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KETONES

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Ketones are organic compounds with a carbonyl group attached to one carbon atom. Ketone peroxides have different toxicity and are discussed in a separate management.

Specific Substances

    A) CONSTITUTENTS OF THE GROUP
    1) Acetonyl acetone (2,5-hexanedione) (110-13-4)
    2) Acetophenone (phenyl methyl ketone, acetyl benzene) (98-86-2)
    3) Benzophenone (119-61-9)
    4) Cycloheptanone (502-42-1)
    5) Cyclohexanone (ketohexamethylene, pimelic ketone) (108-94-1)
    6) Cyclopentanone (120-92-3)
    7) Dibutyl Ketone (5-nonanone) (502-56-7)
    8) Diethyl ketone (DEK, dimethylacetone, 3-pentanone) (96-22-0)
    9) Diisobutyl ketone (isovalerone) (108-83-8)
    10) Ethyl butyl ketone (heptanone-3) (106-35-4)
    11) Ethyl-iso-amyl ketone (624-42-0)
    12) 2-Heptanone (110-53-0)
    13) Isophorone (3,5,5-trimethyl-2-cyclohexene-1-one) (78-59-1)
    14) Methyl butyl ketone (hexanone-2) (591-78-6)
    15) Methylcyclohexanone (583-60-8))
    16) Methyl ethyl ketone (MEK, butanone) (78-93-3)
    17) Methyl isobutyl ketone (MIBK, 4-methylpentanone-2) (108-10-1)
    18) Methyl-isopropenyl ketone (814-78-8)
    19) Methyl propyl ketone (ethyl acetone, pentanone-2) (107-87-9)
    20) 2-Octanone (111-13-7)
    21) 3-Octanone (106-68-3)
    22) Phenyl-ethyl ketone (93-55-0)
    23) Pulgeone (in pennyroyal oil)
    24) Trimethylnonanone (2,6,8-trimethylnonanone-4)
    25) KETONES, LIQUID, N.O.S.

Available Forms Sources

    A) USES
    1) Ketones are organic compounds with a carbonyl group attached to a carbon atom. They are a natural by-product of fatty acid metabolism and have industrial uses as solvents, polymer precursors and in pharmaceuticals. KETONE PEROXIDES are highly reactive and corrosive, and are discussed in a separate document.

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Ketones are organic compounds with a carbonyl group attached to a carbon atom. They are a natural by-product of fatty acid metabolism and have industrial uses as solvents, polymer precursors and in pharmaceuticals. KETONE PEROXIDES are highly reactive and corrosive, and are discussed in a separate document.
    B) TOXICOLOGY: Ketones cover a wide range of substances. There is no underlying common mechanism in which they exert toxic effects, though some have irritant properties.
    C) EPIDEMIOLOGY: Acute toxicity is rare. Several hundred calls are made annually to poison centers, but very few have any major effects.
    D) WITH POISONING/EXPOSURE
    1) INHALATION: Acute inhalation of ketones may cause varying effects, depending on the extent and duration of exposure. Some symptoms reported include mucous membrane irritation, nausea, vomiting, headache, vertigo, incoordination, CNS depression, and cardiorespiratory failure. However, in most cases, recovery is usually rapid without sequelae. Chronic exposures to six-carbon, linear chain ketones (methyl-n-butyl ketone, 2,5-hexanedione) metabolized to gamma-diketones are implicated in axonal neuropathy with secondary myelin damage. This manifests with peripheral neuropathy symptoms with paresthesias and muscle weakness.
    2) OCULAR: Splash exposures of ketones to the eyes may cause varying degrees of irritation, depending on the ketone. Ketone vapors may cause irritation and lacrimation.
    3) INGESTION: Oral irritation, nausea, vomiting, and metabolic acidosis may occur. Ingestion of significant amounts of ketones may cause respiratory depression. Pulmonary aspiration may result in a chemical pneumonitis.
    4) DERMAL: Skin exposures to ketones in liquid or vapor form may result in dermatitis and paresthesias of the affected areas. Contact urticaria has also been reported.
    0.2.20) REPRODUCTIVE
    A) Limited studies have generally documented little or no effect of ketones on reproduction in experimental animals. Human data is lacking. 2,5-Hexanedione has an effect on spermatogenesis in male experimental animals.
    0.2.21) CARCINOGENICITY
    A) No adequate human studies exist for the agents in this category.

