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HERBICIDES: UREA-SUBSTITUTED

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Urea-substituted herbicides are photosynthesis inhibitors used for weed control in agricultural and non-agricultural settings (eg, along railroads, industrial sites). These agents appear to have low systemic toxicity. Severe toxicity may only occur following ingestion.

Specific Substances

    A) Anisuron
    1) CAS 2689-43-2
    Benzthiazuron
    1) CAS 1929-88-0
    Buturon
    1) CAS 3766-60-7
    Chlorbromuron
    1) CAS 13360-45-7
    Chloreturon
    1) CAS 20782-58-5
    Chlorimuron
    1) CAS 99283-00-8
    Chlorotoluron
    1) CAS 15545-48-9
    Chloroxuron
    1) CAS 1982-47-4
    Cumyluron
    1) CAS 99485-76-4
    Cycluron
    1) CAS 2163-69-1
    Daimuron
    1) CAS 42609-52-9
    Difenoxuron
    1) CAS 14214-32-5
    Diflufenzopyr
    1) CAS 109293-97-2
    Dimefuron
    1) CAS 34205-21-5
    Diuron
    1) CAS 330-54-1
    Fenuron
    1) CAS 101-42-8
    Fluometuron
    1) CAS 2164-17-2
    Fluothiuron
    1) CAS 33439-45-1
    Isonoruron
    1) CAS 28805-78-9
    Isoproturon
    1) CAS 34123-59-6
    Isouron
    1) CAS 55861-78-4
    Linuron
    1) CAS 330-55-2
    Methabenzthiazuron
    1) CAS 18691-97-9
    Methiuron
    1) CAS 21540-35-2
    Methyldymron
    1) CAS 42609-73-4
    Metobenzuron
    1) CAS 111578-32-6
    Metobromuron
    1) CAS 3060-89-7
    Metoxuron
    1) CAS 19937-59-8
    Monisouron
    1) CAS 55807-46-0
    Monolinuron
    1) CAS 1746-81-2
    Monuron
    1) CAS 150-68-5
    Neburon
    1) CAS 555-37-3
    Noruron
    1) CAS 18530-56-8
    Parafluron
    1) CAS 7159-99-1
    Phenobenzuron
    1) CAS 3134-12-1
    Siduron
    1) CAS 1982-49-6
    Tebuthiuron
    1) CAS 34014-18-1
    Teflubenzuron
    1) CAS 83121-18-0
    Tetrafluron
    1) CAS 27954-37-6
    Thidiazuron
    1) CAS 51707-55-2
    GENERAL TERMS
    1) Urea herbicides

Available Forms Sources

    A) FORMS
    1) Members of this class of herbicides are chlorophenyl-alkyl (or alkoxy) substituted ureas.
    2) Monuron, the first phenyl urea herbicide, was introduced in 1952. The following urea herbicides are currently available: chlorotoluron, dimefuron, diuron, fluometuron, isoproturon, linuron, methabenthiazuron, metobenzuron, metoxuron, monolinuron, neburon, siduron, and tebuthiuron (Watt et al, 2005).
    B) SOURCES
    1) From 1994 to 2004, 791 cases of exposure to urea herbicides were reported to AAPCC Toxic Exposure Surveillance System (TESS). No fatalities were reported; however, 3 cases were life-threatening and 49 patients developed moderately severe effects. Since these agents are usually marketed in combination with other ingredients (eg, paraquat, metolachlor, aminotriazole), severe toxicity may have been caused by other agents. In Germany in 1996, approximately a ton of isoproturon was released into the atmosphere following an accident at a chemical plant. It was determined that exposure was below the acceptable daily intake (ADI) (Watt et al, 2005).
    C) USES
    1) Urea herbicides are used for weed control in agricultural and non-agricultural settings (eg, along railroads, industrial sites). These agents are usually marketed in combination with other ingredients (eg, paraquat, metolachlor, aminotriazole) (Watt et al, 2005). Technical concentrates are contained in various organic solvent mixtures (generally not petroleum distillates) which may present some toxic hazards.

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: Urea herbicides are used for weed control in agricultural and non-agricultural settings (eg, along railroads, industrial sites). These agents are usually marketed in combination with other ingredients (eg, paraquat, metolachlor, aminotriazole).
    B) TOXICOLOGY: Urea herbicides are photosynthetic inhibitors. They bind to the D-1 quinone-binding protein of the photosystem II complex in chloroplast membrane (beta-chlorophylls) and block the photosynthetic electron transport, stop the fixation of CO2 and products of adenosine triphosphate (ATP) and the reduced form of nicotinamide-adenine dinucleotide phosphate (NADPH2). Methemoglobinemia may occur following the absorption of large amounts, due to aniline metabolites (potent oxidants of hemoglobin).
    C) EPIDEMIOLOGY: Exposures are uncommon and generally occur in agricultural settings.
    D) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: These agents have low systemic toxicity. Eye exposure may result in ocular irritation. Irritation of the respiratory mucous membranes may be observed following prolonged heavy contact. Irritation of skin has been noted upon exposure.
    2) SEVERE TOXICITY: Severe toxicity has only been reported after deliberate ingestion. Nausea, vomiting, abdominal pain, and diarrhea have been reported. Methemoglobinemia may rarely occur following large ingestions, and may be delayed in onset. Patients that have methemoglobin concentrations greater than 30% are more likely to develop severe symptoms. Patients may develop headache, fatigue, weakness, dizziness, syncope, and tachycardia with methemoglobin concentrations 20% to 40%. With methemoglobin concentrations 40% to 60%, dyspnea and increasing respiratory distress may occur. Patients with methemoglobin concentrations greater than 60% may develop coma, seizures, cardiac dysrhythmias, and cardiorespiratory arrest. Hemolysis has also been reported.
    0.2.20) REPRODUCTIVE
    A) Cleft palate was noted after oral administration of buturon and monolinuron to pregnant mice. Administration of 250 mg/kg/day to pregnant rats resulted in bone developmental anomalies and decreased fetal weight.

