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ISOPHORONE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Isophorone, a cyclic ketone, is a colorless to pale yellow liquid with a peppermint to camphor-like odor.

Specific Substances

    A) No Synonyms were found in group or single elements
    1.2.1) MOLECULAR FORMULA
    1) C9-H14-O

Available Forms Sources

    A) FORMS
    1) Commercial isophorone usually contains some (up to 5%) unconjugated isomer, small amounts (up to 1%) of xylitone, and traces of mesitylene, mesityl oxide, phorone, and water (HSDB, 2001).
    2) High purity (99%) isophorone is also available for industrial use (HSDB, 2001).
    B) SOURCES
    1) It can be manufactured by passing acetone over calcium oxide, hydroxide, or carbide either at 350 degrees C and atmospheric pressure in a vapor phase process or at 200-250 degrees C and under pressure in a liquid phase process (HSDB, 2001).
    C) USES
    1) Isophorone is an unsaturated cyclic ketone used as a solvent or cosolvent (for printing inks, adhesives, finishes, lacquers, acrylic, epoxy, polyester, silicone resins, polyvinyl, and nitrocellulose resins), as a leveling agent (for textile printing), and as a chemical feedstock (for the synthesis of 3,5-xylenol,2,3,5-trimethyl-cyclohexanol and 3,5-dimethylaniline). It is also used in a variety of fats, oils, gums, pesticides and herbicides (ACGIH, 1996; Ashford, 1994; Budavari, 1996a; HSDB, 2001; Sittig, 1991a).
    2) Isophorone has a high solvent power for vinyl resins, cellulose ester, ether, and others (Lewis, 1997a).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) Isophorone may be irritating to the eyes, skin, and mucous membranes. Signs and symptoms of exposure may include olfactory changes, faintness, headache, CNS depression, fatigue, malaise, a feeling of suffocation, and nausea. Skin contact may result in dermatitis due to the defatting action of isophorone.
    B) Kidney and liver damage and pulmonary edema have been observed in experimental animals.
    0.2.3) VITAL SIGNS
    A) Decreased respirations may be seen.
    B) Lowered body temperature may be seen when inhaling higher concentrations of isophorone.
    C) Decreased pulse rate may be seen when inhaling higher concentrations of isophorone.
    0.2.4) HEENT
    A) Isophorone is an eye irritant and may cause ocular pain and corneal damage.
    B) Irritation with nasal discharge and sneezing may occur.
    C) Throat irritation may occur during inhalation.
    0.2.5) CARDIOVASCULAR
    A) Tachycardia may be seen.
    0.2.6) RESPIRATORY
    A) Inhalation exposure may produce an anesthetic type of respiratory depression, dyspnea, and gasping.
    B) Aspiration may result in chemical pneumonitis.
    C) Pulmonary edema may result.
    0.2.7) NEUROLOGIC
    A) CNS depression is a significant toxic effect and is seen with prolonged exposures.
    B) Seizures may result from significant exposures.
    0.2.8) GASTROINTESTINAL
    A) Nausea and vomiting may occur.
    0.2.9) HEPATIC
    A) Liver and spleen damage may occur at higher exposures.
    B) Ketones may potentiate the hepatotoxicity of halogenated hydrocarbons.
    0.2.10) GENITOURINARY
    A) Kidney damage may occur at higher exposures.
    0.2.11) ACID-BASE
    A) Metabolic acidosis may be seen following ingestion.
    0.2.13) HEMATOLOGIC
    A) Leukopenia may be seen with exposure to isophorone.
    0.2.14) DERMATOLOGIC
    A) Skin contact may cause dermatitis, paresthesias, and chemical burns.
    0.2.20) REPRODUCTIVE
    A) Teratogenicity has not been reported.
    0.2.21) CARCINOGENICITY
    A) Tumors, especially preputial gland carcinomas, have occurred in animal studies.

