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ENDOSULFAN

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    1) Endosulfan is a chlorinated hydrocarbon pesticide.

Specific Substances

    A) No Synonyms were found in group or single elements
    1.2.1) MOLECULAR FORMULA
    1) C9-H6-Cl6-O3-S

Available Forms Sources

    A) FORMS
    1) ENDOSULFAN, also called ENSURE, THIOSULFAN, and many other trade names, is chemically 1,4,5,6,7,7-hexachloro-5-norbornene-2,3-dimethanol cyclic sulfite (RTECS). It exists as a colorless to brown crystalline or a tan waxy solid with a slight sulfur dioxide odor, is practically insoluble in water, and is soluble in most organic solvents (EOSH, 1982; (Lewis, 1993; Budavari, 1996). The commercial product is a 70%:30% mixture of the alpha and beta stereoisomers (HSDB; (ACGIH, 1991).
    2) Endosulfan is a CHLORINATED HYDROCARBON (ORGANOCHLORINE) pesticide chemically related to ALDRIN and DIELDRIN. These compounds are very toxic because they are LIPOPHILIC -- the high fat solubility makes the NERVOUS SYSTEM the major target organ (EOSH, 1982). Endosulfan appears to be somewhat more toxic than either aldrin or dieldrin, as determined by its greater acute toxicity in experimental animals and more rapid onset of symptoms in exposed workers (ACGIH, 1986). A lethal oral dose is in the range of 1 teaspoon to 1 ounce for an average adult (HSDB).
    3) The commercial product is a mixture of the alpha- and beta- stereoisomers in a 70:30 ratio (Budavari, 1996; ACGIH, 1991; Hayes & Laws, 1991). It smells like sulfur dioxide (Hayes & Laws, 1991). It is decomposed by IRON (ACGIH, 1991).
    4) It is sold as an emulsifiable concentrate (161, 357, or 480 g/L), a wettable powder (164, 329, or 470 g/kg), dusts (30 to 47 g/kg), granules (10, 30, 40, or 50 g/kg), and ultra low volume (242, 497, or 604 g/L) (HSDB). Endosulfan may also be mixed with other active ingredients in some commercial formulations (HSDB).
    B) USES
    1) Endosulfan is used as an insecticide and acaricide (RTECS; (Budavari, 1996).
    2) Endosulfan is currently in a phase-out process to end its use within the United States, due to health risks to farmworkers and wildlife, and its persistence in the environment. The ban on its use is expected to be complete by 2016 (US Environmental Protection Agency, 2012).

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: Endosulfan is a chlorinated hydrocarbon insecticide. This agent is in a phase-out process to end its use within the United States, with a complete ban by 2016.
    B) PHARMACOLOGY: These insecticides are neurotoxic to insects.
    C) TOXICOLOGY: Chlorinated hydrocarbon insecticides are likely to primarily act as "axon poisons", interfering with movement of ions across membranes resulting in CNS excitation and repetitive neuronal firing. Some of the agents are GABA antagonists as well. They may also sensitize myocardial tissue to catecholamines and predispose one to dysrhythmias in a similar manner as chlorinated hydrocarbon solvents.
    D) EPIDEMIOLOGY: Rare exposure. While inadvertent exposures are rarely toxic, large or deliberate exposures have resulted in significant morbidity and death.
    E) WITH POISONING/EXPOSURE
    1) The following are symptoms from chlorinated hydrocarbon insecticides in general. All of these effects may not be documented for endosulfan, but could potentially occur in individual cases.
    2) MILD TO MODERATE TOXICITY: Nausea, vomiting, abdominal pain, tremor, paresthesias, headache, and dizziness.
    3) SEVERE TOXICITY: Seizures (may progress to status epilepticus), myoclonus, agitation, ataxia, confusion, hypotension, dysrhythmias, respiratory failure, metabolic acidosis, and coma. Elevated liver enzymes, renal failure, and thrombocytopenia are rare effects.
    0.2.3) VITAL SIGNS
    A) WITH POISONING/EXPOSURE
    1) Respiratory depression, fever, apnea, and cyanosis may occur. Hyperthermia and recurrent hypotension occurred in related poisoning.
    0.2.20) REPRODUCTIVE
    A) Endosulfan exposure has been associated with congenital hydrocele, undescended testis and congenital inguinal hernia in male children. Endosulfan has been fetotoxic and induced musculoskeletal defects in rats. Effects on testes and sperm were seen in rats. No effects were seen on reproduction in a 3-generational study of rats fed dietary endosulfan.
    0.2.21) CARCINOGENICITY
    A) Carcinogenicity has been demonstrated in animal studies, but insufficient data has accrued from human studies.

Laboratory Monitoring

    A) No specific laboratory markers can identify poisoning with a chlorinated hydrocarbon pesticide.
    B) Obtain serum chemistries, renal function tests, liver enzymes, complete blood count, and urinalysis in patients who are symptomatic or those with deliberate or large exposures.
    C) Obtain creatinine kinase in patients with recurrent seizures or prolonged coma.
    D) Serum or urine concentrations can be obtained to confirm exposure, but will not be useful to guide therapy.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Adequate decontamination of dermal exposures and supportive care are the mainstays of treatment for mild to moderate exposures. Seizures, respiratory depression, and CNS depression indicate a more severe poisoning.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Perform endotracheal intubation and mechanical ventilation in patients with coma, respiratory depression, or recurrent seizures. Treat hypotension with intravenous fluids (10 to 20 mL/kg NS). If hypotension persists, vasopressors may be added, with the precaution that cardiac monitoring is necessary as chlorinated hydrocarbons may sensitize the myocardium to catecholamines and predispose patient to dysrhythmias. Treat seizures with benzodiazepines as a first-line therapy followed by phenobarbital if seizures persist. Propofol infusions and/or neuromuscular blockade (with continuous EEG monitoring) may be necessary in refractory cases. Phenytoin should not be used as it is likely to be of minimal effectiveness, especially with agents that are GABA antagonists (ie, lindane, toxaphene, endrin, hepatachlor, and endosulfan). Hyperthermia may result from neuromuscular agitation and should be aggressively managed with active cooling measures and liberal use of benzodiazepines. Severe metabolic acidosis can be treated with sodium bicarbonate.
    C) DECONTAMINATION
    1) PREHOSPITAL: Because of the risk of seizures and subsequent aspiration, prehospital gastrointestinal decontamination should be avoided.
    2) HOSPITAL: Activated charcoal and orogastric lavage should be used with caution because of the risk of seizures and subsequent risk of pulmonary aspiration. These procedures should only be used in a patient who presents soon after an ingestion and who have adequate airway protection. If the ingestion was very recent and a liquid formulation, nasogastric suction of gastric contents can be considered.
    D) AIRWAY MANAGEMENT
    1) Patients who are comatose or with altered mental status may need endotracheal intubation and mechanical ventilation.
    E) ANTIDOTE
    1) None
    F) ENHANCED ELIMINATION
    1) Dialysis is unlikely to be of benefit because of the large volume of distribution. Cholestyramine may enhance elimination of these compounds, but there is no evidence that it affects clinical outcome.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic patients with minor skin or inhalation exposures can be observed at home.
    2) OBSERVATION CRITERIA: Adults who intentionally ingest endosulfan or any child with an ingestion should be referred to a healthcare facility. Patients with prolonged or repeated dermal applications or inhalational exposures should be referred to a healthcare facility if they become symptomatic. If patients are asymptomatic after 6 hours of observation, they can be discharged after appropriate psychiatric clearance.
    3) ADMISSION CRITERIA: Patients with persistently altered mental status, abnormal vital signs, or recurrent seizures should be admitted to an intensive care setting.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing severe poisonings.
    H) PITFALLS
    1) Phenytoin is likely to be of minimal effectiveness for seizure control.
    I) DIFFERENTIAL DIAGNOSIS
    1) The differential diagnosis is broad and would include anything that can cause seizures.
    0.4.3) INHALATION EXPOSURE
    A) 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 inhaled beta-2 agonist and oral or parenteral corticosteroids.
    0.4.4) EYE EXPOSURE
    A) Irrigate exposed eyes with copious amounts of room temperature water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist, the patient should be seen in a health care facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) If clothing is contaminated remove, and wash skin and hair three times; do an initial soap washing followed by an alcohol washing followed by a soap washing. Leather absorbs pesticides. Hence, leather should not be worn in the presence of pesticides and all contaminated leather should be discarded.