Laboratory Monitoring

    A) Monitor vital signs and mental status.
    B) Monitor serum electrolytes, renal function, and liver enzymes in symptomatic patients.
    C) If pulmonary aspiration is suspected, pulse oximetry monitoring and studies such as a chest x-ray or an arterial blood gas may be useful.
    D) Plasma and urinary concentrations are not widely available or useful in overdose management.
    E) Urinary concentrations of various ketones or ketone metabolites (such as methyl ethyl ketone or cyclohexanol for cyclohexanone-exposed workers) have been used to monitor occupational ketone exposure.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) The mainstay of management of mild to moderate toxicity is decontamination and supportive care.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) For severe toxicity, treatment should be targeted towards symptoms. Recent ingestion of large amounts of ketones may benefit from orogastric aspiration. Patients with obtundation, seizures, significant altered mental status, or severe respiratory symptoms require early intubation. Metabolic acidosis can be treated with bicarbonate therapy, and severely ill patients may benefit from dialysis. INHALATION EXPOSURE: Administer oxygen and assist ventilation as needed. Inhaled beta-2 agonists and oral or parenteral corticosteroids can be used to treat bronchospasm. DERMAL EXPOSURE: Remove contaminated clothing and wash exposed areas thoroughly with soap and water. Treat dermal irritation or burns with standard topical therapy. Those experiencing a hypersensitivity reaction may require treatment with topical or systemic antihistamines and/or corticosteroids. EYE EXPOSURE: Irrigate eyes with copious amounts of room temperature water for at least 15 minutes. If irritation, pain, swelling, lacrimation or photophobia persist, perform a slit lamp examination.
    C) DECONTAMINATION
    1) PREHOSPITAL: GI decontamination is generally not recommended because of the risk of aspiration. Remove contaminated clothing and wash exposed skin. Irrigate exposed eyes.
    2) HOSPITAL: There is no evidence for the use of activated charcoal or gastric lavage. Orogastric aspiration can be considered for large or massive ingestions that have occurred recently. Remove contaminated clothing and wash exposed skin. Irrigate exposed eyes.
    D) AIRWAY MANAGEMENT
    1) In patients who develop severe respiratory issues or CNS depression, early intubation should be performed.
    E) ANTIDOTE
    1) None
    F) ENHANCED ELIMINATION PROCEDURE
    1) Although there are no specific cases of dialysis use for removing ketones, there is significant renal elimination of parent ketones and/or their corresponding alcohol or glucuronides conjugates.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Patients with unintentional exposures with minimal to no symptoms may be managed at home.
    2) OBSERVATION CRITERIA: Patients should be sent do a healthcare facility if their exposure to ketones was in a self-harm attempt or if they were symptomatic. They should be observed for 4 to 6 hours and be clearly improving or asymptomatic prior to discharge.
    3) ADMISSION CRITERIA: Patients with severe symptoms or those who are getting worse after an observation period of 4 or 6 hours should be admitted to the hospital. Depending on the severity of their symptoms, ICU admission may be warranted (eg, intubated patients). Patients should not be discharged until they are clearly improving or asymptomatic.
    4) CONSULT CRITERIA: Consult a medical toxicologist or poison center for patients with severe toxicity in whom the diagnosis is unclear. Physicians who practice occupational medicine may be useful for patients with workplace exposures to ketones. Toxicologists and poison centers are available to help in any cases.
    H) PITFALLS
    1) Ketones and ketone peroxides are 2 different types of exposures, though mixed exposures may occur. Ketone peroxides are highly reactive and corrosive and management of ketones verus ketone peroxides differ.
    I) TOXICOKINETICS
    1) Rapidly absorbed, minimal protein binding. Most are reduced to the corresponding alcohol and eliminated, in urine and expired air, as glucuronide conjugates. Both methyl-isobutyl ketone and n-hexane and its metabolite, 2-hexanone, are metabolized to 2,5-hexanedione. 2,5-hexanedione is thought to produce the characteristic neuropathy produced by these agents. In a case of a mixed ingestion of acetone, methyl ethyl ketone, and cyclohexanone, the half-life of acetone was 18 hours and the half-life of methyl ethyl ketone was 10 hours. Following inhalation, methyl ethyl ketone has a biphasic elimination curve with an initial half-life of 30 minutes and a terminal half-life of 81 minutes.
    J) DIFFERENTIAL DIAGNOSIS
    1) Other substances that may mimic ketone exposures include other irritant chemicals, other hydrocarbons, or neurotoxic substances.
    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 an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

    A) TOXICITY: Minimal toxic doses of ketones are variable and not well defined. Airborne concentrations greater 300 ppm of methyl ethyl ketone may result in discomfort and CNS depression. Methyl-isobutyl ketone produces irritation at an airborne concentration of 100 ppm. Immediately Dangerous To Life or Health Concentrations (IDLHs): Ethyl butyl ketone: 1000 ppm; Methyl (n-amyl) ketone: 800 ppm; Diisobutyl ketone: 500 ppm. NIOSH Pocket Guide RELs: Diethyl ketone: 200 ppm (705 mg/m(3)) TWA; Diisobutyl ketone: 25 ppm (150 mg/m(3)) TWA; methyl isobutyl ketone: 50 ppm (205 mg/m(3)) ST 75 ppm (300 mg/m(3)). ACGIH-TLV: The 8 hour exposure limit TLV-TWA: Methyl isobutyl ketone: 20 ppm; diethyl ketone: 200 ppm; ethyl butyl ketone: 50 ppm (230 mg/m(3)); methyl propyl ketone: 150 ppm.

Clinical Effects

Summary Of Exposure

    A) USES: Ketones are organic compounds with a carbonyl group attached to a carbon atom. They are a natural by-product of fatty acid metabolism and have industrial uses as solvents, polymer precursors and in pharmaceuticals. KETONE PEROXIDES are highly reactive and corrosive, and are discussed in a separate document.
    B) TOXICOLOGY: Ketones cover a wide range of substances. There is no underlying common mechanism in which they exert toxic effects, though some have irritant properties.
    C) EPIDEMIOLOGY: Acute toxicity is rare. Several hundred calls are made annually to poison centers, but very few have any major effects.
    D) WITH POISONING/EXPOSURE
    1) INHALATION: Acute inhalation of ketones may cause varying effects, depending on the extent and duration of exposure. Some symptoms reported include mucous membrane irritation, nausea, vomiting, headache, vertigo, incoordination, CNS depression, and cardiorespiratory failure. However, in most cases, recovery is usually rapid without sequelae. Chronic exposures to six-carbon, linear chain ketones (methyl-n-butyl ketone, 2,5-hexanedione) metabolized to gamma-diketones are implicated in axonal neuropathy with secondary myelin damage. This manifests with peripheral neuropathy symptoms with paresthesias and muscle weakness.
    2) OCULAR: Splash exposures of ketones to the eyes may cause varying degrees of irritation, depending on the ketone. Ketone vapors may cause irritation and lacrimation.
    3) INGESTION: Oral irritation, nausea, vomiting, and metabolic acidosis may occur. Ingestion of significant amounts of ketones may cause respiratory depression. Pulmonary aspiration may result in a chemical pneumonitis.
    4) DERMAL: Skin exposures to ketones in liquid or vapor form may result in dermatitis and paresthesias of the affected areas. Contact urticaria has also been reported.