Laboratory Monitoring

    A) Most patients with urea-substituted herbicide exposures do not need laboratory evaluation.
    B) Laboratory and radiographic evaluation can be targeted to symptoms.
    C) Toxic serum concentrations of the urea-substituted herbicide have not been established.
    D) Monitor vital signs following significant exposure.
    E) Obtain methemoglobin concentrations in all cyanotic patients and patients demonstrating dyspnea or other signs of hypoxia. Monitor CBC for evidence of hemolysis in patients who develop methemoglobinemia.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Symptomatic and supportive care is the mainstay for treatment of urea-substituted herbicide exposure. Wash exposed skin, remove contaminated clothing, and irrigate exposed eyes. Following inhalation exposure, move patient to fresh air.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Obtain a methemoglobin concentration in cyanotic patients. Treat symptomatic methemoglobinemia (usually at methemoglobin concentrations above 20% to 30%) with methylene blue and oxygen therapy. Patients with severe hemolysis may require transfusion.
    C) NATIONAL PESTICIDE TELECOMMUNICATIONS NETWORK
    1) The National Pesticide Information Center (NPIC) is a cooperative effort of Oregon State University and the US EPA. NPIC provides consultation to poison centers and other health care professionals for the management of pesticide poisoning. Calls regarding emergency cases requiring immediate medical response will be transferred to the Oregon Poison Center.
    a) NPIC contact information: phone: 1-800-858-7378. email: npic@ace.orst.edu Hours: 8 AM to 12 PM Pacific time Monday through Friday, excluding holidays.
    D) DECONTAMINATION
    1) PREHOSPITAL: Exposure to urea-substituted herbicides is generally NOT expected to result in significant toxicity. Remove clothing and wash exposed areas with soap and water. If ocular exposure develops, irrigate thoroughly. Consider activated charcoal only after large, recent ingestions in patients who are alert and can protect the airway. Following an inhalational exposure, move patient to fresh air.
    2) HOSPITAL: Consider activated charcoal only after large, recent ingestions in patients who are alert and can protect the airway. If prehospital decontamination has not occurred, wash exposed skin and irrigate exposed eyes thoroughly.
    E) AIRWAY MANAGEMENT
    1) Patients with methemoglobinemia and severe dyspnea, tachypnea, seizure, or evidence of end-organ ischemia may require intubation for airway protection or to minimize excessive work of breathing.
    F) ANTIDOTE
    1) None
    G) METHEMOGLOBINEMIA
    1) Initiate oxygen therapy. Treat with methylene blue if patient is symptomatic (usually at methemoglobin concentrations greater than 20% to 30% or at lower concentrations in patients with anemia, underlying pulmonary or cardiovascular disease). METHYLENE BLUE: INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules and 10 mg/1 mL (1% solution) vials. Additional doses may sometimes be required. Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection. NEONATES: DOSE: 0.3 to 1 mg/kg.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: Patients with a low dose, inadvertent ingestion or exposure who are asymptomatic or with minimal symptoms can be watched at home. In large or self-harm ingestions, or patients with more moderate symptoms may need to be evaluated in the emergency department.
    2) OBSERVATION CRITERIA: Any patient who is symptomatic, has respiratory symptoms or had an intentional self-harm attempt should be observed in the emergency department.
    3) ADMISSION CRITERIA: Patients with significant methemoglobinemia should be admitted.
    4) CONSULT CRITERIA: A medical toxicologist or poison center should be consulted in large exposures, if severe symptoms develop, or if the diagnosis is unclear.
    I) PITFALLS
    1) Onset of methemoglobin is usually delayed by hours, and hemolysis may develop days after ingestion. Careful monitoring and follow-up are important in patients with deliberate ingestions. Pitfalls include not evaluating for other coingestants, such as solvents and surfactants that are other ingredients included with the herbicide.
    J) TOXICOKINETICS
    1) These agents are well absorbed via both the gastrointestinal and respiratory tracts; however, it is not known whether they are also absorbed from the skin. Metabolism: Mono- or di-dealkylated metabolites are produced when urea herbicides are metabolized by oxidation of alkyl chain of the terminal nitrogen atom. Excretion: diuron: Metabolites are excreted in the urine with low amounts of unmetabolized diuron.
    K) DIFFERENTIAL DIAGNOSIS
    1) Other herbicides, fungicides. Other methemoglobin inducing agents such as aniline dyes, dapsone, benzocaine.
    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: Insufficient data in the literature to accurately assess the minimal toxic or lethal dose. Severity of intoxication should be based on clinical findings. These agents appear to have low systemic toxicity. Severe toxicity only occurs following ingestion, not after dermal or inhalation exposure. A woman who ingested approximately 38 mg/kg of 56% diuron and amitrole (20 mg/kg) developed no signs of toxicity. Ingestion of one cup of a 14% solution of monolinuron (approximately 33.6 grams) resulted in methemoglobinemia. Ingestion of 3 mouthfuls of a 14% solution of monolinuron resulted in methemoglobinemia. A man developed anxiety, headache, and vomiting and presented 17 hours after ingesting about 3 L of beer and 250 mL of an herbicide containing 50% metobromuron and 7% propylene glycol in water. He later developed methemoglobinemia and hemolysis, but recovered following supportive therapy.

