Contact Us    Contact Us     |     Feedback
MOBILE VIEW  | 

IMIDAZOLINONE HERBICIDES

Export To Excel

Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Imidazolinone herbicides are a newer class herbicides for use in the control of broad-leafed weeds and grasses in a variety of agricultural crops. They act by interrupting the production of branched-chain amino acids via inhibition of acetohydroxy acid synthase. The imidazolinone ring of this group is amphoteric and can behave as a weak base or a weak acid.
    B) Relative toxicity of these agents is low. However, when ingested in large quantities (greater than 100 mL), a clinical toxic syndrome, including pulmonary complications and other organ effects, can result. It is not clear to what extent the surfactants, contained in the herbicides, may be contributing to the toxidrome.

Specific Substances

    A) IMAZAMETHABENZ
    1) AC 222293
    2) AC 293
    3) AC 263840
    4) Assert
    5) Benzoic acid,2-(4,5-dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1H-imidazol-2-yl)-4 (or 5)-methyl-,methyl ester
    6) CL 222293
    7) Dagger
    8) Imazamethabenz (meta and para)
    9) Imazamethabenz methyl
    10) Molecular formula: C15-H18-N2-O3 (imazamethabenz)
    11) Molecular formula: C16-H20-N2-O3 (imazamethabenz,
    12) methyl)
    13) CAS 100728-84-5 (imazamethabenz)
    14) CAS 81405-85-8 (imazamethabenz, methyl)
    IMAZAMETH
    1) AC 263,222
    2) CL 263,222
    3) Molecular Formula C14-H17-N3-O3
    4) CAS 104098-48-8
    IMAZAMOX, IMAZAPIC, IMAZAPYR
    1) 3-Pyridinecarboxylic acid,2-(4,5-dihydro-4-methyl
    2) -4-(1-methylethyl)-5-oxo-1H-imidazol-2-yl)-
    3) 2-(4,5-Dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1H-imidazol-2-yl) -3-pyridinecarboxylic acid
    4) 2-(4-Isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl) nicotinic acid
    5) Arsenal
    6) Tsung-ch'ing
    7) Assault
    8) Chopper
    9) Contain
    10) Pivot
    11) Molecular formula: C13-H15-N3-O3
    12) CAS 81334-34-1
    IMAZAQUIN
    1) 3-Quinolinecarboxylic acid, 20 (4,5-dihydro-4-methyl-4-(1-methylethyl -5-oxo-1H-imidazol-2-yl)-
    2) 2-(4,5-Dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1H-imidazol-2-yl)- 3-quinolinecarboxylic acid
    3) AC 252214
    4) Imazaquine
    5) Scepter
    6) Partner
    7) Squadron
    8) Ala-scept
    9) Tri-scept
    10) Molecular formula: C17-H17-N3-O3
    11) CAS 81335-37-7
    IMAZETHAPYR
    1) 3-Pyridinecarboxylic acid,2-(4,5-dihydro-4-methyl-4-(1-methylethyl)-5 -oxo-1H-imidazol-2-yl)-5-ethyl-
    2) (RS)-5-Ethyl-2(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinic acid
    3) AC 263,499
    4) Pursuit
    5) Pursuit Plus
    6) Contour
    7) Hammer
    8) Overtop
    9) Passport
    10) Pivot
    11) Molecular formula: C15-H19-N3-O3
    12) CAS 81335-77-5

Available Forms Sources

    A) FORMS
    1) These herbicides are generally available as concentrated aqueous solutions (Nejad et al, 1998; Lee et al, 1999).
    B) USES
    1) The imidazolinones are selective and potent herbicides used to control a wide spectrum of broad-leafed weeds and grasses in a variety of crops, including soybean, alfalfa, wheat and barley, and in non-crop situations (Chin et al, 2002; D'Ascenzo et al, 1998; Lagana et al, 1998). These herbicides are effective at very low concentrations and have low mammalian toxicity. They persist in soil (Anisuzzaman et al, 2000).

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: Imidazlinone herbicides are selective and potent herbicides used to control a wide spectrum of broad-leafed weeds and grasses in a variety of crops, including soybean, alfalfa, wheat, and barley, and in non-crop situations.
    B) EPIDEMIOLOGY: Exposures to imidazlinone herbicides are rare, and serious toxicity has not been reported following inadvertent exposures. Deliberate exposures may produce life-threatening effects.
    C) PHARMACOLOGY: In plants these chemicals inhibit the production of branched chain amino acids.
    D) TOXICOLOGY: The exact mechanism of toxicity is not known. Ingestion is associated with dermal and mucous membrane injury and severe vomiting likely to GI irritation from local tissue injury. Pulmonary injury is likely secondary to aspiration. The mechanism of cardiovascular and CNS effects is not known.
    E) Acute poisoning from ingestion of large quantities of liquid imidazolinone herbicide has resulted in hypotension, pulmonary dysfunction, oral mucosal and gastrointestinal irritation, and transient liver and renal dysfunction. Copious vomiting shortly following ingestion is common. Severe symptoms have included altered consciousness and respiratory distress requiring intubation. It is not known to what extent the surfactant in the formula affects toxicity. Prognosis is generally good following symptomatic therapy.
    F) WITH POISONING/EXPOSURE
    1) OVERDOSE: MILD TO MODERATE TOXICITY: Vomiting and mucous membrane irritation should be expected. Severe vomiting is very common. Some patients may develop depressed mental status, hypotension, and aspiration pneumonitis. Mild elevations in aminotransferases and serum creatinine and mild metabolic acidosis have been reported.
    0.2.20) REPRODUCTIVE
    A) Reproductive and lactation effects of this group of herbicides are not available for humans.
    0.2.21) CARCINOGENICITY
    A) Trends of increased risk of bladder and colon cancer have been reported with chronic exposures of imazethapyr.

