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IOXYNIL AND RELATED AGENTS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Ioxynil and bromoxynil are nitrile and organic cyanide compounds used either alone or in combination as herbicides. They have both contact and systemic activity. They are used primarily by spraying, and are most effective when used post-emergently on annual broad-leaf weeds .
    B) Exposure to ioxynil occurs during manufacture, application, accidental spillage or ingestion, transportation, and via intentional suicide attempts.

Specific Substances

    A) BROMOXYNIL
    1) 2,6-Dibromo-4-cyanophenol
    2) 3,5-Dibromo-4-hydroxybenzonitrile
    3) 4-Hydroxy-3,5-dibromobenzonitrile
    4) MB 10064
    5) CAS 1689-84-5
    IOXYNIL
    1) 4-Cyano-2,6,-diiodophenol benzonitril
    2) 4-Hydroxy-3,5-diiodobenzonitrile
    3) 4-Hydroxy-3,5-diiodophenyl cyanide
    4) CAS 11689-83-4
    5) Actrilawn 10
    6) Mate
    7) NIOSH/RTECS DI 4025000
    8) References: RTECS, 1993
    9) ACP 63303
    10) ACTRIL
    11) BANTROL
    12) BENTROL
    13) CERTOL
    14) CERTROL
    15) IOTOX
    16) LOXYNIL (GERMAN)
    17) M&B 8873
    18) MYLONE (IOXYNIL)
    19) NORTRON
    20) OXYTRIL
    21) TOTRIL

Available Forms Sources

    A) FORMS
    1) Synthesis of ioxynil, as a benzonitrile compound, is accomplished by a single stage halogenation of 4-hydroxybenzonitrile (Carpenter et al, 1964).
    2) Some brand names of ioxynil include:
    1) Actril
    2) Actrilawn 10
    3) Advance
    4) Alpha Briotril
    5) Assassin
    6) Astrol
    7) Atlas Minerva
    8) Atom
    9) Bantrol
    10) Banvel 1C, 1E,1S
    11) Bentrol
    12) Campbell's Oxystat
    13) Centrol
    14) Certrol PA
    15) Crusader S
    16) Deloxil
    17) Dictator
    18) Doublet
    19) EF 500
    20) Escort
    21) FR 1001
    22) Framolene
    23) Glean
    24) Harrier
    25) Hobane
    26) Hotspur
    27) Jaguar
    28) Iotox
    29) Isoproturon
    30) Loxynil
    31) Malet
    32) Masterspray
    33) Mate
    34) Myolone
    35) Musketeer
    36) New Clovotox
    37) Nortron Leyclene
    38) Novacorn
    39) Oxycorn Extra
    40) Oxytril
    41) Oxytril CM
    42) Post-Kite
    43) Springclene
    44) Stellox 380 EC
    45) Stellox 400 EC
    46) Stexal
    47) Super Verdone
    48) Swipe 560 EC
    49) Synox
    50) Terset
    51) Tetrone
    52) Thor
    53) Topper 2 + 2
    54) Totril
    55) Toxynil
    56) Twin Tak
    B) SOURCES
    1) Ioxynil is available through the following manufacturers and distributors:
    1) A H Marks & Company Ltd
    2) Alpha (GB) Ltd
    3) Atlas Interatlas Ltd
    4) Boonhill Ltd
    5) Ciba-Geigy Agrochemicals
    6) Dow Chemical
    7) Du Pont
    8) Embassy Crop Protection
    9) Embetec Crop Protection
    10) Farm Crop Chemicals Ltd
    11) Farm Protection Ltd
    12) FBC Ltd
    13) Hoechst Ltd
    14) Hortichem Ltd
    15) Imperial Chemical Industries
    16) J D Campbell & Sons Ltd
    17) Makhetensim Agan UK Ltd
    18) May & Baker Agrochemicals
    19) Murphy Chemicals Ltd
    20) Pan Britanica Industries Ltd
    21) Rhone-Poluenc Agriculture
    22) Rhone-Poluenc Crop Protections
    23) Rhone-Poluenc Environmental Products
    24) Schering Agrochemicals Ltd
    25) Synchemical Ltd
    26) Union Carbide
    27) Velsicol Chemicals Ltd
    C) USES
    1) Ioxynil and bromoxynil are nitrile and organic cyanide compounds used either alone or in combination as herbicides. They have both contact and systemic activity. They are used primarily by spraying, and are most effective when used post-emergently on annual broad-leaf weeds (Cupples et al, 2005).

