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Administrative data

Endpoint:
basic toxicokinetics in vitro / ex vivo
Type of information:
(Q)SAR
Study period:
2021
Reliability:
1 (reliable without restriction)
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

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2021
Report date:
2021

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
no guideline required
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
tert-butylbenzene
EC Number:
202-632-4
EC Name:
tert-butylbenzene
Cas Number:
98-06-6
Molecular formula:
C10H14
IUPAC Name:
tert-butylbenzene
Test material form:
liquid
Details on test material:
- Name of test material: tert-butylbenzene
- IUPAC name: tert-Butylbenzene
- Molecular formula: C10H14
- Molecular weight: 134.22 g/mol
- Substance type: Organic
- Physical state: Liquid

Test animals

Species:
other: None
Strain:
other: None

Administration / exposure

Route of administration:
other: None
Vehicle:
other: None

Results and discussion

Main ADME resultsopen allclose all
Type:
absorption
Results:
The TK properties of tert-butylbenzene were predicted using ACD/ADME software package:
Maximum passive absorption: 100%;
Transcellular route: 100%;
Paracellular route: 0%.
Type:
other: Permeability
Results:
The TK properties of tert-butylbenzene were predicted using ACD/ADME software package:
Human Jejunum Scale (pH 6.5): 9.78*10-4 cm/s;
Absorption rate: ka = 0.067 min-1.
Type:
other: Caco-2 (pH7.4, rpm 500) to predict cell membrane permeability using Caco-2 model
Results:
The TK properties of tert-butylbenzene were predicted using ACD/ADME software package:
Pe: 245*10-6 cm/s;
Transcellular route: 100%;
Paracellular route: 0%.
Type:
other: blood-brain barrier (BBB) permeation predictive
Results:
The TK properties of tert-butylbenzene were predicted using ACD/ADME software package:
LogPS: -1.0
LogBB: 1.02
Log (PS*fu, brain): -2.9
Type:
other: Oral Bioavailability (F%)
Results:
The TK properties of tert-butylbenzene were predicted using ACD/ADME software package:
Oral Bioavailability: 30% < F% < 70%. Reliability: 0.642. it indicate the substance have a moderate
level of oral bioavailability
Type:
distribution
Results:
The TK properties of tert-butylbenzene were predicted using ACD/ADME software package:
Plasma Protein Binding Ratio (PPB%): 81%, RI=0.56.
LogKaHSA: 3.55. The parameter represents the binding constant between compound and human
serum albumin (HSA). RI=0.66
Type:
other: P-gp Specificity
Results:
The TK properties of tert-butylbenzene were predicted using ACD/ADME software package:
P-gp Inhibitors: Non inhibitor;
P-gp Substrate: Non substrate;
Reliability: High.
Type:
other: CYP450 Inhibitor
Results:
The TK properties of tert-butylbenzene were predicted using ACD/ADME software package:
Non-Inhibitor of CYP450
Type:
metabolism
Results:
The TK properties of tert-butylbenzene were predicted using ACD/ADME software package:
Details show in table 1 of Any other information on results incl. tables
Type:
excretion
Results:
The TK properties of tert-butylbenzene were predicted using ACD/ADME software package:
The substance may be metabolized into the hydroxyl metabolites or carboxylic acid, which can be
excreted via the urine.

Any other information on results incl. tables

Table 1. The metabolic site and reaction of type


 




































NO.



Reaction Type



Reaction Rate



Score



1



CH3-Hydroxylation



0.58



0.61



2



o-Hydroxylation



0.25



0.76



3



m-Hydroxylation



0.222



0.61



4



p-Hydroxylation



0.18



0.66



 


The TK properties of tert-butylbenzene were predicted using DS/ADMET:


BBB Level: DS/ADMET predicted the LogBB of 0.703 and Level of 0. Level 0 indicated the predicted compound could pass the BBB, and the results is accordant with above ACD/ADME-BBB predictions.