Range Of Toxicity

    A) TOXICITY: The estimated lethal oral dose for humans is in the range of 50 to 500 mg/kg. An adult died after ingesting 100 mL.

Clinical Effects

Summary Of Exposure

    A) USES: Endosulfan is a chlorinated hydrocarbon insecticide. This agent is in a phase-out process to end its use within the United States, with a complete ban by 2016.
    B) PHARMACOLOGY: These insecticides are neurotoxic to insects.
    C) TOXICOLOGY: Chlorinated hydrocarbon insecticides are likely to primarily act as "axon poisons", interfering with movement of ions across membranes resulting in CNS excitation and repetitive neuronal firing. Some of the agents are GABA antagonists as well. They may also sensitize myocardial tissue to catecholamines and predispose one to dysrhythmias in a similar manner as chlorinated hydrocarbon solvents.
    D) EPIDEMIOLOGY: Rare exposure. While inadvertent exposures are rarely toxic, large or deliberate exposures have resulted in significant morbidity and death.
    E) WITH POISONING/EXPOSURE
    1) The following are symptoms from chlorinated hydrocarbon insecticides in general. All of these effects may not be documented for endosulfan, but could potentially occur in individual cases.
    2) MILD TO MODERATE TOXICITY: Nausea, vomiting, abdominal pain, tremor, paresthesias, headache, and dizziness.
    3) SEVERE TOXICITY: Seizures (may progress to status epilepticus), myoclonus, agitation, ataxia, confusion, hypotension, dysrhythmias, respiratory failure, metabolic acidosis, and coma. Elevated liver enzymes, renal failure, and thrombocytopenia are rare effects.

Vital Signs

    3.3.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Respiratory depression, fever, apnea, and cyanosis may occur. Hyperthermia and recurrent hypotension occurred in related poisoning.
    3.3.2) RESPIRATIONS
    A) WITH POISONING/EXPOSURE
    1) Aldrin, dieldrin, endrin, chlordane, camphechlor, and DDT are respiratory depressants. It is likely that endosulfan would be similar in this respect.
    2) Apnea and cyanosis can occur with endosulfan poisoning (EPA, 1985).
    3.3.3) TEMPERATURE
    A) WITH POISONING/EXPOSURE
    1) CASE SERIES: Forty-one patients were diagnosed with endosulfan poisoning following a mass exposure; 17.1% (7/41) of these cases developed fever (Durukan et al, 2009).
    2) CASE REPORT: Hyperthermia (41.2 degrees C) was reported in a 47-year-old woman following an intentional ingestion of 250 mL of 35% endosulfan (Moon & Lee, 2013).

