Cyclohexylidenebis[tert-amyl] peroxide

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics, other

Remarks:

G.I. human passive absorption

Type of information:

calculation (if not (Q)SAR)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a (Q)SAR model, with limited documentation / justification, but validity of model and reliability of prediction considered adequate based on a generally acknowledged source

Objective of study:

absorption

Guideline:

other: REACH Guidance on QSARs R.6

Principles of method if other than guideline:

Model to predict either high or low fraction absorbed for an orally administered, passively transported substance on the basis of a new absorption parameter. The model includes only two inputs: the octanol-water partition coefficient (Kow) and the dimensionless oversaturation number (OLumen). The latter is the ratio of the concentration of drug delivered to the gastro-intestinal (GI) fluid to the solubility of the compound in that environment.

Species:

other: Human

Route of administration:

oral: unspecified

Type:

absorption

Results:

Absorption from gastrointestinal tract for 1 mg dose: 100%

Type:

absorption

Results:

Absorption from gastrointestinal tract for 1000 mg dose: 90%

Reference 2

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

Objective of study:

absorption

distribution

excretion

metabolism

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.

Specific details on test material used for the study:

SMILES:
O(OC(C)(C)CC)C1(OOC(C)(C)CC)CCCCC1

Type:

absorption

Results:

Intestinal absorption (human): 92.784%

Type:

distribution

Results:

VDss (human) (log L/kg): 0.242

Type:

distribution

Results:

Fraction unbound (human) : 0.382

Type:

distribution

Results:

BBB permeability (log BB): 0.571

Type:

distribution

Results:

CNS permeability (log PS): -3.485

Type:

excretion

Results:

Total Clearance (log ml/min/kg): 1.602

Type:

excretion

Results:

Renal OCT2 substrate: no

Property	Model Name	Predicted Value	Unit
Absorption	Water solubility	-3.929	Numeric (log mol/L)
Absorption	Caco2 permeability	1.776	Numeric (log Papp in 10^-6cm/s)
Absorption	Intestinal absorption (human)	92.784	Numeric (% Absorbed)
Absorption	Skin Permeability	-2.386	Numeric (log Kp)
Absorption	P-glycoprotein substrate	No	Categorical (Yes/No)
Absorption	P-glycoprotein I inhibitor	No	Categorical (Yes/No)
Absorption	P-glycoprotein II inhibitor	No	Categorical (Yes/No)
Distribution	VDss (human)	0.242	Numeric (log L/kg)
Distribution	Fraction unbound (human)	0.382	Numeric (Fu)
Distribution	BBB permeability	0.571	Numeric (log BB)
Distribution	CNS permeability	-3.485	Numeric (log PS)
Metabolism	CYP2D6 substrate	No	Categorical (Yes/No)
Metabolism	CYP3A4 substrate	No	Categorical (Yes/No)
Metabolism	CYP1A2 inhibitior	No	Categorical (Yes/No)
Metabolism	CYP2C19 inhibitior	No	Categorical (Yes/No)
Metabolism	CYP2C9 inhibitior	No	Categorical (Yes/No)
Metabolism	CYP2D6 inhibitior	No	Categorical (Yes/No)
Metabolism	CYP3A4 inhibitior	No	Categorical (Yes/No)
Excretion	Total Clearance	1.602	Numeric (log ml/min/kg)
Excretion	Renal OCT2 substrate	No	Categorical (Yes/No)

Reference 3

Endpoint:

dermal absorption, other

Remarks:

QSAR

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

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

Principles of method if other than guideline:

IH SkinPerm (v2.04) is a mathematical tool for estimating dermal absorption. The rate of mass build-up (or loss) on the skin comes from the deposition rate onto the skin minus the absorption rate into the Stratum Corneum (SC) and the amount evaporating from the skin to the air.

Species:

other: human

Type of coverage:

open

Vehicle:

unchanged (no vehicle)

Details on study design:

DATA INPUT
Molecular weight: 288.42 g/mol
Temperature: 20 °C
Vapour Pressure: 0.0832 Pa (Epiwin)
Water solubility: 0.088 mg/L
Log Kow: 7.26
Density: 857 mg/cm3
Melting point: 84.93°C (Epiwin)

SCENARIO PARAMETERS
- Instantaneous deposition
Deposition dose*: 1000 mg
Affected skin area**: 1000 cm²
Maximum skin adherence***: 2 mg/cm²
Thickness of stagnant air****: 1 cm
Weight fraction: 1
Timing parameters
. Start deposition: 0 hr
. End time observation: 8 hr
Report parameters
. Calculation (intervals/hr): 10000
. Report (intervals/hr): 100

- Deposition over time
Affected skin area**: 1000 cm²
Maximum skin adherence***: 1 mg/cm²
Dermal deposition rate: 2 mg/cm²/hr
Thickness of stagnant air****: 1 cm
Weight fraction: 1
Timing parameters
. Start deposition: 0 hr
. Duration of deposition: 8hr
. End time observation*: 8 hr
Report parameters
. Calculation (intervals/hr): 10000
. Report (intervals/hr): 100

