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ALACHLOR AND RELATED AGENTS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Alachlor is used in the US as an aniline (chloracetanilide) pesticide and herbicide. Because of possible carcinogenesis, alachlor was taken off the market in Canada in 1986. Butachlor, an analog of alachlor, is not available in the US. Alachlor and butachlor have similar toxicity.

Specific Substances

    A) ALACHLOR
    1) 2,chloro-2',6'-diethyl-N-(methoxymethyl) acetanilide
    2) 2,chloro-N-(2,6-diethyl)phenyl)-N-methoxymethyl acetamide
    3) Acetamide, 2-chloro-N-(2,6-diethylphenyl)-N-(methoxymethyl)-(9CI)
    4) Acetanilide, 2-chloro-2', 6'-diethyl-N-(methoxymethyl)-
    5) Alachlore
    6) Alanex
    7) Alanox
    8) Alatox 480
    9) Alochlor
    10) CP 50144
    11) Lasagrin
    12) Lasso
    13) Lasso micro-tech
    14) LAZO
    15) Metachlor
    16) Methachlor
    17) Pillarzo
    18) CAS 15972-60-8
    BUTACHLOR
    1) 2-Chloro-2',6'-diethyl-N-(butoxymethyl) acetanilide
    2) Acetamide, N-(butoxymethyl)-2-chloro-N-(2,6-diethylphenyl)-(9CI)
    3) Acetanilide, N-(butoxymethyl)-2-chloro-2'6'-diethyl- (8CI)
    4) Acetanilide, 2-chloro-2',6'-diethyl-N-(butoxymethyl)-
    5) Aimchlor
    6) Bilchlor
    7) Butaclor
    8) Butanex
    9) CP 53619
    10) Delchlor
    11) Delchlor 5G
    12) Hiltachlor
    13) Machete
    14) Machette
    15) N-(Butoxymethyl)-2-chloro-2',6'-diethylacetanilide
    16) N-(Butoxymethyl)-2-chloro-N-(2,6-diethylphenyl)acetamide
    17) Pilarsete
    18) Rasayanchlor
    19) CAS 23184-66-9

    1.2.1) MOLECULAR FORMULA
    1) ALACHLOR - C14-H20-CI-N-O2 (HSDB, 2009)
    2) BUTACHLOR - C17-H26-CI-N-O2 (HSDB, 2009)

Available Forms Sources

    A) FORMS
    1) ALACHLOR - Alachlor is used in the United States, South America, and Asia (Lo et al, 2008). It is available as 15% granular, 4 Ib/gal emulsifiable concentrate and 4 Ib/gal flowable formulations, prepack formulation containing 2.5 Ib alachlor and 1.5 Ib of atrazine per gal (HSDB, 2009).
    2) BUTACHLOR - Butachlor, an analog of alachlor, is not available in the US (HSDB, 2009).
    B) USES
    1) ALACHLOR - Used in the US as an aniline (chloracetanilide) pesticide and herbicide. It is also used in South America, and Asia (HSDB, 2009; Lo et al, 2008). Because of possible carcinogenesis, alachlor was taken off the market in Canada in 1986 (Sun, 1986).
    2) BUTACHLOR - Used as a pesticide and herbicide (HSDB, 2009). It is mostly used in South America and Asia (eg; Taiwan) (Lo et al, 2008).

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: Alachlor is used in the US as an aniline (chloracetanilide) pesticide or herbicide. Because of possible carcinogenesis, alachlor was taken off the market in Canada in 1986. Butachlor, an analog of alachlor, is not available in the US.
    B) TOXICOLOGY: The specific mechanism for the development of toxicity following exposure to alachlor or butachlor is unknown.
    C) EPIDEMIOLOGY: Widely used in the world but human data on acute poisoning following exposure are limited.
    D) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE POISONING: COMMON (10% to 23%): Nausea, vomiting, abdominal pain, diarrhea, confusion/agitation, dyspnea or hypoxemia, and mucosa injury. The following adverse effects have also been reported: Drowsiness, weakness, confusion, weakness, , hypertension, bradycardia, tachyarrhythmia, chest tightness, dizziness, eye irritation, mydriasis/miosis, salivation, diaphoresis, fever, rhabdomyolysis, hyponatremia, incontinence, hematuria/proteinuria, abnormal liver enzymes, and leukocytosis. Allergic contact dermatitis has also been reported.
    2) SEVERE POISONING: Profound hypotension, seizures, coma, respiratory failure, acute renal failure, ventricular dysrhythmias.
    0.2.20) REPRODUCTIVE
    A) Alachlor exposure has been associated with reduced semen quality.
    0.2.21) CARCINOGENICITY
    A) The primary concern with alachlor is its carcinogenic and mutagenic potential. It has also been associated with several types of tumors when given to mice and rats for chronic periods.
    B) EPA listed alachlor as a probable human carcinogen in 1984. EPA listed alachlor as oncogenic in rats and mice in 1985 (Budavari, 1996; Sun, 1986).