Heent

    3.4.5) NOSE
    A) WITH POISONING/EXPOSURE
    1) FOAMING: A frothy, white exudate from the nose has appeared in some organochlorine poisonings.
    3.4.6) THROAT
    A) WITH POISONING/EXPOSURE
    1) MOUTH: Foaming at the mouth was observed in a 20-year-old man one hour after ingestion of 200 mL of 30% endosulfan (Shemesh et al, 1988).
    2) HYPERSALIVATION: Forty-one patients were diagnosed with endosulfan poisoning following a mass exposure; 31.7% (13/41) of these cases reported hypersalivation(Durukan et al, 2009).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CONDUCTION DISORDER OF THE HEART
    1) WITH POISONING/EXPOSURE
    a) High concentrations of organochlorine insecticides can cause cardiac dysrhythmias by increasing myocardial irritability (Morgan, 1993).
    b) CASE SERIES: Six patients who developed endosulfan poisoning from eating a dessert contaminated with endosulfan initially presented with nausea, vomiting, and confusion. Symptom onset was approximately 1 hour after consumption. Two of the 6 patients showed ECG abnormalities; one with sinus bradycardia and one with ST-T changes. All patients made a full recovery with supportive care (Bektas et al, 2007).
    c) CASE SERIES: Forty-one patients were diagnosed with endosulfan poisoning following a mass exposure; 24.4% (10/41) of these cases showed dysrhythmias (Durukan et al, 2009).
    d) CASE REPORT: Sinus tachycardia (112 bpm) with incomplete right bundle branch block occurred in a 52-year-old man following consumption of bread contaminated with endosulfan. The patient gradually recovered following supportive care (Oktay et al, 2003).
    e) CASE REPORT: Cardiovascular instability, including the development of bigeminy ventricular premature beats and worsening hypotension, occurred in a 47-year-old woman who intentionally ingested 250 mL of 35% endosulfan. An echocardiogram showed global akinesia with a 20% ejection fraction. Despite vasopressor administration and intravenous lipid emulsion therapy, she continued to deteriorate and died following unsuccessful cardiac resuscitation efforts (Moon & Lee, 2013).
    B) HEART FAILURE
    1) WITH POISONING/EXPOSURE
    a) A case of heart failure has been reported in a 50-year-old woman who ingested 12.3 grams of endosulfan. She recovered without sequelae (Eyer et al, 2004).
    C) LOW BLOOD PRESSURE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 47-year-old woman developed seizures and became comatose after ingesting 250 mL of 35% endosulfan in a suicide attempt. At the time of admission, the patient was hypertensive (150/100 mmHg), tachycardic (142 bpm), and hyperthermic (41.2 degrees C). Arterial blood gas analysis revealed metabolic acidosis, and she was anuric. The patient developed increasing cardiovascular instability with the development of dysrhythmias and hypotension (40 mmHg) that persisted despite vasopressor administration. Following cardiovascular collapse and successful cardiac resuscitation, the patient was given IV lipid emulsion therapy. Although the patient's blood pressure (90/30 mmHg) improved rapidly 10 minutes following administration of lipid emulsion, she again deteriorated hemodynamically approximately 3 hours later, collapsed, and died, despite increased vasopressor administration and cardiac resuscitation efforts (Moon & Lee, 2013).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH POISONING/EXPOSURE
    a) Along with apnea, cyanosis can occur from endosulfan poisoning (EPA, 1985).
    b) CASE SERIES: Forty-one patients were diagnosed with endosulfan poisoning following a mass exposure; 19.5% (8/41) of these cases reported dyspnea (Durukan et al, 2009).
    B) RESPIRATORY FAILURE
    1) WITH POISONING/EXPOSURE
    a) REDUCED GAS EXCHANGE: Severe convulsions can limit pulmonary gas exchange, and this may be an immediate cause of death (Morgan, 1993).
    b) CASE SERIES: Forty-one patients were diagnosed with endosulfan poisoning following a mass exposure; 7 patients were admitted to the ICU. Four patients required mechanical ventilation with a mean weaning time of 2.5 +/- 1 days (Durukan et al, 2009).
    C) PNEUMONITIS
    1) WITH POISONING/EXPOSURE
    a) Aspiration of petroleum distillate solvent is likely to cause a hydrocarbon pneumonitis, which is potentially fatal.
    b) Pulmonary infiltrates have been seen on chest radiography in several patients following ingestion of endosulfan. An increased alveolar-arterial oxygen tension gradient was also evident in these patients. Mechanical ventilation was required in 5 of 6 patients (Blanco-Coronado et al, 1992).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DROWSY
    1) WITH POISONING/EXPOSURE
    a) A 52-year-old man developed drowsiness and decreased responsiveness approximately 10 minutes after eating bread that was later determined to be contaminated with endosulfan. On presentation to the emergency department, the patient had a GCS score of 8. The patient gradually recovered following decontamination with activated charcoal and supportive care (Oktay et al, 2003).
    B) PARESTHESIA
    1) WITH POISONING/EXPOSURE
    a) Early signs of organochlorine poisoning involve hyperesthesia and paresthesia of the face and extremities, headache, dizziness, tremor and incoordination (Morgan, 1993).
    C) SYNCOPE
    1) WITH POISONING/EXPOSURE
    a) Fainting has occurred as an early sign of endosulfan poisoning (Hayes & Laws, 1991).
    D) HEADACHE
    1) WITH POISONING/EXPOSURE
    a) Headache has occurred with organochlorines (HSDB , 1997).
    b) CASE SERIES: Forty-one patients were diagnosed with endosulfan poisoning following a mass exposure; 34.1% (14/41) of these cases reported headache (Durukan et al, 2009).
    E) MYOCLONUS
    1) WITH POISONING/EXPOSURE
    a) As the severity of the poisoning increases, myoclonic jerking movements appear (Morgan, 1993).
    F) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) SUMMARY
    1) Generalized tonic-clonic convulsions occur in severe poisonings (Moon & Lee, 2013; Karatas et al, 2006; Yavuz et al, 2007; Bektas et al, 2007). Coma and respiratory depression may ensue (Morgan, 1993; Satar et al, 2009).
    b) CASE REPORTS
    1) A 20-year-old was unconscious and convulsing on admission one hour after ingesting 200 mL of 30% endosulfan (Shemesh et al, 1988). Seizures occurred in a 36-year-old man who ingested a solution containing 180 grams of endosulfan and in a 50-year-old woman who ingested a solution containing 12.3 grams of endosulfan (Eyer et al, 2004). In a self-poisoning case the intravenous administration of a small dose of endosulfan in xylene caused the rapid onset of severe grand mal seizures (Grimmett et al, 1996).
    2) A 72-year-old man was admitted to the emergency department following a suicidal ingestion of an endosulphan insecticide. Muscle fasciculations and several episodes of seizures developed (Lo et al, 1995a).
    3) A professional agriculture pilot suffered a tonic-clonic seizure approximately 7 hours after a crash and soaking in methomyl and endosulfan, a carbamate and chlorinated hydrocarbon, respectively (Cable & Doherty, 1999). The patient developed cholinergic symptoms consistent with those expected from the carbamate but the seizures were attributed to the organochlorine. A full recovery was attained with no further seizures reported.
    4) A 52-year-old man experienced generalized seizures following consumption of bread contaminated with endosulfan. The patient completely recovered following decontamination with activated charcoal and supportive care (Oktay et al, 2003).
    5) A 28-year-old man presented with seizures and altered mental status after ingesting an unknown amount of endosulfan. He also developed acute renal failure, metabolic acidosis, and rhabdomyolysis, but recovered following supportive treatment, including 3 sessions of hemodialysis (Yadla et al, 2013).