Laboratory Monitoring

    A) The imidazolinone herbicides have been measured in soil by gas chromatography, high-performance liquid chromatography, gas chromatography/mass spectrometry, and nuclear magnetic resonance spectroscopy. None of these methods are readily available for clinical use.
    B) Monitor CBC, serum creatinine, BUN, liver enzymes, serum electrolytes, blood gases, urinalysis, and chest radiograph in symptomatic patients.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Patients with GI irritation should be treated with antiemetic and IV fluids.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Patients with altered mental status or severe vomiting should be intubated to decrease the risk of aspiration.
    C) DECONTAMINATION
    1) PREHOSPITAL: No pre-hospital GI decontamination is recommended. Irrigated affected mucous membranes (oral and ocular) and skin with copious amounts of water.
    2) HOSPITAL: GI decontamination is generally not indicated as these liquids are absorbed rapidly and toxicity is generally limited. Irrigated affected mucous membranes (oral and ocular) and skin with copious amounts of water.
    D) AIRWAY MANAGEMENT
    1) Patients with significant CNS depression should be intubated.
    E) ANTIDOTE
    1) None.
    F) ACUTE LUNG INJURY
    1) Maintain ventilation and oxygenation and evaluate with frequent arterial blood gas or pulse oximetry monitoring. Early use of PEEP and mechanical ventilation may be needed.
    G) HYPOTENSIVE EPISODE
    1) Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min, CHILD: begin infusion at 0.1 mcg/kg/min), titrate to desired response.
    H) ENHANCED ELIMINATION
    1) It has not yet been shown that imidazolinones can be removed by hemodialysis. However, patients with severe imidazolinone toxicity should undergo hemodialysis if they are in renal failure.
    I) PATIENT DISPOSITION
    1) HOME MANAGEMENT: Inadvertent taste ingestions by children can be observed at home if they have no symptoms. Any patient with a history of cough or respiratory difficulty should be referred for evaluation. All patients with self-harm ingestions should be sent to a health care facility for evaluation.
    2) OBSERVATION CRITERIA: Patients with deliberate ingestions and those with symptoms should be sent to a healthcare facility and be observed for 6 hours. Patients can be discharged if they have normal vital signs and mental status.
    3) ADMISSION CRITERIA: Admit patients if vomiting and diarrhea occur, if vital signs are abnormal, if acidosis, increased liver enzymes, renal insufficiency, altered consciousness or respiratory distress develops.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance with patients with severe poisoning or in whom the diagnosis is unclear.
    J) PITFALLS
    1) When managing a suspected overdose with a imidazolinone herbicide, the possibility of coingestion of other agents should be considered.
    K) PHARMACOKINETICS
    1) Detailed pharmacokinetic data are not available.
    L) DIFFERENTIAL DIAGNOSIS
    1) Includes ingestion with another herbicide or insecticide.

Range Of Toxicity

    A) TOXICITY: There are no high quality data to make toxicity estimates. Inadvertent ingestion appears to be very low risk and no fatalities have been reported following ingestions. Clinical toxicity may occur following ingestions of herbicide volumes in adults of greater than 100 mL. Severe symptoms have included coma and respiratory distress requiring intubation. Other symptoms reported include hypotension, acidosis, elevated liver and renal function tests, and copious vomiting.
    B) It is not clear to what extent the surfactant in the herbicides may be contributing to the toxidrome.

Clinical Effects

Vital Signs

    3.3.2) RESPIRATIONS
    A) Labored respirations may occur following large ingestions (Lee et al, 1999). In animal (dog) studies, increases in heart rate and respiration occurred following intraperitoneal doses (1000 mg/kg) of imazaquin (Anon, 1999).
    3.3.3) TEMPERATURE
    A) Fever has been reported in adults following large ingestions of imazapyr (Lee et al, 1999).
    3.3.4) BLOOD PRESSURE
    A) Hypotension has been reported following acute ingestions of imazapyr (Lee et al, 1999). Dogs exhibited decreased blood pressure after an intraperitoneal injection of 1000 mg/kg of imazaquin (Anon, 1999).

Heent

    3.4.3) EYES
    A) Splash injuries to the eye have resulted in conjunctival injection, epithelial injury of the cornea, and chemical burn of the cornea (Lee et al, 1999).
    B) In acute oral studies with imazaquin, rats and mice developed lacrimation, observed from 10 minutes to 5 days after dosing (Anon, 1999).
    C) In rabbit eye irritation studies, no clinical signs of toxicity were noted following instillation of 20% imazaquin into the eyes (Anon, 1999).
    3.4.6) THROAT
    A) Due to the corrosive nature of these compounds, ingestions have been noted to cause ulcerations of the oral mucosa and upper airway. Excessive oral secretions have also been reported. Vomiting and aspiration may also contribute to mucosal irritation (Lee et al, 1999).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) Following ingestions of large amounts of imazapyr (greater than 100 mL), hypotension is common, with shock developing in some cases. Other ingredients, such as surfactants, in these herbicide formulations may contribute to the toxicity (Lee et al, 1999).
    2) CASE REPORT: Following an intentional ingestion of approximately 300 mL of imazapyr, a 32-year-old woman presented to the emergency department hours later with impaired consciousness, shock, and metabolic acidosis. She was treated with sodium bicarbonate, IV fluids, and inotropic agents. She was discharged several days later with full recovery (Lee et al, 1999).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) PULMONARY ASPIRATION
    1) Due to the irritant properties of these herbicides, ingestions of large quantities (usually greater than 100 mL) often cause intense vomiting as well as altered consciousness, due to CNS depressive effects, and subsequent aspiration pneumonitis. Hypoxemia and respiratory distress, often requiring intubation, are generally present. Laryngeal injury is strongly correlated with aspiration pneumonitis in these patients (Lee et al, 1999). Cough may occur.