Vital Signs

    3.3.3) TEMPERATURE
    A) HYPOTHERMIA may occur.

Heent

    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) SUMMARY: Splash contact causes irritation, which may be slight, moderate, or severe, depending on the specific ketone (Clayton & Clayton, 1981):
    a) SEVERE EYE IRRITANTS: May include 3-butyn-2-one, 3-pentyn-2-one, methyl isopropenyl ketone, 2,4-pentanedione, 2,5-hexanedione, and isophorone
    b) MODERATE EYE IRRITANTS: May include methyl ethyl ketone, methyl n-propyl ketone, mesityl oxide, methyl n-amyl ketone, 5-methyl-3-heptanone, cyclohexanone, and acetophenone.
    c) SLIGHT EYE IRRITANTS: May include 3-methyl-2-butanone, methyl n-butyl ketone, methyl isobutyl ketone, methyl n-amyl ketone, methyl isoamyl ketone, ethyl n-butyl ketone, di-n-propyl ketone, 2-octanone, diisobutyl ketone, and trimethyl nonanone.
    2) LACRIMATION: Lacrimation and ocular irritation may occur following exposure to high vapor concentrations (Parmeggiani, 1983).
    3) CORNEAL DAMAGE: Eye exposure may result in ocular pain and corneal damage. Direct contact of the liquid with eyes may cause corneal damage.
    4) ANIMAL DATA
    a) Retinal injury has been reported in rats exposed to 2,5-hexanedione, with injury to both sensory (Backstrom & Collins, 1992) and ganglion (Pasternak et al, 1985) cells.
    b) Subchronic administration of 2,5-hexanedione in the macaque produced an apparently reversible optic neuropathy (Lynch et al, 1989).
    3.4.5) NOSE
    A) WITH POISONING/EXPOSURE
    1) IRRITATION: Ketones are generally strong irritants of mucous membranes, especially of the nose. Sneezing and detection of a strong odor may occur.
    a) HUMAN STUDY: Detection of a strong odor and throat irritation resulted from single, 4 hour exposures to 100 ppm of methyl isobutyl ketone (MIBK), 200 ppm of methyl ethyl ketone (MEK), or from combined exposure to these chemicals at airborne concentrations of 50 ppm (MIBK) and 100 ppm (MEK) (Dick et al, 1992).
    3.4.6) THROAT
    A) WITH POISONING/EXPOSURE
    1) IRRITATION: The ketones are generally strong irritants of mucous membranes, especially of the mouth, and can cause sore throat, coughing, and salivation.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) TACHYARRHYTHMIA
    1) WITH POISONING/EXPOSURE
    a) Tachycardia may occur.

