Metabolism of bis(2-methoxyethyl) ether in the adult male rat: Evaluation of the principal metabolite as a testicular toxicant

Cheever, Kenneth L.; Richards, Donald E.; Weigel, Walter W.; Lal, J.B.; Dinsmore, A.M.; Daniel, F. Bernard

doi:10.1016/0041-008x(88)90345-6

Cited by 40 publications

(22 citation statements)

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“…The same study showed that only trace levels of 2-(2-methoxyethoxy)ethanol or methoxyethoxyacetaldehyde were detected in the urine. Further, cumulative excretion of 14 C-tagged compounds showed rapid excretion (50% of administered dose excreted in 8 h) during rat oral dosing studies (Cheever et al 1988). Study results from this laboratory also demonstrated that rat urinary MEAA is in the free form, not conjugated.…”

Section: Hhs Public Accesssupporting

confidence: 51%

“…MEAA is the predominate metabolite in animals and the urinary levels of this compound are fairly abundant. It was found that male rats dosed with 14 Clabeled parent 2-(2-methoxyethoxy)ethanol excreted 68-70% of the label as the MEAA metabolite by means of ADH conversion (Cheever et al 1988). The same study showed that only trace levels of 2-(2-methoxyethoxy)ethanol or methoxyethoxyacetaldehyde were detected in the urine.…”

Section: Hhs Public Accessmentioning

confidence: 53%

“…The rate of skin penetration and bioavailability from inhalation would be different between the toxic components in JP-8, so that a single biomarker can only be used as an indirect biomarker for the other toxic components in the jet fuel. The metabolic conversion of 2-(2-methoxyethoxy)ethanol to MEAA is also fairly rapid; the half-life was determined to be approximately 8 h in various animal studies (Cheever et al 1988;Daniel et al 1991;Richards et al 1993). MEAA, therefore, represents a biomarker of acute exposure to JP-8.…”

Section: Resultsmentioning

confidence: 99%

“…The deuterated analogs, S-benzyl-d 5 -mercapturic acid and S-phenyl-d 5 -mercapturic acid, were purchased from CDN Isotopes (Quebec, Canada). Standard compounds of (2-methoxyethoxy)acetic acid (MEAA, CAS number 16024-59-9) and the deuterated 2-butoxyacetic acid (d-BAA), used as an internal standard, were synthesized and described previously (Cheever et al 1988;Brown et al 2003). All other reagents used were analytical grade and are regularly available for laboratory use.…”

Section: Chemicals and Reagentsmentioning

confidence: 99%

“…Animal studies demonstrated a rapid conversion of the parent compound to MEAA (Daniel et al 1991;Richards et al 1993). The metabolism of 2-(2-ethoxyethoxy)ethanol is complex, and the mechanism based on animal studies (Cheever et al 1988;Sumner et al 1992) is presented in Figure 3. MEAA is the predominate metabolite in animals and the urinary levels of this compound are fairly abundant.…”

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confidence: 99%

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Evaluation and Comparison of Urinary Metabolic Biomarkers of Exposure for the Jet Fuel JP-8

B’Hymer

Krieg²,

Cheever³

et al. 2012

Journal of Toxicology and Environmental Health, Part A

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A study of workers exposed to jet fuel propellant 8 (JP-8) was conducted at U.S. Air Force bases and included the evaluation of three biomarkers of exposure: S-benzylmercapturic acid (BMA), Sphenylmercapturic acid (PMA), and (2-methoxyethoxy)acetic acid (MEAA). Postshift urine specimens were collected from various personnel categorized as high (n = 98), moderate (n = 38) and low (n = 61) JP-8 exposure based on work activities. BMA and PMA urinary levels were determined by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/ MS), and MEAA urinary levels were determined by gas chromatography-mass spectrometry (GC-MS). The numbers of samples determined as positive for the presence of the BMA biomarker (above the test method's limit of detection [LOD = 0.5 ng/ml]) were 96 (98.0%), 37 (97.4%), and 58 (95.1%) for the high, moderate, and low (control) exposure workgroup categories, respectively. The numbers of samples determined as positive for the presence of the PMA biomarker (LOD = 0.5 ng/ml) were 33 (33.7%), 9 (23.7%), and 12 (19.7%) for the high, moderate, and low exposure categories. The numbers of samples determined as positive for the presence of the MEAA biomarker (LOD = 0.1 μg/ml) were 92 (93.4%), 13 (34.2%), and 2 (3.3%) for the high, moderate, and low exposure categories. Statistical analysis of the mean levels of the analytes demonstrated MEAA to be the most accurate or appropriate biomarker for JP-8 exposure using urinary concentrations either adjusted or not adjusted for creatinine; mean levels of BMA and PMA were not statistically significant between workgroup categories after adjusting for creatinine.Biomarkers of exposure are important tools for use in exposure assessment and toxicological research. As the term implies, biomarkers of exposure are those related to exposure and the internal levels of some agent or chemical. A well-chosen biomarker of exposure should have several qualities. Primarily, the biomarker should be specific for the exposure of interest; some metabolites are common to multiple parent chemical substances and therefore may not be suitably specific biomarkers. Second, the biomarker needs to be associated with the et al. 2003). The fuel is formulated to meet military performance specifications, and therefore, the overall chemical composition varies from batch to batch with the exception of an anti-icing component (NRC 2003). With the many constituent chemicals present at varying concentrations, the best or most accurate biomarker for JP-8 exposure has not been extensively addressed in the literature, and this was the main objective of the current study. Three potential biomarkers of JP-8 exposure were compared since a previous study had investigated only one of these potential biomarkers (B'Hymer et al. 2012). HHS Public AccessThe specifications for JP-8 include a maximum olefin content of 5%, a maximum aromatic content of 22%, and a maximum sulfur content of 0.3%. On average, the composition is approximately 33-61% alkanes, 10-45% cycloalkanes, 12-22%...