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: Ioxynil and bromoxynil are nitrile and organic cyanide compounds used either alone or in combination with chlorophenoxy herbicides. They are used primarily by spraying and are most effective when used post-emergently on annual broad-leaf weeds. Exposure to ioxynil occurs during manufacture, application, accidental spillage or ingestion, transportation, and via intentional suicide attempts.
    B) TOXICOLOGY: The mechanism of action in humans has not yet been determined. Experimental data from rat liver mitochondria suggests that ioxynil uncouples oxidative phosphorylation.
    C) EPIDEMIOLOGY: Exposure is not common; most exposures also involve a chlorophenoxy herbicide. Severe toxicity is rare but has been reported.
    D) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Ioxynil and bromoxynil may cause miosis, eye or skin irritation, diaphoresis, tachycardia, tachypnea, headache, euphoria, agitation, weakness, confusion, vomiting, diarrhea, acidosis, myalgias, transient elevations in liver enzymes, hyperkalemia, and hyperthermia.
    2) SEVERE TOXICITY: Severe exposure to ioxynil or bromoxynil may cause hemorrhage, rhabdomyolysis, syncope, cerebral edema, pulmonary edema, seizures, cardiac arrest, coma, and death.
    0.2.20) REPRODUCTIVE
    A) Ioxynil has been shown to be teratogenic in rats and rabbits. No information is available about excretion in human breast milk. Experiments in cows did not show transfer by this route.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no data were available to assess the carcinogenic potential of this agent.

Laboratory Monitoring

    A) Monitor vital signs and mental status following significant exposure.
    B) Monitor liver enzymes, CBC, electrolytes, fluid balance, and kidney function.
    C) Obtain a chest x-ray in patients with respiratory symptoms to evaluate for pneumonitis and pulmonary edema.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Monitor for and treat electrolyte abnormalities. Administer intravenous fluids and antiemetics as necessary.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Supportive care with attention to monitoring for respiratory depression. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Treat hypotension with intravenous fluids; add vasopressors if necessary.
    C) DECONTAMINATION
    1) PREHOSPITAL: Gastrointestinal decontamination is not recommended because of the risk of CNS depression or seizures and subsequent aspiration. Irrigate exposed eyes. Remove contaminated clothing and wash exposed skin with soap and water.
    2) HOSPITAL: Remove contaminated clothing and wash exposed area extremely thoroughly with soap and water. Remove contaminated lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. Consider activated charcoal in patients with large recent ingestions who are alert and can protect airway. Use with caution in patients with CNS and/or respiratory depression because of the risk of aspiration.
    D) AIRWAY MANAGEMENT
    1) Monitor for respiratory depression. Endotracheal intubation may be needed in rare patients with severe CNS depression or respiratory failure.
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION PROCEDURE
    1) Hemoperfusion and alkaline diuresis have no effect on ioxynil or bromoxynil clearance. The effect of hemodialysis on ioxynil or bromoxynil clearance had not been evaluated. Hemodialysis may be necessary to treat hyperkalemia in rare patients who are not responding to other measures.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: There is no data to support home management after ingestion. Patients with minor irritation after inadvertent skin, eye or inhalation exposure can be monitored at home.
    2) OBSERVATION CRITERIA: Patients with ingestion, and those with more severe symptoms after skin, eye, or inhalation exposure should be referred to a healthcare facility for evaluation and treatment.
    3) ADMISSION CRITERIA: Patients with acute renal insufficiency, elevated liver enzymes, persistent electrolyte abnormalities or CNS effects should be admitted. Patients with hemodynamic instability, severe acidosis, or severe CNS depression should be admitted to an intensive care setting.
    4) CONSULT CRITERIA: Contact a medical toxicologist or your local poison center for any patient with suspected herbicide toxicity.
    H) PITFALLS
    1) Uncouplers of oxidative phosphorylation can mimic sepsis. Consider alternative infectious etiologies in addition to toxic exposures.
    I) DIFFERENTIAL DIAGNOSIS
    1) Consider exposure to 2,6-dichlorobenzonitrile, chlorophenoxy herbicides, 2,4-dinitrophenol, salicylates, and bromethalin - agents that cause uncoupling of oxidative phosphorylation.
    0.4.3) INHALATION EXPOSURE
    A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

    A) TOXICITY: Ingestion of 2 to 3 grams in an adult may lead to death within 45 minutes; 18 grams was lethal within 15 hours in an adult, even with hospital care.

