No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Developmental Toxicity of Diethylene Glycol Monomethyl Ether (diEGME)
Abstract
Diethylene glycol monomethyl ether (diEGME) was one of 15 glycols tested in CD-1 mice using a short-term in vivo reproductive toxicity assay (Chernoff/Kavlock test). Because results were strongly suggestive of potential reproductive toxicity, a teratology study was conducted in Sprague-Dawley rats. Time-mated females were orally dosed on Days 7-16 of gestation with diEGME in distilled water. Doses of 0, 1000, 1495, 2235, 3345, and 5175 mg/kg/day were used in a preliminary dose-finding study. At 5175 mg/kg/day, two of nine rats died, five of five litters were totally resorbed, and maternal extra gestational body weight gain was reduced. At 3345 mg/kg/day, six of nine litters were resorbed but there were no deaths and extra gestational body weight gain was not affected. Visceral and skeletal examinations revealed a dose-related increase in malformations, primarily of the ribs and cardiovascular system. Subsequently, pregnant rats were similarly dosed with 0, 720, or 2165 mg/kg/day. Neither dose was maternally toxic, but fetal body weights and the number of live implantations were significantly reduced at 2165 mg/kg/day. Rib malformations were seen in 9.1% (control), 42.9% (720 mg/kg/day, p less than 0.05), and 80.0% (2165 mg/kg/day, p less than 0.001) of litters. Cardiovascular malformations occurred in 0.0, 4.8, and 71.4% (p less than 0.001) of litters. Diethylene glycol monomethyl ether thus was teratogenic in rats at all doses tested, producing a dose-dependent series of malformations similar to those produced by other members of the glycol ether family.
... There is no metabolism data available from animal studies on diethylene glycol methyl ether (DEGME, CAS 111-77-3) or triethylene glycol methyl ether (TEGME, CAS 112-35-6) ( Table 1). Both of these substances have structures that could in theory, via the cleavage of the ether groups, lead to the formation of EGME and hence MAA and both have toxicity data that shows some evidence of developmental effects, albeit at or exceeding 1000mg/kgbw/day (Doe, 1984;ECETOC, 2005;ECHA, 2018b;Hardin et al., 1986;Schuler et al., 1984;Scortichini et al., 1986;Yamano et al., 1993). This hypothesis is supported by data on 'diglyme' (DEGDME) which shows the cleavage of the ether groups (Cheever et al., 1988;Richards et al., 1993) and from a biomonitoring study of jet fuels containing DEGME as an anti-icing additive which showed the presence of MEAA in urine of workers exposed to the substance (B'hymer et al., 2012). ...
... The metabolism data can be used to explain the developmental toxicity data in rats. In an oral gavage study, pregnant SD rats were dosed with 720 and 2165 mg/kg bodyweight DEGME during GD (gestation day) 7-16 (Hardin et al., 1986). Small but statistically significant increases in total rib malformations (15/111) were seen along with an increase in skeletal variations (reduced ossificationcranial [10/111] and appendicular skeleton [6/111]) in the low dose group. ...
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.
... Kra~avage'~' reported that high oral doses of EB did not have adverse effects on testes of rats. Hardin et al. (5) described teratogenicity in rats following high oral (gavage) doses (2165 mgikg) of diethylene glycol monomethyl ether (DM). However. ...
The methyl, ethyl, and butyl ethers of triethylene glycol (TM, TE, and TB, respectively) were evaluated in three screening studies to assess their potential hazards to humans. The assessments included (1) an in vitro procedure to determine the ability of the materials to penetrate human skin, (2) a 21-day dermal limit test in rabbits to determine potential systemic toxicities, and (3) a screening procedure to evaluate the chemicals' potentials to induce developmental toxicity. In the in vitro dermal absorption procedure, the three test materials crossed human epidermis at molar rates 170-330 times more slowly than the lower molecular weight homolog ethylene glycol methyl ether (EM), a chemical known to induce systemic effects following skin application. In the 21-day dermal study, daily applications of 1000 mg/kg TM, TE, or TB did not produce systemic toxicity in male or female rabbits, including hematologic or testicular effects. The low dermal penetration rate of the triethylene glycol ethers may have played a role in this outcome. In the developmental toxicity screening test, oral doses of 1000 mg/kg given on Days 6-15 of gestation did not produce maternal toxicity in rats and had no effect on viability or growth of offspring, pre-or postnatally, indicating low developmental toxic potential for these compounds. The results of these studies indicate that triethylene glycol methyl, ethyl, and butyl ethers have very low capacities to be absorbed through the skin of exposed individuals, low potentials to produce systemic toxicity following oral or dermal exposures, and do not appear to be selectively toxic to the developing conceptus. The data clearly indicate that triethylene glycol ethers do not exhibit toxicologic profiles comparable to those of the methyl and ethyl ethers of ethylene glycol.
