N-butyl phenyl ether

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Type of information:

(Q)SAR

Adequacy of study:

supporting study

Study period:

2016

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:

1. SOFTWARE: ADMET predictor and GastroPlus

2. MODEL (incl. version number): GastroPlus v9.0 (Simulations Plus Inc, Lancaster, CA, USA); ADMET Predictor v7.2 (Simulations Plus Inc, Lancaster, CA, USA).

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL: Butyl Phenyl Ether SMILES Code
SMILES code: CCCCOc1ccccc1

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
Endpoint (OECD Principle 1):
Endpoint:
i. The absorption fraction (Fa%) of butyl phenyl ether following oral, dermal, and inhalation exposures in humans.
ii. Systemic bioavailability (F%), Cmax, Tmax, and AUC0-168 of butyl phenyl ether following oral, dermal, and inhalation exposures in humans.
iii. The plasma protein binding and volume of distribution (Vd).
iv. The potential metabolism and excretion of butyl phenyl ether in human.

Algorithm (OECD Principle 2):
a. Model or submodel name: For the prediction of Fa%, F%, Cmax, Tmax, and AUC 0-168 of butyl phenyl ether, a PBPK model was utilized in GastroPlus (version 9) to simulate absorption parameters and systemic bioavailability of butyl phenyl ether following a single oral (or inhalation or dermal) dose of 1 mg/kg.bw in a fed 30-year old human (70 kg). The oral dose formulation type was defined to be a suspension with particle size of 50 μm mean diameter. This particle size was selected based on oral PSA (parameter sensitivity analysis) simulation results of Fa% and F% versus the particle size ranging from of 2.5 μm to 250 μm with GastroPlus; for butyl phenyl ether, particle size did not affect absorption. The oral absorption in GastroPlus utilizes the Advanced Compartmental Absorption and Transit (ACAT) model to predict passive absorption across the gut and accounts for soluble and insoluble portions of the administered dose. The inhalation dose formulation type was defined to be a powder with a particle size of 2.5 μm mean diameter. This particle was selected based on the Concawe report (Hext et al., 1999). Particle size of 2.5 μm or less are considered the fine fraction and are associated with a higher risk of health effects. These smaller particles are considered the highly respirable fraction of a particulate atmosphere and can reach the deep alveolar regions of the lung. In the current GastroPlus simulation, the inhalation dose was delivered over 8-hr period. This inhalation simulation model includes up to five (5) compartments: an optional nose, extrathoracic, thoracic, bronchiolar, and alveolar-interstitial. The deposition fractions for each compartment were generated with a built-in predictive model based on the International Commission for Radiological Protection Publication 66 (ICRP 66) deposition model described in GastroPlus.
The dermal dose formulation type was defined to be a water suspension with particle size of 50 μm mean diameter. This particle size was selected based on the dermal PSA (parameter sensitivity analysis) simulation results of Fa% and F% versus the particle size ranging from of 2.5 μm to 250 μm with GastroPlus. Again, particle size did not affect absorption across this particle size range. The dermal absorption simulation model in GastroPlus represents the skin as a collection of the following compartments: stratum corneum, viable epidermis, dermis, subcutaneous tissue, sebum, hair lipid, and hair core. The application surface is 1900 cm2 on human arm. The dose volume and exposure time were 19 mL and 6 hrs, respectively. This surface area, dose volume, and exposure time were selected based on the US EPA dermal exposure assessment report (USEPA, 1992).
Bioavailability predictions for these three exposure routes were made by including metabolism by five major cytochrome (CYP) P450 enzymes (1A2, 2C9, 2C19, 2D6, and 3A4) in human. These QSAR predictions of metabolic clearance [(enzyme kinetics (Km and Vmax) based on recombinant CYP enzymes] were generated using ADMET Predictor (v7.2, Simulations Plus Inc, Lancaster, CA, USA) based on the structure of butyl phenyl ether.

The plasma protein binding and volume of distribution (Vd) were predicted by ADMET Predictor (v7.5, Simulations Plus Inc, Lancaster, CA, USA).
The metabolism and excretion of butyl phenyl ether was proposed based on the CYP metabolism in human predicted by ADMET predictor.

b. Model version: GastroPlus v9.0 (Simulations Plus Inc, Lancaster, CA, USA); ADMET Predictor v7.2 (Simulations Plus Inc, Lancaster, CA, USA).
GastroPlus is a physiologically based pharmacokinetic (PBPK) modeling and simulation software package that simulates intravenous, oral, oral cavity, ocular, inhalation, and dermal/subcutaneous absorption, pharmacokinetics, and pharmacodynamics in human and animals. It was developed for use by the pharmaceutical industry and is licensed for use by most top 25 pharmaceutical companies in the USA and Europe. Within GastroPlus, the ACAT™ (Advanced Compartmental Absorption and Transit) model has been refined numerous times since its inception in 1997 to provide accurate, flexible, and powerful simulations. ADMET Predictor is used for advanced predictive modelling of ADMET
properties. The "ADMET" acronym is commonly used in the pharmaceutical industry to indicate all the phenomena associated with Absorption, Distribution, Metabolism, Elimination, and Toxicity of chemical substances in the human body.

