The effect of ethylene glycol monomethyl ether and diethylene glycol monomethyl ether on hepatic gamma-glutamyl transpeptidase.

In this paper, we determined whether ethylene glycol monomethyl ether (EGME) and diethylene glycol monomethyl ether (diEGME) induce hepatic gamma-glutamyl transpeptidase activity. Male adult Wistar rats weighing 220 g were used as experimental animals. EGME (100, 300 mg/kg per day) and diEGME (500, 1000, 2000 mg/kg per day) were administered by gavage for 1, 2 or 5 days or 4 weeks. In the 4-week study, experimental animals were administered EGME or diEGME once a day orally, 5 days/week. EGME treatment increased the serum gamma-glutamyl transpeptidase (GGT) level significantly, however, diEGME did not. The activities of three other enzymes (SGOT, SGPT and ALP) in serum were not altered by EGME or diEGME treatment and thus there was no biochemical indices of hepatic damage by EGME or diEGME. EGME treatment increased the GGT activities in the liver and lungs. Of the organs examined, the induction of GGT was the greatest in the liver. The inducibility in the liver was 216% for the 5-day treatment and 460% for the 4-week treatment. A dose-dependent increase of hepatic microsomal GGT activity by EGME was observed. On the other hand, renal GGT activities were declined to 72% and 60% of control by the 5-day and 4-week EGME treatments, respectively. DiEGME did not affect the GGT activities in any of the tissues except those of the brain. In the histochemical study, most hepatocytes at the periportal zones were stained with GGT staining after the 4-week treatment. However, the hepatocytes at the central zones were negative.     

Percutaneous toxicity of ethylene glycol monomethyl ether and of dipropylene glycol monomethyl ether in the rat

The subacute percutaneous toxicity of dipropylene glycol monomethyl ether (DPM) in male rats dosed 5 days/week for 4 weeks under both occluded and unoccluded conditions has been assessed and compared to the percutaneous toxicity of ethylene glycol monomethyl ether (EGM). DPM caused no significant changes in the clinical chemistry, haematology, or pathology, whereas EGM caused changes in the haematology and clinical chemistry, and both testicular and bone marrow damage at doses of 1000 mg/kg per day.     

Esterification of 7-theophyllineacetic acid with diethylene glycol monomethyl ether

The kinetics of esterification of 7-theophyllineacetic acid with diethylene glycol monomethyl ether in the presence of dicyclohexylcarbodiimide and 4-dimethylaminopyridine as catalyst was studied. According to the known mechanism, besides the main process, the side-reaction of intramolecular rearrangement with formation of pharmacologically active N-acylurea occurs. The course of the main and the side-process was monitored by RP-HPLC with UV-detection. For that purpose, quantification of both ester and N-acylurea in the reaction mixture was performed. Influence of the concentration of the reactants (acid, alcohol and catalyst) on the progress of esterification and preparation of the by-product was investigated. Based on the obtained results, the reaction conditions leading to maximal yield of the ester and N-acylurea are proposed. The possibility of turning esterification to the synthesis of the side-product was also found. Reactions of the preparation of both the ester and N-acylurea were found to follow first-order kinetics. The rate constants of both processes were estimated.     

Comparative short-term inhalation toxicity of ethylene glycol monomethyl ether and propylene glycol monomethyl ether in rats and mice

Male and female Fischer 344 rats and B6C3F1 mice were exposed to 0, 100, 300, or 1000 ppm ethylene glycol monomethyl ether (EGME) or to 0, 300, 1000, or 3000 ppm propylene glycol monomethyl ether (PGME) 6 hr/day for a total of 9 days during an 11-day interval. Although structurally similar, the biological activities of the two materials were dramatically different. The high concentration of EGME (1000 ppm) had pronounced adverse effects on body weight gain, peripheral blood counts, bone marrow, testes, and lymphoid tissues. Similar but less pronounced changes also occurred in some animals in the 300 ppm EGME group. Exposure to 3000 ppm PGME resulted in increased liver weights in male rats as well as central nervous system depression and decreases in specific gravity of urine of both male and female rats. However, there were no gross or histopathologic changes in either rats or mice which could be attributed to exposure to PGME. Hence the treatment-related changes which occurred in rats and mice exposed to PGME vapors, even at the highest concentration (3000 ppm), would constitute, at most, a minimal effect. Although PGME and EGME have comparable vapor pressures, the potential hazard of exposure to PGME vapors appears to be distinctly less than to EGME vapors.     

