Toxicity Technical Summary - 2-butoxyethanol Effect on Humans

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ETHYLENE GLYCOL MONO-N-BUTYL ETHER
Synonym: butoxyethanol

ETHYLENE GLYCOL MONO-N-BUTYL ETHER
CASRN: 111-76-2
For other data, click on the Table of Contents

To lower currently approved exposure limits...also use of 2-butoxyethanol

http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?./temp/~AAAGlaypx:1

Human Health Effects:

Toxicity Summary:

IDENTIFICATION: 2-Butoxyethanol is a high production volume glycol ether. It is a colorless liquid that is miscible in water and soluble in most organic solvents. 2-Butoxyethanol is used widely as a solvent in surface coatings, such as spray lacquers, quick dry lacquers, enamels, varnishes, varnish removers and latex paint. HUMAN EXPOSURE: Based on limited data, ambient exposures in air are generally in the ug/cu m range. Industrial exposure of the general population to this chemical is most likely from inhalation and dermal absorption during the use of products containing 2-butoxyethanol. Levels of airborne 2-butoxyethanol in occupational settings are typically in the mg/cu m range. The results of in vitro studies indicate that human red blood cells are not as sensitive to the hemolytic effects of 2-butoxyethanol and 2-butoxyacetic acid and also that red blood cells are more sensitive to hemolysis by 2-butoxyacetic acid than to hemolysis by 2-butoxyethanol. ANIMAL STUDIES: 2-Butoxyethanol is readily absorbed following inhalation, oral or dermal exposure. The chemical is metabolized via alcohol and aldehyde dehydrogenases, with the formation of 2-butoxyacetaldehyde and 2-butoxyacetic acid, the principal metabolite, although other metabolic pathways have also been identified. This chemical has moderate acute toxicity and it is irritating to the eyes and skin; it is not a skin sensitizer. The principal effect exerted by 2-butoxyethanol and its metabolite 2-butoxyacetic acid is hematotoxicity, with the rat being the most sensitive species. In rats, adverse effects on the central nervous system, kidneys and liver occur at higher exposure concentrations than do the hemolytic effects. In animals, adverse effects on reproduction and development have not been observed at less than toxic doses. Although the results of in vitro tests for mutagenicity of 2-butoxyethanol were inconsistent, the absence of structural alerts and the negative findings from in vivo studies indicate that 2-butoxyethanol is not mutagenic.
[World Health Organization/International Programme on Chemical Safety. Concise International Chemical Assessment Document No. 10. 2-Butoxyethanol p.4 (1998)]**QC REVIEWED**

Evidence for Carcinogenicity:

WEIGHT-OF-EVIDENCE CHARACTERIZATION: No reliable human epidemiological studies are available that address the potential carcinogenicity of EGBE. ... NTP /the National Toxicology Program/ (1988) reported no evidence of carcinogenic activity in male F344/N rats, and equivocal evidence of carcinogenic activity in female F344/N rats on the basis of increased combined incidences of benign and malignant pheochromocytoma (mainly benign) of the adrenal medulla. They also reported some evidence of carcinogenic activity in male B6C3F1 mice on the basis of increased incidences of hemangiosarcoma of the liver, and some evidence of carcinoma (mainly papilloma). ... because of the uncertain relevance of these tumor increases to humans, the fact that EGBE is generally negative in genotoxic tests and the lack of human data to support the findings in rodents, the human carcinogenic potential of EGBE, in accordance with the recently proposed Guidelines for Carcinogen Risk Assessment (USEPA, 1996), cannot be determined at this time, but suggestive evidence exists from rodent studies. Under existing EPA guidelines (USEPA, 1986), EGBE is judged to be a possible human carcinogen, Group C. HUMAN CARCINOGENICITY DATA: There are currently no human epidemiological studies addressing the potential carcinogenicity of EGBE.
[U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS) for ethylene glycol monobutyl ether (111-76-2) Available from: http://www.epa.gov/ngispgm3/iris on the Substance File List as of March 15, 2000]**QC REVIEWED**

Human Toxicity Excerpts:

SYMPTOMATOLOGY: 1. Central nervous depression, although probably less prominent than with ethylene glycol. 2. No hypocalcemic tetany or metabolic acidosis with the possible exception of poisonings due to ethylene glycol monomethyl ether. 3. Nausea, vomiting, and sometimes diarrhea. 4. Prominent headache. Later abdominal and lumbar pain and costovertebral angle tenderness. 5. Transient polyuria & then oliguria, progressing to anuria. 6. Acute renal failure ... 7. Less critical pathological lesions may appear in brain, lung, liver, meninges and heart. 8. Observations in animals suggest the remote possibility of pulmonary edema, intravascular hemolysis & bone marrow depression, at least with some ether derivatives of ethylene and diethylene glycols. ... /Ethylene glycol (Group B compounds)/
[Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-176]**PEER REVIEWED**

EXPOSURE ... TO HIGH CONCN ... OF ... VAPORS, PROBABLY IN RANGE OF 300-600 PPM FOR SEVERAL HR WOULD BE EXPECTED TO CAUSE RESP & EYE IRRITATION ... /CNS DEPRESSION/, & DAMAGE TO KIDNEY & LIVER.
[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. 3933]**PEER REVIEWED**

FIRST SIGN OF ORGANIC ABNORMALITY ... RESULTING FROM EXCESSIVE EXPOSURE BY ANY ROUTE LIKELY WOULD BE ABNORMAL BLOOD PICTURE CHARACTERIZED BY ERYTHROPENIA, RETICULOCYTOSIS, GRANULOCYTOSIS, & LEUCOCYTOSIS. SOMEWHAT MORE INTENSE EXPOSURE WOULD BE LIKELY TO CAUSE FRAGILITY OF ERYTHROCYTES & HEMATURIA.
[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. 3933]**PEER REVIEWED**

BONE MARROW DAMAGE. /FROM TABLE/
[Dreisbach, R.H. Handbook of Poisoning. 12th ed. Norwalk, CT: Appleton and Lange, 1987. 176]**PEER REVIEWED**

2-Butoxyethanol penetrates the skin readily, and toxic action from excessive skin exposure may be more likely than from vapor inhalation.
[American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I,II, III. Cincinnati, OH: ACGIH, 1991. 163]**PEER REVIEWED**

IT APPEARS THAT THIS CHEMICAL IS ONE OF THE FEW MATERIALS TO WHICH HUMAN IS MORE RESISTANT THAN THE USUAL EXPERIMENTAL ANIMALS. THIS APPEARS TO BE DUE, IN PART AT LEAST, TO THE FACT THAT HUMANS ARE MORE RESISTANT THAN ARE MOST LAB ANIMALS TO THE HEMOLYTIC EFFECTS CAUSED BY THE MATERIAL ITSELF OR ITS METABOLITE.
[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. 3937]**PEER REVIEWED**

... REGARDED AS MOST TOXIC GLYCOL MONOALKYL ETHER USED AS SOLVENT ... .
[Browning, E. Toxicity and Metabolism of Industrial Solvents. New York: American Elsevier, 1965. 610]**PEER REVIEWED**

THE EFFECTS /OF ALKYL DERIV OF ETHYLENE GLYCOL/ ... UPON THE CNS INCLUDE HEADACHE, DROWSINESS, WEAKNESS, SLURRED SPEECH, RECRUDESCENT STUTTERING, STAGGERING GAIT, TREMOR, AND BLURRED VISION. CHANGES OF PERSONALITY ARE OFTEN NOTED ... THESE CHANGES ARE SUCH THAT THE PATIENT, IN THE ABSENCE OF AN ACCURATE OCCUPATIONAL HISTORY, MAY BE TREATED FOR SCHIZOPHRENIA OR NARCOLEPSY. IN ACUTE POISONING WITH THE ETHYLENE GLYCOL MONOALKYL ETHERS, THERE IS ... RENAL INJURY: ALBUMINURIA & HEMATURIA. /ETHYLENE GLYCOL MONOALKYL ETHERS/
[Hamilton, A., and H. L. Hardy. Industrial Toxicology. 3rd ed. Acton, Mass.: Publishing Sciences Group, Inc., 1974. 301]**PEER REVIEWED**

A case of severe poisoning with ethylene glycol butyl ether after massive ingestion is described. Deep coma, metabolic acidosis, hypokalemia hemoglobinuria, oxaluria and a transitory rise in the serum creatinine level were observed. The elimination of the various metabolites butoxyacetic acid and oxalate was assessed in urine and a metabolic pattern for ethylene glycol butyl ether is suggested.
[Rambourg-Schepens MO et al; Hum Toxicol 7 (2): 187-9 (1988)]**PEER REVIEWED**

The effects of 2-butoxyethanol and its metabolites, 2-butoxyacetaldehyde and butoxyacetic acid, on erythrocytes from humans were investigated in vitro. ... Incubation of human blood with butoxyacetic acid showed minimal swelling or hemolysis of erythrocytes with minimal decline in blood ATP levels at butoxyacetic acid concentrations several-fold higher than required to cause complete hemolysis of rat erythrocytes. ... Human erythrocytes are comparatively insensitive to the hemolytic effects of butoxyacetic acid in vitro.
[Ghanayem BI; Biochem Pharmacol 38 (10): 1679-84 (1989)]**PEER REVIEWED**

A case of acute poisoning with ethylene glycol butyl ether is reported in a chronic alcoholic abuser. On admission the 53 yr old patient was comatose with metabolic acidosis, shock and noncardiogenic pulmonary edema confirmed by hemodynamic study. Following supportive treatment and hemodialysis the outcome was favorable. ...
[Bauer P et al; Intensive Care Med 18 (4): 250-1 (1992)]**PEER REVIEWED**

In several, single, 8 hour exposures of humans at concentrations of 200 or 100 ppm, no objective effects were seen except for urinary excretion of butoxyacetic acid. No increased osmotic fragility was observed in these short term exposures. Subjectively, these concentrations were found to be uncomfortable, and mild eye, nose, and throat irritation followed exposure.
[American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I,II, III. Cincinnati, OH: ACGIH, 1991. 163]**PEER REVIEWED**

No clinical signs of adverse effects nor subjective complaints occurred among seven male volunteers exposed at 20 ppm for 2 hours during light physical exercise.
[American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I,II, III. Cincinnati, OH: ACGIH, 1991. 163]**PEER REVIEWED**

Human Toxicity Values:

The lethal oral dose /of ethylene glycols/ in humans is approximately 1.4 ml/kg, which would be equivalent to approximately 100 ml for a 70-kg person. /Ethylene glycols/
[Amdur, M.O., J. Doull, C.D. Klaasen (eds). Casarett and Doull's Toxicology. 4th ed. New York, NY: Pergamon Press, 1991. 703]**PEER REVIEWED**

Skin, Eye and Respiratory Irritations:

Irritation of eyes, nose and throat ...
[Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens, 1985. 2nd ed. Park Ridge, NJ: Noyes Data Corporation, 1985. 155]**PEER REVIEWED**

Medical Surveillance:

Consider the points of attack (liver, kidneys, lymphoid system, skin, blood, eyes, respiratory system) in placement and periodic physical examinations.
[Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens, 1985. 2nd ed. Park Ridge, NJ: Noyes Data Corporation, 1985. 155]**PEER REVIEWED**

Probable Routes of Human Exposure:

The most probable route of human exposure to ethylene glycol mono-n-butyl ether is by inhalation, dermal contact and ingestion. Workplace exposures have been documented(2-6). Drinking water supplies have been shown to contain ethylene glycol mono-n-butyl ether(1).
[(1) Lucas SV; GC/MS Anal of Org in Drinking Water Concentrates and Advanced Treatment Concentrates Vol 1 USEPA-600/1-84-020A (NTIS PB85-128239) p 397 (1984) (2) Lehmann E et al; pp. 31-41 in Safety and Health Aspects of Organic Solvents. Riihimaki V, Ulfvarson U eds Alan R Liss Inc. (1986) (3) Hahn WJ, Werschulz PO; Evaluation of Alternatives to Toxic Organic Paint Strippers. NTIS PB86 219-177/AS USEPA 600/S2-86/063 (1986) (4) Clapp DE et al; Environ Health Perspective 57: 91-5 (1984) (5) Shah JJ, Heyerdahl EK; National Ambient VOC Database Update USEPA 600/3-88/010 (1988) (6) Yasuhara, A et al; Agric Bio Chem 50: 1765-70 (1986)]**PEER REVIEWED**

THERE IS ... HAZARD OTHER THAN VAPOR THAT MUST NOT BE OVERLOOKED WHEN HANDLING THIS MATERIAL--THAT OF POSSIBLE ABSORPTION OF TOXIC QUANTITIES THROUGH SKIN, BECAUSE OF LOW VAPOR PRESSURE ... @ ROOM TEMP, HAZARD FROM SKIN ABSORPTION COULD WELL BE GREATER, OR CONTRIBUTE SUBSTANTIALLY TO OVER-ALL HAZARD.
[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. 3938]**PEER REVIEWED**

FROM INDUST POINT OF VIEW, ONLY ONE CASE OF POSSIBLE SYSTEMIC INJURY WAS THAT OF MAN WHO WAS REPORTED ... AS HAVING HAD TWO ISOLATED ATTACKS OF HEMATURIA, WITH 5 MO INTERVAL. ... HIS EXPOSURE ... INCL BUTYL CARBITOL AS WELL AS BUTYL CELLOSOLVE.
[Browning, E. Toxicity and Metabolism of Industrial Solvents. New York: American Elsevier, 1965. 612]**PEER REVIEWED**

OCCUPATIONAL EXPOSURES TO BUTYL CELLOSOLVE, ETHANOL, & XYLENE IN FILAMENT-DRAW DEPARTMENT OF ELECTRICAL RESISTOR MFR FACILITY DID NOT POSE A HEALTH HAZARD.
[GILLES ET AL; US NTIS PB REP; ISS PB-273739 (1976) 16 PP]**PEER REVIEWED**

NIOSH (NOES Survey as of 3/28/89) has estimated that 1,680,764 workers are potentially exposed to ethylene glycol mono-n-butyl ether in the USA(1). According to the National Ambient Volatile Organic Compounds (VOCs) Database, the median workplace atmospheric concn of ethylene glycol mono-n-butyl ether is 0.075 ppbV for 14 samples(3). Workers at paint stripping operations that used stripping agents containing ethylene glycol mono-n-butyl ether were exposed to it(2).
[(1) NIOSH; National Occupational Exposure Survey (NOES) (1989) (2) Hahn WJ, Werschulz PO; Evaluation of Alternatives to Toxic Organic Paint Strippers. NTIS PB86 219-177/AS USEPA 600/S2-86/063 (1986) (3) Shah JJ, Heyerdahl EK; National Ambient VOC Database Update USEPA-600/3-88/010 (1988)]**PEER REVIEWED**

Personal exposures to atmospheric ethylene glycol mono-n-butyl ether at a specialty chemical production facility in June of 1981 ranged from undetected levels to 0.1 ppm; indoor air concn within the facility were as high as 1.7 ppm(2). A national survey of workplaces in the Federal Republic of Germany showed that workers were exposed to solvents containing ethylene glycol mono-n-butyl ether with a 0.4% frequency of occurrence(1).
[(1) Lehmann E et al; pp 31-41 in Safety and Health Aspects of Organic Solvents. Riihimaki V, Ulfvarson U eds Alan R Liss Inc. (1986) (2) Clapp DE et al; Environ Health Perspective 57: 91-5 (1984)]**PEER REVIEWED**

A study initiated in 1983, which surveyed the workplace atmospheres of 336 businesses in Belgium, showed that ethylene glycol mono-n-butyl ether was present in 25 of 94 air samples taken from sites that utilize printing pastes; 10 of 81 samples from where painting took place; 1 of 20 samples from automobile repair shops; and 17 of 67 samples from sites where various materials such as varnishes, sterilization agents and cleaners are employed(1). The geometric mean concn of ethylene glycol mono-n-butyl ether in the air of printing shops was 4.1 mg/cu m with a range of 1.5 to 17.7 mg/cu m; 18.8 mg/cu m with a range of 3.4 to 93.6 mg/cu m for painting areas; 5.9 mg/cu m for car repair shops; and 8.5 mg/cu m with a range of 0.2 to 1775 mg/cu m for various industries(1).
[(1) Veulemans H et al; Am Indust Hyg Assoc J 48: 671-7 (1987)]**PEER REVIEWED**

Ethylene glycol mono-n-butyl ether was identified as a volatile emission from used machine cutting oils in an automobile manufacturing facility in Japan(1). Non-occupational exposures may occur among populations with contaminated drinking water supplies(2). Because ethylene glycol mono-n-butyl ether is a component of solvent based building materials such as silicone caulk(3), human exposures may occur at construction sites and areas that have undergone remodelling(SRC).
[(1) Yasuhara A et al; Agric Bio Chem 50: 1765-70 (1986) (2) Lucas SV; GC/MS Anal of Org in Drinking Water Concentrates and Advanced Treatment Concentrates Vol 1 USEPA-600/1-84-020A (NTIS PB85-128239) p 397 (1984) (3) Tichenor BA, Mason MA; JAPCA 38: 264-8 (1988)]**PEER REVIEWED**

Exposure of cleaning women and cleaners of cars to ethylene glycol mono-n-butyl ether resulted in urine levels of <0.1-7.33 ppm (time-weighted averages)(1). It was established that the predominant route of exposure to ethylene glycol mono-n-butyl ether was through skin penetration(1). Ethylene glycol mono-n-butyl ether was identified in air from automotive repair shops in Sydney, Australia in 8 out of 70 samples at an average concentration of 2.0 mg/cu m(2).
[(1) Vincent R et al; Appl Occup Environ Hyg 8: 580-6 (1993) (2) Winder C, Turner PJ; Am Occup Hyg 36: 385-94 (1992)]**PEER REVIEWED**

Emergency Medical Treatment:

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The following Overview, *** ETHYLENE GLYCOL BUTYL ETHER ***, is relevant for this HSDB record chemical.

Life Support:

  o   This overview assumes that basic life support measures

      have been instituted.

Clinical Effects:

  SUMMARY OF EXPOSURE

   0.2.1.1 ACUTE EXPOSURE

     o   CHILDREN ingesting small amounts (less than 15

         milliliters) of dilute household products (less than

         10% ethylene glycol butyl ether (EGBE)) generally do

         not develop evidence of toxicity.

     o   ADULTS - Acidosis, CNS depression, renal injury,

         hematuria, oxaluria, ARDS, and hypotension have been

         reported after ingestion of 30 to 60 mL of pure EGBE in

         adults.

     o   ANIMALS - Appears to be 5 to 6 times more orally toxic

         than ethylene glycol in animals by weight.

      1.  Because metabolites are an important component in the

          human toxicity of ethylene glycol and presumably its

          ethers, comparison of relative toxicity using LD50

          data cannot be reliably used to predict human

          experience.

     o   OTHER ROUTES OF EXPOSURE - Absorbed through skin,

         lungs, and gastrointestinal tract.

      1.  Exposure to vapors may cause eye and mucous membrane

          irritation.

  HEENT

   0.2.4.1 ACUTE EXPOSURE

     o   Transient conjunctivitis has been reported after

         instillation into rabbit eyes.

  CARDIOVASCULAR

   0.2.5.1 ACUTE EXPOSURE

     o   Severe hypotension may develop after massive oral

         ingestion.  Ventricular dysrhythmias were reported in

         one case.

  RESPIRATORY

   0.2.6.1 ACUTE EXPOSURE

     o   Non-cardiogenic pulmonary edema (ARDS) has been

         reported in one case after ingestion of 500 mL of a

         9.1% solution.

     o   Aspiration may occur following large ingestions.

  NEUROLOGIC

   0.2.7.1 ACUTE EXPOSURE

     o   CNS depression, including coma, may occur following

         massive ingestions.

     o   Seizures have been reported following ingestions.

  HEPATIC

   0.2.9.1 ACUTE EXPOSURE

     o   Liver necrosis, secondary to hemolysis, has been

         reported in animals.

  GENITOURINARY

   0.2.10.1 ACUTE EXPOSURE

     o   EGBE may have somewhat more renal toxicity than other

         glycol ethers.

  ACID-BASE

   0.2.11.1 ACUTE EXPOSURE

     o   Metabolic acidosis has been consistently described

         after massive ingestion.

  HEMATOLOGIC

   0.2.13.1 ACUTE EXPOSURE

     o   Hemolytic anemia, non-hemolytic anemia,

         thrombocytopenia, and DIC have been reported in

         overdose.  Erythropenia, reticulocytosis,

         granulocytosis, and leukocytosis may occur.  More

         intense exposure is likely to cause fragility of

         erythrocytes and hematuria.

  REPRODUCTIVE HAZARDS

    o   Fetal toxicity has only been observed in animals at

        maternally toxic doses.

Laboratory:

  o   Obtain CBC, electrolytes (particularly calcium and

      potassium), urinalysis (look for oxalate crystals and

      hemoglobin) and blood gases in all asymptomatic patients

      with a history of exposure or patients who are

      symptomatic.

  o   Blood ethanol, methanol, and ethylene glycol levels may be

      useful in assessing ingestions of mixtures.

  o   The presence of butoxyacetic acid in the urine can be

      considered evidence of exposure to ethylene glycol butyl

      ether (EGBE).

Treatment Overview:

  ORAL EXPOSURE

    o   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.

    o   Animal data are suggestive that ethanol therapy may

        inhibit the formation of toxic metabolites.

     1.  LOADING DOSE (INTRAVENOUS) - Administer 7.6 to 10 mL/kg

         IV of 10% ETOH in D5W over 30 minutes to achieve a

         blood ETOH concentration of 100 to 130 mg/dL (21.7 to

         28.2 mmol/L).  A loading dose of 10 mL/kg of 10% ETOH

         should produce a peak blood ethanol level of about 130

         mg/dL (28.2 mmol/L) depending on the rate of

         administration.

     2.  LOADING DOSE (ORAL) - Administer 0.80 to 1.0 mL/kg

         orally of 95% ETOH in 6 oz of orange juice over 30

         minutes.  Begin the maintenance infusion concurrent

         with the loading dose.

     3.  PRECAUTION - Monitor blood glucose and ethanol during

         ethanol therapy, ethanol induced hypoglycemia may occur

         in children.

    o   MONITOR - ARTERIAL pH and BLOOD GASES in symptomatic

        patients, or following large ingestions of EGBE.

    o   ACIDOSIS - Treat acidosis with IV sodium bicarbonate.

        Begin with 1 to 2 mEq/kg in adults and 1 mEq/kg in

        children, repeat every 1 to 2 hours as required.