ADMET_Absoption_Level: DS/ADMET predicted the ADMET_AlogP98 of 2.77 and level of 0. Level 0 represented the predicted compound could be absorbed in jejunum, which is accordant with above ACD/ADME-Absorption predictions.


ADMET_CYP2D6: The calculated ADMET_CYP2D6_Probability: 0.001, Level:0. It meant the predicted compound would not be an inhibitor of CYP2D6, which was congruent with ACD/ADME-P450 predictions.


ADMET_PPB_Level: DS/ADMET predicted ADMET_AlogP98 of 2.77 and level of 2. It suggested that the binding ratio on plasma proteins is less than 90%. As like ACD/ADME- Distribution predictions (81%), DS/ADMET also suggested that predicted compound could bind with plasma protein in a relatively low level.


 

Applicant's summary and conclusion

Conclusions:
In summary, two ADME prediction softwares, ACD/ADME and DS/ADMET, respectively, were applied to predict TK properties of tert-butylbenzene. According to the calculated data from two different software packages in combination with reported experimental data of the similar compound Styrene, it was predicted that tert-butylbenzene could be absorbed in GI, and it could pass the BBB easily to have a distribution in CNS. The compound would have a moderate level of oral bioavailability between 30% and 70%. Furthermore, it would bind with blood plasma protein with a low binding ratio less than 90%. As reported, the compound dosed by oral-gavage to rats may have distribution in respiratory system, mouth, eye, nose, abdomen, perineal area, and brain. According to literature, the acute inhalation toxicity LC50 of tert-butylbenzene is about 4.6mg/L of air and clinical observations included salivation, lachrymation, a high stepping gait, dyspnoea, fasiculations, tremors, endophthalamus, and convulsions. In addition, the compound would not be an inhibitor or substrate of P-gp. Moreover, tert-butylbenzene would not be an inhibitor of CYP450 and it might be hydroxylated into the metabolites 2-methyl-2-phenylpropan-1-ol, 2,3-dihydroxyl-t-butylbenzene, or Pivalic acid, then excreted via the urine.
Executive summary:

In this endpoint, it was performed to predict TK properties of tert-butylbenzene applying both ACD/ADME (v 5.0) and DS/ADMET (v 2.5.5) software packages, respectively.


ACD/ADME predicted data indicated that: (1) this compound could be absorbed in small intestine; (2) it may pass the BBB easily; (3) its oral bioavailability may be at a middle level of between 30% and 70%; (4) it could bind with plasma proteins with a relatively low binding ratio of 81%; (5) it would be neither an inhibitor nor a substrate of P-gp; and (6) it would not be an inhibitor of CYP450 neither, and it could be metabolized into corresponding metabolites. The DS/ADMET-estimated data suggested: (1) the compound could pass the BBB; (2) it could be absorbed in small intestine; (3) it would not be an inhibitor of CYP450 2D6; (4) its binding ratio on plasma protein would be less than 90%.


By combining the estimated data from both softwares and corresponding literature reported pharmacokinetics of the similar compound Styrene, it was predicted that tert-Butylbenzene could be absorbed in small intestine and its oral bioavailability would be at a middle level with a F% between 30% and 70%. It may pass the BBB easily to have a distribution in brain. Its binding ratio on plasma proteins would be at a relatively low level less than 90%. As literature reported, the compound could have distributions in respiratory system, eye, nose, mouth, perineal area, and abdomen after oral gavage. It would be a non-inhibitor or non-substrate of P-gp. The compound would not be an inhibitor of CYP450 neither. According to ACD/ADME metabolism model prediction and literature reports of metabolisms of this compound, it was suggested that tert-Butylbenzene may be hydroxylated into metabolites 2-methyl-2-phenylpropan-1-ol, 2,3-dihydroxyl-t-butylbenzene, or pivalic acid, excreted via the urine.