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) PULMONARY ASPIRATION
    1) WITH POISONING/EXPOSURE
    a) Direct pulmonary aspiration of liquid ketones can result in chemical pneumonitis.
    B) ACUTE RESPIRATORY INSUFFICIENCY
    1) WITH POISONING/EXPOSURE
    a) Exposure can produce an anesthetic type of respiratory depression, dyspnea, and gasping.
    b) CASE REPORT: Respiratory depression which necessitated endotracheal intubation developed in a chronic ethanol abuser who ingested 240 mL of a cleaning solution containing methanol and methyl ethyl ketone (Price et al, 1994).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM DEFICIT
    1) WITH POISONING/EXPOSURE
    a) Ingestion or inhalation of high concentrations of ketones can result in CNS depression. Effects include headache, dizziness, fainting, tremor, incoordination, decreased body temperature, depressed respirations and heart rate, dyspnea, gasping, coma, and death.
    b) Trimethylnonanone is a possible exception and may not cause CNS depression.
    c) CASE REPORT: Ingestion of 240 mL of a cleaning solution containing methyl ethyl ketone and methanol resulted in significant CNS and respiratory depression. The adult case was aroused only with painful stimuli and required endotracheal intubation. Blood levels of methyl ethyl ketone and methanol were 124 mg/dL and 202 mg/dL, respectively. Blood levels of 2-butanol (24 mg/dL) were also detected (Price et al, 1994).
    B) SECONDARY PERIPHERAL NEUROPATHY
    1) WITH POISONING/EXPOSURE
    a) Peripheral neuropathy has been reported in humans exposed to methyl-n-butyl ketone (Mendell et al, 1974), 2,5-hexanedione (Couri & Milks, 1985), and methyl ethyl ketone (Parmeggiani, 1983) combined with exposure to toluene (Welch et al, 1991), n-hexane (Altenkirch et al, 1982) and methyl n-butyl ketone (Krasavage et al, 1981). Methyl-n-butyl ketone is highly neurotoxic in humans (Bos et al, 1991).
    1) Experimental animal studies have demonstrated that methyl ethyl ketone alone does not cause peripheral neuropathy, but potentiates the central and peripheral neuropathy caused by n-hexane (Altenkirch et al, 1978), 2,5-hexanedione (Ralston et al, 1985), methyl n-butyl ketone, and possibly other neurotoxic solvents (Hathaway et al, 1991; Krasavage et al, 1981).
    b) The principal clinical manifestations are bilateral paresthesias and muscle weakness which principally involves the arms and legs. As shown in experimental animal studies, the effects are due to nerve degeneration and secondary myelin damage. Only six-carbon, linear chain ketones metabolized to gamma-diketones (ie, methyl n-butyl ketone) are implicated (Krasavage et al, 1981).
    C) PARESTHESIA
    1) WITH POISONING/EXPOSURE
    a) Skin exposure to vapor or liquid may result in paresthesia in exposed areas.
    D) LACK OF EFFECT
    1) HUMAN STUDY: Single 4 hour exposures to 100 ppm of methyl isobutyl ketone (MIBK), 200 ppm of methyl ethyl ketone (MEK), or combined exposure to these chemicals (50 ppm MIBK, 100 ppm MEK) did not result in significant effects on neurobehavioral performance in males and females, combined. Minor, sex-associated deficits in 3 tests correlated with increased blood levels of MEK and/or MIBK (Dick et al, 1992).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) VOMITING
    1) WITH POISONING/EXPOSURE
    a) Inhalation may cause nausea and vomiting (Browning, 1965; Parmeggiani, 1983).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER DAMAGE
    1) WITH POISONING/EXPOSURE
    a) Ketones have been shown to potentiate the hepatotoxic effects of halogenated hydrocarbons (ie, chloroform and carbon tetrachloride) (Plaa & Vezina, 1987). This includes acetone, methyl ethyl ketone, and methyl isobutyl ketone (Raymond & Plaa, 1996) and is evidently due to cytochrome p-450 activation (Raymond & Plaa, 1995).
    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEPATOCELLULAR DAMAGE
    a) RATS: Ketone pretreatment has potentiated chloroform-associated hepatotoxicity in a rat model (Hewitt & Brown, 1984).
    2) HEPATOCELLULAR INJURY
    a) ANIMAL DATA: High-level exposure to a variety of ketones has produced hepatocellular injury with elevated transaminases and/or hepatic enlargement. Specific examples include benzophenone (Burdock et al, 1991); methyl-isobutyl ketone (Phillips et al, 1987); methyl isoamyl ketone (Katz et al, 1986); and methyl-ethyl ketone (Cavender et al, 1983).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ABNORMAL RENAL FUNCTION
    1) WITH POISONING/EXPOSURE
    a) Acute human exposure to phenyl-ethyl ketone during clean up of a spill resulted in acute bladder dysfunction with urinary retention and pain for several hours in one male and one female employee. Exposure was thought to be by inhalation alone, as protection was provided for other routes of entry (HSDB , 1998).
    3.10.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) ABNORMAL RENAL FUNCTION
    a) RATS: Ketone pretreatment has potentiated chloroform-associated nephrotoxicity in a rat model (Hewitt & Brown, 1984).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Metabolic acidosis has been reported in a 47-year-old woman with chickenpox who mistakenly ingested butanone (methyl ethyl ketone). The patient's plasma butanone concentration was 13.2 millimoles/L (95 mg/dL) and the plasma lactate concentration on admission was increased at 14.3 millimoles/L (129 mg/dL) (Kopelman & Kalfayan, 1983).
    b) CASE REPORT: Absence of a significant anion gap metabolic acidosis was reported in a chronic ethanol abuser who ingested 240 mL of a cleaning fluid containing methanol and methyl ethyl ketone. Naproxen (10 g) was also ingested.
    1) Respiratory depression was present and arterial blood gas results were consistent with respiratory acidosis (pH 7.25; pCO2 49 mm Hg). An osmolar gap of 99 mOsmols/L was reported. Blood levels of methyl ethyl ketone and methanol were 202 mg/dL and 124 mg/dL, respectively. Blood levels of 2-butanol (24 mg/dL) were also detected (Price et al, 1994).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) DERMATITIS
    1) WITH POISONING/EXPOSURE
    a) Skin exposure to vapor or liquid may result in dermatoses and paraesthesia in exposed areas.
    B) URTICARIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Contact urticaria has been reported after chronic exposure to methyl ethyl ketone (Varigos & Nurse, 1986).

Immunologic

    3.19.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) METABOLIC DISORDER
    a) In rats, acute, single oral exposures to 2,5-hexanedione at 0.1 to 0.5 times the LD50 resulted in reversible thymic atrophy which was not seen with repeated exposures over 1 week, suggesting recovery in spite of continued dosing. Alterations in the lymphoid populations of various lymphatic organs were noted under both acute and subchronic exposure conditions (Upreti et al, 1986).
    b) Similar changes in cell population were noted in mice receiving similar doses. In addition, decreases in delayed type hypersensitivity, plaque-formation, phagocytosis by adherent cells, and resistance to endotoxin shock were noted (Upreti & Shanker, 1987).
    c) In vitro exposure of human polymorphonuclear leukocytes to 2,5-hexanedione, but not to 2-hexanone or 2-hexanol, resulted in altered chemotaxis but not altered chemiluminescence, evidently as a result of changes in cell membrane fluidity (Governa et al, 1986).