Laboratory Monitoring

    A) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring complete blood count, urinalysis, and liver and kidney function tests is suggested for patients with significant exposure.
    B) The urine can be tested for an increase in conjugated glucuronic acid.
    C) If respiratory tract irritation is present, monitor chest x-ray.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) DILUTION -
    1) MILK OR WATER
    a) DILUTION: If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. Dilution may only be helpful if performed in the first seconds to minutes after ingestion. The ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting.
    B) In general, gastric emptying is NOT INDICATED unless there is a history of large ingestion. Gastric emptying is not indicated following accidental ingestion of small amounts.
    C) Activated charcoal may cause vomiting, which may increase the risk of aspiration. Activated charcoal may be indicated in patients who have coingested an adsorbable toxic substance.
    D) IN SYMPTOMATIC PATIENTS - (coughing, choking, tachypnea, etc) monitor blood gases to assure adequate ventilation. Admit patient for observation.
    E) ACIDOSIS
    1) Treat metabolic acidosis (pH less than 7.1) with IV sodium bicarbonate.
    F) SEIZURES
    1) INITIAL TREATMENT
    a) SEIZURES: Administer a benzodiazepine; DIAZEPAM (ADULT: 5 to 10 mg IV initially; repeat every 5 to 20 minutes as needed. CHILD: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed) or LORAZEPAM (ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist. CHILD: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue).
    1) Consider phenobarbital or propofol if seizures recur after diazepam 30 mg (adults) or 10 mg (children greater than 5 years).
    2) Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.
    2) REFRACTORY SEIZURES
    a) REFRACTORY SEIZURES: Consider continuous infusion of midazolam, propofol, and/or pentobarbital. Hyperthermia, lactic acidosis and muscle destruction may necessitate use of neuromuscular blocking agents with continuous EEG monitoring.
    G) ACUTE LUNG INJURY
    1) ACUTE LUNG INJURY: Maintain ventilation and oxygenation and evaluate with frequent arterial blood gases and/or pulse oximetry monitoring. Early use of PEEP and mechanical ventilation may be needed.
    H) ANTIBIOTICS - Are indicated only if bacterial superinfection of the lungs occurs.
    I) STEROIDS - May not be of benefit for isophorone pneumonitis.
    0.4.3) INHALATION EXPOSURE
    A) DECONTAMINATION/FRESH AIR
    1) 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.
    B) INHALATION INJURY/CORROSIVES
    1) INHALATION: Administer oxygen. If respiratory symptoms develop obtain chest x-ray, monitor pulse oximetry and/or blood gases. Treat bronchospasm with inhaled beta2-adrenergic agonists. If acute lung injury develops, consider PEEP. Evaluate for esophageal, dermal and eye burns as indicated.
    0.4.4) EYE EXPOSURE
    A) HOME IRRIGATION PROTOCOL
    1) 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
    a) 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).
    2) BURNS/IRRITATION -
    a) Treat dermal irritation or burns with standard topical therapy. Patients developing dermal hypersensitivity reactions may require treatment with systemic or topical corticosteroids or antihistamines.

Range Of Toxicity

    A) INHALATION - The minimal toxic or lethal dose is variable and not well defined in the literature. Toxic effects by inhalation depend on airborne concentration, time of exposure and underlying diseases.
    1) Isophorone vapor was irritating to the eyes, nose, and throat of unconditioned volunteers exposed for 15 minutes to an airborne concentration of 23 ppm. The highest tolerable level for an 8-hour exposure was judged to be 10 ppm.
    2) Workers exposed to airborne concentrations of 5 to 8 ppm for 1 month complained of fatigue and malaise, which disappeared when airborne levels were reduced to 1 to 4 ppm.
    3) Workers exposed to airborne concentrations of 40, 85, 200, and 400 ppm had eye, nose, and throat irritation. Some complained of nausea, headache, dizziness, faintness, inebriation, and a feeling of suffocation at the higher concentrations.

Clinical Effects

Summary Of Exposure

    A) Isophorone may be irritating to the eyes, skin, and mucous membranes. Signs and symptoms of exposure may include olfactory changes, faintness, headache, CNS depression, fatigue, malaise, a feeling of suffocation, and nausea. Skin contact may result in dermatitis due to the defatting action of isophorone.
    B) Kidney and liver damage and pulmonary edema have been observed in experimental animals.

Vital Signs

    3.3.1) SUMMARY
    A) Decreased respirations may be seen.
    B) Lowered body temperature may be seen when inhaling higher concentrations of isophorone.
    C) Decreased pulse rate may be seen when inhaling higher concentrations of isophorone.
    3.3.2) RESPIRATIONS
    A) Decreased respirations may be seen when inhaling higher concentrations of isophorone.
    3.3.3) TEMPERATURE
    A) Hypothermia may be noted.
    B) Hypothermia may be seen following inhalation or ingestion of isophorone (Clayton & Clayton, 1982).
    3.3.5) PULSE
    A) Decreased pulse rate may be seen when inhaling higher concentrations of isophorone.

