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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 [ 14 C]-phenoxyethanol ([ 14 C]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 (CL int,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 (AUC ss ) in kidney and liver (and lung for inhalations), which are known target organs of exhibiting toxicity of PE, as well as AUC ss in plasma of PE and PAA were obtained from the model.

Ethylene glycol ethers are a well-known series of solvents and hydraulic fluids derived from the reaction of ethylene oxide and monoalcohols. Use of methanol as the alcohol results in a series of mono, di and triethylene glycol methyl ethers. The first in the series, monoethylene glycol methyl ether (EGME or 2-methoxyethanol) is well characterised and metabolises in vivo to methoxyacetic acid (MAA), a known reproductive toxicant. Metabolism data is not available for the di and triethylene glycol ethers (DEGME and TEGME respectively). This study evaluated the metabolism of these two substances in male rats following single oral gavage doses of 500, 1000 and 2000 mg/kg for DEGME and 1000 mg/kg for TEGME. As for EGME, the dominant metabolite of each was the acid metabolite derived by oxidation of the terminal hydroxyl group. Elimination of these metabolites was rapid, with half-lives <4 h for each one. Both substances were also found to produce small amounts of MAA (~0.5% for TEGME and ~1.1% for DEGME at doses of 1000 mg/kg) through cleavage of the ether groups in the molecules. These small amounts of MAA produced can explain the effects seen at high doses in reproductive studies using DEGME and TEGME., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

This study describes the development of a simple LC-ESI-MS/MS method with polarity switching for the simultaneous analysis of phenoxyethanol (PE) and its major metabolite, phenoxyacetic acid (PAA), in rat plasma, urine, and 7 different tissues. The assay was validated to demonstrate the linearity, precision, accuracy, LLOQ, recovery, and stability by using the matrix matched QC samples. The assay achieved the LLOQ of 10 and 20 ng/mL of PE and PAA, respectively, for plasma samples and the LLOQ of 20 and 50 ng/mL of PE and PAA, respectively, for urine and tissue samples. This method was successfully applied to the percutaneous absorption, distribution, metabolism, and excretion studies in rats. The absolute topical bioavailability of PE was 75.4% and 76.0% for emulsion and lotion, respectively. Conversion of PE to PAA was extensive, with the average AUCPAA-to-AUCPE ratio being 4.4 and 5.3 for emulsion and lotion, respectively. The steady-state tissue-to-plasma PE concentration ratio (Kp) was higher than unity for kidney, spleen, heart, brain, and testis and was lower (≤0.6) for lung and liver, while the metabolite Kp ratio was higher than unity for kidney, liver, lung, and testis and was lower (≤0.3) for other tissues. Findings of this study may be useful to evaluate the relationship between exposure and toxic potential of PE in risk assessment., (Copyright © 2015 Elsevier B.V. All rights reserved.)

2-Phenoxyethanol (PhE) has been shown to induce hepatotoxicity, renal toxicity, and hemolysis at dosages ≥ 400 mg/kg/day in subchronic and chronic studies in multiple species. To reduce uncertainty associated with interspecies extrapolations and to evaluate the margin of exposure (MOE) for use of PhE in cosmetics and baby products, a physiologically-based pharmacokinetic (PBPK) model of PhE and its metabolite 2-phenoxyacetic acid (PhAA) was developed. The PBPK model incorporated key kinetic processes describing the absorption, distribution, metabolism and excretion of PhE and PhAA following oral and dermal exposures. Simulations of repeat dose rat studies facilitated the selection of systemic AUC as the appropriate dose metric for evaluating internal exposures to PhE and PhAA in rats and humans. Use of the PBPK model resulted in refinement of the total default UF for extrapolation of the animal data to humans from 100 to 25. Based on very conservative assumptions for product composition and aggregate product use, model-predicted exposures to PhE and PhAA resulting from adult and infant exposures to cosmetic products are significantly below the internal dose of PhE observed at the NOAEL dose in rats. Calculated MOEs for all exposure scenarios were above the PBPK-refined UF of 25., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The aim of the study was to investigate the suitability of butoxyethoxyacetic acid (BEAA) as a biomarker of exposure to water-based cleaning agents containing diethylene glycol mono butyl ether (DEGBE). The study was performed in two printing plants where water-based products containing 10-15% DEGBE were used for rubber and blanket washes. Thirty nine newspaper pressroom workers (exposed) and 19 employees of newspaper despatch departments (controls) were investigated. By questionnaire, the workers were asked about the use of personal protective measures. BEAA was determined in post-shift urine using GC-MS. The BEAA concentration in the urine of exposed workers ranged up to 75.1 mg/l (median 6.3 mg/l), whereas in urine samples of the controls the BEAA level was below or around the determination limit of 0.5 mg/l. A protective effect on DEGBE uptake was observed with the use of protective gloves. This observation implies that dermal penetration of DEGBE may be important in exposure monitoring.