Clinical Effects

Summary Of Exposure

    A) USES: Urea herbicides are used for weed control in agricultural and non-agricultural settings (eg, along railroads, industrial sites). These agents are usually marketed in combination with other ingredients (eg, paraquat, metolachlor, aminotriazole).
    B) TOXICOLOGY: Urea herbicides are photosynthetic inhibitors. They bind to the D-1 quinone-binding protein of the photosystem II complex in chloroplast membrane (beta-chlorophylls) and block the photosynthetic electron transport, stop the fixation of CO2 and products of adenosine triphosphate (ATP) and the reduced form of nicotinamide-adenine dinucleotide phosphate (NADPH2). Methemoglobinemia may occur following the absorption of large amounts, due to aniline metabolites (potent oxidants of hemoglobin).
    C) EPIDEMIOLOGY: Exposures are uncommon and generally occur in agricultural settings.
    D) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: These agents have low systemic toxicity. Eye exposure may result in ocular irritation. Irritation of the respiratory mucous membranes may be observed following prolonged heavy contact. Irritation of skin has been noted upon exposure.
    2) SEVERE TOXICITY: Severe toxicity has only been reported after deliberate ingestion. Nausea, vomiting, abdominal pain, and diarrhea have been reported. Methemoglobinemia may rarely occur following large ingestions, and may be delayed in onset. Patients that have methemoglobin concentrations greater than 30% are more likely to develop severe symptoms. Patients may develop headache, fatigue, weakness, dizziness, syncope, and tachycardia with methemoglobin concentrations 20% to 40%. With methemoglobin concentrations 40% to 60%, dyspnea and increasing respiratory distress may occur. Patients with methemoglobin concentrations greater than 60% may develop coma, seizures, cardiac dysrhythmias, and cardiorespiratory arrest. Hemolysis has also been reported.

Heent

    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) Urea substituted herbicides may produce irritation to the eyes.

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) IRRITATION SYMPTOM
    1) Irritation of the respiratory mucous membranes may occur on prolonged heavy contact.
    a) CASE REPORT: Within 24 hours after termination of heavy inhalation exposure to diuron and 2,4-D, two men experienced chest discomfort and productive cough. Chest x-ray and pulmonary function tests were normal (Torrington, 1983).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM DEFICIT
    1) CNS depression from hypoxemia may occur if significant methemoglobinemia develops.
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) ATAXIA
    a) RATS: Drowsiness and ataxia were seen in rats within 2 hours of receiving a lethal dose (Boyd & Krupta, 1970).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTROINTESTINAL TRACT FINDING
    1) Nausea, vomiting, abdominal pain, and diarrhea may be observed following ingestion (Watt et al, 2005).