Reproductive

    3.20.1) SUMMARY
    A) Limited studies have generally documented little or no effect of ketones on reproduction in experimental animals. Human data is lacking. 2,5-Hexanedione has an effect on spermatogenesis in male experimental animals.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) Cyclohexanone administration to pregnant rats by inhalation on days 5 to 20 of gestation at airborne concentrations up to 500 ppm produced a slight increase in rudimentary ribs, but no other significant skeletal or other alterations were noted and the authors felt it unlikely that this compound was teratogenic (Samimi et al, 1989). Another single generation inhalation study in rats was negative at exposure levels as high as 1400 ppm (HSDB , 1998). In mice exposed to up to 1400 ppm, increased visceral malformations were seen, but maternal toxicity was present and the study was felt to be negative overall (HSDB , 1998).
    2) Methyl-isobutyl ketone exposure by inhalation in pregnant rats and mice during organogenesis at airborne concentrations up to 3000 ppm produced no treatment related effects (Tyl et al, 1987).
    3) A single generation teratogenicity study with methyl ethyl ketone was negative in rats (HSDB , 1998). In mice, inhalation exposures up to 3000 ppm produced no malformations but did induce fetal weight loss and a minor trend to misaligned sternebrae (considered a non-specific finding) (Schwetz et al, 1991).
    4) A single generation inhalation teratology study of isophorone in rats and mice at airborne concentrations up to 115 ppm revealed no treatment-related effects (HSDB , 1998).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) 2,5-Hexanedione reduced the fertility of female mice with long-term administration, evidently due to an effect on the number of growing oocytes (Siracusa et al, 1992).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) No adequate human studies exist for the agents in this category.
    3.21.3) HUMAN STUDIES
    A) CARCINOMA
    1) In a study of MEK dewaxing plant workers and isopropanol production workers, overall cancer mortality was decreased in the MEK group. In the combined data there was a significant increase in buccal and nasopharyngeal cancers and a decreased incidence of lung neoplasms (Alderson & Rattan, 1980).
    2) Workers exposed to MEK in a lubricant dewaxing facility had a non-significant increase in prostate cancer risk. These individuals had multiple chemical exposures in addition to MEK, and risk did not appear to be associated specifically with MEK exposure (Wen et al, 1985).
    3.21.4) ANIMAL STUDIES
    A) CARCINOMA
    1) Isophorone was associated with possible increases in hepatocellular cancers and mesenchymal tumors of the integument in male mice, with an increase in lymphoma in low dose, but not high dose animals (ie, no dose-response relationship). In rats, males had increased carcinomas of the preputial gland. No associations were noted in the females of either species at dosages up to 500 mg/kg/day, 5 days per week, for 103 weeks.

Genotoxicity

    A) Extremely limited data are available for this class of agents. For many specific ketones, no data are available. Some studies report positive findings, but this category of agents appears to be generally non-mutagenic or only weakly mutagenic.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and mental status.
    B) Monitor serum electrolytes, renal function, and liver enzymes in symptomatic patients.
    C) If pulmonary aspiration is suspected, pulse oximetry monitoring and studies such as a chest x-ray or an arterial blood gas may be useful.
    D) Plasma and urinary concentrations are not widely available or useful in overdose management.
    E) Urinary concentrations of various ketones or ketone metabolites (such as methyl ethyl ketone or cyclohexanol for cyclohexanone-exposed workers) have been used to monitor occupational ketone exposure.
    4.1.2) SERUM/BLOOD
    A) Plasma concentrations are not widely available or useful in overdose management.
    B) Monitor serum electrolytes, renal function, and liver enzymes in symptomatic patients.
    4.1.3) URINE
    A) Urinary concentrations are not widely available or useful in overdose management.
    B) Urinary concentrations of various ketones or ketone metabolites (such as methyl ethyl ketone or cyclohexanol for cyclohexanone-exposed workers) have been used to monitor occupational ketone exposure.
    C) Reported assays of some possible utility include urinary MEK in MEK-exposed workers (Yoshikawa et al, 1995; Ong et al, 1991b; Imbriani et al, 1989) and urinary cyclohexanol in cyclohexanone-exposed workers (Ong et al, 1991a).
    4.1.4) OTHER
    A) OTHER
    1) Monitor vital signs and mental status.
    2) If pulmonary aspiration is suspected, pulse oximetry monitoring and studies such as a chest x-ray or an arterial blood gas may be useful.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with severe symptoms or those who are getting worse after an observation period of 4 or 6 hours should be admitted to the hospital. Depending on the severity of their symptoms, ICU admission may be warranted (eg, intubated patients). Patients should not be discharged until they are clearly improving or asymptomatic.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Patients with unintentional exposures with minimal to no symptoms may be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist or poison center for patients with severe toxicity in whom the diagnosis is unclear. Physicians who practice occupational medicine may be useful for patients with workplace exposures to ketones. Toxicologists and poison centers are available to help in any cases.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients should be sent do a healthcare facility if their exposure to ketones was in a self-harm attempt or if they were symptomatic. They should be observed for 4 to 6 hours and be clearly improving or asymptomatic prior to discharge.

Monitoring

    A) Monitor vital signs and mental status.
    B) Monitor serum electrolytes, renal function, and liver enzymes in symptomatic patients.
    C) If pulmonary aspiration is suspected, pulse oximetry monitoring and studies such as a chest x-ray or an arterial blood gas may be useful.
    D) Plasma and urinary concentrations are not widely available or useful in overdose management.
    E) Urinary concentrations of various ketones or ketone metabolites (such as methyl ethyl ketone or cyclohexanol for cyclohexanone-exposed workers) have been used to monitor occupational ketone exposure.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) GI decontamination is generally not recommended because of the risk of aspiration. Remove contaminated clothing and wash exposed skin. Irrigate exposed eyes.
    6.5.2) PREVENTION OF ABSORPTION
    A) There is no evidence for the use of activated charcoal or gastric lavage. Orogastric aspiration can be considered for large or massive ingestions that have occurred recently.
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) The mainstay of management of mild to moderate toxicity is decontamination and supportive care.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) For severe toxicity, treatment should be targeted towards symptoms. Recent ingestion of large amounts of ketones may benefit from orogastric aspiration. Patients with obtundation, seizures, significant altered mental status, or severe respiratory symptoms require early intubation. Metabolic acidosis can be treated with bicarbonate therapy, and severely ill patients may benefit from dialysis. INHALATION EXPOSURE: Administer oxygen and assist ventilation as needed. Inhaled beta-2 agonists and oral or parenteral corticosteroids can be used to treat bronchospasm. DERMAL EXPOSURE: Remove contaminated clothing and wash exposed areas thoroughly with soap and water. Treat dermal irritation or burns with standard topical therapy. Those experiencing a hypersensitivity reaction may require treatment with topical or systemic antihistamines and/or corticosteroids. EYE EXPOSURE: Irrigate eyes with copious amounts of room temperature water for at least 15 minutes. If irritation, pain, swelling, lacrimation or photophobia persist, perform a slit lamp examination.
    B) MONITORING OF PATIENT
    1) Monitor vital signs and mental status.
    2) Monitor serum electrolytes, renal function, and liver enzymes in symptomatic patients.
    3) If pulmonary aspiration is suspected, pulse oximetry monitoring and studies such as a chest x-ray or an arterial blood gas may be useful.
    4) Plasma and urinary concentrations are not widely available or useful in overdose management.
    5) Urinary concentrations of various ketones or ketone metabolites (such as methyl ethyl ketone or cyclohexanol for cyclohexanone-exposed workers) have been used to monitor occupational ketone exposure.
    C) ACIDOSIS
    1) METABOLIC ACIDOSIS: Treat severe metabolic acidosis (pH less than 7.1) with sodium bicarbonate, 1 to 2 mEq/kg is a reasonable starting dose(Kraut & Madias, 2010). Monitor serum electrolytes and arterial or venous blood gases to guide further therapy.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    6.9.2) TREATMENT
    A) IRRITATION SYMPTOM
    1) Treat dermal irritation or burns with standard topical therapy. Patients developing dermal hypersensitivity reactions may require treatment with systemic or topical corticosteroids or antihistamines.
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

