Abstract
2-Phenoxyethanol (PE), ethylene glycol monophenyl ether, is widely used as a preservative in cosmetic products as well as in non-cosmetics. Since PE has been used in many types of products, it can be absorbed via dermal or inhaled route for systemic exposures. In this study, the pharmacokinetic (PK) studies of PE and its major metabolite, phenoxyacetic acid (PAA), after dermal (30 mg and 100 mg) and inhaled administration (77 mg) of PE in rats were performed. PE was administered daily for 4 days and blood samples were collected at day 1 and day 4 for PK analysis. PE was rapidly absorbed and extensively metabolized to form PAA. After multiple dosing, the exposures of PE and PAA were decreased presumably due to the induction of metabolizing enzymes of PE and PAA. In dermal mass balance study using [14C]-phenoxyethanol ([14C]PE) as a microtracer, most of the PE and its derivatives were excreted in urine (73.03%) and rarely found in feces (0.66%). Based on these PK results, a whole-body physiologically-based pharmacokinetic (PBPK) model of PE and PAA after dermal application and inhalation in rats was successfully developed. Most of parameters were obtained from the literatures and experiments, and intrinsic clearance at steady-state (CLint,ss) were optimized based on the observed multiple PK data. With the developed model, systemic exposures of PE and PAA after dermal application and inhalation were simulated following no-observed-adverse-effect level (NOAEL) of 500 mg/kg/day for dermal application and that of 12.7 mg/kg/day for inhalation provided by the Environmental Protection Agency. The area under the concentration–time curve at steady state (AUCss) in kidney and liver (and lung for inhalations), which are known target organs of exhibiting toxicity of PE, as well as AUCss in plasma of PE and PAA were obtained from the model.
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Data availability
The data are available upon the reasonable request to the corresponding author.
Abbreviations
- AC:
-
Aerosol concentration
- AMS:
-
Accelerator mass spectrometer
- AUC:
-
Area under the plasma concentration–time curve
- AUCinf :
-
Area under the plasma concentration–time curve from time zero to infinity
- AUClast :
-
Area under the plasma concentration–time curve within time span zero to last
- AUCPAA/AUCPE :
-
Metabolic ratio calculated by phenoxyacetic acid AUC/phenoxyethanol AUC ratio
- Carterial :
-
Drug concentrations in arterial blood compartments
- CL:
-
Clearance
- CLint :
-
Intrinsic clearance
- Cmax :
-
Maximum observed drug concentration in plasma
- Css :
-
Concentration at steady-state
- CT :
-
Concentration of drug in tissue
- CV:
-
Coefficient of variation
- CYP:
-
Cytochrome P450s
- D:
-
Duration of exposure to the aerosol
- ESI:
-
Electrospray ionization
- fu :
-
Unbound fraction in plasma
- fu ,hep :
-
Unbound fraction in hepatocytes
- IS:
-
Internal standard
- IVIVE:
-
In vitro-in vivo extrapolation
- Kper :
-
Permeability coefficient through skin
- Kp ,T :
-
Tissue:plasma partition coefficient
- LC–MS/MS:
-
Liquid chromatography tandem mass spectrometry
- LLOQ:
-
Lower limit of quantification
- LSC:
-
Liquid scintillation counting
- MRM:
-
Multiple reaction monitoring
- NOAEL:
-
No-observed-adverse-effect level
- p :
-
Original model parameter value
- PBPK:
-
Physiologically-based pharmacokinetic
- PK:
-
Pharmacokinetic
- QC:
-
Quality control
- QT :
-
Tissue blood flow
- RMV:
-
Represents respiratory minute volume, which is the respiratory rate multiplied by the tidal volume
- RSD:
-
Relative standard deviation
- SA:
-
Surface area of applied PE formulation
- t ½ :
-
Terminal elimination half-life
- Tmax :
-
Time to reach maximum (peak) plasma concentration following drug administration
- Vd :
-
Volume of distribution
- VT :
-
Volume in tissue compartment
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Acknowledgements
We especially thank the support from Professor Kyung-Min Lim in Ewha Womans University, Professor Ok-Nam Bae in Hanyang University, and Professor Soo Kyung Bae in the Catholic University of Korea, Republic of Korea.
Funding
This study was funded by the Korea Ministry of Environment (MOE) as “the Environmental Health Action Program” and “Technology Program for establishing biocide safety management” (2019002490005 1485016231 and 2019002490004 1485016253) and also supported by a grant of the Korea Institute of Radiological and Medical Sciences (KIRAMS), funded by Ministry of Science and ICT(MSIT), Republic of Korea (No. 50539-2020).
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All authors were involved in the conception and design of the study and data interpretation. MK and SHB drafted the paper, conducted PK studies, and performed PBPK modeling. JBP and MK conducted PK studies and JS and CSY conducted sample analysis. All authors critically revised the paper and approved it for submission.
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The animal experiment was approved by the Institutional Animal Care and Use Committee (IACUC) of the Korea Institute of Radiological & Medical Sciences (KIRAMS), Republic of Korea (approval number: Kirams2019-45). In addition, all animal experimental procedures were carried out in accordance with the revised Guidelines for Ethical Conduct in the care and Use of Animals and the rules of Good Laboratory Practice.
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Kwon, M., Park, J.B., Kwon, M. et al. Pharmacokinetics of 2-phenoxyethanol and its major metabolite, phenoxyacetic acid, after dermal and inhaled routes of exposure: application to development PBPK model in rats. Arch Toxicol 95, 2019–2036 (2021). https://doi.org/10.1007/s00204-021-03041-z
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DOI: https://doi.org/10.1007/s00204-021-03041-z