Embryotoxic effects of ethylene glycol monomethyl ether in mice

An embryotoxicity study on ethylene glycol monomethyl ether (EGM) was carried out in ICR mice. They were given EGM daily at 6 dose levels (31.25, 62.5, 125, 250, 500 or 1000 mg/kg body wt) by gastric intubation on days 7 through 14 gestation. On day 18 of gestation all fetuses were examined. Marked and dose-related embryotoxic effects were observed. Skeletal and gross anomalies, reduced fetal weight and feral death were all observed at lower dosages of EGM, while marked leucopenia of the dams occured at the highest dose.     

Diethylene glycol monomethyl ether, ethylene glycol monomethyl ether and the metabolite, 2-methoxyacetic acid affect in vitro chondrogenesis

Diethylene glycol monomethyl ether (DEGME), ethylene glycol monomethyl ether (EGME) and their common metabolite, methoxyacetic acid (MAA) have been associated with adverse reproductive effects. The objective of this research is to investigate the effects of DEGME, EGME and MAA on in vitro chondrogenesis and the mechanisms by which these effects occur. Micromass cultures were exposed to DEGME, EGME or MAA for 5 days and proteoglycan abundance and cell proliferation determined. Longer-term 9- and 14-day cultures were exposed to MAA and apoptosis analyzed. All three chemicals decreased proteoglycan abundance and cell proliferation at the highest dose tested (100 μL/mL). However, only MAA showed a dose-dependent effect for both parameters at 0.01, 10, and 100 μL/mL. Furthermore, micromass cultures show an increase in apoptotic cells which when treated with MAA suggest that cell death could result from induced apoptosis. These results suggest that effects of DEGME and EGME are the result of generalized toxicity, but their metabolite MAA induces mitochondrial-mediated apoptosis during in vitro chondrogenesis.     

Diethylene glycol monomethyl ether,ethylene glycol monomethyl ether and the metabolite, 2-methoxyacetic acid affect in vitro chondrogenesis

Diethylene glycol monomethyl ether (DEGME), ethylene glycol monomethyl ether (EGME) and their common metabolite, methoxyacetic acid (MAA) have been associated with adverse reproductive effects. The objective of this research is to investigate the effects of DEGME, EGME and MAA on in vitro chondrogenesis and the mechanisms by which these effects occur. Micromass cultures were exposed to DEGME, EGME or MAA for 5 days and proteoglycan abundance and cell proliferation determined. Longer-term 9- and 14-day cultures were exposed to MAA and apoptosis analyzed. All three chemicals decreased proteoglycan abundance and cell proliferation at the highest dose tested (100 μL/mL). However, only MAA showed a dose-dependent effect for both parameters at 0.01, 10, and 100 μL/mL. Furthermore, micromass cultures show an increase in apoptotic cells which when treated with MAA suggest that cell death could result from induced apoptosis. These results suggest that effects of DEGME and EGME are the result of generalized toxicity, but their metabolite MAA induces mitochondrial-mediated apoptosis during in vitro chondrogenesis.     

Toxicity review of ethylene glycol monomethyl ether and its acetate ester

Ethylene glycol monomethyl ether (EGME) and its acetate ester (EGMEA) are highly flammable, colorless, moderately volatile liquids with very good solubility properties. They are used in paints, lacquers, stains, inks and surface coatings, silk-screen printing, photographic and photo lithographic processes, for example, in the semiconductor industry, textile and leather finishing, production of food-contact plastics, and as an antiicing additive in hydraulic fluids and jet fuel. EGME and EGMEA are efficiently absorbed by inhalation as well as via dermal penetration. Dermal absorption may contribute substantially to the total uptake following skin contact with liquids or vapours containing EGME or EGMEA. EGMEA is rapidly converted to EGME in the body and the two substances are equally toxic in animals. Therefore, the two substances should be considered as equally hazardous to man. Effects on peripheral blood, testes, and sperm have been reported at occupational exposure levels ranging between 0.4 and 10 ppm EGME in air, and with additional, possibly substantial, dermal exposure. Severe malformations and disturbed hematopoiesis have been linked with exposure to EGME and EGMEA at unknown, probably high, levels. Embryonic deaths in monkeys and impaired spermatogenesis in rabbits have been reported after daily oral doses of 12 and 25 mg per kg body weight, respectively. In several studies, increased frequency of spontaneous abortions, disturbed menstrual cycle, and subfertility have been demonstrated in women working in the semiconductor industry. The contribution of EGME in relation to other exposure factors in the semiconductor industry is unclear.     