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM DEFICIT
    1) Following ingestions of large amounts of imazapyr, CNS depression, ranging from mild sedation, ataxia, and stupor to coma may occur. Ingestions of greater than 100 mL in adults resulted in depressed levels of consciousness. Severe CNS depressant effects may also result in respiratory depression (Lee et al, 1999).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) CNS DEPRESSION
    a) MICE: CNS depression was reported in mice given 300 mg/kg of either intraperitoneal or oral imidazolinone glyoxylate suspensions. Physiological signs in these animals included depression, lacrimation, body drop, loss of spontaneous activity, and Staub tail phenomenon. Onset of effects occurred within 6 minutes (Heindel & Chun, 1973).
    b) MICE/RATS: Following an acute oral dose of imazaquin, decreased spontaneous motor activity, sedation, and prone posture were noted in both mice and rats (Anon, 1999).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA, VOMITING AND DIARRHEA
    1) Abdominal pain, nausea, vomiting, and diarrhea commonly occur following ingestions of imidazolinone herbicides. Intense vomiting may often result in aspiration and subsequent respiratory damage. Ulcerated oral mucosa has been reported, and may be a result of vomiting (Lee et al, 1999).
    a) Imazapyr is a weak acid (pH of a 1% solution, 3.0 to 3.5) and may itself induce irritation to the GI tract. If chest or abdominal pain occurs following ingestion, endoscopic examination should be performed.
    3.8.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) DIARRHEA
    a) Following an acute oral dose of imazaquin to rats, salivation, and diarrhea developed about 30 minutes after dosing and resolved within 2 hours (Anon, 1999).
    2) SALIVA INCREASED
    a) An acute inhalation study of imazaquin in rats resulted in salivation and nasal discharge soon after the exposure. All effects resolved by day 4 (Anon, 1999).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) Following ingestions of large quantities of the concentrates (greater than 100 mL in adults), mild transient elevations of serum liver transaminase levels have been reported. Mildly elevated liver enzymes (AST 74 Units/L, ALT 41 Units/L and LDH 596 Units/L) and hyperbilirubinemia were reported in a 32-year-old woman following an ingestion of approximately 300 mL of imazapyr concentrate. The patient responded to symptomatic treatment (Lee et al, 1999)

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ABNORMAL RENAL FUNCTION
    1) Mild elevation of serum creatinine has been reported following ingestions (Lee et al, 1999).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) Metabolic acidosis may occur following imidazolinone herbicide ingestions (Lee et al, 1999).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LEUKOCYTOSIS
    1) Leukocytosis may be a common laboratory finding following large ingestions (Lee et al, 1999).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) SKIN IRRITATION
    1) The imidazolinone herbicides concentrates are weak acids, and if in contact with skin, may cause dermal irritation.
    3.14.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) LACK OF EFFECT
    a) Following an acute dermal exposure to 20% imazaquin, no signs of toxicity were noted in rats (Anon, 1999).
    b) In a primary skin irritation study in rabbits, only very slight erythema was observed in all animals (n=6) and edema was observed in half the animals following application of a 20% imazaquin solution. This herbicide was considered to be nonirritating to rabbit skin (Anon, 1999).

Reproductive

    3.20.1) SUMMARY
    A) Reproductive and lactation effects of this group of herbicides are not available for humans.
    3.20.2) TERATOGENICITY
    A) LACK OF EFFECT
    1) ANIMAL STUDIES
    a) Imazaquin was shown to have no embryo-fetal toxicity nor teratogenicity in rats or rabbits when administered to pregnant rat dams during gestation days 6 to 15 at doses up to 500 mg/kg/day and to pregnant rabbits during gestation days 6 to 18 at the same dose (Anon, 1999).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS81405-85-8 (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
    B) IARC Carcinogenicity Ratings for CAS114311-32-9 (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
    C) IARC Carcinogenicity Ratings for CAS81334-34-1 (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
    D) IARC Carcinogenicity Ratings for CAS81335-37-7 (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
    E) IARC Carcinogenicity Ratings for CAS81335-77-5 (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) Trends of increased risk of bladder and colon cancer have been reported with chronic exposures of imazethapyr.
    3.21.3) HUMAN STUDIES
    A) CARCINOMA
    1) Trends of increased risk of bladder and colon cancer were reported among pesticide applicators enrolled in the Agricultural Health Study who were chronically exposed to imazethapyr (Koutros et al, 2009).
    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) LACK OF EFFECT
    a) IMAZAQUIN: The only negative effect found in an 18-month oncogenicity study of CD-1 mice was decreased body weight gain in females. The mice were tested at concentrations of 250, 1000 and 4000 ppm, with a NOEL of 1000 ppm (EPA, 1992).
    b) IMAZETHAPYR: No carcinogenic effects were observed in a study where mice were fed diets containing 0, 1000, 5000 or 10,000 ppm of imazethapyr for 18 months. A similar 2 year study of mice fed diets of up to 10,000 ppm imazethapyr also showed no carcinogenic effects (EPA, 1992).

Genotoxicity

    A) Imazaquin has been shown to be non-mutagenic and non-clastogenic in reverse mutation assays and in chromosomal aberration assays (Anon, 1999).

Summary Of Exposure

    A) USES: Imidazlinone herbicides are selective and potent herbicides used to control a wide spectrum of broad-leafed weeds and grasses in a variety of crops, including soybean, alfalfa, wheat, and barley, and in non-crop situations.
    B) EPIDEMIOLOGY: Exposures to imidazlinone herbicides are rare, and serious toxicity has not been reported following inadvertent exposures. Deliberate exposures may produce life-threatening effects.
    C) PHARMACOLOGY: In plants these chemicals inhibit the production of branched chain amino acids.
    D) TOXICOLOGY: The exact mechanism of toxicity is not known. Ingestion is associated with dermal and mucous membrane injury and severe vomiting likely to GI irritation from local tissue injury. Pulmonary injury is likely secondary to aspiration. The mechanism of cardiovascular and CNS effects is not known.
    E) Acute poisoning from ingestion of large quantities of liquid imidazolinone herbicide has resulted in hypotension, pulmonary dysfunction, oral mucosal and gastrointestinal irritation, and transient liver and renal dysfunction. Copious vomiting shortly following ingestion is common. Severe symptoms have included altered consciousness and respiratory distress requiring intubation. It is not known to what extent the surfactant in the formula affects toxicity. Prognosis is generally good following symptomatic therapy.
    F) WITH POISONING/EXPOSURE
    1) OVERDOSE: MILD TO MODERATE TOXICITY: Vomiting and mucous membrane irritation should be expected. Severe vomiting is very common. Some patients may develop depressed mental status, hypotension, and aspiration pneumonitis. Mild elevations in aminotransferases and serum creatinine and mild metabolic acidosis have been reported.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) The imidazolinone herbicides have been measured in soil by gas chromatography, high-performance liquid chromatography, gas chromatography/mass spectrometry, and nuclear magnetic resonance spectroscopy. None of these methods are readily available for clinical use.
    B) Monitor CBC, serum creatinine, BUN, liver enzymes, serum electrolytes, blood gases, urinalysis, and chest radiograph in symptomatic patients.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor serum creatinine, BUN, liver enzymes, and serum electrolytes in symptomatic patients.
    B) HEMATOLOGIC
    1) Monitor CBC in symptomatic patients.
    C) ACID/BASE
    1) Monitor blood gases in symptomatic patients.
    4.1.3) URINE
    A) URINALYSIS
    1) Monitor urine output and perform urinalysis in symptomatic patients.

