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Diethylene glycol (DEG; CAS Number 111-46-6) is a widely used industrial liquid chemical with a potential for human exposure. In view of the established teratogenic effects caused by ethylene glycol in laboratory animals, the developmental toxicity of DEG was investigated in mice and rats, species known to be sensitive to the developmental toxicity of ethylene glycol. Timed-pregnant CD-1 mice and CD rats were dosed daily by gavage with undiluted DEG over gestational days (gd) 6-15. Based on probe studies, mouse dosages were 0 (distilled water), 559, 2795 and 11,180 mg/kg/day, and those for rats 0, 1118, 4472 and 8944 mg/kg/day. They were examined daily for clinical signs of toxicity, and body weights, food consumption and water consumption measured periodically throughout gestation. At necropsy, on gd 18 (mice) or gd 21 (rats), dams were examined for gross pathology and body, gravid uterus, liver and kidney weights were measured. Maternal rat kidneys were examined histologically. Fetuses were weighed, sex determined, and examined for external, visceral and skeletal variations and malformations. With mice there was maternal toxicity at 11,180 mg/kg/day (mortality, signs, increased water consumption) and at 2795 mg/kg/day (increased water consumption). Implantations were comparable across all groups. Fetal body weights were significantly reduced at 11,180 mg/kg/day. There were no increases in variations or malformations, either total, by category, or individually. With rats, maternal toxicity was present at 8944 mg/kg/day (mortality, signs, reduced body weight gain, reduced food consumption, increased water consumption, increased liver weight, increased kidney weight, and renal histopathology), and 4472 mg/kg/day (increased water consumption). There were no treatment-related effects on corpora lutea or implantations. Fetal body weights were reduced at 8944 mg/kg/day. There were no significant effects with respect to total or individual external or visceral variations. Individual skeletal variations were significantly increased at 8944 mg/kg/day (poorly ossified interparietal, poorly ossified thoracic centra number 10 and number 13, and bilobed thoracic centrum number 10) and 4472 mg/kg/day (split anterior arch of atlas and bilobed thoracic centrum number 10). This pattern of delayed ossification is consistent with reduced fetal body weight. Malformations, total, by category, or individually, were similar between the control and DEG groups. Thus, under the conditions of these studies, the no-observed-effect-level (NOEL) for DEG given by gavage over gd 6-15 was 559 mg/kg/day with the mouse and 1118 mg/kg/day with the rat for maternal toxicity, and 2795 mg/kg/day with mice and 1118 mg/kg/day with rats for developmental toxicity (fetotoxicity). There were no indications of embryotoxicity or teratogenic effects at any dosage in either species.

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 hygiene survey was performed to identify exposure to EGEEA of two groups of shipyard painters, a low exposure group (n = 30) and a high exposure group (n = 27). Urinary ethoxyacetic acid and methyl hippuric acid as well as haemoglobin, packed cell volume, red cell indices, total and differential white blood cell counts (WBCs), and platelet count for the shipyard painters and the control subjects were measured., Results: The mean (range) exposure concentration (ppm) to EGEEA in the high and low exposure groups were 3.03 (not detectable to 18.27), 1.76 (not detectable to 8.12), respectively. The concentrations of methyl hippuric acid and ethoxyacetic acid in the high exposure group were significantly higher than those in the control group. The mean WBCs in the high exposure group were significantly lower than in the control group, and a significant proportion, six (11%) of the 57 painters, were leucopenic; none of the controls were affected., Conclusion: The high rate of possible haematological effects among shipyard painters and a hygienic evaluation of their working environment in the present study suggests that EGEEA might be toxic to bone marrow.