*Default value defined according to the internal validation study
**Estimated skin surface of two hands of an adult.
***The skin adherence field is greyed out and a default of -1 is indicated if the substance is a liquid at 25°C. Smart logic is built into IH SkinPerm; the program recognizes whether a substance is a solid or liquid at standard temperature (25°C) based on the physicochemical properties. For substances
that are solids at 25°C a maximum adherence value up to 2 mg/cm² is allowed based on studies of soil-on-skin adherence. If the deposition rate results in an increase above the input figure (0.2-2 mg/cm²), it is assumed that the surplus disappears just by removal from the skin.
*** 3 cm if clothing involved, 1 cm if bare skin involved

Time point:

8 h

Dose:

1000 mg

Parameter:

percentage

Absorption:

0.8 %

Remarks on result:

other: Instantaneous deposition

Time point:

8 h

Dose:

1 mg/cm²/h

Parameter:

percentage

Absorption:

0.1 %

Remarks on result:

other: Deposition over time for 8 hr

Conclusions:

The dermal absorption of cyclohexylidenebis[tert-amyl] peroxide is estimated to be low (<= 10%).

Executive summary:

The dermal absorption of cyclohexylidenebis[tert-amyl] peroxide leads to the following results, obtained using the SkinPerm v2.04 model according to the input data:

	Instantaneous deposition	Deposition over time End time observation 8 hr
Total deposition (mg) or deposition rate (mg/cm²/hr)	1000	1
Fraction absorbed (%)	0.796	0.0995
Amount absorbed (mg)	7.96	7.96
Lag time stratum corneum (min)	3.37
Max. derm. abs. (mg/cm²/h)	0.0000498

Reference 4

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

Objective of study:

metabolism

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:

Xenosite P450 Metabolism 1.0 is a software predicting site of metabolism (SOM) of a molecule for cytP4501A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4 CYP isoforms. Xenosite P450 Metabolism 1.0 computes a probability score varying between 0 and 1 (a high probability to be a SOM is characterized by a high score), which reflects both the confidence of the model that a particular atom is metabolised and the statistical likelihood that its prediction for that atom is correct, but they do not explicit model selectivity (which molecules are substrates of a given CYP enzyme).

Species:

other: Human

Type:

metabolism

Results:

The substance is predicted to be metabolized by cytP450 isoforms on the ter-amyl radical and the cyclohexyl ring.

Metabolites identified:

no

Executive summary:

The metabolism of cyclohexylidenebis[tert-amyl] peroxide by cytP450 was evaluated by the Xenosite P450 Metabolism 1.0 software. XenoSite is able to predict the site of metabolism (SOM) of a molecule for cytP4501A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4 CYP isoforms. Xenosite computes a probability score varying between 0 and 1 (a high probability to be a SOM is characterized by a high score), which reflects both the confidence of the model that a particular atom is metabolised and the statistical likelihood that its prediction for that atom is correct, but they do not explicit model selectivity (which molecules are substrates of a given CYP enzyme). Cyclohexylidenebis[tert-amyl] peroxide is predicted to be metabolized by cytP450 isoforms on the ter-amyl radical and the cyclohexyl ring.

Description of key information

No data on toxicokinetics, metabolism and distribution are available for cyclohexylidenebis[tert-amyl] peroxide.

ABSORPTION

The assessment of the toxicokinetics of cyclohexylidenebis[tert-amyl] peroxide is based on the available toxicological data and the physicochemical properties as suggested by the REACH Guidance Chapter R.7c:

Molecular weight: 288 g/mole 

Vapeur pressure: 100 Pa @ 25°C

Water solubility: 0.088 mg/L at 20°C 

Partition coefficient log Kow = 7.26

Based on its physicochemical properties, cyclohexylidenebis[tert-amyl] peroxide is expected to be well absorbed by the respiratory and gastro-intestinal tracts. Limited absorption is expected through the skin.

Oral route

Cyclohexylidenebis[tert-amyl] peroxide is a highly lipophilic substance (log Kow 7.26) with a very low water solubility, therefore its absorption may be limited by its inability to dissolve into GI fluids and hence make contact with the mucosal surface. However, as any highly lipophilic and poorly soluble in water compounds, it may be taken up by micellular solubilisation. In contact with the acidic pH of the stomach, the dissolved fraction of cyclohexylidenebis[tert-amyl] peroxide will be hydrolysed to tert-amyl hydroperoxide and cyclohexanone. However, the low water solubility of cyclohexylidenebis[tert-amyl] peroxide is a very limiting factor to the exposure to the degradation products after hydrolysis in the stomach.

Using a model to predict either high or low fraction absorbed for an orally administered, passively transported substance, the rates of absorption of cyclohexylidenebis[tert-amyl] peroxide were 100 and 90% for a dose of 1 and 1000 mg, respectively (Danish QSAR). Similarly, oral human absorption rates of 92% was predicted by the pkCSM method (Pires et al., 2015). Similar absorption rates were estimated for cyclohexylidenebis[tert-butyl] peroxide used in read across.

