The following information was generated from the Hazardous Substances Data Bank (HSDB), a database of the National Library of Medicine's TOXNET system (http://toxnet.nlm.nih.gov) on October 30, 2009.

Query: The chemical name was identified. The following terms were added from ChemIDplus: methyldiglyme dimethyl carbitol dimethoxydiglycol CAS Registry Number: 111-96-6

NAME: DIETHYLENE GLYCOL DIMETHYL ETHER

HSN: 72

RN: 111-96-6

HUMAN HEALTH EFFECTS:

HUMAN TOXICITY EXCERPTS: /GENOTOXICITY/ 2-Methoxyethanol and bis(2-methoxyethyl)ether were subjected to the ... unscheduled DNA synthesis (UDS) assay in human embryo fibroblasts ... UDS in fibroblasts were not increased by either compound. [McGregor DB et al; Toxicol. Appl. Pharmacol. 70 (2): 303-16 (1983)] **PEER REVIEWED** <a

href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt= Abstract&list_uids=6623472" target=new>PubMed Abstract

/OTHER TOXICITY INFORMATION/ The ethers of diethylene glycol are lower in toxicity than the ethers of ethylene glycol, but they have many similar characteristics. /Diethylene glycol ethers/ [International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I&II. Geneva, Switzerland: International Labour Office, 1983., p. 975] **PEER REVIEWED**

/EPIDEMIOLOGY STUDIES/ Ethylene glycol ethers (EGEs) including diglyme are used in the manufacture of semiconductors. Epidemiological studies of semiconductor populations evaluated potential adverse reproductive outcomes. ... In each of these studies, workers were exposed to mixtures including diglyme but not to diglyme alone. ... Exposure to EGEs was determined using questionnaires from subjects about the work performed and an assessment of the work environment by industrial hygienists, but no measurements of personal or area exposures were made. Workers in the fabrication area were considered exposed to EGEs. For the retrospective study, information on pregnancy outcomes and potential confounders (age, smoking, ethnicity, education, income, year of pregnancy, and stress) was obtained through a comprehensive interviewer-administered interview of female employees. The prospective study of early fetal loss and fecundity (probability of conception per menstrual cycle) was conducted in a subset of female employees from five plants. Daily diaries and measurements of daily urinary human chorionic gonadotrophin (hCG) levels for 6 months were collected in addition to the comprehensive interview. Of the 891 medically verified pregnancies identified for the retrospective study, 774 (86.9%) were live births, 113 (12.7%) were spontaneous abortions, and 4 (0.4%) were stillbirths. The overall unadjusted relative risk (RR) for spontaneous abortions was 1.45 (95% confidence interval [CI] = 1.02–2.05) and changed little after adjusting for confounders (adjusted RR =1.43; 95%CI = 0.95–2.09). When stratified by work group, the risk of spontaneous abortion was statistically significantly increased for female workers in the photolithography group (RR = 1.67; 95% CI = 1.04–2.55) and in the etching group (RR = 2.08; 95% CI = 1.27–3.19). For women working with higher levels of EGE only in masking, the risk for spontaneous abortion was increased 3-fold (RR = 3.38; 95% CI = 1.61–5.73). In the prospective study, no statistically significant differences were detected in the overall rate of spontaneous abortions between fabrication and non-fabrication workers or when pregnancy outcomes were examined by work group. However, the ability to conceive was lower among female workers exposed to EGEs (fertility rate [FR] = 0.37; 95% CI = 0.11–1.19). /Ethylene glycol ethers/ [International Programme on Chemical Safety; Concise International Chemical Assessment Document Number 41: Diethylene Glycol Dimethyl Ether (2002). Available from, as of February 20, 2007: http://www.inchem.org/pages/cicads.html ] **PEER REVIEWED**

/EPIDEMIOLOGY STUDIES/ Painters exposed to the solvent 2-methoxyethanol, which is also a metabolite of diglyme, were found to have an increased prevalence of oligospermia and azoospermia. ... Semen samples from 73 painters and 40 controls from a shipyard were analysed. The painters were exposed by inhalation to 0–17.7 mg 2-methoxyethanol/ cu m (mean 2.6 mg/cu m) and to 0–80.5 mg 2-ethoxyethanol (= ethylene glycol monoethyl ether)/cu m (mean 9.9 mg/cu m). Skin contact with 2-methoxyethanol and 2-ethoxyethanol was also considered possible. Exposure to numerous other substances, including organic solvents and metals, was also known to occur. While no effects were seen in hormone levels or in sperm viability, motility, and morphology, the prevalence of those with oligospermia differed between the groups. The proportion of men with a sperm density 100 million/cm3 was higher in the exposed group than in the unexposed group (33% vs. 20%; P = 0.20). The proportion of those with oligospermia among painters who did not smoke compared with controls was 36% vs. 16% (P = 0.05). The proportion of those with oligospermia was similar between painters and controls who smoked (30% vs. 38%; P = 0.49). The proportion of painters with azoospermia was 5% compared with 0% in the controls. /2-Methoxyethanol/ [International Programme on Chemical Safety; Concise International Chemical Assessment Document Number 41: Diethylene Glycol Dimethyl Ether (2002). Available from, as of February 20, 2007: http://www.inchem.org/pages/cicads.html ] **PEER REVIEWED**

PROBABLE ROUTES OF HUMAN EXPOSURE: NIOSH (NOES Survey 1981-1983) has statistically estimated that 207 workers (52 of these are female) are potentially exposed to diethylene glycol dimethyl ether in the US(1). Occupational exposure to diethylene glycol dimethyl ether may occur through inhalation and dermal contact with this compound at workplaces where diethylene glycol dimethyl ether is produced or used(SRC). Monitoring data indicate that the general population may be exposed to diethylene glycol dimethyl ether via inhalation of vehicle exhaust and ingestion of contaminated drinking water(SRC). [(1) NIOSH; NOES. National Occupational Exposure Survey conducted from 1981-1983. Estimated numbers of employees potentially exposed to specific agents by 2-digit standard industrial classification (SIC). Available at http://www.cdc.gov/noes/ as of Jan 2007.] **PEER REVIEWED**

EMERGENCY MEDICAL TREATMENT:EMERGENCY MEDICAL TREATMENT:

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DATABASE SHOULD BE CONSULTED FOR ASSISTANCE IN THE DIAGNOSIS OR TREATMENT OF SPECIFIC CASES. The use of the POISINDEX(R) and MEDITEXT(R) databases is at your sole risk. The POISINDEX(R) and MEDITEXT(R) databases are provided "AS IS" and "as available" for use, without warranties of any kind, either expressed or implied. Micromedex makes no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the POISINDEX(R) and MEDITEXT(R) databases. ALL IMPLIED WARRANTIES

OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Micromedex does not assume any responsibility or risk for your use of the POISINDEX(R) or MEDITEXT(R) databases. Copyright 1974-2009 Thomson MICROMEDEX. All Rights Reserved. Any duplication, replication, "downloading," sale, redistribution or other use for commercial purposes is a violation of Micromedex' rights and is strictly prohibited.<p>The following Overview, *** GLYCOL ETHERS ***, is relevant for this HSDB record chemical.

LIFE SUPPORT: o This overview assumes that basic life support measures

have been instituted.

CLINICAL EFFECTS:

0.2.1 SUMMARY OF EXPOSURE

0.2.1.1 ACUTE EXPOSURE A) Based on animal comparative data, the glycol ethers may be more acutely toxic than ethylene glycol; however, this model does not account for toxicity of metabolites. Toxicity in humans following ingestions may be dependent on the metabolic products. 1) Human overdose experience is limited to extremely large ingestions in adults. Experience with smaller

amounts or low concentrations is insufficient to predict whether animal data suggesting significant acute toxicity are relevant to humans. B) CNS depression, renal injury, hyperventilation, hemolysis, and metabolic acidosis have occurred after large ingestions. Onset of symptoms may be delayed for up to 18 hours.

0.2.3 VITAL SIGNS

0.2.4 HEENT

0.2.4.1 ACUTE EXPOSURE A) Eye irritation is generally slight, but may be severe with the propyl ether.

0.2.5 CARDIOVASCULAR

0.2.5.1 ACUTE EXPOSURE A) Severe hypotension and ventricular dysrhythmias are rare effects of large ingestions of ethylene glycol butyl ether (EGBE).

0.2.6 RESPIRATORY

0.2.6.1 ACUTE EXPOSURE A) ARDS was reported in one case after ingestion of 500 mL of 9.1% ethylene glycol butyl ether (EGBE).

0.2.7 NEUROLOGIC

0.2.7.1 ACUTE EXPOSURE A) Ataxia, tremor, somnolence, lethargy, headache, dysarthria, blurred vision, coma, and personalitychanges have been reported after chronic inhalation. B) Coma has been described after ingestion of 30 to 100 mL of pure glycol ethers in adults.

0.2.8 GASTROINTESTINAL

0.2.8.1 ACUTE EXPOSURE A) Hemorrhagic gastritis was seen in a case of fatal poisoning with methyl ether.

0.2.9 HEPATIC

0.2.9.1 ACUTE EXPOSURE A) Fatty degeneration of the liver was noted on autopsy after a poisoning with methyl ether.

0.2.10 GENITOURINARY

0.2.10.1 ACUTE EXPOSURE A) Renal tubular necrosis with proteinuria has been seen following oral ingestion. Oxalate crystals were seen in the urine in one patient.

0.2.11 ACID-BASE

0.2.11.1 ACUTE EXPOSURE A) Metabolic acidosis has been consistently described after large oral ingestions.

0.2.12 FLUID-ELECTROLYTE

0.2.12.1 ACUTE EXPOSURE A) Hypocalcemia and hypokalemia have been noted.

0.2.13 HEMATOLOGIC

0.2.13.1 ACUTE EXPOSURE A) Hemolytic anemia, non-hemolytic anemia, thrombocytopenia, and DIC have been reported in

overdose.

0.2.20 REPRODUCTIVE HAZARDS A) Teratogenic effects have been observed at maternally non-toxic doses for the methyl ether and ethyl ether of ethylene glycol.