An accurate description of developing embryos' exposure to a xenobiotic is a desirable component of mechanism-based risk assessments for humans exposed to potential developmental toxicants during pregnancy. 2-Methoxyethanol (2-ME), a solvent used in the manufacture of semiconductors, is embryotoxic and teratogenic in all species tested including nonhuman primates. 2-Methoxyacetic acid (2-MAA) is the primary metabolite of 2-ME and the proximate embryotoxic agent. The objective of the work described here was to adapt an existing physiologically based pharmacokinetic (PBPK) model for 2-ME and 2-MAA kinetics during midorganogenesis in mice to rats on gestation days (GD) 13 and 15. Blood and tissue data were analyzed using the extrapolated PBPK model that was modified to simulate 2-ME and 2-MAA kinetics in maternal plasma and total embryo tissues in pregnant rats. The original mouse model was simplified by combining the embryos and placenta with the richly perfused tissue compartment. The model includes a description of the growth of the developing embryo and changes in the physiology of the dam during pregnancy. Biotransformation pathways of 2-ME to either ethylene glycol (EG) or to 2-MAA were described as first-order processes based on the data collected from rats by Green et al., (Occup. Hyg. 2, 67-75, 1996). Tissue partition coefficients (PCs) for 2-ME and 2-MAA were determined for a variety of maternal tissues and the embryos. Model simulations closely reflected the biological measurement of 2-ME and 2-MAA concentrations in blood and embryo tissue following gavage or iv administration of 2-ME or 2-MAA. The PBPK model for rats as described here is well suited for extrapolation to pregnant women and for assessment of 2-MAA dosimetry under various conditions of possible human exposure to 2-ME., (Copyright 2000 Academic Press.)

Male painters are commonly exposed to ethylene glycol monoethyl ether (EGE), a well known reproductive toxic agent causing testicular atrophy, in the form of solvent mixture containing toluene (TOL) and xylene (XYL). This study was carried out to determine the effect of exposing male rats to solvent mixture containing TOL and XYL on the EGE (200 mg/kg) on testicular atrophy and production of toxic metabolite, ethoxyacetic acid (EAA) from EGE. Compared to the extent of testes atrophy observed upon EGE administration alone, the combined administration of EGE (200 mg/kg) with TOL (250 mg/kg) and XYL (500 mg/kg) for 4 weeks has reduced the extent of testes atrophy by 25%. The combined administration delayed the time for appearance of the highest plasma concentration (t(max)) of EAA from 3 to 6 h and also decreased the highest concentration (Cmax) as well as the total amount of plasma EAA (AUC(0-18 h)) by 45 and 29%, respectively. This explained the diminished testicular atrophy in male rats observed when EGE was administered in a solvent mixture containing TOL and XYL. This study suggested that testicular toxicity observed in male painters caused by EGE may be decreased when they are exposed to EGE in the form of solvent mixture containing TOL and XYL.

Objectives: To estimate dermal absorption of vaporous and liquid 2-methoxyethanol (ME) and 2-ethoxyethanol (EE) in volunteers., Methods: Five volunteers (two men and three women) were dermally exposed to vaporised and liquid ME and EE. Dermal exposure on an area of about 1000 cm2 (forearm and hand) to vapours of ME and EE (4000 mg/m3 ME and 3700 mg/m3 EE) lasted for 45 minutes. Duration of exposure to liquid ME and EE on an area of 27 cm2 (forearm) was 15 minutes. Dermal uptake was assessed by measurement of the main metabolites in urinary methoxyacetic acid (MAA) and ethoxyacetic acid (EAA). For each volunteer, excretion of metabolites was compared with a reference inhalatory exposure., Results: Mean (SD) absorption rates of ME and EE vapour were 36 (11) and 19 (6) cm/h respectively. The mean (SD) absorption rates of the liquid ME and EE amounted to 2.9 (2.0) and 0.7 (0.3) mg/cm2.h., Conclusions: Vaporised and liquid ME and EE are readily absorbed through the skin. In the combined inhalatory and dermal exposure when whole body surface is exposed to vapour, the uptake through the skin is estimated to be 55% of the total uptake of ME and 42% of EE. Dermal uptake resulting from skin contact of both hands and forearms (about 2000 cm2) with liquid ME and EE for 60 minutes would exceed inhalatory uptake of the eight hour occupational exposure limit by 100 times at 16 mg/m3 of ME and 20 times at 19 mg/m3 of EE. The substantial skin uptake of ME and EE indicates that in assessing the health risks biological monitoring and use of biological exposure indices are preferable to environmental monitoring.