Dose-dependent toxicity of ethylene glycol monomethyl ether vapour in the rat

Wistar male rats were exposed by inhalation to 50, 100 or 400 ppm of ethylene glycol monomethyl ether (EGME) for 1 to 2 weeks. The overall hepatic drug oxidation reactions, O-deethylation of 7-ethoxycoumarin and 7-ethoxyresorufin and cytochrome P-450 content were only slightly affected by the EGME exposures. NADPH cytochrome c reductase activity showed a tendency toward a dose-dependent decrease in liver, the activity being 73% and 64% of that in the controls after one and two weeks of exposure, at 400 ppm respectively. UDP glucuronosyl transferase activity exhibited a dose-dependent enhancement in liver microsomes after exposure for two weeks to EGME. The enhancement was 1.3- 1.7- and 3.0 fold with exposure to 50, 100 and 400 ppm of EGME respectively. After exposure for one week the UDPglucuronosyltransferase activity in kidney microsomes was similarly enhanced. A dose-related increase in measurable UDPglucuronosyltransferase activity was also obtained in Triton X-100 treated hepatic microsomes. GSH levels of the liver and kidneys in EGME treated animals showed a tendency towards a dose-dependent increase. The activities of low-Km and high-Km aldehyde dehydrogenases in liver were decreased 6 - 14% of that in the controls with exposure to 400 ppm of EGME when glycolaldehyde was used as a substrate. Serum alanine aminotransferase activity was not influenced by inhalation exposures to EGME.     

Effects of sulpiride and ethylene glycol monomethyl ether on endometrial carcinogenicity in Donryu rats

Sulpiride and ethylene glycol monomethyl ether (EGME) are known ovarian toxicants that stimulate prolactin (PRL) secretion, resulting in hypertrophy of the corpora lutea and increased progesterone (P4) production. The purpose of the present study was to investigate how the PRL stimulatory agents affected uterine carcinogenesis and to clarify the effects of PRL on endometrial adenocarcinoma progression in rats. Ten‐week‐old female Donryu rats were treated once with N‐ethyl‐N′‐nitro‐N‐nitrosoguanidine (20 mg kg^?1), followed by treatment with sulpiride (200 ppm) or EGME (1250 ppm) from 11 weeks of age to 12 months of age. Sulpiride treatment inhibited the incidence of uterine adenocarcinoma and precancerous lesions of atypical endometrial hyperplasia, whereas EGME had no effect on uterine carcinogenesis. Sulpiride markedly prevented the onset of persistent estrus throughout the study period, and EGME delayed and inhibited the onset of persistent estrus. Moreover, sulpiride‐treated animals showed high PRL and P4 serum levels without changes in the levels of estradiol‐17β, low uterine weights and histological luteal cell hypertrophy. EGME did not affect serum PRL and P4 levels. These results suggest that the prolonged low estradiol‐17β to P4 ratio accompanied by persistent estrous cycle abnormalities secondary to the luteal stimulatory effects of PRL may explain the inhibitory effects of sulpiride on uterine carcinogenesis in rats. Copyright © 2015 John Wiley & Sons, Ltd.     

