Reaction mass of docosyl acrylate and octadecyl acrylate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Remarks:

Physiologically-based pharmacokinetic (PBPK) modeling

Type of information:

calculation (if not (Q)SAR)

Adequacy of study:

key study

Study period:

March - April 2023

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

accepted calculation method

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2023

Report date:

2023

Materials and methods

Objective of study:

absorption

distribution

toxicokinetics

Principles of method if other than guideline:

Physiologically Based Pharmacokinetic Models
The Simcyp Animal Simulator Version 22 Release 1 (Certara UK) was used for PBPK simulations (https://www.certara.com/software/simcyp-pbpk/ ). A whole body PBPK model, which allows for the addition of further specific organs, or a minimal PBPK model was used in simulations. (further details see attachment)

GLP compliance:

no

Results and discussion

Main ADME results

Type:

absorption

Results:

see attachment results

Any other information on results incl. tables

In a first step a physiologically-based pharmacokinetic (PBPK) models for 2-ethylhexyl acrylate (2EHA) and 2-ethylhexanol (2EH) were developed in the rat. Tissue distribution was predicted using a mechanistic tissue composition method (Rodgers et al., 2005, Rodgers and Rowland 2006) (Simcyp method 2). The tissue distribution models were parameterised using estimates of the log of the octanol-water partition coefficient (LogP) and predicted values for fraction unbound (fu) and blood:plasma ratio (B/P). For 2EH, a minimal PBPK model was parameterised with a single adjusting compartment to capture the biphasic time course of the compound in blood and for 2EHA, a full body PBPK model was used.

Metabolism of 2EHA to 2EH was parameterised using in vitro metabolism data in rat liver microsomes and rat plasma. Clearance of total 2EH-related radioactivity was included in the model based on urinary and expired CO2-reported mass balance data after intravenous (IV) dosing. The developed 2EH PBPK model in the rat was able to show close agreement between observed and predicted plasma concentration-time data from orally administered 2EH (70.6 mg/kg body weight (BW)) when assuming administration as a solution with precipitation and first pass intestinal extraction (20%). Considering the high predicted permeability and observed high intrinsic solubility, predicted fraction absorbed (fa) was 1.00 and was insensitive to critical supersaturation ratio (CSR) and precipitation rate constant (PRC) values. The 2EH model was subsequently modelled as a primary metabolite of 2EHA following oral 2EHA administration (100 mg/kg BW). When simulated as a solution with precipitation, considering intrinsic solubility of 2EHA, the CSR of 10 and a PRC of 0.3 1/h were found to capture observed fa (approximately 0.90) in line with in vivo data.

The same assumptions of absorption model settings were applied to 7 chemically related acrylate esters with varying chain lengths, lipophilicity, solubility and physical states. Chemicals with a solid physical state at 20°C were assumed to be administered as a solid (requiring the compound to dissolve in the intestine before absorption can take place). Predicted fa ranged from 0.0001 to 1.00. In general, the larger compounds (chain length >14) with higher log octanol/buffer partition coefficient (LogPo:w) (>8), lower intrinsic solubility (<2x10-6 mg/mL) and a solid physical state at 20oC resulted in lower predicted fa values.

Predicted fa in rat for a series of chemically related acrylate esters with varying chain lengths.

Absorption predictions were based on the settings utilised in a PBPK model built to describe absorption and exposure of 2-ethylhexyl acrylate and its metabolite 2-ethyl hexanol. :

Compound Name	Side Chain Length	LogPow	Aqueous Solubility (mg/ml)	Physical state at 20°C	Predicted Rat fa
Ethyl acrylate	2	1.18	1.00E-02	Liquid	1.00
2 -Ethylhexanol		2.9	9.00E-01	Liquid	1.00
2 -Ethylhexyl acrylate	8	4	1.00E-02	Liquid	0.91
Dodecyl acrylate	12	6.13	2.00E-04	Liquid	0.81
Tetradecyl acrylate	14	7.11	2.00E-06	Liquid	0.77
Hexadecyl acrylate	16	8.09	1.19E-06	Solid paste	0.0150
Octadecyl acrylate	18	9.08	2.61E-10	Solid paste	0.0001
Icosyl acrylate	20	10.06	2.70E-08	Solid paste	0.0022
Docosyl acrylate	22	11.04	1.50E-09	Solid	0.0006