Ethoxyacetic Acid Research Articles

Peptide and Protein Mimetics Inhibiting Amyloid β-Peptide Aggregation

Protein misfolding is related to some fatal diseases including Alzheimer's disease (AD). Amyloid beta-peptide (Abeta) generated from amyloid precursor protein can aggregate into amyloid fibrils, which are known to be a major component of Abeta deposits (senile plaques). The fibril formation of Abeta is typical of a nucleation-dependent process through self-recognition. Moreover, during fibrillization, several metastable intermediates such as soluble oligomers, including Abeta-derived diffusible ligands (ADDLs) and Abeta*56, are produced, which are thought to be the most toxic species to neuronal cells. Therefore, construction of molecules that decrease the Abeta aggregates, including soluble oligomers, protofibrils, and amyloid fibrils, might further our understanding of the mechanism(s) behind fibril formation and enable targeted drug discovery against AD. To this aim, various peptides and peptide derivatives have been constructed using the "Abeta binding element" based on the structural models of Abeta amyloid fibrils and the mechanisms of self-assembly. The central hydrophobic amino acid sequence, LVFF, of Abeta is a key sequence to self-assemble into amyloid fibrils. By combination of this core sequence with a hydrophobic or hydrophilic moiety, such as cholic acid or aminoethoxy ethoxy acetic acid units, respectively, good inhibitors of Abeta aggregation can be designed and synthesized. A peptide, LF, consisting of the sequence Ac-KQKLLLFLEE-NH 2, was designed based on the core sequence of Abeta but with a simplified amino acid sequence. The LF peptide can form amyloid-like fibrils that efficiently coassemble with mature Abeta1-42 fibrils. The LF peptide was also observed to immediately transform the soluble oligomers of Abeta1-42, which are thought to pose toxicity in AD, into amyloid-like fibrils. On the other hand, two Abeta-like beta-strands with a parallel orientation were embedded in green fluorescent protein (GFP), comprised of a beta-barrel structure, to make pseudo-Abeta beta-sheets on its surface. The GFP variant P13H binds to Abeta1-42 and inhibits Abeta1-42 oligomerization effectively in a substoichiometric condition. Thus, molecules capable of binding to Abeta can be designed based on structural similarities with the Abeta molecule. The peptide and protein mimetics based on the structural features of Abeta might lead to the development of drug candidates against AD.

NP1EC Degradation Pathways Under Oxic and Microxic Conditions

The degradation pathway of nonylphenol ethoxyacetic acid (NP1EC) and the conditions favoring dicarboxylated alklyphenol ethoxyacetic acid (CAnP1EC; where n = the number of aliphatic carbon atoms) formation were studied in oxic microcosms constructed with organic carbon-poor soil from the Mesa soil aquifer treatment (SAT) facility (Arizona) and pristine organic carbon-rich sediments from Coyote Creek (California). Results suggest that the availability of dissolved oxygen determines the dominant biodegradation pathway; ether cleavage and the formation of NP is favored by oxic conditions, while alkyl chain oxidation and the formation of CAP1ECs is favored under microxic conditions. In the Mesa microcosms, para-NP1EC was transformed to para-nonylphenol (NP) before being rapidly transformed to nonyl alcohols via ipso-hydroxylation. In the Coyote Creek microcosms, large quantities of CAP1ECs were observed. Initially, CA8P1ECs were the dominant metabolites, but as biodegradation continued, CAP1ECs became the dominant metabolites. Compared to the CAsP1ECs, the number of CA6P1ECs peaks observed was small (< 6) even though their concentrations were high. Several novel metabolites, tentatively identified as 3-alkylchroman-4-carboxylic acids (with alkyl groups ranging from C2 to C5), were formed in the Coyote Creek microcosms. These metabolites are presumably formed from ortho-CAP1ECs by intramolecular ring closure.

