tert-butylbenzene

Basic toxicokinetics

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

Test material information

Constituent 1

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 results

Main ADME results 1

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%.

Main ADME results 2

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.

Main ADME results 3

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%.

Main ADME results 4

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

Main ADME results 5

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

Main ADME results 6

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

Main ADME results 7

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.

Main ADME results 8

Type:

other: CYP450 Inhibitor

Results:

The TK properties of tert-butylbenzene were predicted using ACD/ADME software package:
Non-Inhibitor of CYP450

Main ADME results 9

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

Main ADME results 10

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.