A physiologically based pharmacokinetic (PBPK) model was created to describe the disposition of 2-methoxyethanol (2-ME) and its teratogenic metabolite, 2-methoxyacetic acid (2-MAA), in the pregnant CD-1 mouse. The model's foundation is a mathematical description of the physiological changes that occur during gestation (O'Flaherty et al., Toxicol. Appl. Pharmacol. 112, 245-256, 1992). The PBPK model was developed and validated with data collected on Gestation Day (GD) 11. Absorption, distribution, and oxidation of 2-ME to 2-MAA and ethylene glycol (EG) were simulated. Flow-limited disposition of 2-ME in maternal tissues was described using in vitro-determined tissue partition coefficients (PCs). The maximum velocity (Vmax) of 2-ME oxidation to 2-MAA was calculated from literature-based in vitro data. Vmax for EG formation, and Michaelis constants for 2-MAA and EG pathways, were estimated from optimized simulations of plasma 2-ME and metabolite levels obtained after intravenous injection of 5-600 mg 2-ME.kg-1.2-MAA disposition and elimination in the dam were described by a nonphysiological one-compartment model, which was linked to the 2-ME model, based on the volume of distribution (0.510 liters.kg-1) and overall elimination rate constant (0.124 hr-1) calculated from iv 2-MAA plasma concentration-time courses. Transfer of 2-MAA between the placenta and conceptus was described as a diffusion-limited process to more accurately simulate the higher concentrations of 2-MAA determined in embryonic compartments compared with maternal plasma levels. Subsequent 2-MAA disposition within the embryo proper and surrounding fluid of the GD 11 conceptus was adequately described using embryo/blood (0.94) and extraembryonic fluid/blood (1.33) PCs. Extension of the PBPK model to oral and subcutaneous 2-ME administrations required optimization of first-order absorption rates; model simulations agreed closely with measured 2-ME/2-MAA levels. With refinements and further validation, the PBPK model of 2-ME/2-MAA disposition should prove helpful for extrapolation throughout gestation and between species.

The embryotoxic effects of 2-methoxyethanol (2-ME) were studied in non-human primates to better assess the risk for women of child-bearing age exposed to this agent. Macaca fascicularis females were treated daily throughout the organogenetic phase of pregnancy (days 20-45) by gavage and the fetuses collected at day 100 by Caesarean section. At the highest dose (0.47 mmole/kg), all eight pregnancies ended in death of the embryo. One of these dead embryos was abnormal, missing a digit on each forelimb. At the middle dose (0.32 mmole/kg), three of 10 pregnancies ended in embryonic death, presumably due to 2-ME exposure and three of 13 pregnancies met a similar fate at the low dose (0.16 mmole/kg). In each of these two groups, an additional pregnancy was lost to abortion, but both were thought to be spontaneous, which usually occurs in 10-20% of untreated macaque pregnancies. These results indicate that 2-ME is a potent toxin to the developing primate embryo and thereby furthers the concern about exposure of pregnant women to this agent, although maternal toxicity was evident in nearly all treated pregnancies and was especially severe in the high-dosage animals. Distribution of the major metabolite of 2-ME, 2-methoxyacetic acid (2-MAA), indicated a long half-life (ca. 20 h), resulting in accumulation of metabolite in maternal serum after repeated daily dosing. Transplacental studies revealed uniform distribution in the embryo and extraembryonic fluids at a concentration similar to that in maternal serum. The yolk sac, on the other hand, accumulated a very high concentration of 2-MAA, but the embryotoxic significance of this observation is unknown.

The uptake of EGME and the urinary excretion of its major metabolite (MAA) was studied in seven male volunteers during experimental exposure to EGME at rest. The exposure concentration was set at 16 mg/m3, the present Threshold Limit Value. A high retention (0.76) remained unchanged during the 4-h exposure period. In combination with a constant pulmonary ventilation and a fixed exposure concentration this resulted in an uptake rate that showed no significant variation in time. The total amount of EGME inhaled corresponded to a dose of only 0.25 mg/kg. During and up to 120 h after the start of the exposure, MAA was detected in the urine. The elimination half-life was on average 77.1 h. The total amount of MAA excreted was calculated by extrapolation and averaged 85.5% of the inhaled EGME. The pharmacokinetic data are compared with those obtained from other human exposure studies to ethylene glycol ethers (EGEE and EGBE).