Laboratory Monitoring

    A) Monitor vital signs including temperature, serum electrolytes, renal function, and liver enzyme levels in symptomatic patients.
    B) Monitor neurologic exam for mental status changes, seizures and coma.
    C) Monitor ECG and institute continuous cardiac monitoring in symptomatic patients.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Management will primarily be symptomatic and supportive. Manage mild hypotension with IV fluids.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treat seizures with benzodiazepines. Treat severe hypotension with fluids and vasopressors if necessary. Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary. If symptoms are severe, endotracheal intubation and assisted ventilation may be indicated. Obtain a baseline chest x-ray in symptomatic patients; repeat as indicated.
    C) DECONTAMINATION
    1) PREHOSPITAL: Activated charcoal is not recommended because of the potential for somnolence and rarely, seizures.
    2) HOSPITAL: Consider activated charcoal in a patient with a potentially toxic ingestion who is able to maintain airway or if airway is protected. Gastric lavage for very large, recent ingestions, protect airway first.
    D) DILUTION
    1) Immediately dilute with 4 to 8 ounces (120 to 240 mL) of water or milk (not to exceed 4 ounces/120 mL in a child).
    E) AIRWAY MANAGEMENT
    1) Insure adequate ventilation and perform endotracheal intubation early in patients with coma, seizures or significant CNS depression.
    F) ANTIDOTE
    1) None
    G) SEIZURES
    1) Administer IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur.
    H) HYPOTENSIVE EPISODES
    1) Treat hypotension with intravenous fluids, add vasopressors if unresponsive to fluids.
    I) PATIENT DISPOSITION
    1) OBSERVATION CRITERIA: All patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions who are symptomatic should be observed in a healthcare facility.
    2) ADMISSION CRITERIA: Patients with renal or hepatic toxicity, cardiotoxicity, seizures, or other persistent neurotoxicity, should be admitted.
    3) CONSULT CRITERIA: Consult a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity (ie, dysrhythmias, seizures) or in whom the diagnosis is unclear.
    J) PITFALLS
    1) When managing a suspected alachlor or butachlor overdose, the possibility of coingestion of other agents should be considered.
    K) PHARMACOKINETICS
    1) Alachlor and butachlor are absorbed by oral, inhalation, and dermal routes (less than 10%). Both are metabolized in the liver. Excretion: alachlor: 87% in urine, 9.7% feces; butachlor: 40% urine, 60% feces. Elimination half life: alachlor, biphasic, initial phase half life 0.2 to 10.6 hours, then slowed to half life of 5 to 16 days. Butachlor, half-lives of high and low concentrations of butachlor were 11.6 and 23.1 days, respectively.
    L) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause CNS depression, cardiotoxicity, or elevated liver enzymes.
    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) Remove contaminated clothing and remove particulate matter adherent to skin. Irrigate exposed skin with copious amounts of water for at least 15 minutes or longer, depending on the concentration, amount and duration of exposure to the chemical. A physician may need to examine the area if irritation or pain persists after washing.

Range Of Toxicity

    A) Three patients died after ingesting up to 1800 to 3750 mg/kg of alachlor. In a retrospective study of human alachlor (median dose 1079 mg/kg (range 75 to 4510)) and butachlor (median dose 180 mg/kg (range 17 to 2880) poisoning, 28 out of 102 patients with oral exposure were asymptomatic. Minor, moderate, major effects were reported in 56, 13, and 2 patients, respectively.