    c) CASE SERIES
    1) In a retrospective review of endosulfan exposures (n=23), seizures were reported in 82.6% (n =19) of the cases. Five patients (21.7%) presented with seizures as the initial symptom after exposure. Generalized tonic-clonic seizures were observed in 16 patients (69.6%) and focal motor seizures were observed in three patients (13%). All patients were treated with intravenous diazepam for seizure control (Karatas et al, 2006).
    2) A 3-week outbreak of convulsions in India was associated with wheat flour contaminated with endosulfan which was used to prepare food items (Dewan et al, 2004).
    3) Forty-one patients were diagnosed with endosulfan poisoning following a mass exposure; 22% (9/41) of these cases reported convulsions (Durukan et al, 2009).
    4) In a report of 18 cases of unintentional endosulfan poisoning in northern India after crop spraying, all victims developed seizure activity during the 24 hour period following the spraying (Chugh et al, 1998). Other prominent symptoms included: confusion, dizziness, and irritability. In these cases phenobarbital was effectively used to treat seizure activity; all cases recovered without permanent sequelae.
    d) STATUS EPILEPTICUS
    1) CASE REPORT: A 43-year-old man intentionally ingested 100 milliliters of endosulfan (18.8 g endosulfan, 260 mg/kg body weight) and developed seizures within approximately 60 minutes of ingestion (Boereboom et al, 1998). Despite aggressive chemical therapy the patient continued to have seizures; EEG showed a sustained epileptic state. A CT scan showed massive cerebral edema on hospital day 2, and a repeat EEG on day 3 showed no electrical response. Autopsy revealed cerebral herniation secondary to cerebral edema.
    2) CASE REPORT: A 32-year-old man developed refractory status epilepticus following ingestion of an unknown amount of endosulfan dissolved in kerosene. The patient presented to the hospital with vomiting, hyperreflexia, and generalized seizures that initially lasted for 1 to 2 minutes and progressing up to 20 minutes, refractory to treatment with phenobarbitone (4 grams, 60 mg/kg), and diazepam (80 mg). He was treated with an Infusion of thiopentone and bolus doses of atracurium (without EEG monitoring). He died 24 hours post-admission, following a cardiac arrest (Roberts et al, 2004).
    3) CASE REPORT/CHILD: A 2-year-old child presented with generalized status epilepticus after unintentionally ingesting an unknown amount of endosulfan. Three hours post-presentation, the seizures were under control following administration of lorazepam, phenytoin, sodium-valproate, and levetiracetam (Kamate & Jain, 2011).
    G) TREMOR
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: Forty-one patients were diagnosed with endosulfan poisoning following a mass exposure; 26.8% (11/41) of these cases reported tremor (Durukan et al, 2009).
    H) CLOUDED CONSCIOUSNESS
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: Forty-one patients were diagnosed with endosulfan poisoning following a mass exposure; 29.3% (12/41) of these cases reported confusion (Durukan et al, 2009).
    I) COMA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 47-year-old woman developed seizures and became comatose after ingesting 250 mL of 35% endosulfan in a suicide attempt. At the time of admission, the patient was hypertensive (150/100 mmHg), tachycardic (142 bpm), and hyperthermic (41.2 degrees C). Arterial blood gas analysis revealed metabolic acidosis, and she was anuric. The patient developed increasing cardiovascular instability with the development of dysrhythmias and hypotension (40 mmHg) that persisted despite vasopressor administration. Following cardiovascular collapse and successful cardiac resuscitation, the patient was given IV lipid emulsion therapy. Although the patient's blood pressure (90/30 mmHg) improved rapidly 10 minutes following administration of lipid emulsion, she again deteriorated hemodynamically approximately 3 hours later, collapsed, and died, despite increased vasopressor administration and cardiac resuscitation efforts (Moon & Lee, 2013).
    J) TOXIC ENCEPHALOPATHY
    1) WITH POISONING/EXPOSURE
    a) BASAL GANGLIA LESIONS: In a single case of acute endosulfan poisoning a 16-year-old girl with seizures, psychosis and cortical blindness had bilateral reversible MRI lesions of the caudate, putamen and occipital cortex; with sparing of the internal capsule and thalamus (Pradhan et al, 1997).
    K) DEMENTIA
    1) WITH POISONING/EXPOSURE
    a) PERMANENT DAMAGE: Severe mental impairment was evident one year after ingestion of endosulfan in one case. It is not clear if the brain damage was due to a direct effect of endosulfan, or to the hypoxemia accompanying convulsions and respiratory insufficiency (Shemesh et al, 1988).
    L) SECONDARY PERIPHERAL NEUROPATHY
    1) WITH POISONING/EXPOSURE
    a) Occasional reports have associated peripheral neuropathy with exposure to organochlorines.
    M) CEREBRAL EDEMA
    1) WITH POISONING/EXPOSURE
    a) Severe cerebral edema was observed at autopsy in a 36-year-old man who ingested 180 grams of endosulfan (Eyer et al, 2004).
    N) AMNESIA
    1) WITH POISONING/EXPOSURE
    a) Impaired memory and coordination has occurred following ingestion of endosulphan (Shemesh et al, 1988).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) CNS FINDING
    a) Neonatal rats were more sensitive to the neurological effects of endosulfan than adult animals (Seth et al, 1986).
    b) Endosulfan was suggested to produce learning and memory deficit in immature male rats given endosulfan (2mg/kg/d) by oral administration for 90 days (Paul V et al, 1994).
    1) Further studies demonstrated motor stimulation and learning and memory deficits in both sexes, with motor stimulation being noted in males (Paul et al, 1995). These effects have been associated with alterations of adrenergic neurotransmitters (Lakshmana & Raju, 1994).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH POISONING/EXPOSURE
    a) When ingested, endosulfan can cause nausea, vomiting, gagging, and foaming at the mouth (Karatas et al, 2006; EPA, 1985; Bektas et al, 2007; Yavuz et al, 2007).
    b) INCIDENCE: In a report of unintentional exposure to endosulfan during crop spraying, all 18 patients developed nausea, vomiting and abdominal pain within the first 24 hours of exposure (Chugh et al, 1998). Other symptoms included seizures, confusion, and irritability. All patients recovered following supportive care.
    c) CASE SERIES: In a retrospective review of endosulfan exposures (n=23), nausea and vomiting were reported in 21 of the cases (91.3%). In 17 of the patients, nausea and vomiting were the initial symptoms after exposure to endosulfan (Karatas et al, 2006).
    d) CASE SERIES: Forty-one patients were diagnosed with endosulfan poisoning following a mass exposure; 56.1% (23/41) of these cases reported nausea and 48.8% (20/41) reported vomiting (Durukan et al, 2009).
    B) DIARRHEA
    1) WITH POISONING/EXPOSURE
    a) Diarrhea may occur with endosulfan (Karatas et al, 2006; EPA, 1985).
    b) CASE SERIES: Forty-one patients were diagnosed with endosulfan poisoning following a mass exposure; 31.7% (13/41) of these cases reported diarrhea (Durukan et al, 2009).
    C) ABDOMINAL PAIN
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: Forty-one patients were diagnosed with endosulfan poisoning following a mass exposure; 39% (16/41) of these cases reported abdominal pain (Durukan et al, 2009).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER DAMAGE
    1) WITH POISONING/EXPOSURE
    a) Permanent hepatic damage may occur from exposure to endosulfan (OHM/TADS , 1990).