Hepatic

    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEPATIC ENZYMES INCREASED
    a) RATS: Application of technical grade isoproturon to the skin of rats caused significant increases in liver weights and alterations in liver enzymes in the absence of clinical signs (Dikshith et al, 1990).
    b) RATS: Diuron and chlorotoluron were potent inducers of microsomal enzymes in the livers of rats (Schoket & Vincze, 1990).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) URINARY SYSTEM FINDING
    1) Some metabolites may cause irritation of the urinary tract.
    B) ACUTE RENAL FAILURE SYNDROME
    1) WITH POISONING/EXPOSURE
    a) Patients with hemolysis may develop acute renal failure (Watt et al, 2005).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) METABOLIC ACIDOSIS
    1) WITH POISONING/EXPOSURE
    a) Patients with methemoglobinemia may develop metabolic acidosis (Watt et al, 2005).
    b) CASE REPORT: A 36-year-old alcoholic man developed anxiety, headache, and vomiting and presented 17 hours after ingesting about 3 L of beer and 250 mL of an herbicide containing 50% metobromuron and 7% propylene glycol in water. He was cyanotic and had "ashen grey" skin color. Laboratory analysis revealed metabolic acidosis (pH 7.33, anion gap 10 mmol/L, lactate 8.4 mmol/L), a 0.5 g/L ethanol blood concentration, and an 80% MetHb concentration. Following supportive treatment, including 3 doses of methylene blue (on days 1, 4, and 8) and vitamin C therapy, his MetHb gradually normalized on day 11. On day 4, he also developed hemolysis (hemoglobin 8 g/dL, haptoglobin greater than 0.07 g/L, Heinz bodies). He recovered on day 12 following supportive therapy and was discharged home on day 14 (Turcant et al, 2000).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) METHEMOGLOBINEMIA
    1) Methemoglobinemia may occur following absorption of large amounts, due to chloroaniline metabolites. Patients may have a slate grey skin color and tongue with methemoglobin concentrations 10% to 15%. With methemoglobin concentrations 20% to 40%, patients may develop headache, fatigue, weakness, dizziness, syncope, and tachycardia. With methemoglobin concentrations 40% to 60%, dyspnea and increasing respiratory distress may occur. With methemoglobin concentrations greater than 60%, patients may develop coma, seizures, cardiac dysrhythmias, and cardiorespiratory arrest (Watt et al, 2005).
    a) METOBROMURON
    1) CASE REPORT: A 36-year-old alcoholic man developed anxiety, headache, and vomiting and presented 17 hours after ingesting about 3 L of beer and 250 mL of an herbicide containing 50% metobromuron and 7% propylene glycol in water. He was cyanotic and had "ashen grey" skin color. Laboratory analysis revealed metabolic acidosis (pH 7.33, anion gap 10 mmol/L, lactate 8.4 mmol/L), a 0.5 g/L ethanol blood concentration, and an 80% MetHb concentration. Following supportive treatment, including 3 doses of methylene blue (on days 1, 4, and 8) and vitamin C therapy, his MetHb gradually normalized on day 11. On day 4, he also developed hemolysis (hemoglobin 8 g/dL, haptoglobin greater than 0.07 g/L, Heinz bodies). He recovered on day 12 following supportive therapy and was discharged home on day 14 (Turcant et al, 2000).
    b) MONOLINURON WITH PARAQUAT
    1) CASE REPORT: Ingestion of one cupful of a product containing 10% paraquat and 14% monolinuron resulted in methemoglobinemia (36%) 43 hours postingestion (Proudfoot, 1982).
    2) CASE REPORT: Ingestion of 3 mouthfuls of a preparation containing 10% paraquat and 14% monolinuron resulted in methemoglobinemia (18.7%) 10 hours postingestion in a 32-year-old man. Hemolysis developed later, with full recovery (Ng et al, 1982).
    3) CASE REPORT: A 59-year-old man who ingested a mouthful of the monolinuron/paraquat combination developed methemoglobinemia (52%), and ultimately died of paraquat toxicity (Casey & Vale, 1993).
    B) HEMOLYSIS
    1) MONOLINURON: Hemolysis has been noted as a late finding following monolinuron ingestion (Proudfoot, 1982; Ng et al, 1982).
    2) MONOLINURON: Ingestion of 3 mouthfuls of a preparation containing 10% paraquat and 14% monolinuron resulted in methemoglobinemia (18.7%) 10 hours postingestion in a 32-year-old man. Hemolysis developed later, with full recovery (Ng et al, 1982).
    3) Four patients developed severe intravascular hemolysis following ingestion of urea herbicides. At least 3 patients had Heinz body formation and one had positive Schum's test (Watt et al, 2005).
    4) CASE REPORT: A 36-year-old alcoholic man developed anxiety, headache, and vomiting and presented 17 hours after ingesting about 3 L of beer and 250 mL of an herbicide containing 50% metobromuron and 7% propylene glycol in water. He was cyanotic and had "ashen grey" skin color. Laboratory analysis revealed metabolic acidosis (pH 7.33, anion gap 10 mmol/L, lactate 8.4 mmol/L), a 0.5 g/L ethanol blood concentration, and an 80% MetHb concentration. Following supportive treatment, including 3 doses of methylene blue (on days 1, 4, and 8) and vitamin C therapy, his MetHb gradually normalized on day 11. On day 4, he also developed hemolysis (hemoglobin 8 g/dL, haptoglobin greater than 0.07 g/L, Heinz bodies). He recovered on day 12 following supportive therapy and was discharged home on day 14 (Turcant et al, 2000).
    C) SULFHEMOGLOBINEMIA
    1) CASE REPORT: Sulfhemogolbinemia (7%) was noted in a patient who drank a product containing monoluron (Proudfoot, 1982).
    3.13.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) SULFHEMOGLOBINEMIA
    a) RATS/DOGS: Sulfhemoglobinemia has been observed in rats and dogs given repeated large doses of diuron (125 and 250 ppm in diet for 2 years) (Hodge et al, 1967).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) SKIN IRRITATION
    1) Irritation of skin has been noted upon exposure (Torrington, 1983).
    B) CHLORINE ACNE
    1) Propanil-chloracne has been described in chemical workers due to tetrachloroazobenzene contaminants in urea herbicide derivatives (Morse & Baker, 1979).