Clinical Effects

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH POISONING/EXPOSURE
    a) Headache may occur after either ingestion, dermal exposure, or inhalation (Conso et al, 1977).
    B) SYNCOPE
    1) WITH POISONING/EXPOSURE
    a) Syncope has been reported after exposure by any route (Conso et al, 1977).
    C) DROWSY
    1) WITH POISONING/EXPOSURE
    a) Drowsiness and coma have been seen when ingested alone or with chlorophenoxy compounds (Flanagan et al, 1990; Abi Khalil F, Alvoet C & Ectors M et al, 1987).
    D) COMA
    1) WITH POISONING/EXPOSURE
    a) Drowsiness and coma have been seen when ingested alone or with chlorophenoxy compounds (Flanagan et al, 1990; Abi Khalil F, Alvoet C & Ectors M et al, 1987).
    b) BROMOXYNIL: In a study of 7 patients with inhalational exposure to bromoxynil, coma developed in 5 patients (Wang, 2005; Zhang et al, 2005).
    E) EUPHORIA
    1) WITH POISONING/EXPOSURE
    a) Euphoria has been reported after ingestion (Abi Khalil F, Alvoet C & Ectors M et al, 1987).
    F) PSYCHOMOTOR AGITATION
    1) WITH POISONING/EXPOSURE
    a) Agitation has been reported after ingestion (Abi Khalil F, Alvoet C & Ectors M et al, 1987).
    b) BROMOXYNIL: In a study of 7 patients with inhalational exposure to bromoxynil, irritability developed in 5 patients (Wang, 2005; Zhang et al, 2005).
    G) CEREBRAL EDEMA
    1) WITH POISONING/EXPOSURE
    a) Cerebral edema and pulmonary edema were observed during an autopsy of a 54-year-old male, with a prior gastrectomy, who died approximately 45 minutes after ingestion of approximately 2 to 3 grams of an unknown fluid. Chemical analysis of the remaining fluid determined that it contained ioxynil at a concentration of 11.3% (HSDB , 2001).
    H) DIZZINESS
    1) WITH POISONING/EXPOSURE
    a) BROMOXYNIL: In a study of 7 patients with inhalational exposure to bromoxynil, dizziness developed in all 7 patients (Wang, 2005; Zhang et al, 2005).
    I) CLOUDED CONSCIOUSNESS
    1) WITH POISONING/EXPOSURE
    a) BROMOXYNIL: In a study of 7 patients with inhalational exposure to bromoxynil, confusion developed in 5 patients (Wang, 2005; Zhang et al, 2005).
    J) HYPERREFLEXIA
    1) WITH POISONING/EXPOSURE
    a) BROMOXYNIL: In a study of 7 patients with inhalational exposure to bromoxynil, tendon hyperreflexia developed in 3 patients (Wang, 2005; Zhang et al, 2005).
    K) ASTHENIA
    1) WITH POISONING/EXPOSURE
    a) BROMOXYNIL: In a study of 7 patients with inhalational exposure to bromoxynil, limb weakness developed in all 7 patients (Wang, 2005; Zhang et al, 2005).
    L) NEUROLOGICAL DEFICIT
    1) WITH POISONING/EXPOSURE
    a) BROMOXYNIL: In a study of 7 patients with inhalational exposure to bromoxynil, sensory impairment developed in 1 patient (Wang, 2005; Zhang et al, 2005).
    M) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) BROMOXYNIL: In a study of 7 patients with inhalational exposure to bromoxynil, 3 patients were initially misdiagnosed with organophosphate poisoning and were given atropine 1 to 2 mg IV. Although 2 of these patients were improving, their condition deteriorated rapidly and they developed seizures, cardiac arrest, and died within 3 hours of receiving atropine. (Wang, 2005; Zhang et al, 2005).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH POISONING/EXPOSURE
    a) Vomiting may occur after exposures to ioxynil (HSDB , 2001; Conso et al, 1977).
    b) BROMOXYNIL: In a study of 7 patients with inhalational exposure to bromoxynil, vomiting developed in all 7 patients (Wang, 2005; Zhang et al, 2005).
    c) BROMOXYNIL WITH 2-METHYL-4-CHLOROPHENOXYACETIC ACID: CASE REPORT: A 37-year-old man developed nausea, vomiting, diarrhea, diaphoresis, tachycardia, tachypnea, and agitation within 8 hours after intentionally ingesting 200 mL of an herbicide containing MCPA 200 g/L and bromoxynil 200 g/L, mixed with a hydrocarbon solvent. Despite supportive care, including continuous veno-venous hemodialysis, his condition deteriorated, with development of hyperthermia with hypotension. Approximately 20 hours post-ingestion, the patient died following development of asystolic cardiac arrest with failed resuscitation. Serum MCPA concentrations obtained 2 hours post-ingestion and 19 hours post-ingestion were 83.9 mcg/mL and 100 mcg/mL, respectively (Berling et al, 2015).
    B) WEIGHT LOSS FINDING
    1) WITH POISONING/EXPOSURE
    a) Weight loss may occur after exposures to ioxynil (Conso et al, 1977) and may be due to excessive sweating, fever, and emesis (HSDB , 2001).
    C) DIARRHEA
    1) WITH POISONING/EXPOSURE
    a) Diarrhea has been seen when ingested with chlorophenoxy compounds (Flanagan et al, 1990).
    b) BROMOXYNIL: In a study of 7 patients with inhalational exposure to bromoxynil, diarrhea developed in 2 patients (Wang, 2005; Zhang et al, 2005).
    D) THIRST FINDING
    1) WITH POISONING/EXPOSURE
    a) Excessive thirst may occur after either inhalation or ingestion (Conso et al, 1977).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) Transient elevations in creatinine phosphokinase, LDH, aldolase, and SGOT have occurred and have been associated with myalgia (HSDB , 2001; Conso et al, 1977).
    b) BROMOXYNIL: In a study of 7 patients with inhalational exposure to bromoxynil, elevated lactate dehydrogenase and aspartate aminotransferase developed in 2 patients (Wang, 2005; Zhang et al, 2005).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ACUTE RENAL FAILURE SYNDROME
    1) WITH POISONING/EXPOSURE
    a) Acute renal failure may develop in cases where dehydration occurs from vomiting and diarrhea (Conso et al, 1977; Smysl et al, 1977).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) WITH POISONING/EXPOSURE
    a) Hyperkalemic metabolic acidosis may be seen after intoxication with ioxynil (Smysl et al, 1977; Conso et al, 1977).
    b) BROMOXYNIL: In a study of 7 patients with inhalational exposure to bromoxynil, respiratory alkalosis with metabolic acidosis developed in 3 patients (Wang, 2005; Zhang et al, 2005).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) HEMORRHAGE
    1) WITH POISONING/EXPOSURE
    a) One lethal ingestion of 2 to 3 grams showed lung, adrenal, and kidney hemorrhages (Smysl et al, 1977).
    B) LEUKOCYTOSIS
    1) WITH POISONING/EXPOSURE
    a) BROMOXYNIL: In a study of 7 patients with inhalational exposure to bromoxynil, elevated white blood cells developed in 2 patients (Wang, 2005; Zhang et al, 2005).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH POISONING/EXPOSURE
    a) May be irritating to the skin on prolonged exposure (May & Baker, 1990).
    B) EXCESSIVE SWEATING
    1) WITH POISONING/EXPOSURE
    a) Excessive sweating may be seen after exposure (HSDB , 2001; Conso et al, 1977).
    b) BROMOXYNIL: In a study of 7 patients with inhalational exposure to bromoxynil, excessive sweating developed in all 7 patients (Wang, 2005; Zhang et al, 2005).
    C) ERYTHEMA
    1) WITH POISONING/EXPOSURE
    a) BROMOXYNIL: In a study of 7 patients with inhalational exposure to bromoxynil, redness of skin developed in 5 patients (Wang, 2005; Zhang et al, 2005).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE PAIN
    1) WITH POISONING/EXPOSURE
    a) Myalgias of the legs may be seen after exposure (Conso et al, 1977).
    B) RHABDOMYOLYSIS
    1) WITH POISONING/EXPOSURE
    a) BROMOXYNIL: In a study of 7 patients with inhalational exposure to bromoxynil, elevated CK developed in 2 patients (Wang, 2005; Zhang et al, 2005).