... For diEGME, in vivo effects were found in contrast to no observed effects in zebrafish embryos exposed to MEAA. In a developmental toxicity study, Hardin et al. observed effects of diEGME in rats after exposure from GD7-16 (Hardin et al., 1986). However, the potency of diEGME was considerably lower than that of EGME and EGEE which might be the reason why we did not measure any effects in the ZET with MEAA. ...
The zebrafish embryotoxicity test (ZET) is a fast and simple method to study chemical toxicity after exposure of the complete vertebrate embryo during embryogenesis in ovo. We developed a novel quantitative evaluation method to assess the development of the zebrafish embryo based on specific endpoints in time, the general morphology score (GMS) system. For teratogenic effects a separate scoring list was developed. The relative effects of eight glycol ethers and six 1,2,4-triazole anti-fungals were evaluated in this system and results were compared with in vivo developmental toxicity potencies. Methoxyacetic acid and ethoxyacetic acid appeared as the most potent glycol ether metabolites, inducing growth retardation and malformations. Other glycol ethers showed no developmental toxicity. Flusilazole appeared the most potent triazole, followed by hexaconazole, cyproconazole, triadimefon, myclobutanil and triticonazole, respectively. In general, the potency ranking of the compounds within their class in the ZET was comparable to their in vivo ranking. In conclusion, the ZET with the GMS system appears an efficient and useful test system for screening embryotoxic properties of chemicals within the classes of compounds tested. This alternative test method may also be useful for the detection of embryotoxic properties of other classes of chemicals.
... According to the author's experience among lacquerers, it seems impossible to reach such levels in any workplace if 2-(2-alkoxyethoxy)ethanols exist in the vapour phase. In animal experiments the critical effect of DEGME has been reported to be fetal toxicity (Hardin et al., 1986; Scortichini et al., 1984; Yamano et al., 1993). The critical effect of DEGEE has been damage to the kidneys and liver, as well as some minor effects on reproduction (Lundberg, 1996). ...
2-Methoxyacetic and 2-ethoxyacetic acids are well known toxic metabolites of 2-alkoxyethanols. The use of 2-alkoxyethanols is now restricted, and the regulations have forced manufacturers to find substitutive solvents, 2-(2-alkoxyethoxy)ethanols. 2-(2-Alkoxyethoxy)ethanols resemble 2-alkoxyethanols, and their most hazardous similarity is their ability to metabolize to the 2-(2-alkoxyethoxy)acetic acids. In the present study, floor lacquerers' (n = 22) inhalation and total exposure to 2-(2-alkoxy)ethoxyethanols was measured. The measurements of inhalation exposure were done with charcoal tubes, and total exposure was biomonitored by urinalysis of 2-(2-alkoxyethoxy)acetic acids. The 8h inhalation exposures of floor lacquerers to 2-(2-methoxyethoxy)ethanol (DEGME), 2-(2-ethoxyethoxy)ethanol (DEGEE) and 2-(2-butoxyethoxy)ethanol (DEGBE) were in average 0.23 +/- 0.07 ppm (average+/-S.D., n = 3), 0.08 +/- 0.07 ppm (n = 16), and 0.05 +/- 0.03 ppm (n = 16), respectively. The excretions of 2-(2-methoxyethoxy)acetic acid (MEAA), 2-(2-ethoxyethoxy)acetic acid (EEAA) and 2-(2-butoxyethoxy)acetic acid (BEAA) were in average 4.9 +/- 4.3 mmol/mol creatinine, 9.3 +/- 8.0 mmol/mol creatinine and 9.2 +/- 7.4 mmol/mol creatinine, respectively. A linear relationship was found between the urinary 2-(2-alkoxyethoxy)acetic acid concentrations and the preceding 8-h occupational exposure to 2-(2-alkoxyethoxy)ethanol.