Reproductive

    3.20.1) SUMMARY
    A) Cleft palate was noted after oral administration of buturon and monolinuron to pregnant mice. Administration of 250 mg/kg/day to pregnant rats resulted in bone developmental anomalies and decreased fetal weight.
    3.20.2) TERATOGENICITY
    A) CLEFT PALATE
    1) BUTURON - Cleft palate was noted after oral administration to pregnant mice (Matthiaschk & Roll, 1977).
    2) MONOLINURON - Cleft palate was noted after oral administration to pregnant mice (Matthiaschk & Roll, 1977). Oral administration to mice also produced effects on litter size, pre- and post-implantation mortality, and fetal death (RTECS , 1992).
    B) SKELETAL MALFORMATION
    1) DIURON - No adverse reproductive or teratogenic effects were seen after 6 mg/kg/day in rats (Hodge et al, 1967). Administration of 250 mg/kg/day to pregnant rats resulted in bone developmental anomalies and decreased fetal weight (Khera et al, 1979). No effect was seen at 125 mg/kg/day (Khera et al, 1979).
    2) LINURON - A high incidence of malformations were seen in rat fetuses following oral maternal administration (Khera et al, 1978).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Most patients with urea-substituted herbicide exposures do not need laboratory evaluation.
    B) Laboratory and radiographic evaluation can be targeted to symptoms.
    C) Toxic serum concentrations of the urea-substituted herbicide have not been established.
    D) Monitor vital signs following significant exposure.
    E) Obtain methemoglobin concentrations in all cyanotic patients and patients demonstrating dyspnea or other signs of hypoxia. Monitor CBC for evidence of hemolysis in patients who develop methemoglobinemia.

Methods

    A) CHROMATOGRAPHY
    1) Concentrations of some of these herbicides and their metabolites can be measured in urine by liquid chromatographic techniques at government, industry, and university laboratories.
    2) Although analysis of urea herbicides by TLC and GC methods has been described, urea herbicides are thermolabile and elute in the form of isocyanates and/or anilines after GC analysis.
    a) Diuron and its metabolites have been analyzed in blood and urine by HPLC (Van Boven et al, 1990) and by liquid chromatography/mass spectrometry with a moving-belt interface (Verheij et al, 1989).
    3) In one case report, liquid chromatography with diode-array detection was used to determine metobromuron plasma concentration and elimination half-life. Liquid chromatography-electrospray mass spectrometry was used to determine several metabolites in plasma (normetobromuron, bromophenylurea, bromoacetanilide) and urine (n-methyl bromophenylurea) (Turcant et al, 2000).
    B) OTHER
    1) Occurrence of methemoglobinemia and sulfhemoglobinemia can be detected spectrophotometrically.

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) Toxicity is minimal with a urea-substituted herbicide exposure. However, patients who have severe toxicity including persistent signs of respiratory irritation or methemoglobinemia can be considered for admission for further evaluation.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Patients with a low dose, inadvertent ingestion or exposure who are asymptomatic or with minimal symptoms can be watched at home. In large or self-harm ingestions, or patients with more moderate symptoms may need to be evaluated in the emergency department.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) A medical toxicologist or poison center should be consulted in large exposures, if severe symptoms develop, or if the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Any patient who is symptomatic, has respiratory symptoms or had an intentional self-harm attempt should be observed in the emergency department.

Monitoring

    A) Most patients with urea-substituted herbicide exposures do not need laboratory evaluation.
    B) Laboratory and radiographic evaluation can be targeted to symptoms.
    C) Toxic serum concentrations of the urea-substituted herbicide have not been established.
    D) Monitor vital signs following significant exposure.
    E) Obtain methemoglobin concentrations in all cyanotic patients and patients demonstrating dyspnea or other signs of hypoxia. Monitor CBC for evidence of hemolysis in patients who develop methemoglobinemia.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Exposure to urea-substituted herbicides is generally NOT expected to result in significant toxicity. Remove clothing and wash exposed areas with soap and water. If ocular exposure develops, irrigate thoroughly. Consider activated charcoal only after large, recent ingestions in patients who are alert and can protect the airway. Following an inhalational exposure, move patient to fresh air.
    6.5.2) PREVENTION OF ABSORPTION
    A) Consider activated charcoal only after large, recent ingestions in patients who are alert and can protect the airway. If prehospital decontamination has not occurred, wash exposed skin and irrigate exposed eyes thoroughly.
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY: Symptomatic and supportive care is the mainstay for treatment of urea-substituted herbicide exposure. Wash exposed skin, remove contaminated clothing, and irrigate exposed eyes. Following inhalation exposure, move patient to fresh air.
    2) MANAGEMENT OF SEVERE TOXICITY: Obtain a methemoglobin concentration in cyanotic patients. Treat symptomatic methemoglobinemia (usually at methemoglobin concentrations above 20% to 30%) with methylene blue and oxygen therapy. Patients with severe hemolysis may require transfusion.
    B) MONITORING OF PATIENT
    1) Most patients with urea-substituted herbicide exposures do not need laboratory evaluation.
    2) Laboratory and radiographic evaluation can be targeted to symptoms.
    3) Toxic serum concentrations of the urea-substituted herbicide have not been established.
    4) Monitor vital signs following significant exposure.
    5) Obtain methemoglobin concentrations in all cyanotic patients and patients demonstrating dyspnea or other signs of hypoxia. Monitor CBC for evidence of hemolysis in patients who develop methemoglobinemia.
    C) PROCEDURE EDUCATION
    1) If symptoms and signs of a severe toxicosis appear following exposure to these compounds, absorption of other or additional toxins should be strongly suspected.
    2) A careful inquiry into recent chemical exposures should be pursued to avoid overlooking more serious toxic exposures.
    3) If technical concentrate has been swallowed, identity of the solvent should be determined from the manufacturer.
    D) METHEMOGLOBINEMIA
    1) SUMMARY
    a) Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.
    2) METHYLENE BLUE
    a) INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules (Prod Info PROVAYBLUE(TM) intravenous injection, 2016) and 10 mg/1 mL (1% solution) vials (Prod Info methylene blue 1% intravenous injection, 2011). REPEAT DOSES: Additional doses may be required, especially for substances with prolonged absorption, slow elimination, or those that form metabolites that produce methemoglobin. NOTE: Large doses of methylene blue may cause methemoglobinemia or hemolysis (Howland, 2006). Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection (Prod Info methylene blue 1% intravenous injection, 2011; Herman et al, 1999). NEONATES: DOSE: 0.3 to 1 mg/kg (Hjelt et al, 1995).
    b) CONTRAINDICATIONS: G-6-PD deficiency (methylene blue may cause hemolysis), known hypersensitivity to methylene blue, methemoglobin reductase deficiency (Shepherd & Keyes, 2004)
    c) FAILURE: Failure of methylene blue therapy suggests: inadequate dose of methylene blue, inadequate decontamination, NADPH dependent methemoglobin reductase deficiency, hemoglobin M disease, sulfhemoglobinemia, or G-6-PD deficiency. Methylene blue is reduced by methemoglobin reductase and nicotinamide adenosine dinucleotide phosphate (NADPH) to leukomethylene blue. This in turn reduces methemoglobin. Red blood cells of patients with G-6-PD deficiency do not produce enough NADPH to convert methylene blue to leukomethylene blue (do Nascimento et al, 2008).
    d) DRUG INTERACTION: Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome (U.S. Food and Drug Administration, 2011; Stanford et al, 2010; Prod Info methylene blue 1% IV injection, 2011).
    3) TOLUIDINE BLUE OR TOLONIUM CHLORIDE (GERMANY)
    a) DOSE: 2 to 4 mg/kg intravenously over 5 minutes. Dose may be repeated in 30 minutes (Nemec, 2011; Lindenmann et al, 2006; Kiese et al, 1972).
    b) SIDE EFFECTS: Hypotension with rapid intravenous administration. Vomiting, diarrhea, excessive sweating, hypotension, dysrhythmias, hemolysis, agranulocytosis and acute renal insufficiency after overdose (Dunipace et al, 1992; Hix & Wilson, 1987; Winek et al, 1969; Teunis et al, 1970; Marquez & Todd, 1959).
    c) CONTRAINDICATIONS: G-6-PD deficiency; may cause hemolysis.