        Monitor blood gases to adjust dose.

    o   FOMEPIZOLE -

     1.  Fomepizole is a specific antagonist of alcohol

         dehydrogenase is an alternative to ethanol but is not

         FDA approved for the treatment of  ethylene glycol

         ether poisonings.

      a.  DOSE - In one study a loading dose of 15

          milligrams/kilogram intravenous infusion over 30

          minutes is followed by doses of 10 milligrams/kilogram

          every 12 hours for 4 doses, then 15

          milligrams/kilogram every 12 hours until ethylene

          glycol levels are below 20 milligrams/deciliters.

          Dose needs to be adjusted during hemodialysis.  See

          main treatment section.

    o   THIAMINE/PYRIDOXINE -

     1.  Administer thiamine and pyridoxine 100 mg IV daily.

    o   HEMODIALYSIS -

     1.  Has not been shown to effectively remove EGBE but may

         be used to correct severe  acid-base and/or

         fluid-electrolyte abnormalities that persist  despite

         conventional therapy.

Range of Toxicity:

  o   ORAL - Available animal data suggest that, based on

      comparisons of oral LD50 values in the same species,

      ethylene glycol butyl ether is 5 to 6 times more acutely

      toxic than ethylene glycol; however, this model does not

      account for toxicity of metabolites.

  o   Severe toxicity has been described in adults who ingested

      30 to 63.5 mL of pure EGBE.

  o   Children ingesting small amounts (less than 10

      milliliters) of dilute household products (less than 10%

      ethylene glycol butyl ether) generally do not develop

      evidence of poisoning.

[Rumack BH: POISINDEX(R) Information System. Micromedex, Inc., Englewood, CO, 2002; CCIS Volume 113, edition exp August, 2002. Hall AH & Rumack BH (Eds):TOMES(R) Information System. Micromedex, Inc., Englewood, CO, 2002; CCIS Volume 113, edition exp August, 2002.] **PEER REVIEWED**

Animal Toxicity Studies:

Toxicity Summary:

Evidence for Carcinogenicity:

Non-Human Toxicity Excerpts:

Tests of the liquid by dropping on rabbit eyes induces reddening and swelling of the conjunctiva with slight clouding of the corneal epithelium. The degree of injury judged 24 hours after the application of a single drop has been graded 4 on a scale of 1 to 10. Rabbit eyes in contact with the liquid for eight minutes before irrigation with water have recovered completely in four days.
[Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 163]**PEER REVIEWED**

ON EXCISED BEEF CORNEA ... /IT REDUCED/ ADHESION OF EPITHELIUM TO STROMA ... .
[Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 163]**PEER REVIEWED**

... RATS OF DIFFERENT AGES /WERE EXPOSED/ TO VARIOUS CONCN OF VAPOR. ... 1-YR-OLD RATS WERE MORE SUSCEPTIBLE THAN YOUNG, ACTIVELY GROWING RATS. AT ... 375 PPM OLD ADULTS DIED AFTER 7 HR WHILE 6-WK-OLD RATS SURVIVED 8 HR AT 500 PPM.
[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. 3935]**PEER REVIEWED**

... REPEATED INHALATION STUDIES ... AT HIGH CONCN, RATS EXHIBITED HEMORRHAGE OF LUNG, CONGESTION OF VISCERA, LIVER INJURY, HEMOGLOBINURIA, & MARKED ERYTHROCYTE FRAGILITY. FEMALES WERE MORE SENSITIVE THAN MALES.
[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. 3935]**PEER REVIEWED**

GUINEA PIGS ... AT HIGH CONCN, CONGESTION & CLOUDY SWELLING OF TUBULES OF KIDNEYS ... BUT NO INCR IN FRAGILITY OF ERYTHROCYTES ... @ ANY CONCN STUDIED. MICE WERE ... AS RESISTANT AS GUINEA PIGS, WITH EXCEPTION THAT THEIR ERYTHROCYTES WERE AS FRAGILE AS THOSE OF RAT.
[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. 3935]**PEER REVIEWED**

... RATS /WERE MAINTAINED/ ... ON DIETS CONTAINING 2.0, 0.5, 0.125, & 0.03% ... AT TOP LEVEL, GROWTH DEPRESSION & INCR KIDNEY & LIVER WEIGHTS ... AT 0.5% ... GROWTH DEPRESSION & INCR LIVER WT ... .
[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. 3933]**PEER REVIEWED**

... 2 DOGS /WERE/ EXPOSED TO VAPOR CONCN OF 415 PPM 7 HR/DAY, 5 DAYS/WK, FOR 12 WK. ... THERE WAS INCR IN NUMBER OF CALCIUM OXALATE CRYSTALS IN URINE & ... RETENTION OF UREA IN BLOOD ... .
[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. 3935]**PEER REVIEWED**

DOGS EXPOSED TO HIGH CONCN SUFFERED CONGESTION OF KIDNEYS & LUNG, WT LOSS, INCR FRAGILITY OF ERYTHROCYTES, NASAL & EYE INFECTIONS, APATHY, ANOREXIA, NAUSEA, & ... CHANGES IN CIRCULATING BLOOD. LEUCOCYTES ... INCR. WHEREAS ... HEMOGLOBIN ... DECR. ... INCR IN PLASMA FIBRINOGEN.
[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. 3937]**PEER REVIEWED**

MONKEYS EXPOSED TO 200 PPM SUFFERED MARKED REDUCTION IN NUMBER OF CIRCULATING RED BLOOD CELLS & IN HEMOGLOBIN CONCN. ... FEMALE MONKEYS EXCRETED 309 MG OF BUTOXYACETIC ACID OVER A 48-HR PERIOD AFTER RECEIVING THE 48-HR EXPOSURE.
[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. 3937]**PEER REVIEWED**

CHRONIC. LUNG ... SLIGHT TO MODERATE CONGESTION; SOMETIMES BRONCHOPNEUMONIA. SPLEEN, CONGESTION & FOLLICULAR PHAGOCYTOSIS ... .
[Browning, E. Toxicity and Metabolism of Industrial Solvents. New York: American Elsevier, 1965. 612]**PEER REVIEWED**

... BY INHALATION /MEDIAN LETHAL DOSE/, FOR RATS, 432 PPM 7 HR/DAY, 5 DAYS/WK FOR 30 DAYS; FOR GUINEA PIGS, 494 PPM KILLED ONLY 2 OUT OF 10; FOR DOGS, 617 PPM AFTER 13 1/2 HR EXPOSURES IN 2 DAYS. ACUTE. SLUGGISHNESS, ROUGH COAT, PROSTRATION & ... /CNS DEPRESSION/ IN HIGH CONCN ... CORNEAL OR LENS OPACITY.
[Browning, E. Toxicity and Metabolism of Industrial Solvents. New York: American Elsevier, 1965. 611]**PEER REVIEWED**

ACUTE. SLUGGISHNESS, ROUGH COAT, PROSTRATION & ... /SRP: CNS DEPRESSION/ IN ANIMALS DYING FROM ORAL DOSE ... IN MICE ... DYSPNEA WAS CONSTANT SIGN & WITH HIGH CONCN ... CORNEAL OR LENS OPACITY.
[Browning, E. Toxicity and Metabolism of Industrial Solvents. New York: American Elsevier, 1965. 611]**PEER REVIEWED**

INHALATION (84 MG/CU M, 6 HR DAILY, 3 DAYS/WK, FOR 4 MO) CAUSED ADAPTATION IN RATS & MICE, PROBABLY CONSISTING OF CHANGES OF ENZYME SYSTEMS OF ERYTHROCYTES, PROTECTING HEMOGLOBIN & ERYTHROCYTE MEMBRANE FROM PEROXIDATION. 3-HR, 6 DAYS/WK FAILED TO INDUCE ADAPTATION.
[LOMONOVA ET AL; GIG TR PROF ZABOL 2: 38 (1977)]**PEER REVIEWED**

HIGH DOSES OF ORALLY ADMIN ETHYLENE GLYCOL MONOALKYL ETHERS PRODUCED TESTICULAR ATROPHY & LEUKOPENIA IN MICE. A DOSE RESPONSE RELATION WAS OBSERVED. /ETHYLENE GLYCOL MONOALKYL ETHERS/
[NAGANO K ET AL; SANGYO IGAKU 21 (1): 29 (1979)]**PEER REVIEWED**

Fifty pregnant CD-1 mice were given 1,180 mg/kg/day of ethylene glycol monobutyl ether in water by gavage on days 6-13 of gestation and allowed to deliver. Ethylene glycol monobutyl ether caused 20% mortality in treated dams but had no effect on the offspring of treated animals.
[Hardin BD et al; Teratog Carcinog Mutagen 7: 29-48 (1987)]**PEER REVIEWED**

The reproductive effects of ethylene glycol monomethyl ether and propylene glycol monomethyl ether inhalation were investigated in rats. To determine the effects on testis and hematology, male Wistar rats were exposed to 100 or 300 ppm ethylene glycol monomethyl ether or 200 or 600 ppm propylene glycol monomethyl ether for 6 hr per day for 10 consecutive days in an inhalation chamber. The teratogenic potential on the developing embryo was assessed by exposing pregnant female rats to 100 or 300 ppm ethylene glycol monomethyl ether and 200 or 600 ppm propylene glycol monomethyl ether for 6 hr per day on days 6 to 17 of gestation. Other studies investigated the teratogenic potential of diethylene ethylene monomethyl ether in the postnatal development test, effect on route of administration on teratogenic potential of ethylene glycol monomethyl ether, effect of ethylene glycol monoisopropyl ether on the testis and blood, effect of a single inhalation exposure to ethylene glycol monomethyl ether, ethylene glycol monoisopropyl ether, ethylene glycol monomethyl ether, and ethylene glycol monobutyl ether, and exposure of a single exposure to ethylene glycol monomethyl ether on the testis of male rats. Ethylene glycol monomethyl ether caused testicular atrophy at 300 ppm and showed teratogenic potential at 100 ppm; propylene glycol monomethyl ether did not cause testicular atrophy or affect embryonic development at 600 ppm by inhalation. Diethylene glycol monomethyl ether showed no teratogenic potential when administered subutaneously in rats up to 1,000 ul/kg, whereas ethylene glycol monomethyl ether had effects at 40 ul/kg. Ethylene glycol monomethyl ether caused testicular changes in rats after a single exposure to 600 ppm or more for 4 hr. Ethylene glycol monoethyl ether caused a reduction in testicular weight following a single exposure to saturated vapor of 17 mg/l for 3 hours; ethylene glycol monoisopropyl ether at 15 mg/l and ethylene glycol monobutyl monobutyl ether at 4 mg/l showed no effect on the testis.
[Doe JE; Environ Health Perspect 57: 199-206 (1984)]**PEER REVIEWED**

