2-(3-oxazolidinyl)ethyl methacrylate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, 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, but not (completely) 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. The plasma protein binding and volume of distribution (Vd).
iII. 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% 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% 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% 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.
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

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 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) with additional predictions upon knowledge of other methacrylate substances.

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

Main ADME results

Main ADME results 1

Type:

absorption

Results:

The predicted fractional absorption (Fa%) and systemic bioavailability (F%) values for oxazolidinyl ethyl methacrylate from oral, dermal, and inhalation exposures and the predicted Cmax values are summarized in Table 1.

Main ADME results 2

Type:

distribution

Results:

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

Main ADME results 3

Type:

metabolism

Results:

OXEMA will be rapidly ester hydrolyzed to methacrylic acid (MAA) and Oxazolidine-3-ethanol. MAA is quickly degraded to carbon dioxide and water. Oxazolidine-3-ethanol will be further metabolized and conjugated to form glucuronides and/or sulfates.

Main ADME results 4

Type:

excretion

Results:

The various conjugate forms (such as sulfates, glucuronides) and acids 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.

Main ADME results 5

Type:

other: Accumulation

Results:

On the basis of low volume of distribution, oxazolidinyl ethyl methacrylate is not expected to bioaccumulate.

Any other information on results incl. tables

Absorption

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 tooxazolidinyl ethyl methacrylateby GastroPlus are 100%, 99.1%, and 81.6%, respectively. Metabolism via ester hydrolysis is outside the applicability domain of GastroPlus and therefore systemic bioavailability simulations using this modeling program are not considered reliable for this chemistry. Due to the expected rapid primary ester hydrolysis and subsequent metabolism (see below), the predicted systemic bioavailability of OXEMA is expected to be negligible as has been demonstrated for other short chain methacrylate esters (Gelbke et al., 2017). 

 

Metabolism

No metabolism data are available for OXEMA. Methacrylate esters are well known to be primarily metabolized via rapidly enzymatic ester hydrolysis to methacrylic acid and the corresponding alcohol (Gelbke et al. 2017). The ester hydrolysis occurs by carboxylesterases that are widely distributed throughout the body and have a high activity within many tissues, including the liver, blood, gastro-intestinal tract, nasal epithelium and skin (Satoh and Hosokawa, 1998; Junge and Krisch, 1975; Bogdanffy et al., 1987; Frederick et al., 1994). Rapid hydrolysis of short chain methacrylate esters has been confirmed for the olfactory and nasal respiratory tract, the blood, skin and liver of rats and humans (Jones, 2002). This reaction typically occurs within minutes to less than an hour in the blood and/or liver. 

OXEMA, as short-chain methacrylate ester, is expected to undergo enzymatic hydrolysis to form methacrylic acid (MAA) and Oxazolidine-3-ethanol (Figure 1). Upon formation, MAA then enters a rapid physiologic degradation pathway with a very short half-life and is cleared predominantly via the liver forming carbon dioxide and water (Bratt and Hathway, 1977). The Oxazolidine-3-ethanol metabolite will be further metabolized by CYP450 and aldehyde dehydrogenase (ADH) (Figure 2). The resulting metabolites will be further conjugated to form glucuronides and/or sulfates.

Distribution

The predicted human plasma protein binding upon absorption OXEMA is 30.1%. The volume of distribution in humans is estimated to be low (1.0 L/kg).On the basis of low volume of distribution, and predicted metabolism and excretion,oxazolidinyl ethyl methacrylateis not expected to bioaccumulate in humans.

 

Excretion

No intact OXEMA is likely to be excreted due to the rapid ester hydrolysis and further metabolism. The resulting phase II metabolite ofOxazolidine-3-ethanol(glucuronide and sulfide conjugates) will also be excreted to urine and feces while the carbon dioxide will be exhaled from MAA.

References

Bogdanffy, MS, Randall, HW, Morgan, KT (1987). Biochemical quantitation and histochemical localization of carboxylesterase in the nasal passages of the Fischer-344 rat and B6C3F1 mouse. Toxicol. Appl. Pharmacol. 88: 183-194

Bratt H, Hathway DE (1977). Fate of methyl methacrylate in rats. Brit. J. Cancer 36: 114-119.

Frederick, CB, Udinsky, JR, Finch, L (1994). The regional hydrolysis of ethyl acrylate to acrylic acid in the rat nasal cavity. Toxicol. Letters 70: 49-56

Gelbke, HP, Ellis-Hutchings, RG, Mullerschon, H, Murphy, S, Pemberton, M (2017). Toxicological assessment of lower alkyl methacrylate esters by a category approach. Regul. Toxicol. Pharmacol. 92: 104-127.

Jones, RDO (2002). Using physiologically based pharmacokinetic modelling to predict the pharmacokinetics and toxicity of methacrylate esters. A Thesis submitted to Univ. of Manchester for the degree of Doctor of Philosophy.

Junge, W, Krisch, K (1975). The carboxylesterases/amidases of mammalian liver and their possible significance. Crit. Rev. Food Sci. Nutrition 371-434

Satoh, T, Hosokawa, M (1998). The Mammalian carboxylesterases: From models to functions. Ann. Rev. Pharmacol. Toxicol. 38: 257-288. Medicine and Biology 283: 333-335

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).
Based on the metabolism prediction by ADMET predictor, oxazolidinyl ethyl methacrylate will be metabolized to hydroxylated metabolites (by human CYP 2C19, CYP 2D6). Some of the oxazolidine ring hydroxylated metabolites will be further converted to the corresponding aldehydes. 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 aldehydes will be further metabolized to the corresponding acids and excreted in urine. Also this ester can be potentially hydrolyzed by esterases to oxazolidinyl ethanol and methacrylic acid which will also be metabolized to water soluble phase II metabolites (such as glucuronides and sulfates). The resulting phase II metabolites will also be excreted to urine and feces.
On the basis of low volume of distribution, and predicted metabolism and excretion, oxazolidinyl ethyl methacrylate is not expected to bioaccumulate in humans.

Executive summary:

To assess the absorption, distribution, and excretion 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). Metabolism via ester hydrolysis is outside the applicability domain of GastroPlus but methacrylate esters are well known to be primarily metabolized via rapidly enzymatic ester hydrolysis to methacrylic acid (MAA) and the corresponding alcohol. MAA is then rapidly degraded and cleared predominantly via the liver forming carbon dioxide and water. The Oxazolidine-3-ethanol metabolite will be further metabolized by CYP450 and aldehyde dehydrogenase (ADH) and the resulting metabolites will be further conjugated to form glucuronides and/or sulfates.On the basis of low volume of distribution, and predicted metabolism and excretion,oxazolidinyl ethyl methacrylateis not expected to bioaccumulate in humans.