Clinical Effects

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CARDIOVASCULAR FINDING
    1) WITH POISONING/EXPOSURE
    a) In a retrospective study of human alachlor (n=63) and butachlor (n=70) poisoning in Taiwan, cardiovascular effects (hypotension, hypertension, bradycardia, tachyarrhythmia, and chest tightness) were reported in 10 (16%) alachlor-exposed patients and 8 (11%) butachlor-exposed patients (p = 0.45). The estimated median ingested amounts for alachlor and butachlor were 1079 mg/kg (range 75 to 4510) and 180 mg/kg (range 17 to 2880), respectively (Lo et al, 2008).
    b) CASE REPORT: A 40-year-old woman presented with agitation, diaphoresis, dry mouth, and mydriasis after ingesting 1800 mg/kg of alachlor in a suicide attempt. Her condition progressively worsened and she developed hypotension, tachycardia, acute renal failure, metabolic acidosis, and deep coma within 3 hours of ingestion. Despite supportive treatment, she died due to profound shock 24 hours after ingestion (Lo et al, 2008).
    c) CASE REPORT: A 76-year-old woman with a past medical history of atrial fibrillation developed confusion, vomiting, watery diarrhea, and hand tremor after ingesting approximately 3750 mg/kg of alachlor. One hour after ingestion, she presented comatose (Glasgow Coma Score of 9) and an ECG showed multiple premature ventricular contractions. Her condition deteriorated and she developed hypotension, bradycardia, and generalized seizures. Despite supportive treatment, she died 32 hours post-ingestion (Lo et al, 2008).
    d) CASE REPORT: A 72-year-old woman developed hypotension after ingesting 2250 mg/kg of alachlor in a suicide attempt. Despite aggressive supportive therapy, her condition worsened and she developed profound shock, hyponatremia (serum sodium 129 mmol/L) and hypokalemia (serum potassium 2.5 mmol/L) and died 12 hours after ingestion (Lo et al, 2008).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) RESPIRATORY FAILURE
    1) WITH POISONING/EXPOSURE
    a) In a retrospective study of human alachlor (n=63) and butachlor (n=70) poisoning in Taiwan, dyspnea, hypoxia, and respiratory failure necessitating endotracheal intubation were reported in 9 (14%) alachlor-exposed patients and 7 (10%) butachlor-exposed patients (p = 0.45). The estimated median ingested amounts for alachlor and butachlor were 1079 mg/kg (range 75 to 4510) and 180 mg/kg (range 17 to 2880), respectively (Lo et al, 2008).
    b) CASE REPORT: A 65-year-old man presented with a generalized tonic seizure and respiratory failure within 4 hours after intentionally ingesting 300 mL of alachlor. The patient was mechanically ventilated and given midazolam followed by phenytoin for seizure control. The patient subsequently developed fever and rhabdomyolysis, but was weaned from mechanical ventilation approximately 22 days post-ingestion (Seok et al, 2012).
    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) PULMONARY CARCINOMA
    a) Bronchioalveolar tumors were reported in female mice given 260 mg/kg/day for 2 years (Hoffmann D, 1984).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH POISONING/EXPOSURE
    a) In a retrospective study of human alachlor (n=63) and butachlor (n=70) poisoning in Taiwan, drowsiness, weakness, confusion, agitation, seizure, and coma were reported in 17 (27%) alachlor-exposed patients and 14 (20%) butachlor-exposed patients (p = 0.34). The estimated median ingested amounts for alachlor and butachlor were 1079 mg/kg (range 75 to 4510) and 180 mg/kg (range 17 to 2880), respectively. Dizziness was reported in 6 (6%) of 102 patients with alachlor or butachlor oral exposures and 12 (39%) of 31 patients with other pathways of exposure (p less than 0.01) (Lo et al, 2008).
    B) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) ALACHLOR
    1) CASE REPORT: A 76-year-old woman with a past medical history of atrial fibrillation developed with confusion, vomiting, watery diarrhea, and hand tremor after ingesting approximately 3750 mg/kg of alachlor. One hour after ingestion, she presented comatose (Glasgow Coma Score of 9) and an ECG showed multiple premature ventricular contractions. Her condition deteriorated and she developed hypotension, bradycardia, and generalized seizures. Despite supportive treatment, she died 32 hours post-ingestion (Lo et al, 2008).
    2) CASE REPORT: A 65-year-old man presented with a generalized tonic seizure and respiratory failure within 4 hours after intentionally ingesting 300 mL of alachlor. The patient was mechanically ventilated and given midazolam followed by phenytoin for seizure control. The patient subsequently developed fever and rhabdomyolysis, but was weaned from mechanical ventilation approximately 22 days post-ingestion (Seok et al, 2012).
    b) BUTACHLOR
    1) CASE REPORT: A 78-year-old woman ingested approximately 500 mL of a herbicide containing butachlor and chlornitrofen and subsequently developed hematochezia, hematemesis, generalized seizures, hepatotoxicity, nephrotoxicity, and coma. Despite supportive care, the patient died nine days post-ingestion (Lin et al, 2001).
    C) COMA
    1) WITH POISONING/EXPOSURE
    a) ALACHLOR
    1) CASE REPORT: A 40-year-old woman presented with agitation, diaphoresis, dry mouth, and mydriasis after ingesting 1800 mg/kg of alachlor in a suicide attempt. Her condition progressively worsened and she developed hypotension, tachycardia, acute renal failure, metabolic acidosis, and deep coma within 3 hours of ingestion. Despite supportive treatment, she died due to profound shock 24 hours after ingestion (Lo et al, 2008).
    2) CASE REPORT: A 76-year-old woman with a past medical history of atrial fibrillation developed with confusion, vomiting, watery diarrhea, and hand tremor after ingesting approximately 3750 mg/kg of alachlor. One hour after ingestion, she presented comatose (Glasgow Coma Score of 9) and an ECG showed multiple premature ventricular contractions. Her condition deteriorated and she developed hypotension, bradycardia, and generalized seizures. Despite supportive treatment, she died 32 hours post-ingestion (Lo et al, 2008).