Reproductive Toxicity of Ethylene Glycol Monoethyl Ether in Aldh2 Knockout Mice

Ethylene glycol monoethyl ether (EGEE) can cause damage to testes and sperm, and its metabolites are believed to play an important role in its toxicity. Aldehyde dehydrogenase 2 (ALDH2) is involved in the metabolism of this chemical. To investigate whether and how the enzyme affects the toxicity of EGEE, we conducted experiments comparing Aldh2 knockout mice with wild-type mice. Administration of EGEE at 100 and 600 mg/kg/day for one week did not induce any significant change in the weight and body weight ratios of testes, prostate and epididymides in either Aldh2 knockout or wild-type mice. However, motion of sperm from the spermaduct, as analyzed with a Hamilton-Thorne Sperm analyzer, was slightly decreased in the low dose group, and significantly lower in the high dose group; and the percentage of progressive sperm was also reduced in the two EGEE groups. This effect of EGEE treatment was observed in the wild-type, but not in the Aldh2 knockout mice. Sperm motion from the cauda epididymides was not affected. On the other hand, the concentration of ethoxyacetic acid, a metabolite of EGEE, in 24 h pooled urine of EGEE-treated Aldh2 knockout mice was not significantly lower than that of the wild-type mice on most days of urine sampling. These results suggest that inactivation of the ALDH2 enzyme due to gene mutation may be linked to differences in the susceptibility to EGEE-induced sperm toxicity.

Gas Chromatography Analysis of Urinary Alkoxyacetic Acids as Biomarkers of Exposure to Aliphatic Alkyl Ethers

Analysis of alkoxyacetic acids has received considerable research interest in toxicology because these compounds have been reported as metabolites and biomarkers of exposure to widely used industrial chemicals such as alkyl-substituted ethylene glycols and other aliphatic ethers. This paper describes an improved method for the determination of methoxyacetic acid (MAA), ethoxyacetic acid (EAA), and butoxyacetic acid (BAA) in rat urine. Solid-phase extraction with Bakerbond(T) C18 bonded silica cartridges was successfully employed to isolate the acids from rat urine. The acids were then converted to methyl esters with diazomethane derivatization and analyzed using a gas chromatograph (GC) equipped with a mass spectrometry (MS) and a GC with flame ionization detector (FID). Employing GC-MS under selected ion monitoring detection, the lowest detection concentrations for MAA, EAA, and BAA were determined to be from 2 to 4 ng/mL urine in 1 mL of sample size. This method is 5 to 10 times more sensitive than that using GC-FID. The method described here is superior to the existing ones reported in the literature in that it employs an easy sample treatment procedure and gives much higher recoveries, making it suitable for routine assays. The utility of this new method was demonstrated in a toxicology study of aliphatic alkyl ethers.

Prediction of in vivo embryotoxic effect levels with a combination of in vitro studies and PBPK modelling

The new EU legislations for chemicals (Registration, Evaluation and Authorization of Chemicals, REACH) and cosmetics (Seventh Amendment) stimulate the acceptance of in vitro and in silico approaches to test chemicals for their potential to cause reproductive effects. In the current study seven compounds with known in vivo developmental effects were tested in the embryonic stem cell test (EST). The EST correctly classified 5-fluorouracil, methotrexate, retinoic acid, 2-ethoxyacetic acid and 2-methoxyacetic acid for their in vivo embryotoxic potential. The toxicity of 2-methoxyethanol and 2-ethoxyethanol was underestimated due to a lack of metabolic capacity in the EST. This study further investigated the possibility to use in silico techniques to extrapolate in vitro effect concentrations determined in the EST to in vivo exposure levels. This approach was evaluated by comparing in silico predicted in vivo effect levels with effect levels measured in rodents. The in vivo effect levels of 2-methoxyethanol, 2-ethoxyethanol, methotrexate and retinoic acid were correctly predicted with in silico modelling. Contrary, in vivo embryotoxicity of 5-fluorouracil was overestimated following this approach. It is concluded that a combination of in vitro and in silico techniques appears to be a promising alternative test method for risk assessment of embryotoxic compounds.