    b) CASE REPORT: Liver transplantation was anticipated after an endosulfan exposure. The patient's liver enzymes gradually increased over a five day period from the time of exposure. Serum bilirubin levels were within normal limits. The patient developed hepatic encephalopathy and then was transferred for liver transplantation. The patient was discharged after a complete recovery without the need for liver transplantation (Karatas et al, 2006).
    B) INCREASED LIVER ENZYMES
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: Six patients who developed endosulfan poisoning from eating a dessert contaminated with endosulfan initially presented with nausea, vomiting, and confusion. Symptom onset was approximately 1 hour following consumption. Laboratory results showed elevated white blood cell counts in all 6 patients, as well as elevated glucose, aminotransferases, and LDH levels. All patients made a full recovery following supportive care (Bektas et al, 2007).
    C) LARGE LIVER
    1) WITH POISONING/EXPOSURE
    a) Lo et al (1995) describe a postmortem finding of hepatic centrovenular congestion and slight prominence of bile canaliculi following a suicidal ingestion of endosulphan insecticide in a 79-year-old man (Lo et al, 1995).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) URINARY INCONTINENCE
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: Forty-one patients were diagnosed with endosulfan poisoning following a mass exposure; 14.6% (6/41) of these cases reported urinary incontinence (Durukan et al, 2009).
    B) ABNORMAL RENAL FUNCTION
    1) WITH POISONING/EXPOSURE
    a) Permanent kidney damage may occur from exposure to endosulfan (OHM/TADS , 1990).
    C) CRUSH SYNDROME
    1) WITH POISONING/EXPOSURE
    a) Acute tubular necrosis in the absence of rhabdomyolysis has been reported following acute endosulfan poisoning (Lo et al, 1995; Chan, 1995).
    D) ACUTE RENAL FAILURE SYNDROME
    1) WITH POISONING/EXPOSURE
    a) A patient with acute intoxication by endosulfan developed acute renal failure with normal urine flow and elevation of serum aminotransferases. The patient later became anuric and was put on hemodialysis. Eight days later the patient died (Blanco-Coronado et al, 1992).
    b) A 72-year-old man developed acute tubular necrosis following an intentional ingestion of endosulphan insecticide. Plasma albumin level dropped, and urinary protein excretion increased. Renal function continued to deteriorate, and the patient died of cardiopulmonary arrest 10 days after the ingestion (Lo et al, 1995).
    c) CASE SERIES: Forty-one patients were diagnosed with endosulfan poisoning following a mass exposure; 7 patients were treated in the ICU. One of the ICU patients died five hours after treatment commenced due to acute renal failure and disseminated intravascular coagulation(Durukan et al, 2009).
    d) CASE REPORT: A 28-year-old man developed acute renal failure (serum creatinine 8.4 mg/dL, urine output 900 mL) with metabolic acidosis and rhabdomyolysis after ingesting an unknown amount of endosulfan. After 3 hemodialysis sessions, the patient's urine output increased to 2.5 L/day, and his serum creatinine concentration decreased to 2.7 mg/dL at hospital discharge (Yadla et al, 2013).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) WITH POISONING/EXPOSURE
    a) SUMMARY: Severe metabolic acidosis may be a consequence of severe convulsions, and the acidosis may be an immediate cause of death (Morgan, 1993).
    b) Six patients with acute endosulfan intoxication from oral exposures were reported with severe metabolic acidosis secondary to seizures, with high anion gap associated with hyperglycemia (Blanco-Coronado et al, 1992).
    c) CASE REPORT: A 72-year-old man was admitted to the emergency department with seizures and resulting metabolic acidosis following a suicidal ingestion of endosulfan insecticide (Lo et al, 1995a).
    d) CASE REPORT: A 50-year-old man presented 2 hours after eating a homemade pastry with nausea, vomiting, altered mental status, tachycardia (135 bpm) and seizure activity. Blood gas values revealed metabolic acidosis (pH 6.95, pCO2 50.1 mmHg, pO2 94.2 mmHg, HCO3 12.9 mmol/L), and bicarbonate hemodialysis was initiated. The patient's acidosis normalized after 2 hours of hemodialysis. He received atropine and pralidoxime for suspected organophosphate toxicity, and all lab abnormalities and pulmonary function returned to normal within days. A later toxicologic analysis of the pastry revealed endosulfan (Yavuz et al, 2007).
    e) CASE REPORT: Six patients from the same family presented with unintentional endosulfan poisoning following ingestion of endosulfan-contaminated soup. One patient developed decompensated metabolic acidosis (pH 7.08; pCO2 23 mm Hg; pO2 93 mm Hg; HCO3 4.8 mmol/L). The patient did not respond to initial bicarbonate therapy and required one hemodialysis treatment. Following symptomatic and supportive treatment, the patient made a full recovery with no sequelae (Satar et al, 2009).
    f) CASE REPORT: A 28-year-old man developed seizures, altered mental status, metabolic acidosis (pH 7.38; serum bicarbonate 15.8 mEq/L), acute renal failure, and rhabdomyolysis after ingesting an unknown amount of endosulfan. The patient gradually recovered following supportive treatment, including 3 hemodialysis sessions (Yadla et al, 2013).
    g) CASE REPORT: Metabolic acidosis (pH 6.94, PaCO2 53 mmHg, PaO2 100 mmHg, HCO3 8.4 mEq/L) occurred in a 47-year-old woman who intentionally ingested 250 mL of 35% endosulfan (Moon & Lee, 2013).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) THROMBOCYTOPENIC DISORDER
    1) WITH POISONING/EXPOSURE
    a) Oral endosulfan intoxications have resulted in thrombocytopenia and leukocytosis (Blanco-Coronado et al, 1992; Lo et al, 1995a).
    B) LEUKOCYTOSIS
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: Six patients who developed endosulfan poisoning from eating a dessert contaminated with endosulfan initially presented with nausea, vomiting, and confusion. Symptom onset was approximately 1 hour following consumption. Laboratory results showed elevated white blood cell counts in all 6 patients, as well as elevated glucose, aminotransferases, and LDH levels. All patients made a full recovery following supportive care (Bektas et al, 2007).
    b) CASE REPORT: Yavuz et al (2007) reported 2 cases of endosulfan poisoning that included leukocytosis (WBC = 27X10(3)/mcL and 18X10(3)/mcL, respectively) among the presenting findings (Yavuz et al, 2007).
    c) Oral endosulfan intoxications have resulted in thrombocytopenia and leukocytosis (Blanco-Coronado et al, 1992; Lo et al, 1995a).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) SKIN IRRITATION
    1) WITH POISONING/EXPOSURE
    a) Endosulfan in solution in oily media, surfactants or emulsifiers may result in skin irritation (CHRIS , 1997).
    B) SKIN ABSORPTION
    1) WITH POISONING/EXPOSURE
    a) Endosulfan is rapidly absorbed through the skin, especially in commercial formulations containing xylene solvent (OHM/TADS , 1990).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) RHABDOMYOLYSIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Rhabdomyolysis (serum creatinine phosphokinase 15700 international units/L) associated with acute renal failure was reported in a 28-year-old man who ingested an unknown amount of endosulfan (Yadla et al, 2013).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPERGLYCEMIA
    1) WITH POISONING/EXPOSURE
    a) Six patients with acute endosulfan intoxication from oral exposures developed hyperglycemia (Blanco-Coronado et al, 1992).
    b) CASE REPORT (CHILD): Hyperglycemia (blood sugar 321 mg/dL) was reported in a 2-year-old child who unintentionally ingested an unknown amount of endosulfan (Kamate & Jain, 2011).