    3) CASE REPORT: A 75-year-old woman became hypotensive and comatose within 3 hours after intentionally ingesting 300 mL of alachlor. The patient developed cardiogenic shock and died 24 hours post-ingestion (Seok et al, 2012).
    b) BUTACHLOR
    1) CASE REPORT: A 78-year-old woman ingested approximately 500 mL of a herbicide containing butachlor and chlornitrofen and subsequently developed hematochezia, hematemesis, generalized seizures, hepatotoxicity, nephrotoxicity, and coma. Despite supportive care, the patient died nine days post-ingestion (Lin et al, 2001).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) CNS STIMULATION
    a) CNS excitation, such as agitation, tremors, and spasms, were the first manifestations seen in animals fatally poisoned.
    2) COMA
    a) CNS depression, leading to coma, was seen in later stages of toxicity in fatally poisoned animals (Izmerov, 1985).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTROINTESTINAL TRACT FINDING
    1) WITH POISONING/EXPOSURE
    a) In a retrospective study of human alachlor (n=63) and butachlor (n=70) poisoning in Taiwan, nausea, vomiting, abdominal pain, and diarrhea were reported in 25 (40%) alachlor-exposed patients and 31 (44%) butachlor-exposed patients (p = 0.59). The estimated median ingested amounts for alachlor and butachlor were 1079 mg/kg (range 75 to 4510) and 180 mg/kg (range 17 to 2880), respectively. Salivation was reported in 8 (8%) of 102 patients following oral exposure to alachlor or butachlor (Lo et al, 2008).
    b) CASE REPORT: Dry mouth developed in a 40-year-old woman after ingesting 1800 mg/kg of alachlor in a suicide attempt (Lo et al, 2008).
    c) CASE REPORT: Vomiting and watery diarrhea developed in a 76-year-old woman after ingesting approximately 3750 mg/kg of alachlor (Lo et al, 2008).
    d) CASE REPORT: A 78-year-old woman ingested approximately 500 mL of a herbicide containing butachlor and chlornitrofen and subsequently developed hematochezia, hematemesis, generalized seizures, hepatotoxicity, nephrotoxicity, and coma. Despite supportive care, the patient died nine days post-ingestion (Lin et al, 2001).
    e) According to a retrospective analysis of cases involving chloracetanilide herbicide poisoning, nausea and vomiting were the most frequently reported manifestations, occurring in 31.4% and 45.7% of patients (n=35), respectively (Seok et al, 2012).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) In a retrospective study of human alachlor (n=63) and butachlor (n=70) poisoning in Taiwan, abnormal liver enzymes was reported in 3 (3%) of 102 patients with oral exposure to alachlor or butachlor and 1 (1%) of 31 patients with other pathways of exposure (p = 0.94). The estimated median ingested amounts for alachlor and butachlor were 1079 mg/kg (range 75 to 4510) and 180 mg/kg (range 17 to 2880), respectively (Lo et al, 2008).
    b) CASE REPORT: A 78-year-old woman ingested approximately 500 mL of a herbicide containing butachlor and chlornitrofen and subsequently developed hematochezia, hematemesis, generalized seizures, hepatotoxicity, nephrotoxicity, and coma. Despite supportive care, the patient died nine days post-ingestion (Lin et al, 2001).
    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEPATOCELLULAR DAMAGE
    a) Hepatotoxicity occurred in mice given 14 mg/kg/day for 2 years (Hoffmann D, 1984).
    b) In a six-month dog feeding study, technical grade alachlor was tested at the following dosages: 5, 25, 50, and 75 mg/kg/day and showed dose-related hepatotoxicity at all of the above dosages. The no-observable-effect-level (NOEL) was < 5.0 mg/kg/day (LDT) (Hoffmann D, 1984).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ACUTE RENAL FAILURE SYNDROME
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 40-year-old woman presented with agitation, diaphoresis, dry mouth, and mydriasis after ingesting 1800 mg/kg of alachlor in a suicide attempt. Her condition progressively worsened and she developed hypotension, tachycardia, acute renal failure, metabolic acidosis, and deep coma within 3 hours of ingestion. Despite supportive treatment, she died due to profound shock 24 hours after ingestion (Lo et al, 2008).
    B) INCONTINENCE
    1) WITH POISONING/EXPOSURE
    a) In a retrospective study of human alachlor (n=63) and butachlor (n=70) poisoning in Taiwan, incontinence was reported in 1 (1%) of 102 patients with oral exposure to alachlor or butachlor. The estimated median ingested amounts for alachlor and butachlor were 1079 mg/kg (range 75 to 4510) and 180 mg/kg (range 17 to 2880), respectively (Lo et al, 2008).
    C) BLOOD IN URINE
    1) WITH POISONING/EXPOSURE
    a) In a retrospective study of human alachlor (n=63) and butachlor (n=70) poisoning in Taiwan, hematuria and proteinuria were reported in 3 (3%) of 102 patients with oral exposure to alachlor or butachlor and 1 (1%) of 31 patients with other pathways of exposure (p = 0.94). The estimated median ingested amounts for alachlor and butachlor were 1079 mg/kg (range 75 to 4510) and 180 mg/kg (range 17 to 2880), respectively (Lo et al, 2008).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) METABOLIC ACIDOSIS
    1) WITH POISONING/EXPOSURE
    a) Metabolic acidosis developed in a 40-year-old woman who also experienced hypotension, tachycardia, acute renal failure, and deep coma after ingesting 1800 mg/kg of alachlor in a suicide attempt. Despite supportive treatment, she died due to profound shock 24 hours after ingestion (Lo et al, 2008).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LEUKOCYTOSIS
    1) WITH POISONING/EXPOSURE
    a) In a retrospective study of human alachlor (n=63) and butachlor (n=70) poisoning in Taiwan, leukocytosis was reported in 3 (3%) of 102 patients with oral exposure to alachlor or butachlor and 1 (1%) of 31 patients with other pathways of exposure (p = 0.94). The estimated median ingested amounts for alachlor and butachlor were 1079 mg/kg (range 75 to 4510) and 180 mg/kg (range 17 to 2880), respectively (Lo et al, 2008).
    3.13.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) ANEMIA
    a) Hemoglobin as well as erythrocyte count were lowered when 104 mg/kg was given to test animals for 4 months.