Inhalation Exposure

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

Eye Exposure

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

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Abstracts

Case Reports

    A) SPECIFIC AGENT
    1) DIURON
    a) Suicidal ingestion of a product containing 56% diuron and amitrole (20 mg/kg) in a 39-year-old woman resulted in no signs or symptoms. Some 3,4-dichloroaniline was present in the urine (Geldmacher-von Mallinckrodt & Schussler, 1971).
    b) A 77-year-old patient, who presented with severe sedation, died in hospital after an overdose of unknown products. Routine HPLC detected small amounts of temazepam in the plasma as well as other unknown compounds. Because the unknown compounds were thermolabile, LC/MC was used to identify the compounds as diuron and four of its metabolites (Verheij et al, 1989).
    c) A 38-year-old woman was brought to the emergency department in a comatose state. Cholinesterase activity was completely inhibited due to ingestion of an unreported amount of parathion. Further toxicology screening of the patient's blood detected two unidentified compounds which were later determined by GC/MS to be dichloroaniline derivatives of the urea herbicide, diuron. The patient died after 2 days of treatment, which included hemoperfusion (Van Boven et al, 1990).
    2) MONOLINURON
    a) Ingestion of one cupful of a product containing 10% paraquat and 14% monolinuron (approximately 33.6 grams) in a 63-year-old woman resulted in methemoglobinemia (36%), sulfhemoglobinemia (7%), and Heinz body hemolytic anemia 43 hours postingestion. The hemoglobin fell to 6.4 g/dL over the next 5 days, followed by complete recovery (Proudfoot, 1982).
    b) Ingestion of three mouthfuls of a preparation containing 10% paraquat and 14% monolinuron resulted in methemoglobinemia (18.7%) 10 hours postingestion in a 32-year-old man. Hemolysis developed later, with full recovery (Ng et al, 1982).

Range Of Toxicity

Summary

    A) TOXICITY: Insufficient data in the literature to accurately assess the minimal toxic or lethal dose. Severity of intoxication should be based on clinical findings. These agents appear to have low systemic toxicity. Severe toxicity only occurs following ingestion, not after dermal or inhalation exposure. A woman who ingested approximately 38 mg/kg of 56% diuron and amitrole (20 mg/kg) developed no signs of toxicity. Ingestion of one cup of a 14% solution of monolinuron (approximately 33.6 grams) resulted in methemoglobinemia. Ingestion of 3 mouthfuls of a 14% solution of monolinuron resulted in methemoglobinemia. A man developed anxiety, headache, and vomiting and presented 17 hours after ingesting about 3 L of beer and 250 mL of an herbicide containing 50% metobromuron and 7% propylene glycol in water. He later developed methemoglobinemia and hemolysis, but recovered following supportive therapy.

