Dibenzylbenzene, ar-methyl derivative

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics, other

Remarks:

G.I. human passive absorption

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:

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.

Specific details on test material used for the study:

SMILES (used for QSAR prediction): c1(C)c(Cc2ccccc2)c(Cc2ccccc2)ccc1

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%

Executive summary:

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, respectively.

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.

Type:

absorption

Results:

Intestinal absorption (human): 97%

Type:

distribution

Results:

VDss (human) (log L/kg): 0.426

Type:

distribution

Results:

Fraction unbound (human) : 0.102

Type:

distribution

Results:

BBB permeability (log BB): 0.906

Type:

distribution

Results:

CNS permeability (log PS): -0.998

Type:

excretion

Results:

Total Clearance (log ml/min/kg): 0.176

Type:

excretion

Results:

Renal OCT2 substrate: no

Details on absorption:

Intestinal absorption in humans is expected to be high (ca. 97%) for the various compounds investigated.

Details on distribution in tissues:

The mean VDss was calculated to be 0.426 log L/kg, which is close to the threshold of 0.45 log L/kg, above which the VDss is considered as high. Therefore, the distribution is the body of DBT can be expected to be close to its concentration in blood plasma.
The mean BBB permeability was calculated to be 0.906, and is therefore expected to cross the blood-brain barrier and be distributed in brain. In addition, the mean CNS permeability is calculated to be > -2, meaning the substance is expected to penetrate the CNS.
The compounds are expected to have a low fraction unbound to serum proteins.

Details on excretion:

Total clearance was calculated to be 0.176 log(ml/min/kg), suggesting clearance of the compounds will be low. The compounds are not expected to be OCT2 substrates.

	1,4-dibenzyl-2-methylbenzene	1,2-dibenzyl-3-methylbenzene	1,3-dibenzyl-2-methylbenzene	1,3-dibenzyl-4-methylbenzene	1,2-dibenzyl-4-methylbenzene	1,3-dibenzyl-3-methylbenzene	Dibenzyl toluene
	Cc1cc(Cc2ccccc2)ccc1Cc1ccccc1	Cc1cccc(Cc2ccccc2)c1Cc1ccccc1	Cc1c(Cc2ccccc2)cccc1Cc1ccccc1	Cc1ccc(Cc2ccccc2)cc1Cc1ccccc1	Cc1ccc(Cc2ccccc2)c(Cc2ccccc2)c1	Cc1cc(Cc2ccccc2)cc(Cc2ccccc2)c1
Model Name	Predicted Value	Predicted Value	Predicted Value	Predicted Value	Predicted Value	Predicted Value	Mean predicted value	Unit
Absorption
Water solubility	-6.817	-6.729	-6.773	-6.809	-6.73	-6.801	-6.777	Numeric (log mol/L)
Caco2 permeability	1.466	1.62	1.485	1.489	1.753	1.634	1.575	Numeric (log Papp in 10^-6cm/s)
Intestinal absorption (human)	97.364	98.101	97.956	97.262	97.435	97.31	97.571	Numeric (% Absorbed)
Skin Permeability	-2.711	-2.718	-2.714	-2.712	-2.707	-2.706	-2.711	Numeric (log Kp)
P-glycoprotein substrate	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Categorical (Yes/No)
P-glycoprotein I inhibitor	No	No	No	No	No	No	No	Categorical (Yes/No)
P-glycoprotein II inhibitor	No	No	No	No	No	No	No	Categorical (Yes/No)
Distribution
VDss (human)	0.46	0.392	0.433	0.432	0.401	0.439	0.426	Numeric (log L/kg)
Fraction unbound (human)	0.106	0.112	0.113	0.103	0.088	0.089	0.102	Numeric (Fu)
BBB permeability	0.925	0.912	0.941	0.922	0.853	0.88	0.906	Numeric (log BB)
CNS permeability	-0.995	-1.032	-1.018	-0.985	-0.981	-0.977	-0.998	Numeric (log PS)
Metabolism
CYP2D6 substrate	No	No	No	No	No	No	No	Categorical (Yes/No)
CYP3A4 substrate	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Categorical (Yes/No)
CYP1A2 inhibitior	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Categorical (Yes/No)
CYP2C19 inhibitior	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Categorical (Yes/No)
CYP2C9 inhibitior	No	Yes	No	No	No	No	Inconclusive	Categorical (Yes/No)
CYP2D6 inhibitior	No	No	No	No	No	No	No	Categorical (Yes/No)
CYP3A4 inhibitior	No	No	No	No	No	No	No	Categorical (Yes/No)
Excretion
Total Clearance	0.175	0.19	0.168	0.179	0.185	0.16	0.176	Numeric (log ml/min/kg)
Renal OCT2 substrate	No	No	No	No	No	No	No	Categorical (Yes/No)

Reference 3

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).