Summary Of Exposure

    A) USES: Alachlor is used in the US as an aniline (chloracetanilide) pesticide or herbicide. Because of possible carcinogenesis, alachlor was taken off the market in Canada in 1986. Butachlor, an analog of alachlor, is not available in the US.
    B) TOXICOLOGY: The specific mechanism for the development of toxicity following exposure to alachlor or butachlor is unknown.
    C) EPIDEMIOLOGY: Widely used in the world but human data on acute poisoning following exposure are limited.
    D) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE POISONING: COMMON (10% to 23%): Nausea, vomiting, abdominal pain, diarrhea, confusion/agitation, dyspnea or hypoxemia, and mucosa injury. The following adverse effects have also been reported: Drowsiness, weakness, confusion, weakness, , hypertension, bradycardia, tachyarrhythmia, chest tightness, dizziness, eye irritation, mydriasis/miosis, salivation, diaphoresis, fever, rhabdomyolysis, hyponatremia, incontinence, hematuria/proteinuria, abnormal liver enzymes, and leukocytosis. Allergic contact dermatitis has also been reported.
    2) SEVERE POISONING: Profound hypotension, seizures, coma, respiratory failure, acute renal failure, ventricular dysrhythmias.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH POISONING/EXPOSURE
    1) FEVER: In a retrospective study of human alachlor (n=63) and butachlor (n=70) poisoning in Taiwan, fever was reported in 5 (5%) of 102 patients with oral exposure to alachlor or butachlor exposures and 1 (3%) of 31 patients with other pathways of exposure (p = 0.69). The estimated median ingested amounts for alachlor and butachlor were 1079 mg/kg (range 75 to 4510) and 180 mg/kg (range 17 to 2880), respectively (Lo et al, 2008).

Heent

    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) MYDRIASIS/MIOSIS: In a retrospective study of human alachlor (n=63) and butachlor (n=70) poisoning in Taiwan, mydriasis/miosis was reported in 4 (4%) of 102 patients with oral exposure to alachlor or butachlor and 1 (3%) of 31 patients with other pathways of exposure (p = 0.86). The estimated median ingested amounts for alachlor and butachlor were 1079 mg/kg (range 75 to 4510) and 180 mg/kg (range 17 to 2880), respectively (Lo et al, 2008).
    2) CASE REPORT: Mydriasis developed in a 40-year-old woman after ingesting 1800 mg/kg of alachlor in a suicide attempt (Lo et al, 2008).
    3) IRRITATION: Alachlor may be irritating to the eyes (Morgan, 1983; Izmerov, 1985; HSDB , 2001).
    B) ANIMAL STUDIES
    1) LESIONS: Ocular lesions occurred in rats given 14 mg/kg/day for 2 years (Hoffmann D, 1984).
    2) PIGMENT DISPERSION SYNDROME: Pigment dispersion syndrome (PDS) was a primary effect of chronic, high-dose alachlor feedings in rats. Degenerative changes in the uvea were characterized by pigment disruption and dispersion, inflammation, and atrophy. 150 of the highest exposed workers in an alachlor production plant were evaluated for ocular changes. No exposed worker had eye defects meeting the study criteria for PDS (Ireland et al, 1994).
    3.4.5) NOSE
    A) WITH POISONING/EXPOSURE
    1) IRRITATION: Mucous membrane irritation of the nasal passages is possible (Izmerov, 1985).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH POISONING/EXPOSURE
    a) Allergic skin reactions have occurred in humans (Gosselin et al, 1984).
    b) Won et al (1993) reported a case of allergic contact dermatitis in a 32-year- old farmer following use of the herbicides alachlor and paraquat in her fields. Contact occurred from socks which got wet from the herbicides and remained on until the work was finished. Marked erythematous papules and vesicles were evident on her lower extremities. Patch tests confirmed an allergic dermatitis from alachlor (Won et al, 1993).
    B) SKIN FINDING
    1) WITH POISONING/EXPOSURE
    a) In a retrospective study of human alachlor (n=63) and butachlor (n=70) poisoning in Taiwan, mucosal injuries and other skin effects were reported in 10 (16%) alachlor-exposed patients and 13 (19%) butachlor-exposed patients (p = 0.68). The estimated median ingested amounts for alachlor and butachlor were 1079 mg/kg (range 75 to 4510) and 180 mg/kg (range 17 to 2880), respectively. Diaphoresis was reported in 2 (2%) of 102 patients with oral exposure to alachlor or butachlor and 3 (10%) of 31 patients with other pathways of exposure (p = 0.05). Six out of 22 patients with dermal exposure developed dermal pain, skin rash, or bulla formation (Lo et al, 2008).
    b) CASE REPORT: Diaphoresis developed in a 40-year-old woman after ingesting 1800 mg/kg of alachlor in a suicide attempt (Lo et al, 2008).
    C) ERYTHEMA MULTIFORME
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 38-year-old farmer presented to the emergency department with a 15-day history of pruritus of the mouth, chin, and extremities. Physical exam revealed confluent erythematous to violaceous maculopatches with bullae and erosions on his torso, and upper and lower extremities bilaterally. He had been occupationally exposed to alachlor and butachlor for 3 days prior to developing pruritus. He continued to use the herbicides for 5 days after onset of symptoms, presented to a local clinic with pruritus and maculopatches with bullae on his forearms and was treated with systemic and topical steroids and antihistamines for 10 days. He continued to use the herbicides and on the 10th day of treatment presented to the emergency department. Histopathological examination indicated mild to moderate exocytosis with diffuse spongiosis and necrotic keratinocytes in the epidermis, and superficial perivascular lymphocytic infiltrate with neutrophils and eosinophils, establishing the diagnosis of erythema multiforme major. Following treatment with systemic and topical steroids, the patient recovered with residual pigmentations of the right leg and forearm, and was discharged 18 days later (Kim et al, 2011).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) RHABDOMYOLYSIS
    1) WITH POISONING/EXPOSURE
    a) In a retrospective study of human alachlor (n=63) and butachlor (n=70) poisoning in Taiwan, rhabdomyolysis was reported in 1 (1%) of 102 patients with oral exposure to alachlor or butachlor and 0 (0%) of 31 patients with other pathways of exposure (p = 0.58). The estimated median ingested amounts for alachlor and butachlor were 1079 mg/kg (range 75 to 4510) and 180 mg/kg (range 17 to 2880), respectively (Lo et al, 2008).
    b) CASE REPORT: Rhabdomyolysis was reported in a 65-year-old man who intentionally ingested 300 mL of alachlor (Seok et al, 2012).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) IMMUNE SYSTEM FINDING
    1) LACK OF EFFECT
    a) No significant dose-related effect on functioning of the immunocompetent cells could be found when mononuclear cells from human peripheral blood were exposed to analytical alachlor (Flaherty et al, 1992).