Previous NIOSH studies demonstrated the embryo- and fetotoxicity and teratogenicity of ethylene glycol monoethyl ether applied to the shaved skin of pregnant rats. In the present study ethylene glycol monoethyl ether acetate, ethylene glycol monobutyl ether, and diethylene glycol monoethyl ether were tested in the same experimental model, using distilled water as the negative control and ethylene glycol monoethyl ether as a positive control. Water or undiluted glycols were applied four times daily on days 7 to 16 gestation to the shaved interscapular skin with automatic pipetter. Volumes of ethylene glycol monoethyl ether (0.25 ml), ethylene glycol monoethyl ether acetate (0.35 ml), and diethylene glycol monoethyl ether (0.35 ml) were approximately equimolar (2.6 mmole per treatment). Ethylene glycol monobutyl ether at 0.35 ml four times daily (approximately 2.7 mmole per treatment) killed 10 of 11 treated rats, and was subsequently tested at 0.12 ml (0.9 mmole) per treatment. Ethylene glycol monoethyl ether and ethylene glycol monoethyl ether acetate treated rats showed a reduction in body weight relative to water controls that was associated with completely resorbed litters and significantly fewer live fetuses per litter. Visceral malformations and skeletal variations were significantly increased in ethylene glycol monoethyl ether and ethylene glycol monoethyl ether acetate groups over the negative control group. No embryotoxic, fetotoxic, or teratogenic effects were detected in the ethylene glycol monobutyl ether or diethylene glycol monoethyl ether treated litters.
[Hardin BD et al; Environ Health Perspect 57: 69-74 (1984)]**PEER REVIEWED**

Mice were intubated during gestation and were evaluated for signs of toxicity. In the teratology probe, uterine contents were examined at term. In the postnatal study, offspring were examined and weighed through day 22 postpartum. Ethylene glycol monoethyl ether produced embryo lethality and malformations, and decreased fetal weight at a dose level which was not maternally toxic in the teratology probe. In the postnatal study, ethylene glycol monoethyl ether decreased litter size and neonatal body weight; while litter size continued to decrease beyond neonatal period, body weights of surviving pups were not significantly different from control. Pups exposed prenatally to ethylene glycol monoethyl ether developed kinked tail which was not apparent in fetuses or neonates. Maternally toxic doses levels of ethylene glycol monobutyl ether ethanol were associated with increased embryo lethality in teratology probe studies. In postnatal studies, there were no significant effects on pup growth or survival at maternally toxic dose levels. The teratology probe measures resorption incidence which may be a more sensitive index of prenatal death than number of live born. Neither fetal weight nor neonatal weight reliably predict permanent alteration of growth.
[Wier PJ et al; Teratogenesis Carcinog Mutagen 7 (1): 55-64 (1987)]**PEER REVIEWED**

Structure activity studies with nine glycol alkyl ethers were conducted with a cellular leukemia transplant model in male Fischer rats to measure the effects on neoplastic progression in transplant recipients. Chemicals were given ad libitum in the drinking water simultaneously with the transplants and continued throughout the study. In all 20 million leukemic cells were injected sc into syngeneic rats, which after 60 days resulted in a 10-fold increase in relative spleen weights, a 100-fold increase in white blood cell counts, and a 50% reduction in red blood cell indices and platelet counts. Ethylene glycol monomethyl ether given at a dose of 2.5 mg/ml in the drinking water completely eliminated all clinical, morphological, and histopathological evidence of leukemia, whereas the same dose of ethylene glycol monoethyl ether reduced these responses by about 50%. Seven of the glycol ethers were ineffective as anti-leukemic agents, including ethylene glycol, the monopropyl, monobutyl, and monophenyl ethylene glycol ethers, diethylene glycol, and the monomethyl and monoethyl diethylene glycol ethers. Ethylene glycol monomethyl ether more than double the latency period of leukemia expression and extended survival for at least 21 days. A minimal effective dose for a 50% reduction in the leukemic responses was 0.25 mg/ml ethylene glycol monomethyl ether in the drinking water (15 mg/kg body weight), whereas a 10-fold higher dose of 2-ethylene glycol monoethyl ether was required for equivalent antileukemic activity. In addition, the in vitro exposure of a leukemic spleen mononuclear cell culture to ethylene glycol monomethyl ether caused a dose- and time-dependent reduction in the number of leukemia cells after a single exposure to 1-100 uM concentrations, whereas the ethylene glycol monomethyl ether metabolite, 2-methoxyacetic acid, was only half as effective.
[Dieter MP et al; Cancer Chemother Pharmacol 26 (3): 173-80 (1990)]**PEER REVIEWED**

Studies were conducted on the percutaneous absorption, distribution, excretion, and hemolytic activity of n-butoxyethanol. Rats receiving a subcutaneous dose of (14)C-labeled n-butoxyethanol excreted the radioactivity in the urine (79%), expired air (10%), and feces (0.5%) within 72 hr. Of the organs analyzed, thymus and spleen showed elevated specific radioactivities as compared with blood. A percutaneous application of n-butoxyethanol on rats, under nonocclusive conditions, showed 25-29% absorption within 48 hr. Peak blood levels of n-butoxyethanol occurred at 2 hr after application; butoxyacetic acid was found to be the major metablite. Comparison of in vitro skin penetration data showed the following absorption pattern of n-butoxyethanol: hairless rat much greater than pig greater than human skin. Hemolysis and associated hematological changes were noted in the rats which received single dermal applications of 260-500 mg/kg of n-butoxyethanol. In vitro, butoxy acetic acid showed markedly greater hemolytic ability on rat erythrocytes than did n-butoxyethanol. Human erythrocytes showed no hemolysis when incubated with n-butoxyethanol or butoxy acetic acid at concentrations that are hemolytic to rat erythrocytes. An intravenous dose of 62.5 mg/kg of n-butoxyethanol does not result in hemolysis or hemoglobinuria in the rat. The rat may be an animal model with increased susceptibility to the effects of n-butoxyethanol compared with humans because of its rapid percutaneous absorptive ability and its greater hemolytic sensitivity.
[Bartnik FG et al; Fundam Appl Toxicol 8 (1): 59-70 (1987)]**PEER REVIEWED**

2-Butoxyethanol causes acute hemolytic anemia in rats, and activation of 2-butoxyethanol to butoxyacetic acid, presumably through the intermediate 2-butoxyacetaldehyde, is a prerequisite for development of hematotoxicity. The effects of 2-butoxyethanol and its metabolites, 2-butoxyacetaldehyde and butoxyacetic acid, on erythrocytes from rats were investigated in vitro. At 20 mM, 2-butoxyethanol caused hemolysis of rat erythrocytes accompanied by a decrease in hematocrit. In contrast, incubation of 2-butoxyacetaldehyde or butoxyacetic acid with rat blood caused time- and concentration-dependent swelling of red blood cells followed by hemolysis; butoxyacetic acid was significantly more efficacious than 2-butoxyacetaldehyde. Addition of aldehyde dehydrogenase and its co-factors potentiated the effect of 2-butoxyacetaldehyde on rat erythrocytes. Incubation of rat blood with butoxyacetic acid or 2-butoxyacetaldehyde cused a time- and concentration-dependent decrease in blood ATP concentration. The decrease in blood ATP was greater with butoxyacetic acid than with 2-butoxycetaldehyde and was not induced by 2-butoxyethanol. Butoxyacetic acid caused no significant changes in the concentration of reduced glutathione and glucose-6-phosphate dehydrogenase in rat erythrocytes. The hemolytic effect of 2-butoxyethanol can be attributed primarily to its metabolite butoxyacetic acid, and hemolysis of rat erythrocytes by butoxyacetic acid or 2-butoxyacetaldehyde is preceded by swelling and ATP depletion.
[Ghanayem BI; Biochem Pharmacol 38 (10): 1679-84 (1989)]**PEER REVIEWED**

Male rats were given ethylene glycol monomethyl ether or ethylne glycol monobutyl ether per os for 4 consecutive days at doses of 100 or 500 mg/kg body wt/day for ethylene glycol monobutyl ether, and 500 or 1000 mg/kg body wt/day for ethylene glycol monobutyl ether. Animals were examined on days 1, 4, 8, and 22 after the final treatment. Both ethylene glycol monomethyl ether and ethylene glycol monobutyl ether produced thymic atrophy and lymphocytopenia and, in the case of ethylene glycol monobutyl ether, neutropenia also. Hemolytic anemia induced by ethylene glycol monobutyl ether resulted in splenic extramedullary hemopoiesis, hyperplasia of both spleen and bone marrow, and reticulocytosis. Apart from residual slight increases in spleen weight, mean red cell volume, and mean corpuscular hemoglobin at the end of the recovery period, other effects were reversible. With ethylene glycol monomethyl ether, reduction in the numbers of circulating red cells was only slight. Treatment with ethylene glycol monomethyl ether also abolished splenic extramedullary hemopoiesis which partially recovered on day 4, followed by a marked response on day 8, and return to the control values on day 22. Femoral bone marrow was hemorrhagic 1 day after treatment with ethylene glycol monomethyl ether which appeared to be associated with sinus endothelial cell damage. By day 4 the histologic appearance of the marrow was normal. Testicular atrophy was also produced in ethylene glycol monomethyl ether-treated animals. Ethylene glycol monomethyl ether and ethylene glycol monobutyl ether differ considerably in the spectrum of toxic changes induced, and apart from testicular atrophy, these changes were largely reversible within a short time of the end of treatment.
[Grant D et al; Toxicol Appl Pharmacol 77 (2): 187-200 (1985)]**PEER REVIEWED**

Structurally related alkyl glycol ethers were examined for their ability to block junction-mediated intercellular communication. Interruption of intercellular communication was measured in vitro by an assay that depends on the transfer of metabolites via gap junctions, ie, metablic cooperation. All compounds tested ethylene glycol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, and ethylene glycol monobutyl ether were able to block metabolic cooperation in vitro. The potencies of the compounds were inversely related to the length of the aliphatic chain, the dose required for maximum blockage increasing as the aliphatic chain shortened. Cytotoxicity, as measured by cell survival, was also related to the structure of the compound, generally increasing with increased length of the aliphatic chain.
[Loch-Caruso R et al; Environ Health Perspect 57: 119-23 (1984)]**PEER REVIEWED**

Timed-pregnant Fischer 344 rats and New Zealand White rabbits were exposed to ethylene glycol monobutyl ether vapors by inhalation on gestational days 6 through 15 (rats) or 6 through 18 (rabbits) at concentrations of 0, 25, 50, 100 or 200 ppm. The animals were sacrificed on gestational day 21 (rats) or 29 (rabbits). In rats, exposure to 200 or 100 ppm resulted in maternal toxicity (clinical signs, decreased body weight and weight gain, decreased absolute and relative organ weights, decreased food and water consumption and evidence of anemia), embryotoxicity (increased number of totally resorbed litters and decreased number of viable implantations per litter) and fetotoxicity (reductions in skeletal ossification). No increase in fetal malformations was observed in any exposure group relative to controls. At 50 or 25 ppm, there was no maternal, embryo or fetal toxicity (including malformations) in rats. In rabbits, exposure to 200 ppm resulted in maternal toxicity (apparent exposure-related increases in deaths and abortions, clinical signs, decreased weight during exposure and reduced gravid uterine weight at sacrifice) and embryotoxicity (reduced number of total and viable implantations per litter). No treatment-related fetotoxicity was seen. No treatment-related increase in fetal malformations or variations were seen at any exposure concentration tested. There was no evidence of maternal, embryo, or fetal toxicity (including malformations) at 100, 50 or 25 ppm in rabbits.
[Tyl RW et al; Environ Health Perspect 57: 47-68 (1984)]**PEER REVIEWED**