Immunologic

    3.19.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) DISORDER OF IMMUNE FUNCTION
    a) Both humoral and cellular immunity were suppressed in rats receiving up to 20 ppm endosulfan in the diet for 8 to 22 weeks (Banerjee & Hussain, 1986).

Reproductive

    3.20.1) SUMMARY
    A) Endosulfan exposure has been associated with congenital hydrocele, undescended testis and congenital inguinal hernia in male children. Endosulfan has been fetotoxic and induced musculoskeletal defects in rats. Effects on testes and sperm were seen in rats. No effects were seen on reproduction in a 3-generational study of rats fed dietary endosulfan.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) SKELETAL MALFORMATION
    a) Endosulfan has increased post-implantation mortality and skeletal malformations in mice (RTECS , 1997) and rats (Gupta et al, 1978). In the latter study, there were significant maternal toxicity and deaths in the mothers, such that endosulfan would not be considered teratogenic (p 11).
    b) Endosulfan was not teratogenic in rats (Schardein, 1993). When given at doses up to 10 mg/kg on days 6 through 14 of gestation, endosulfan increased fetal mortality and resorptions, and induced skeletal defects (Gupta et al, 1978).
    3.20.3) EFFECTS IN PREGNANCY
    A) ANIMAL STUDIES
    1) LACK OF EFFECT
    a) No effects on fertility were seen when rats were given up to 5 mg/kg endosulfan orally for 30 days (Dikshith et al, 1984).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Those chlorinated hydrocarbon insecticides which are more rapidly metabolized, such as endosulfan, are less likely to be detected in breast milk (Morgan, 1993).
    2) The daily intake of total organochlorine pesticides residues calculated for the suckling infant was significantly higher when compared with the acceptable daily intake (ADI) as recommended by FAO/WHO (FAO/WHO, 1970).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS115-29-7 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.2) SUMMARY/HUMAN
    A) Carcinogenicity has been demonstrated in animal studies, but insufficient data has accrued from human studies.
    3.21.3) HUMAN STUDIES
    A) HUMANS
    1) LACK OF INFORMATION
    a) With few exceptions, the delayed effects of pesticides on human health have been difficult to detect. Perhaps the health risks are sufficiently small that they are below the power of epidemiologic studies to detect (Sharp et al, 1986).
    b) The International Agency for Research on Cancer (IARC) has listed some of these agents (eg, DDT) as "probably carcinogenic to humans", although it also categorizes them as being inadequately assessed for human carcinogenic potential (IARC, 1982).
    c) Their carcinogenicity has been demonstrated in animal studies, but insufficient data has accrued from human studies.
    3.21.4) ANIMAL STUDIES
    A) ANIMAL STUDIES
    1) Endosulfan was designated neoplastic in mice by RTECS criteria with lung, thorax or respiratory tumors. In another study it was termed an equivocal tumorigenic agent in mice by RTECS criteria with lung, thorax or respiratory and liver tumors observed (RTECS , 1997).
    2) In the NCI Carcinogenesis Bioassay (Feed) no evidence of carcinogenicity was found in the mouse and rat systems (RTECS , 1997). Endosulfan was carcinogenic in male and female rats at all sites; it also induced liver tumors in female mice (Reuber, 1981).
    3) ATSDR has concluded that available data do NOT provide evidence that endosulfan is a carcinogen in experimental animals (ATSDR, 1993).
    4) Endosulfan was not carcinogenic in mice (Naqvi & Vaishnavi, 1993). Endosulfan was not carcinogenic at dietary levels as high as 75 ppm in rats and 18 ppm in mice fed for 24 months (Hack et al, 1995).

Genotoxicity

    A) Endosulfan has been genotoxic at the mutational and chromosomal levels.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) No specific laboratory markers can identify poisoning with a chlorinated hydrocarbon pesticide.
    B) Obtain serum chemistries, renal function tests, liver enzymes, complete blood count, and urinalysis in patients who are symptomatic or those with deliberate or large exposures.
    C) Obtain creatinine kinase in patients with recurrent seizures or prolonged coma.
    D) Serum or urine concentrations can be obtained to confirm exposure, but will not be useful to guide therapy.
    4.1.2) SERUM/BLOOD
    A) Concentrations of endosulfan in the blood from three fatal poisonings ranged from 400 to 800 mcg/ dL (Coutselinis et al, 1978).
    B) In another fatal poisoning, endosulfan was present in the blood at a concentration of 30 mg/L (3,000 mcg/dL) (Bernardelli & Gennari, 1987).
    C) Blood chlorinated hydrocarbon levels are not clinically useful following acute exposure. For most compounds they reflect cumulative exposure over a period of months or years rather than recent exposure (Coye et al, 1986).
    D) Obtain serum chemistries, renal function tests, liver enzymes, complete blood count, and urinalysis in patients who are symptomatic or those with deliberate or large exposures.
    E) Obtain creatinine kinase in patients with recurrent seizures or prolonged coma.

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 persistently altered mental status, abnormal vital signs, or recurrent seizures should be admitted to an intensive care setting.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic patients with minor skin or inhalation exposures can be observed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing severe poisonings.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Adults who intentionally ingest endosulfan or any child with an ingestion should be referred to a healthcare facility. Patients with prolonged or repeated dermal applications or inhalational exposures should be referred to a healthcare facility if they become symptomatic. If patients are asymptomatic after 6 hours of observation, they can be discharged after appropriate psychiatric clearance.