0.2.21 CARCINOGENICITY

0.2.21.1 IARC CATEGORY A) IARC Carcinogenicity Ratings for CAS111-76-2 (IARC,

2004): 1) IARC Classification a) Listed as: 2-Butoxyethanol b) Carcinogen Rating: 3 1) The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category. B) IARC Carcinogenicity Ratings for CAS109-86-4 (IARC,
2004): 1) Not Listed C) IARC Carcinogenicity Ratings for CAS110-80-5 (IARC,2004): 1) Not Listed D) IARC Carcinogenicity Ratings for CAS109-59-1 (IARC,
2004): 1) Not Listed

0.2.22 GENOTOXICITY A) Ethylene glycol n-butyl ether and the aldehyde metabolite of ethylene glycol monomethyl ether (methoxyacetaldehyde) displayed mutagenic potency in the Salmonella typhimurium assay. In contrast, EGME, EGEE, EALD, BALD and the acid metabolites gave negative responses with all strains of Salmonella typhimurium used in the assay (Hoflack et al, 1995).

LABORATORY: A) Blood ethanol, methanol, and ethylene glycol levels may be useful in assessing concurrent ingestions, but are not useful in assessing glycol ether toxicity.

TREATMENT OVERVIEW:

0.4.2 ORAL EXPOSURE A) Emesis is contraindicated due to rapid GI absorption and potential for rapid progression to coma. B) GASTRIC LAVAGE: Consider after ingestion of a potentially life-threatening amount of poison if it can be performed soon after ingestion (generally within 1 hour). Protect airway by placement in Trendelenburg and left lateral decubitus position or by endotracheal intubation. Control any seizures first. 1) CONTRAINDICATIONS: Loss of airway protective reflexes

or decreased level of consciousness in unintubated patients; following ingestion of corrosives; hydrocarbons (high aspiration potential); patients at risk of hemorrhage or gastrointestinal perforation; and trivial or non-toxic ingestion. C) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old. D) Correct severe acidosis (pH < 7.1) with IV NaHCO3. 1 to 2 mEq/kg is a useful starting dose. Monitor ABGs. E) Ethanol (ETOH) may inhibit the formation of toxic metabolites, but there are no controlled human studies documenting efficacy. 1) LOADING DOSE - Administer 7.6 to 10 mL/kg of 10% ETOH

in D5W IV over 30 minutes. 2) MAINTENANCE DOSE - Administer 1.39 mL/kg/hr of 10% ETOH in D5W by IV infusion. Aim at achieving and maintaining 100 to 130 mg/dL blood ethanol levels. 3) PRECAUTION - Monitor blood glucose and ETOH levels. F) HEMODIALYSIS - Consider hemodialysis in patients with severe toxicity. Maintenance ETOH dose must be modified during dialysis. INDICATIONS: a) severe acid-base and/or fluid-electrolyte abnormalities despite conventional therapy; or b) renal failure.

0.4.3 INHALATION EXPOSURE A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation,bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with inhaled beta2 agonist and oral or parenteral corticosteroids.

0.4.4 EYE EXPOSURE A) DECONTAMINATION: Irrigate exposed eyes with copious amounts of room temperature water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist, the patient should be seen in a health care facility.

0.4.5 DERMAL EXPOSURE A) OVERVIEW 1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water. A physician may need to examine the area if irritation or pain persists.

RANGE OF TOXICITY: A) Adults have developed severe toxicity after ingestion of 30 to 100 mL, and death after 240 mL (methoxyethanol).

ANIMAL TOXICITY STUDIES:

NON-HUMAN TOXICITY EXCERPTS: /LABORATORY ANIMALS: Acute Exposure/ Wistar rats (males and females) were exposed to diglyme vapors in an "inhalation risk test" using air "saturated" with diglyme and an exposure period of 7 hours. After exposure, animals were maintained for a 14-day observation period after which they were sacrificed and subjected to a gross necropsy. All animals survived exposure and a 14-day observation period. No macroscopic findings were observed at necropsy 14 days after the exposure. Clinical signs were restlessness, narrowing of palpebral fissures, and irregular breathing in rats. Based on the vapor pressure the concentration could have been as high as 3800 ppm (21 mg/L) but the /actual/ nominal concentration calculated by the weight loss of test material and the flow rate of the apparatus ... calculates to 11.14 mg/L or about 2000 ppm. [EPA/Office of Pollution Prevention and Toxics; High Production Volume (HPV) Challenge Program's Robust Summaries and Test Plans. Available from the Database Query page at: http://www.epa.gov/hpv/pubs/hpvrstp.htm on Diglyme as of February 7, 2007] **PEER REVIEWED**

/LABORATORY ANIMALS: Acute Exposure/ Young adult ChR-CD male rats were administered /diglyme/ by intragastric intubation as a water solution in single doses ranging from 1500 to 23000 mg/kg. Surviving animals were observed for 14 days and were sacrificed and necropsied. ... / All animals given doses higher than 7,500 mg/kg died./ Clinical effects /observed at/ lethal doses/ include/ ataxia, loss of muscle tone, lethargy, prostration, labored respirations, and belly-to-cage posture at 7,500 mg/kg and above; pallor at 17,000 mg/kg and above; loss of righting reflex at 25,000 mg/kg. /Clinical effects observed at/ nonlethal doses included lethargy, belly-to-cage posture and ruffled fur at 1,500 mg/kg and above; prostration at 5,000 mg/kg on day of dosing; ruffled fur at 5,000 mg/kg on day after dosing; weight loss 1-2 days at 2,250 mg/kg and above. Diglyme is slightly toxic when administered orally to young adult ChR-CD male rats in single doses; its Approximate Lethal Dose is 7,500 mg/kg of body weight. [EPA/Office of Pollution Prevention and Toxics; High Production Volume (HPV) Challenge Information System (HPVIS). Available from the Database Query page at: http://www.epa.gov/hpvis/index.html on Ethane,1-1'-oxybis[2-methoxy- (CAS # 111-96-6) as of February 21, 2007.]**PEER REVIEWED**

/LABORATORY ANIMALS: Acute Exposure/ Described as slightly irritating in the rabbit skin and eye irritation tests. [European Chemicals Bureau; IUCLID Dataset, bis (2-methoxyethyl) ether (CAS # 111-96-6) p.28-9. Available from, as of February 7, 2007: http://ecb.jrc.it/esis/esis.php ]

**PEER REVIEWED**

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ ... In an in vivo mouse sperm abnormality test, groups of 10 male B6C3F1 mice were exposed for 7 hr/day to vapor concentrations of 250 ppm for 5 days or 1000 ppm for 4 days. Because of toxicity in the high-exposure group, exposure was reduced by 1 day. The mice were maintained for 35 days without further exposure, then sacrificed and examined. Significant increases in sperm head abnormalities were observed in the highest exposure group, but no significant exposure-related effects were observed in the low-exposure group. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. V7 211] **PEER REVIEWED**

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ The onset of testicular pathology in the rat and possible recovery over an 8 wk period were evaluated after the administration of up to 20 daily oral doses of bis(2-methoxyethyl)ether (diglyme) at 5.1 mmol/kg body weight (684 mg/kg body weight). Primary and secondary spermatocyte degeneration and spermatidic growth cells were observed after six to eight treatments. In addition, the testes-to-body weight ratio was significantly reduced by the tenth day of treatment and continued to be depressed eight weeks after discontinuation of the treatment. Testicular LDH-X activity, a pachytene spermatocyte marker enzyme, was significantly decreased in animals by the eighteenth day of treatment with diglyme. [Cheever KL et al; Toxicol Ind Health 5 (6): 1099-110 (1989)] **PEER REVIEWED**

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ ... To assess the inhalation toxicity of diglyme, groups of 20 male and 10 female rats were exposed by nose-only inhalation 6 hr/day, 5 days/wk for 2 wk 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). ... Exposure to diglyme produced a variety of concentration-related hematological, 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 hematopoietic 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. [Valentine R et al; Food Chem Toxicol 37 (1): 75-86 (1999)] **PEER REVIEWED** <a

href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt= Abstract&list_uids=10069485"target=new>PubMed Abstract

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ In four male JCL-ICR mice that received diglyme in the drinking-water for 25 days at a level of 2% (approximately 7000 mg/kg body weight, assuming an intake of 7 mL/day and a body weight of 20 g), the number of total white blood cells was more than doubled compared with controls. This increase was not, however, statistically significant. [International Program on Chemical Safety/Commission of the European Communities; International Chemical Safety Card on Diethylene Glycol Dimethyl Ether (2002). Available from, as of February 20, 2007: http://www.inchem.org/pages/icsc.html ] **PEER

REVIEWED**

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ In this study, measured concentrations of 0, 3.1, 9.9, 30, or 98 ppm were used to expose rats by inhalation for 10 exposures followed by a 14-day recovery period. Mean body weights of rats exposed to 98 ppm were significantly lower than those of controls at the end of the exposure period. The weights of testes, seminal vesicles, prostate, and epididymides were similar to controls. Microscopic examination of the testes revealed minimal or mild testicular atrophy in the 100 ppm group. Findings at lower concentrations were not considered to be compound related. It was concluded that the target organ is the male reproductive system and the NOEL for male rats is 30 ppm under these conditions. [EPA/Office of Pollution Prevention and Toxics; High Production Volume (HPV) Challenge Information System (HPVIS). Available from the Database Query page at: http://www.epa.gov/hpvis/index.html on Ethane,1-1'-oxybis[2-methoxy- (CAS # 111-96-6) as of February 21, 2007.] **PEER REVIEWED**

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ The reproductive toxicity potential of chemicals were screened in Female CD-1 mice: ethylene glycol dimethyl ether, diethylene gycol dimethyl ether, triethylene glycol dimethyl ether, diethylene glycol diethyl ether. The dose lethal to 10% of the mice was the maximum tolerated dose. Pregnant mice received eight doses, once daily, of the chemicals based on their maximum tolerated doses. Ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, and triethylene glycol dimethyl ether had LD50s of 2525.8, 2978.7, and 4136.7 mg/kg, respectively, and maximum tolerated doses of 2000.0, 2000.0, and 3500 mg/kg, respectively. These compounds significantly affect reproductive indices. No ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, or triethylene glycol dimethyl ether groups delivered any viable pups. Diethylene glycol diethyl ether moderately, but not significantly, reduced reproductive indices. Maternal lethality was significant in ethylene glycol dimethyl ether and diethylene glycol dimethyl ether groups. [Plasterer MR et al; J Toxicol Environ Health 15 (1): 25-38 (1985)] **PEER REVIEWED**