Heent

    3.4.1) SUMMARY
    A) Isophorone is an eye irritant and may cause ocular pain and corneal damage.
    B) Irritation with nasal discharge and sneezing may occur.
    C) Throat irritation may occur during inhalation.
    3.4.3) EYES
    A) Isophorone is an eye irritant.
    B) IRRITATION - Conjunctival irritation and ocular burns with lacrimation may occur with eye contact (Lewis, 1993).
    C) CORNEAL DAMAGE - Eye exposure may result in ocular pain and corneal damage. Direct contact of the liquid with eyes may cause corneal damage (Lewis, 1993).
    D) CORNEAL IRRITATION (ANIMAL) - Isophorone can cause irritation, lacrimation, and possible opacity and necrosis of the cornea (experimental) (Lewis, 1993).
    3.4.5) NOSE
    A) Irritation with nasal discharge and sneezing may occur.
    B) IRRITATION - Isophorone is a systemic irritant by the inhalation route; olfactory changes may occur, as well as nasal discharge and sneezing (Lewis, 1993).
    3.4.6) THROAT
    A) Throat irritation may occur during inhalation.
    B) Workers exposed to 40, 85, 200, and 400 ppm experienced eye, nose, and throat irritation (Clayton & Clayton, 1982). Sore throat, coughing, and salivation may occur.

Cardiovascular

    3.5.1) SUMMARY
    A) Tachycardia may be seen.
    3.5.2) CLINICAL EFFECTS
    A) TACHYARRHYTHMIA
    1) Tachycardia may be seen.
    2) Tachycardia has been reported with other ketones, and thus may occur with isophorone exposure (Karhunen et al, 1990).

Respiratory

    3.6.1) SUMMARY
    A) Inhalation exposure may produce an anesthetic type of respiratory depression, dyspnea, and gasping.
    B) Aspiration may result in chemical pneumonitis.
    C) Pulmonary edema may result.
    3.6.2) CLINICAL EFFECTS
    A) DISORDER OF RESPIRATORY SYSTEM
    1) Isophorone may cause severe lung irritation, chemical pneumonia, or noncardiogenic pulmonary edema.
    B) ACUTE RESPIRATORY INSUFFICIENCY
    1) Isophorone is a lung irritant during short-term and chronic exposures, especially at higher concentrations (Anon, 1991). Workers exposed to 40 to 400 ppm experienced difficulty breathing, respiratory depression, and gasping (Clayton & Clayton, 1982).
    C) PNEUMONIA
    1) Direct aspiration of liquid isophorone into the lungs can result in chemical pneumonia.
    D) ACUTE LUNG INJURY
    1) No data exists concerning isophorone causing noncardiogenic pulmonary edema, but it is reasonable to expect that this may occur, since other ketones have been reported to cause this effect.
    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) IRRITATION
    a) The response of guinea pigs and rats to repeated inhalation of the vapors indicates that it is one of the most toxic of the ketones. In animal toxicity studies, death was occasionally due to lung irritation (Lewis, 1993).
    2) RESPIRATORY INSUFFICIENCY
    a) LUNG DAMAGE - Repeated exposures of animals at concentrations of 50 ppm or more produced evidence of kidney and lung damage. No effects were seen at 25 ppm (Hathaway et al, 1991).
    3) PULMONARY EDEMA
    a) Rats and guinea pigs exposed to 500 ppm over 6 weeks experienced pulmonary inflammation and edema (Clayton & Clayton, 1982; Smyth et al, 1942).

Neurologic

    3.7.1) SUMMARY
    A) CNS depression is a significant toxic effect and is seen with prolonged exposures.
    B) Seizures may result from significant exposures.
    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM DEFICIT
    1) CNS depression is a significant toxic effect and is seen with prolonged exposures.
    2) Workers exposed to 40, 85, 200, and 400 ppm experienced signs of CNS depression. Some complained of nausea, headache, dizziness, faintness, inebriation, tremor, incoordination, and a feeling of suffocation at the higher concentrations (Clayton & Clayton, 1982).
    B) FATIGUE
    1) Workers exposed to 5 to 8 ppm for 1 month complained of fatigue and malaise which disappeared when air levels were reduced to 1 to 4 ppm (Hathaway et al, 1991).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) CNS DEPRESSION
    a) In animal experiments, death during exposure was usually due to CNS depression (Lewis, 1993).

Gastrointestinal

    3.8.1) SUMMARY
    A) Nausea and vomiting may occur.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) Inhalation may result in gastrointestinal irritation, nausea, and vomiting (Browning, 1965; Parmeggiani, 1983).

Hepatic

    3.9.1) SUMMARY
    A) Liver and spleen damage may occur at higher exposures.
    B) Ketones may potentiate the hepatotoxicity of halogenated hydrocarbons.
    3.9.2) CLINICAL EFFECTS
    A) LIVER DAMAGE
    1) Short and long term exposures have been reported to have toxic effects on the liver and spleen (Anon, 1991).
    2) Ketones have been shown to potentiate the hepatotoxic effects of halogenated hydrocarbons (eg, chloroform and carbon tetrachloride) (Plaa & Vezina, 1987).
    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEPATOCELLULAR DAMAGE
    a) Repeated exposures of animals at concentrations of 50 ppm or more produced evidence of kidney and lung damage, and, to a lesser extent, liver damage. No effects were seen at 25 ppm (Hathaway et al, 1991).
    2) HEPATOMEGALY
    a) Hepatocytomegaly and coagulative necrosis were seen in male mice chronically fed high doses of isophorone over two years (NTP, 1986).