Reproductive

    3.20.1) SUMMARY
    A) Alachlor exposure has been associated with reduced semen quality.

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS15972-60-8 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.2) SUMMARY/HUMAN
    A) The primary concern with alachlor is its carcinogenic and mutagenic potential. It has also been associated with several types of tumors when given to mice and rats for chronic periods.
    B) EPA listed alachlor as a probable human carcinogen in 1984. EPA listed alachlor as oncogenic in rats and mice in 1985 (Budavari, 1996; Sun, 1986).
    3.21.3) HUMAN STUDIES
    A) CARCINOMA
    1) EPA listed alachlor as a probable human carcinogen in 1984 (Sun, 1986).
    2) The incidence of cancer among pesticide applicators exposed to alachlor was investigated from 1993 to 2000 in the Agricultural Health Study. A significant increasing trend for incidence of all lymphohematopoietic cancers associated with lifetime exposure-days and intensity-weighted exposure-days was found. Among applicators in the highest exposure category, the risks of leukemia (rate ratio 2.83, 95% CI 0.74 to 10.9) and multiple myeloma (risk ratio 5.66, 95% CI 0.70 to 45.7) were increased (Lee et al, 2004).
    3) In a study of manufacturing workers exposed to alachlor, there was no excess in cancer mortality and no cases of the types of cancers found in animal toxicology studies (nasal, thyroid, stomach). The incidence of cancer was slightly higher than for the control population, but this did not reach statistical significance. There was a statistically significant increased incidence of chronic myeloid leukemia (CML) in the exposed population (2 cases), but not among the workers with the longest duration of exposure and the longest latency period since exposure. One of the patients with CML was diagnosed three years after first exposure, which does not support a causal relationship with alachlor.
    a) There was also a somewhat increased incidence of malignant melanoma in the exposed population, but not in the workers with the longest, highest level of exposure and the longest latency since exposure. Overall, this data does not support a relationship between alachlor exposure and cancer(Acquavella et al, 2004).
    3.21.4) ANIMAL STUDIES
    A) CARCINOMA
    1) A two year rat feeding/oncogenic study using technical alachlor stabilized with epoxidized soybean oil at 0.5, 2.5 and 15 mg/kg/day dosage levels indicated that alachlor is oncogenic in male and female rats.
    2) Nasal turbinate tumors increased significantly (p <0.01) in both sexes at 15 mg/kg/day. The same type of tumor occurred in one mid-dose female. An increase was noted in the incidence of thyroid follicular cell tumors in the high dose male group (13.3% in the high dose compared to 6.7% in control).
    3) Two additional kinds of tumors, thymus lymphosarcoma and adrenal pheochromocytoma, increased significantly (p < 0.05) in the high dose females. Nasal submucosal gland hyperplasia significantly increased (p < 0.01) in both sexes at the high dose level (Hoffmann D, 1984).
    B) GASTRIC CARCINOMA
    1) In a two year rat feeding study, technical alachlor was tested at the following dosages: 14, 42 and 126 mg/kg/day and showed statistically significant increase in the following tumors at 42 mg/kg/day and above, nasal turbinates and stomach tumors in both sexes.
    a) Thyroid follicular tumors were observed in males at 126 mg/kg/day. Ocular lesions and hepatotoxicity occurred at the lowest dose tested (LDT) (Hoffmann D, 1984).
    C) PULMONARY CARCINOMA
    1) In an eighteen month mouse study, the chemical was tested at the following dosages: 26, 78 and 260 mg/kg/day and showed a statistically significant increase in lung bronchioalveolar tumors in females at 260 mg/kg/day (highest dose tested (HDT)) (Hoffmann D, 1984).

Genotoxicity

    A) This agent has shown positive mutagenic response in several bacteria and IN VITRO models.
    B) In one bacteria study, alachlor was found to be genotoxic for Saccharomyces but not Salmonella (Plewa et al, 1984). It has been shown to be mutagenic in Salmonella and other micro-organisms with other authors (RTECS , 2001).
    C) In a three generation rat reproduction study, technical alachlor was tested at the following dosages: 10 and 30 mg/kg/day and showed the following effects: reproduction NOEL at 10 mg/kg/day, and reproduction low-effect-level (LEL) at 30 mg/kg/day (kidney effects in F2 and F3 pups) (Hoffmann D, 1984).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs including temperature, serum electrolytes, renal function, and liver enzyme levels in symptomatic patients.
    B) Monitor neurologic exam for mental status changes, seizures and coma.
    C) Monitor ECG and institute continuous cardiac monitoring in symptomatic patients.

Methods

    A) CHROMATOGRAPHY
    1) Alachlor concentration can be detected with gas liquid chromotography (Ammann et al, 1976).
    B) IMMUNOASSAY
    1) Enzyme-linked immunosorbent assay (ELISA) has been used to measure levels of alachlor in herbicide preparations (Harbison, 1998).