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ ... Diethylene glycol dimethyl ether (0, 25, 50, 100 or 175 mg/kg/day) was administered by gavage in distilled water to timed-pregnant New Zealand White rabbits (15-22 dams/group) during major organogenesis (gestational days 6-19). Exposure of New Zealand White rabbit to diethylene glycol dimethyl ether at 25 mg/kg/day during major organogenesis produced no adverse maternal or developmental effects. Doses of 50 and 100 mg/kg/day were associated with adverse developmental effects, but did not produce distinctive evidence of maternal toxicity. The incidence of adverse developmental effects was further increased at a dose associated withincreased maternal mortality (eg, 175 mg/kg/day). The principal manifestations of developmental toxicity were increased resorptions and a higher incidence of major malformations among surviving fetuses. [Price CJ; Govt Reports Announcements & Index Issue 20 (1987)] **PEER

REVIEWED**

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ ... Diethylene glycol dimethyl ether (0, 62.5, 125, 250, or 500 mg/kg/day) was administered by gavage in distilled water to timed-pregnant CD-1 mice during major organogenesis (gestational days 6-15). No maternal deaths, morbidity, or treatment-related clinical signs were observed. Reduced maternal weight gain during treatment at greater than or equal to 250 mg/kg/day was primarily attributed to compromised pregnancy status resulting in reduced gravid uterine weight. Maternal weight gain during gestation corrected for gravid uterine weight, and relative liver weight (% body weight) were not affected. Average fetal body weight/litter was significantly reduced at greater than or equal to 125 mg/kg/day. The percentage of postimplantation loss/litter (5, 8, 7, 12, and 50% for control through high dose) and the percentage of malformed live fetuses/litter (0.4, 0, 2, 24, and 96%) were significantly increased at greater than or equal to 250 mg/kg/day. Developmental defects involved primarily the neural tube, limbs and digits, craniofacial structures, abdominal wall, cardiovascular system, urogenital organs, and both the axial and appendicular skeleton. Oral administration of diethylene glycol dimethyl ether during major organogenesis did not produce any distinctive signs of maternal toxicity, but did produce selective and profound adverse effects upon fetal growth, viability and morphological development at greater than or equal to 125 mg/kg/day. [Price CJ et al; Fundam Appl Toxicol 8 (1): 115-26 (1987)] **PEER REVIEWED**

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Male rats were exposed to 0, 110, 370, or 1100 ppm bis(2-methoxyethyl)ether (diglyme) 6 hr/day, 5 days/week for 2 weeks. One group of male rats was exposed to 300 ppm 2-methoxyethanol for 2 weeks as a positive control. Exposed rats were killed after 10 days of exposure and 14, 42, or 84 days post-exposure, respectively. At 110 ppm diglyme, spermatocytes in pachytene and meiotic division at spermatogenic stages XII-XIV were mainly affected. At 370 ppm diglyme, affected germ cells were similar to those seen at 110 ppm diglyme, but round spermatids at spermatogenic stages I-VII were also affected. The testes regained normal spermatogenesis by 84 days post exposure. At 1100 ppm diglyme or 300 ppm 2-methoxyethanol marked testicular atrophy was found affecting all spermatogenic stages. Damaged seminiferous tubules were lined with regenerating pachytene spermatocytes at 14 days post exposure and with spermatocytes and round spermatids after 42 days post exposure. Most but not all testes in rats exposed to 300 ppm 2-methoxyethanol or 1100 ppm diglyme had normal morphology after 84 days post exposure. Based on the observation of germ cell damage, spermatozoa population in the epididymal tubules, reversibility of spermatogenesis after various post exposure periods, testicular toxicity induced by 300 ppm 2-methoxyethanol was more severe than that seen at 370 ppm diglyme but was slightly less remarkable than that of 1100 ppm diglyme. [Lee KP et al; Toxicol 59 (3): 239-58 (1989)] **PEER REVIEWED**

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ 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, 304 mg/kg, ethylene glycol dimethylether, 361 mg/kg, diethylene glycol dimethyl ether 537 mg/kg, triethylene glycol dimethyl ether, 713 mg/kg. Fetuses were collected on gestation day 18. 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 ethylene glycol dimethyl ether. There was no treatment-related pattern of gross external malformations other than paw defects. Only triethylene glycol dimethyl ether failed to produce a significant incidence of malformations. Paw defects were present in 87.5% of ethylene glycol monomethyl ether treated litters (68.5% of fetuses), 86.7% of ethylene glycol dimethyl ether treated litters (33.8% of fetuses), and 77.8% of diethylene glycol dimethyl ether 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 may be attributable to in vivo conversion to a common teratogen, methoxyacetic acid. [Hardin BD, Eisenmann CJ; Teratol 35 (3): 321-8 (1987)] **PEER REVIEWED**

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ 2-Methoxyethanol and bis(2-methoxyethyl)ether were subjected to the... dominant lethal test in male rats, ... and the sperm abnormality test in mice. In vivo test animals were exposed to atmospheric concentrations of 25 or 500 ppm 2-methoxyethanol and 250 or 1000 ppm bis(2-methoxyethyl)ether. ...There was evidence from the dominant lethal tests that both compounds have profound effects upon male rat fertility during the meiotic phase. Pregnancy frequency was greatly reduced and preimplantation losses were large. In addition, there was evidence of postimplantation losses. Sperm abnormalities were increased in mice exposed to both compounds, but particularly bis(2-methoxyethyl)ether. These effects on male reproductive cells were confined to the higher concentrations of both compounds. [McGregor DB et al; Toxicol Appl Pharmacol 70 (2): 303-16 (1983)] **PEER REVIEWED** <a

href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt= Abstract&list_uids=6623472" target=new>PubMed Abstract

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ ... To assess the potential developmental toxicity of diglyme (diethylene glycol dimethyl ether), 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 hr/day for Days 7 through 16 of 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 diglymegroups (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. [Driscoll CD et al; Drug Chem Toxicol 21 (2): 119-36 (1998)]

**PEER REVIEWED** <a

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/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ ... In the present study, 0, 25, 50, 100, or 175 mg/kg/day diethylene glycol dimethyl ether (diEGdiME) ... was administered by gavage in distilled water to timed-pregnant New Zealand white rabbits (15-25 dams/group) during major organogenesis [Gestational Days (gd) 6-19]. Treated females were euthanized on gd 30, uterine contents were examined, and live fetuses were examined for morphological alterations. ... Evidence of maternal toxicity, per se, was observed only at 175 mg/kg/day with 15% mortality among treated females compared to 4% among controls. No significant maternal toxicity was observed in the 25 mg/kg/day group, and only minimal maternal toxicity (decreased maternal weight gain during treatment) was observed at 50 and 100 mg/kg/day compared to the vehicle control group. The no-observed-adverse-effect level for developmental toxicity in rabbits for diEGdiME was 50 mg/kg/day. The incidences of prenatal mortality and malformed live fetuses were significantly above controls at 100 and 175 mg/kg/day. Malformations observed most frequently included fusion of ribs to each other and hydronephrosis; clubbing of the limbs without underlying bone deformities, a variation, was also observed. [Schwetz BA et al; Fundam Appl Toxicol 19 (2): 238-45 (1992)] **PEER REVIEWED** <a

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/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Pregnant CD-I mice were treated by gavage at a dosage of 3000 mg/kg/day from day 7 to 14 of gestation. Maternal mortality was nearly 25% in the treated mice, and none of the surviving mice delivered any viable offspring. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. V7 212] **PEER REVIEWED**

/GENOTOXICITY/ Bis(2-methoxyethyl) ether was tested for mutagenicity using the Salmonella/microsome preincubation assay, using the standard protocol approved by the National Toxicology Program. Bis(2-methoxyethyl) ether was tested in ...5 Salmonella typhimurium strains (TA 1535, TA 1537, TA 97, TA98, and TA 100) in the presence and absence of rat and hamster liver S-9, at doses of 0.1, 0.33, 1.0, 3.3, and 10 mg/plate. Bis(2-methoxyethyl) ether was negative in these tests and the highest ineffective dose tested in any Salmonella typhimurium strain was 10 mg/plate. [Mortelmans K et al; Environ Mutagen 8: 1-119 (1986)] **PEER REVIEWED**

/GENOTOXICITY/ Described as negative in the Escherichia coli WP2 uvrA mutation test with metabolic activation [European Chemicals Bureau; IUCLID Dataset, bis (2-methoxyethyl) ether (CAS # 111-96-6) p.39. Available from, as of February 7, 2007: http://ecb.jrc.it/esis/esis.php ] **PEER

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/GENOTOXICITY/ 2-Methoxyethanol and bis(2-methoxyethyl)ether were subjected to the following assays for genetic toxicity: Ames' test, ... sex-linked recessive lethal (SLRL) test in Drosophila, ... /and/ bone marrow metaphase analysis in male and female rats. In vivo test animals were exposed to atmospheric concentrations of 25 or 500 ppm 2-methoxyethanol and 250 or 1000 ppm bis(2-methoxyethyl)ether. Point mutations in Ames' test ... were not increased by either compound, while the SLRL test gave ambiguous results which deserve further investigation. Chromosomal aberration frequencies were not increased in rat bone marrow. [McGregor DB et al; Toxicol. Appl. Pharmacol. 70 (2): 303-16 (1983)]