Maximum Tolerated Exposure

    A) CASE REPORTS
    1) DIURON AND AMITROLE: A 39-year-old woman who ingested approximately 38 mg/kg of 56% diuron and amitrole (20 mg/kg) developed no signs of toxicity (Geldmacher-von Mallinckrodt & Schussler, 1971).
    2) MONOLINURON: Ingestion of one cup of a 14% solution of monolinuron (approximately 33.6 grams) resulted in methemoglobinemia in a 63-year-old woman (Proudfoot, 1982).
    3) MONOLINURON: Ingestion of 3 mouthfuls of a 14% solution of monolinuron resulted in methemoglobinemia (Ng et al, 1982).
    4) METOBROMURON: A 36-year-old alcoholic man developed anxiety, headache, and vomiting and presented 17 hours after ingesting about 3 L of beer and 250 mL of an herbicide containing 50% metobromuron and 7% propylene glycol in water. He later developed methemoglobinemia and hemolysis, but recovered following supportive therapy (Turcant et al, 2000).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) METOBROMURON: In one case report, a man ingested about 3 L of beer and 250 mL of an herbicide containing 50% metobromuron and 7% propylene glycol in water and developed methemoglobinemia and hemolysis. Metobromuron plasma concentration of 4.9 mg/L and elimination half-life of 5 hours were obtained (Turcant et al, 2000).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (ORAL)MOUSE:
    1) 4700 mg/kg
    B) LD50- (ORAL)RAT:
    1) 6400 mg/kg
    C) LD50- (ORAL)RAT:
    1) 1500-4000 mg/kg
    D) LD50- (ORAL)RAT:
    1) 1800-2215 mg/kg
    E) LD50- (ORAL)RAT:
    1) 1053 mg/kg
    F) LD50- (ORAL)RAT:
    1) 1100 mg/kg
    G) LD50- (ORAL)RAT:
    1) >4000 mg/kg
    H) LD50- (ORAL)MOUSE:
    1) >1000 mg/kg
    I) LD50- (ORAL)RAT:
    1) Male, 3700 mg/kg
    2) Female, 5400 mg/kg
    J) LD50- (ORAL)RAT:
    1) 1000 mg/kg
    2) >7750 mg/kg
    K) LD50- (ORAL)RAT:
    1) 6416-8900 mg/kg
    L) LD50- (ORAL)MOUSE:
    1) 3350 mg/kg
    M) LD50- (ORAL)RAT:
    1) Male, 1826 mg/kg
    2) Female, 2417 mg/kg
    N) LD50- (ORAL)MOUSE:
    1) 2542 mg/kg
    O) LD50- (ORAL)RAT:
    1) 1600 mg/kg
    P) LD50- (ORAL)RAT:
    1) >5000 mg/kg
    2) >7500 mg/kg
    Q) LD50- (ORAL)MOUSE:
    1) 579 mg/kg
    R) LD50- (ORAL)RAT:
    1) 644 mg/kg
    S) LD50- (ORAL)MOUSE:
    1) >5000 mg/kg
    T) LD50- (ORAL)RAT:
    1) 5000 mg/kg

Pharmacology Toxicology

Toxicologic Mechanism

    A) Urea herbicides are photosynthetic inhibitors. They bind to the D-1 quinone-binding protein of the photosystem II complex in chloroplast membrane (beta-chlorophylls) and block the photosynthetic electron transport, stop the fixation of CO2 and products of adenosine triphosphate (ATP) and the reduced form of nicotinamide-adenine dinucleotide phosphate (NADPH2) (Watt et al, 2005).
    B) METHEMOGLOBINEMIA: Methemoglobinemia may occur following absorption of large amounts, due to aniline metabolites (potent oxidants of hemoglobin) (Watt et al, 2005).
    1) In one case report, a man ingested about 3 L of beer and 250 mL of an herbicide containing 50% metobromuron and 7% propylene glycol in water and developed methemoglobinemia and hemolysis. It was suggested that methemoglobinemia was caused by the metabolism of metobromuron to bromoaniline and bromoacetanilide (Turcant et al, 2000).