Therefore, according to the REACH Guidance, a default value of 100% oral absorption will be used for cyclohexylidenebis[tert-amyl] peroxide and cyclohexylidenebis[tert-butyl] peroxide.

Inhalation route

Cyclohexylidenebis[tert-amyl] peroxide is a substance with a low volatility, its vapour pressure is 100 Pa at 25°C. As any highly lipophilic and poorly soluble in water compounds, cyclohexylidenebis[tert-amyl] peroxide may be taken up by micellular solubilisation.

Therefore, according to the REACH Guidance, a default value of 100% inhalation absorption will be used for cyclohexylidenebis[tert-amyl] peroxide and cyclohexylidenebis[tert-butyl] peroxide.

Dermal absorption

The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Therefore if the water solubility is below 1 mg/l, dermal uptake is likely to be low. Above a logP of 6, the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin. Uptake into the stratum corneum itself may be slow.

The rate of absorption was estimated using the IH SkinPerm model using a Kp derived from the EPI Dermwin model. For an instantaneous deposition of 1000 mg over 1000 cm² of skin or a deposition over time of 1 mg/cm²/h, the absorption rates were 0.8% and 0.1%, respecticely. Similar absorption rates were estimated for cyclohexylidenebis[tert-butyl] peroxide used in read across.

Therefore, according to the REACH Guidance, a default value of 10% skin absorption will be used for cyclohexylidenebis[tert-amyl] peroxide and cyclohexylidenebis[tert-butyl] peroxide.

DISTRIBUTION

Once absorbed via the gastrointestinal tract it is likely that Cyclohexylidenebis[tert-amyl] peroxide will be distributed systemically into cells due to their lipophilic properties and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues. No high first pass effect in the liver is expected due to lack of functional groups, which are only introduced by enzymatic reactions. According to the pkCSM method (Pireset al., 2015) for predicting small-molecule pharmacokinetic properties, the substance is expected to have a low fraction unbound to serum proteins, and to readily cross the blood-brain barrier.

 

pkCSM method Model Name	Predicted Value	Interpretation
Steady state volume of distribution (VDss human) (log L/kg)	0.242	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 unbound to serum proteins (human) (Fu)	0.382	the predicted fraction that would be unbound in plasma is calculated
Blood Brain Barrier (BBB) permeability (log BB)	0.571	a logBB > 0.3 is considered to readily cross the blood-brain barrier
CNS permeability (blood-brain permeability- surface area product, log PS)	-3.485	Compounds with a logPS > -2 are considered to penetrate the CNS, while those with logPS < -3 are considered as unable to penetrate the CNS

METABOLISM

Gastric hydrolysis

The rate of hydrolysis of 1,1-di(tert-amylperoxy)cyclohexane (tested in presence of isododecane) as a function of pH has been studied according to the OECD 111 Guideline and GLP requirements (Chastenet, 2017). To simulate the gastric hydrolysis, the test was also performed at pH 1.2 and 37°C. In these conditions, the half life was determined to be < 10 min.

At the tested concentrations, the concentration of hypothetical hydrolysis products (tert-amyl hydroperoxide and cyclohexanone) was too low to allow their detection. However, in a similar study performed at higher concentrations with the analogue substance cyclohexylidenebis[tert-butyl] peroxide a fast hydrolysis was also observed and the degradation products were identified as tert-butyl hydroperoxide and cyclohexanone (TOXI-COOP ZRT., 2013).

In silico cytochrome P450 metabolism

The metabolism ofcyclohexylidenebis[tert-amyl] peroxide by cytP450 was evaluated by the Xenosite P450 Metabolism 1.0 software. XenoSite is able to predict the site of metabolism (SOM) of a molecule for cytP4501A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4 CYP isoforms. Xenosite computes a probability score varying between 0 and 1 (a high probability to be a SOM is characterized by a high score), which reflects both the confidence of the model that a particular atom is metabolised and the statistical likelihood that its prediction for that atom is correct, but they do not explicit model selectivity (which molecules are substrates of a given CYP enzyme). Cyclohexylidenebis[tert-amyl] peroxide is not predicted to be metabolized by cyt P450 isoforms.

In vivo Rat metabolism & rat liver S9 metabolism simulators

In vivo Rat metabolism & rat liver S9 metabolism simulators of the OECD QSAR Toolbox were used to predict the metabolism of cyclohexylidenebis[tert-amyl] peroxide. In vivo, the substance is predicted to be metabolized by oxydation of the cyclohexyl group and/or ter-amyl radical, by hydrolysis of one or two peroxide functions and further oxydation of the hydrolysis products like ter-amyl alcohol, cyclohexanol and monocyclohexylidene[tert-amyl] peroxide. Rat liver S9 metabolism similator predicted a similar metabolism.

EXCRETION

A high clearance rate of 40 ml/min/kg was predicted for 1,1-di(tert-amylperoxy)cyclohexane by the pkCSM platform (Pires et al., 2015).

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100