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NATIONAL TOXICOLOGY PROGRAM STUDIES: ... Diethylene glycol dimethyl ether (0, 62.5, 125, 250 or 500 mg/kg/day) was administered to CD-1® mice by gavage (by mouth) on gestational days (gd) 6-15. Mice were monitored daily during treatment for evidence of maternal toxicity and were sacrificed on gd 17 (20-24 confirmed pregnancies per group). ... Diethylene glycol dimethyl ether-treated dams failed to exhibit treatment-related clinical signs, death, or differences from control in corrected maternal body weight gain (i.e., gestational weight gain minus gravid uterine weight) or relative maternal liver weight. However, intact maternal body weight (i.e., including gravid uterine weight) was reduced at 250 and 500 mg diethylene glycol dimethyl ether/kg/day on gd 15 and 17, as were maternal weight gain during treatment and gestation. Gravid uterine weight in diethylene glycol dimethyl ether-treated groups was significantly reduced at all doses in a dose-related manner. There were dose-related and significant increases at 250 and 500 mg/kg/day in the percentage of nonlive implants per litter (4.88%, 8.41%, 7.05%, 12.02% and 50.41% in the vehicle control through high-dose groups, respectively), as well as the percentage of adversely affected implants per litter (5.25%, 8.41%, 9.35%, 32.29% and 96.93% nonlive or malformed in the vehicle control through high-dose groups, respectively). The mean live litter size was significantly less than control at 500 mg/kg/day and was marginally reduced at all lower dose levels. The average fetal body weight per litter was significantly reduced at and above 125 mg diethylene glycol dimethyl ether/kg/day. Examination of fetuses for anatomical malformations revealed a dose-dependent trend toward an increased percentage of malformed live fetuses per litter, and the difference from control was statistically significant in the 250 and 500 mg diethylene glycol dimethyl ether/kg/day groups. The mean percent malformed live fetuses per litter was 0.37%, 0.00%, 2.47%, 23.86% and95.82% in the vehicle through high-dose groups, respectively. The proportion of litters with gross, visceral or skeletal malformations was increased at the high dose, and the proportion of litters with gross or skeletal malformations was increased in the 250 mg/kg/day group. The types of malformations observed in the present study were quite diverse. Major malformations affected primarily the development of the neural tube, limbs and digits, craniofacial structures, abdominal wall, cardiovascular system, urogenital organs, and both the axial and appendicular skeleton. The two most frequently observed malformations were fused ribs in 74% of high dose fetuses and exencephaly in 54% of high dose fetuses. In summary, exposure of timed-pregnant CD-1® mice to diethylene glycol dimethyl ether throughout major organogenesis produced no notable evidence of maternal toxicity. The lowest dose level, 62.5 mg/kg/day, appeared to be a no observed effect level for indices of fetal development. At higher doses, diethylene glycol dimethyl ether produced profound adverse effects upon fetal growth ( greater than or equal to 125 mg/kg/day), fetal viability (greater than or equal to 250 mg/kg/day), and fetal morphological development (greater than or equal to 250 mg/kg/day). At the highest dose, all 23 litters contained at least one malformed fetus compared to 1 of 21 control litters, and 94% of the high-dose fetuses were malformed compared to 0.35% of the fetuses in the control group. Thus, diethylene glycol dimethyl ether posed an extreme degree of risk to the embryo or fetus at dose levels which did not cause observable toxicity to the maternal organism. [Department of Health & Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Teratologic Evaluation of Diethylene Glycol Dimethyl Ether (CAS NO. 111-96-6) Administered to CD-1® Mice on Gestational Days 6 through 15, NTP Study No. TER85061 (August 30, 1985 ) Available from, as of August 15, 2002: http://ntp.niehs.nih.gov/index.cfm?objectid=0847FF31-90CC-C685-

88B4D7EAC975BD44 ] **PEER REVIEWED**

In the present study, diethylene glycol dimethyl ether (0, 25, 50, 100 or 175 mg/kg/day ) was administered by gavage in distilled water to timed-pregnant New Zealand White (NZW) rabbits (15-22 dams/group) during major organogenesis (gestational days (gd) 6-19) based on preliminary rangefinding studies. Treated females were sacrificed on gd 30, uterine contents were examined, and live fetuses examined for malformations. Evidence of maternal toxicity, per se, was observed only at 175 mg/kg/day . At this high dose, the mortality among treated females was 15.4% as compared to 4% among controls. No significant maternal toxicity was observed in the 25 mg/kg/day group, and only minimal maternal toxicity (maternal weight gain during treatment) was observed at 50 mg/kg/day as compared to the vehicle control group. However, even these lower doses appeared to contribute to significant dose-related trends for indices of maternal body weight, weight gain, and gravid uterine weight maternal. The lowest dose of diethylene glycol dimethyl ether (25 mg/kg/day ) appeared to be a no-observed-effect level (NOEL) for developmental toxicity in New Zealand White rabbits. At 50 mg/kg/day , apparent adverse effects on prenatal growth, viability and morphological development were in accord with significant dose-response relationships observed across all groups. At 100 and 175 mg/kg/day , adverse effects upon fetal weight were in accord with significant dose-response relationships, but individual treatment groups did not differ significantly from controls. The incidence of resorptions and malformed live fetuses, as well as other cumulative indices which included these endpoints, were significantly above controls at 100 and 175 mg/kg/day . Major malformations affected the development ofthe digits, craniofacial structures, abdominal wall, cardiovascular system, urogenital organs and axial skeleton. The most frequently observed individual defects were fusion of ribs to each other (19%), hydronephrosis (23%), and clubbing of the limbs (19%) without underlying bone deformities (i.e., of presumed neuromuscular origin). In conclusion, exposure of New Zealand White rabbits to diethylene glycol dimethyl ether at 25 mg/kg/day during major organogenesis produced no adverse maternal or developmental effects. Doses of 50 and 100 mg/kg/day were associated with adverse developmental effects, but did not produce distinctive evidence of maternal toxicity. The incidence of adverse developmental effects was further increased at a dose associated with increased maternal mortality (e.g., 175 mg/kg/day). The principal manifestations of developmental toxicity were increased resorptions and a higher incidence of major malformations among surviving fetuses. [Department of Health & Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Diethylene glycol dimethyl ether (CAS No. 111-96-6) Administered to New Zealand White Rabbits on Gestation Days 6 Through 19, NTP Study No. TER86062 (May 5, 1987) Available from, as of August 15,

2002: http://ntp.niehs.nih.gov/index.cfm?objectid=0847FF31-90CC-C685-

88B4D7EAC975BD44 ] **PEER REVIEWED**

NON-HUMAN TOXICITY VALUES: LD50 Mouse oral 2978 mg/kg bw [European Chemicals Bureau; IUCLID Dataset, bis (2-methoxyethyl) ether (CAS # 111-96-6) p.26. Available from, as of February 7, 2007: http://ecb.jrc.it/esis/esis.php ] **PEER REVIEWED**

LD50 Rat oral 4760 mg/kg bw [European Chemicals Bureau; IUCLID Dataset, bis (2-methoxyethyl) ether (CAS # 111-96-6) p.25. Available from, as of February 7, 2007: http://ecb.jrc.it/esis/esis.php ] **PEER REVIEWED**

LC50 Rat inhalation > 11 mg/L/7 hr [European Chemicals Bureau; IUCLID Dataset, bis (2-methoxyethyl) ether (CAS # 111-96-6) p.27. Available from, as of February 7, 2007: http://ecb.jrc.it/esis/esis.php ] **PEER

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ECOTOXICITY VALUES: LC50 Rana brevipoda porosa /(Frog)/ 8300 mg/kg bw for 48 hr /Conditions of bioassay not specified in source examined/ [Verschueren, K. Handbook of Environmental Data on Organic Chemicals. Volumes 1-2. 4th ed. John Wiley & Sons. New York, NY. 2001, p. 845] **PEER REVIEWED**

LC50 Leuciscus idus /(Ide)/ > 2000 mg/L for 96 hr /Conditions of bioassay not specified in source examined/ [Verschueren, K. Handbook of Environmental Data on Organic Chemicals. Volumes 1-2. 4th ed. John Wiley & Sons. New York, NY. 2001, p. 845] **PEER REVIEWED**

TSCA TEST SUBMISSIONS: Subchronic toxicity was evaluated in 5 groups of 20 male CD rats exposed nose-only by inhalation to diglyme (diethylene glycol dimethyl ether) at air concentrations of 0, 3.1, 9.9, 30, and 98 ppm for 6 hours/day, 5 days/week, over 2 weeks. An interim sacrifice of 10 rats from each treatment group was performed immediately after the last dosing. The remaining 10 rats were sacrificed after a 14-day observation period. No mortalities were reported. A slight depression in body weight and body weight gain was observed during days 1 to 12 of the study in the groupexposed to 98 ppm (p < 0.05). After the 2-week recovery period, testicular atrophy and exfoliated degenerative germ cells were observed among the rats exposed to 98 ppm. No treatment-related clinical signs, gross lesions, or organ weight changes were observed. Hematology, urinalysis, and clinical chemistry results were not reported.[Haskell Lab.; Subchronic Inhalation Toxicity Study with Diglyme with Cover Letter Dated 05/16/89 (1989), EPA Document No. FYI-OTS- 0589-0553, Fiche No. OTS0000553-2] **UNREVIEWED**

Reproductive toxicity was evaluated in groups of 10 pregnant Charles River CD female mice receiving an oral gavage dose of diethylene glycol dimethyl ether at 10 ml/kg body weight on gestation days 7 through 14. Maternal mortality, clinical observations and gross necropsy were not reported. There was a significant reduction (p < 0.05) in the number of live pups per litter.[Department of Health & Human Services; Results of Testing Fifteen Glycol Ethers in a Short-Term In Vivo Reproductive Toxicity Assay With Attachments, EPA Doc. 40-8385037, Fiche No. OTS0521552]

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METABOLISM/PHARMACOKINETICS:

METABOLISM/METABOLITES: The effect of enzyme induction on the metabolism of bis(2-methoxyethyl)ether (diglyme) was studied in rats. Male Sprague-Dawley rats were administered 5.1 mmol/kg diglyme or 0.1% phenobarbital in their drinking water for 22 days. Other rats were pretreated with 5.1 mmol/kg diglyme or 0.1% phenobarbital administered in their drinking water for 22 days, and then given a single oral dose of 5.1 mmol/kg (14)C labeled diglyme. Urine samples were collected at 6 to 96 hours post dosing and analyzed for diglyme metabolites. Phenobarbital and diglyme caused significant decreases in hexobarbital sleeping time, phenobarbital showing the greater effect. Pretreatment with phenobarbital or diglyme did not significantly affect cumulative excretion of (14)C activity. Cumulative excretion of methoxyacetic acid, a minor metabolite, was significantly increased by both phenobarbital and diglyme, phenobarbital showing the greater effect. /It was concluded/ that pretreating rats with diglyme or phenobarbital increases the extent of cleavage of the ether bond in diglyme, forming 2-methoxyethanol, a precursor of methoxyacetic acid, a putative reproductive toxicant. [Cheever KL et al; Toxicol and Ind Health 5 (3): 601-7 (1989)] **PEER

