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BISPYRIBAC SODIUM

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Bispyribac sodium is a selective, systemic post-emergence herbicide used to control weeds.

Specific Substances

    1) Bispyribac-sodium
    2) Bispyribac-NA
    3) Sodium 2,6-bis[(4,6-dimethoxypyrimidin-2-yl)oxy] benzoate
    4) CAS 125401-92-5
    5) Chemical Formula: C(19)H(17)N(4)NaO(8)
    6) KIH-2023
    1.2.1) MOLECULAR FORMULA
    1) C(19)H(17)N(4)NaO(8) (Bayer CropScience AG, 2011; Kumiai Chemical Industry Co., Ltd, 2011)

Available Forms Sources

    A) FORMS
    1) Nominee(R) a product marked in Sri Lanka is sold as 2 bottles: one contains bispyribac 400 g/L with a solvent, and the other contains a nonionic surfactant containing polyethylene glycol (Bandara Gawarammana et al, 2010; Kumiai Chemical Industry Co., Ltd, 2011).
    B) SOURCES
    1) Chemical Family: Bispyribac sodium belongs to the Pyrimidinyl carboxy compounds (Kumiai Chemical Industry Co., Ltd, 2011).
    C) USES
    1) Bispyribac sodium, an inhibitor of acetolactate synthase, is used as a systemic post-emergent herbicide for control of weeds (Bayer CropScience AG, 2011; Bandara Gawarammana et al, 2010).

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: Bispyribac sodium is a selective, systemic post-emergence herbicide used to control weeds.
    B) TOXICOLOGY: Bispyribac sodium belongs to the Pyrimidinyl carboxy compounds. It has a low acute toxicity profile. It is not a dermal sensitizer. Chronic and subchronic studies in animals, suggest that the liver and bile duct are target organs.
    C) EPIDEMIOLOGY: Overdose is rare in the US but more common in Asia. There have been reports of intentional ingestion which have resulted in several deaths, although the mechanism is not fully understood. In one study, a case fatality rate of 2.73% was observed.
    D) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Gastrointestinal events appear common and include vomiting, epigastric burning and diarrhea (infrequent). Mild alterations in consciousness were observed in individuals ingesting bispyribac only.
    2) SEVERE TOXICITY: Seizures have been observed in patients with significant toxicity. Coingestion of ethanol may contribute to more severe toxicity. Asystolic cardiac arrest has been observed in 3 fatal cases of intentional ingestion of bispyribac; ethanol was coingested in 2 of the cases.
    3) DERMAL: Bispyribac sodium is not a dermal sensitizer. In animal studies, systemic toxicity was not observed following dermal application.
    0.2.20) REPRODUCTIVE
    A) At the time of this review, there is no evidence of increased susceptibility of rats or rabbits to in utero or in postnatal exposure to bispyribac-sodium.
    0.2.21) CARCINOGENICITY
    A) Based on animal studies, bispyribac sodium in not anticipated to pose a cancer risk to humans.

Laboratory Monitoring

    A) After significant overdose, monitor serum electrolytes, renal function and liver enzymes.
    B) Monitor vital signs and mental status.
    C) Institute continuous cardiac monitoring and obtain an ECG.
    D) Bispyribac plasma concentrations are not widely available and are not helpful to guide clinical management. They may not correlate with clinical signs and symptoms