Summary Of Exposure

    A) USES: Ioxynil and bromoxynil are nitrile and organic cyanide compounds used either alone or in combination with chlorophenoxy herbicides. They are used primarily by spraying and are most effective when used post-emergently on annual broad-leaf weeds. Exposure to ioxynil occurs during manufacture, application, accidental spillage or ingestion, transportation, and via intentional suicide attempts.
    B) TOXICOLOGY: The mechanism of action in humans has not yet been determined. Experimental data from rat liver mitochondria suggests that ioxynil uncouples oxidative phosphorylation.
    C) EPIDEMIOLOGY: Exposure is not common; most exposures also involve a chlorophenoxy herbicide. Severe toxicity is rare but has been reported.
    D) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Ioxynil and bromoxynil may cause miosis, eye or skin irritation, diaphoresis, tachycardia, tachypnea, headache, euphoria, agitation, weakness, confusion, vomiting, diarrhea, acidosis, myalgias, transient elevations in liver enzymes, hyperkalemia, and hyperthermia.
    2) SEVERE TOXICITY: Severe exposure to ioxynil or bromoxynil may cause hemorrhage, rhabdomyolysis, syncope, cerebral edema, pulmonary edema, seizures, cardiac arrest, coma, and death.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH POISONING/EXPOSURE
    1) FEVER may occur after either inhalation or ingestion (HSDB , 2001; Conso et al, 1977).
    2) BROMOXYNIL: In a study of 7 patients with inhalational exposure to bromoxynil, fever developed in 4 patients (Wang, 2005; Zhang et al, 2005).
    3) BROMOXYNIL WITH 2-METHYL-4-CHLOROPHENOXYACETIC ACID: CASE REPORT: A 37-year-old man developed tachypnea (30 breaths/min) approximately 8 hours after intentionally ingesting 200 mL of an herbicide containing MCPA 200 g/L and bromoxynil 200 g/L, mixed with a hydrocarbon solvent. Prior to the tachypnea, the patient had developed nausea, vomiting, diarrhea, tachycardia, diaphoresis, and agitation. Despite supplemental oxygen, his tachypnea worsened (greater than 50 breaths/min). Following rapid sequence intubation, approximately 16 hours post-ingestion, his respiratory rate decreased from 56 to 36, however his tachycardia and diaphoresis persisted, and he developed hyperthermia (40 degrees C) and hypotension. Despite symptomatic therapy, his temperature continued to increase (42.5 degrees C), and 20 hours post-ingestion, he died following development of asystolic cardiac arrest with failed resuscitation. Serum MCPA concentrations obtained 2 hours post-ingestion and 19 hours post-ingestion were 83.9 mcg/mL and 100 mcg/mL, respectively (Berling et al, 2015).