Abstracts

Case Reports

    A) ADULT
    1) A 47-year-old woman accidentally ingested methyl ethyl ketone. On presentation, she was comatose and hyperventilating. There was severe metabolic acidosis (pH 7.19), and blood glucose was 293 mg/dL. A sodium bicarbonate infusion was started, which resulted in obvious clinical improvement. The patient regained consciousness within 12 hours and made a complete and uneventful recovery (Kopelman & Kalfayan, 1983).

Range Of Toxicity

Summary

    A) TOXICITY: Minimal toxic doses of ketones are variable and not well defined. Airborne concentrations greater 300 ppm of methyl ethyl ketone may result in discomfort and CNS depression. Methyl-isobutyl ketone produces irritation at an airborne concentration of 100 ppm. Immediately Dangerous To Life or Health Concentrations (IDLHs): Ethyl butyl ketone: 1000 ppm; Methyl (n-amyl) ketone: 800 ppm; Diisobutyl ketone: 500 ppm. NIOSH Pocket Guide RELs: Diethyl ketone: 200 ppm (705 mg/m(3)) TWA; Diisobutyl ketone: 25 ppm (150 mg/m(3)) TWA; methyl isobutyl ketone: 50 ppm (205 mg/m(3)) ST 75 ppm (300 mg/m(3)). ACGIH-TLV: The 8 hour exposure limit TLV-TWA: Methyl isobutyl ketone: 20 ppm; diethyl ketone: 200 ppm; ethyl butyl ketone: 50 ppm (230 mg/m(3)); methyl propyl ketone: 150 ppm.

Maximum Tolerated Exposure

    A) Immediately Dangerous To Life or Health Concentrations (IDLHs): Ethyl butyl ketone: 1000 ppm; Methyl (n-amyl) ketone: 800 ppm; Diisobutyl ketone: 500 ppm (National Institute for Occupational Safety and Health, 2007).
    B) NIOSH Pocket Guide RELs: Diethyl ketone: 200 ppm (705 mg/m(3)) TWA; Diisobutyl ketone: 25 ppm (150 mg/m(3)) TWA; methyl isobutyl ketone: 50 ppm (205 mg/m(3)) ST 75 ppm (300 mg/m(3)) (National Institute for Occupational Safety and Health, 2007)
    C) ACGIH-TLV: The 8 hour exposure limit TLV-TWA: Methyl isobutyl ketone: 20 ppm; diethyl ketone: 200 ppm; ethyl butyl ketone: 50 ppm (230 mg/m(3)); methyl propyl ketone: 150 ppm (American Conference of Governmental Industrial Hygienists, 2010).
    D) Exposure to airborne concentrations greater than 300 ppm of methyl ethyl ketone may result in discomfort and CNS depression. Methyl-isobutyl ketone produces irritation at an airborne concentration of 100 ppm (Hjelm et al, 1990).

Pharmacology Toxicology

Toxicologic Mechanism

    A) Animals exposed to HIGH concentrations of most of the ketones sustained damage to lungs (emphysema), liver, kidneys, and brain (edema), but such has not been found in long term occupational epidemiologic studies in humans.