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Monitor neurologic function. Assess airway. Replace fluid and electrolytes, if significant vomiting occurs.
    B) SEVERE TOXICITY
    1) Treatment is primarily symptomatic and supportive. Treat seizures with IV benzodiazepines, barbiturates. Intubate patients with significant CNS depression.
    C) DECONTAMINATION
    1) PREHOSPITAL: GI decontamination is NOT recommended due to the potential risk of CNS depression and seizures following a significant ingestion. Spontaneous vomiting has occurred after ingestion of bispyribac sodium. DERMAL: Remove contaminated clothing and wash skin thoroughly with soap and water. OCULAR: Irrigate exposed eyes.
    2) HOSPITAL: Spontaneous vomiting is likely to occur. Activated charcoal may be indicated following a significant ingestion, if performed soon after exposure and the patient is alert and able to protect the airway.
    D) AIRWAY MANAGEMENT
    1) Monitor airway function following a significant exposure. Perform endotracheal intubation in patients with significant CNS depression or in a patient unable to protect their airway.
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION
    1) It is unknown if hemodialysis, hemoperfusion and plasmapheresis are likely to be useful following an oral exposure.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Patients with a dermal exposure involving a minimal body surface area can be managed at home with soap and water decontamination. Children who are asymptomatic with a minor "taste" exposure can be observed at home, if a responsible adult is present.
    2) OBSERVATION CRITERIA: Children with a significant ingestion or any adult with an intentional ingestion should be observed for 6 hours. Patients who remain asymptomatic 6 hours after ingestion are unlikely to develop significant symptoms and can be discharged to home following a mental health evaluation.
    3) ADMISSION CRITERIA: Any patient with ongoing symptoms (ie, CNS depression, seizures) should be admitted for further monitoring and treatment.
    4) CONSULT CRITERIA: Consult a poison center or toxicologist for a significant ingestion and/or dermal exposure. A mental health specialist should be consulted for all intentional ingestions.
    H) TOXICOKINETICS
    1) Limited data. Peak plasma concentration was observed at approximately 3 hours postingestion in adults after intentional ingestion of bispyribac sodium. An estimated elimination half-life of 13 and 16 hours was observed in 2 adults.
    I) PITFALLS
    1) Failure to consider another source of exposure (ie, other pesticides or ingestion of the surfactant accompanying bispyribac sodium containing polyethylene glycol). Failure to consider other coingestions (ie, ethanol) that may contribute to CNS depression.
    J) DIFFERENTIAL DIAGNOSIS
    1) Ingestion of other herbicide products or other chemicals. Underlying conditions (ie, seizure disorder) that may contribute to the signs and symptoms observed.

Range Of Toxicity

    A) TOXICITY: A toxic dose has not been established. An adult died approximately 6 hours after ingesting 90 mL of bispyribac sodium 400 g/L (approximately 36 g dose). There have been several other reports of fatalities due to cardiac arrest following the ingestion of bispyribac sodium; ethanol had been coingested in several of these deaths. However, based on a limited number of cases, intentional ingestion of bispyribac herbicide in most adults produced minimal toxicity (eg, vomiting, epigastric pain, and diarrhea).