Inhibitory Effect of Ethylene Glycol Monoethyl Ether on Rat Sperm Motion

Ethylene glycol monoethyl ether (EGEE) is known to have testicular toxicity. To elucidate whether EGEE has any effect on sperm motion, especially in the case of short time exposure, we conducted a series of in vivo experiments with rats, as well as an in vitro study with rat sperm. Sperm from cauda epididymides and spermaducts was analyzed for the change in motion with a Hamilton-Thorne Sperm analyzer. Administration of EGEE at 600 mg/kg/d for five weeks significantly decreased total and progressive motility of sperm to 15-30% of controls, in both the cauda epididymis and the spermaduct. The time-course experiment using a single dose of 1,000 mg/kg showed that damage to sperm motion was evident at 12-24 h after EGEE administration. Addition of EGEE to the medium of sperm had no effect on its motion, but the metabolite ethoxyacetic acid showed a significant inhibitory effect. These results suggest that besides its toxicity to spermatogenesis, the metabolite of EGEE may also directly affect the motion of mature sperm.

Dicarboxylic degradation products of nonylphenol polyethoxylates: Determination and structural elucidation in water samples by solid-phase extraction and gas chromatography-mass spectrometry after methylation

A reliable method combining solid-phase extraction, derivatization and gas chromatography-chemical ionization mass spectrometry (GC-CI-MS) was developed for the measurement, in river and sewage effluent water, of four select model compounds of dicarboxylic metabolites (dm-CA 5–8P1EC) and other dicarboxylic metabolites (CA 5–8P1ECs) of nonylphenol polyethoxylates. These selected isomers were referred as dm-CA 5–8P1ECs because they have an α,α-dimethyl configuration (expressed as “dm”), five to eight C atoms and a carboxyl group in the alkyl chain, and an ethoxy acetic acid group. The derivatization of terminal carboxyl groups was successful with (trimethylsilyl)diazomethane. The best extraction conditions were obtained using an Oasis HLB cartridge as a sorbent bed and 4 ml of MTBE/methanol (9:1, v/v) elution mixture. The method detection limits of 0.03–0.07 μg/l for dm-CA 5–8P1ECs were attained in 500 ml pure water. The recovery was then evaluated for pure water, river and sewage effluent water samples. The high recoveries of typically >89% for each isomer indicated the high performance of the method. Although dm-CA 5–8P1ECs were not detected in the collected water samples, 21 isomers of CA 5–8P1ECs were identified by CI-MS and the tentative structures of six out of them were elucidated, mainly limited to the branch at α-C atom, by studying the EI-mass spectra. The relative concentrations of individual CA 5–8P1EC metabolites were calculated based on dm-CA 5–8P1ECs. The results showed that the main degradation on the nonyl chain occurred via the elimination of two carbon-units and the concentrations in Japan were much lower than those in Taiwan and Italy.

Determination of urinary metabolites of alkyl cellosolves by solid phase extraction and GC/FID.

Alkyl cellosolves include ethylene glycol monomethylether, ethylene glycol monoethylether, ethylene glycol monobuthylether. And their urine metabolites are methoxyacetic acid, ethoxyacetic acid and butoxyacetic acid. The current analytical method for urinary alkoxyacetic acid is liquid-liquid phase extraction. But the liquid-liquid phase extraction method needs a more complex pre-treatment process and has a low recovery rate. We determined the appropriate extraction solvent and its flow rate. We also evaluated the non-absorptive rate and recovery rate according to particle size. Finally we developed a convenient solid phase extraction method for the analysis of urine cellosolve metabolites. As a result, the recovery rates for methoxyacetic acid, ethoxyacetic acid and butoxyacetic acid were 100.4 +/- 1.6%, 100.2 +/- 1.8% and 100.7 +/- 10.0% respectively, when acetone was used as the extraction solution. The most appropriate flow rate was 0.1 ml/min. At a particle size of 140-200 mesh, non-absorption percentages for methoxyacetic acid, ethoxyacetic acid, butoxyacetic acid were 3.2 +/- 0.3%, 1.0 +/- 0.1% and 1.1 +/- 0.1%, and the recovery rates according to particle size were similar. Further evaluation of the recovery rate and non-absorptive rate according to the mini column shape, stationary phase and recovery rate with various extracting solutions is required.