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) Obtain a chest radiograph in symptomatic patients.

Methods

    A) CHROMATOGRAPHY
    1) Imidazolinone herbicides have been measured by reversed-phase liquid chromatography-electrospray ionization-mass spectrometry with an electrospray interface (LC-ESI-MS) (D'Ascenzo et al, 1998; Nejad et al, 1998; Lagana et al, 1998) and liquid chromatography with UV detection (Lagana et al, 1998). Furlong et al (2000) developed a high-performance liquid chromatography/electrospray ionization-mass spectrometry for identification and quantification of imidazolinone herbicides in environmental samples. These herbicides were quantitated to 10 ng/L (Furlong et al, 2000).
    2) A multiresidue gas chromatographic/mass spectrometer method for trace level analysis of imidazolinone herbicides in environmental samples such as water, soybean, and soil was described. The procedures used in this study, have eliminated time-consuming steps involving a series of solid-phase extraction cartridges in complex matrixes, i.e., soil or soybean. Recoveries have been in the range of 80% to 116% (Anisuzzaman et al, 2000).
    B) IMMUNOASSAY
    1) Chin et al (2002) described the use of haptens and monoclonal antibodies for the direct and indirect competition enzyme immunoassays (EIAs) of imidazolinone herbicides. Imazethapyr, imazaquin, imazapic, and imazamox were detected in the 3 to 30 ng/mL range while imazapyr and imazamethabenz-methyl were detected in the 300 to 500 ppb range (Chin et al, 2002).

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) Admit patients if vomiting and diarrhea occur, if vital signs are abnormal, or if acidosis, increased liver enzymes, renal insufficiency, altered consciousness or respiratory distress develops.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Inadvertent taste ingestions by children can be observed at home if they have no symptoms. Any patient with a history of cough or respiratory difficulty should be referred for evaluation. All patients with self-harm ingestions should be sent to a health care facility for evaluation.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance with patients with severe poisoning or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with deliberate ingestions and those with symptoms should be sent to a healthcare facility and be observed for 6 hours. Patients can be discharged if they have normal vital signs and mental status. Observe all patients following significant exposures for at least 6 hours.

Monitoring

    A) The imidazolinone herbicides have been measured in soil by gas chromatography, high-performance liquid chromatography, gas chromatography/mass spectrometry, and nuclear magnetic resonance spectroscopy. None of these methods are readily available for clinical use.
    B) Monitor CBC, serum creatinine, BUN, liver enzymes, serum electrolytes, blood gases, urinalysis, and chest radiograph in symptomatic patients.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) EMESIS/NOT RECOMMENDED
    1) Emesis is not recommended, although spontaneous vomiting may occur. Concentrated solutions may cause esophageal erosion; it is not known if lower concentrations are less irritating or if the surfactant is an irritant.
    6.5.2) PREVENTION OF ABSORPTION
    A) EMESIS/NOT RECOMMENDED
    1) Emesis is not recommended, although spontaneous vomiting may occur. Concentrated solutions may cause esophageal erosion; it is not known if lower concentrations are less irritating or if the surfactant is an irritant.
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor CBC, serum creatinine, BUN, liver enzymes, serum electrolytes, blood gases, urinalysis, and chest radiograph in symptomatic patients. The imidazolinone herbicides have been measured in soil by gas chromatography, high-performance liquid chromatography, gas chromatography/mass spectrometry, and nuclear magnetic resonance spectroscopy. None of these methods are readily available for clinical use.
    B) ENDOSCOPIC PROCEDURE
    1) Consider endoscopy in patients with signs or symptoms of mucous membrane irritation following ingestion.
    C) FLUID/ELECTROLYTE BALANCE REGULATION
    1) Vomiting and diarrhea may be prolonged with large ingestions, resulting in fluid and electrolyte loss. Monitor and replace as necessary.
    D) 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).
    E) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer norepinephrine.
    2) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

Enhanced Elimination

    A) HEMODIALYSIS
    1) It has not yet been shown that imidazolinones can be removed by hemodialysis. However, patients with severe imidazolinone toxicity should undergo hemodialysis if they are in renal failure.

Range Of Toxicity

Summary

    A) TOXICITY: There are no high quality data to make toxicity estimates. Inadvertent ingestion appears to be very low risk and no fatalities have been reported following ingestions. Clinical toxicity may occur following ingestions of herbicide volumes in adults of greater than 100 mL. Severe symptoms have included coma and respiratory distress requiring intubation. Other symptoms reported include hypotension, acidosis, elevated liver and renal function tests, and copious vomiting.
    B) It is not clear to what extent the surfactant in the herbicides may be contributing to the toxidrome.

Maximum Tolerated Exposure

    A) ADULT
    1) Toxicity in 5 adults was reported following ingestions of 100 to 300 milliliters of imazapyr. Of these, all presented with copious vomiting, and most developed aspiration pneumonitis resulting in compromised respiratory function. Decreased level of consciousness was apparent in 4/5 victims. Significant metabolic acidosis was apparent in 2 cases and hypotension and shock were reported in 2 cases. Other effects included elevated liver and renal function tests, leucocytosis, fever, and laryngolaryngitis (Lee et al, 1999).