Currently, the selection of HLVs as part of a health risk assessment is based little if at all on an understanding of the methods used to determine it. Consequently, risk assessors tend to use the most conservative value for human health. This article describes the different methods for determining HLVs, analyses their key points and discusses possible changes in HLV selection criteria. HLVs are determined for two types of toxic effects: those considered to have a threshold below which they cause no harm (e.g., noncarcinogenic effects) and those where harm is assumed to be probable at any level of exposure (i.e., no-threshold effects, as currently thought to be the case for mutagenesis). Their construction is generally divided into three parts: i) choice of a critical effect; ii) determination of a critical dose; iii) extrapolation into the low-dose range. For threshold effects, the latter involves the application of uncertainty factors to account for variabilities and uncertainties (for example, extrapolations from animal studies to humans, interindividual variability of human responses). For no-threshold effects, the HLV is usually determined by linear mathematical modelling, with the curve passing through the origin. Two key items influence the numerical value of the HLV: the experimental data, which determine the critical effect and the critical dose, and the biological (pharmacokinetic and pharmacodynamic) data. Styrene and EGBE are used as examples to illustrate this influence. This analysis of the current methods for determining HTVs reveals three trends: i) the calling into question of the formal separation between the methods for the two types of effects, and, in particular, the development of the benchmark dose approach; ii) the importance of improving our biological knowledge to reduce the uncertainties due to interspecies extrapolations; and iii) the development of probabilistic approaches to the characterization of uncertainty. These changes necessitate the development in France of high-level expertise in toxicology and of procedures to structure the elaboration of HTVs.
The second edition of this popular text systematically addresses all aspects of treatment of infertility using Chinese medicine. Clinically focused and with a new easy-to-navigate design, the book begins by covering all the essential fundamentals you will need to understand and treat infertility, before going on to look at what Chinese medicine offers in the way of treatment for functional infertility in men and women, gynecological disorders which contribute to infertility and relevant lifestyle factors. Jane Lyttleton importantly devotes a large part of the book to discussing ways in which Chinese medicine and Western medicine might work together to overcome infertility, and details the increased experience over the past decade in working with IVF patients and their specialists. Leaps forward have also been made in the understanding of conditions such as Polycystic ovarian syndrome and immune infertility. New Features: Greatly expanded section on the place of Chinese medicine and IVF in treatment of infertility. New information on Polycystic ovarian disease and immune infertility and how Chinese medicine approaches their treatment. Updated and balanced advice on pre-conception care. Clinically focused, with easy-to-navigate design.
BACKGROUND
Shortened and bent long bones and bent scapulae are sometimes reported in fetuses with wavy ribs (Carney and Kimmel, ). Wavy ribs are typically seen in the presence of maternal and developmental toxicity, are transient and reversible postnatally, and are considered to be variations rather than malformations. METHODS
We further assessed the literature cited in Kimmel and Carney () as well as papers published since then to determine under what conditions bent long bones in the absence of gross limb defects and bent scapulae were reported and whether information was available on the transient or permanent nature of these effects. RESULTSLong bone and/or scapular changes almost always occurred at a lower incidence than wavy ribs. In every case, maternal and fetal toxicity occurred at the same dose levels. In a few studies, pups were followed sequentially after birth and bent long bones and scapulae were transient in nature and appeared normal by the time of weaning. Rabbits were much less likely to show wavy ribs or long bone and scapular changes at birth, even in the presence of severe maternal and fetal toxicity. This species difference may be due in part to the great increase in bone mass and remodeling that occurs during the first few postnatal weeks in rodents, but which takes place during the longer fetal period in rabbits. CONCLUSION
Our conclusion from this review is that bent long bones and scapulae, like wavy ribs, appear to be secondary to maternal and developmental toxicity, are transient, and like wavy ribs should be considered variations rather than malformations
Increasing exposure of pregnant mothers to various industrial solvents due to voluntary abuse or involuntary exposure in the work place is raising the possibility of production of teratological effects in the offsprings. Ethanol, which can be broadly categorized as a solvent and which is also extensively abused, is well known for its teratological deragements in humans, termed as “fetal alcohol syndrome” as well as in animals. Benzene and its derivatives (xylene and toluene), alcohols, glycols and glycol ethers, and other solvents have also been reported to produce various types of teratogenic effects in animal (e.g., mice, rats, and rabbits) studies. In the case of toluene, some teratogenic anomalies have been reported in three children of mothers exposed to pure toluene vapor throughout the pregnancy.