Health Effects of Exposure to Ethylene Glycol Monoethyl Ether in Female Workers

Ethylene glycol monoethyl ether (EGEE) is a solvent commonly used in industry. To find the health effect of the solvent exposure in women, we did an investigation on 32 female workers exposed to EGEE in factories manufacturing photopolymer sensitization plate, and 20 subjects working in the same companies without potential exposure to the solvent. The mean age was 35.0 and 33.9 yr in the two groups, respectively. The mean concentration of the urinary metabolite (ethoxyacetic acid) was 120.87 mg/g creatinine (geometric mean) in the exposed group, and 2.71 mg/ g creatinine in the control group. Average RBC count and hemoglobin levels were normal in both groups. However, there were 2 subjects in the exposed group with an RBC count and hemoglobin concentration slightly lower than the standard. Out of 20 controls, 5 subjects reported irregular menstruation, and in comparison, 4 out of 32 exposed females had the same complaint. The most common health complaints were dizziness and swelling of the legs, with the same frequencies seen in both groups. Overall, our study suggests that although female workers were exposed to high concentrations of EGEE, subsequent health problems possibly due to such exposure were not significant.

高速液体クロマトグラフ／質量分析法を用いたアルキルフェノールエトキシレート及び関連物質の定量

Alkylphenolpolyethoxylates (APEOs) have been widely used as nonionic surfactants in various industrial and commercial products. There are two different degradation pathways of APEO. One is the gradual degradation of AP(n)EO to AP(n-1)EO, to subsequent degradation products, and finally to alkylphenol (AP). The other is through the formation of alkylphenol ethoxy acetic acid (APEC). We examined the quantitation method for these substances related to APEO [NP(1-15)EO, OP(1-10)EO, NP(1-10)EC] by high-performance liquid chromatography/mass spectrometry. Method detection limits (MDL), calculated from the replicate analyses of spiked deionized water, were 0.0018 [NP(4)EO]-0.0095[NP(8)EO] (μg·l-1), 0.0048[OP(5)EO]-0.0090[OP(7)EO] (μg·l-1), 0.0038[NP(8)EC]-0.0072[NP(5)EC] (μg·l-1). The quantitation method that we developed has sufficiently low detection limits and can be applied to the influent and final effluent of a sewage treatment plant.

Percutaneous Penetration and Metabolism of 2-Ethoxyethanol

Percutaneous absorption and cutaneous metabolism of 2-ethoxyethanol were assessed in vivo and with an in vitro flow-through diffusion system. Topical application of undiluted 14C-ethoxyethanol to occluded rat skin in vivo resulted in 25% of the dose being absorbed after 24 h. The major routes of excretion included the urine (15%), expiration as carbon dioxide (6%), and feces (1.2%), while little of the dose remained in the carcass (1.3%). Free ethoxyethanol, ethoxyacetic acid, and glycine conjugate were detected in urine. Permeation rates of ethoxyethanol through unoccluded rat split skin (20%) were greater than rat whole skin (11%), while absorption through human split skin (8%) was lower than the rat. Absorption of undiluted ethoxyethanol through occluded rat split skin in vitro (22%) most accurately predicted absorption through rat skin in vivo. However, ethoxyethanol absorption (29%) was enhanced by application in methanol. First pass metabolism of ethoxyethanol was not detected during percutaneous penetration through viable human or rat skin in vitro or rat skin in vivo. However, rat skin cytosol had the potential to metabolize ethoxyethanol, suggesting that the rapid penetration through skin in vivo prevented metabolism and that systemic exposure after skin contact with 2-ethoxyethanol is likely to be to the parent compound. In conclusion, the in vitro system provided a reasonable estimate of dermal absorption for the rat in vivo and comparison of human and rat skin in vitro indicated 2-ethoxyethanol absorption in humans is about one-third of that in the rat.