Animal Toxicology

Treatment

    11.2.1) SUMMARY
    A) GENERAL TREATMENT
    1) Begin treatment immediately.
    2) Keep animal warm and do not handle unnecessarily.
    3) Sample vomitus, blood, urine, and feces for analysis.
    B) ANIMAL POISON CONTROL CENTERS
    1) ASPCA Animal Poison Control Center, An Allied Agency of the University of Illinois, 1717 S. Philo Rd, Suite 36, Urbana, IL 61802, website www.aspca.org/apcc
    2) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
    3) The following 24-hour phone number is available: (888) 426-4435. A fee may apply. Please inquire with the poison center. The agency will make follow-up calls as needed in critical cases at no extra charge.
    11.2.2) LIFE SUPPORT
    A) GENERAL
    1) MAINTAIN VITAL FUNCTIONS: Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.
    11.2.4) DECONTAMINATION
    A) GASTRIC DECONTAMINATION
    1) GENERAL TREATMENT
    a) EMESIS AND LAVAGE - If within 2 hours of exposure, induce emesis with 1 to 2 milliliters/kilogram syrup of ipecac per os. Dogs may vomit more readily with 1 tablet (6 milligrams) apomorphine diluted in 3 to 5 milliliters water and instilled into the conjunctival sac or per os. Dogs may also be given apomorphine intravenously at 40 micrograms/kilogram. Do not use an emetic if the animal is hypoxic. In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage. Pass large bore stomach tube and instill 5 to 10 milliliters/kilogram water or lavage solution, then aspirate. Repeat 10 times (Kirk, 1986).
    1) CAUTION - Carefully examine patients with chemical exposure before inducing emesis. If signs of oral, pharyngeal, or esophageal irritation, a depressed gag reflex, or central nervous system excitation or depression are present, EMESIS SHOULD NOT BE INDUCED.
    b) ACTIVATED CHARCOAL - Administer activated charcoal. Dose: 2 grams/kilogram per os or via stomach tube. Avoid aspiration by proper restraint, careful technique, and if necessary tracheal intubation.
    c) CATHARTIC - Administer a dose of a saline cathartic such as magnesium or sodium sulfate (sodium sulfate dose is 1 gram/kilogram). If access to these agents is limited, give 5 to 15 milliliters magnesium oxide (Milk of Magnesia) per os for dilution.
    d) INHALATION - Move patient to fresh air. Monitor patient for respiratory distress. Emergency airway support and supplemental oxygen with assisted ventilation may be needed. If a cough or difficulty in breathing develops, evaluate for respiratory tract irritation or bronchitis.
    e) DERMAL - In case of dermatologic exposure, bathe in mild detergent (animal shampoo or Ivory liquid). Wear gloves to avoid human exposure. Clip hair as necessary to facilitate removal.
    11.2.5) TREATMENT
    A) DOGS/CATS
    1) MAINTAIN VITAL FUNCTIONS - as necessary.
    2) VENTILATORY SUPPORT including oxygen, intubation, and artificial ventilation may be necessary.
    3) SUPPORTIVE CARE - Other supportive care may be necessary for several days.
    4) MONITOR hepatic panels and treat for hepatic insult as necessary. Also monitor for methemoglobinemia and sulfhemoglobinemia.

Range Of Toxicity

    11.3.2) MINIMAL TOXIC DOSE
    A) ACUTE OVERDOSE
    1) LD50 (Hartley & Kidd, 1987)
    1) RAT (ORAL): 1826 to 3600 mg/kg
    2) MICE (ORAL): 3350 mg/kg
    3) PIGEON (ORAL): 5000 mg/kg
    4) RAT (DERMAL): 3170 mg/kg
    2) PROTEIN DEFICIENCY - Acute toxicity was found to be more prevalent in protein-deficient animals at lower doses of diuron (Boyd & Krupa, 1970).

Continuing Care

    11.4.1) SUMMARY
    11.4.1.2) DECONTAMINATION/TREATMENT
    A) GENERAL TREATMENT
    1) Begin treatment immediately.
    2) Keep animal warm and do not handle unnecessarily.
    3) Sample vomitus, blood, urine, and feces for analysis.
    B) ANIMAL POISON CONTROL CENTERS
    1) ASPCA Animal Poison Control Center, An Allied Agency of the University of Illinois, 1717 S. Philo Rd, Suite 36, Urbana, IL 61802, website www.aspca.org/apcc
    2) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
    3) The following 24-hour phone number is available: (888) 426-4435. A fee may apply. Please inquire with the poison center. The agency will make follow-up calls as needed in critical cases at no extra charge.
    11.4.2) DECONTAMINATION
    11.4.2.2) GASTRIC DECONTAMINATION
    A) GASTRIC DECONTAMINATION
    1) GENERAL TREATMENT
    a) EMESIS AND LAVAGE - If within 2 hours of exposure, induce emesis with 1 to 2 milliliters/kilogram syrup of ipecac per os. Dogs may vomit more readily with 1 tablet (6 milligrams) apomorphine diluted in 3 to 5 milliliters water and instilled into the conjunctival sac or per os. Dogs may also be given apomorphine intravenously at 40 micrograms/kilogram. Do not use an emetic if the animal is hypoxic. In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage. Pass large bore stomach tube and instill 5 to 10 milliliters/kilogram water or lavage solution, then aspirate. Repeat 10 times (Kirk, 1986).
    1) CAUTION - Carefully examine patients with chemical exposure before inducing emesis. If signs of oral, pharyngeal, or esophageal irritation, a depressed gag reflex, or central nervous system excitation or depression are present, EMESIS SHOULD NOT BE INDUCED.
    b) ACTIVATED CHARCOAL - Administer activated charcoal. Dose: 2 grams/kilogram per os or via stomach tube. Avoid aspiration by proper restraint, careful technique, and if necessary tracheal intubation.
    c) CATHARTIC - Administer a dose of a saline cathartic such as magnesium or sodium sulfate (sodium sulfate dose is 1 gram/kilogram). If access to these agents is limited, give 5 to 15 milliliters magnesium oxide (Milk of Magnesia) per os for dilution.
    d) INHALATION - Move patient to fresh air. Monitor patient for respiratory distress. Emergency airway support and supplemental oxygen with assisted ventilation may be needed. If a cough or difficulty in breathing develops, evaluate for respiratory tract irritation or bronchitis.
    e) DERMAL - In case of dermatologic exposure, bathe in mild detergent (animal shampoo or Ivory liquid). Wear gloves to avoid human exposure. Clip hair as necessary to facilitate removal.

References

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