Investigated the teratogenicity of five compounds. Each chemical was vaporized and administered to pregnant rats in one to three concentrations for 7 hr/day on gestation days 7 to 15, and dams were sacrificed on day 20. At concentrations which were apparently not maternally toxic, 2-methoxyethanol was highly embryotoxic, producing complete resorptions at 200 ppm; increased resorptions, reduced fetal weights and skeletal and cardiovascular defects occured at both 100 and 50 ppm. 2-Ethoxyethyl acetate at 600 ppm induced complete resorption of litters; 390 ppm reduced fetal weights and induced skeletal and cardiovascular defects, but only a single defect was observed at 130 ppm. 2-Butoxyethanol evidenced slight maternal toxicity at 200 ppm but produced no increase in congenital defects at that concentration. Neither 2-(2-ethoxyethoxy)ethanol (100 ppm) nor 2-methylaminoethanol (150 ppm) was maternally toxic or embryotoxic. Shorter alkyl chained glycol ethers produced greater embryotoxicity than those having longer chains, and the ester produced effects equivalent to the ether.
[Nelson BK et al; Environ Health Perspect 57: 261-71 (1984)]**PEER REVIEWED**

In F344 male rats, 2-butoxyethanol causes severe acute hemolytic anemia resulting in significant increase in the concentration of free plasma hemoglobin. Secondary to the hemolytic effects, 2-butoxyethanol also caused hemoglobinuria as well as histopathologic changes in the liver and kidney. The hemolytic effects of 2-butoxyethanol were age dependent with older rats being more sensitive than younger rats. There was a higher portion of the administered dose eliminated as carbon dioxide a higher portion of the administered dose was excreted in the urine of young rats. Analysis of the urinary metabolites showed that the ratio of butoxyacetic acid 2-butoxyethanol glucuronide + 2-butoxyethanol sulfate (previously thought to reflect an activation/detoxification index of 2-butoxyethanol) was higher in old rats. The increase in the activation/detoxification index in older rats is caused by decreased degradation of butoxyacetic acid to carbon dioxide and by depressed urinary excretion of butoxyacetic acid in the urine of older rats.
[Ghanayem BI et al; Toxicol Appl Pharmacol 91 (2): 222-34 (1987)]**PEER REVIEWED**

2-Butoxyethanol given orally to mice for 5 weeks at a dose of 1000 mg/kg produced no change in absolute or relative testis weights.
[American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I,II, III. Cincinnati, OH: ACGIH, 1991. 162]**PEER REVIEWED**

Exposure of pregnant rats at 100 ppm or rabbits at 200 ppm during organogenisis resulted in maternal toxicity and embryotoxicity, including a decrease number of viable implantations per litter. Slight fetotoxicity in the form of poorly ossified or unossified skeletal elements was also observed in rats. Teratogenic effects were not observed in either species.
[American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I,II, III. Cincinnati, OH: ACGIH, 1991. 162]**PEER REVIEWED**

... ... Conclusions: Under the conditions of these 2 yr inhalation studies, there was no evidence of carcinogenic activity of 2-butoxyethanol in male F344/N rats exposed to 31.2, 62.5 or 125 ppm. There was equivocal evidence of carcinogenic activity of 2-butoxyethanol in female F344/N rats based on incr incidences of benign or malignant pheochromocytoma (mainly benign) of the adrenal medulla. There was some evidence of carcinogenic activity of 2-butoxyethanol in male B6C3F1 mice based on incr incidences of hemangiosarcoma of the liver. ... There was some evidence of carcinogenic activity of 2-butoxyethanol in female B6C3F1 mice based on incr incidences of forestomach squamous cell papilloma or carcinoma (mainly papilloma).
[Toxicology & Carcinogenesis Studies of 2-Butoxyethanol in F344/N Rats and B6C3F1 Mice p.6 Technical Report Series No. 484 (2000) NIH Publication No. 00-3974 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709]**QC REVIEWED**

National Toxicology Program Studies:

... 2 Year Study in Rats: Groups of 50 male and 50 female F344/N rats were exposed to 2-butoxyethanol by inhalation at concn of 0, 31.2, 62.5 or 125 ppm 6 hr/day, 5 days per week for 104 weeks. ... 2 Year Study in Mice: Groups of 50 male and 50 female B6C3F1 mice were exposed to 2-butoxyethanol by inhalation at concn of 0, 62.5, 125 or 250 ppm 6 hr/day 5 days per week for 104 weeks. ... Conclusions: Under the conditions of these 2 yr inhalation studies, there was no evidence of carcinogenic activity of 2-butoxyethanol in male F344/N rats exposed to 31.2, 62.5 or 125 ppm. There was equivocal evidence of carcinogenic activity of 2-butoxyethanol in female F344/N rats based on incr incidences of benign or malignant pheochromocytoma (mainly benign) of the adrenal medulla. There was some evidence of carcinogenic activity of 2-butoxyethanol in male B6C3F1 mice based on incr incidences of hemangiosarcoma of the liver. ... There was some evidence of carcinogenic activity of 2-butoxyethanol in female B6C3F1 mice based on incr incidences of forestomach squamous cell papilloma or carcinoma (mainly papilloma).
[Toxicology & Carcinogenesis Studies of 2-Butoxyethanol in F344/N Rats and B6C3F1 Mice p.6 Technical Report Series No. 484 (2000) NIH Publication No. 00-3974 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709]**QC REVIEWED**

Non-Human Toxicity Values: ***

LD50 Rat oral 1.48 g/kg
[Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 239]**PEER REVIEWED**

LD50 Mouse oral 1.2 g/kg
[Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983. 315]**PEER REVIEWED**

LD50 Rabbit oral 0.32 g/kg
[Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983. 315]**PEER REVIEWED**

LD50 Guinea pig oral 1.2 g/kg
[Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983. 315]**PEER REVIEWED**

LD50 Rabbit dermal 400 mg/kg
[American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I,II, III. Cincinnati, OH: ACGIH, 1991. 162]**PEER REVIEWED**

Ecotoxicity Values:

LC50 Lepomis macrochirus 1490 ppm/96 hr. (Static bioassay in fresh water at 23 deg C, mild aeration applied after 24 hr).
[Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983. 315]**PEER REVIEWED**

LC50 Menidia beryllina 1250 ppm/96 hr (static bioassay in synthetic seawater at 23 deg C, mild aeration applied after 24 hr).
[Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983. 315]**PEER REVIEWED**

LC50 Crangon crangon (brown shrimp) 800 mg/l/48 hr (range: 600-1000 mg/l). /Conditions of bioassay not specified/
[Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983. 314]**PEER REVIEWED**

LC50 Poecilia reticulata (guppy) 983 ppm/7 day. /Conditions of bioassay not specified/
[Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983. 314]**PEER REVIEWED**

TSCA Test Submissions:

Teratogenicity was evaluated in mated Fischer 344 rats (30/group) exposed by inhalation to ethylene glycol mono-butyl ether (EGBE) at nominal concentrations (number of pregnant rats) of 0 (21), 100 (21), 200 (16) or 300 (24) ppm on gestation days (GD) 6-15 for 6 hrs/day. The rats were sacrificed on GD 21. There were significant differences observed between pregnant treated and control animals in the following: decreased maternal body weight gain and decrease in food consumption (all treated groups during exposure), increased food consumption (200 and 300 ppm groups, post-exposure), decreased water consumption (200 and 300 ppm, exposure period), decreased uterine and liver absolute weights (300 ppm), increased non-viable implantations and percent pre-implantation loss and decreased viable implantations and percent live implantations (300 ppm), increased incidence of ventricular septal defect, and absent and severely shortened innominate artery (300 ppm). There were no significant differences observed between pregnant treated and control animals in the following: post-exposure water consumption, weights of thymus and spleen, relative weights of uterus and liver, numbers of corpora lutea, and total implantations.
[Bushy Run Research Center, Union Carbide Corp.; Inhalation Teratological Potential of Ethylene Glycol Monobutyl Ether in the Rat. (1983), EPA Document No. 88-8300481, Fiche No. OTS0503697] **UNREVIEWED**

Teratogenicity was evaluated in pregnant Fischer 344 rats (36/group) exposed by inhalation to ethylene glycol mono-butyl ether (EGBE) at nominal concentrations of 0, 25, 50, 100 or 200 ppm on gestation days (GD) 6-15. The rats were sacrificed on GD 21. There were significant differences observed between treated and control animals in the following: increase in number of totally resorbed litters (200 ppm group), increased incidence of clinical observations including cold and pale extremities, abnormal tails, fur and urogenital areas stained, urogenital wetness and encrustation, occult blood (200 ppm), periocular wetness and perinasal encrustation (100 and 200 ppm), decreased body weight (200 ppm), decreased body weight gain (100 and 200 ppm, exposure period, 200 ppm post-exposure period also), decreased food consumption (100 and 200 ppm, exposure period), increased water consumption (100 ppm, post-exposure), decreased gravid uterine weight and increased relative and absolute spleen and relative kidney weights (200 ppm), decreased red blood cell count and mean corpuscular hemoglobin volume and increased mean corpuscular volume and corpuscular hemoglobin level (100 and 200 ppm), increased hemoglobin and hematocrit levels (200 ppm), decreased viable implants and percent live fetuses and increased non-viable implants and embryonic resorptions (200 ppm), increased number of litters with 1 or more cases of unossified skeletal elements (100 and 200 ppm) including anterior arch of the atlas and cervical centra, cervical arches, sternebrae, and proximal phalanges (200 ppm), unossified cervical centrum (100 ppm), and decreased incidence of bilobed cervical centrum 5 (100 and 200 ppm). There were no significant differences observed between treated and control animals in the following: pregnancy rates, early deliveries, dead fetuses, liver and thymus and absolute kidney weights, numbers of corpora lutea, total implants, dead fetuses, pre-implantation loss, fetal sex ratio, mean litter weight, external, visceral, skeletal or total malformations.
[Bushy Run Research Center, Union Carbide Corp.; A Teratologic Evaluation of Ethylene Glycol Monobutyl Ether in Fischer 344 Rats and New Zealand White Rabbits Following Inhalation Exposure. (1984), EPA Document No. 88-8400598, Fiche No. OTS0503697] **UNREVIEWED**

Teratogenicity was evaluated in pregnant New Zealand white rabbits (24/group) exposed by inhalation to ethylene glycol mono-butyl ether (EGBE) at nominal concentrations of 0, 25, 50, 100 or 200 ppm on gestation days (GD) 6-18. The rats were sacrificed on GD 29. There were significant differences observed between treated and control animals in the following: decreased maternal body weight (200 ppm group on GD 15), increased hemoglobin and hematocrit levels (100 ppm group), decreased gravid uterine weight (200 ppm), reduced number of total implants and viable implants/litter (200 ppm), increased number of litters with fusion of papillary muscles in left ventricle (100 ppm), and reduced ossification of sternebra 6 and rudimentary rib (200 ppm). There were no significant differences observed between treated and control animals in the following: maternal mortality, number of spontaneous abortions, pregnancy rates, maternal body weight gain, number of non-viable implants, pre-implantation losses, percent live fetuses, sex ratio, fetal body weights/litter, and number of fetuses or of litters with one or more affected fetuses with pooled external, visceral, skeletal or total malformations.
[Bushy Run Research Center, Union Carbide Corp.; A Teratologic Evaluation of Ethylene Glycol Monobutyl Ether in Fischer 344 Rats and New Zealand White Rabbits Following Inhalation Exposure. (1984), EPA Document No. 88-8400598, Fiche No. OTS0503697] **UNREVIEWED**