Final report on the safety assessment of ethoxyethanol and ethoxyethanol acetate.

Ethoxyethanol is an ether alcohol described as a solvent and viscosity-decreasing agent for use in cosmetics. Ethoxyethanol Acetate is the ester of Ethoxyethanol and acetic acid described as a solvent for use in cosmetics. Although these ingredients have been used in the past, neither ingredient is in current use. Ethoxyethanol is produced by reacting ethylene oxide with ethyl alcohol. Ethoxyethanol Acetate is produced via an esterification of Ethoxyethanol and acetic acid, acetic acid anhydride, or acetic chloride. Ethoxyethanol is metabolized to ethoxyacetaldehyde, which is further metabolized to ethoxyacetic acid, which is also a metabolite of Ethoxyethanol Acetate. Low to moderate acute inhalation toxicity is seen in animals studies. Acute oral toxicity studies in several species reported kidney damage, including extreme tubular degeneration. Kidney damage was also seen in acute dermal toxicity studies in rats and rabbits. Minor liver and kidney damage was also seen in short-term studies of rats injected subcutaneously with Ethoxyethanol, but was absent in dogs dosed intravenously. Mixed toxicity results were also seen in subchronic tests in mice and rats. Ethoxyethanol and Ethoxyethanol Acetate were mild to moderate eye irritants in rabbits; mild skin irritants in rabbits, and nonsensitizing in guinea pigs. Most genotoxicity tests were negative, but chromosome aberrations and sister-chromatid exchanges were among the positive results seen. Numerous reproductive and developmental toxicity studies, across several species, involving various routes of administration, indicate that Ethoxyethanol and Ethoxyethanol Acetate are reproductive toxicants and teratogens. Mild anemia was reported in individuals exposed occupationally to Ethoxyethanol, which resolved when the chemical was not used. Reproductive effects have been noted in males exposed occupationally to Ethoxyethanol. Although there are insufficient data to determine the potential carcinogenic effects of Ethoxyethanol or Ethoxyethanol Acetate, there is evidence that these chemicals are absorbed across human skin and that they are reproductive and developmental toxicants via dermal exposure. Therefore, these ingredients are unsafe for use in cosmetic formulations.

Identification of photocatalytic degradation products of non-ionic polyethoxylated surfactants in wastewaters by solid-phase extraction followed by liquid chromatography-mass spectrometric detection.

The photodegradation of non-ionic surfactants (nonylphenol- and alcohol-polyethoxylates, NPEOx and CnEOx) was investigated in different waters with and without a photoinducter (Fe(III)). Deionized water and industrial effluent spiked at 0.5 mg/L with C10EO6 and NPEO9 were irradiated using a xenon arc lamp. Aliquots of the test solutions were taken at different time intervals and were preconcentrated using solid phase extraction (SPE) with C18 cartridges. Liquid chromatography-atmospheric pressure chemical ionization-mass spectrometry (LC-APCI-MS) was used to identify the chemical species generated from phototransformation of non-ionic surfactants. The intermediates detected included nonylphenol diethoxylate (NPEO2) and nonylphenol ethoxy acetic acid (NPE2C). Much smaller amounts of degradation products of NPEO9 having only the alkyl chain carboxylated were also formed in the photocatalysis experiment. The identified C10EO6 photoproducts included fatty alcohols and acids. Polyethylene glycols (PEGs) were also formed as the consequence of the central scission of C10EO6 and the deethoxylation of NPEO9. The photodegradation in wastewater samples was more efficient than in deionized water being the half-life (t(1/2)) of C10EO6, 48 h and 29 h in deionized water and wastewater, respectively, and for NPEO9, 17 h and 14 h in deionized water and wastewater, respectively. When induced photodegradation was undertaken, the t(1/2) for NPEO9 was 21 min and 29 min in deionized water and wastewater, respectively. Disappearance of parent compounds was observed after 120 h from the beginning of the photodegradation experiment, or after 210 min of irradiation for the photocatalysis.