Heent

    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) Prolonged contact after a splash exposure may produce irritation and slight conjunctival swelling (May & Baker, 1990).
    2) Pupillary constriction was noted in a mixed ioxynil-chlorophenoxy herbicide ingestion (Dickey et al, 1988).
    3) BROMOXYNIL: In a study of 7 patients with inhalational exposure to bromoxynil, miosis developed in 5 patients (Wang, 2005; Zhang et al, 2005).

Reproductive

    3.20.1) SUMMARY
    A) Ioxynil has been shown to be teratogenic in rats and rabbits. No information is available about excretion in human breast milk. Experiments in cows did not show transfer by this route.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) RABBITS - Severe ossification defects of the skull, including anophthalmia, microphthalmia and hydrocephalus, as well as abnormalities of the spine and ribs, were seen in rabbits given 15, 30, and 60 mg/kg from day to 5 to 20 days postcoitum (May & Baker, 1990).
    2) RATS - Similar abnormalities were seen in rats given 5, 15, or 35 mg/kg from days 5 to 17 postcoitum (May & Baker, 1990).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) HUMANS
    1) Effects unknown
    B) ANIMAL STUDIES
    1) COWS - Ioxynil given orally to cows (5 ppm) was not detected in the milk (May & Baker, 1990).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS1689-83-4 (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 CAS1689-84-5 (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) At the time of this review, no data were available to assess the carcinogenic potential of this agent.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the carcinogenic potential of this agent.

