestinal absorption (human)	93.44	93.406	92.559	93.235	92.624	Numeric (% Absorbed)
Absorption	Skin Permeability	-2.167	-2.156	-1.837	-2.109	-1.92	Numeric (log Kp)
Absorption	P-glycoprotein substrate	Yes	Yes	Yes	Yes	Yes	Categorical (Yes/No)
Absorption	P-glycoprotein I inhibitor	No	No	No	No	No	Categorical (Yes/No)
Absorption	P-glycoprotein II inhibitor	No	No	No	No	No	Categorical (Yes/No)
Distribution	VDss (human)	0.033	0.062	0.121	0.081	0.066	Numeric (log L/kg)
Distribution	Fraction unbound (human)	0.657	0.68	0.629	0.654	0.603	Numeric (Fu)
Distribution	BBB permeability	0.064	0.11	0.638	0.226	0.601	Numeric (log BB)
Distribution	CNS permeability	-2.08	-2.307	-2.226	-2.356	-1.946	Numeric (log PS)
Metabolism	CYP2D6 substrate	No	No	No	No	No	Categorical (Yes/No)
Metabolism	CYP3A4 substrate	No	No	No	No	No	Categorical (Yes/No)
Metabolism	CYP1A2 inhibitior	No	No	No	No	No	Categorical (Yes/No)
Metabolism	CYP2C19 inhibitior	No	No	No	No	No	Categorical (Yes/No)
Metabolism	CYP2C9 inhibitior	No	No	No	No	No	Categorical (Yes/No)
Metabolism	CYP2D6 inhibitior	No	No	No	No	No	Categorical (Yes/No)
Metabolism	CYP3A4 inhibitior	No	No	No	No	No	Categorical (Yes/No)
Excretion	Total Clearance	0.281	0.232	0.273	0.282	0.351	Numeric (log ml/min/kg)
Excretion	Renal OCT2 substrate	No	No	No	No	No	Categorical (Yes/No)

Applicant's summary and conclusion

Executive summary:

The evaluation of propane-2-thiol, propane-1-thiol, butane-1-thiol, butane-2-thiol and 2-methyl propane-2-thiol in the pkCSM method for predicting small-molecule absorption, distribution, metabolism, and excretion (ADME) properties does not show any significant differences. For all substances, the intestinal absorption (human) is estimated to be high (> 90%), the skin absorption to be low , the steady state distribution volumes are of the same order, the fraction unbound to serum proteins are all above 0.6, none of the substances are substrate or/and inhibitor of cyt P450 metabolism and the total clearence values range between 0.23 and 0.35.