The number of chemicals in commerce which have not been evaluated for potential developmental toxicity is large. Because of the time and expense required by conventional developmental toxicity tests, an abbreviated assay is needed that will preliminarily evaluate otherwise untested chemicals to help prioritize them for conventional testing. A proposed short-term in vivo assay has been used in a series of studies in which a total of 60 chemicals were tested. Some were independently tested two or four times each. In this preliminaly test, pregnant mice were dosed during mid-pregnancy and were then allowed to deliver litters. Litter size, birth weight, and neonatal growth and survival to postnatal day 3 were recorded as indices of potential developmental toxicity. Results in this assay and conventional mouse teratology tests were generally concordant. Conventional data were available for 14 chemicals (ten teratogens, one fetotoxin, three nonteratogens), of which 11 (nine teratogens, one fetotoxin, one nonteratogen) produced evidence of developmental toxicity. This included conventional data for three chemicals (ethylene glycol, diethylene glycol dimethyl ether, and triethylene glycol dimethyl ether) that were untested before the present study. As high priority candidates for conventional testing on the basis of results here, all were subsequently studied in a standard teratology assay and were confirmed to be teratogenic in mice. Additionally, one of them (ethylene glycol) plus a fourth high priority candidate for conventional study (diethylene glycol monomethyl ether) were subsequently tested in rats and were found to be teratogenic in that species.
A test procedure for the determination of (2-methoxyethoxy)acetic acid (MEAA) was adapted and applied to urine samples from jet fuel (JP-8)-exposed mice using capillary gas chromatography with a mass selective detector (MSD). MEAA is a metabolite and proposed biomarker for exposure to 2-(2-methoxyethoxy)ethanol, a glycol ether component in the formulation of JP-8. The collected urine samples were spiked with deuterated butoxyacetic acid internal standard, and extracted with ethyl acetate, and esterified with ethanol and sulfuric acid, and the esters of the glycol ethers were extracted with methylene chloride. The chromatographic conditions used easily separate the MEAA ethyl ester from interferences within mouse urine. The application of this procedure to urine samples collected from mice demonstrated that MEAA was detectable after oral (2000 mg/kg) or dermal (50 mu L) exposure for 7 days to JP-8 at levels as high as 8.5 or 6.5 mu g/mL, respectively. This pilot demonstration indicated that total urinary MEAA was a viable biomarker for the two routes of JP-8 exposure in laboratory mice.
An embryotoxic oral dose of bis(2-methoxyethyl) ether (DGDME), 3.73 mmol/kg body wt (500 mg/kg), administered on the 11th day of gestation to pregnant CD-1 mice was metabolized predominantly by O-demethylation to 2-(2-methoxyethoxy)ethanol with subsequent oxidation to (2-methoxyethoxy)acetic acid. Urinary excretion of this metabolite over 48 hr amounted to 63 +/- 2% of the dose. A smaller percentage of the administered dose was metabolized at the central ether linkage to produce 2-methoxyethanol, which was further metabolized by alcohol dehydrogenase to methoxyacetic acid. Urinary excretion of methoxyacetic acid, a potent developmental toxicant, amounted to 28 +/- 1% of the administered dose by 48 hr and was the second most prominent urinary metabolite. Unchanged DGDME and methoxyacetic acid were detected in the embryonic tissues from these animals, and embryos harvested after the initial 6-hr period showed detectable amounts of only methoxyacetic acid. The average amount of methoxyacetic acid per embryo was calculated to be 1.5 +/- 1.0 mumol (5.9 mmol/kg body wt) at the 6-hr termination time. This finding suggests that the reported teratogenic effects of DGDME are due to methoxyacetic acid formed, either in the fetus or by hepatic metabolism in the dam with subsequent distribution to the embryonic tissue. These results suggest that such developmental toxicity may occur with structurally similar aprotic ethylene glycol ethers in which metabolic O-dearylation would yield 2-methoxy-ethanol.
