Di-tert-pentyl peroxide

Endpoint summary

Description of key information

There is no experimental absorption, distribution, metabolism and excretion (ADME) data on DTA.

Absorption and Distribution

Oral route

Oral absorption is favoured for molecular weights below 500 g/mol. Based on the high log Kow of 4.7, DTA can be regarded as lipophilic substance. Such lipophilic compound may be taken up by micellular solubilisation. This mechanism may be of particular importance, as the substances are only slightly soluble and would otherwise be poorly absorbed. DTA showed adverse effects at 1000 mg/kg bw/day in repeated dose toxicity studies when administered in corn oil. Therefore it can be assumed that at least some absorption across the gastrointestinal tract occurs when administered in repeated dosages. DTA is not expected to hydrolyse in water.

Using a model to predict either high or low fraction absorbed for an orally administered, passively transported substance, the rates of absorption were 100 and 90% for a dose of 1 and 1000 mg of DTA, respectively (Danish QSAR database).

As well, high absorption rates were also predicted with the pkCSM method (ca. 95%) (Pires et al., 2015) and the ADMETlab platform (70-90%) (Dongsheng Cao et al., 2018).

Inhalation exposure

Based on the relatively high vapour pressure of DTA, inhalation exposure is likely. If the substance reaches the lung, they may be absorbed by micellular solubilisation.

Dermal exposure

Based on physical-chemical properties of DTA, the substance is not likely to penetrate skin to a large extent as the high log Kow value and low water solubility do not favour dermal penetration. Between water solubility of 1-100 mg/l absorption is anticipated to be low to moderate. For substances with a log Kow between 4 and 6, the rate of penetration is limited by the rate of transfer between the stratum corneum and the epidermis. Only the uptake into the stratum corneum will be high.

The dermal absorption rates of DTA was estimated with IH SkinPerm v2.04 model (AIHA, 2018). Compared to in vitro data from OECD 428 studies, IH skinPerm allowed the estimation of the dermal absorption rate with a good confidence and a low frequency (ca. 2%) of underestimation for liquids (Arkema’s internal validation study, 2018). According to the data input, IH SkinPerm v2.04 model leads to the following results according to the input data:

Fraction absorbed (%)*	Instantaneous deposition	Deposition over time
Di-tert-pentyl peroxide	0.7	1.24

*End time observation 8 hr

The skin absorption is therefore very limited.

Distribution

When reaching the body, DTA may be distributed into cells due to their lipophilic properties and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues.

The pkCSM (Pires et al., 2015) and the ADMETlab platforms (Dongsheng Cao et al., 2018) allow to predict some parameters related to distribution.

 

Parameters	Predicted Value DTA	Interpretation
pkCSM
Steady state volume of distribution (VDss human) (log L/kg)	0.087	VDss is considered low if below 0.71 L/kg (log VDss < -0.15) and high if above 2.81 L/kg (log VDss > 0.45
Fraction unboundto serum proteins (human) (Fu)	0.536	the predicted fraction that would be unbound in plasma is calculated
Blood Brain Barrier (BBB) permeability (log BB)	0.519	a logBB > 0.3 is considered to readily cross the blood-brain barrier
CNS permeability(blood-brain permeability- surface area product, log PS)	-2.796	Compounds with a logPS > -2 are considered to penetrate the CNS, while those with logPS < -3 are considered as unable to penetrate the CNS
ADMETlab
PPB (Plasma Protein Binding)	65.363 %	Significant with drugs that are highly protein-bound and have a low therapeutic index.
VD (Volume Distribution)	0.16 L/kg	Optimal: 0.04-20L/kg; Range: <0.07L/kg: Confined to blood, Bound to plasma protein or highly hydrophilic; 0.07-0.7L/kg: Evenly distributed; >0.7L/kg: Bound to tissue components (e.g., protein, lipid),highly lipophilic.
BBB (Blood–Brain Barrier)	+++ (0.986)	BB ratio >=0.1: BBB+; BB ratio <0.1: BBB- These features tend to improve BBB permeation: H-bonds (total) < 8–10; MW < 400–500; No acids.

  

Metabolism

There is no metabolism data on DTA, but it is thought that DTA will be enzymatically hydrolysed to tert-amyl alcohol (TAA). In this case, excretion would probably occur in urine.

In silico cytochrome P450 metabolism

Cytochrome P450s play a fundamental role in the oxidative metabolism of xenobiotics. The reactivity of DTA with cytP450 was evaluated in three models available online.

The evaluation of DTA in the pkCSM method (Pires et al., 2015) for predicting small-molecule pharmacokinetic and toxicity properties does not show any inhibitor effects in the cytochrome P450 metabolism. 

Model Name	Predicted Value DTA	Unit
CYP2D6 substrate	No	Categorical (Yes/No)
CYP3A4 substrate	No	Categorical (Yes/No)
CYP1A2 inhibitor	No	Categorical (Yes/No)
CYP2C19 inhibitor	No	Categorical (Yes/No)
CYP2C9 inhibitor	No	Categorical (Yes/No)
CYP2D6 inhibitor	No	Categorical (Yes/No)
CYP3A4 inhibitor	No	Categorical (Yes/No)

 

As well, no interactions with cytochrome P450 metabolism were predicted with the ADMETlab platform (Dongsheng Cao et al., 2018).

Property	Predicted values* DTA (Probability#)
P450 CYP1A2 inhibitor	--- (0.086)
P450 CYP1A2 Substrate	- (0.47)
P450 CYP3A4 inhibitor	--- (0.005)
P450 CYP3A4 substrate	--- (0.282)
P450 CYP2C9 inhibitor	--- (0.059)
P450 CYP2C9 substrate	- (0.378)
P450 CYP2C19 inhibitor	--- (0.097)
P450 CYP2C19 substrate	- (0.356)
P450 CYP2D6 inhibitor	--- (0.206)
P450 CYP2D6 substrate	- (0.421)

 *Predicted values : 0-0.1 (---) ; 0.1-0.3 (--) ; 0.3-0.5 (-); 0.5-0.7 (+) ; 0.7-0.9 (++) ; 0.9-1.0 (+++)

#Probability of the positive (+)

XenoSite Cytochrome P450 Prediction Models (Dang et al., 2016) provide predictions of regio-selectivity (which atoms on a molecule are likely to be oxidized by a given CYP enzyme), but they do not explicit model selectivity (which molecules are substrates of a given CYP enzyme). For DTA, the oxidation by cytP4502B6 appears to be the most potent.

 

In silico UGT-Mediated Metabolism

Sites of uridine diphosphate glucunosyltransferases (UGTs) metabolism of DTA was predicted with the XenoSite platform (Dang et al., 2016) . The peroxide group was predicted the site for UGT metabolism. 

Excretion

The evaluation of DTA in the pkCSM (Pires et al., 2015) and ADMETlab (Dongsheng Cao et al., 2018) platforms allow to predict some parameters related to excretion.

 

pkCSM model name	Predicted Value DTA
Total Clearance (log ml/min/kg)	1.605
Renal Organic Cation Transporter 2 (OCT2) substrate	No

 

ADMET lab property	Predicted values DTA	Meaning & Preference
T1/2(Half Life Time)	1.775 h	Range: >8h: high; 3h< Cl < 8h: moderate; <3h: low
CL (Clearance Rate)	1.744 mL/min/kg	Range: >15 mL/min/kg: high; 5mL/min/kg< Cl < 15mL/min/kg: moderate; <5 mL/min/kg: low

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100