Acute oral toxicity was evaluated in 4 groups of 10 male albino rats (Wistar strain) administered PolySolv EB (ethylene glycol mono-n-butyl ether) by gavage at 0.67, 1.31, 2.56 and 5.0 g/kg dose levels. Mortality was observed within 14 days of dosing in 3 rats at the 1.31 g/kg dose level, 8 rats at the 2.56 g/kg dose level and all rats at the 5.0 g/kg dose level. The LD50 was calculated to be 1.59 g/kg with 95% confidence limits of 1.11 - 2.27 g/kg. Clinical observations include piloerection and lethargy at the 1.31 and 2.56 g/kg dose levels, flaccidity at the 2.56 g/kg dose level, and ataxia at the 5.0 g/kg dose level. Gross necropsy revealed dark liver and kidney in 3, and enlarged kidney in 4 rats at the 1.31 g/kg dose level; red intestine in 1 and blood in the bladder in all rats at the 2.56 g/kg dose level; blood in the bladder in all rats at the 5.0 g/kg dose level.
[Olin Corp.; Report on Acute Dermal Toxicity in Rabbits, (1976), EPA Doc. No. 86-890000171, Fiche. No. OTS0516708] **UNREVIEWED**

Acute oral toxicity was evaluated using 5 groups of 5 Charles River COBS male rats administered ethlyene glycol mono-n-butyl ether by gavage (dose levels not reported). Mortality occurred within 14 days after dosing, but the LD50 value was not reported. Clinical observations included inactivity, labored breathing, rapid respiration, anorexia, slight to moderate weakness, tremors and prostration. Gross necropsy of animals dying within 14 days of dosing revealed bloody urine, and blood in the stomach and intestine. These conditions were not observed in animals surviving through 14 days.
[Eastman Kodak Co.; Comparative Toxicity of Nine Glycol Ethers: I. Acute Oral LD50, (1981), EPA Doc. No. 86-890000206, Fiche No. OTS0516743] **UNREVIEWED**

Acute oral toxicity was evaluated using 5 groups of 5 Charles River COBS CD-1 male mice administered ethlyene glycol mono-n-butyl ether by gavage (dose levels not reported). Mortality occurred within 14 days after dosing, but the LD50 value was not reported. Clinical observations included inactivity, labored breathing, rapid respiration, anorexia, slight to moderate weakness, tremors and prostration. Gross necropsy of animals dying within 14 days of dosing revealed bloody urine and blood in the stomach and intestines. These conditions were not observed in animals surviving through 14 days.
[Eastman Kodak Co.; Comparative Toxicity of Nine Glycol Ethers: I. Acute Oral LD50, (1981), EPA Doc. No. 86-890000206, Fiche No. OTS0516743] **UNREVIEWED**

Acute oral toxicity was evaluated in groups of male and female Sherman rats (total number not reported) administered single doses of a 10% water dilution of butyl Cellosolve (ethylene glycol mono-n-butyl ether) by gavage (number of dose levels not reported). Mortality was observed within 14 days of dosing. The oral LD50 value for males was calculated (using Thompson's method) to be 2.9 g/kg, and for females, 2.3 g/kg. Clinical observations included sluggishness, rough coat, prostration and narcosis. Gross necropsy revealed congested or hemorrhagic lungs, mottled liver, congested kidneys and bloody urine.
[Union Carbide Corp.; Butyl Cellosolve: I. Acute and Subacute Toxicity, (1984), EPA Doc. No. 86-890000263, Fiche No. OTS0516797] **UNREVIEWED**

Acute oral toxicity was evaluated in groups of 5 rats (sex and strain not reported) administered single doses (method of administration not reported) of ethylene glycol n-butyl ester ether at dose levels of 0.252, 0.5, and 1.0 g/kg. Mortality was observed within 4 days of dosing in 3 animals at 0.5 g/kg and 2 at 1.0 mg/kg; the LD50 was 0.47 g/kg. Clinical observations included drowsiness and blood in the urine. Gross necropsy findings were not reported.
[Dow Chem Co,; Results of Rang Finding Toxicological Tests on Dowanol EB (sanitized), (1959), EPA Doc. No. 86-890001175S, Fiche No. OTS0520315] **UNREVIEWED**

Acute oral toxicity was evaluated in groups of 5 male Wistar rats administered single doses of butyl oxide by oral gavage at dose levels of 1.25, 2.50, 5.0, and 10.0 ml/kg of body weight. Mortality was observed within 1 day of dosing in 2 animals of the 2.50 ml/kg group, and in 5 rats of each of the 5.0 and 10.0 ml/kg groups; the LD50 was 2.68 ml/kg of body weight. Clinical observations included bloody saliva, sluggishness, difficult breathing and an unsteady gait. Gross necropsy revealed dark livers, stomach distention, red kidneys and adrenals, and blood was found in the intestines.
[Bushy Run Research Ctr.; Butyl Cellosolve Range Finding Toxicity Studies with Attachments and Cover Sheet and Letter Dated 060689, (1980), EPA Doc. 86-890000938, Fiche No. OTS0520376] **UNREVIEWED**

Acute oral toxicity was evaluated in 5 groups of 3 female CDF Fischer-344 rats receiving ethylene glycol mono-n-butyl ether by oral gavage at dose levels of 130, 250, 300, 500, 1000, or 2000 mg/kg. Mortality was observed at the 2 highest dose levels. The oral LD50 ranged from 1000 and 2000 mg/kg. Clinical observations included staining of perineal region, rough hair coat, lethargy, rapid shallow breathing and palpebral closure. Gross necropsy findings were not reported.
[Dow Chemical Co.; Dowanol EB Crude: Acute Toxicological Properties and Industrial Handling Hazards With Attachment, (1981), EPA Doc. 86-890001225, Fiche No. OTS0520735] **UNREVIEWED**

Acute dermal toxicity was evaluated in 4 groups of 4 New Zealand white rabbits (sex not reported) administered single doses of PolySolv EB (ethylene glycol mono-n-butyl ether) on clipped and abraded skin at dose levels of 0.25, 0.5, 1.0 and 2.0 g/kg. Mortalities were observed winthin 14 days of dosing in 0/4 rabbits at dose level 0.25 g/kg, 1/4 rabbits at the 0.5 g/kg dose level, and all animals at the two highest dose levels. The Litchfield and Wilcoxon LD50 was calculated to be 0.58 g/kg with 95% confidence limits of 0.31 and 0.85 g/kg. Clinical observations include blood in the urine, yellow cornea, flaccidity, lacrimation and anorexia. Gross necropsy revealed blood in the bladder, as well as discolored liver, kidney and intestines.
[Olin Corp.; Report on Acute Dermal Toxicity in Rabbits, (1976), EPA Doc. No. 86-890000171, Fiche. No. OTS0516708] **UNREVIEWED**

Acute dermal toxicity was evaluated in rabbits (number, sex distribution and strain not reported) administered single doses (dose levels not reported) of 2-butoxyethanol by open application. The LD50 was 2.0 mL/kg (specific mortalities, clinical observations and gross necropsy not reported).
[Eastman Kodak Co.; Material Safety Data Sheet, Environmental Safety Data Sheet, and Acute Oral LD50 for 2-Butoxyethanol with Cover Letter Dated 04/19/89, (1988), EPA Doc. No. 86890000198, Fiche No. OTS0516735] **UNREVIEWED**

Acute dermal toxicity was evaluated in rabbits (sex and strain not reported) receiving dermal applications of ethylene glycol mono-n-butyl ether at dose levels of 0.2 g/kg (group of 10) or 0.252 g/kg (group of 4). Mortality was observed within 2 to 7 days of dosing in 4 animals of the 0.252 g/kg group. No mortalities were observed at the 0.2 g/kg dose level. A dermal LD50 was not reported. Clinical observations included slight initial weight loss and slight to moderate irritation of the skin at both dose levels. Gross necropsy results were not reported.
[Dow Chem Co,; Results of Range Finding Toxicological Tests on Dowanol EB (sanitized), (1959), EPA Doc. No. 86-890001175S, Fiche No. OTS0520315] **UNREVIEWED**

Acute dermal toxicity was evaluated in groups of 4 male New Zealand white rabbits receiving single applications of butyl oxide to clipped intact skin of the trunk at dose levels of 0.5 and 1.0 ml/kg body weight. Mortality was observed within 1 to 2 days of dosing in 1 animal of the 0.5 ml/kg group and in all animals exposed to 1.0 ml/kg body weight. The LD50 was 0.630 ml/kg body weight (95% confidence limit = 0.386 to 1.03 ml/kg). Erythema and necrosis were noted in the high dose groups. Gross necropsy revealed included blood in the urine, orange-red colored lungs and livers, dark colored spleens, dark red kidneys, orange colored peritoneal and intestines.
[Bushy Run Research Ctr.; Butyl Cellosolve Range Finding Toxicity Studies with Attachments and Cover Sheet and Letter Dated 060689, (1980), EPA Doc. 86-890000938, Fiche No. OTS0520376] **UNREVIEWED**

An acute inhalation toxicity study was conducted with groups of male and female albino Wistar rats (3/sex/group) receiving whole body exposure to the vapors of ethylene glycol monobutyl ether in a dynamic air flow chamber. The vapor was generated in a glass flask containing the test substance maintained at 20 +/- 1 degrees celsius. Maximum exposure was for 7 hours, but if deaths occurred during either the exposure period or observation period, exposures were repeated at shorter intervals. During the 7 hour exposure, no animals died, but 3 females and 1 male animals died between day 1 and day 3 of the 14 day observation period. Therefore the test was repeated, and two additional test were performed at exposure times of 1 and 3 hours. No deaths were reported for the 1 hour group rats and only one 3 hour exposed female animal died on the day 1 of the observation period. Post exposure observations were lethargy (7 & 3 hour group rats), blood in urine (all exposures), piloerection (7 & 3 hour), paleness of eyes and feet (all exposures) and necrosis at the ends of the tail (7 hour). Seven hour group males appeared to recover by day 11; 3 hour males by day 1 and females by days 6-8; and 1 hour males by day 1 and females by day 2. The theoretical saturated concentration of ethylene glycol monobutyl ether at 20 degrees celsius was calculated to be 617ppm and the concentrations by weight loss estimation were calculated to be 769, 771 and 828ppm for the 7, 3 and 1 hour exposure, respectively.
[Shell Toxicology Laboratory (Tunstall); Test Standardization: Inhalation Toxicity testing of 8 Chemical According to the OECD Inhalation Hazard Test, (1982), EPA Document No. 878212113, Fiche No. OTS0205969 ] **UNREVIEWED**

Acute 7-hour inhalation toxicity of different industrial formulations of ethylene glycol monobutyl ether (Dowanol EB, n-butyl oxitol - USA (BO-USA), and n-butyl oxitol - Europe (BO-Europe) was evaluated in 3 groups of 4 male albino rabbits (strain not reported) exposed to the nominal concentration of 410 ppm. A fourth group served as negative control. A 1-week observation period followed exposure. The number dead or moribund by group were 3, 1, and 4 in the Dowanol EB, BO-USA, and BO-Europe groups, respectively. Clinical signs reported were poor coordination and loss of equilibrium. Changes in body weight and necropsy results were not reported.
[Dow Chem Co.; Inhalation Toxicity Studies on Three Samples of Ethylene Glycol Monobutyl Ether (No Date), EPA Document No. 86-890001224, Fiche No. OTS0520734] **UNREVIEWED**