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The testicular toxicity of bis(2-methoxyethyl)ether (diglyme) was studied in rats. Male Sprague-Dawley-rats were given 0.051, or 5.1 mmol/kg (14)C labeled diglyme orally. Approximately 86 to 90% of each dose was excreted

in the urine over 96 hours. Less than 5% of the doses was excreted in the feces. Only trace amounts of radiolabel were found in the expired air as volatile organic compounds. The principal urinary metabolites were (2-methoxyethoxy)acetic acid and methoxyacetic acid which accounted for around 70 and 6% of the doses, respectively. Smaller amounts of N-(methoxyacetyl)glycine, diglycolic acid, 2-methoxyethanol, and 2-(2-methoxyethoxy)ethanol were found. Only unchanged diglyme was found in the volatile organic fraction of the expired air. ... Diglyme metabolism proceeds primarily through an O-demethylation pathway, followed by oxidation to (2-methoxyethoxy)acetic acid. The lack of toxicity of 2-(2-methoxyethoxy)ethanol and (2-methoxyethoxy)acetic acid suggests that the testicular toxicity of diglyme may be due to methoxyacetic acid, aminor metabolite. [Cheever KL; Toxicol and Appl Pharmacol 94 (1): 150-9 (1988)] **PEER REVIEWED**

The metabolism of ... bis(2-methoxyethyl)ether (diglyme) was studied in isolated rat hepatocytes and in the intact rat. Male Sprague-Dawley rats (190-220 g) were used in both studies. Hepatocytes, isolated by a two-step in situ collagenase perfusion of the liver, were cultured as monolayers and incubated with [14C]diglyme at 1, 10, 30, and 50 uM for up to 48 hr. For the in vivo study, rats were given single oral doses of [14C]diglyme at 5.1 mmol/kg bw, and urine was collected for up to 96 hr. Radioactive compounds in the culture medium or in the urine were separated by high performance liquid chromatography and quantified with an in-line radioactivity monitor. Metabolites were identified by comparison of their chromatographic retention times and their mass spectra with those of authentic compounds. The principal metabolite from hepatocytes and in the urine was (2-methoxyethoxy)acetic acid (MEAA). This metabolite accounted for approximately 36% of the radioactivity in the 48-hr culture medium and about 67% of the administered dose in the 48-hr urine. Other prominent metabolites common to both systems included 2-(2-methoxyethoxy)ethanol, methoxyacetic acid (MAA), 2-methoxyethanol, and diglycolic acid. The diglyme metabolite profiles from urine and from hepatocytes were qualitatively similar, demonstrating that, in the rat, hepatocytes serve as a good model system for predicting the urinary metabolites of diglyme. Moreover, MEAA was shown to be the metabolite best suited for use as a short-term biological marker of exposure to diglyme. [Richards DE et al; Arch Toxicol 67 (8): 531-7 (1993)] **PEER REVIEWED** <a

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An embryotoxic oral dose of bis(2-methoxyethyl) ether (DGDME), 3.73 mmol/kg bw (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 umol (5.9 mmol/kg bw) 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. ... [Daniel FB et al; Fundam Appl Toxicol 16 (3): 567-75 (1991)] **PEER REVIEWED** <a

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The principal pathway of biotransformation of diglyme involvesO-demethylation with subsequent oxidation to form the main metabolite 2-methoxyethoxyacetic acid, which accounts for about 60-70% of the dose in the urine of rats and pregnant mice after 48-96 hr. In addition, cleavage (O-dealkylation) of the central ether bond results in the formation of 2-methoxyethanol, which is subsequently oxidized to 2-methoxyacetic acid.

This metabolite accounts for about 5-15% of the dose in the urine of rats after 48-96 hr. ... Also, humans may form this metabolite in higher concentrations. Based on nmol 2-methoxyethanol generated per nmol P-450,

human microsomes were found to be 7 times more effective than rat microsomes in converting diglyme to 2-methoxyethanol. ...Repeated doses of diglyme or induction with phenobarbital or ethanol increases the cleavage of the central ether linkage of diglyme as a result of cytochrome P-450 enzyme induction in the liver. Although the main metabolite in rat urine is 2-methoxyethoxyacetic acid, numerous studies indicate that 2-methoxyacetic acid is the metabolite responsible for the toxicity of diglyme for the male reproductive organs. [International Programme on Chemical Safety; Concise International Chemical Assessment Document Number 41: Diethylene Glycol Dimethyl Ether (2002). Available from, as of February 20, 2007: http://www.inchem.org/pages/cicads.html ] **PEER

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Although the main metabolite in rat urine is 2-methoxyethoxyacetic acid, numerous studies indicate that 2-methoxyacetic acid is the metabolite responsible for the toxicity of diglyme for the male reproductive organs. 2-methoxyacetic acid was transferred to the fetus and found as the sole metabolite in the fetus (no parent compound was detected in the fetus either) after dosing diglyme to mice at day 11 or 12 of pregnancy. The highest levels for the average embryo (whole embryos analysed) were detected at 6 hr after dosing. Significantly lower amounts were detected in blood taken from the dam at that time point. [International Programme on Chemical Safety; Concise International Chemical Assessment Document Number 41: Diethylene Glycol Dimethyl Ether (2002). Available from, as of February 20, 2007: http://www.inchem.org/pages/cicads.html ] **PEER

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ABSORPTION, DISTRIBUTION & EXCRETION: The major route of elimination is through the urine. Ninety-six hours after oral application of 6.84 mg diglyme/kg body weight to male Sprague-Dawley rats, 90% of the dose was excreted via urine, 3.6% as carbon dioxide, and 2.9% in the feces. Only 1.7% of the dose remained in the carcass. [International Programme on Chemical Safety; Concise International Chemical Assessment Document Number 41: Diethylene Glycol Dimethyl Ether (2002). Available from, as of February 20, 2007: http://www.inchem.org/pages/cicads.html ] **PEER REVIEWED**

Although the main metabolite in rat urine is 2-methoxyethoxyacetic acid, numerous studies indicate that 2-methoxyacetic acid is the metabolite responsible for the toxicity of diglyme for the male reproductive organs. 2-methoxyacetic acid was transferred to the fetus and found as the sole metabolite in the fetus (no parent compound was detected in the fetus either) after dosing diglyme to mice at day 11 or 12 of pregnancy. The highest levels for the average embryo (whole embryos analysed) were detected at 6 hr after dosing. Significantly lower amounts were detected in blood taken from the dam at that time point. [International Programme on Chemical Safety; Concise International Chemical Assessment Document Number 41: Diethylene Glycol Dimethyl Ether (2002). Available from, as ofFebruary 20, 2007: http://www.inchem.org/pages/cicads.html ] **PEER

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... The skin absorption rates of a group of glycol ethers /were evaluated/ in vitro ... using the Franz cell method with human skin. ... A permeation profile was obtained and steady state, lag time and permeation constant flux was calculated for ... ethylene glycol diethyl ether (EGDEE) and diethylene glycol dimethyl ether (DEGDME). ... solvents were tested in their pure form and with 70% acetone. ... For all solvents tested the lag time was less than 2 hr, and for the majority of them was about 60 min ... Flux at steady state ranged between 0.017 +/- 0.005 and 3.435 +/- 1.897 mg/cm(2)/hr and permeation rate was from 0.0192 to 1.02 x 10(-3) cm/hr ... [Larese Filon F et al; Int Arch Occup Environ Health 72 (7): 480-4 (1999)]

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BIOLOGICAL HALF-LIFE: The /diglyme/ metabolite 2-methoxyacetic acid has shown evidence of accumulation in animals and humans. In humans, its half-life was calculated as 77.1 hr. [International Programme on Chemical Safety; Concise International Chemical Assessment Document Number 41: Diethylene Glycol Dimethyl Ether (2002). Available from, as of February 20, 2007: http://www.inchem.org/pages/cicads.html ] **PEER REVIEWED**

PHARMACOLOGY:

ENVIRONMENTAL FATE & EXPOSURE:

ENVIRONMENTAL FATE/EXPOSURE SUMMARY: Diethylene glycol dimethyl ether's production and use as a solvent and an anhydrous reaction medium for organo-metallic synthesis or as a solubilizer may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 2.96 mm Hg at 25 deg C indicates diethylene glycol dimethyl ether will exist solely as a vapor in the atmosphere. Vapor-phase diethylene glycol dimethyl ether will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 22 hours. Diethylene glycol dimethyl ether does not contain chromophores that absorb at wavelengths > 290 nm and therefore is not expected to be susceptible to direct photolysis by sunlight. If released to soil, diethylene glycol dimethyl ether is expected to have very high mobility based upon an estimated Koc of 15. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 5.2X10-7 atm-cu m/mole. Diethylene glycol dimethyl ether may volatilize from dry soil surfaces based upon its vapor pressure. Biodegradation of diethylene glycol dimethyl ether in soil and water may be an important environmental fate process based on a study done where it was degraded 33% after 25 days and a 7 day lag period using an activated sludge from an industry producing the chemical. If released into water, diethylene glycol dimethyl ether is not expected to adsorb to suspended solids and sediment based upon the estimated Koc. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's estimated Henry's Law constant. An estimated BCF of 3 suggests the potential for bioconcentration in aquatic organisms is low.Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions. Occupational exposure to diethylene glycol dimethyl ether may occur through inhalation and dermal contact with this compound at workplaces where diethylene glycol dimethyl ether is produced or used. Monitoring data indicate that the general population may be exposed to diethylene glycol dimethyl ether via inhalation of vehicle exhaust and ingestion of contaminated drinking water. (SRC) **PEER

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PROBABLE ROUTES OF HUMAN EXPOSURE: NIOSH (NOES Survey 1981-1983) has statistically estimated that 207 workers (52 of these are female) are potentially exposed to diethylene glycol dimethyl ether in the US(1). Occupational exposure to diethylene glycol dimethyl ether may occur through inhalation and dermal contact with this compound at workplaces where diethylene glycol dimethyl ether is produced or used(SRC). Monitoring data indicate that the general population may be exposed to diethylene glycol dimethyl ether via inhalation of vehicle exhaust and ingestion of contaminated drinking water(SRC). [(1) NIOSH; NOES. National Occupational Exposure Survey conducted from 1981-1983. Estimated numbers of employees potentially exposed to specific agents by 2-digit standard industrial classification (SIC). Available at http://www.cdc.gov/noes/ as of Jan 2007.] **PEER REVIEWED**