Demonstration of residual bone marrow effect in mice exposed to ethylene glycol monomethyl ether

Ethylene glycol monomethyl ether (EGMME) has been reported to cause hematopoietic abnormalities in man. We have shown that mice exposed to EGMME post-natally have suppressed bone marrow cellularity and progenitor cells 8 weeks post-exposure which returns to normal values by 16 weeks. Studies were designed to determine whether EGMME exposed mice that recovered had evidence of residual marrow stem cell injury. B6C3F1 mice were injected subcutaneously with EGMME on days 1-5 after birth at doses of 0, 100, 200 and 400 mg/kg per day, allowed to recover, and stressed with 200 rads whole body irradiation at 15 and 21 weeks post-exposure. Bone marrow functions were examined during the recovery period. Mice that had been exposed to EGMME were more sensitive to irradiation and recovery of marrow cellularity and progenitor cell numbers occurred more slowly than in unexposed controls. This indicates that EGMME can cause persistent residual damage of bone marrow progenitor cells in mice, an effect that would not be apparent with routine hematological techniques.     

Developmental phase-specific and dose-related teratogenic effects of ethylene glycol monomethyl ether in CD-1 mice

Several animal species have shown a teratogenic response to inhaled or ingested ethylene glycol monomethyl ether (EGME). The present study examined the developmental phase specificity and dose-response characteristics of EGME-induced embryotoxicity. Pregnant CD-1 mice (vaginal plug positive day = gestation Day [gd]0) received multiple or single doses of EGME by gavage between gd 7 and 14. Fetuses were examined on gd 18 for external and skeletal malformations. EGME was not maternally toxic after multiple doses of 250 mg/kg or a single administration of up to 500 mg/kg. EGME induced embryotoxicity as manifested by reduced gd 18 fetal weights and increased resorptions. The observed malformations were specifically related to the developmental stage at the time of exposure. Exencephaly resulted after EGME exposure between gd 7 to 10 whereas paw anomalies (syndactyly, oligodactyly, and stunted digit No. 1) predominated during later stages of development. Paw anomalies were maximal after administration on gd 11, and forepaws exhibited greater susceptibility than hindpaws. The no observed effect dose for the induction of digit malformations after a single administration of EGME on gd 11 was 100 mg/kg. At 175 mg EGME/kg digit anomalies were induced without any concurrent reduction in fetal body weight while at 250 mg/kg and above, digit anomalies occurred concurrently with reduced fetal body weight.     

Calcium homeostasis in pregnant rats treated with ethylene glycol monomethyl ether (EGME)

The industrial solvent ethylene glycol monomethyl ether (EGME) is a known teratogen that has been reported to alter calcium metabolism in guinea pigs during chronic exposure. Because of the tremendous demand of reproduction on maternal calcium stores, the effects of EGME on calcium and vitamin D metabolism during gestation were examined. Timed pregnant rats were treated by gavage with 0, 50, or 100 mg/kg EGME in 10 ml/kg distilled water on Days 9-15 of gestation (sperm = Day 1) and examined on Days 16 and 21. Virgin rats were treated for 7 days with 0 or 100 mg/kg EGME and examined 5 days later. EGME exposure did not affect body or kidney weight in virgin or pregnant rats, but liver weight was reduced in near-term pregnant rats treated with 100 mg/kg EGME. EGME (50 mg/kg) reduced litter size and fetal body weight and caused a significant number of live fetuses to have visceral abnormalities. EGME (100 mg/kg) caused all fetuses to be resorbed. In nonpregnant rats, 100 mg/kg did not affect serum 1,25-dihydroxyvitamin D (1,25(OH)2D3), 25-hydroxyvitamin D, ionic calcium, total calcium, or parathyroid hormone. EGME appeared to have a dose-dependent effect on calcium and vitamin D metabolism during gestation. On Day 21 of gestation, total calcium and ionic calcium were increased and 1,25(OH)2D3 was reduced in rats treated with EGME compared with nontreated controls. However, significant alterations in calcium homeostasis were evident only in dams that completely resorbed their litters. The changes in calcium and vitamin D metabolism during gestation appear to be secondary to the EGME-induced loss of litters.     

