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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.

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:
other: REACH Guidance on QSARs R.6
Qualifier:
according to
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)

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:
other: REACH Guidance on QSARs R.6
Qualifier:
according to
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.

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:
other: REACH Guidance on QSARs R.6
Qualifier:
according to
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

Additional information


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