Diglyme [1,1'-oxybis(2-methoxyethane)] is an organic solvent belonging to the glycol ether class of compounds. To assess the inhalation toxicity of diglyme, groups of 20 male and 10 female rats were exposed by nose-only inhalation 6 hours/day, 5 days/week for 2 weeks to either 0 (control), 110, 370 or 1100 ppm diglyme. To compare potency, 2-methoxyethanol was also tested at 300 ppm. Rats were sacrificed either immediately following exposure, after a 14-day recovery period, or after 42 and 84 days of recovery (males only). Parameters investigated included in-life observations and body weights, clinical pathology, and histopathology with organ weights. Exposure to diglyme produced a variety of concentration-related haematological, clinical chemical and histopathological changes in both sexes. The most striking effect produced in all test groups was cellular injury involving the testes, seminal vesicles, epididymides and prostate. Although these effects were more severe at the higher concentrations tested, partial or complete recovery was seen by 84 days post-exposure. Changes in the haematopoietic system occurred in both sexes and involved the bone marrow, spleen, thymus, leucocytes and erythrocytes. The testicular effects of diglyme were somewhat less pronounced than those seen with 2-methoxyethanol. The no-observed-effect level (NOEL) for repeated inhalation exposure to diglyme in female rats is 370 ppm. For males, all concentrations tested produced effects to the reproductive system, hence a no-observed-effect level could not be demonstrated.

Diglyme (Diethylene glycol dimethyl ether, CAS No. 111-96-6) is a glycol ether which has been used in solvent formulations. To assess the potential developmental toxicity of this chemical, groups of pregnant Crl:CD BR rats were exposed to either 0 (control, room air only), 25, 100, or 400 ppm diglyme by inhalation for 6 hrs/day for Days 7 through 16 or gestation (day on which the copulation plug was detected was designation Day 1 G). All female rats were euthanized on day 21G and the fetuses were examined. An additional group of rats was treated with 25 ppm 2-methoxethanol (2ME) to serve as a positive control and for comparison of relative potencies. Maternal toxicity evident as depressed feed consumption at 400 ppm and increased liver weights at 100 ppm. There were no dams in the 400 ppm group with live fetuses (all litters consisted on resorbed conceptuses). Embryo viability was unaffected by concentrations of diglyme as high as 100 ppm. 2ME produced increased liver weights and depressed feed consumption at 25 ppm. Embryo-fetal toxicity was evident as a concentration-related decrease in fetal weight at diglyme concentrations as high as 100 ppm (and with 2ME). There were no fetuses derived from the 400 ppm diglyme-treated dams. A low incidence of structural malformations was observed in all diglyme groups (as well as with 2ME). The incidence of variations, (primarily delayed skeletal ossification and rudimentary ribs) was increased in the 25 and 100 ppm diglyme groups. The incidence and severity in the diglyme and 2ME groups exposed to 25 ppm was essentially the same suggesting similar potency for producing structural variations. In this study, diglyme was embryolethal at 400 ppm; a level that otherwise was only marginally toxic to the dam. Maternal and fetal toxicity also were demonstrated at 100 ppm. Although the fetal defects detected following diglyme exposure at 25 ppm were not significantly different from control values (with the exception of the incidence of skeletal developmental variations), the pattern, type, and incidence of variations were similar to those seen at 100 ppm, suggesting that 25 ppm was an effect level that approaches the lower end of the developmental toxicity response curve. Therefore, the no-observable-effect level (NOEL) for diglyme exposure in the dam is 25 ppm and a NOEL was not clearly demonstrated for the conceptus.

Diethylene glycol was tested for prenatal toxicity after oral administration (gavage) to pregnant Himalayan rabbits. The substance was administered to 15 female rabbits per group by stomach tube in daily doses of 100, 400, or 1000 mg/kg body wt from Day 7 postinsemination (p.i.) through Day 19 p.i. The control group received the vehicle only (twice distilled water). There were no compound-related effects on the dams concerning food consumption, body weight, body weight gain, or clinical or necropsy observations even at the highest dose of 1000 mg/kg body wt/day. All data obtained on gestational parameters also revealed no biologically relevant differences between the control and treated groups. The fetal external, soft tissue, and skeletal findings, which were classified as malformations, variations, and/or retardations, were seen in the treated fetuses at a frequency similar to the corresponding and/or historical controls. Thus, under the conditions of this study, no signs of maternal toxicity or embryo-/fetotoxicity were induced by diethylene glycol. Therefore, a no-observable-adverse-effect level for diethylene glycol of > 1000 mg/kg body wt/day was established for both the maternal and the developing Himalayan rabbit.