c. Predicted value (model result):
Absorption: The PSA simulation results showed that both Fa% and F% were not impacted by particle sizes ranging from 2.5 μm to 250 μm in either oral exposure or dermal exposure; therefore 50 μm diameter particle size was applied for both oral and dermal simulations. At 1 mg/kg exposure dose level in a fed 30-year old human (70 kg), the predicted fractional absorption (Fa%) values for oral, dermal, and inhalation exposures to butyl phenyl ether in human by GastroPlus are 100%, 99.7%, and 53.1%, respectively. The predicted systemic bioavailability (F%) values for butyl phenyl ether from oral, dermal, and inhalation exposures are 99.4%, 99.7%, and 53.1%, respectively; the predicted Cmax values are 0.374, 0.111, and 0.105 μg/mL respectively. At the dermal exposure level of 3.46 mg/kg, the predicted Cmax is only 0.382 μg/mL, indicating that approximately 3.46 mg/kg dermal exposure level is required to produce the oral Cmax level of 0.374 μg/mL.

Distribution:
The predicted human plasma protein binding upon absorption for butyl phenyl ether is 86.0%. Higher protein binding values generally indicate lower bioavailability to interact with other target sites. The volume of distribution in humans was estimated to be low (6.7 L/kg), which indicates low distribution to body tissues.

Accumulation: On the basis of low volume of distribution, butyl phenyl ether is not expected to bioaccumulate.

Metabolism:
Based on the metabolism prediction by ADMET predictor, butyl phenyl ether will be metabolized to the hydroxylated metabolites and butyl aldehyde (by human CYP enzymes). The formed hydroxylated metabolites can also be further metabolized to water soluble metabolites (such as glucuronides and sulfates). The formed butyl aldehyde will be further metabolized to butyric acid.

Excretion:
The various conjugate forms (such as sulfates, glucuronides) of the above proposed metabolites would be more water-soluble than the parent compound; therefore, these metabolites would be expected to be excreted in urine and faeces.

d. Input for prediction: SMILES codes:
i. butyl phenyl ether: CCCCOc1ccccc1

5. APPLICABILITY DOMAIN
Descriptor values: Applicability domain (OECD principle 3):
a. Domains: Defined by GastroPlus and ADMET Predictor.
i. Descriptor domain: In general, ADMET Predictor and GastroPlus apply only to small organic molecules composed of the following elements: C, N, O, S, P, H, F, Cl, Br, I, B and their isotopes. Other elements (in particular metals) are not supported. In addition, the program limits the size and complexity of input molecules to no more than 256 bonds and no more than 20 ionizable groups. Butyl phenyl ether meets these GastroPlus/ADMET predictor criteria.
ii. Structural fragment domain: ADMET Predictor and GastroPlus use calculated descriptors for each chemical structure as inputs to its predictive models; it does not use structural fragments
iii. Mechanism domain: ADMET Predictor and GastroPlus models use QSAR/QSPR (quantitative structure-activity relationship/ quantitative structure-property relationship) methodology, which is a subset of statistical-correlative modelling. It does not consider mechanisms of action, at least not explicitly.
iv. Metabolic domain: Metabolism is considered relevant and is considered in the assessment as part of the GastroPlus/ADMET predictor modeling.

6. ADEQUACY OF THE RESULT
Regulatory purpose: The predicted information is adequate to support hazard characterization (classification and labeling) as well as chemical risk assessment.
Approach for regulatory interpretation of the model result: The oral, dermal, and inhalation Fa% and F% of butyl phenyl ether are predicted by the GastroPlus QSAR program. The plasma protein binding and volume of distribution (Vd) of butyl phenyl ether are predicted by ADMET Predictor. The potential metabolism and excretion of butyl phenyl ether are proposed according to human CYP metabolism predicted by ADMET Predictor.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2016

Report date:

2016

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

Test guideline

Qualifier:

no guideline followed

Version / remarks:

QSAR Prediction Reporting Format (QPRF) v 1.1

Principles of method if other than guideline:

To assess the ADME potential of butyl phenyl ether in humans, the widely accepted QSAR programs, ADMET predictor (v7.2, Simulations Plus Inc, Lancaster, CA, USA), and GastroPlus (v9.0, Simulations Plus Inc, Lancaster, CA, USA) were used.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

N-butyl phenyl ether

EC Number:

214-426-1

EC Name:

N-butyl phenyl ether

Cas Number:

1126-79-0

Molecular formula:

C10H14O

IUPAC Name:

butoxybenzene

Specific details on test material used for the study:

CAS number: 1126-79-0
EC number: 214-426-1
Chemical name: Butyl phenyl ether
SMILES: CCCCOc1ccccc1

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

(Fa%): oral, dermal, and inhalation are 100%, 99.7%, and 53.1%, respectively. (F%): oral, dermal, and inhalation exposures are 99.4%, 99.7%, and 53.1%, respectively. Predicted Cmax values are 0.374, 0.111, and 0.105 μg/mL respectively.