Workplace Standards

    A) ACGIH TLV Values for CAS81405-85-8 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) ACGIH TLV Values for CAS114311-32-9 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    C) ACGIH TLV Values for CAS81334-34-1 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    D) ACGIH TLV Values for CAS81335-37-7 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    E) ACGIH TLV Values for CAS81335-77-5 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    F) NIOSH REL and IDLH Values for CAS81405-85-8 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    G) NIOSH REL and IDLH Values for CAS114311-32-9 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    H) NIOSH REL and IDLH Values for CAS81334-34-1 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    I) NIOSH REL and IDLH Values for CAS81335-37-7 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    J) NIOSH REL and IDLH Values for CAS81335-77-5 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    K) Carcinogenicity Ratings for CAS81405-85-8 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    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
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    L) Carcinogenicity Ratings for CAS114311-32-9 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    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
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    M) Carcinogenicity Ratings for CAS81334-34-1 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    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
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    N) Carcinogenicity Ratings for CAS81335-37-7 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Assessed under the IRIS program. ; Listed as: Imazaquin
    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
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    O) Carcinogenicity Ratings for CAS81335-77-5 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Assessed under the IRIS program. ; Listed as: Pursuit
    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
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    P) OSHA PEL Values for CAS81405-85-8 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

    Q) OSHA PEL Values for CAS114311-32-9 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

    R) OSHA PEL Values for CAS81334-34-1 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

    S) OSHA PEL Values for CAS81335-37-7 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

    T) OSHA PEL Values for CAS81335-77-5 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (ORAL)RAT:
    1) > 5g/kg ((RTECS, 2002))
    B) LD50- (ORAL)MOUSE:
    1) >2 g/kg ((RTECS, 2002))
    C) LD50- (ORAL)RAT:
    1) 4073 mg/kg ((RTECS, 2002))
    D) LD50- (ORAL)MOUSE:
    1) 1752 mg/kg ((RTECS, 2002))
    E) LD50- (ORAL)RAT:
    1) >5 g/kg ((RTECS, 2002))
    F) LD50- (ORAL)MOUSE:
    1) >5 g/kg ((RTECS, 2002))
    G) IMAZAMETHABENZ
    H) IMAZAPYR
    1) LD50- (ORAL)RAT:
    a) >5 g/kg ((RTECS, 2002))
    I) IMAZAQUIN
    J) IMAZETHAPYR

Pharmacology Toxicology

Pharmacologic Mechanism

    A) The imidazolinone herbicides are potent broad-leaf weed killers that act by blocking biosynthesis of valine, leucine, and isoleucine (which are absent in mammals) through inhibition of acetohydroxy acid synthase in plants (D'Ascenzo et al, 1998; Lee et al, 1999).

Toxicologic Mechanism

    A) The exact mechanism of poisoning from the imidazolinone herbicides is not clear at the time of this review.

Physicochemical

Physical Characteristics

    A) IMAZAPYR - As a liquid in the herbicide formulation (Arsenal(R)), this product is clear blue with a slight ammonium odor (MSDS, 1993). Imazapyr is a weak acid. The pH of a 1% solution is reported to be 3.0 to 3.5 (Lee et al, 1999).
    B) IMAZAQUIN - is a colorless to tan solid, with crystals formed from hexane plus ethyl acetate. It has a slightly pungent odor. Technical imazaquin is reported to be an odorless white solid (HSDB , 1999).
    C) IMAZETHAPYR - is a colorless crystal with a melting point of 172 to 175 degrees C (HSDB , 1999).

Ph

    A) IMAZAPYR - pH of a 1% solution is reported to be 3.0 to 3.5 (Lee et al, 1999).

Molecular Weight

    1) Imazamethabenz: 288.35
    2) Imazapyr: 261.28
    3) Imazaquin: 311.34
    4) Imazethapyr: 289.33