Genitourinary

    3.10.1) SUMMARY
    A) Kidney damage may occur at higher exposures.
    3.10.2) CLINICAL EFFECTS
    A) ABNORMAL RENAL FUNCTION
    1) Kidney damage may occur at higher exposures.
    3.10.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) NEPHROPATHY TOXIC
    a) Repeated exposures of animals at concentrations of 50 ppm or more produced evidence of kidney and lung damage, and, to a lesser extent, liver damage. No effects were seen at 25 ppm (Hathaway et al, 1991).
    b) Nephropathy and a variety of proliferative lesions of the kidney were seen in rats fed high concentrations of isophorone. Male rats also exhibited increased mineralization of the medullary collecting ducts (Bucher et al, 1986).
    c) Albuminuria was seen in guinea pigs and rats inhaling 500 ppm isophorone (Smyth et al, 1942).

Acid-Base

    3.11.1) SUMMARY
    A) Metabolic acidosis may be seen following ingestion.
    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) Metabolic acidosis has been reported following ingestion of other ketones. It is reasonable to assume that it may be seen with isophorone (Kopelman & Kalfayan, 1983).

Hematologic

    3.13.1) SUMMARY
    A) Leukopenia may be seen with exposure to isophorone.
    3.13.2) CLINICAL EFFECTS
    A) LEUKOPENIA
    1) Leukopenia may be seen with exposure to isophorone.
    3.13.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) LEUKOPENIA
    a) A single short term exposure to airborne irritant concentrations of isophorone produced leukopenia without any change in differential or red blood cell counts in rats (Brondeau et al, 1990).

Dermatologic

    3.14.1) SUMMARY
    A) Skin contact may cause dermatitis, paresthesias, and chemical burns.
    3.14.2) CLINICAL EFFECTS
    A) CONTACT DERMATITIS
    1) Skin contact may cause dermatitis, paresthesias, and chemical burns.
    2) Repeated or prolonged skin contact with the liquid may cause dermatitis because of its defatting action (Hathaway et al, 1991). Paraesthesia may also result.
    B) CHEMICAL BURN
    1) Short dermal exposure may cause first-degree burns, while longer exposure may cause second-degree burns (CHRIS , 1994).
    C) CASE REPORT
    1) Four cases of occupational contact dermatitis due to isophorone diisocyanate have been reported (Rothe, 1976).
    2) Three cases of contact allergic dermatitis to isophorone diamine in workers employed in the epoxy resin hardening industry have been reported (Lachapelle et al, 1978).
    3.14.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) URTICARIA
    a) Contact allergic hypersensitivity reactions were seen in mice sensitized with isophorone-diisocyanate (Stern et al, 1989).

Reproductive

    3.20.1) SUMMARY
    A) Teratogenicity has not been reported.
    3.20.2) TERATOGENICITY
    A) SUMMARY
    1) Teratogenicity has not been reported.
    B) ANIMAL STUDIES
    1) LACK OF EFFECT
    a) An unpublished study conducted by a commercial laboratory found no teratogenicity of isophorone in rats and mice at inhaled doses up to 115 ppm (Exxon, 1985).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS78-59-1 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.2) SUMMARY/HUMAN
    A) Tumors, especially preputial gland carcinomas, have occurred in animal studies.
    3.21.3) HUMAN STUDIES
    A) SUMMARY
    1) Tumors, especially preputial gland carcinomas, have occurred in animal studies.
    B) CARCINOMA
    1) CLASS C - Isophorone is classifed as C; possible human carcinogen based on limited evidence of one tumor type in one sex of one animal species as shown by an increase of preputial gland carcinomas in male rats (NTP, 1986; (Bucher et al, 1986).
    2) POTENCY FACTOR - The human carcinogen potency factor for isophorone is 0.0041/(mg/kg/day) for oral exposure (Anon, 1986).
    C) ANIMAL STUDIES
    1) TUMORS - Affecting the kidney, ureter, and bladder have occurred in the mouse at a dose of 258 g/kg/2Y (RTECS , 1994).
    2) RENAL - Tubular cell tumors have been found in male rats exposed to isophorone, associated with alpha-2u-globulin, considered to be of questionable relevance to humans (NTP, 1986).
    3) ADENOMAS - In male mice given high oral doses of isophorone, exposure appeared to be associated with increased incidence of hepatocellular adenomas or carcinomas (combined incidence: control, 18/48; low-dose, 18/50; and high-dose, 29/50) and of mesenchymal tumors of the integumentary system such as fibromas, fibrosarcomas, neurofibrosarcomas or sarcomas (incidence of combined tumors: control, 6/48; low-dose, 8/50; and high-dose, 14/50) (NTP, 1986).
    4) LEUKEMIAS - An increased incidence of lymphomas or leukemias was reported in low-dose male mice (18/50) when compared to vehicle controls or high-dose males (8/48 and 5/50, respectively) (NTP, 1986).