References

General Bibliography

    1) Alderson MR & Rattan NS: Mortality of workers on an isopropyl alcohol plant and two MEK dewaxing plants. Br J Ind Med 1980; 37:85-89.
    2) Allard EK, Blanchard KT, & Boekelheide K: Exogenous stem cell factor (SCF) compensates for altered endogenous SCF expression in 2,5-hexanedione-induced testicular atrophy in rats. Biol Reprod 1996; 55:185-193.
    3) Altenkirch H, Stoltenburg G, & Wagner HM: Experimental studies on hydrocarbon nephropathies induced by methyl-ethyl-ketone (MEK). J Neurol 1978; 219:159-170.
    4) Altenkirch H, Wagner HM, & Stoltenburg-Didinger G: Potentiation of hexacarbon-neurotoxicity by methyl-ethyl-ketone (MEK) and other substances: clinical and experimental aspects. Neurobehav Toxicol Teratol 1982; 4:623-627.
    5) American Conference of Governmental Industrial Hygienists : ACGIH 2010 Threshold Limit Values (TLVs(R)) for Chemical Substances and Physical Agents and Biological Exposure Indices (BEIs(R)), American Conference of Governmental Industrial Hygienists, Cincinnati, OH, 2010.
    6) Backstrom B & Collins VP: The effects of 2,5-hexanedione on rods and cones of the retina of albino rats. Neurotoxicology 1992; 13:199-202.
    7) Basler A: Aneuploidy-inducing chemicals in yeast evaluated by the micronucleus test. Mutat Res 1986; 174:11-13.
    8) Boekelheide K & Hall SJ: 2,5-Hexanedione exposure in the rat results in long-term testicular atrophy despite the presence of residual spermatogonia. J Androl 1991; 12:18-26.
    9) Boekelheide K: Rat testis during 2,5-hexanedione intoxication and recovery. I. Dose response and the reversibility of germ cell loss. Toxicol Appl Pharmacol 1988; 92:18-27.
    10) Bos PM, de Mik G, & Bragt PC: Critical review of the toxicity of methyl n-butyl ketone: risk from occupational exposure. Am J Ind Med 1991; 20:175-194.
    11) Browning E: Toxicity and Metabolism of Industrial Solvents, Elsevier, Amsterdam, The Netherlands, 1965, pp 412-458.
    12) Burdock GA, Pence DH, & Ford RA: Safety evaluation of benzophenone. Food Chem Toxicol 1991; 29:741-750.
    13) Burgess JL, Kirk M, Borron SW, et al: Emergency department hazardous materials protocol for contaminated patients. Ann Emerg Med 1999; 34(2):205-212.
    14) Cavender FL, Casey HW, & Salem H: A 90-day vapor inhalation toxicity study of methyl ethyl ketone. Fundam Appl Toxicol 1983; 3:264-270.
    15) Clayton GD & Clayton FE: Patty's Industrial Hygiene and Toxicology, Vol 2A, Toxicology, 3rd ed, John Wiley & Sons, New York, NY, 1981.
    16) Couri DC & Milks MM: Hexacarbon neuropathy: tracking a toxin. Neurotoxicol 1985; 6:65-72.
    17) Cunningham J, Sharkawi M, & Plaa GL: Pharmacological and metobolic interactions between ethanol and methyl n-butyl ketone, methyl isobutyl ketone, methyl ethyl ketone, or acetone in mice. Fundam Appl Toxicol 1989; 13:102-109.
    18) Dick RB, Krieg EF, & Setzer J J: Neurobehavioral effects from acute exposures on methyl isobutyl ketone and methyl ethyl ketone. Fundam Appl Toxicol 1992; 19:453-473.
    19) Governa M, Valentino M, & Visona I: Impairment of human polymorphonuclear leukocyte chemotaxis by 2,5-hexanedione. Cell Biol Toxicol 1986; 2:33-39.
    20) HSDB : Hazardous Substances Data Bank. National Library of Medicine. Bethesda, MD (Internet Version). Edition expires 1998; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    21) Hathaway GJ, Proctor NH, & Hughes JP: Methyl ethyl ketone, in: Proctor and Hughes' Chemical Hazards of the Workplace, 3rd ed, Van Nostrand Reinhold, New York, NY, 1991, pp 397-398.
    22) Hewitt WR & Brown EM: Nephrotoxic interactions between ketonic solvents and halogenated aliphatic chemicals. Fundam Appl Toxicol 1984; 4:902-908.
    23) Hjelm EW, Hagberg M, & Iregren A: Exposure to methyl isobutyl ketone: toxicokinetics and occurrence of irritative and CNS symptoms in man. Internat Arch Occup Environ Health 1990; 62:19-26.
    24) Imbriani M, Ghittori S, & Pezzagno G: Methyl ethyl ketone (MEK) in urine as biological index of exposure. G Ital Med Lav 1989; 11:255-261.
    25) Katz GV, Renner ER Jr, & Terhaar CJ: Subchronic inhalation toxicity of methyl isoamyl ketone in rats. Fundam Appl Toxicol 1986; 6:498-505.
    26) Kopelman PG & Kalfayan PY: Severe metabolic acidosis after ingestion of butanone (Letter). Br Med J 1983; 286:21-22.
    27) Krasavage WJ, O'Donoghue JL, & Divincenzo GD: Ketones, in: Clayton GD & Clayton FE (Eds), Patty's Industrial Hygiene and Toxicology, 3rd ed, Vol 2, John Wiley & Sons, New York, NY, 1981, pp 1332-1426.
    28) Kraut JA & Madias NE: Metabolic acidosis: pathophysiology, diagnosis and management. Nat Rev Nephrol 2010; 6(5):274-285.
    29) Larsen JJ, Lykkegaard M, & Ladefoged O: Infertility in rats induced by 2,5-hexanedione in combination with acetone. Pharmacol Toxicol 1991; 69:43-46.
    30) Liira J, Riihimaki V, & Engstrom K: Coexposure of man to m-xylene and methyl ethyl ketone: Kinetics and metabolism. Scand J Work Environ Health 1988a; 14:322-327.
    31) Liira J, Riihimaki V, & Engstrom K: Effects of ethanol on the kinetics of methyl ethyl ketone in man. Br J Ind Med 1990; 47:235.
    32) Liira J, Riihimaki V, & Pfaffli P: Kinetics of methyl ethyl ketone in man: absorption, distribution and elimination in inhalation exposure. Internat Arch Occup Environ Health 1988b; 60:195-200.