References

General Bibliography

    1) 40 CFR 372.28: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Lower thresholds for chemicals of special concern. National Archives and Records Administration (NARA) and the Government Printing Office (GPO). Washington, DC. Final rules current as of Apr 3, 2006.
    2) 40 CFR 372.65: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Chemicals and Chemical Categories to which this part applies. National Archives and Records Association (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Apr 3, 2006.
    3) 49 CFR 172.101 - App. B: Department of Transportation - Table of Hazardous Materials, Appendix B: List of Marine Pollutants. National Archives and Records Administration (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Aug 29, 2005.
    4) 62 FR 58840: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 1997.
    5) 65 FR 14186: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    6) 65 FR 39264: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    7) 65 FR 77866: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    8) 66 FR 21940: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2001.
    9) 67 FR 7164: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2002.
    10) 68 FR 42710: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2003.
    11) 69 FR 54144: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2004.
    12) AIHA: 2006 Emergency Response Planning Guidelines and Workplace Environmental Exposure Level Guides Handbook, American Industrial Hygiene Association, Fairfax, VA, 2006.
    13) 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.
    14) Anisuzzaman AKM, Amin M, & Ogg N: Synthesis of dimethyl derivatives of imidazolinone herbicides: their use in efficient gas chromatographic methods for the determination of these herbicides. J Agric Food Chem 2000; 48:5893-5902.
    15) Anon: Summary of toxicity studies on imazaquin and it's ammonium salt (technical information). J Pesticide Sci 1999; 24:245-249.
    16) Artigas A, Bernard GR, Carlet J, et al: The American-European consensus conference on ARDS, part 2: ventilatory, pharmacologic, supportive therapy, study design strategies, and issues related to recovery and remodeling.. Am J Respir Crit Care Med 1998; 157:1332-1347.
    17) Brower RG, Matthay AM, & Morris A: Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Eng J Med 2000; 342:1301-1308.
    18) Cataletto M: Respiratory Distress Syndrome, Acute(ARDS). In: Domino FJ, ed. The 5-Minute Clinical Consult 2012, 20th ed. Lippincott Williams & Wilkins, Philadelphia, PA, 2012.
    19) Chin TE, Wong RB, & Pont JL: Haptens and monoclonal antibodies for immunoassay of imidazolinone herbicides. J Agric Food Chem 2002; 50:3380-3389.
    20) D'Ascenzo G, Gentili A, & Marchese S: Development of a method based on liquid chromatography-electrospray mass spectrometry for analyzing imidazolinone herbicides in environmental water at part-per-trillion levels. J Chromatography A 1998; 800:109-119.
    21) DFG: List of MAK and BAT Values 2002, Report No. 38, Deutsche Forschungsgemeinschaft, Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area, Wiley-VCH, Weinheim, Federal Republic of Germany, 2002.
    22) EPA: Federal Register: Pesticide Tolerances for Imazethapyr. Rules and Regulations, 57, Government Printing Office, Washington, DC, 1992, pp 102.
    23) EPA: Search results for Toxic Substances Control Act (TSCA) Inventory Chemicals. US Environmental Protection Agency, Substance Registry System, U.S. EPA's Office of Pollution Prevention and Toxics. Washington, DC. 2005. Available from URL: http://www.epa.gov/srs/.
    24) Furlong ET, Burkhardt MR, & Gates PM: Routine determination of sulfonylurea, imidazolinone, and sulfonamide herbicides at nanogram-per-liter concentrations by solid-phase extraction and liquid chromatography/mass spectrometry. Sci Total Environ 2000; 248:135-146.
    25) HSDB : Hazardous Substances Data Bank. National Library of Medicine. Bethesda, MD (Internet Version). Edition expires 1999; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    26) Haas CF: Mechanical ventilation with lung protective strategies: what works?. Crit Care Clin 2011; 27(3):469-486.
    27) Heindel ND & Chun MC: Synthesis and CNS depressant activity of imidazolinone glyoxylates. J Pharm Sci 1973; 62:496-498.
    28) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans : IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: 1,3-Butadiene, Ethylene Oxide and Vinyl Halides (Vinyl Fluoride, Vinyl Chloride and Vinyl Bromide), 97, International Agency for Research on Cancer, Lyon, France, 2008.
    29) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans : IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Formaldehyde, 2-Butoxyethanol and 1-tert-Butoxypropan-2-ol, 88, International Agency for Research on Cancer, Lyon, France, 2006.
    30) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans : IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Household Use of Solid Fuels and High-temperature Frying, 95, International Agency for Research on Cancer, Lyon, France, 2010a.
    31) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans : IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Smokeless Tobacco and Some Tobacco-specific N-Nitrosamines, 89, International Agency for Research on Cancer, Lyon, France, 2007.
    32) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans : IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Some Non-heterocyclic Polycyclic Aromatic Hydrocarbons and Some Related Exposures, 92, International Agency for Research on Cancer, Lyon, France, 2010.
    33) IARC: List of all agents, mixtures and exposures evaluated to date - IARC Monographs: Overall Evaluations of Carcinogenicity to Humans, Volumes 1-88, 1972-PRESENT. World Health Organization, International Agency for Research on Cancer. Lyon, FranceAvailable from URL: http://monographs.iarc.fr/monoeval/crthall.html. As accessed Oct 07, 2004.
    34) International Agency for Research on Cancer (IARC): IARC monographs on the evaluation of carcinogenic risks to humans: list of classifications, volumes 1-116. International Agency for Research on Cancer (IARC). Lyon, France. 2016. Available from URL: http://monographs.iarc.fr/ENG/Classification/latest_classif.php. As accessed 2016-08-24.
    35) International Agency for Research on Cancer: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. World Health Organization. Geneva, Switzerland. 2015. Available from URL: http://monographs.iarc.fr/ENG/Classification/. As accessed 2015-08-06.
    36) Kleinman ME, Chameides L, Schexnayder SM, et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 14: pediatric advanced life support. Circulation 2010; 122(18 Suppl.3):S876-S908.
    37) Kollef MH & Schuster DP: The acute respiratory distress syndrome. N Engl J Med 1995; 332:27-37.
    38) Koutros S , Lynch CF , Ma X , et al: Heterocyclic aromatic amine pesticide use and human cancer risk: results from the U.S. Agricultural Health Study. Int J Cancer 2009; 124(5):1206-1212.
    39) Lagana A, Fago G, & Marino A: Simultaneous determination of imidazolinone herbicides from soil and natural waters using soil extraction followed by liquid chromatography with UV detection or liquid chromatography/electrospray mass spectroscopy. Anal Chem 1998; 70:121-130.
    40) Lee HL, Chen KW, & Wu MH: Acute poisoning with a herbicide containing imazapyr (Arsenal): A report of six cases. Clin Toxicol 1999; 37:83-89.
    41) MSDS: Material Safety Data Sheet, Imazapyr (Arsenal(R)), American Cyanamid Co, Wayne, NJ, 1993.
    42) NFPA: Fire Protection Guide to Hazardous Materials, 13th ed., National Fire Protection Association, Quincy, MA, 2002.
    43) NHLBI ARDS Network: Mechanical ventilation protocol summary. Massachusetts General Hospital. Boston, MA. 2008. Available from URL: http://www.ardsnet.org/system/files/6mlcardsmall_2008update_final_JULY2008.pdf. As accessed 2013-08-07.
    44) NRC: Acute Exposure Guideline Levels for Selected Airborne Chemicals - Volume 1, Subcommittee on Acute Exposure Guideline Levels, Committee on Toxicology, Board on Environmental Studies and Toxicology, Commission of Life Sciences, National Research Council. National Academy Press, Washington, DC, 2001.
    45) NRC: Acute Exposure Guideline Levels for Selected Airborne Chemicals - Volume 2, Subcommittee on Acute Exposure Guideline Levels, Committee on Toxicology, Board on Environmental Studies and Toxicology, Commission of Life Sciences, National Research Council. National Academy Press, Washington, DC, 2002.
    46) NRC: Acute Exposure Guideline Levels for Selected Airborne Chemicals - Volume 3, Subcommittee on Acute Exposure Guideline Levels, Committee on Toxicology, Board on Environmental Studies and Toxicology, Commission of Life Sciences, National Research Council. National Academy Press, Washington, DC, 2003.
    47) NRC: Acute Exposure Guideline Levels for Selected Airborne Chemicals - Volume 4, Subcommittee on Acute Exposure Guideline Levels, Committee on Toxicology, Board on Environmental Studies and Toxicology, Commission of Life Sciences, National Research Council. National Academy Press, Washington, DC, 2004.
    48) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 1,2,3-Trimethylbenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2006k. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d68a&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    49) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 1,2,4-Trimethylbenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2006m. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d68a&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    50) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 1,2-Butylene Oxide (Proposed). United States Environmental Protection Agency. Washington, DC. 2008d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648083cdbb&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    51) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 1,2-Dibromoethane (Proposed). United States Environmental Protection Agency. Washington, DC. 2007g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064802796db&disposition=attachment&contentType=pdf. As accessed 2010-08-18.