ARTIFICIAL POLLUTION SOURCES: Diethylene glycol dimethyl ether's production and use as a solvent and an anhydrous reaction medium for organo-metallic synthesis(1) or as a solubilizer(2) may result in its release to the environment through various waste streams(SRC). [(1) Lewis RJ Sr; Hawley's Condensed Chemical Dictionary 14th ed. John Wiley & Sons, Inc. New York, NY p. 373 (2001) (2) Ashford RD; Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., p. 301 (1994)] **PEER REVIEWED**

ENVIRONMENTAL FATE: TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 15(SRC), determined from a log Kow of -0.36(2) and a regression-derived equation(3), indicates that diethylene glycol dimethyl ether is expected to have very high mobility in soil(SRC). Volatilization of diethylene glycol dimethyl ether from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 5.2X10-7 atm-cu m/mole(SRC), derived from its vapor pressure, 2.96 mm Hg(4), and assigned value for water solubility of 1X10+6 mg/L (miscible)(5). Diethylene glycol dimethyl ether is expected to volatilize from dry soil surfaces(SRC) based upon its vapor pressure(4). Diethylene glycol dimethyl ether was degraded 33% after 25 days and a 7 day lag period using an activated sludge from an industry producing the chemical(6), indicating that biodegradation may be an important environmental fate process in soil(SRC). [(1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 299 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) (4) Daubert TE, Danner RP; Data Compilation, Tables of Properties of Pure Compounds, NY, NY: Design Inst for Phys Prop Data, Am Inst for Phys Prop Data (1989) (5) Riddick JA et al; Organic Solvents NY: John Wiley & Sons Inc (1984) (6) Roy D et al; J Environ Sci Health Part A 29:129-47 (1994)] **PEER REVIEWED**AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 15(SRC), determined from a log Kow of -0.36(2) and a regression-derived equation(3), indicates that diethylene glycol dimethyl ether is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 5.2X10-7 atm-cu m/mole(SRC), derived from its vapor pressure, 2.96 mm Hg(4), and assigned value for water solubility of 1X10+6 mg/L (miscible)(5). According to a classification scheme(6), an estimated BCF of 3(SRC), from its log Kow(2) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Diethylene glycol dimethyl ether was biodegraded 33% after 25 days and a 7 day lag period using an activated sludge from an industry producing the chemical(8), indicating that biodegradation may be an important environmental fate process in water(SRC). [(1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) measured log Kow ref e.g. Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 299 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (4) Daubert TE, Danner RP; Data Compilation, Tables of Properties of Pure Compounds NY, NY: Design Inst for Phys Prop Data, Am Inst for Phys Prop Data (1989) (5) Riddick JA et al; Organic Solvents NY: John Wiley & Sons Inc (1984) (6) Franke C et al; Chemosphere 29: 1501-14 (1994) (7) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (8) Roy D et al; J Environ Sci Health Part A 29:129-47 (1994)] **PEER REVIEWED**

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), diethylene glycol dimethyl ether, which has a vapor pressure of 2.96 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase diethylene glycol dimethyl ether is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 22 hours(SRC), calculated from its rate constant of 1.75X10-11 cu cm/molecule-sec at 25 deg C(3). Diethylene glycol dimethyl ether does not contain chromophores that absorb at wavelengths > 290 nm and therefore is not expected to be susceptible to direct photolysis by sunlight(4). [(1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Daubert TE, Danner RP; Data Compilation, Tables of Properties of Pure Compounds, Design Inst for Phys Prop Data, Am Inst for Phys Prop Data, NY, NY (1989) (3) Atkinson R; J Phys Chem Ref Data. Monograph No. 1 (1989) (4) Silverstein RM, Bassler GC; Spectrometric Id Org Cmpd NY: J Wiley & Sons Inc p. 148-69 (1963)]

**PEER REVIEWED**

ENVIRONMENTAL BIODEGRADATION: AEROBIC: Diethylene glycol dimethyl ether had a 37.0% COD removal at 30 deg C from a starting concentration of 600 mg COD/L (time period not given) indicating little degradation compared to 95% degradation of ethylene glycol monophenyl ether(1). Diethylene glycol dimethyl ether was degraded 33% after 25 days and a 7 day lag period using an activated sludge from an industry producing the chemical(2). 40% was removed in a 1% salt solution after 25 days with a 20 day lag period, higher salt concentrations inhibited the degradation of diethylene glycol dimethyl ether(2). [(1) Cowan RM, Kwon J; pp. 273-82 in Hazard Ind Wastes, 31st Technomic Pub Co., Inc., p 273-82 (1999) (2) Roy D et al; J Environ Sci Health Part A 29: 129-47 (1994)] **PEER REVIEWED**ENVIRONMENTAL ABIOTIC DEGRADATION: The rate constant for the vapor-phase reaction of diethylene glycol dimethyl ether with photochemically-produced hydroxyl radicals has been measured as 1.75X10-11 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of about 22 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Diethylene glycol dimethyl ether is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(2). Diethylene glycol dimethyl ether does not contain chromophores that absorb at wavelengths > 290 nm and therefore is not expected to be susceptible to direct photolysis by sunlight(3). [(1) Atkinson R; J Phys Chem Ref Data. Monograph No. 1 (1989) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5, 8-12 (1990) (3) Silverstein RM, Bassler GC; Spectrometric Id Org Cmpd NY: J Wiley & Sons Inc p. 148-69 (1963)]

**PEER REVIEWED**

ENVIRONMENTAL BIOCONCENTRATION: An estimated BCF of 3 was calculated in fish for diethylene glycol dimethyl ether(SRC), using a log Kow of -0.36(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC). [(1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 299 (1995) (2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (3) Franke C et al; Chemosphere 29: 1501-14 (1994)] **PEER

REVIEWED**

SOIL ADSORPTION/MOBILITY: The Koc of diethylene glycol dimethyl ether is estimated as 15(SRC), using a log Kow of -0.36(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that diethylene glycol dimethyl ether is expected to have very high mobility in soil. [(1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 299 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 17-28 (1983)] **PEER REVIEWED**

VOLATILIZATION FROM WATER/SOIL: The Henry's Law constant for diethylene glycol dimethyl ether is estimated as 5.2X10-7 atm-cu m/mole(SRC) derived from its vapor pressure, 2.96 mm Hg(1), and assigned value for water solubility of 1X10+6 mg/L (miscible)(2). This Henry's Law constant indicates that diethylene glycol dimethyl ether is expected to be essentially nonvolatile from water surfaces(3). Diethylene glycol dimethyl ether's estimated Henry's Law

constant indicates that volatilization from moist soil surfaces is not expected to occur(SRC). The potential for volatilization of diethylene glycol dimethyl ether from dry soil surfaces may exist(SRC) based upon its vapor pressure(1). [(1) Daubert TE, Danner RP; Data Compilation, Tables of Properties of Pure Compounds. NY, NY: Design Inst for Phys Prop Data, Am Inst for Phys Prop Data (1989) (2) Riddick JA et al; Organic Solvents NY: John Wiley & Sons Inc (1984) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990)] **PEER REVIEWED**ENVIRONMENTAL WATER CONCENTRATIONS: DRINKING WATER: Diethylene glycol dimethyl ether was listed as a contaminant found in drinking water(1). [(1) Kool HJ et al; Crit Rev Env Control 12: 307-57 (1982)] **PEER REVIEWED**

EFFLUENT CONCENTRATIONS: Diethylene glycol dimethyl ether was found at concentrations of 400 mg/L in activated sludge from the waste treatment facility of the industry producing the chemical(1). [(1) Roy D et al; J Environ Sci Health Part A 29: 129-47 (1994)] **PEER REVIEWED**

Diethylene glycol dimethyl ether in diluted vehicle exhaust from a light-duty truck using different fuel types(1). Testing Phase diesel + diethylene glycol diethyl ether diesel diesel + diethylene glycol dimethyl ether diesel + 2-ethylhexyl nitrate Cold start Not detected Not detected 66 ug/cu m 17 ug/cu m Hot start Not detected Not detected 74 ug/cu m 15 ug/cu m [(1) Cao X-L, Zhu J; Chemosphere 45: 911-7 (2001)] **PEER

REVIEWED**

ENVIRONMENTAL STANDARDS & REGULATIONS:

TSCA REQUIREMENTS: Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, exposure, and use to EPA as cited in the preamble in 51 FR 41329. [40 CFR

712.30; U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available from, as of March 1, 2007: http://www.gpoaccess.gov/ecfr ] **PEER REVIEWED**

Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Diethylene glycol dimethyl ether is included on this list. [40 CFR 716.120; U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available from, as of March 1, 2007: http://www.gpoaccess.gov/ecfr ] **PEER REVIEWED**

ATMOSPHERIC STANDARDS: This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Diethylene glycol dimethyl ether is produced, as an intermediate or final product, by process units covered under this subpart. [40 CFR 60.489; U.S. National

Archives and Records Administration's Electronic Code of Federal Regulations. Available from, as of March 1, 2007: http://www.gpoaccess.gov/ecfr ] **PEER REVIEWED**

CHEMICAL/PHYSICAL PROPERTIES:

MOLECULAR FORMULA: C6-H14-O3 [Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 14th Edition. John Wiley & Sons, Inc. New York, NY 2001., p. 373] **PEERREVIEWED**

MOLECULAR WEIGHT: 134.17 [O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 557] **PEER REVIEWED**

COLOR/FORM: Colorless liquid [Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 14th Edition. John Wiley & Sons, Inc. New York, NY 2001., p. 373]

**PEER REVIEWED**

ODOR: Mild odor [Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 14th Edition. John Wiley & Sons, Inc. New York, NY 2001., p. 373] **PEER

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BOILING POINT: 162 deg c at 760 mm Hg; 116 deg C at 200 mm Hg; 75 deg c at 35 mm Hg; 20 dg C at 3 mm Hg [O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 557] **PEER REVIEWED**

MELTING POINT: -68 deg C [Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I. 3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994., p. V3: 2648] **PEER REVIEWED**

DENSITY/SPECIFIC GRAVITY: Sp gr: 0.9451 at 20 deg C/20 deg C [O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 557] **PEER

REVIEWED**

OCTANOL/WATER PARTITION COEFFICIENT: log Kow = -0.36 [Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995., p. 25] **PEER REVIEWED**