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 renal or hepatic toxicity, cardiotoxicity, seizures, or other persistent neurotoxicity, should be admitted.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity (ie, dysrhythmias, seizures) or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) All patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions who are symptomatic should be observed in a healthcare facility.

Monitoring

    A) Monitor vital signs including temperature, serum electrolytes, renal function, and liver enzyme levels in symptomatic patients.
    B) Monitor neurologic exam for mental status changes, seizures and coma.
    C) Monitor ECG and institute continuous cardiac monitoring in symptomatic patients.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Activated charcoal is not recommended because of the potential for somnolence and rarely, seizures.
    B) DILUTION
    1) DILUTION: If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. Dilution may only be helpful if performed in the first seconds to minutes after ingestion. The ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting (Caravati, 2004).
    6.5.2) PREVENTION OF ABSORPTION
    A) Consider activated charcoal in a patient with a potentially toxic ingestion who is able to maintain airway or if airway is protected. Gastric lavage for very large, recent ingestions, protect airway first.
    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).
    C) GASTRIC LAVAGE
    1) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).
    a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.
    2) PRECAUTIONS:
    a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
    b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.
    3) LAVAGE FLUID:
    a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
    b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
    c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.
    4) COMPLICATIONS:
    a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
    b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).
    5) CONTRAINDICATIONS:
    a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is symptomatic and supportive; there are no specific antidotes.
    B) MONITORING OF PATIENT
    1) Monitor vital signs including temperature, serum electrolytes, renal function, and liver enzyme levels in symptomatic patients.
    2) Monitor neurologic exam for CNS depression.
    3) Monitor ECG and consider continuous cardiac monitoring in symptomatic patients.
    C) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    D) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2010; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.
    6.7.2) TREATMENT
    A) RESPIRATORY FINDING
    1) Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary. If symptoms are severe, endotracheal intubation and assisted ventilation may be indicated. Obtain a baseline chest x-ray in symptomatic patients; repeat as indicated.
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Eye Exposure

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

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) Remove contaminated clothing and remove particulate matter adherent to skin. Irrigate exposed skin with copious amounts of water for at least 15 minutes or longer, depending on the concentration, amount and duration of exposure to the chemical. A physician may need to examine the area if irritation or pain persists after washing.

Enhanced Elimination

    A) SUMMARY
    1) No studies have addressed the utilization of extracorporeal elimination techniques in poisoning with this agent.

Range Of Toxicity

Summary

    A) Three patients died after ingesting up to 1800 to 3750 mg/kg of alachlor. In a retrospective study of human alachlor (median dose 1079 mg/kg (range 75 to 4510)) and butachlor (median dose 180 mg/kg (range 17 to 2880) poisoning, 28 out of 102 patients with oral exposure were asymptomatic. Minor, moderate, major effects were reported in 56, 13, and 2 patients, respectively.

Minimum Lethal Exposure

    A) CASE REPORTS
    1) ALACHLOR: A 40-year-old woman presented with agitation, diaphoresis, dry mouth, and mydriasis after ingesting 1800 mg/kg of alachlor in a suicide attempt. Her condition progressively worsened and she developed hypotension, tachycardia, acute renal failure, metabolic acidosis, and deep coma within 3 hours of ingestion. Despite supportive treatment, she died due to profound shock 24 hours after ingestion (Lo et al, 2008).
    2) ALACHLOR: A 76-year-old woman with a past medical history of atrial fibrillation developed confusion, vomiting, watery diarrhea, and hand tremor after ingesting approximately 3750 mg/kg of alachlor. One hour after ingestion, she presented comatose (Glasgow Coma Score of 9) and an ECG showed multiple premature ventricular contractions. Her condition deteriorated and she developed hypotension, bradycardia, and generalized seizures. Despite supportive treatment, she died 32 hours post-ingestion (Lo et al, 2008).
    3) ALACHLOR: A 72-year-old woman developed hypotension after ingesting 2250 mg/kg of alachlor in a suicide attempt. Despite aggressive supportive therapy, her condition worsened and she developed profound shock, hyponatremia (serum sodium 129 mmol/L) and hypokalemia (serum potassium 2.5 mmol/L) and died 12 hours later (Lo et al, 2008).
    4) ALACHLOR: A 75-year-old woman became hypotensive and comatose within 3 hours after intentionally ingesting 300 mL of alachlor. The patient developed cardiogenic shock and died 24 hours post-ingestion (Seok et al, 2012).
    5) BUTACHLOR: A 78-year-old woman ingested approximately 500 mL of a herbicide containing butachlor and chlornitrofen and subsequently developed hematochezia, hematemesis, generalized seizures, hepatotoxicity, nephrotoxicity, and coma. Despite supportive care, the patient died nine days post-ingestion (Lin et al, 2001).
    B) ANIMAL DATA
    1) Rats who inhaled 32.6 milligrams/liter died (Gosselin et al, 1984).
    2) Rats given 52 and 104 milligrams/kilogram for 4 months showed no toxicity, but did exhibit changes in blood catalase and peroxidase. BUN increased as did cholinesterase (Izmerov, 1985).
    3) Rats given 1, 3.5 and 10.4 milligrams/kilogram/day for 11 months showed no sign of toxicity.
    4) Rats who had 1000 milligrams/kilogram acutely applied to skin and those that had 100 milligrams/kilogram/day applied for 2 weeks showed no signs or symptoms (Izmerov, 1985).
    5) The minimum lethal human dose to this agent has not been delineated.