Air and biological monitoring of solvent exposure during graffiti removal

The principal aim of the study was to estimate the level of exposure to organic solvents of graffiti removers, and to identify the chemicals used in different cleaning agents. A secondary objective was to inform about the toxicity of various products and to optimise working procedures. Exposure to organic solvents was determined by active air sampling and biological monitoring among 38 graffiti removers during an 8-h work shift in the Stockholm underground system. The air samples and biological samples were analysed by gas chromatography. Exposure to organic solvents was also assessed by a questionnaire and interviews. Solvents identified were N-methylpyrrolidone (NMP), dipropylene glycol monomethyl ether (DPGME), propylene glycol monomethyl ether (PGME), diethylene glycol monoethyl ether (DEGEE), toluene, xylene, pseudocumene, hemimellitine, mesitylene, ethylbenzene, limonene, nonane, decane, undecane, hexandecane and gamma-butyrolactone. The 8-h average exposures [time-weighted average (TWA)] were below 20% of the Swedish permissible exposure limit value (PEL) for all solvents identified. In poorly ventilated spaces, e.g. in elevators etc., the short-term exposures exceeded occasionally the Swedish short-term exposure limit values (STEL). The blood and urine concentrations of NMP and its metabolites were low. Glycol ethers and their metabolites (2-methoxypropionic acid (MPA), ethoxy acetic acid (EAA), butoxy acetic acid (BAA), and 2-(2-methoxyethoxy) acetic acid (MEAA)) were found in low concentrations in urine. There were significant correlation between the concentrations of NMP in air and levels of NMP and its metabolites in blood and urine. The use of personal protective equipment, i.e. gloves and respirators, was generally high. Many different cleaning agents were used. The average exposure to solvents was low, but some working tasks included relatively high short-term exposure. To prevent adverse health effects, it is important to inform workers about the health risks and to restrict the use of the most toxic chemicals. Furthermore, it is important to develop good working procedures and to encourage the use of personal protection equipment.

A Toxicokinetic Study of Inhaled Ethylene Glycol Ethyl Ether Acetate and Validation of a Physiologically Based Pharmacokinetic Model for Rat and Human

The solvents ethylene glycol monoethyl ether acetate (EGEEA) and ethylene glycol monoethyl ether (EGEE), at sufficiently high doses, are known to be rodent developmental toxicants, exerting their toxic effects through the action of their metabolite 2-ethoxyacetic acid (2-EAA). Thus risks associated with exposure to these compounds are best evaluated based on a measure of the internal dose of 2-EAA. The goals of the work reported here were to develop physiologically based pharmacokinetic (PBPK) models of EGEEA and EGEE for pregnant rats and humans. These models were used to identify human exposure levels (ppm in air) equivalent to the rat no observed effect level (NOEL) and lowest observed effect level (LOEL) for developmental effects (Hanley et al., 1984). We exposed pregnant Sprague–Dawley rats to concentrations of EGEEA corresponding to the NOEL and LOEL. Maternal blood, urine, and fetal tissue concentrations of EGEE and 2-EAA measured in these experiments were used to validate the rat EGEEA and EGEE models. Data collected by other researchers were used to validate the capabilities of the rodent EGEEA and EGEE models to predict the kinetics in humans. The models for estimating circulating blood concentrations of 2-EAA were considered valid based on the ability of the model to accurately predict 2-EAA concentrations in rat blood, urine, and fetal tissue. The human inhaled concentration equivalent to the rat NOEL for EGEEA (50 ppm) was predicted to be 25 ppm using the maternal blood average daily area under the curve (AUC) and 40 ppm using the maximum concentration achieved in maternal blood (Cmax). The human inhaled concentration equivalent to the rat LOEL for EGEEA (100 ppm) was determined to be 55 ppm using the maternal blood average daily AUC and 80 ppm using the maternal blood Cmax.