Adult male CD rats and CD-1 mice were given a single oral dose of ethylene glycol monomethyl ether (EGM) at 0, 500, 750, 1,000, or 1500 mg/kg. Groups of 10 were killed at weekly intervals after dosing for analysis of sperm counts and morphology or testicular histology; further groups of 10 were sequentially mated to pairs of virgin females to test for dominant lethality or gross foetal malformations in the F1 generation (F1 abnormalities).
EGM was found to deplete the spermatocytes of both species severely, principally pachytene cells, but with other stages affected with increasing dose. A delay in the progression of spermatogenesis may account for a discrepancy between the apparent stage-specificity of damage deduced from lowered sperm counts and that observed histologically. In the rat, morphological abnormalities were observed in sperm that had been exposed as spermatocytes; in the mouse, however, the sensitive cells were the late spermatocytes and early spermatids. In all these parameters there was an indication of a dose-response relationship in both rats and mice. In the mating studies EGM induced a dose-related decrease in fertility 5 weeks after dosing in the rat, but complete sterility in all but the lowest dose after 6 weeks. In contrast, EGM had no effect on the reproductive capacity of the mouse. There was no statistically significant evidence for the induction of dominant lethal mutations or F1 abnormalities in either species.
A single oral dose of cyclophosphamide (CTX) at 100 mg/kg induced a significant increase in dominant lethality in both species. CTX reduced the number of total implants in the rat and induced a nonsignificant increase in the number of abnormal offspring sired by treated male mice.
Time-mated CD-1 mice were orally dosed on gestation day 11 (plug = 0) with distilled water (control) or one of four glycol ethers at a dose of 4 mmol/kg: ethylene glycol monomethyl ether (EGME, 304 mg/kg), ethylene glycol dimethyl ether (EGdiME, 361 mg/kg), diethylene glycol dimethyl ether (diEGdiME, 537 mg/kg), triethylene glycol dimethyl ether (triEGdiME, 713 mg/kg). Fetuses were collected on gestation day 18, weighed, and examined for gross external malformations. Fetuses were cleared and stained to examine paws. There were no signs of treatment-related maternal toxicity, and intrauterine survival was unaffected by glycol ether treatments. Fetal body weights were significantly reduced only in litters treated with EGdiME. There was no treatment-related pattern of gross external malformations other than paw defects. Only triEGdiME failed to produce a significant incidence of malformations. Paw defects were present in 87.5% of EGME-treated litters (68.5% of fetuses), 86.7% of EGdiME-treated litters (33.8% of fetuses), and 77.8% of diEGdiME-treated litters (39.7% of fetuses). Hindpaw defects predominated over forepaw, and syndactyly was the most common malformation. The incidences of oligodactyly and short digits were also significantly increased. The similarity of malformations produced by these methyl-substituted glycol ethers is proposed to be attributable to in vivo conversion to a common teratogen, methoxyacetic acid.
The effects of oral treatment of Wistar rats with diethylene glycol monomethyl ether (diEGME) were examined. In a preliminary dose-finding study with non-pregnant rats, diEGME treatment at doses up to 4,000 mg/kg/day on 11 consecutive days decreased relative weights of thymus and pituitary gland, white and red blood cell counts, hemoglobin concentrations and hematocrit levels. In pregnant rats, treatment at doses of > 3,000 mg/kg/day (over gestation days 7-17) caused total resorption of all litters. In teratology and postnatal studies, pregnant rats were treated with diEGME at doses of 0, 200, 600, and 1,800 mg/kg/day from day 7 through 17 of gestation. At 200 mg/kg, there were no adverse effects on either dams, fetuses, or neonates. At 600 mg/kg, dams were not affected, but fetal body weights were decreased, and fetal thymus and ossification were adversely affected. At 1,800 mg/kg, maternal thymus weights and food consumption were decreased, and visceral malformations of the cardiovascular system were seen in 28.0% of the fetuses. Only 6.3% of the pups delivered by dams treated with 1,800 mg/kg of diEGME survived for 4 days after birth. Thus, diEGME was teratogenic in Wistar rats, but the spectrum differed from that in Sprague-Dawley rats. In addition to teratogenicity, diEGME had significant adverse effects on postnatal development. The most sensitive organ to diEGME was the thymus in both dams and fetuses.