Maximum Tolerated Exposure

    A) In a retrospective study of human alachlor (n=63) and butachlor (n=70) poisoning in Taiwan, 28 out of 102 patients with oral exposure were asymptomatic. The estimated median ingested amounts for alachlor and butachlor were 1079 mg/kg (range 75 to 4510) and 180 mg/kg (range 17 to 2880), respectively. Minor, moderate, major effects (gastrointestinal (eg; nausea and vomiting, abdominal pain), CNS (eg; drowsiness, weakness, seizures, coma), respiratory (eg; dyspnea, respiratory failure), cardiovascular (eg; hypotension, hypertension, tachyarrhythmia), and dermal effects (eg; mucosa injury) were reported in 56, 13, and 2 patients, respectively (Lo et al, 2008).

Workplace Standards

    A) ACGIH TLV Values for CAS15972-60-8 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Editor's Note: The listed values are recommendations or guidelines developed by ACGIH(R) to assist in the control of health hazards. They should only be used, interpreted and applied by individuals trained in industrial hygiene. Before applying these values, it is imperative to read the introduction to each section in the current TLVs(R) and BEI(R) Book and become familiar with the constraints and limitations to their use. Always consult the Documentation of the TLVs(R) and BEIs(R) before applying these recommendations and guidelines.
    a) Adopted Value
    1) Alachlor
    a) TLV:
    1) TLV-TWA: 1 mg/m(3)
    2) TLV-STEL:
    3) TLV-Ceiling:
    b) Notations and Endnotes:
    1) Carcinogenicity Category: A3
    2) Codes: IFV, SEN
    3) Definitions:
    a) A3: Confirmed Animal Carcinogen with Unknown Relevance to Humans: The agent is carcinogenic in experimental animals at a relatively high dose, by route(s) of administration, at site(s), of histologic type(s), or by mechanism(s) that may not be relevant to worker exposure. Available epidemiologic studies do not confirm an increased risk of cancer in exposed humans. Available evidence does not suggest that the agent is likely to cause cancer in humans except under uncommon or unlikely routes or levels of exposure.
    b) IFV: Inhalable fraction and vapor.
    c) SEN: The designation SEN refers to the potential for an agent to produce sensitization, as confirmed by human or animal data. The notation does not imply that this is the critical effect or that this is the sole basis for the TLV. Although, for those TLVs that are based on sensitization, the TLV is meant to protect workers from induction of this effect, but cannot protect workers who have already become sensitized. The notation should be used to assist in identifying sensitization hazards and reducing respiratory, dermal, and conjunctival exposures to sensitizing agents in the workplace. Please see "Definitions and Notations" (in TLV booklet) for full definition.
    c) TLV Basis - Critical Effect(s): Hemosiderosis
    d) Molecular Weight: 269.8
    1) For gases and vapors, to convert the TLV from ppm to mg/m(3):
    a) [(TLV in ppm)(gram molecular weight of substance)]/24.45
    2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:
    a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance
    e) Additional information:

    B) NIOSH REL and IDLH Values for CAS15972-60-8 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS15972-60-8 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A3 ; Listed as: Alachlor
    a) A3 :Confirmed Animal Carcinogen with Unknown Relevance to Humans: The agent is carcinogenic in experimental animals at a relatively high dose, by route(s) of administration, at site(s), of histologic type(s), or by mechanism(s) that may not be relevant to worker exposure. Available epidemiologic studies do not confirm an increased risk of cancer in exposed humans. Available evidence does not suggest that the agent is likely to cause cancer in humans except under uncommon or unlikely routes or levels of exposure.
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Assessed under the IRIS program. ; Listed as: Alachlor
    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

    D) OSHA PEL Values for CAS15972-60-8 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ALACHLOR
    1) LD50- (ORAL)MOUSE:
    a) 462 mg/kg (RTECS, 2003)
    2) LD50- (ORAL)RAT:
    a) 930 mg/kg (RTECS, 2003)
    b) 1200 mg/kg (RTECS, 2003)
    3) LD50- (SKIN)RAT:
    a) > 2 g/kg (RTECS, 2003)
    B) BUTACHLOR
    1) LD50- (ORAL)MOUSE:
    a) 4140 mg/kg (RTECS, 2003)
    2) LD50- (ORAL)RAT:
    a) 1740 mg/kg (RTECS, 2003)

Pharmacology Toxicology

Toxicologic Mechanism

    A) Alachlor is an aniline (chloracetanilide) pesticide and herbicide The specific mechanism for the development of toxicity following exposure to alachlor or butachlor is unknown.

Physicochemical

Physical Characteristics

    A) ALACHLOR - An odorless, colorless to yellow crystals or colorless to white crystalline solid or cream to wine-red colored solid; soluble in acetone, benzene, chloroform, ethanol, ether, and ethyl acetate (HSDB, 2009).
    B) BUTACHLOR - Amber liquid or light yellow oil with faint, sweet odor; soluble in most organic solvents, including acetone, benzene, and ethanol (HSDB, 2009).

Molecular Weight

    A) ALACHLOR - 269.8 (HSDB, 2009)
    B) BUTACHLOR - 311.9 (HSDB, 2009)

References

General Bibliography

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