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Section: Hhs Public Accesssupporting

confidence: 51%

Section: Hhs Public Accessmentioning

confidence: 53%

Section: Resultsmentioning

confidence: 99%

Section: Chemicals and Reagentsmentioning

confidence: 99%

mentioning

confidence: 99%

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Evaluation and Comparison of Urinary Metabolic Biomarkers of Exposure for the Jet Fuel JP-8

B’Hymer

Krieg²,

Cheever³

et al. 2012

Journal of Toxicology and Environmental Health, Part A

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Ethers of Ethylene Glycol and Derivatives

Kelsey

2023

Patty's Toxicology

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E series Glycol ethers are alkyl ethers of ethylene glycol along with their acetate esters. They are commonly used in paints and cleaners and typically have a higher boiling point in conjunction with the favorable solvent properties of lower‐molecular weight ethers, esters, and alcohols. They are colorless liquids that have mild earthy or fruity odors. The ethers are miscible with water and/or with numerous organic solvents making them useful as solvents in oil‐water compositions. Their relatively slow rate of evaporation also makes them useful as solvents and coalescing agents in paints and inks. The surface tension and solvent properties of the ethers make them useful in cleaners. Other uses of the ethers include process solvents and deicers. The ethers of the higher glycols are used as hydraulic fluids. Occupational exposure to glycol ethers occurs dermally and by inhalation. Most glycol ethers have low acute, single‐dose toxicity to humans. The most notable and well‐known effect relevant to humans is toxicity to male fertility and developmental toxicity produced by those glycol ethers that can metabolize to produce significant amounts of methoxyacetic acid such as methoxy ethanol and the methyl glymes.

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Ethers of Ethylene Glycol and Derivatives

Boatman¹,

Knaak²

2001

Patty's Toxicology

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There are currently seven U.S. manufacturers of ethers and other derivatives of ethylene glycol (EG), diethylene glycol (DEG), and higher glycols. Five of them are members of the American Chemistry Council (ACC) Glycol Ethers' Panel. The glycol ethers most commonly encountered industrially are colorless liquids that have mild ethereal odors. Alkyl glycol ethers are manufactured in a closed, continuous process by reacting ethylene oxide with an anhydrous alcohol in the presence of a suitable catalyst. Depending on the molar ratios of the reactants and other process parameters, the product mixtures obtained contain varying amounts of the monoethylene‐, diethylene‐, triethylene‐, and higher glycol ethers. Typically, the products in these mixtures are separated and purified by fractional distillation. The miscibility of most of these ethers with water and with a large number of organic solvents makes them especially useful as solvents in oil–water compositions. Their relatively slow rate of evaporation also makes them useful as solvents and coalescing agents in paints. Other uses include inks, cleaners, chemical intermediates, process solvents, brake fluids, and deicers. The ethers of the higher glycols are used as hydraulic fluids. An estimate of the U.S. production and use of representative ethylene glycol ethers is presented. Production of ethylene glycol ethers (total) in Western Europe amounted to 245 thousand metric tons in 1995. Occupational exposure to glycol ethers occurs dermally and by inhalation. Ingestion is not a concern in industrial exposure, although some cases of intentional ingestion of consumer products containing ethylene glycol ethers have been reported. A number of analytical methods have been published that are suitable for detecting glycol ethers in environmental air samples. Glycol ethers generally have low acute, single‐dose toxicity, and LD 50 values generally range from 1.0 to 4.0 g/kg of body weight. In animals and humans, high‐dose administrations (>350 mg/kg) result in central nervous system depression, although the results from many studies show no specific damage to neural tissues. Other toxicological effects attributable to glycol ethers are associated with metabolism to the corresponding alkoxyacetic acids. In the case of EGME, EGEE, and certain other glycol ether derivatives, significant reproductive, developmental, hematologic, and immunologic effects have been associated with the formation of either methoxyacetic (MAA) or ethoxyacetic acids (EAA). For other glycol ether derivatives substituted with propyl, butyl, or higher homologues, developmental effects secondary to maternal toxicity (without teratogenic effects), as well as hematologic effects, are observed. Ethylene glycol ethers and acetates may enter the environment from manufacturing effluents and emissions and as a result of their use in commercial products.

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Metabolism of bis(2-methoxyethyl) ether in the adult male rat: Evaluation of the principal metabolite as a testicular toxicant

Cited by 40 publications

References 20 publications

Evaluation and Comparison of Urinary Metabolic Biomarkers of Exposure for the Jet Fuel JP-8

Evaluation and Comparison of Urinary Metabolic Biomarkers of Exposure for the Jet Fuel JP-8

Ethers of Ethylene Glycol and Derivatives

Ethers of Ethylene Glycol and Derivatives

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