Ethylene glycol (EG; CAS No. 107-21-1) is teratogenic to mice by whole-body exposure to an aerosol at high concentrations, but results were confounded by possible exposure from ingestion after grooming and/or from percutaneous absorption. Therefore, CD-1 mice were exposed to EG on Gestational Days (GD) 6 through 15, 6 hr/day by occluded cutaneous application at 0, 12.5, 50, or 100% (undiluted) EG (0.1 ml/animal, equivalent to approximately 0, 404, 1677, or 3549 mg/kg/day [10 ml/kg, positive control gavage (PCGG)], 30 females/group. Dams were weighed and evaluated daily (including application site) for clinical signs and water consumption throughout gestation. On GD 18, maternal uterus, liver, and paired kidneys were weighed; kidneys of 0 and 100% and the PCGG were examined microscopically. Corpora lutea and implantation sites were recorded. Live fetuses were weighed, sexed, and examined for structural alterations. For cutaneously exposed dams, there was no treatment-related maternal, no differences in pre- or postimplantation loss in fetal body weights/litter, and no increased incidences of any fetal malformations. Two skeletal variations, increased at 100% may represent effects of restraint stress and/or findings due to chance. In the PCGG, 8 females (26.7%) died, water consumption was increased, fetal body weights/litter were reduced, and fetal malformations and variations were increased. PCGG kidneys exhibited tubular nephrosis and tubular cell degeneration, with no oxalate crystals, documenting renal toxicity at this oral dose in mice. Minimal-grade renal tubular lesions observed in 3 mice (of 30) at 100% EG may represent treatment-related or incidental findings. Therefore, exposure of pregnant CD-1 to 0, 12.5, 50 or 100% EG during organogenesis by occluded cutaneous application resulted in minimal or no observable maternal or developmental toxicity at 100% (approximately 3549 mg/kg/day), the NOEL.

Previous studies have indicated that ethylene glycol (EG) is a developmental toxicant in rats and mice primarily when ingested. This study was designed to establish no-observed-effect levels (NOELs) for developmental toxicity of EG administered by gavage in both rodent species. Dams were administered EG on Gestation Days 6-15; rats were given 0, 150, 500, 1000, or 2500 mg EG/kg/day; mice were dosed with 0, 50, 150, 500, or 1500 mg EG/kg/day. In rat dams given 2500 mg EG/kg/day, water consumption was increased during treatment and body weights were reduced throughout gestation; liver and kidney weights were increased at euthanization (Gestation Day 21). Relative liver weights were also increased at 1000 mg/kg/day. Effects observed in rat fetuses at 2500 mg/kg/day included the following: hydrocephaly; gastroschisis; umbilical hernia; fused, duplicated, or missing arches, centra, and ribs; poor ossification in thoracic and lumbar regions; and reduced body weights. Reduced body weights, duplicated or missing ribs, centra, and arches, and poor ossification were also observed in rat fetuses at 1000 mg/kg/day. In mice, there was no apparent treatment-related maternal toxicity. In mouse fetuses (Gestation Day 18), effects were observed at 1500 mg/kg/day and included reduced body weights, fused ribs and arches, poor ossification in thoracic and lumbar centra, and increased occurrence of an extra 14th rib. At 500 mg/kg/day, slight reductions in fetal body weight and increased incidences of extra ribs were observed. Under conditions of these studies, NOELs for developmental toxicity were 500 mg/kg/day for rats and 150 mg/kg/day for mice, indicating that mice were more susceptible than rats to the teratogenic effects of EG.