Specific details on test material used for the study:

SMILES:
Cc1cc(Cc2ccccc2)ccc1Cc1ccccc1 : 1,4-dibenzyl-2-methylbenzene
Cc1cccc(Cc2ccccc2)c1Cc1ccccc1 : 1,2-dibenzyl-3-methylbenzene
Cc1c(Cc2ccccc2)cccc1Cc1ccccc1 : 1,3-dibenzyl-2-methylbenzene
Cc1ccc(Cc2ccccc2)cc1Cc1ccccc1 : 1,3-dibenzyl-4-methylbenzene
Cc1ccc(Cc2ccccc2)c(Cc2ccccc2)c1 : 1,2-dibenzyl-4-methylbenzene
Cc1cc(Cc2ccccc2)cc(Cc2ccccc2)c1 : 1,3-dibenzyl-3-methylbenzene

Type:

metabolism

Results:

Dibenzyl toluene is metabolized by cytP450, preferentially on the methyl radical

Metabolites identified:

no

Executive summary:

The metabolism of dibenzyl toluene 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). According to the cyt P450 isoforms and the substance isomers, dibenzyl toluene is preferentially metabolized on the methyl radical.

Reference 4

Endpoint:

dermal absorption, other

Remarks:

QSAR

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

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: 272.39 g/mol
Temperature: 20 °C
Vapour Pressure: 0.001 Pa
Water solubility: 0.018 mg/L
Log Kow: 6.59 (Epiwin)
Density: 1044 mg/cm3
Melting point: -38.5°C

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:

0.06 %

Remarks on result:

other: Instantaneous deposition

Time point:

8 h

Dose:

1 mg/cm²/h

Parameter:

percentage

Absorption:

0.008 %

Remarks on result:

other: Deposition over time for 8 hr

Conclusions:

The dermal absorption of dibenzyl toluene is estimated to be low (<= 10%).

Executive summary:

The dermal absorption of dibenzyl toluene 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 (%)	0.06	0.008
Amount absorbed (mg)	0.678	0.678
Lag time stratum corneum (min)	4.17
Max. derm. abs. (mg/cm²/h)	4.24 10e-5

Therefore, the dermal  absorption of dibenzyl toluene is estimated to be low (<= 10%).

Key value for chemical safety assessment

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

There are no specific toxicokinetic data available for dibenzyl toluene (DBT).

 

Absorption:

oral exposure:

Based on the chemical structure and the physico-chemical properties of the material basic toxicokinetic properties can be estimated. The water solubility of DBT is low. The logPow is > 6. Since only dissolved material is likely to be absorbed in the gastrointestinal tract, water solubility might be the limiting factor. Due to the higher low Pow the material might absorb to proteins. Nevertheless, based on structural considerations, as well as systemtic effects observed in animal experiments with oral application it can reasonably be assumed that absorption via the gastrointestinal tract does occur.

Once absorbed via the gastrointestinal tract it is likely that the material will be distributed systemically. No high first pass effect in the liver is expected due to lack of functional groups, which are only introduced by enzymatic reactions. Data from in vitro experiments indicate metabolic pathways via oxidation and demethylation reactions. Overall, the resulting metabolic intermediates are more soluble and/or include functional groups that enable further elimination via phase 2 reactions (e.g. glucuronidation, sulfation). Hence, despite the relatively high lipophilicity a bioaccumulation in fatty tissues is not expected.

Using a model to predict either high or low fraction absorbed for an orally administered (Danish QSAR), passively transported substance, the rates of absorption were 100 and 90% for a dose of 1 and 1000 mg, respectively. Therefore the abosrption rate is estimated at 100% for human risk assessment

 

Inhalation exposure:

Dibenzyltoluene has a low vapour pressure, therefore the inhalation exposure is limited. If the substance reaches the lung, they may be absorbed by micellar solubilisation. An estimated rate of absorption by inhalation is estimated at 100% for risk assessment.

 

Dermal exposure:

The dermal absorption of dibenzyl toluene 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 (%)	0.06	0.008
Amount absorbed (mg)	0.678	0.678

 

The skin absorption is therefore very limited, considered at 10% for risk assessment.

 

Distribution

According to the pkCSM method (Pireset al., 2015) for predicting small-molecule pharmacokinetic properties, DBT is expected to havea high steady state volume of distribution, a low fraction unbound to serum proteins, and to readily cross the blood-brain barrier and penetrate the CNS.

 

Metabolism

The metabolism of dibenzyl toluene 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). According to the cyt P450 isoforms and the substance isomers, dibenzyl toluene is preferentially metabolized on the methyl radical.