SOLUBILITIES: Miscible with alcohol, ether, hydrocarbon solvents [O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 557] **PEER REVIEWED**

Soluble in benzene [Lide, D.R. CRC Handbook of Chemistry and Physics 86TH Edition 2005-2006. CRC Press, Taylor & Francis, Boca Raton, FL 2005, p. 3-168] **PEER REVIEWED**

In water, miscible [Riddick, J.A., W.B. Bunger, Sakano T.K. Techniques of Chemistry 4th ed., Volume II. Organic Solvents. New York, NY: John Wiley and Sons., 1985., p. 299] **PEER REVIEWED**

SPECTRAL PROPERTIES: Index of refraction: 1.4097 at 20 deg C/D [Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I. 3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994., p. V3: 2648] **PEER REVIEWED**IR: 18544 (Sadtler Research Laboratories IR Grating Collection) [Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I. 3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994., p. V3: 2648] **PEER

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NMR: 9286 (Sadtler Research Laboratories Spectral Collection) [Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I. 3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994., p. V3: 2648] **PEER REVIEWED**

MASS: 61161 (NIST/EPA/MSDC Mass Spectral database, 1990 version) [Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I. 3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994., p. V3: 2648] **PEER

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Raman: 259 (Sadtler Research Laboratories spectral collecction) [Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I. 3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994., p. V3: 2648] **PEER

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VAPOR PRESSURE: 2.96 mm Hg at 25 deg C (est) [Daubert, T.E., R.P. Danner. Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, 1989.] **PEER REVIEWED**

VISCOSITY: 1.089 cP at 20 deg C [Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 14th Edition. John Wiley & Sons, Inc. New York, NY 2001., p. 373] **PEER REVIEWED**

OTHER CHEMICAL/PHYSICAL PROPERTIES: Diethylene glycol dimethyl ether dissolves vinyl chloride copolymers, postchlorinated poly (vinyl chloride), polymethacrylate, polystyrene, polychloroprene, and cellulose acetate. It does not dissolve rubber and polyethylene, and swells poly(vinyl chloride). It also dissolves sodium borohydride, other covalent inroganic metal compounds, and sodium. [Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present., p. VA24: 498 (1997)] **PEER REVIEWED**

Henry's Law constant = 5.23X10-7 atm-cu m/mol at 25 deg C (est) [SRC; The Physical Properties Database (PHYSPROP). Syracuse, NY: Syracuse Res Corp. Available from, as of Dec 15, 2006: http://www.syrres.com/esc/physprop.htm ] **PEER REVIEWED**

Hydroxyl radical reaction rate constant = 1.75X10-11 cu cm/molec-sec at 25 deg C [Atkinson R; J Phys Chem Ref Data Monograph No. 1 (1989)] **PEER

REVIEWED**

CHEMICAL SAFETY & HANDLING:

FIRE POTENTIAL: Combustible [Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 14th Edition. John Wiley & Sons, Inc. New York, NY 2001., p. 373] **PEER

REVIEWED**

NFPA HAZARD CLASSIFICATION:Health: 1.1= Materials that, on exposure, would cause significant irritation, but only minor residual injury, including those requiring the use of an approved air-purifying respirator. These materials are only slightly hazardous to health and only breathing protection is needed. [Fire Protection Guide to Hazardous Materials. 13 ed. Quincy, MA: National Fire Protection Association, 2002., p. 325-44] **PEER REVIEWED**

Flammability: 2. 2= This degree includes materials that must be moderately heated before ignition will occur and includes Class II and IIIA combustible liquids and solids and semi-solids that readily give off ignitible vapors. Water spray may be used to extinguish fires in these materials because the materials can be cooled below their flash points. [Fire Protection Guide to Hazardous Materials. 13 ed. Quincy, MA: National Fire Protection Association, 2002., p. 325-44] **PEER REVIEWED**

Reactivity: 1. 1= This degree includes materials that are normally stable, but that may become unstable at elevated temperatures and pressures and materials that will react with water with some release of energy, but not violently. Fires involving these materials should be approached with caution. [Fire Protection Guide to Hazardous Materials. 13 ed. Quincy, MA: National Fire Protection Association, 2002., p. 325-44] **PEER REVIEWED**

FLASH POINT: 153 DEG F (67 DEG C) (CLOSED CUP) [Fire Protection Guide to Hazardous Materials. 13 ed. Quincy, MA: National Fire Protection Association, 2002., p. 325-44] **PEER REVIEWED**

EXPLOSIVE LIMITS & POTENTIAL: Presence of carbon dioxide in solutions of the hydride in dimethyl or bis(2-methoxyethyl)ether can cause a violent decomposition on warming the residue from evaporation. Presence of aluminum chloride tends to increase the vigour of decomposition to explosion. [Bretherick, L. Handbook of Reactive Chemical Hazards. 4th ed. Boston, MA: Butterworth-Heinemann Ltd., 1990, p. 40] **PEER REVIEWED**

HAZARDOUS REACTIVITIES & INCOMPATIBILITIES: Glycol ethers, glycols, ketones, and alcohols undergo violent decomposition in contact with 68-72% perchloric acid [Fire Protection Guide to Hazardous Materials. 13 ed. Quincy, MA: National Fire Protection Association, 2002., p. 491-142] **PEER REVIEWED**

Light, heat and oxygen (air) promote formation of potentially explosive peroxides. These may be removed by stirring with a suspension of iron oxide in aqueous alkali. [Bretherick, L. Handbook of Reactive Chemical Hazards. 4th ed. Boston, MA: Butterworth-Heinemann Ltd., 1990, p. 662]

**PEER REVIEWED**

Presence of carbon dioxide in solutions of the hydride in dimethyl or bis(2-methoxyethyl) ether can cause a violent decomposition on warming the residue from evaporation. Presence of aluminium chloride tends to increase the vigour of decomposition to explosion. Lithium tetrahydroaluminate may behave similarly, but is generally more stable. [Bretherick, L. Handbook of Reactive Chemical Hazards. 4th ed. Boston, MA: Butterworth-Heinemann Ltd., 1990, p. 40] **PEER REVIEWED**

The peroxide-free ether, being dried by distillation at 162 DEG C under inert atmosphere at ambient pressure, exploded violently when the heatingbath temperature had been raised to 200 DEG C towards the end of distillation. This was attributed to local overheating of an insulating crust of hydride in contact with oxygen-containing organic material. [Bretherick, L. Handbook of Reactive Chemical Hazards. 4th ed. Boston, MA: Butterworth-Heinemann Ltd., 1990, p. 43] **PEER REVIEWED**

Glycol ethers, glycols, ketones, and alcohols undergo violent decomposition in contact with 68-72% perchloric acid [Fire Protection Guide to Hazardous Materials. 13 ed. Quincy, MA: National Fire Protection Association, 2002., p. 491-142] **PEER REVIEWED**

HAZARDOUS DECOMPOSITION: When heated to decomposition it emits toxic fumes of /nitrogen oxides/. [Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 507] **PEER REVIEWED**

DISPOSAL METHODS: SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations. **PEER REVIEWED**

OCCUPATIONAL EXPOSURE STANDARDS:

NIOSH RECOMMENDATIONS: NIOSH recommends reducing exposure to lowest feasible concn & preventing contact with the skin. /Glycol ethers/ [NIOSH/CDC. NIOSH Recommendations for Occupational Safety and Health Standards 1988, Aug. 1988. (Suppl. to Morbidity and Mortality Wkly. Vol. 37 No. 5-7, Aug. 26, 1988). Atlanta, GA: National Institute for Occupational Safety and Health, CDC, 1988., p. 16] **PEER REVIEWED**

MANUFACTURING/USE INFORMATION:

MAJOR USES: Solvent; reaction medium for Grignard and similar syntheses. [O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006.., p. 537] **PEER REVIEWED**

Diethylene glycol dimethyl ether is used as a solvent in chemical reactions involving metals and organometallic compounds. [Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present., p. VA24 498] **PEER

REVIEWED**

Solubilizer [Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994., p. 301] **PEERREVIEWED**

Used in production of plastics. [Sheftel, V.O.; Indirect Food Additives and Polymers. Migration and Toxicology. Lewis Publishers, Boca Raton, FL. 2000., p. 671] **PEER REVIEWED**

MANUFACTURERS: Arch Chemicals, Inc., 501 Merritt 7, P.O. Box 5204, Norwalk, CT 06856-5204, (203) 229-2900; Performance Products; Production site: Brandenburg, KY 40108 /Glycol ethers/ [SRI Consulting. 2006 Directory of Chemical Producers-United States. Menlo Park, CA. 2006, p. 657] **PEER

REVIEWED**

The Dow Chemical Co., 2030 Dow Center, Midland, MI 48642, (989) 636-1000; Production sites: Midland, MI 48667; Plaquemine, LA 70764; Seadrift, TX 77983; Taft, LA 70057 /Glycol ethers/ [SRI Consulting. 2006 Directory of Chemical Producers-United States. Menlo Park, CA. 2006, p. 657] **PEER

REVIEWED**

Eastman Chemical Co., P.O. Box 511, Kingsport, TN 37662, (423) 229-2000; Eastman Div., Eastman Rd., Kingsport, TN; Production site: Longview, TX 75607 /Glycol ethers/ [SRI Consulting. 2006 Directory of Chemical Producers-United States. Menlo Park, CA. 2006, p. 657] **PEER REVIEWED**

Equistar Chemicals, LP, /subsidiary of Lyondell Chemical Co.,/ One Houston Center, 1221 McKinney St., Suite 700, Houston, TX 77010, (713) 652-7200; Production site: Bayport, TX 77507 /Glycol ethers/ [SRI Consulting. 2006 Directory of Chemical Producers-United States. Menlo Park, CA. 2006, p. 657] **PEER REVIEWED**

Lyondell Chemical Co., 1221 McKinney St., Suite 700, Houston, TX 77010, (713) 652-7200; Production site: Bayport, TX /Glycol ethers, propylene glycol monoethers only/ [SRI Consulting. 2006 Directory of Chemical Producers-United States. Menlo Park, CA. 2006, p. 657] **PEER REVIEWED**

Shell Chemical Co., One Shell Plaza, P.O. Box 2463, Houston, TX 77252-2463, (713) 241-6161; Production site: Geismar, LA 70734 /Glycol ethers; plant is currently idle/ [SRI Consulting. 2006 Directory of Chemical Producers-United States. Menlo Park, CA. 2006, p. 657] **PEER