Artificially inseminated New Zealand white (NZW) rabbits were administered ethylene glycol (EG) by gavage on Gestational Days (GD) 6 through 19 at doses of 0, 100, 500, 1000, or 2000 mg/kg/day, with 23-24 inseminated animals per group. Clinical signs were recorded and water consumption was measured daily; does were weighed on GD 0, 6-19, 25, and 30. At necropsy (GD 30), maternal liver, kidney, and gravid uterine weights were recorded. Histopathologic examination was performed on kidneys from 10 does/dose and for all unscheduled deaths. Ovarian corpora lutea were counted and uterine implantation sites (total sites, resorptions, dead and live fetuses) were recorded. All live fetuses were weighed, sexed, and examined for external, visceral, and skeletal malformations and variations. EG resulted in profound maternal toxicity at 2000 mg/kg/day (42% mortality; three early deliveries and one spontaneous abortion) associated with renal pathology and unaccompanied by any other indicators of maternal toxicity. Renal lesions at 2000 mg/kg/day involved the cortical renal tubules and included intraluminal oxalate crystals, epithelial necrosis, and tubular dilatation and degeneration. No dose-related maternal toxicity occurred at 100-1000 mg/kg/day. There was no indication of developmental toxicity at any dose tested, including no effects on pre- or postimplantation loss, number of fetuses, fetal body weight, or sex ratio (% male fetuses) per litter, and no evidence of teratogenicity. The "no observable adverse effect level" (NOAEL) for maternal toxicity was therefore 1000 mg/kg/day and the NOAEL for developmental toxicity was at least 2000 mg/kg/day in this study. The sensitivity of NZW rabbits relative to that of Sprague-Dawley rats and Swiss mice for maternal and developmental toxicity from gavage administration of EG during organogenesis can be determined for maternal toxicity: rabbits > mice > rats, and for developmental toxicity, mice >> rats >> rabbits.

2-Methoxyethanol (2-ME) was applied as a single dermal dose on the backs of collared, pregnant Sprague-Dawley rats on Gestation Days (GD) 10, 11, 12, 13, or 14 at doses of 0 and 2000 mg/kg, and at doses of 0, 250, 500, and 1000 mg/kg on GD 12. Except for a transient loss in body weight observed the day after 2-ME administration, no signs of maternal toxicity were observed. On GD 20, dams were necropsied and the fetuses evaluated for normal development. Resorptions were significantly (p less than 0.05) increased in dams exposed to 2-ME on GD 10. Fetal body weights were reduced at dose levels of 1000 and 2000 mg/kg, but statistically significant differences were found only on GD 10 and 12. Significant increases in external, visceral, and skeletal malformations were observed in fetuses exposed to 2-ME at dose levels of 500 mg/kg or greater. Defects of the cardiovascular and urinary systems were the prominent visceral malformations observed. Limb defects (especially those pertaining to the digits) and vertebral column defects (primarily of the tail) were the most frequently observed skeletal defects. At the 2000 mg/kg dose level, 2-ME was teratogenic regardless of the GD of administration. Based on the results of this study, the no observed adverse effect level for developmental toxicity for a single dermal dose of 2-ME applied on GD 12 was determined to be 250 mg/kg.

To determine the potential developmental toxicity of ethylene glycol monopropyl ether (EGPE), groups of pregnant New Zealand white rabbits were exposed to target concentrations of 0, 125, 250, or 500 ppm EGPE vapors for 6 hr a day on Days 6-18 of gestation. Maternal effects included a slight reduction in feed consumption during the first week of treatment at the 250- and 500-ppm exposure levels and slightly reduced body weight gain at the 500-ppm level compared to those of the controls, but the differences were not statistically significant. One doe exposed to 500 ppm had red-colored urine during the 24-hr period following the second exposure. Hematologic determinations, absolute and relative organ weights, and observations at necropsy revealed no treatment-related maternal effects. Reproductive indices, i.e., pregnancy rate, number of corpora lutea, implantation sites, viable fetuses, early and late resorptions, fetal body weights, fetal sex ratio, and the gravid uterine and corrected body weights, were not affected by exposures to EGPE. The occurrences of external and internal soft tissue malformations and variations and the incidences of skeletal malformations in the EGPE-exposed groups were not significantly different from those in the control group. Common skeletal variations, in many instances, were seen less frequently in EGPE-exposed fetuses than in control fetuses. In those cases where the incidence of fetuses with a skeletal variation was greater for EGPE-exposed fetuses than that for control fetuses, the number of litters involved was not significantly different from that of the control group. Thus, EGPE vapor concentrations as high as 500 ppm did not produce teratogenicity or other developmental toxicity in the rabbit conceptus.