Clinical Effects

Summary Of Exposure

    A) USES: Bispyribac sodium is a selective, systemic post-emergence herbicide used to control weeds.
    B) TOXICOLOGY: Bispyribac sodium belongs to the Pyrimidinyl carboxy compounds. It has a low acute toxicity profile. It is not a dermal sensitizer. Chronic and subchronic studies in animals, suggest that the liver and bile duct are target organs.
    C) EPIDEMIOLOGY: Overdose is rare in the US but more common in Asia. There have been reports of intentional ingestion which have resulted in several deaths, although the mechanism is not fully understood. In one study, a case fatality rate of 2.73% was observed.
    D) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Gastrointestinal events appear common and include vomiting, epigastric burning and diarrhea (infrequent). Mild alterations in consciousness were observed in individuals ingesting bispyribac only.
    2) SEVERE TOXICITY: Seizures have been observed in patients with significant toxicity. Coingestion of ethanol may contribute to more severe toxicity. Asystolic cardiac arrest has been observed in 3 fatal cases of intentional ingestion of bispyribac; ethanol was coingested in 2 of the cases.
    3) DERMAL: Bispyribac sodium is not a dermal sensitizer. In animal studies, systemic toxicity was not observed following dermal application.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CARDIAC ARREST
    1) WITH POISONING/EXPOSURE
    a) In a prospective, observational study of acute intentional bispyribac herbicide ingestion in adults (n=110), 3 deaths occurred due to asystolic cardiac arrest. Ethanol was coingested in 2 of the cases. An exact mechanism was not determined (Bandara Gawarammana et al, 2010).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) RESPIRATORY FINDING
    1) WITH POISONING/EXPOSURE
    a) In an observational study of bispyribac sodium ingestion (n=73) in adults, 8 (11%) patients had rhonchi on admission. In most cases, symptoms resolved within a few hours only one patient had rhonchi 9 days after exposure (Ashrafdeen et al, 2008).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) ALTERED MENTAL STATUS
    1) WITH POISONING/EXPOSURE
    a) In a prospective, observational study of acute intentional bispyribac herbicide ingestion in adults (n=110), a decrease (range: 3 to 14) in Glasgow Coma Score (GCS) was observed in 11 patients. However, a correlation between GCS and plasma concentrations of bispyribac (on admission) was not observed in this study (Bandara Gawarammana et al, 2010).
    B) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) In a prospective, observational study of acute intentional bispyribac herbicide ingestion in adults (n=110), tonic-clonic seizures were observed in 2 patients who coingested ethanol. The symptoms were observed shortly after admission along with a lower Glasgow Coma Score (3 and 12). Both died of cardiac arrest at 15 and 6 hours postingestion, respectively (Bandara Gawarammana et al, 2010).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) VOMITING
    1) WITH POISONING/EXPOSURE
    a) Vomiting is likely to occur following ingestion of bispyribac sodium (Bandara Gawarammana et al, 2010; Ashrafdeen et al, 2008).
    b) In a prospective, observational study of acute intentional bispyribac herbicide ingestion in adults (n=110), vomiting occurred in 51 (46.3%) patients. Symptoms developed soon after ingestion (Bandara Gawarammana et al, 2010).
    B) EPIGASTRIC PAIN
    1) WITH POISONING/EXPOSURE
    a) Epigastric pain has been reported following the ingestion of bispyribac sodium (Bandara Gawarammana et al, 2010; Ashrafdeen et al, 2008).
    b) In a prospective, observational study of acute intentional bispyribac herbicide ingestion in adults (n=110), epigastric pain (burning) occurred in 11 (10%) patients. Symptoms resolved 24 hours after ingestion (Bandara Gawarammana et al, 2010).
    C) DIARRHEA
    1) WITH POISONING/EXPOSURE
    a) Diarrhea has occurred infrequently following ingestion of bispyribac sodium (Bandara Gawarammana et al, 2010; Ashrafdeen et al, 2008).
    b) In a prospective, observational study of acute intentional bispyribac herbicide ingestion in adults (n=110), diarrhea was reported in one patient (Bandara Gawarammana et al, 2010).

Hepatic

    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) In animal studies (ie, rats, mice and dogs), the liver and bile duct were found to be the target organs in subchronic and chronic toxicity studies (Environmental Protection Agency, 2011).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) DERMATOLOGICAL TEST FINDING
    1) WITH POISONING/EXPOSURE
    a) Bispyribac sodium is not a dermal sensitizer (Environmental Protection Agency, 2011).
    b) In animal studies, repeated dermal application of bispyribac at the dose limit did not produce dermal irritation or systemic toxicity (Environmental Protection Agency, 2011).

Reproductive

    3.20.1) SUMMARY
    A) At the time of this review, there is no evidence of increased susceptibility of rats or rabbits to in utero or in postnatal exposure to bispyribac-sodium.
    3.20.3) EFFECTS IN PREGNANCY
    A) ANIMAL STUDIES
    1) In a prenatal developmental study in rats, no toxicity occurred in dams or their fetuses administered bispyribac sodium at doses up to 1000 mg/kg/day (highest dose tested). In rabbits, dams developed lethargy, diarrhea and decreased body weight gain at 300 mg/kg/day; fetal events were not observed (Environmental Protection Agency, 2011).
    2) In a 2-generation reproductive study, parents developed mild bile duct hyperplasia at bispyribac sodium doses of 75.7 mg, but no reproductive effects occurred. The offspring developed decreased body weights and body-weight gains, liver weights, and increased incidence of consolidation and circumscribed areas of the liver at doses of 759 mg/kg/day (Environmental Protection Agency, 2011).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) LACK OF EFFECT: In a 2-generation reproductive study, parents developed mild bile duct hyperplasia at bispyribac sodium doses of 75.7 mg, but no reproductive effects occurred (Environmental Protection Agency, 2011).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) Based on animal studies, bispyribac sodium in not anticipated to pose a cancer risk to humans.
    3.21.3) HUMAN STUDIES
    A) SUMMARY
    1) Based on 2 rodent carcinogenicity studies, bispyribac sodium in not anticipated to pose a cancer risk to humans (Environmental Protection Agency, 2011).
    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) No evidence of carcinogenicity was observed in 2 rodent carcinogenicity studies (Environmental Protection Agency, 2011).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) After significant overdose, monitor serum electrolytes, renal function and liver enzymes.
    B) Monitor vital signs and mental status.
    C) Institute continuous cardiac monitoring and obtain an ECG.
    D) Bispyribac plasma concentrations are not widely available and are not helpful to guide clinical management. They may not correlate with clinical signs and symptoms

