Benzyltoluene

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.

Specific details on test material used for the study:

SMILES (used for QSAR prediction): c1(C)c(Cc2ccccc2)cccc1

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.

Specific details on test material used for the study:

SMILES:
Cc1ccccc1Cc1ccccc1 : Benzene, 1-methyl-2-(phenylmethyl)-
Cc1ccc(Cc2ccccc2)cc1 : Benzene, 1-methyl-4-(phenylmethyl)-
Cc1cccc(Cc2ccccc2)c1 : Benzene, 1-methyl-3-(phenylmethyl)-

Type:

absorption

Results:

Intestinal absorption (human): 96%

Type:

distribution

Results:

VDss (human) (log L/kg): 0.714

Type:

distribution

Results:

Fraction unbound (human) : 0.042

Type:

distribution

Results:

BBB permeability (log BB): 0.642

Type:

distribution

Results:

CNS permeability (log PS): -1.258

Type:

excretion

Results:

Total Clearance (log ml/min/kg): 0.197

Type:

excretion

Results:

Renal OCT2 substrate: no

	Benzene, 1-methyl-2-(phenylmethyl)-	Benzene, 1-methyl-4-(phenylmethyl)-	Benzene, 1-methyl-3-(phenylmethyl)-	Benzyl toluene
	Cc1ccccc1Cc1ccccc1	Cc1ccc(Cc2ccccc2)cc1	Cc1cccc(Cc2ccccc2)c1
Model Name	Predicted Value	Predicted Value	Predicted Value	Mean predicted value	Unit
Absorption
Water solubility	-4.774	-4.695	-4.695	-4.721	Numeric (log mol/L)
Caco2 permeability	1.503	1.51	1.646	1.553	Numeric (log Papp in 10^-6cm/s)
Intestinal absorption (human)	96.25	96.078	96.33	96.219	Numeric (% Absorbed)
Skin Permeability	-1.995	-1.959	-1.947	-1.967	Numeric (log Kp)
P-glycoprotein substrate	Yes	No	Yes	Inconclusive	Categorical (Yes/No)
P-glycoprotein I inhibitor	No	No	No	No	Categorical (Yes/No)
P-glycoprotein II inhibitor	No	No	No	No	Categorical (Yes/No)
Distribution
VDss (human)	0.756	0.692	0.695	0.714	Numeric (log L/kg)
Fraction unbound (human)	0.042	0.048	0.035	0.042	Numeric (Fu)
BBB permeability	0.657	0.649	0.621	0.642	Numeric (log BB)
CNS permeability	-1.267	-1.246	-1.261	-1.258	Numeric (log PS)
Metabolism
CYP2D6 substrate	No	No	No	No	Categorical (Yes/No)
CYP3A4 substrate	Yes	Yes	Yes	Yes	Categorical (Yes/No)
CYP1A2 inhibitior	Yes	Yes	Yes	Yes	Categorical (Yes/No)
CYP2C19 inhibitior	Yes	Yes	Yes	Yes	Categorical (Yes/No)
CYP2C9 inhibitior	Yes	Yes	Yes	Yes	Categorical (Yes/No)
CYP2D6 inhibitior	No	No	No	No	Categorical (Yes/No)
CYP3A4 inhibitior	No	No	No	No	Categorical (Yes/No)
Excretion
Total Clearance	0.204	0.19	0.198	0.197	Numeric (log ml/min/kg)
Renal OCT2 substrate	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:
M1: Cc1ccccc1Cc1ccccc1 : Benzene, 1-methyl-2-(phenylmethyl)-
M2 Cc1ccc(Cc2ccccc2)cc1 : Benzene, 1-methyl-4-(phenylmethyl)-
M3: Cc1cccc(Cc2ccccc2)c1 : Benzene, 1-methyl-3-(phenylmethyl)-

Type:

metabolism

Results:

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

Metabolites identified:

no

Executive summary:

The metabolism of benzyl 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, benzyl toluene is preferentially metabolized on the methyl radical.

Reference 4

Endpoint:

dermal absorption, other

Remarks:

QSAR

Type of information:

(Q)SAR

Adequacy of study:

key study

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: 182.27 g/mol
Temperature: 20 °C
Vapour Pressure: 0.66 Pa
Water solubility: 0.038 mg/L
Log Kow: 4.31
Density: 995 mg/cm3
Melting point: -71.5°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:

0.01 %

Remarks on result:

other: Instantaneous deposition

Time point:

8 h

Dose:

1 mg/cm²/h

Parameter:

percentage

Absorption:

0.001 %

Remarks on result:

other: Deposition over time for 8 hr

Conclusions:

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

Executive summary:

The dermal absorption of benzyl 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 (%)	0.01	0.001
Amount absorbed (mg)	0.127	0.127
Lag time stratum corneum (min)	4.93
Max. derm. abs. (mg/cm²/h)	7.92 10e-6

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

Description of key information

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

Absorption

Oral route

Oral absorption is favored for molecular weights below 500 g/mol. Based on the high log Kow of 4.31 -4.40, benzyl toluene can be regarded as lipophilic substance. Such lipophilic compound may be taken up by micellar solubilisation. This mechanism may be of particular importance, as the substances are only slightly soluble and would otherwise be poorly absorbed. Benzyl toluene showed adverse effects in acute and repeated dose toxicity studies when administered by oral gavage. Therefore it can be assumed that absorption across the gastrointestinal tract occurs. Benzyl toluene is not expected to hydrolyze 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 benzyl toluene, respectively (Danish QSAR database). According to the pkCSM method (Pires et al., 2015) for predicting small-molecule pharmacokinetic properties, BT is also expected to be readily absorbed (96%) by the oral route. Therefore, for human risk assessment, a default absorption rate of 100% will be used.

Inhalation exposure

Benzyl toluene has a low vapour pressure, therefore the inhalation exposure is limited. If the substance reaches the lung, they may be absorbed by micellar solubilisation.

 

Dermal exposure

Based on physical-chemical properties of benzyl toluene, the substance is not likely to penetrate skin to a large extent as the high log Kow value and low water solubility do not favor 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 benzyl toluene 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:

Fraction absorbed (%)*	Instantaneous deposition	Deposition over time
Benzyl toluene	0.01	0.001

*End time observation 8 hr

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

 

Distribution

Once absorbed via the gastrointestinal tract it is likely that BT 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, BT 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

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. The metabolism of benzyl 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, benzyl toluene is preferentially metabolized on the methyl radical. 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.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100