Undiluted 2-ethoxyethanol or water (control) was applied to the skin of pregnant Sprague-Dawley rats on days 7--16 of gestation (sperm = day 1). Applications were made 4 times daily in volumes of 0.25 or 0.50 ml 2-ethoxyethanol. Females exhibited ataxia following treatment of the high-dose group, and weight gain was significantly (p less than u. 0.001) reduced in the last half of gestation. Litters were collected by caesarian section on day 21 of gestation, and fetuses were examined for external defects. Half of the fetuses were cleared and stained in alizarin red S for skeletal examinations, and half were examined for visceral defects by the Wilson technique. Intrauterine death was 100% in the high-dose group. In the lower dosage group, there was a significant increase in the number of pregnant females with 100% dead implants (p less than 0.001), a significant reduction in the number of live fetuses per litter (p less than 0.001), a significant reduction in fetal body weight (p less than 0.001), and a significant increase in the incidence of skeletal variations (p less than 0.05) and cardiovascular malformations (p less than 0.05).

Diethylene glycol monomethyl ether (DEGME) was applied to the skin of pregnant rabbits on Days 6 through 18 of gestation in order to assess the fetotoxic and teratogenic potential by the dermal route. Rabbits were treated with 0, 50, 250, or 750 mg/kg/day of DEGME, and fetuses were examined for external, visceral, and skeletal alterations. Topical application of the highest dose, 750 mg/kg/day, produced slight embryotoxicity, fetotoxicity, and toxicity in the maternal animal. Maternal effects were characterized by decreased weight gain and a concurrent physiologic decrease in red blood cells and packed cell volume values. In addition, a slight increase in embryonic resorptions was observed. The fetal alterations observed, mild forelimb flexure, slight-to-moderate dilation of the renal pelvis, retrocaval ureter, cervical spurs, and delayed ossification of the skull and sternebral bones, are considered to be indicative of fetotoxicity but not teratogenicity. Slight fetotoxicity in the form of delayed ossification of the skull and cervical spurs was seen in the 250 mg/kg/day dose group. No adverse maternal, embryonic, or fetal effects were observed at 50 mg/kg/day.

2-Phenoxyethanol was applied to the clipped skin of pregnant rabbits on Days 6 through 18 of gestation in order to assess the fetotoxic and teratogenic potential by the dermal route. Rabbits were treated with 0, 300, 600, or 1000 mg/kg/day of 2-phenoxyethanol, and fetuses were examined for external, visceral, and skeletal alterations. Dermal application of 1000 mg/kg/day produced maternal toxicity as evidenced by intravascular hemolysis of red blood cells and death in some animals. Maternal toxicity was observed in rabbits treated with 600 mg 2-phenoxyethanol/kg/day but at a lower incidence than that observed at 1000 mg/kg/day. Nine rabbits in the 1000 mg/kg/day dose group and five rabbits at 600 mg/kg/day died or were sacrificed in extremis. Rabbits in the two highest dose groups which survived until Day 28 of gestation showed no evidence of treatment-related effects. No signs of maternal toxicity were seen at 300 mg/kg/day. Examination of rabbit fetuses indicated that, at the dosages tested, 2-phenoxyethanol was not embryotoxic, fetotoxic, or teratogenic.