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) Any patient with ongoing symptoms (ie, CNS depression, seizures) should be admitted for further monitoring and treatment.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Patients with a dermal exposure involving a minimal body surface area can be managed at home with soap and water decontamination. Children who are asymptomatic with a minor "taste" exposure can be observed at home, if a responsible adult is present.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or toxicologist for a significant ingestion and/or dermal exposure. A mental health specialist should be consulted for all intentional ingestions.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Children with a significant ingestion or any adult with an intentional ingestion should be observed for 6 hours. Patients who remain asymptomatic 6 hours after ingestion are unlikely to develop significant symptoms and can be discharged to home following a mental health evaluation.

Monitoring

    A) After significant overdose, monitor serum electrolytes, renal function and liver enzymes.
    B) Monitor vital signs and mental status.
    C) Institute continuous cardiac monitoring and obtain an ECG.
    D) Bispyribac plasma concentrations are not widely available and are not helpful to guide clinical management. They may not correlate with clinical signs and symptoms

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Emesis is NOT recommended due to the potential risk of CNS depression and seizures following a significant ingestion. Spontaneous vomiting has occurred after ingestion of bispyribac sodium. DERMAL: Remove contaminated clothing and wash skin thoroughly with soap and water.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Emesis is NOT indicated. Spontaneous vomiting is likely to occur. Activated charcoal may be indicated following a significant ingestion, if performed soon after exposure and patient is alert and can protect the airway. Monitor CNS function and manage airway, as necessary.
    B) 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) Treatment is symptomatic and supportive. Monitor neurologic function. Assess airway. Replace fluid and electrolytes, if significant vomiting occurs. Treat seizures with IV benzodiazepines, barbiturates. Intubate patients with CNS depression.
    B) ANTIDOTE
    1) There is no known antidote for bispyribac sodium.
    C) AIRWAY MANAGEMENT
    1) Monitor airway function following a significant exposure. Perform endotracheal intubation in patients with significant CNS depression or in a patient unable to protect their airway.
    D) MONITORING OF PATIENT
    1) Monitor vital signs and mental status. Institute continuous cardiac monitoring and perform an ECG. Monitor serum electrolytes, renal function and liver enzymes.
    E) SEIZURE
    1) Limited data. Seizures developed in 2 adults after ingesting bispyribac and ethanol. CNS depression was also present. Both patients died of an asystolic cardiac arrest (Bandara Gawarammana et al, 2010).
    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).

Enhanced Elimination

    A) SUMMARY
    1) It is unknown if hemodialysis, hemoperfusion and plasmapheresis are likely to be useful following an oral exposure.

Range Of Toxicity

Summary

    A) TOXICITY: A toxic dose has not been established. An adult died approximately 6 hours after ingesting 90 mL of bispyribac sodium 400 g/L (approximately 36 g dose). There have been several other reports of fatalities due to cardiac arrest following the ingestion of bispyribac sodium; ethanol had been coingested in several of these deaths. However, based on a limited number of cases, intentional ingestion of bispyribac herbicide in most adults produced minimal toxicity (eg, vomiting, epigastric pain, and diarrhea).