Acute 7-hour inhalation toxicity of different industrial formulations of ethylene glycol monobutyl ether (Dowanol EB, n-butyl oxitol - USA (BO-USA), and n-butyl oxitol - Europe (BO-Europe) was evaluated in 3 groups of 2 male beagle dogs exposed to the nominal concentration of 410 ppm. A fourth group served as negative control. A 1-week observation period followed exposure. No dogs died. The only clinical sign reported was salivation during exposure. No body weight changes are mentioned. No animals were sacrificed for necropsy.
[Dow Chem Co.; Inhalation Toxicity Studies on Three Samples of Ethylene Glycol Monobutyl Ether (No Date), EPA Document No. 86-890001224, Fiche No. OTS0520734] **UNREVIEWED**

Acute 7-hour inhalation toxicity of different industrial formulations of ethylene glycol monobutyl ether (Dowanol EB, n-butyl oxitol - USA (BO-USA), and n-butyl oxitol - Europe (BO-Europe) was evaluated in 3 groups of 8 male guinea pigs (strain not reported) exposed to 410 ppm (nominal). A fourth group served as negative control. A 1-week observation period followed exposure. No mortalities were observed. Clinical signs, changes in body weight, and necropsy results are not reported.
[Dow Chem Co.; Inhalation Toxicity Studies on Three Samples of Ethylene Glycol Monobutyl Ether (No Date), EPA Document No. 86-890001224, Fiche No. OTS0520734] **UNREVIEWED**

Acute toxicity was evaluated in groups of 4 female Sprague-Dawley rats receiving a single intraperitoneal injection of n-butyl Oxidol or Dowanol EB Glycol Ether (ethylene glycol monobutyl ether) at dose levels of 200, 252, 316, or 398 mg/kg bw, then observed for two weeks. The LD50 was 252-317 mg/kg bw. All treated rats had bloody urine and nasal porphryin secretion; those treated with the two higher doses of n-butyl Oxidol also displayed tremors. Surviving rats gained weight throughout the recovery period. The authors concluded that both types of ethylene glycol monobutyl ether have similar toxicity when injected intraperitoneally in rats.
[Dow Chemical Company; Toxicity Studies of N-Butyl Oxide and Dowanol EB Glycol Ether, (1972), EPA Document No. 86-890001223, Fiche No. OTS0520733] **UNREVIEWED**

The effects of ethylene glycol butyl ether (EGBE) at concentration of 0.05, 0.1, 0.25, 0.4, and 0.5% on in vitro human erythrocyte fragility was evaluated employing 0.68% sodium chloride and 37 degrees C incubation. Hemolytic activity was reported to be 1.5, 20.5 and 70.9% at EGBE concentrations of 0.25, 0.4 and 0.5% respectively. This activity was compared to the hemolysis activity of rat, rabbit and dog erythrocytes under the same conditions. Rat hemolytic activity was reported to be 2.5, 51.5 and 62.0% and rabbit activity was 2.8, 83.7, and 72.0% at EGBE concentrations of 0.25, 0.4 and 0.5% respectively. Dog hemolytic activity was 46.8, 36.2, 41.2 and 62.3% at EGBE concentrations of 0.05, 0.1, 0.4, and 0.5% respectively.
[Imperial Chemical Industries PLC Central Toxicology Laboratory; Ethylene Glycol Butyl Ether and Butoxyacetic acid: Their Effects on Erythrocyte Fragility in Four Species, (1985), EPA Document No. 40-8578134, Fiche No. OTS0512447] **UNREVIEWED**

Subchronic toxicity was evaluated in groups of 10 male Charles River COBS albino rats receiving once daily oral gavage doses of undiluted ethylene glycol monobutyl ether at dose levels of 222, 443, or 885 mg/kg body weight/day, 5 days a week for 6 weeks. Mortality was observed in 2 high dose group rats and 1 middle dose group rat during the treatment period. Clinical observations included lethargy, and red discolored urine. A dose dependent decrease in body weight gain observed throughout the treatment period was only statistically significant (ANOVA, p < 0.05) at the high dose level. Effects on hematological parameters included a dose dependent decrease in hemoglobin concentration, red blood cell count, and mean corpuscular hemoglobin concentrations (MCHC); hemoglobin concentrations and red blood cell counts were reduced (p < 0.05) at all doses, while MCHC was lower (p < 0.05) than control at the middle and high dose levels. Mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) showed a dose-dependent increase which was significant (p < 0.05) at all levels for MCH and at the middle and high dose levels for MCV. Slight but significant (p < 0.05) increases were seen in serum glutamic pyruvic transaminase in the high dose group, and alkaline phosphatase was significantly increased in the middle and high dose groups. Relative liver weights were increased (p < 0.05) at all dose levels, while relative weights of the kidneys, heart, brain and spleen were increased in the middle and high dose groups. Gross necropsy examination revealed darkened, enlarged spleens in the middle and high dose groups. Treatment related histopathology included hepatocytomegaly (in the high dose group); focal hemosiderin in livers (high and mid groups); and hyalin droplet degeneration, splenic congestion, minor hemosiderin accumulation in the proximal convoluted tubules of the kidney, hyperkeratosis and acanthosis in the stomach (in all groups).
[Eastman Kodak Company Toxicology Section; The Subchronic Oral Toxicity of Ethylene Glycol Monobutyl Ether in Male Rats, EPA Document No. 88-8300509, Fiche No. OTS0503697] **UNREVIEWED**

Subchronic oral toxicity was evaluated in 4 groups of 10 male rats (strain not reported) administered ethylene glycol monobutyl ether by gavage at dose levels of 0, 222, 443 and 885 mg/kg/day for 5 days/week over 6 weeks. Mortalities included 2 rats at the 885 mg/kg/day dose level and 1 rat at the 443 mg/kg/day level. Clinical observations included lethargy at the 443 and 885 mg/kg/day treatment levels, as well as rough coat and piloerection at the 885 mg/kg/day dose level. A dose-related weight reduction was observed, but reduced food consumption was significant (statistical test and significance level not reported) only at the 885 mg/kg/day dose level. Dose-related decreases in red blood cell count and in hemoglobin concentration were observed. Elevated liver weights, increased serum alkaline phosphatase concentration (443, 885 mg/kg/day) and increased serum glutamic pyruvic transaminase concentration (885 mg/kg/day) were observed. Serum glucose was reduced in rats at the 885 mg/kg/day treatment level. Gross necropsy revealed enlarged dark spleens at the 443 and 885 mg/kg/day treatment levels. Histopathological evaluation revealed hepatocytomegally and focal hemosiderin in the liver at the two highest dose levels, as well as hemosiderin in the kidney, splenic congestion, and hyperkeratosis and acanthosis in the stomach at all dose levels. Urinalysis was not reported.
[Eastman Kodak Co.; The Subchronic Oral Toxicity of Ethylene Glycol Monobutyl Ether in Male Rats; (1983); EPA Doc. No. 86-890000196, Fiche No. OTS0516733] **UNREVIEWED**

Subchronic oral toxicity was evaluated in 3 groups of 10 male albino Charles River rats administered diethylene glycol monomethyl ether by gavage at dose levels equivalent to 1/2, 1/4 and 1/8 of the acute LD50 (actual dose levels not reported) 5 days/week for 6 weeks. An additional group of 10 untreated rats was used as a negative control. Compound-related mortality was not observed. The only clinical sign of toxicity was bloody urine and blood around the nares in one rat at the highest dose level. Significant (p < 0.05) weight loss was observed only in rats at the highest treatment level. No treatment-related hematological or clinical biochemistry effects were reported. Reduction in relative testis weight was observed in rats at the highest dose level. Gross necropsy revealed no abnormalities in treated rats, but histopathologic examination revealed testicular atrophy.
[Eastman Kodak Co.; Comparative Toxicity of Nine Glycol Ethers: Six Weeks Repeated Dose Study; (1986); EPA Doc. No. 86-890000196, Fiche No. OTS0516733] **UNREVIEWED**

Subchronic toxicity was evaluated in groups of 10 male albino rats (CR, COBS, CD, BR) given doses of ethylene glycol mono-n-butyl ether equivalent to 0, 1/2, 1/4 or 1/8 of the acute oral LD50 for the test compound in rats (more specific information regarding doses was not reported), by oral gavage, 5 days/week for six weeks. No effect was noted on mortality. Food consumption and body weights were reduced only in rats from the high-dose group. Dose-related effects were seen on hematological parameters, but not serum chemistry. Relative spleen weights increased in rats from the mid- and high-dose groups, liver weights increased in rats from the high-dose group and smaller than normal thymuses were observed in two rats from the high-dose group. Rats given mid- or high-dose levels had bloody urine, lethargy, unkempt hair coats, piloerection, rales, slight weakness and inactivity. Diffuse hemorrhage of the thymus was observed in one high-dose rat. Rats given the test compound (response to specific dose levels was not reported) had hepatocytomegally, anisokaryosis, and lack of cytoplasmic basophilia in livers, and congestion and extramedullary hematopoiesis in spleens.
[Eastman Kodak Company; Comparative Toxicology of Nine Glycol Ethers: III. Six Weeks Repeated Dose Study, (1966), EPA Document No. 86-890000206, Fiche No. OTS0516743] **UNREVIEWED**

Subchronic toxicity was evaluated in groups of 10 male albino rats (CR, COBS, CD, BR) given doses of ethylene glycol mono-n-butyl ether equivalent to 0, 1/2, 1/4 or 1/8 of the acute oral LD50 for the test compound in rats (more specific information regarding doses was not reported), by oral gavage, 5 days/week for six weeks. No effect was noted on mortality. Food consumption and body weights were reduced only in rats from the high-dose group. Mean hemoglobin concentration and total erythrocyte count were reduced, and mean corpuscular hemoglobin was increased, in rats from all treatment groups. Rats from the mid- and high-dose groups had increased in mean corpuscular volume and decreased mean corpuscular hemoglobin concentration. Treatment did not alter serum chemistry. Relative spleen weights increased in rats from the mid- and high-dose groups, and liver weights increased and smaller than normal thymuses were observed in rats from the high-dose group. Rats given mid- or high-dose levels had bloody urine, lethargy, unkempt hair coats, piloerection, rales, slight weakness and inactivity. Diffuse hemorrhage of the thymus was observed in one high-dose animal. Rats given the test compound (response to specific dose levels was not reported) had hepatocytomegally, anisokaryosis, and lack of cytoplasmic basophilia in livers, and congestion and extramedullary hematopoiesis in spleens.
[Eastman Kodak Company; Comparative Toxicology of Nine Glycol Ethers: III. Six Weeks Repeated Dose Study, (1966), EPA Document No. 86-890000206, Fiche No. OTS0516743] **UNREVIEWED**

Subchronic dermal toxicity was evaluated in groups of 20 New Zealand White rabbits (10 male and 10 female) receiving occluded applications of ethylene glycol monobutyl ether at doses of 10, 50 or 150 mg/kg body weight, 5 days/week for 13 weeks. Mortality was observed in 1 low dose group female, 1 mid dose and 1 high dose group male during the treatment period. Clinical observations included red feces, red liquid material on cage lining, anorexia, congestion, nasal discharge, and emaciation. Slight to moderate erythema and edema, along with scaling and flaking were observed at the treatment site. Treatment related changes in food consumption, body weights, or organ to body weight ratios were not observed at any dose level. Additionally, the test article did not induce changes in hematology, or in serum chemistry parameters. Treatment related pathological effects were not observed on gross or microscopic examination of the adrenals, aorta bone, brain, epidymis, esophagus, eyes, gall bladder, heart, intestines, kidneys, liver, lung, lymph node, mammary gland, ovaries, pancreas, parathyroids, pituitary, prostate, sciatic nerve, seminal vesicles, skeletal muscle, spleen, stomach, submandibular salivary gland, testes, thyroids, thymus, tongue, trachea, urinary bladder, uterus, or vagina.
[WIL Research Laboratories, Inc.; 90-Day Subchronic Dermal Toxicity Study in Rabbits with Ethylene Glycol Monobutyl Ether (1983), EPA Document No. FYI-AX-0683-0178SU, Fiche No. OTS0000178-1] **UNREVIEWED**