Monitoring

    A) No specific laboratory markers can identify poisoning with a chlorinated hydrocarbon pesticide.
    B) Obtain serum chemistries, renal function tests, liver enzymes, complete blood count, and urinalysis in patients who are symptomatic or those with deliberate or large exposures.
    C) Obtain creatinine kinase in patients with recurrent seizures or prolonged coma.
    D) Serum or urine concentrations can be obtained to confirm exposure, but will not be useful to guide therapy.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital GI decontamination is generally not recommended because of the risk of seizures and aspiration. Remove contaminated clothing and wash exposed skin with soap and water.
    6.5.2) PREVENTION OF ABSORPTION
    A) EMESIS/NOT RECOMMENDED
    1) Emesis is not recommended due to potential CNS depression or seizures.
    B) ACTIVATED CHARCOAL
    1) SUMMARY: Activated charcoal and orogastric lavage should be used with caution because of the risk of seizures and subsequent risk of pulmonary aspiration. These procedures should only be used in a patient who presents soon after an ingestion and who have adequate airway protection. If the ingestion was very recent and a liquid formulation, nasogastric suction of gastric contents can be considered.
    2) 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.
    3) 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) MONITORING OF PATIENT
    1) No specific laboratory markers can identify poisoning with a chlorinated hydrocarbon pesticide.
    2) Obtain serum chemistries, renal function tests, liver enzymes, complete blood count, and urinalysis in patients who are symptomatic or those with deliberate or large exposures.
    3) Obtain creatinine kinase in patients with recurrent seizures or prolonged coma.
    4) Serum or urine concentrations can be obtained to confirm exposure, but will not be useful to guide therapy.
    B) 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).
    7) RECURRING SEIZURES
    a) If seizures are not controlled by the above measures, patients will require endotracheal intubation, mechanical ventilation, continuous EEG monitoring, a continuous infusion of an anticonvulsant, and may require neuromuscular paralysis and vasopressor support. Consider continuous infusions of the following agents:
    1) MIDAZOLAM: ADULT DOSE: An initial dose of 0.2 mg/kg slow bolus, at an infusion rate of 2 mg/minute; maintenance doses of 0.05 to 2 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: 0.1 to 0.3 mg/kg followed by a continuous infusion starting at 1 mcg/kg/minute, titrated upwards every 5 minutes as needed (Loddenkemper & Goodkin, 2011).
    2) PROPOFOL: ADULT DOSE: Start at 20 mcg/kg/min with 1 to 2 mg/kg loading dose; maintenance doses of 30 to 200 mcg/kg/minute continuous infusion dosing, titrated to EEG; caution with high doses greater than 80 mcg/kg/minute in adults for extended periods of time (ie, longer than 48 hours) (Brophy et al, 2012); PEDIATRIC DOSE: IV loading dose of up to 2 mg/kg; maintenance doses of 2 to 5 mg/kg/hour may be used in older adolescents; avoid doses of 5 mg/kg/hour over prolonged periods because of propofol infusion syndrome (Loddenkemper & Goodkin, 2011); caution with high doses greater than 65 mcg/kg/min in children for extended periods of time; contraindicated in small children (Brophy et al, 2012).
    3) PENTOBARBITAL: ADULT DOSE: A loading dose of 5 to 15 mg/kg at an infusion rate of 50 mg/minute or lower; may administer additional 5 to 10 mg/kg. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: A loading dose of 3 to 15 mg/kg followed by a maintenance dose of 1 to 5 mg/kg/hour (Loddenkemper & Goodkin, 2011).
    4) THIOPENTAL: ADULT DOSE: 2 to 7 mg/kg, at an infusion rate of 50 mg/minute or lower. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusing dosing, titrated to EEG (Brophy et al, 2012)
    b) Endotracheal intubation, mechanical ventilation, and vasopressors will be required (Brophy et al, 2012) and consultation with a neurologist is strongly advised.
    c) Neuromuscular paralysis (eg, rocuronium bromide, a short-acting nondepolarizing agent) may be required to avoid hyperthermia, severe acidosis, and rhabdomyolysis. If rhabdomyolysis is possible, avoid succinylcholine chloride, because of the risk of hyperkalemic-induced cardiac dysrhythmias. Continuous EEG monitoring is mandatory if neuromuscular paralysis is used (Manno, 2003).
    8) In one series of 18 cases of endosulfan poisoning, hydantoins were not effective in controlling seizures, but phenobarbitone was (Chugh et al, 1998).
    C) CONTRAINDICATED TREATMENT
    1) Do NOT give oils by mouth. They tend to increase intestinal absorption of these lipophilic toxicants.
    2) Do NOT administer adrenergic amines, which further increase myocardial irritability and produce refractory ventricular arrhythmias (Dreisbach, 1983; Bryson, 1986).
    D) CHOLESTYRAMINE
    1) Cholestyramine (4 grams every eight hours) accelerated excretion of kepone and chlordane in excessively exposed workers, and probably would have a similar effect on other slowly excreted organochlorines which are trapped in the enterohepatic circulation (Cohn et al, 1978) Garrettson et al, 1984, 1985; (Boylan et al, 1978).
    E) PULMONARY ASPIRATION
    1) Evaluate the patient for pulmonary complications, especially if the ingested product contained a petroleum solvent.
    F) EXPERIMENTAL THERAPY
    1) IV LIPID EMULSION THERAPY/CASE REPORT: A 47-year-old woman developed increasing cardiovascular instability with hypotension (40 mmHg) and persistent dysrhythmias after ingesting 250 mL of 35% endosulfan. Following cardiovascular collapse and successful cardiac resuscitation, the patient was given IV lipid emulsion therapy. She received a 1.5 mL/kg IV bolus of 20% lipid emulsion followed by an IV infusion of 1.5 mL/kg over a 20-minute period. The patient's blood pressure rapidly increased approximately 10 minutes following administration of lipid emulsion (90/30 mmHg); however, approximately 3.5 hours later, the patient's hemodynamic status again deteriorated, and she died, despite increased vasopressor administration and cardiac resuscitation efforts (Moon & Lee, 2013).

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 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. Rescue personnel and bystanders should avoid direct contact with contaminated skin, clothing, or other objects (Burgess et al, 1999). Since contaminated leather items cannot be decontaminated, they should be discarded (Simpson & Schuman, 2002).
    2) Do an alcohol washing followed by a soap washing after the initial soap washing.

Enhanced Elimination

    A) EXTRACORPOREAL ELIMINATION
    1) HEMODIALYSIS: Due to endosulfan's large volume of distribution, hemodialysis is unlikely to be of benefit; however, dialysis may be necessary in patients who develop renal failure after overdose.
    a) CASE REPORT: A 28-year-old man developed acute renal failure (serum creatinine 8.4 mg/dL, urine output 900 mL) with metabolic acidosis and rhabdomyolysis after ingesting an unknown amount of endosulfan. After 3 hemodialysis sessions, the patient's urine output increased to 2.5 L/day, and his serum creatinine concentration decreased to 2.7 mg/dL at hospital discharge (Yadla et al, 2013).
    2) HEMOPERFUSION: Effectiveness not known due to limited experience.
    3) Exchange transfusion, extracorporeal, and peritoneal dialysis have not proven effective in management of these poisonings. There has been little or no experience with charcoal hemoperfusion in organochlorine poisonings.