Main ADME results 2

Type:

distribution

Results:

The predicted human plasma protein binding upon absorption for butyl phenyl ether by any exposure route is 86.0%. The volume of distribution in humans was estimated to be low (6.7 L/kg).

Main ADME results 3

Type:

metabolism

Results:

ADMET predictor: butyl phenyl ether metabolizes to the hydroxylated metabolites and butyl aldehyde. The hydroxylated metabolites can be further metabolized to water soluble metabolites. The butyl aldehyde will be further metabolized to butyric acid.

Main ADME results 4

Type:

excretion

Results:

The formed hydroxylated metabolites can also be further metabolized to water soluble metabolites (such as glucuronides and sulfates), which will be mainly excreted into urine and feces.

Applicant's summary and conclusion

Conclusions:

At 1 mg/kg exposure dose level in a fed 30-year old human (70 kg), the predicted fractional absorption (Fa%) values of oral, dermal, and inhalation for butyl phenyl ether in human by GastroPlus are 100%, 99.7%, and 53.1%, respectively. The predicted systemic bioavailability (F%) values for butyl phenyl ether from oral, dermal, and inhalation exposures are 99.4%, 99.7%, and 53.1%, respectively; the predicted Cmax values are 0.374, 0.111, and 0.105 μg/mL respectively (Table 1). At the dermal exposure level of 3.46 mg/kg, the predicted Cmax is only 0.382 μg/mL, indicating that approximately 3.46 mg/kg dermal exposure level is required to produce the oral Cmax level of 0.374 μg/mL. The predicted human plasma protein binding upon absorption for butyl phenyl ether by any exposure route is 86.0%. The volume of distribution in humans was estimated to be low (6.7 L/kg).

Based on the metabolism prediction by ADMET predictor, butyl phenyl ether will be metabolized to the hydroxylated metabolites and butyl aldehyde (by human CYP enzymes). The formed hydroxylated metabolites can also be further metabolized to water soluble metabolites (such as glucuronides and sulfates), which will be mainly excreted into urine and feces. The formed butyl aldehyde will be further metabolized to butyric acid.

On the basis of low volume of distribution, and predicted metabolism and excretion, butyl phenyl ether is not expected to bioaccumulate in humans.

The final result is considered adequate for a regulatory conclusion.

Executive summary:

Experimental data on absorption, distribution, metabolism and excretion (ADME) are not available for butyl phenyl ether. To assess the ADME potential of butyl phenyl ether in humans, the widely accepted QSAR programs, ADMET predictor (v7.2, Simulations Plus Inc, Lancaster, CA, USA), and GastroPlus (v9.0, Simulations Plus Inc, Lancaster, CA, USA) were used.

At 1 mg/kg exposure dose level in a fed 30-year old human (70 kg), the predicted fractional absorption (Fa%) values for oral, dermal, and inhalation exposures to butyl phenyl ether by GastroPlus are 100%, 99.7%, and 53.1%, respectively; the predicted systemic bioavailability (F%) values for butyl phenyl ether from oral, dermal, and inhalation exposures are 99.4%, 99.7%, and 53.1%, respectively; the predicted Cmax values are 0.374, 0.111, and 0.105 μg/mL respectively. At the dermal exposure level of 3.46 mg/kg, the predicted Cmax is only 0.382 μg/m, indicating that a dermal exposure of approximately 3.46 mg/kg is required to produce the oral Cmax level of 0.374 μg/mL. The predicted human plasma protein binding upon absorption for butyl phenyl ether is 86.0%. The volume of distribution in humans is estimated to be low (6.7 L/kg).

Based on the metabolism prediction by ADMET predictor, butyl phenyl ether will be metabolized to hydroxylated metabolites and butyl aldehyde (by human CYP enzymes). The formed hydroxylated metabolites can also be further metabolized to water soluble metabolites (such as glucuronides and sulfates), which will be mainly excreted into urine and feces. The formed butyl aldehyde will be further metabolized to butyric acid.

On the basis of low volume of distribution, and predicted metabolism and excretion, butyl phenyl ether is not expected to bioaccumulate in humans.