Rat model for renal effects of 2-alkoxyalcohols and their acetates.

Male Wistar rats were given ethanediol (9.4 g/l), 2-ethoxyethylacetate (5.4 g/l), 2-butoxyethylacetate (2.9 g/l) and 1,2-propanediol (40 g/l) respectively in their drinking water for 2 weeks. Urine was collected during the last 24 h of the exposure. There was a marked increase in the oxalic acid excretion by the rats given ethanediol while rats given the alkoxyacetates excreted large amounts of ethoxyacetic and butoxyacetic acid, respectively. While not increased compared with controls, the excretion of oxalic acid by the latter group of rats was correlated to the excretion of the respective alkoxyacetic acids. The ammonia and glycosaminoglycan excretion was also smaller than that of controls. The urinary activity of succinate dehydrogenase was decreased in rats given the alkoxyacetates but not in animals exposed to ethanediol or propanediol. The data show that oxalic acid is actually a minor metabolite of the alkoxyacetates while the biochemical effects in kidney are associated more with the alkoxyacetic acid load. Alkoxyacetic acids seem to be inhibitors of renal succinate dehydrogenase, which may account for the decreased ammonia and glycosaminoglycan excretion.

Evaluation of exposure to ethylene glycol monoethyl ether acetates and their possible haematological effects on shipyard painters.

OBJECTIVES: To evaluate exposure to mixed solvents containing ethylene glycol monoethyl ether acetate (EGEEA) in shipyard painters, to determine if EGEEA is toxic to the bone marrow. METHODS: An industrial...

Elimination of methoxyacetic acid and ethoxyacetic acid in rat

1. The pharmacokinetics of methoxyacetic acid (MAA) and ethoxyacetic acid (EAA) have been determined in the male and female rat following bolus intravenous administration at 100 mg/kg. The plasma-concentration data of MAA fitted well to a one-compartment model, and the plasma-concentration data of EAA to a two-compartment model. 2. The elimination half-life of MAA estimated from plasma data was higher in females (18.6 ± 2.0 h) than in males (13.2 ± 0.4 h). There was no difference in the elimination half-lives estimated from urine data. The apparent volume of distribution was lower in the male than in the female rat estimated from plasma data only, while AUC, total and non-renal clearances and the relative amount MAA excreted unchanged in urine was similar in the male and female rat. 3. Clearance of EAA is higher than of MAA, and this appears as a result of metabolic capacity. The elimination half-lives of EAA were similar in the male and female rat, 9.4 ± 3.7 and 10.5 ± 2.6 h respectively. AUC was higher in the female compared with the male rat. The fraction of EAA eliminated during the distribution phase was 44.0 ± 15.4 and 41.0 ± 17.4% in the male and female rat respectively. The initial volume of distribution, the apparent volume of distribution, total and non-renal clearance are higher in the male compared with the female rat.

Urinary 2-Ethoxyacetic Acid for Biological Monitoring of Workers Exposed to 2-Ethoxyethyl Acetate

Urinary 2-Ethoxyacetic Acid for Biological Monitoring of Workers Exposed to 2-Ethoxyethyl Acetate

Decreased formation of ethoxyacetic acid from ethylene glycol monoethyl ether and reduced atrophy of testes in male rats upon combined administration with toluene and xylene

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 ( C max) 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.