One research emphasis within the Department of Defense has been to seek the replacement of operational compounds with alternatives that pose less potential risk to human and ecological systems. Alternatives to glycol ethers, such as diethylene glycol monomethyl ether (M-DE), were investigated for use as jet fuel system ice-inhibiting agents (FSIIs). This group of chemicals includes three derivatives of 1,3-dioxolane-4-methanol (M-1, M-2, and M-3) and a 1,3-dioxane (M-27). In addition, M-DE was evaluated as a reference compound. Our approach was to implement an in vitro test battery based on primary rat hepatocyte cultures to perform initial toxicity evaluations. Hepatocytes were exposed to experimental chemicals (0, 0.001, 0.01, 0.1, 1, 10 mM dosages) for periods up to 24 h. Samples were assayed for lactate dehydrogenase (LDH) release, MTT dye reduction activity, glutathione level, and rate of protein synthesis as indicators of toxicity. Of the compounds tested, M-1, especially at the 10-mM dose, appeared to be more potent than the other chemicals, as measured by these toxicity assays. M-DE, the current FSII, elicited little response in the toxicity assays. Although some variations in toxicity were observed at the 10-mM dose, the in vitro toxicities of the chemicals tested (except for M-1) were not considerably greater than that of M-DE.
An accurate and precise procedure was developed for the detection and quantification of (2-methoxyethoxy)acetic acid (MEAA), a metabolite and biomarker for human exposure to 2-(2-methoxyethoxy)ethanol. The compound 2-(2-methoxyethoxy)ethanol has a wide array of industrial applications including its use as an additive in military jet fuel. Exposure to 2-(2-methoxyethoxy)ethanol is a health concern owing to its toxicity which includes developmental and teratogenic properties. Sample preparation consisted of liquid-liquid extraction (LLE) and esterification of MEAA to produce the ethyl ester. Measurement was by a gas chromatograph (GC) equipped with a mass selective detector (MSD) using a HP-1 capillary column. Recovery studies of spiked blank urine demonstrated good accuracy and precision; recovery varied between 95 and 103% with relative standard deviations of 8.6% and less. The limit of detection (LOD) for this procedure was found to range from 0.02 to 0.08 microg/ml equivalent levels of MEAA in urine. These data and other aspects of the validation of this procedure will be discussed.
Several extraction and derivatization procedures were evaluated for the quantification of (2-methoxyethoxy)acetic acid (MEAA) in urine. MEAA is a metabolite and a biomarker for exposure to 2-(2-methoxyethoxy)ethanol, a glycol ether with widespread use in various industrial applications and the specific use as an anti-icing additive in the military jet fuel formulation JP-8. Quantification of glycol ether biomarkers is an active area of analytical research. Various sample preparation procedures were evaluated: liquid-liquid extraction (LLE) using ethyl acetate yielded the highest recovery, and solid-phase extraction (SPE) gave low recovery of MEAA. Two derivatization procedures were thoroughly investigated and validated, namely, silylation of MEAA with N-methyl-N-(tert-butyldimethylsilyl)trifluoroacetamide (MTBSTFA), and esterification of MEAA using ethanol. Quantification was performed by gas chromatography (GC) with a mass spectrometer as detector and using a polydimethylsiloxane (HP-1) capillary column. Deuterated 2-butoxyacetic acid (d-BAA) was used as an internal standard. Recovery studies of spiked human urine demonstrated the accuracy and precision of both procedures. The limit of detection (LOD) and other figures of merit for both derivatization procedures will be discussed in detail. Applications of these analysis procedures are also discussed.
Delayed (or incomplete) ossification of developing fetal bones and wavy ribs are some of the most common skeletal variations encountered in regulatory guideline developmental toxicity studies. Although they tend to be regarded as minor effects, they can be quite sensitive and consequently may influence the study lowest-observed-adverse-effect levels (LOAELs), and thus, impact classification, labeling, and risk assessment. In this study, we review the underlying mechanisms of these skeletal variations, evaluate different scenarios in which they have been observed, offer guidance for their interpretation, and comment on their use for risk assessment. Both minor delays in ossification and wavy ribs seem to be readily repairable via postnatal skeletal remodeling, are not mechanistically linked to malformation, and often are seen in the presence of maternal or fetal toxicity. As such, these minor variations would not generally be considered adverse in and of themselves but should be interpreted in the context of other maternal and fetal findings, information available on normal skeletogenesis patterns, mode of action of the test agent, and historical control incidence using a weight of evidence approach.
