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EC number: 258-649-2 | CAS number: 53585-53-8
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Link to relevant study record(s)
- 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.
- 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.
- 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.
- 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%).
Referenceopen allclose all
|
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) |
Description of key information
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.
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