Genotoxicity

    A) At the time of this review, no data were available to assess the mutagenic or genotoxic potential of this agent.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) TACHYCARDIA
    1) WITH POISONING/EXPOSURE
    a) Tachycardia has been seen when ingested with chlorophenoxy compounds (Dickey et al, 1988; Flanagan et al, 1990).
    b) BROMOXYNIL: In a study of 7 patients with inhalational exposure to bromoxynil, tachycardia developed in 5 patients (Wang, 2005; Zhang et al, 2005).
    c) BROMOXYNIL WITH 2-METHYL-4-CHLOROPHENOXYACETIC ACID: CASE REPORT: A 37-year-old man developed nausea, vomiting, diarrhea, diaphoresis, tachycardia, tachypnea, and agitation within 8 hours after intentionally ingesting 200 mL of an herbicide containing MCPA 200 g/L and bromoxynil 200 g/L, mixed with a hydrocarbon solvent. Despite supportive care, including continuous veno-venous hemodialysis, his condition deteriorated, with development of hyperthermia with hypotension. Approximately 20 hours post-ingestion, the patient died following development of asystolic cardiac arrest with failed resuscitation. Serum MCPA concentrations obtained 2 hours post-ingestion and 19 hours post-ingestion were 83.9 mcg/mL and 100 mcg/mL, respectively (Berling et al, 2015).
    B) CARDIAC ARREST
    1) WITH POISONING/EXPOSURE
    a) Cardiac arrest has been seen when ingested with chlorophenoxy compounds (Dickey et al, 1988; Flanagan et al, 1990). Cardiac effects may be enhanced by hyperkalemia (Paris, 1983).
    b) BROMOXYNIL: In a study of 7 patients with inhalational exposure to bromoxynil, 3 patients with severe intoxication were initially misdiagnosed with organophosphate poisoning and were given atropine 1 to 2 mg IV. Although 2 of these patients were improving, their condition deteriorated rapidly and they developed seizures, cardiac arrest, and died within 3 hours of receiving atropine. (Wang, 2005; Zhang et al, 2005).
    c) BROMOXYNIL WITH 2-METHYL-4-CHLOROPHENOXYACETIC ACID: CASE REPORT: A 37-year-old man developed nausea, vomiting, diarrhea, diaphoresis, tachycardia, tachypnea, and agitation within 8 hours after intentionally ingesting 200 mL of an herbicide containing MCPA 200 g/L and bromoxynil 200 g/L, mixed with a hydrocarbon solvent. Despite supportive care, including continuous veno-venous hemodialysis, his condition deteriorated, with development of hyperthermia with hypotension. Approximately 20 hours post-ingestion, the patient died following development of asystolic cardiac arrest with failed resuscitation. Serum MCPA concentrations obtained 2 hours post-ingestion and 19 hours post-ingestion were 83.9 mcg/mL and 100 mcg/mL, respectively (Berling et al, 2015).
    C) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) BROMOXYNIL WITH 2-METHYL-4-CHLOROPHENOXYACETIC ACID: CASE REPORT: A 37-year-old man developed nausea, vomiting, diarrhea, diaphoresis, tachycardia, tachypnea, and agitation within 8 hours after intentionally ingesting 200 mL of an herbicide containing MCPA 200 g/L and bromoxynil 200 g/L, mixed with a hydrocarbon solvent. Despite supportive care, including continuous veno-venous hemodialysis, his condition deteriorated, with development of hyperthermia with hypotension. Approximately 20 hours post-ingestion, the patient died following development of asystolic cardiac arrest with failed resuscitation. Serum MCPA concentrations obtained 2 hours post-ingestion and 19 hours post-ingestion were 83.9 mcg/mL and 100 mcg/mL, respectively (Berling et al, 2015).
    D) TIGHT CHEST
    1) WITH POISONING/EXPOSURE
    a) BROMOXYNIL: In a study of 7 patients with inhalational exposure to bromoxynil, chest tightness developed in all 7 patients (Wang, 2005; Zhang et al, 2005).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) HYPERVENTILATION
    1) WITH POISONING/EXPOSURE
    a) Hyperventilation has been seen when ingested with chlorophenoxy compounds (Dickey et al, 1988; Flanagan et al, 1990; Abi Khalil F, Alvoet C & Ectors M et al, 1987).
    b) BROMOXYNIL WITH 2-METHYL-4-CHLOROPHENOXYACETIC ACID: CASE REPORT: CASE REPORT: A 37-year-old man developed tachypnea (30 breaths/min) approximately 8 hours after intentionally ingesting 200 mL of an herbicide containing MCPA 200 g/L and bromoxynil 200 g/L, mixed with a hydrocarbon solvent. Prior to the tachypnea, the patient had developed nausea, vomiting, diarrhea, tachycardia, diaphoresis, and agitation. Despite supplemental oxygen, his tachypnea worsened (greater than 50 breaths/min). Following rapid sequence intubation, approximately 16 hours post-ingestion, his respiratory rate decreased from 56 to 36, however his tachycardia and diaphoresis persisted, and he developed hyperthermia (40 degrees C) and hypotension. Despite symptomatic therapy, his temperature continued to increase (42.5 degrees C), and 20 hours post-ingestion, he died following development of asystolic cardiac arrest with failed resuscitation. Serum MCPA concentrations obtained 2 hours post-ingestion and 19 hours post-ingestion were 83.9 mcg/mL and 100 mcg/mL, respectively (Berling et al, 2015).
    B) ACUTE LUNG INJURY
    1) WITH POISONING/EXPOSURE
    a) Pulmonary edema has been seen when ingested with chlorphenoxy compounds and a hydrocarbon solvent (Dickey et al, 1988).
    b) Pulmonary edema and cerebral edema were observed during an autopsy of a 54-year-old male, with a prior gastrectomy, who died approximately 45 minutes after ingestion of approximately 2 to 3 grams of an unknown fluid. Chemical analysis of the remaining fluid determined that it contained ioxynil at a concentration of 11.3% (HSDB , 2001).
    C) DYSPNEA
    1) WITH POISONING/EXPOSURE
    a) BROMOXYNIL: In a study of 7 patients with inhalational exposure to bromoxynil, dyspnea developed in 5 patients (Wang, 2005; Zhang et al, 2005).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and mental status following significant exposure.
    B) Monitor liver enzymes, CBC, electrolytes, fluid balance, and kidney function.
    C) Obtain a chest x-ray in patients with respiratory symptoms to evaluate for pneumonitis and pulmonary edema.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor liver enzymes and serum electrolytes (especially potassium).
    B) HEMATOLOGIC
    1) Monitor CBC.

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) Ioxynil is often mixed in a hydrocarbon base. Ingestion may result in pulmonary edema. Monitoring the chest x-ray may be useful in these cases.

Methods

    A) CHROMATOGRAPHY
    1) Ioxynil can be determined in biological specimens using HPLC (Flanagan & Ruprah, 1989).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with acute renal insufficiency, elevated liver enzymes, persistent electrolyte abnormalities or CNS effects should be admitted. Patients with hemodynamic instability, severe acidosis, or severe CNS depression should be admitted to an intensive care setting.
    6.3.1.2) HOME CRITERIA/ORAL
    A) There is no data to support home management after ingestion. Patients with minor irritation after inadvertent skin, eye or inhalation exposure can be monitored at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Contact a medical toxicologist or your local poison center for any patient with suspected herbicide toxicity.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with ingestion, and those with more severe symptoms after skin, eye, or inhalation exposure should be referred to a healthcare facility for evaluation and treatment.