Prenatal ethylene glycol monomethyl ether (EGME) exposure produces electrocardiographic changes in the rat

The purpose of the present study was to determine if electrocardiographic (EKG) changes observed in fetuses exposed in utero to ethylene glycol monomethyl ether (EGME) persisted beyond the fetal/neonatal period. Groups of pregnant Sprague-Dawley rats were gavaged on gestation days 7-13 (sperm = day 0) with 0, 50, or 75 mg/kg EGME. Body weight prior to delivery was reduced and gestation was prolonged in EGME-treated dams. EGME treatment reduced the percentage of pregnant dams that delivered, litter size, and pup weight. There were no survivors beyond 3 days of age in the 75 mg/kg EGME group. The number of litters surviving through weaning and weight gain of male and female offspring through 8 weeks of age were reduced in the 50 mg/kg EGME group. In this same group, heart weight was unaffected, but heart/body weight ratios were increased when rats were 8 weeks old. EKGs were obtained from unanesthetized and unrestrained rats at 3 and 6 weeks of age. Prenatal EGME exposure increased the QRS interval in 3- and 6-week-old rats, and increased the T wave in 6-week-old rats. Thirty-six and 54% of 3- and 6-week old litters, respectively, had one or more individuals that were classified as having an intraventricular conduction delay (double R wave and QRS interval of 14 msec or longer). No microscopic heart abnormalities were associated with the observed intraventricular conduction delay.     

Screening method for ethylene glycol and diethylene glycol in glycerin-containing products

This paper describes a capillary gas chromatographic method with flame ionization detection for the identification/quantification of ethylene glycol (EG) and diethylene glycol (DEG) in glycerin. The validation study shows that the proposed method is specific, sensitive, precise, and accurate. The linear range of the method was 0.013–0.031 mg/mL for EG and 0.012–0.030 mg/mL for DEG. Wider ranges may be achievable but were not investigated. The limit of detection of EG and DEG were determined as 0.0018% and 0.0036% (w/w) respectively, and at this concentration the signal-to-noise ratios for EG and DEG were approximately 3:1. The method was also used to determine EG and DEG in toothpaste. The results were compared to those obtained by thin-layer chromatography (TLC) and showed greater sensitivity and specificity.     

Pharmacokinetics and biotransformation of diethylene glycol and ethylene glycol in the rat

1. 14C-Diethylene glycol (DEG), administered orally to rats at 1, 5, and 10 ml/kg, gave elimination half-lives of 6, 6, and 10 h, respectively, from urinary excretion data. Half-logarithmic plots of urinary 14C excretion rates versus time indicated zero-order elimination for the first 9 and 18 h after oral doses of 5 and 10 ml of 14C-DEG/kg, respectively. 14C-DEG urinary elimination kinetics changed into first-order 6, 9, and 18 h after oral doses of 1, 5, and 10 ml/kg, with a half-life of 3 h. 2. After oral doses of 3 and 5 ml ethylene glycol (EG)/kg, half-lives of 4.5 and 4.1 h were estimated from cumulative urinary excretion data for non-metabolized EG. A half-life of 2 h was determined from half-logarithmic plots of urinary excretion rates of non-metabolized EG after the same oral doses of EG. 3. The urinary concentrations of non-metabolized DEG and its metabolite, 2-hydroxyethoxyacetic acid (2-HEAA), determined by high-resolution n.m.r. spectroscopy in the urine of rats doses with DEG were 61-68% and 16-31% dose, respectively. 4. Urinary concentrations of non-metabolized EG and its metabolite, glycolic acid (GA), determined by n.m.r., gave 62-67% for non-metabolized EG and 28.7% for GA following oral doses of EG. 5. Oxidation of DEG and EG in rats was accompanied by a change of urinary pH, reflecting metabolic acidosis. 6. Comparison of the KM for DEG oxidation in vitro by ADH with that of ethanol oxidation, showed a 680-fold difference in substrate affinity. DEG inhibited ethanol oxidation non-competitively, the Ki being 0.44 M.     