REVIEWED**

METHODS OF MANUFACTURING: Ethylene glycol ethers are produced by reacting ethylene oxide with alcohols in the presence of either acidic or basic catalysts. Temperature, pressure, mole ratios of reactants, and catalysts are chosen to yield the desired product mix. [CHEMICAL PRODUCTS SYNOPSIS: Glycol Ethers, 1983]

**PEER REVIEWED**

Diethylene glycol + dimethyl sulfate (ether formation) [Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994., p. 301] **PEER REVIEWED**

Ethylene glycol monoethers are usually produced by reaction of ethylene oxide with the appropriate alcohol. A mixture of homologues is obtained ... The glycol monoethers can be converted to diethers by alkylation with common alkylating agents, such as dimethyl sulfate or alkyl halides ( Williamson synthesis). Glycol dimethyl ethers are formed by treatment ofdimethyl ether with ethylene oxide. /Ethers/ [Ullmann's Encyclopedia of Industrial Chemistry. 6th ed.Vol 1: Federal Republic of Germany: Wiley-VCH Verlag GmbH & Co. 2003 to Present, p. V12 601 (2003)] **PEER

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GENERAL MANUFACTURING INFORMATION: Diglyme can be effectively used as an odor-attractant solvent without reducing the attractiveness of the chemical additive, eg, decanoic acid, trimethylammonium decanoate, and trimethylamine. Odorants dissolved in diglyme can be added to aqueous solutions, such as coyote urine. Also, diglyme has a low freezing point so its use as an odor solvent increases the temperature range in which an odor can be effectively used. [Scrivner JH et al; J Wildl Manage 49 (2): 519-21 (1985)] **PEER REVIEWED**

FORMULATIONS/PREPARATIONS: Grade: Technical [Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 14th Edition. John Wiley & Sons, Inc. New York, NY 2001., p. 373]

**PEER REVIEWED**

U. S. PRODUCTION: (1972) PROBABLY GREATER THAN 4.54X10+5 GRAMS **PEER REVIEWED**

(1975) PROBABLY GREATER THAN 4.54X10+5 GRAMS **PEER REVIEWED**

(1982) 4.72X10+10 g /Diethylene glycol ethers/ [CHEMICAL PRODUCTS SYNOPSIS: Glycol Ethers, 1983] **PEER REVIEWED**

(2006) 1,612 million lb annual capacity /Glycol ethers/ [SRI Consulting. 2006 Directory of Chemical Producers-United States. Menlo Park, CA. 2006, p. 657] **PEER REVIEWED**

Production volumes for non-confidential chemicals reported under the Inventory Update Rule. Year Production Range (pounds) 1986 >1 million - 10

million 1990 >1 million - 10 million 1994 >1 million - 10 million 1998 >1 million - 10 million 2002 >1 million - 10 million [US EPA; Non-confidential Production Volume Information Submitted by Companies for Chemicals Under the 1986-2002 Inventory Update Rule (IUR). Ethane, 1,1'-oxybis[2-methoxy- (111-96-6). Available from, as of March 6, 2007: http://www.epa.gov/oppt/iur/tools/data/2002-vol.htm ] **PEER REVIEWED**

This chemical is listed as a High Production Volume (HPV) (65FR81686). Chemicals listed as HPV were produced in or imported into the U.S. in > 1 million pounds in 1990 and/or 1994. The HPV list is based on the 1990 Inventory Update Rule. (IUR) (40 CFR part 710 subpart B; 51FR21438). [EPA/Office of Pollution Prevention and Toxics; High Production Volume (HPV) Challenge Program. Available from, as of March 6, 2007: http://www.epa.gov/hpv/pubs/general/opptsrch.htm ] **PEER REVIEWED**

U. S. IMPORTS: (1984) 9.43X10+9 g /Diethylene glycol esters, ethers, etc/ [BUREAU OF THE CENSUS. U.S. IMPORTS FOR CONSUMPTION AND GENERAL IMPORTS 1984 p.361]

**PEER REVIEWED**

LABORATORY METHODS:ANALYTIC LABORATORY METHODS: Gas chromatography is likely to be the analytical method for final analysis. Infrared absorption is sometimes used. /Glycol ethers/ [Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982., p. 3910] **PEER REVIEWED**

SAMPLING PROCEDURES: In instances where materials are very soluble in water, samples of air can be taken effectively by scrubbing through water. /Glycol ethers/ [Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982., p. 3910] **PEER REVIEWED**

SPECIAL REFERENCES:

SPECIAL REPORTS: Hardin BD, Lyon JP; Environmental Health Perspectives 57: 273-5 (1984). Proceedings from a NIOSH symposium on the toxic effects of glycol ethers

are reviewed.

European Chemicals Bureau; IUCLID Dataset, bis (2-methoxyethyl) ether (CAS # 111-96-6) p.28-9. Available from the Database Query page at: http://ecb.jrc.it/esis/esis.php as of February 7, 2007.

EPA/Office of Pollution Prevention and Toxics; High Production Volume (HPV) Challenge Program's Robust Summaries and Test Plans. Available from the Database Query page at: http://www.epa.gov/hpv/pubs/hpvrstp.htm on Diglyme as of February 7, 2007

International Programme on Chemical Safety; Concise International Chemical Assessment Document Number 41: Diethylene Glycol Dimethyl Ether (2002). Available from the Database Query page at: http://www.inchem.org/pages/cicads.html as of February 20, 2007.

SYNONYMS AND IDENTIFIERS:

RELATED HSDB RECORDS: 97 [2-METHOXYETHANOL] (metabolite)

SYNONYMS: BIS(2-METHOXYETHYL) ETHER [O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006.., p. 537] **PEER REVIEWED**

DIGLYCOL METHYL ETHER [Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 14th Edition. John Wiley & Sons, Inc. New York, NY 2001., p. 373] **PEER REVIEWED**

DIGLYME [Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 14th Edition. John Wiley & Sons, Inc. New York, NY 2001., p. 373] **PEER

REVIEWED**

DIMETHYL CARBITOL **PEER REVIEWED**

ETHANE, 1,1'-OXYBIS(2-METHOXY- [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York,N.Y. (2001)., p. V7 210] **PEER REVIEWED**

ETHANOL, 2,2'-OXYBIS-, DIMETHYL ETHER **PEER REVIEWED**

ETHER, BIS(2-METHOXYETHYL) **PEER REVIEWED**

GLYME-2 **PEER REVIEWED**

2-(2-METHOXYETHOXY)-1-METHOXYETHANE **PEER REVIEWED**

(2-METHOXYETHYL) ETHER **PEER REVIEWED**

POLY-SOLV **PEER REVIEWED**

2,5,8-TRIOXANONANE [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. V7 210] **PEER REVIEWED**

DIMETHYLDIGLYCOL [Verschueren, K. Handbook of Environmental Data on Organic Chemicals. Volumes 1-2. 4th ed. John Wiley & Sons. New York, NY. 2001, p. 844] **PEER REVIEWED**

DIMETHOXYDIETHYLENEGLYCOL [Verschueren, K. Handbook of Environmental Data on Organic Chemicals. Volumes 1-2. 4th ed. John Wiley & Sons. New York, NY. 2001, p. 844] **PEER REVIEWED**

DYME [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. V7 210]

**PEER REVIEWED**

DGdiME [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. V7 210] **PEER REVIEWED**

DIETHYL GLYCOL DIMETHYL ETHER [Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 507] **PEER REVIEWED**

FORMULATIONS/PREPARATIONS: Grade: Technical [Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 14th Edition. John Wiley & Sons, Inc. New York, NY 2001., p. 373]

**PEER REVIEWED**

ADMINISTRATIVE INFORMATION:

HAZARDOUS SUBSTANCES DATABANK NUMBER: 72

LAST REVISION DATE: 20071011 LAST REVIEW DATE: Reviewed by SRP on 5/14/2007

UPDATE HISTORY: Complete Update on 2007-10-11, 44 fields added/edited/deleted Complete Update on 03/05/2003, 2 fields added/edited/deleted. Field Update on 02/14/2003, 1 field added/edited/deleted. Field Update on 11/08/2002, 1 field added/edited/deleted. Complete Update on 05/13/2002, 1 field added/edited/deleted. Complete Update on 02/13/2002, 1 field added/edited/deleted. Complete Update on 01/18/2002, 3 fields added/edited/deleted. Field Update on 01/14/2002, 1 field added/edited/deleted.Complete Update on 08/09/2001, 1 field added/edited/deleted. Complete Update on 05/16/2001, 1 field added/edited/deleted. Complete Update on 03/28/2000, 1 field added/edited/deleted. Complete Update on 02/08/2000, 1 field added/edited/deleted. Complete Update on 02/02/2000, 1 field added/edited/deleted. Complete Update on 11/18/1999, 1 field added/edited/deleted. Complete Update on 09/21/1999, 1 field added/edited/deleted. Complete Update on 08/26/1999, 1 field added/edited/deleted. Complete Update on 03/19/1999, 1 field added/edited/deleted. Complete Update on 09/11/1998, 1 field added/edited/deleted. Complete Update on 06/02/1998, 1 field added/edited/deleted. Complete Update on 02/25/1998, 1 field added/edited/deleted. Complete Update on 10/17/1997, 1 field added/edited/deleted. Complete Update on 09/17/1997, 1 field added/edited/deleted. Complete Update on 05/08/1997, 1 field added/edited/deleted. Complete Update on 03/27/1997, 1 field added/edited/deleted. Complete Update on 01/24/1997, 1 field added/edited/deleted. Complete Update on 12/12/1996, 33 fields added/edited/deleted. Field Update on 10/12/1996, 1 field added/edited/deleted. Complete Update on 01/18/1996, 1 field added/edited/deleted. Complete Update on 12/19/1994, 1 field added/edited/deleted. Complete Update on 03/25/1994, 1 field added/edited/deleted. Field update on 12/10/1992, 1 field added/edited/deleted. Complete Update on 11/06/1991, 44 fields added/edited/deleted. Complete Update on 05/07/1991, 41 fields added/edited/deleted. Complete Update on 04/16/1990, 1 field added/edited/deleted. Field update on 03/06/1990, 1 field added/edited/deleted. Complete Update on 05/26/1987, 25 fields added/edited/deleted. Created 19830401 by SYS