Range Of Toxicity

Summary

    A) TOXICITY: The estimated lethal oral dose for humans is in the range of 50 to 500 mg/kg. An adult died after ingesting 100 mL.

Minimum Lethal Exposure

    A) The estimated lethal oral dose for humans is in the range of 50 to 500 mg/kg.
    B) Based on its acute toxicity in animals, endosulfan would be HIGHLY TOXIC, or of intermediate toxicity relative to other organochlorines such as toxaphene, endrin, aldrin and dieldrin. The estimated lethal oral dose for humans is in the range of 50 to 500 mg/kg (1 teaspoon to 1 ounce for a 150-pound person) (EPA, 1985).
    C) CASE REPORT: A 48-year-old man ingested 100 mL of endosulfan and developed almost immediate seizure activity that was unresponsive to treatment. The EEG showed status epilepticus(Boereboom et al, 1998). On hospital day 4, the patient died of cerebral herniation.
    D) CASE REPORT: A 47-year-old woman developed seizures and became comatose after ingesting 250 mL of 35% endosulfan in a suicide attempt. At the time of admission, the patient was hypertensive (150/100 mmHg), tachycardic (142 bpm), and hyperthermic (41.2 degrees C). Arterial blood gas analysis revealed metabolic acidosis, and she was anuric. The patient developed increasing cardiovascular instability with the development of dysrhythmias and hypotension (40 mmHg) that persisted despite vasopressor administration. Following cardiovascular collapse and successful cardiac resuscitation, the patient was given IV lipid emulsion therapy. Although the patient's blood pressure (90/30 mmHg) improved rapidly 10 minutes following administration of lipid emulsion, she again deteriorated hemodynamically approximately 3 hours later, collapsed, and died, despite increased vasopressor administration and cardiac resuscitation efforts (Moon & Lee, 2013).
    E) ANIMAL DATA
    1) Female rats were more sensitive than males to endosulfan (Gupta, 1976).

Maximum Tolerated Exposure

    A) CASE REPORT: A 20-year-old survived an ingestion of approximately 200 mL of 30% endosulfan. At one year follow-up his mentation was severely impaired and he required carbamazepine to prevent seizures (Shemesh et al, 1988).
    B) ANIMAL DATA
    1) The no-effect chronic oral dose for rats was 30 ppm for 2 years (HSDB , 1997).

Workplace Standards

    A) ACGIH TLV Values for CAS115-29-7 (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) Endosulfan
    a) TLV:
    1) TLV-TWA: 0.1 mg/m(3)
    2) TLV-STEL:
    3) TLV-Ceiling:
    b) Notations and Endnotes:
    1) Carcinogenicity Category: A4
    2) Codes: IFV, Skin
    3) Definitions:
    a) A4: Not Classifiable as a Human Carcinogen: Agents which cause concern that they could be carcinogenic for humans but which cannot be assessed conclusively because of a lack of data. In vitro or animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other categories.
    b) IFV: Inhalable fraction and vapor.
    c) Skin: This refers to the potential significant contribution to the overall exposure by the cutaneous route, including mucous membranes and the eyes, either by contact with vapors or, of likely greater significance, by direct skin contact with the substance. It should be noted that although some materials are capable of causing irritation, dermatitis, and sensitization in workers, these properties are not considered relevant when assigning a skin notation. Rather, data from acute dermal studies and repeated dose dermal studies in animals or humans, along with the ability of the chemical to be absorbed, are integrated in the decision-making toward assignment of the skin designation. Use of the skin designation provides an alert that air sampling would not be sufficient by itself in quantifying exposure from the substance and that measures to prevent significant cutaneous absorption may be warranted. Please see "Definitions and Notations" (in TLV booklet) for full definition.
    c) TLV Basis - Critical Effect(s): LRT irr; liver and kidney dam
    d) Molecular Weight: 406.95
    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 CAS115-29-7 (National Institute for Occupational Safety and Health, 2007):
    1) Listed as: Endosulfan
    2) REL:
    a) TWA: 0.1 mg/m(3)
    b) STEL:
    c) Ceiling:
    d) Carcinogen Listing: (Not Listed) Not Listed
    e) Skin Designation: [skin]
    1) Indicates the potential for dermal absorption; skin exposure should be prevented as necessary through the use of good work practices and gloves, coveralls, goggles, and other appropriate equipment.
    f) Note(s):
    3) IDLH: Not Listed

    C) Carcinogenicity Ratings for CAS115-29-7 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A4 ; Listed as: Endosulfan
    a) A4 :Not Classifiable as a Human Carcinogen: Agents which cause concern that they could be carcinogenic for humans but which cannot be assessed conclusively because of a lack of data. In vitro or animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other categories.
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Assessed under the IRIS program. ; Listed as: Endosulfan
    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 ; Listed as: Endosulfan
    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 CAS115-29-7 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) References: RTECS, 1997 HSDB, 1997
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 7 mg/kg
    2) LD50- (ORAL)MOUSE:
    a) 7360 mcg/kg
    3) LD50- (INTRAPERITONEAL)RAT:
    a) 8 mg/kg
    4) LD50- (ORAL)RAT:
    a) 18 mg/kg
    5) LD50- (SKIN)RAT:
    a) 34 mg/kg

Pharmacology Toxicology

Toxicologic Mechanism

    A) The principal neurotoxic action of these compounds is that of "axon poison," affecting primarily the CNS nerve cells. Essentially, the organochlorines interfere with the normal flux of Na+ and K+ ions across the axon membrane as nerve impulses pass, increasing neuronal irritability. This results in disturbance of mental processes, sensory aberrations, and convulsions (Morgan, 1993).

Physicochemical

Physical Characteristics

    A) Endosulfan a brown to colorless powder or liquid, smells like sulfur dioxide (EPA, 1985), and has a terpene-like (Sittig, 1991) and pungent odor (AAR, 1996).
    B) The material may be a wettable powder or a water emulsifiable liquid (AAR, 1996).
    C) It sinks in water (CHRIS , 1997).
    D) At 15 degrees C and 1 atm endosulfan is a solid (CHRIS , 1997).
    E) colorless in water (OHM/TADS , 1991)
    F) Endosulfan is a mixture of two stereoisomers: alpha-endosulfan (I) and beta-endosulfan (II) (HSDB , 1997).

Molecular Weight

    A) 406.93

Other

    A) ODOR THRESHOLD
    1) Not Listed (CHRIS , 1997)

References

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