Teratology study of diethylene glycol mono-n-butyl ether in rats

The teratogenicity of diethylene glycol mono-n-butyl ether (DEGMBE) was studied in Wistar rats. The pregnant rats were fed a diet containing DEGMBE from day 0 through day 20 of pregnancy. The dietary concentrations of DEGMBE were 0, 0.04, 0.2 and 1% and the daily intakes of DEGMBE were 0, 25, 115 and 633 mg/kg, respectively. In the DEGMBE-treated groups, the maternal body weight gain during pregnancy was significantly reduced, but neither decrease in food consumption during pregnancy nor any clinical sign of toxicity was observed. No significant differences between the DEGMBE-treated groups and the control group were found in the pre- and postimplantation losses, the number of live fetuses per litter, the sex ratio of live fetuses, the fetal body weight and the placental weight. External, skeletal and internal examinations of the fetuses revealed no evidence of teratogenesis. In the postnatal development of the offspring from the dams given DEGMBE, a high survival rate and good growth of the offspring were noted. It could be concluded that DEGMBE has no adverse effects on the pre- and postnatal development of the offspring in rats.     

Ornithine decarboxylase activity in the neonatal rat heart following prenatal exposure to ethylene glycol monomethyl ether

In mammals, ornithine decarboxylase (ODC) activity is highest during periods of rapid cellular growth and development, and the normal pattern of ODC activity during this period is sensitive to chemical and drug exposure. The industrial solvent ethylene glycol monomethyl ether (EGME) is teratogenic to rats and mice, with the heart being particularly sensitive. Basal ODC activity and ODC activity following an isoproterenol challenge were used to assess heart function in 3-, 9-, 16- and 22-day-old offspring from dams treated with 25 mg/kg EGME by gavage on days 7-13 or 13-19 of gestation. Reproductive outcome was not affected by EGME and none of the offspring had gross physical abnormalities. Gestation length was prolonged by both EGME treatments, but the increase was statistically significant only in the group treated on days 7-13 gestation. ODC activity per mg protein was greatest in 3-day-old rats and dropped off sharply during the following 3 weeks. In 3-day-old rats exposed on days 7-13 of gestation, ODC activity was 54% of that found in controls. ODC activity was comparable to that in controls in 3-day-old rats exposed on days 13-19 of gestation. Isoproterenol increased ODC activity in all groups, but additional functional abnormalities were not revealed by the isoproterenol challenge.     

Effect of hexachlorobenzene on the activities of hepatic alcohol metabolizing enzymes

To study the effect of experimental hepatic porphyria on the activities of hepatic alcohol metabolizing enzymes, female rats received a chow diet containing 0.05% hexachlorobenzene (HCB). After long-term HCB treatment for 60 days hepatic porphyria developed as evidenced by increased hepatic delta-aminolevulinic acid synthase activity and enhanced urinary excretion of delta-aminolevulinic acid, porphobilinogen and total porphyrins. Concomitantly, the activities of the hepatic microsomal ethanol oxidizing system (MEOS) were strikingly augmented by 213% (P less than 0.05) and 177% (P less than 0.01) when expressed per g of liver wet weight or per 100 g of body weight, respectively, whereas hepatic alcohol dehydrogenase activities remained virtually unchanged. Moreover, hepatic catalase showed only a trend for a slightly lower enzymic activity under these experimental conditions. The present data therefore show that experimental hepatic porphyria is associated with alterations of hepatic MEOS activities, which in turn may be a factor for the manifestation of human hepatic porphyrias in the course of alcohol consumption.     

Comparison of the teratogenic potential of inhaled ethylene glycol monomethyl ether in rats, mice, and rabbits

Studies to assess the effects of inhaled ethylene glycol monomethyl ether (EGME) on embryonal and fetal development were conducted on groups of Fischer 344 rats, CF-1 mice, and New Zealand White rabbits. Rabbits and rats were exposed to vapor concentrations of 0, 3, 10, or 50 ppm for 6 hr/day on Days 6 through 18, or Days 6 through 15 of gestation, respectively; mice were exposed to 0, 10, or 50 ppm on Days 6 through 15 of gestation. Exposure of pregnant rabbits to 50 ppm produced significant increases in the incidence of malformations, minor variations, and resorptions, as well as a decrease in fetal body weight. Rats and mice exposed to 50 ppm showed no evidence of a teratogenic effect, although indications of slight fetotoxicity were observed in both species. Transient decreases in maternal body weight gain among rats, mice, and rabbits exposed to 50 ppm were the only consistent signs of maternal effects. No significant treatment-related effects on fetal development were observed in any of the species tested at 10 ppm of EGME or below.