Genotoxicity

    A) MUTAGENICITY - Mutations have occurred in mammalian somatic cells.
    B) CHROMOSOME ABERRATIONS - Sister chromatid exchange has occurred in hamster cells.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring complete blood count, urinalysis, and liver and kidney function tests is suggested for patients with significant exposure.
    B) The urine can be tested for an increase in conjugated glucuronic acid.
    C) If respiratory tract irritation is present, monitor chest x-ray.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring complete blood count, urinalysis, and liver and kidney function tests is suggested for patients with significant exposure.
    4.1.3) URINE
    A) URINARY LEVELS
    1) The urine can be tested for an increase in conjugated glucuronic acid.

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) If respiratory tract irritation is present, monitor chest x-ray.

Methods

    A) CHROMATOGRAPHY
    1) AIR - Isophorone may be determined in air by NIOSH Method 2508. This method uses adsorption on a solid sorbent tube (petroleum-based charcoal), desorption with carbon disulfide, and analysis by gas chromatography (HSDB , 1994).
    2) High performance liquid chromatography may also be used (HPLC) (Wu et al, 1986).
    3) WATER - Isophorone in municipal and industrial discharges may be determined by US Environmental Protection Agency (EPA) Method 609, Nitroaromatics and Isophorone.
    4) This method is a gas chromatography method with electron capture detection. The method detection limit is 15.7 mcg/L (HSDB , 1994).

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) IN SYMPTOMATIC PATIENTS - (coughing, choking, tachypnea, etc) monitor blood gases to assure adequate ventilation. Admit the patient for observation.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Accidental ingestions of small quantities of isophorone can safely be handled at home by home monitoring provided the patient is asymptomatic, there is access to a follow-up mechanism, and no suspicious indications of child abuse or attempted suicide exist.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Admit and obtain chest x-ray in all symptomatic patients.
    B) If symptoms develop obtain chest x-ray. Observe patient for 6 hours. Discharge if asymptomatic.
    6.3.3) DISPOSITION/INHALATION EXPOSURE
    6.3.3.1) ADMISSION CRITERIA/INHALATION
    A) IN SYMPTOMATIC PATIENTS - (coughing, choking, tachypnea, etc) monitor blood gases to assure adequate ventilation. Admit the patient for observation.
    B) Admit and obtain chest x-ray in all symptomatic patients.
    6.3.3.5) OBSERVATION CRITERIA/INHALATION
    A) If symptoms develop obtain chest x-ray. Observe patient for 6 hours. Discharge if asymptomatic.

Monitoring

    A) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring complete blood count, urinalysis, and liver and kidney function tests is suggested for patients with significant exposure.
    B) The urine can be tested for an increase in conjugated glucuronic acid.
    C) If respiratory tract irritation is present, monitor chest x-ray.