Monitoring

    A) Monitor vital signs and mental status following significant exposure.
    B) Monitor liver enzymes, CBC, electrolytes, fluid balance, and kidney function.
    C) Obtain a chest x-ray in patients with respiratory symptoms to evaluate for pneumonitis and pulmonary edema.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is not recommended because of the risk of CNS depression or seizures and subsequent aspiration. Irrigate exposed eyes. Remove contaminated clothing and wash exposed skin with soap and water.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive. Monitor for and treat electrolyte abnormalities. Administer intravenous fluids and antiemetics as necessary.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Supportive care with attention to monitoring for respiratory depression. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Treat hypotension with intravenous fluids; add vasopressors if necessary.
    B) MONITORING OF PATIENT
    1) Monitor vital signs and mental status following significant exposure.
    2) Monitor liver enzymes, CBC, electrolytes, fluid balance, and kidney function.
    3) Obtain a chest radiograph in patients with respiratory symptoms to evaluate for pneumonitis and pulmonary edema.
    C) 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).
    D) SEIZURE
    1) Are not commonly seen.
    2) 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).
    3) 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 .
    4) 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).
    5) 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).
    6) 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).
    7) 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).

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Inhalation exposure may occur during manufacture (spraying or drying process) (Conso et al, 1977).
    B) 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.
    C) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    D) 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) 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).
    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 exposure may occur during spraying or by materials being splashed on the skin while applying or measuring the material.
    B) 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).

Enhanced Elimination

    A) SUMMARY
    1) Hemoperfusion and alkaline diuresis have no effect on ioxynil or bromoxynil clearance. The effect of hemodialysis on ioxynil or bromoxynil clearance had not been evaluated. Hemodialysis may be necessary to treat hyperkalemia in rare patients who are not responding to other measures.
    B) HEMOPERFUSION
    1) Hemoperfusion did not have an effect on ioxynil clearance.
    2) A patient who had a serum level of 0.3 gram per liter prior to hemoperfusion had a level of 0.285 gram per liter at 2, 4, and 5 hours after hemoperfusion was begun. The patient died (Abi Khalil F, Alvoet C & Ectors M et al, 1987).
    C) FORCED ALKALINE DIURESIS
    1) Forced alkaline diuresis did not effect ioxynil clearance, but 3 of 3 patients treated for a mixed ioxynil-chlorphenoxy compound exposure lived, while 3 of 4 given supportive care alone died (Flanagan et al, 1990).
    2) The mechanism by which forced alkaline diuresis might have been efficacious helped is unknown, more research is needed.
    3) In general, forced diuresis has NOT been found to be efficacious in poisonings, and this procedure has largely been abandoned by clinical toxicologists.
    D) DIALYSIS
    1) HYPERKALEMIA: May require peritoneal dialysis or hemodialysis if potassium levels rise rapidly and are not controlled by other measures.

Abstracts

Case Reports

    A) ACUTE EFFECTS
    1) A 54-year-old man ingested a "small amount" of an 11.3% ioxynil solution. The amount of pure ioxynil was estimated to be about 2 to 3 grams. The patient died on the way to the hospital, within 45 minutes of ingesting the solution. Autopsy showed hyperemia of all organs, and edema of the lungs and brain. The lungs, liver, adrenal glands, and kidneys all showed extensive evidence of hemorrhage. The patient had been drinking alcohol, and had a gastrectomy (Smysl et al, 1977).
    B) ORAL
    1) A 26-year-old attempted suicide by ingesting 75 mL of an ioxynil solution (estimated to contain about 18 grams of pure ioxynil). Agitation, euphoria, sedation, and tachypnea were seen within 20 minutes. The patient was decontaminated with lavage and charcoal, and respirations were assisted. Within 90 minutes of the ingestion, hemoperfusion was performed. The patient died 15 hours postadmission. Hemoperfusion did not appear to be effective (Abi Khalil F, Alvoet C & Ectors M et al, 1987).
    C) ADULT
    1) Four workers in an ioxynil and bromoxynil manufacturing plant developed unusual sweating and thirst. Fever, headache, dizziness, vomiting, asthenia, weight loss, and lower extremity myalgia were noted as well. The onset of these symptoms was gradual. The myalgia was associated with transient elevations in creatinine phosphokinase, LDH, aldolase, and SGOT. A muscle biopsy showed no abnormalities. Symptoms resolved without sequalae when the men were no longer exposed (Conso et al, 1977).

Range Of Toxicity

Summary

    A) TOXICITY: Ingestion of 2 to 3 grams in an adult may lead to death within 45 minutes; 18 grams was lethal within 15 hours in an adult, even with hospital care.

