Di-tert-pentyl peroxide

Additional toxicological data

Administrative data

Endpoint:

additional toxicological information

Type of information:

(Q)SAR

Adequacy of study:

other information

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

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

Type of study / information:

Absorption, distribution, metabolism, and excretion (ADME) and toxicity properties

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

Version / remarks:

August 2016

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:

di-tert-amyl peroxide (DTA): CCC(C)(C)OOC(C)(C)CC
di-tert-butyl peroxide (DTB): CC(C)(C)OOC(C)(C)C

Results and discussion

Any other information on results incl. tables

Property	Model Name	Predicted Value DTA	Predicted Value DTB	Unit
Absorption	Water solubility	-2.609	-2.576	Numeric (log mol/L)
Absorption	Caco2 permeability	1.592	1.371	Numeric (log Papp in 10^-6cm/s)
Absorption	Intestinal absorption (human)	94.66	95.32	Numeric (% Absorbed)
Absorption	Skin Permeability	-2.095	-1.6	Numeric (log Kp)
Absorption	P-glycoprotein substrate	No	No	Categorical (Yes/No)
Absorption	P-glycoprotein I inhibitor	No	No	Categorical (Yes/No)
Absorption	P-glycoprotein II inhibitor	No	No	Categorical (Yes/No)
Distribution	VDss (human)	0.087	-0.103	Numeric (log L/kg)
Distribution	Fraction unbound (human)	0.536	0.403	Numeric (Fu)
Distribution	BBB permeability	0.519	0.583	Numeric (log BB)
Distribution	CNS permeability	-2.796	-1.506	Numeric (log PS)
Metabolism	CYP2D6 substrate	No	No	Categorical (Yes/No)
Metabolism	CYP3A4 substrate	No	No	Categorical (Yes/No)
Metabolism	CYP1A2 inhibitior	No	No	Categorical (Yes/No)
Metabolism	CYP2C19 inhibitior	No	No	Categorical (Yes/No)
Metabolism	CYP2C9 inhibitior	No	No	Categorical (Yes/No)
Metabolism	CYP2D6 inhibitior	No	No	Categorical (Yes/No)
Metabolism	CYP3A4 inhibitior	No	No	Categorical (Yes/No)
Excretion	Total Clearance	1.605	1.22	Numeric (log ml/min/kg)
Excretion	Renal OCT2 substrate	No	No	Categorical (Yes/No)
Toxicity	AMES toxicity	No	No	Categorical (Yes/No)
Toxicity	Max. tolerated dose (human)	0.812	0.935	Numeric (log mg/kg/day)
Toxicity	hERG I inhibitor	No	No	Categorical (Yes/No)
Toxicity	hERG II inhibitor	No	No	Categorical (Yes/No)
Toxicity	Oral Rat Acute Toxicity (LD50)	2.088	1.715	Numeric (mol/kg)
Toxicity	Oral Rat Chronic Toxicity (LOAEL)	2.237	2.306	Numeric (log mg/kg_bw/day)
Toxicity	Hepatotoxicity	No	No	Categorical (Yes/No)
Toxicity	Skin Sensitisation	Yes	Yes	Categorical (Yes/No)
Toxicity	T.Pyriformis toxicity	0.715	0.333	Numeric (log ug/L)
Toxicity	Minnow toxicity	1.054	1.006	Numeric (log mM

Applicant's summary and conclusion

Executive summary:

The evaluation of DTA and DTB in the pkCSM method for predicting small-molecule pharmacokinetic and toxicity properties does not show any significant differences in the absorption, distribution, metabolism, and excretion (ADME) and toxicity properties.