Oral Exposure

    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Dilution with milk or water is recommended.
    2) In general, gastric emptying is NOT INDICATED unless there is a history of large ingestion. Gastric emptying is not indicated following accidental ingestion of small amounts.
    3) Activated charcoal may cause vomiting, which may increase the risk of aspiration. Activated charcoal may be indicated in patients who have coingested an adsorbable toxic substance.
    4) Gastric lavage should be reserved for a patient who is lethargic or obtunded.
    B) DILUTION
    1) DILUTION: If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. Dilution may only be helpful if performed in the first seconds to minutes after ingestion. The ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting (Caravati, 2004).
    C) EMESIS/NOT RECOMMENDED
    1) Do NOT induce emesis. In general, gastric emptying is NOT INDICATED unless there is a history of large ingestion. Gastric emptying is not indicated following accidental ingestion of small amounts.
    6.5.3) TREATMENT
    A) SUPPORT
    1) IN SYMPTOMATIC PATIENTS - (coughing, choking, tachypnea, etc) monitor blood gases to assure adequate ventilation. Admit the patient for observation and obtain a chest x-ray.
    2) ACIDOSIS - Treat metabolic acidosis (pH less than 7.1) with IV sodium bicarbonate.
    3) SEIZURES - Treat symptomatically with diazepam, phenytoin, or phenobarbital.
    4) PULMONARY EDEMA - Treat symptomatically.
    5) STEROIDS - May not be of benefit in treating isophorone pneumonitis.
    6) ANTIBIOTICS - Are indicated only if bacterial superinfection of the lungs occurs.
    B) MONITORING OF PATIENT
    1) COUGHING - If the patient is symptomatic upon arrival at the medical facility, pulmonary aspiration of gastric contents has probably already occurred. Monitor arterial blood gases or pulse oximetry in cases of severe aspiration pneumonitis to ensure adequate ventilation and oxygenation.
    2) CHEST X-RAY - Admit and obtain chest x-ray in all symptomatic patients.
    a) If symptoms develop obtain chest x-ray. Observe patient for 6 hours. Discharge if asymptomatic.
    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.
    2) Repeat doses of no more than one-half the original amount may be given no more often than every 10 minutes if required (American Heart Association, 1987).
    D) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    E) ACUTE LUNG INJURY
    1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
    2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).
    a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)
    3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
    4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
    5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
    6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
    7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).
    F) CORTICOSTEROID
    1) Steroids have not been shown to be of benefit in treating isophorone pneumonitis.
    G) GENERAL TREATMENT
    1) PARENTERAL EXPOSURE - Ensure medical follow-up for potential pneumonitis or local reaction. Aggressive management of local abscesses with incision, drainage, and appropriate antibiotics is indicated.

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.
    6.7.2) TREATMENT
    A) SUPPORT
    1) CAUSTIC INHALATION: Administer humidified oxygen, and remove from exposure. Monitor patient for respiratory distress; if a cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, and pneumonitis.
    2) Patients with upper airway burns may develop significant edema abruptly; early intubation is advised.
    3) Determine pulse oximetry and/or blood gases, obtain chest x-ray, perform endotracheal intubation and provide mechanical ventilation as clinically indicated.
    4) Administer inhaled beta2-adrenergic agonists in patients with bronchospasm (National Heart,Lung,and Blood Institute, 2007). If acute lung injury develops, consider PEEP (Haas, 2011; Leaver & Evans, 2007; Stolbach & Hoffman, 2011).
    5) Evaluate for esophageal, dermal and eye burns as indicated.
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

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.

Range Of Toxicity

Summary

    A) INHALATION - The minimal toxic or lethal dose is variable and not well defined in the literature. Toxic effects by inhalation depend on airborne concentration, time of exposure and underlying diseases.
    1) Isophorone vapor was irritating to the eyes, nose, and throat of unconditioned volunteers exposed for 15 minutes to an airborne concentration of 23 ppm. The highest tolerable level for an 8-hour exposure was judged to be 10 ppm.
    2) Workers exposed to airborne concentrations of 5 to 8 ppm for 1 month complained of fatigue and malaise, which disappeared when airborne levels were reduced to 1 to 4 ppm.
    3) Workers exposed to airborne concentrations of 40, 85, 200, and 400 ppm had eye, nose, and throat irritation. Some complained of nausea, headache, dizziness, faintness, inebriation, and a feeling of suffocation at the higher concentrations.

Minimum Lethal Exposure

    A) ADULT
    1) The minimum lethal human dose to this agent has not been delineated.
    B) ANIMAL DATA
    1) RATS: The minimum lethal airborne concentration (exposed by inhalation) was 885 ppm for 6 hours and 1840 ppm for 4 hours (ACGIH, 1996; Bingham et al, 2001).
    2) GUINEA PIGS: Daily injection of 0.2-0.6 gram of isophorone for 6 days resulted in death with increased albuminuria (HSDB , 2001).
    3) MICE: Inhalation of >3500 mg/kg of isophorone for 6 hours resulted in death with acute pulmonary edema (HSDB , 2001).
    4) DOGS: Intravenously injected isophorone at the concentration of >10 mg/kg resulted in death with respiratory stimulation, change in pulse rate, and convulsions (HSDB , 2001).

