2-(3-oxazolidinyl)ethyl methacrylate

Dermal absorption

Administrative data

Endpoint:

dermal absorption, other

Type of information:

(Q)SAR

Adequacy of study:

supporting study

Study period:

2018

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): ADMET predictor (v7.2, Simulations Plus Inc, Lancaster, CA, USA) and GastroPlus (v9.0, Simulations Plus Inc, Lancaster, CA, USA).

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL: C=C(C)C(=O)OCCN1CCOC1

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
Endpoint (OECD Principle 1):
a. Endpoint:
i. The absorption fraction (Fa%) of oxazolidinyl ethyl methacrylate following oral, dermal, and inhalation exposures in humans.
ii. Systemic bioavailability (F%), Cmax, Tmax, and AUC0-168 of oxazolidinyl ethyl methacrylate 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 oxazolidinyl ethyl methacrylate in humans.
Algorithm (OECD Principle 2):
a. Model or submodel name: For the prediction of Fa%, F%, Cmax, Tmax, and AUC 0-168 of oxazolidinyl ethyl methacrylate, a PBPK model was utilized in GastroPlus (version 9) to simulate absorption parameters and systemic bioavailability of oxazolidinyl ethyl methacrylate 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 25 µm mean radius. This particle size was selected based on oral PSA (parameter sensitivity analysis) simulation results of Fa% and F% versus the particle size ranging from radius values of 2.5 µm to 250 µm with GastroPlus; for oxazolidinyl ethyl methacrylate, particle size from this range did not affect absorption. Therefore, the particle size (2.5 µm radius) was finally used in simulations for oxazolidinyl ethyl methacrylate. 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 1.25 µm mean radius. This particle was selected based on the Concawe report (Hext et al., 1999). Particle sizes of 1.25 µm or less (radius) 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 25 µm mean radius. 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 radius values 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 oxazolidinyl ethyl methacrylate.
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 oxazolidinyl ethyl methacrylate was initially proposed based on the CYP metabolism in human predicted by ADMET predictor. The metabolism and excretion was also proposed based on ester structure.
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.

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. oxazolidinyl ethyl methacrylate 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.
b. Structural analogues: n.a.
c. Considerations on structural analogues: n.a.

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 oxazolidinyl ethyl methacrylate are predicted by the GastroPlus QSAR program. The plasma protein binding and volume of distribution (Vd) of oxazolidinyl ethyl methacrylate are predicted by ADMET Predictor. The potential metabolism and excretion of oxazolidinyl ethyl methacrylate are proposed according to human CYP metabolism predicted by ADMET Predictor.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2018

Materials and methods

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 oxazolidinyl ethyl methacrylate in humans, the toxicokinetics of oxazolidinyl ethyl methacrylate was estimated via 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).

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

2-(3-oxazolidinyl)ethyl methacrylate

EC Number:

256-260-2

EC Name:

2-(3-oxazolidinyl)ethyl methacrylate

Cas Number:

46235-93-2

Molecular formula:

C9H15NO3

IUPAC Name:

2-(1,3-oxazolidin-3-yl)ethyl 2-methylprop-2-enoate

Specific details on test material used for the study:

CAS number: 46235-93-2
EC number: 256-260-2
Chemical name: Oxazolidinyl Ethyl Methacrylate
Input for prediction: SMILES codes: xazolidinyl ethyl methacrylate: C=C(C)C(=O)OCCN1CCOC1

Results and discussion

Any other information on results incl. tables

Predicted value (model result):

Absorption:

The PSA simulation results showed that Fa% was not impacted by particle sizes ranging from radius values of 2.5µm to 250µm in either oral exposure or dermal exposure.  Therefore, 25µm radius 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 oxazolidinyl ethyl methacrylate in human by GastroPlus are 100%, 99.1%, and 81.6%, respectively (Table1). 

Distribution:

The predicted human plasma protein binding upon absorption for oxazolidinyl ethyl methacrylate is 30.1%. 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 (1.00 L/kg), which indicates low distribution to body tissues.

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 oxazolidinyl ethyl methacrylate in human by GastroPlus are 100%, 99.1%, and 81.6%, respectively. The predicted human plasma protein binding upon absorption for oxazolidinyl ethyl methacrylate by any exposure route is 30.1%. The volume of distribution in humans was estimated to be low (1.00 L/kg).

Executive summary:

Experimental data on absorption, distribution, metabolism and excretion (ADME) are not available foroxazolidinyl ethyl methacrylate. To assess the ADME potential ofoxazolidinyl ethyl methacrylatein humans, the toxicokinetics ofoxazolidinyl ethyl methacrylate was estimatedviathe widely accepted QSAR programs, ADMET predictor (v7.2, Simulations Plus Inc, Lancaster, CA, USA)andGastroPlus (v9.0, Simulations Plus Inc, Lancaster, CA, USA).

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 oxazolidinyl ethyl methacrylate by GastroPlus are 100%, 99.1%, and 81.6%, respectively. The predicted human plasma protein binding upon absorption for oxazolidinyl ethyl methacrylateis 30.1%. The volume of distribution in humans is estimated to be low (1.0 L/kg).