Minimum Lethal Exposure

    A) SUMMARY
    1) At the time of this review, a minimum lethal dose has not been established. An adult died approximately 6 hours after ingesting 90 mL of bispyribac sodium 400 g/L (approximately 36 g dose)(Ashrafdeen et al, 2008).
    B) CASE SERIES
    1) In a prospective, observational study of acute intentional bispyribac herbicide ingestion in adults (n=110), 3 deaths occurred due to asystolic cardiac arrest. Each patient experienced CNS depression and in 2 of the cases ethanol had also been ingested. An exact mechanism was not determined (Bandara Gawarammana et al, 2010).

Maximum Tolerated Exposure

    A) SUMMARY
    1) At the time of this review, a maximum tolerated dose has not been established.
    B) CASE SERIES
    1) In a prospective, observational study of acute intentional bispyribac herbicide ingestion in adults (n=110), most patients developed minimal toxicity (eg, vomiting, epigastric pain and diarrhea) and recovered. Three deaths occurred due to asystolic cardiac arrest; ethanol was coingested in 2 of the cases. An exact mechanism was not determined (Bandara Gawarammana et al, 2010).
    C) ANIMAL DATA
    1) In a rat chronic/carcinogenicity study, clinical symptoms (eg, macroscopic and microscopic changes in the liver, decreased body weights) occurred at 404 mg/kg/day (the highest dose tested). Clinical events were not found to be dose-dependent (Environmental Protection Agency, 2011).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) In a prospective observational study of intentional bispyribac ingestion in adults (n=110), bispyribac was quantified in 53 patients at the time of ED admission. The peak plasma concentration occurred approximately 3 hours after ingestion (Bandara Gawarammana et al, 2010).

Pharmacology Toxicology

Toxicologic Mechanism

    A) Bispyribac sodium is an inhibitor of acetolactate synthase. At the time of this review, the mechanism of toxicity in humans remains unknown (Bandara Gawarammana et al, 2010). It has a low acute toxicity profile. The liver and bile duct were target organs following chronic and subchronic exposure in rats, mice, and dogs (Environmental Protection Agency, 2011).

Physicochemical

Physical Characteristics

    A) A white odorless solid powder (as the pure active ingredient) (Kumiai Chemical Industry Co., Ltd, 2011). Bispyribac sodium is highly soluble in water and methanol and slightly soluble in acetone (Wu & Mei, 2011).

Molecular Weight

    A) 452.4 (Bayer CropScience AG, 2011; Kumiai Chemical Industry Co., Ltd, 2011; Wu & Mei, 2011)

References

General Bibliography

    1) AMA Department of DrugsAMA Department of Drugs: AMA Evaluations Subscription, American Medical Association, Chicago, IL, 1992.
    2) Ashrafdeen M, Shukry M, Dawson A, et al: Acute intentional self-poisoning with a selective herbicide Bispyribac sodium (BPS): a prospective observational study. J Med Toxicol 2008; 4(3):206-207.
    3) Bandara Gawarammana I, Roberts DM, Mohamed F, et al: Acute human self-poisoning with bispyribac-containing herbicide Nominee: a prospective observational study. Clin Toxicol (Phila) 2010; 48(3):198-202.
    4) Bayer CropScience AG: Bispyribac-sodium. Bayer CropScience AG. Monheim, Germany. 2011. Available from URL: http://compendium.bayercropscience.com/BAYER/CropScience/CropCompendium/BCSCropComp.nsf/id/bispyribac_sodium.htm. As accessed 2011-07-07.
    5) Brophy GM, Bell R, Claassen J, et al: Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012; 17(1):3-23.
    6) Chamberlain JM, Altieri MA, & Futterman C: A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children. Ped Emerg Care 1997; 13:92-94.
    7) Chin RF , Neville BG , Peckham C , et al: Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study. Lancet Neurol 2008; 7(8):696-703.
    8) Choonara IA & Rane A: Therapeutic drug monitoring of anticonvulsants state of the art. Clin Pharmacokinet 1990; 18:318-328.
    9) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    10) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    11) Environmental Protection Agency: Bispyribac-sodium; Pesticide Tolerances. Fed Reg 2011; 76(22):5711-5716.
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