Maximum Tolerated Exposure

    A) ADULT
    1) Isophorone vapor was irritating to the eyes, nose, and throat of unconditioned volunteers exposed for 15 minutes to an airborne concentration of 25 ppm in a 1200 cubic feet chamber (HSDB , 2001).
    2) Workers exposed to airborne concentrations of 5 to 8 ppm for 1 month complained of fatigue and malaise, which disappeared when airborne levels were reduced to 1 to 4 ppm (Hathaway et al, 1991).
    3) Eye irritation was reported at a concentration as low as 25 ppm. In addition, nose and throat irritations were reported at concentrations above 40 ppm. Irritated conjunctiva, nausea, headache, dizziness, faintness, inebriation, and a feeling of suffocation were reported at concentrations of 200 and 400 ppm (ACGIH, 1996; Grant & Schuman, 1993).
    4) "Although isophorone may be more toxic and irritative than lower-molecular-weight ketones at equivalent concentrations, it poses less of an inhalation hazard because of its relatively low volatility (Hathaway et al, 1996)
    5) At a concentration of 200 ppm, 1 minute exposure was reported to be intolerable (HSDB , 2001).
    6) CARCINOGENICITY RATINGS:
    a) According to the EPA: C - possible human carcinogen (no human carcinogenicity data and limited animal carcinogenicity data) (HSDB , 2001)
    b) According to the American Conference of Governmental Industrial Hygienists: A3 - confirmed animal carcinogen with unknown relevance to humans (ACGIH, 2001)
    B) ANIMAL DATA
    1) Certain strains of male rats that synthesize alpha(2u)-globulin may be more susceptible to kidney damage when exposed to isophorone, as compared to monkeys, guinea pigs, dogs, mice, female rats, and male NBR rats that do not synthesize the hepatic form of alpha(2u)-globulin (Hathaway et al, 1996).
    2) Repeated exposures of animals to airborne concentrations of 50 ppm or more caused damages in kidney, lung, and, to a lesser extent, liver. No effects were seen at airborne levels of 25 ppm (Hathaway et al, 1996).
    3) Male and female Charles River CD rats were exposed to isophorone at air concentrations of 0.25 mg/L. The duration was 6 hours a day, 5 days a week, for a total of 6 weeks. The following was observed (HSDB , 2001):
    a) Male:
    1) Transient nasal bleeding
    2) Increased percentages of lymphocytes
    3) Decreased percentages of neutrophils
    4) Increased hemoglobin concentration
    5) Lower terminal body weights
    6) Decreased absolute and relative liver weights
    b) Female:
    1) Transient nasal bleeding
    2) Increased percentages of lymphocytes
    3) Decreased percentages of neutrophils
    4) Increased hemoglobin concentration
    4) Rats, guinea pigs, or mice exposed to isophorone at an airborne concentration of 619 ppm for 6 hours developed slight lacrimation but no deaths occurred (ACGIH, 1996).
    5) "Respiratory depression to 50% of the normal frequency has been reported in rats exposed to a concentration of approximately 30 ppm" (Bingham et al, 2001).
    6) In a 2 year bioassay in rats and mice (conducted by gavage on a 5 day a week treatment schedule) at levels of 0, 250, and 500 mg/kg, the following was reported (Bingham et al, 2001):
    a) No evidence of carcinogenicity in mice.
    b) No evidence of carcinogenicity in female rats. In male rats, renal tumors, preputial gland tumors, hyperplasia of the renal pelvis, tubular hyperplasia were reported.

Workplace Standards

    A) ACGIH TLV Values for CAS78-59-1 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Editor's Note: The listed values are recommendations or guidelines developed by ACGIH(R) to assist in the control of health hazards. They should only be used, interpreted and applied by individuals trained in industrial hygiene. Before applying these values, it is imperative to read the introduction to each section in the current TLVs(R) and BEI(R) Book and become familiar with the constraints and limitations to their use. Always consult the Documentation of the TLVs(R) and BEIs(R) before applying these recommendations and guidelines.
    a) Adopted Value
    1) Isophorone
    a) TLV:
    1) TLV-TWA:
    2) TLV-STEL:
    3) TLV-Ceiling: 5 ppm
    b) Notations and Endnotes:
    1) Carcinogenicity Category: A3
    2) Codes: Not Listed
    3) Definitions:
    a) A3: Confirmed Animal Carcinogen with Unknown Relevance to Humans: The agent is carcinogenic in experimental animals at a relatively high dose, by route(s) of administration, at site(s), of histologic type(s), or by mechanism(s) that may not be relevant to worker exposure. Available epidemiologic studies do not confirm an increased risk of cancer in exposed humans. Available evidence does not suggest that the agent is likely to cause cancer in humans except under uncommon or unlikely routes or levels of exposure.
    c) TLV Basis - Critical Effect(s): Eye and URT irr; CNS impair; malaise; fatigue
    d) Molecular Weight: 138.21
    1) For gases and vapors, to convert the TLV from ppm to mg/m(3):
    a) [(TLV in ppm)(gram molecular weight of substance)]/24.45
    2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:
    a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance
    e) Additional information:

    B) NIOSH REL and IDLH Values for CAS78-59-1 (National Institute for Occupational Safety and Health, 2007):
    1) Listed as: Isophorone
    2) REL:
    a) TWA: 4 ppm (23 mg/m(3))
    b) STEL:
    c) Ceiling:
    d) Carcinogen Listing: (Not Listed) Not Listed
    e) Skin Designation: Not Listed
    f) Note(s):
    3) IDLH:
    a) IDLH: 200 ppm
    b) Note(s): Not Listed

    C) Carcinogenicity Ratings for CAS78-59-1 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A3 ; Listed as: Isophorone
    a) A3 :Confirmed Animal Carcinogen with Unknown Relevance to Humans: The agent is carcinogenic in experimental animals at a relatively high dose, by route(s) of administration, at site(s), of histologic type(s), or by mechanism(s) that may not be relevant to worker exposure. Available epidemiologic studies do not confirm an increased risk of cancer in exposed humans. Available evidence does not suggest that the agent is likely to cause cancer in humans except under uncommon or unlikely routes or levels of exposure.
    2) EPA (U.S. Environmental Protection Agency, 2011): C ; Listed as: Isophorone
    a) C : Possible human carcinogen.
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed ; Listed as: Isophorone
    5) MAK (DFG, 2002): Category 3B ; Listed as: Isophorone
    a) Category 3B : Substances for which in vitro or animal studies have yielded evidence of carcinogenic effects that is not sufficient for classification of the substance in one of the other categories. Further studies are required before a final decision can be made. A MAK value can be established provided no genotoxic effects have been detected. (Footnote: In the past, when a substance was classified as Category 3 it was given a MAK value provided that it had no detectable genotoxic effects. When all such substances have been examined for whether or not they may be classified in Category 4, this sentence may be omitted.)
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS78-59-1 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Listed as: Isophorone
    2) Table Z-1 for Isophorone:
    a) 8-hour TWA:
    1) ppm: 25
    a) Parts of vapor or gas per million parts of contaminated air by volume at 25 degrees C and 760 torr.
    2) mg/m3: 140
    a) Milligrams of substances per cubic meter of air. When entry is in this column only, the value is exact; when listed with a ppm entry, it is approximate.
    3) Ceiling Value:
    4) Skin Designation: No
    5) Notation(s): Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) References: Bingham et al, 2001 Budavari, 2000 HSDB, 2001 ) (OHM/TADS, 2001; RTECS, 2001
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 400 mg/kg (Bingham et al, 2001)
    2) LD50- (ORAL)MOUSE:
    a) 2000 mg/kg (Bingham et al, 2001)
    b) 2690 mg/kg
    c) >3200 mg/kg (Bingham et al, 2001)
    d) male, 2000-2400 mg/kg (Budavari, 1996)
    3) LD50- (INTRAPERITONEAL)RAT:
    a) 400-800 mg/kg (Bingham et al, 2001)
    4) LD50- (ORAL)RAT:
    a) 1000-3450 mg/kg (HSDB, 2001)
    b) 1870 mg/kg
    c) 2150 mg/kg (Bingham et al, 2001)
    d) 2330 mg/kg (OHM/TADS, 2001)
    e) 2370 mg/kg (Bingham et al, 2001)
    f) >3000 mg/kg (OHM/TADS, 2001)
    g) >3200 mg/kg (Bingham et al, 2001)
    h) male, 2500-2900 mg/kg (Budavari, 1996)
    i) female, 1900-2300 mg/kg (Budavari, 1996)
    5) LD50- (SKIN)RAT:
    a) 1390 mg/kg
    6) TCLo- (INHALATION)HUMAN:
    a) 25 ppm -- caused changes in sense organs and respiratory system
    7) TCLo- (INHALATION)MOUSE:
    a) Female, 115 ppm for 6H at 6-15 D of pregnancy -- caused maternal effects
    8) TCLo- (INHALATION)RAT:
    a) Female, 115 ppm for 6H at 6-15 D of pregnancy -- caused maternal effects
    b) 208 mg/m(3) for 6H/4W-intermittent -- caused changes in liver and body weights
    c) 500 ppm for 8H/6W-intermittent -- caused urological changes, respiratory changes, liver changes, changes in sense organs, and death

Pharmacology Toxicology

Toxicologic Mechanism

    A) Isophorone is reduced in the body to a secondary alcohol and eliminated as a glucuronide conjugate. Experimental animals exposed to HIGH concentrations of isophorone had damage of the lungs (emphysema), liver, kidneys, and brain. Similar effects have not been found in long-term occupational epidemiologic studies in humans.

Physicochemical

Physical Characteristics

    A) Isophorone is a colorless to pale yellow liquid with a peppermint to camphor-like odor (ACGIH, 1996; Lewis, 2000).
    B) It is lighter than water and floats on water ((CHRIS, 2001)).

Molecular Weight

    A) 138.23

References

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