Minimum Lethal Exposure

    A) CASE REPORTS
    1) A 54-year-old man, with a prior gastrectomy, died 45 minutes after swallowing a small amount of an unknown fluid. Chemical analysis revealed that the remaining fluid was ioxynil (concentration of 11.3%). Amount ingested was estimated to be 2 to 3 grams. Autopsy showed hyperemia of all organs, pulmonary edema, and edema of the brain (HSDB , 2001; Smysl et al, 1977).
    2) A 26-year-old attempted suicide by ingesting 75 mL of an ioxynil solution (estimated to contain about 18 grams of pure ioxynil). Agitation, euphoria, sedation, and tachypnea were seen within 20 minutes. The patient was decontaminated with lavage and charcoal, and respirations were assisted. Within 90 minutes of the ingestion, hemoperfusion was performed. The patient died 15 hours postadmission. Hemoperfusion did not appear to be effective (Abi Khalil F, Alvoet C & Ectors M et al, 1987).
    3) BROMOXYNIL WITH 2-METHYL-4-CHLOROPHENOXYACETIC ACID: CASE REPORT: A 37-year-old man developed nausea, vomiting, diarrhea, diaphoresis, tachycardia, tachypnea, and agitation within 8 hours after intentionally ingesting 200 mL of an herbicide containing MCPA 200 g/L and bromoxynil 200 g/L, mixed with a hydrocarbon solvent. Despite supportive care, including continuous veno-venous hemodialysis, his condition deteriorated, with development of hyperthermia with hypotension. Approximately 20 hours post-ingestion, the patient died following development of asystolic cardiac arrest with failed resuscitation. Serum MCPA concentrations obtained 2 hours post-ingestion and 19 hours post-ingestion were 83.9 mcg/mL and 100 mcg/mL, respectively (Berling et al, 2015).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) A dose of 2 to 3 grams of ioxynil resulted in a plasma concentration of 0.013 gram per liter. This dose was lethal but the case was complicated by the ingestion of ethanol and a prior gastrectomy (Smysl et al, 1977).
    2) The plasma to whole blood ratio is approximately 2:1 in patients who have died from ingestion of this agent alone or in combination with chlorphenoxy agents (Abi Khalil F, Alvoet C & Ectors M et al, 1987; Dickey et al, 1988; Flanagan et al, 1990).
    3) In fatal cases where patients have ingested either ioxynil alone or in combination with chlorphenoxy agents, the plasma/whole blood concentrations have ranged from 0.04 gram/liter to 0.67 gram/liter (Abi Khalil F, Alvoet C & Ectors M et al, 1987; Dickey et al, 1988; Flanagan et al, 1990).

Workplace Standards

    A) ACGIH TLV Values for CAS1689-83-4 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) ACGIH TLV Values for CAS1689-84-5 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    C) NIOSH REL and IDLH Values for CAS1689-83-4 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    D) NIOSH REL and IDLH Values for CAS1689-84-5 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    E) Carcinogenicity Ratings for CAS1689-83-4 :
    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

    F) Carcinogenicity Ratings for CAS1689-84-5 :
    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: Bromoxynil
    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

    G) OSHA PEL Values for CAS1689-83-4 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

    H) OSHA PEL Values for CAS1689-84-5 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (ORAL)RAT:
    1) 110 mg/kg -- ioxynil alone
    2) 120 mg/kg -- ioxynil salt in formulation
    3) 190 mg/kg -- ioxynil octanoate
    B) LD50- (SKIN)RAT:
    1) >210 mg/kg -- ioxynil salt as in formulation
    2) >912 mg/kg -- ioxynil octanoate

Pharmacology Toxicology

Toxicologic Mechanism

    A) The mechanism of action in humans has not yet been proven. Experimental data from rat liver mitochondria suggests that ioxynil uncouples oxidative phosphorylation (Parker, 1965).
    B) It has been suggested that if ioxynil were metabolized to cyanide ion (thus inhibiting cytochrome oxidase), some of the toxic effects might be explained. Classical cyanide poisoning clinical effects have not been reported with ioxynil exposure, nor has there been evidence of the production of cyanide in metabolic studies (Parker, 1965).
    C) Ioxynil has been shown to bind to human thyroxine-binding prealbumin but not to thryroxine-binding globulin and albumin. Because the majority of circulating thyroid hormones are carried on thyroxine-binding globulin, it is unlikely that there would be a significant effect on thyroid transport in humans (Ogilvie & Ramsden, 1988).

Physicochemical

Physical Characteristics

    A) IOXYNIL: A colorless, odorless powder
    B) IOXYNIL (TECHNICAL GRADE): A cream-colored powder. Has a faint phenolic odor.
    C) IOXYNIL SODIUM: A white solid
    D) IOXYNIL OCTANOATE: A waxy, cream-colored solid

Molecular Weight

    A) 370.9 (Ioxynil)
    B) 497.1 (Ioxynil Octanoate)
    C) 392.9 (Ioxynil Sodium)

Animal Toxicology

Range Of Toxicity

    11.3.2) MINIMAL TOXIC DOSE
    A) FISH
    1) Harlequin fish LC50 (48 hours) is 3.3 mg/L for the sodium salt and 4 mg/L for the octanoate salt (Worthing, 1987).
    B) OTHER
    1) Bees: Ioxynil is slightly toxic to bees (Waterson, 1988).

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