    33) Lynch JJ 3rd, Merigan WH, & Eskin TA: Subchronic dosing of macaques with 2,5-hexanedione causes long-lasting motor dysfunction but reversible visual loss. Toxicol Appl Pharmacol 1989; 98:166-180.
    34) Mendell JR, Saida K, & Ganasia MF: Toxic polyneuropathy produced by methyl n-butyl ketone. Science 1974; 185:787-789.
    35) Naradzay J & Barish RA: Approach to ophthalmologic emergencies. Med Clin North Am 2006; 90(2):305-328.
    36) National Heart,Lung,and Blood Institute: Expert panel report 3: guidelines for the diagnosis and management of asthma. National Heart,Lung,and Blood Institute. Bethesda, MD. 2007. Available from URL: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf.
    37) National Institute for Occupational Safety and Health: NIOSH Pocket Guide to Chemical Hazards, U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, Cincinnati, OH, 2007.
    38) O'Donoghue JL, Haworth SR, & Curren RD: Mutagenicity studies on ketone solvents: methyl ethyl ketone, methyl isobutyl ketone, and isophorone. Mutat Res 1988; 206:149-161.
    39) Ong CN, Chia SE, & Phoon WH: Monitoring of exposure to cyclohexanone through the analysis of breath and urine. Scand J Work Environ Health 1991a; 17:430-435.
    40) Ong CN, Sia GL, & Ong HY: Biological monitoring of occupational exposure to methyl ethyl ketone. Internat Arch Occup Environ Health 1991b; 63:319-324.
    41) Parmeggiani L: Encyclopaedia of Occupational Health and Safety, 3rd ed, vol 1, International Labour Office, Geneva, Switzerland, 1983.
    42) Pasternak T, Flood DG, & Eskin TA: Selective damage to large cells in the cat retinogeniculate pathway by 2,5-hexanedione. J Neurosci 1985; 5:1641-1652.
    43) Peate WF: Work-related eye injuries and illnesses. Am Fam Physician 2007; 75(7):1017-1022.
    44) Phillips RD, Moran EJ, & Dodd DE: A 14-week vapor inhalation toxicity study of methyl isobutyl ketone. Fundam Appl Toxicol 1987; 9:380-388.
    45) Plaa GL & Vezina M: Potentialisation de l'hepatotoxicite par des cetones on des agents cetogenes (French). L'Union Med Canada 1987; 116:96-108.
    46) Price EA, D'Alessandro A, & Kearney T: Osmolar gap with minimal acidosis in combined methanol and methyl ethyl ketone ingestion. Clinical Toxicology 1994; 32:79-84.
    47) Ralston WH, Hilderbrand RL, & Uddin DE: Potentiation of 2,5-hexanedione neurotoxicity by methyl ethyl ketone. Toxicol Appl Pharmacol 1985; 81:319-327.
    48) Raymond P & Plaa GL: Ketone potentiation of haloalkane-induced hepato- and nephrotoxicity. II. Implication of monooxygenases. J Toxicol Environ Health 1995; 46:317-328.
    49) Raymond P & Plaa GL: Ketone potentiation of haloalkane-induced hepatotoxicity: CC14 and ketone treatment on hepatic membrane integrity. J Toxicol Environ Health 1996; 49:285-300.
    50) Rosiepen G, Chapin RE, & Weinbauer GF: The duration of the cycle of the seminiferous epithelium is altered by administration of 2,5-hexanedione in the adult Sprague-Dawley rat. J Androl 1995; 16:127-135.
    51) Sakata M, Kikuchi J, & Haga M: Disposition of acetone, methyl ethyl ketone and cyclohexanone in acute poisoning. J Toxicol - Clin Toxicol 1989; 27:76-77.
    52) Samimi BS, Harris SB, & de Peyster A: Fetal effects of inhalation exposure to cyclohexanone vapor in pregnant rats. Toxicol Ind Health 1989; 5:1035-1043.
    53) Schwetz BA, Mast TJ, & Weigel RJ: Developmental toxicity of inhaled methyl ethyl ketone on Swiss mice. Fundam Appl Toxicol 1991; 16:742-748.
    54) Sharkawi M & Elfassy B: Inhibition of mouse liver alcohol dehydrogenase by methyl N-butyl ketone. Toxicol Lett 1985; 25:185-189.
    55) Shibata E, Huang J, & Hisanaga N: Effects of MEK on kinetics of n-hexane metabolites in serum. Arch Toxicol 1990; 64:247-250.
    56) Siracusa G, Bastone A, & Sbraccia M: Effects of 2,5-hexanedione on the ovary and fertility. An experimental study in mice. Toxicology 1992; 75:39-50.
    57) Tyl RW, France KA, & Fischer LC: Developmental toxicity evaluation of inhaled methyl isobutyl ketone in Fischer 344 rats and CD-1 mice. Fundam Appl Toxicol 1987; 8:310-327.
    58) Upreti RK & Shanker R: 2,5-Hexanedione-induced immunomodulatory effect in mice. Environ Res 1987; 43:48-59.
    59) Upreti RK, Singh KP, & Saxena AK: Effect of 2,5-hexanedione on lymphoid organs of rats: a preliminary report. Environ Res 1986; 39:188-198.
    60) Varigos GA & Nurse DS: Contact urticaria from methyl ethyl ketone. Contact Dermatitis 1986; 15:259-260.
    61) Welch L, Kirshner H, & Heath A: Chronic neuropsychological and neurological impairment following acute exposure to a solvent mixture of toluene and methyl ethyl ketone (MEK). Clinical Toxicology 1991; 29:435-445.
    62) Wen CP, Tsai SP, & Weiss NS: Long-term mortality study of oil refinery workers. IV. Exposure to the lubricating-dewaxing process. J Natl Cancer Inst 1985; 74:11-18.
    63) Yasui T, Zhao W, & Misumi J: Influence of different doses of methyl ethyl ketone on 2,5-hexanedione concentrations in the sciatic nerve, serum, and urine of rats. Sangyo Eiseigaku Zasshi 1995; 37:19-24.
    64) Yoshikawa M, Kawamoto T, & Murata K: Biological monitoring of occupational exposure to methyl ethyl ketone in Japanese workers. Arch Environ Contam Toxicol 1995; 29:135-139.