Subchronic toxicity was evaluated in 3 female and 3 male New Zealand White rabbits exposed to unoccluded doses of diethylene glycol butyl ether as a 1.5% solution in distilled water at a level of 2.0 mg/kg/day for 28 days. There were no mortalities. Clinical observations included slight dermal reaction. Necropsy revealed compound-related abberations in none of the treated animals.
[Proctor and Gamble; Information on Diethylene Glycol (Mono) Butyl Ether (DGBE) Diethylene Glycol with Cover Letter Dated 052284, (1984), EPA Doc No 40-8478029, Fiche No OTS0512397] **UNREVIEWED**

Subchronic dermal toxicity was evaluated in 5 groups of 10 New Zealand White rabbits (1:1 sex ratio/group) exposed dermally under occlusive patches to 2-butoxyethanol at nominal dose levels of 0, 0.02, 0.1, 0.2, and 0.4 ml/kg for 6 hours/day, on 9 of 11 consecutive days. Residual test compound was removed with absorbant material, but not washed off, after each exposure. Animals were sacrificed after a 14-day observation period. No treatment-related mortality or ophthalmologic effects were observed. Dose-related progressive erythema, edema, and necrosis were observed at the site of application. Both hemoglobinuria and proteinuria were observed at the 2 highest dose levels, and both were reversible after cessation of dosing. Both reduced red blood cell count and a decrease over time of urinary hemoglobin were observed in the highest dose group. No treatment-related changes were observed in clinical chemistry, body weight, organ weight, or histopathologic data. A gross thickening of the skin at the site of treatment was observed.
[Bushy Run Res. Ctr.; Butyl Cellosolve 9-day Dermal Application to Rabbits (1980), EPA Document No. 86-890000168, Fiche No. OTS0516705] **UNREVIEWED**

Subchronic dermal toxicity was evaluated in 4 groups of 20 New Zealand White rabbits (1:1 sex ratio per group) dermally exposed to 0, 10, 50, and 150 mg/kg, respectively. Rabbits were dosed under an occlusive dressing for 6 hours/day, 5 days/week, over a 90-day period. It was not reported whether the site of application was washed after each 6-hour dosing. No treatment-related changes in mortality, clinical signs, food consumption rate, body weight, hematological parameters, serum chemistry, organ weights, gross pathological parameters, or histopathological parameters were observed.
[WIL Research Laboratories, Inc.; 90-Day Subchronic Dermal Toxicity Study in Rabbits with Ethylene Glycol Monobutyl Ether (1983), EPA Document No. 86-890000237, Fiche No. OTS0516772] **UNREVIEWED**

Subchronic dermal toxicity was evaluated in groups of 5 male and 5 female New Zealand White rabbits receiving daily dermal (occluded) applications of 1 ml/day of 0, 5, 25, 50, or 100% concentrations of butyl CELLOSOLVE for a total of 9 applications over an 11-day period. There were no treatment-related mortalities. Clinical observations included dermal irritation (necrosis, edema, and erythema). Females in the 100% (undiluted) butyl CELLOSOLVE group displayed significantly reduced (p < 0.05) body weights. Hematological examination revealed significant (p < 0.05) reductions in the mean erythrocyte counts, hemoglobin, and mean corpuscular hemoglobin concentrations and increased mean corpuscular hemoglobin in females administered the undiluted material. Urinalysis revealed hemoglobin in the urine (males at 100%), increased urinary protein levels (males and females at 100%), and the presence of blood (females at 50 and 100%). Clinical biochemical anlaysis was not reported. Gross necropsy findings included thickening of the skin of males at 100%. There were no treatment-related organ/body weight changes. Histopathological examination of the kidneys revealed interstitial nephritis and tubular changes in rabbits exposed to the undiluted material.
[Bushy Run Research Center; Butyl Cellosolve 9-Day Repeated Dermal Application to Rabbits with Attachments, Cover Sheet and Letter Dated 06/06/89, (1980), EPA Doc. No. 86-890000947, Fiche No. OTS0520385] **UNREVIEWED**

Subchronic inhalation toxicity was evaluated in 4 groups of Fischer 344 rats exposed by inhalation to ethylene glycol monomethyl ether (butyl CELLOSOLVE) at air concentrations of 0 ppm (15 female, 16 male), 20 ppm (8 female, 8 male), 86 ppm (8 female, 8 male), and 245 ppm (15 female, 16 male), respectively, for 6 hours/day for 9 days. Rats were sacrificed either shortly after the final exposure or after a 14-day observation period. No mortalities were observed. Audible respiration, nasal discharge, and red-stained urine were seen in the highest exposure group. Transient body weight gain decreases occurred in the 2 highest exposure groups. Increases were observed in the 245 ppm group in mean corpuscular volume, nucleated red cells, reticulocytes and lymphocytes (males only), and decreases were seen in erythrocyte count, hemoglobin, and mean corpuscular hemoglobin concentration. Groups exposed to 86 ppm showed an increase in mean corpuscular volume and a decrease in hemoglobin. After the 14-day observation period, only the leukocyte count recovered to control levels. The mean liver/body weight ratio was elevated in females and males of the 2 highest and in the highest exposure groups, respectively. The incidence of gross lesions was not treatment-related. Evaluations of treatment effects on urinalysis, clinical chemistry, and histopathology were not reported.
[Bushy Run Res. Ctr.; Butyl Cellosolve 9-Day Vapor Inhalation Study on Rats (1981), EPA Document No. 86-890000169, Fiche No. OTS0516706] **UNREVIEWED**

Subchronic inhalation toxicity was evaluated in 4 groups of 32 Fischer 344 rats (1:1 sex ratio per group) exposed by inhalation to ethylene glycol monomethyl ether (butyl CELLOSOLVE) at air concentrations of 0, 5, 25, and 77 ppm for 6 hours/day, 5 days/week over 13 weeks. An interim sacrifice of 6 rats of each sex was executed after 30 exposures. No treatment-related effects were observed in male rats at any exposure level, with respect to mortality, clinical signs (via the Irwin Screen Test), mean body weight, food consumption rate, clinical chemistry, urinalysis, hematology, gross necropsy, and histopathology. Females in the highest exposure group exhibited a transitory depression of weight gain in the first weeks of exposure, as well as minimal reductions in red blood cell count, hemoglobin, and hematocrit. No other treatment-related effects were observed in the females.
[Bushy Run Res. Ctr.; Butyl Cellosolve Rat 90-Day Inhalation Study (1981), EPA Document No. 86-890000170, Fiche No. OTS0516707] **UNREVIEWED**

Hemolysis was evaluated in vitro with human erythrocytes (suspended in veronal buffered isotonic saline) exposed to ethylene glycol butyl ether (EGBE) for 1 hour. The percent hemolysis for 0.1, 0.25, 0.4, or 0.5% EGBE was 0, 1.5, 20.5, and 70.9%, respectively.
[Central Toxicology Lab; Ethylene Glycol Butyl Ether and Butoxyacetic Acid: Their Effects on Erythrocyte Fragility in Four Species, (not reported), EPA Document No. 86-8900000727, Fiche No. OTS0521233] **UNREVIEWED**

Hemolysis was evaluated in vitro with rat erythrocytes (suspended in veronal buffered isotonic saline) exposed to ethylene glycol butyl ether (EGBE) for 1 hour. The percent hemolysis for 0.1, 0.25, 0.3, 0.4, and 0.5% EGBE was 0, 2.5, 0, 51.5, and 62%, respectively.
[Central Toxicology Lab; Ethylene Glycol Butyl Ether and Butoxyacetic Acid: Their Effects on Erythrocyte Fragility in Four Species, (not reported), EPA Document No. 86-8900000727, Fiche No. OTS0521233] **UNREVIEWED**

Hemolysis was evaluated in vitro with dog erythrocytes (suspended in veronal buffered isotonic saline) exposed to ethylene glycol butyl ether (EGBE) for 1 hour. The percent hemolysis for 0.05, 0.1, 0.4, and 0.5% EGBE was 46.8, 36.2, 41.2, and 62.3%, respectively.
[Central Toxicology Lab; Ethylene Glycol Butyl Ether and Butoxyacetic Acid: Their Effects on Erythrocyte Fragility in Four Species, (not reported), EPA Document No. 86-8900000727, Fiche No. OTS0521233] **UNREVIEWED**

Hemolysis was evaluated in vitro with rabbit erythrocytes (suspended in veronal buffered isotonic saline) exposed to ethylene glycol butyl ether (EGBE) for 1 hour. The percent hemolysis for 0.1, 0.25, 0.4, or 0.5% EGBE was 0, 2.8, 83.7, and 72.0%, respectively.
[Central Toxicology Lab; Ethylene Glycol Butyl Ether and Butoxyacetic Acid: Their Effects on Erythrocyte Fragility in Four Species, (not reported), EPA Document No. 86-8900000727, Fiche No. OTS0521233] **UNREVIEWED**

In an absorption study, the permeability of human abdominal skin to 2-butoxyethanol was measured in vitro using Franz-type glass diffusion cells. Epidermal layers from human skin were exposed for 8 hours to a solution containing radiolabeled test compound in the donor chamber and the appearance of radioactivity was measured in the receptor chamber. Damage to skin was calculated by comparing the water absorption rates of skin before and after exposure to the test compound. The rate of absorption of the test compound across human skin was 0.20 mg/cm2/hr. Exposure to the test chemical did not alter the permeability of skin to water.
[Central Toxicology Lab; 2-butylethanol, 2-ethoxyethanol, 2-ethoxyethyl acetate, 2-methoxyethanol, and 1-methoxypropan-2-ol: Absorption Through Human Skin In Vitro, (1982), EPA Document No. 86-890000943; Fiche No. OTS0520381] **UNREVIEWED**

In an absorption study, the permeability of human abdominal skin to 2-butoxyethanol was measured in vitro using Franz-type glass diffusion cells. Epidermal layers from human skin were exposed for 8 hours to a solution containing radiolabeled test compound in the donor chamber and the appearance of radioactivity was measured in the receptor chamber. Damage to skin was calculated by comparing the water absorption rates of skin before and after exposure to the test compound. The rate of absorption of the test compound across human skin was 0.20 mg/cm2/hr. Exposure to the test chemical did not alter the permeability of skin to water.
[Central Toxicology Lab; Glycol ethers (2-methoxyethanol, 2-ethoxyethanol, 2-butoxyethanol, 2-ethoxyethyl acetate, and 1-methoxypropan-2-ol: Relationships Between Human Skin Absorption and Inhaled Doses, (1982), EPA Document No. 86-890000944; Fiche No. OTS0520382] **UNREVIEWED**

Metabolism of Dowanol EB (ethylene glycol mono-n-butyl ether) was evaluated in vitro with an equine liver alcohol dehydrogenase assay obtained from