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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.

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.)

Exposure to ethylene glycol monomethyl ether (EGME), a glycol ether compound found in numerous industrial products, or to its active metabolite, 2-methoxyacetic acid (2-MAA), increases the incidence of developmental defects. Using an in vitro limb bud culture system, we tested the hypothesis that the effects of EGME on limb development are mediated by 2-MAA-induced alterations in acetylation programming. Murine gestation day 12 embryonic forelimbs were exposed to 3, 10, or 30 mM EGME or 2-MAA in culture for 6 days to examine effects on limb morphology; limbs were cultured for 1 to 24 hr to monitor effects on the acetylation of histones (H3K9 and H4K12), a nonhistone protein, p53 (p53K379), and markers for cell cycle arrest (p21) and apoptosis (cleaved caspase-3). EGME had little effect on limb morphology and no significant effects on the acetylation of histones or p53 or on biomarkers for cell cycle arrest or apoptosis. In contrast, 2-MAA exposure resulted in a significant concentration-dependent increase in limb abnormalities. 2-MAA induced the hyperacetylation of histones H3K9Ac and H4K12Ac at all concentrations tested (3, 10, and 30 mM). Exposure to 10 or 30 mM 2-MAA significantly increased acetylation of p53 at K379, p21 expression, and caspase-3 cleavage. Thus, 2-MAA, the proximate metabolite of EGME, disrupts limb development in vitro, modifies acetylation programming, and induces biomarkers of cell cycle arrest and apoptosis., (© 2014 Wiley Periodicals, Inc.)

Background: This study was conducted as part of an ILSI-HESIconsortium effort to assess the utility of circulating inhibin B as an early biomarker of testicular toxicity in rats., Methods: Two known testicular toxicants were selected for use in this study: ethylene glycol monomethyl ether (EGME) and dibromoacetic acid (DBAA). EGME (200 mg/kg/day), DBAA (250 mg/kg/day), or vehicle control (0.2% hydroxypropyl methylcellulose [HPMC]) was administered orally to male rats for 3, 6, or 14 consecutive days. On study days 4, 7, and 15, serum was collected for evaluation of inhibin B levels from all surviving animals and a subset of animals was necropsied from each of the control, EGME, and DBAAgroups., Results: Administration of EGMEresulted in spermatocyte degeneration in late stage tubules and spermatocyte depletion to stage III on day 4, progressing to loss of spermatocytes and round spermatids to stage VI by day 7 and continued germ cell loss and degeneration of elongating spermatids by day 15. Inhibin B levels among EGME-treated animals progressively decreased relative to their respective controls at all time points. Administration of DBAA was associated with spermatid retention at all three time points and abnormal residual bodies at days 7 and 15. Inhibin B levels among DBAA-treated animals decreased progressively relative to their respective controls on days 7 and 15., Conclusions: Serum inhibin B levels in rats provided a signal of testicular toxicity for each of these known testicular toxicants administered at high levels; however, histopathology provided the earliest evidence of toxic effects., (© 2013 Wiley Periodicals, Inc.)

These studies define the site and mechanisms of reproductive toxicity of ethylene glycol monomethyl ether (EGME) in a nongravid female animal model using in vivo and in vitro methods. In vivo studies assessed vaginal cytology and histology, ovarian histology, and serum hormones in 80- to 90-day-old, adult, regularly cycling, female Sprague-Dawley rats treated daily with EGME or vehicle by oral gavage. Dose-response and time-course studies (four to nine rats per group per treatment) determined that 300 mg/kg EGME suppressed cyclicity without systemic toxicity within 3 to 8 days, and doses less than 100 mg/kg had no effect. Pathogenesis studies (six to nine rats per time and treatment) determined that 300 mg/kg EGME elevated serum progesterone within 32 hr after dosing, while serum estradiol, FSH, LH, and prolactin remained at baseline levels. In EGME-treated rats, cyclicity was suppressed, ovulation was inhibited, and corpora lutea were hypertrophied. Thus, EGME appeared to target the ovarian luteal cell. To further examine the toxicity in vitro, luteal cells were recovered from 23-day-old, hCG-primed Sprague-Dawley rats and treated with 0-10 mM methoxy acetic acid (MAA), the proximate toxic metabolite of EGME. MAA (1-10 mM) maintained elevated progesterone levels as production declined in untreated cells at 24 and 48 hr of culture. Progesterone production was maintained independent of LH-stimulated cAMP levels. MAA decreased ATP, but only at 48 hr and at 2.5 mM or greater concentrations. Thus, these studies establish that the ovarian luteal cell is a target of EGME and MAA in vivo and in vitro and that the effect on luteal cell progesterone production is likely independent of LH-stimulated cAMP pathways.

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.

The teratogen 2-methoxyethanol (2-ME), an industrial solvent, was administered to pregnant CD-1 mice either as a single subcutaneous (sc) bolus dose (100-250 mg/kg) or via constant-rate infusion from sc implanted osmotic minipumps (34.7 or 69.4 mg/kg/hr for up to 12 hr) on gestation Day 11, when embryonic paw development is maximally sensitive to perturbation by this agent. The sc entry route most closely reflects likely human exposures via dermal penetration, while bolus and constant-rate infusion administrations were contrasted to mimic potential occupational exposure scenarios. The pharmacokinetic profiles of 2-methoxyacetic acid (2-MAA), the proximate toxic metabolite of 2-ME, were quantitated, generating peak concentration (Cmax) and total 2-MAA exposure values (24-hr area under the concentration-time curve; AUC) in the maternal plasma, extraembryonic fluid, and embryo. The total 2-ME dose (mg/kg) required to achieve similar 2-MAA levels (Cmax or AUC) in these compartments was 2- to 3-fold higher by constant-rate infusion than by bolus injection; therefore, no simple association existed between 2-MAA levels and the total 2-ME dose, when the dose rate was not considered. Similarly, there was no good correlation between the combined total 2-ME doses and the fetal malformation rate, although clear dose-response patterns for paw malformations were observed in litters and fetuses for each individual dosing regimen. However, the combined 2-MAA pharmacokinetic data from each of the dosing regimens demonstrated that during the phase of maximum susceptibility of paw morphogenesis to disruption by 2-MAA (from gd 11 to gd 11.5), a strong linear correlation existed between fetal malformation incidence and 2-MAA AUC levels in either maternal plasma or embryonic compartments (linear correlation coefficient, r2 0.91-0.92). The correlation with Cmax was less favorable (r2 0.74-0.81) over the dose range studied. In a further experiment designed to investigate the importance of AUC vs Cmax regarding 2-ME teratogenicity, infusion of 2-ME (34.7 mg/kg/hr for 8 hr) beginning 2.5 hr after bolus loading (175 mg/kg) provided an increased 24-hr 2-MAA AUC without increased Cmax. This resulted in greater than 70% of the fetuses having various digit malformations (micro-, syn-, ectro-, and polydactyly), compared to only 32-35% of fetuses with mostly stunted digits when either dose was applied singularly. These data support total 2-MAA exposure (AUC levels), rather than peak 2-MAA concentrations, as the principle determinant of teratogenesis following exposure to 2-ME.(ABSTRACT TRUNCATED AT 400 WORDS)