An unknown acidic compound was detected in a number of urine samples from patients with a suspected metabolic disorder and some patients treated with chemotherapy. The structure of this compound has been characterized as (2-ethoxyethoxy)acetic acid, using a gas chromatography/mass spectrometry/ computer system.The authentic compound was synthesized and compared with the unknown. Urinary (2-ethoxyethoxy)acetic acid is assumed to be formed endogenously from an exogenous precursor, probably 2-(2-ethoxyethoxy)ethanol.
1. An intraperitoneal dose of [14C]isopropyl Oxitol is rapidly metabolized in the rat. 2. The major routes of excretion of radioactivity are the urine (73% dose) and in the expired air as [14C]carbon dioxide (14% 3. The major urinary metabolites were characterized as isopropoxyacetic acid (30% of the urinary radioactivity), N-isopropoxyacetyl glycine (46% and ethanediol (13% 4. The metabolism of the compound in the dog is similar to that in the rat. © 1971 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.
The discovery that ethylene glycol monomethyl ether (EGME) could affect the testis and the developing fetus in laboratory animals prompted further work to understand the effect of EGME and to examine additional glycol ethers to see if they showed EGME's reprotoxicity. Propylene glycol monomethyl ether (PGME) was shown not to cause testicular atrophy or to affect the development of rats at 600 ppm by inhalation, whereas EGME caused testicular atrophy at 300 ppm and showed teratogenic potential at 100 ppm. Diethylene glycol monomethyl ether (diEGME) was found to show no teratogenic potential when administered subcutaneously in rats at up to 1000 microL/kg, whereas EGME had effects at 40 microL/kg. EGME has been shown to cause effects on the testis in rats after a single exposure to 600 ppm or above for 4 hr. The effects can be seen as little as 24 hr after exposure. Ethylene glycol monoethyl ether (EGEE) also causes a reduction in testicular weight following a single exposure to saturated vapor for 3 hr (17 mg/l), but ethylene glycol monoisopropyl ether (EGPE) at 15 mg/l and ethylene glycol monobutyl ether (EGBE) at 4 mg/l showed no effect on the testis.
Ethylene glycol alkyl ethers are frequently used in industry, and accidents due to them occur. Impaired hematopoietic function and genital injury in animal experiments have been reported. Of various alkyl radicals, those with a methyl radical strongly injure them. Ethylene glycol dimethyl ether (EGDME) was administered to pregnant mice on the 7th, 8th, 9th, and 10th days of pregnancy, which is the early stage of organ formation, for examination of its effect on feti, with special reference to the presence or absence of teratogenicity. Of 97 female mice mated and sampled, 490 mg/kg of EGDME was administered to 28 as Group A, 350 mg/kg to 23 as Group B, and 250 mg/kg to 23 as Group C. Only distilled water was given to 23 mice as a control group. 1. The mother mice showed no noteworthy ecological changes after conception in any group, but showed uneventful weight gain. No weight loss or abortion due to EGDME was observed in the experimental groups. 2. As a result of the oral administration of EGDME to pregnant mice, 20% of feti died in Group A, 13.1% in Group B, and 12.6% in Group C, the fetal mortality rate increasing with increasing dosage. 3. Surface deformity was observed in 19.2% in Group A, 5.1% in Group B, and 0.3% in Group C, the rate of deformity being high in large-dose groups. External brain was most frequent, and palpebral patency, caudal defect, peritoneal hernia, and cleft palate were observed in a small number of mice each. 4. As skeletal deformity, defect of the parietal bone was observed in the mice with external brain, but no other cranial abnormality was observed. Abnormalities of cervical vertebrae appeared in 45.9% in Group A, 33.6% in Group B, and 14.6% in Group C. Costal fusion occurred in 71.2% in Group A, 54.3% in Group B, and 21.5% in Group C.