    52) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 1,3,5-Trimethylbenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2006l. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d68a&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    53) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 2-Ethylhexyl Chloroformate (Proposed). United States Environmental Protection Agency. Washington, DC. 2007b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648037904e&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    54) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Acrylonitrile (Proposed). United States Environmental Protection Agency. Washington, DC. 2007c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648028e6a3&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    55) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Adamsite (Proposed). United States Environmental Protection Agency. Washington, DC. 2007h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    56) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Agent BZ (3-quinuclidinyl benzilate) (Proposed). United States Environmental Protection Agency. Washington, DC. 2007f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064803ad507&disposition=attachment&contentType=pdf. As accessed 2010-08-18.
    57) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Allyl Chloride (Proposed). United States Environmental Protection Agency. Washington, DC. 2008. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648039d9ee&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    58) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Aluminum Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    59) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Arsenic Trioxide (Proposed). United States Environmental Protection Agency. Washington, DC. 2007m. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480220305&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    60) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Automotive Gasoline Unleaded (Proposed). United States Environmental Protection Agency. Washington, DC. 2009a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7cc17&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    61) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Biphenyl (Proposed). United States Environmental Protection Agency. Washington, DC. 2005j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064801ea1b7&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    62) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Bis-Chloromethyl Ether (BCME) (Proposed). United States Environmental Protection Agency. Washington, DC. 2006n. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648022db11&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    63) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Boron Tribromide (Proposed). United States Environmental Protection Agency. Washington, DC. 2008a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064803ae1d3&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    64) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Bromine Chloride (Proposed). United States Environmental Protection Agency. Washington, DC. 2007d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648039732a&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    65) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Bromoacetone (Proposed). United States Environmental Protection Agency. Washington, DC. 2008e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064809187bf&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    66) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Calcium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    67) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Carbonyl Fluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2008b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064803ae328&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    68) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Carbonyl Sulfide (Proposed). United States Environmental Protection Agency. Washington, DC. 2007e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648037ff26&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    69) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Chlorobenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2008c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064803a52bb&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    70) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Cyanogen (Proposed). United States Environmental Protection Agency. Washington, DC. 2008f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064809187fe&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    71) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Dimethyl Phosphite (Proposed). United States Environmental Protection Agency. Washington, DC. 2009. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7cbf3&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    72) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Diphenylchloroarsine (Proposed). United States Environmental Protection Agency. Washington, DC. 2007l. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    73) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ethyl Isocyanate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648091884e&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    74) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ethyl Phosphorodichloridate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480920347&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    75) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ethylbenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2008g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064809203e7&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    76) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ethyldichloroarsine (Proposed). United States Environmental Protection Agency. Washington, DC. 2007j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    77) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Germane (Proposed). United States Environmental Protection Agency. Washington, DC. 2008j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963906&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    78) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Hexafluoropropylene (Proposed). United States Environmental Protection Agency. Washington, DC. 2006. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064801ea1f5&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    79) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ketene (Proposed). United States Environmental Protection Agency. Washington, DC. 2007. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020ee7c&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    80) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Magnesium Aluminum Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    81) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Magnesium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    82) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Malathion (Proposed). United States Environmental Protection Agency. Washington, DC. 2009k. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064809639df&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    83) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Mercury Vapor (Proposed). United States Environmental Protection Agency. Washington, DC. 2009b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a8a087&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    84) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methyl Isothiocyanate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008k. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963a03&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    85) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methyl Parathion (Proposed). United States Environmental Protection Agency. Washington, DC. 2008l. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963a57&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    86) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methyl tertiary-butyl ether (Proposed). United States Environmental Protection Agency. Washington, DC. 2007a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064802a4985&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    87) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methylchlorosilane (Proposed). United States Environmental Protection Agency. Washington, DC. 2005. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5f4&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    88) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methyldichloroarsine (Proposed). United States Environmental Protection Agency. Washington, DC. 2007i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    89) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methyldichlorosilane (Proposed). United States Environmental Protection Agency. Washington, DC. 2005a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c646&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    90) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Nitrogen Mustard (HN1 CAS Reg. No. 538-07-8) (Proposed). United States Environmental Protection Agency. Washington, DC. 2006a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d6cb&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    91) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Nitrogen Mustard (HN2 CAS Reg. No. 51-75-2) (Proposed). United States Environmental Protection Agency. Washington, DC. 2006b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d6cb&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    92) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Nitrogen Mustard (HN3 CAS Reg. No. 555-77-1) (Proposed). United States Environmental Protection Agency. Washington, DC. 2006c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d6cb&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    93) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Nitrogen Tetroxide (Proposed). United States Environmental Protection Agency. Washington, DC. 2008n. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648091855b&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    94) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Nitrogen Trifluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2009l. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963e0c&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    95) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Parathion (Proposed). United States Environmental Protection Agency. Washington, DC. 2008o. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963e32&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    96) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Perchloryl Fluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2009c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7e268&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    97) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Perfluoroisobutylene (Proposed). United States Environmental Protection Agency. Washington, DC. 2009d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7e26a&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    98) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phenyl Isocyanate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008p. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648096dd58&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    99) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phenyl Mercaptan (Proposed). United States Environmental Protection Agency. Washington, DC. 2006d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020cc0c&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    100) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phenyldichloroarsine (Proposed). United States Environmental Protection Agency. Washington, DC. 2007k. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    101) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phorate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008q. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648096dcc8&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    102) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phosgene (Draft-Revised). United States Environmental Protection Agency. Washington, DC. 2009e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a8a08a&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    103) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phosgene Oxime (Proposed). United States Environmental Protection Agency. Washington, DC. 2009f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7e26d&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    104) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Potassium Cyanide (Proposed). United States Environmental Protection Agency. Washington, DC. 2009g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7cbb9&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    105) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Potassium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    106) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Propargyl Alcohol (Proposed). United States Environmental Protection Agency. Washington, DC. 2006e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020ec91&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    107) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Selenium Hexafluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2006f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020ec55&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    108) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Silane (Proposed). United States Environmental Protection Agency. Washington, DC. 2006g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d523&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    109) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Sodium Cyanide (Proposed). United States Environmental Protection Agency. Washington, DC. 2009h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7cbb9&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    110) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Sodium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    111) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Strontium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    112) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Sulfuryl Chloride (Proposed). United States Environmental Protection Agency. Washington, DC. 2006h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020ec7a&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    113) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Tear Gas (Proposed). United States Environmental Protection Agency. Washington, DC. 2008s. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648096e551&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    114) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Tellurium Hexafluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2009i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7e2a1&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    115) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Tert-Octyl Mercaptan (Proposed). United States Environmental Protection Agency. Washington, DC. 2008r. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648096e5c7&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    116) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Tetramethoxysilane (Proposed). United States Environmental Protection Agency. Washington, DC. 2006j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d632&disposition=attachment&contentType=pdf. As accessed 2010-08-17.
    117) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Trimethoxysilane (Proposed). United States Environmental Protection Agency. Washington, DC. 2006i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d632&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    118) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Trimethyl Phosphite (Proposed). United States Environmental Protection Agency. Washington, DC. 2009j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7d608&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    119) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Trimethylacetyl Chloride (Proposed). United States Environmental Protection Agency. Washington, DC. 2008t. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648096e5cc&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    120) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Zinc Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    121) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for n-Butyl Isocyanate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008m. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064808f9591&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    122) 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.
    123) National Research Council : Acute exposure guideline levels for selected airborne chemicals, 5, National Academies Press, Washington, DC, 2007.
    124) National Research Council: Acute exposure guideline levels for selected airborne chemicals, 6, National Academies Press, Washington, DC, 2008.
    125) National Research Council: Acute exposure guideline levels for selected airborne chemicals, 7, National Academies Press, Washington, DC, 2009.
    126) National Research Council: Acute exposure guideline levels for selected airborne chemicals, 8, National Academies Press, Washington, DC, 2010.
    127) Nejad H, Safarpour MM, & Cavalier T: Capillary electrophoresis determinative and LC-MS confirmatory method for screening selected imidazolinone herbicides from soil. J Cap Elec 1998; 5:81-87.
    128) Peberdy MA , Callaway CW , Neumar RW , et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care science. Part 9: post–cardiac arrest care. Circulation 2010; 122(18 Suppl 3):S768-S786.
    129) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
    130) RTECS : Registry of Toxic Effects of Chemical Substances. National Institute for Occupational Safety and Health. Cincinnati, OH (Internet Version). Edition expires 2002; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    131) Stolbach A & Hoffman RS: Respiratory Principles. In: Nelson LS, Hoffman RS, Lewin NA, et al, eds. Goldfrank's Toxicologic Emergencies, 9th ed. McGraw Hill Medical, New York, NY, 2011.
    132) U.S. Department of Energy, Office of Emergency Management: Protective Action Criteria (PAC) with AEGLs, ERPGs, & TEELs: Rev. 26 for chemicals of concern. U.S. Department of Energy, Office of Emergency Management. Washington, DC. 2010. Available from URL: http://www.hss.doe.gov/HealthSafety/WSHP/Chem_Safety/teel.html. As accessed 2011-06-27.
    133) U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project : 11th Report on Carcinogens. U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program. Washington, DC. 2005. Available from URL: http://ntp.niehs.nih.gov/INDEXA5E1.HTM?objectid=32BA9724-F1F6-975E-7FCE50709CB4C932. As accessed 2011-06-27.
    134) U.S. Environmental Protection Agency: Discarded commercial chemical products, off-specification species, container residues, and spill residues thereof. Environmental Protection Agency's (EPA) Resource Conservation and Recovery Act (RCRA); List of hazardous substances and reportable quantities 2010b; 40CFR(261.33, e-f):77-.
    135) U.S. Environmental Protection Agency: Integrated Risk Information System (IRIS). U.S. Environmental Protection Agency. Washington, DC. 2011. Available from URL: http://cfpub.epa.gov/ncea/iris/index.cfm?fuseaction=iris.showSubstanceList&list_type=date. As accessed 2011-06-21.
    136) U.S. Environmental Protection Agency: List of Radionuclides. U.S. Environmental Protection Agency. Washington, DC. 2010a. Available from URL: http://www.gpo.gov/fdsys/pkg/CFR-2010-title40-vol27/pdf/CFR-2010-title40-vol27-sec302-4.pdf. As accessed 2011-06-17.
    137) U.S. Environmental Protection Agency: List of hazardous substances and reportable quantities. U.S. Environmental Protection Agency. Washington, DC. 2010. Available from URL: http://www.gpo.gov/fdsys/pkg/CFR-2010-title40-vol27/pdf/CFR-2010-title40-vol27-sec302-4.pdf. As accessed 2011-06-17.
    138) U.S. Environmental Protection Agency: The list of extremely hazardous substances and their threshold planning quantities (CAS Number Order). U.S. Environmental Protection Agency. Washington, DC. 2010c. Available from URL: http://www.gpo.gov/fdsys/pkg/CFR-2010-title40-vol27/pdf/CFR-2010-title40-vol27-part355.pdf. As accessed 2011-06-17.
    139) U.S. Occupational Safety and Health Administration: Part 1910 - Occupational safety and health standards (continued) Occupational Safety, and Health Administration's (OSHA) list of highly hazardous chemicals, toxics and reactives. Subpart Z - toxic and hazardous substances. CFR 2010 2010; Vol6(SEC1910):7-.
    140) U.S. Occupational Safety, and Health Administration (OSHA): Process safety management of highly hazardous chemicals. 29 CFR 2010 2010; 29(1910.119):348-.
    141) United States Environmental Protection Agency Office of Pollution Prevention and Toxics: Acute Exposure Guideline Levels (AEGLs) for Vinyl Acetate (Proposed). United States Environmental Protection Agency. Washington, DC. 2006. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d6af&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    142) Willson DF, Truwit JD, Conaway MR, et al: The Adult Calfactant in Acute Respiratory Distress Syndrome (CARDS) Trial. Chest 2015; Epub:Epub.
    143) Wilson DF, Thomas NJ, Markovitz BP, et al: Effect of exogenous surfactant (calfactant) in pediatric acute lung injury. A randomized controlled trial. JAMA 2005; 293:470-476.