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NEONICOTINOID INSECTICIDES

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) The nicotinoids are a new class of insecticides with a distinct mode of action. They have been previously referred to as nitro-quanidines, neonicotinyls, neonicotinoids, chloronicotines, and more recently as the chloronicotinyls. In this management they will be referred to as neonicotinoids. The neonicotinoids are similar to and modeled after the natural nicotine. These compounds are effective due to their action on nicotinic acetylcholine receptors in the nervous system of insects.
    B) This group of insecticides is further divided into the chloronicotinyl neonicotinoids, chloropyridine neonicotinoids, and the chlorothiazole neonicotinoids. These chemicals are also known as systemic nitroguanidine insecticides, belonging to the neonicotinoid family. These insecticides are used both as insecticides in agriculture and as topical ectoparasiticides in veterinary practice. They have an excellent safety profile and are classified by the EPA as "organophosphate alternatives". They are members of the Group 4A insecticides.
    C) First generation nicotinoids are chloropyridinyl derivatives while second generation nicotinoids are chlorothiazolyl derivatives.

Specific Substances

    A) ACETAMIPRID (first generation)
    1) Mospilan
    CLOTHIANIDIN (second generation)
    1) TI-435
    DESMETHYLTHIAMETHOXAM (second generation)
    1) Desmethylthiamethoxam
    DINOTEFURAN
    1) Dinoterfuran
    FLONICAMID
    1) Flonicamid
    IMIDACLOPRID (first generation)
    1) 2-Imidazolidinimine, 1-((6-chloro-3-pyridinyl)
    2) methyl)-N-nitro-
    3) 1-[(6-Chloro-3-pyridinyl)methyl]-4,5-dihydro-
    4) N-nitro-1H-imidazol-2-amine
    5) Admire(R) 2F
    6) BAY-NTN 33893
    7) Confidor
    8) Confidor 200 SL
    9) Confidor SL
    10) Gaucho(R)
    11) Marathon(R)
    12) Merit (insecticide)
    13) NTN 33893
    14) Premise
    15) Provado(R)
    16) Tie-Boo-Tzang
    17) Molecular Formula: C9-H10-Cl-N5-O2
    18) CAS 105827-78-9
    19) CAS 138261-41-3
    NITENPYRAM (second generation)
    1) 1,1-Ethanediamine, N-((6-chloro-3-pyridinyl)
    2) methyl)-N-ethyl-N'-methyl-2-nitro-, (E)-
    3) Bestguard
    4) (E)-Nitenpyram
    5) TI 304
    6) Molecular Formula: C11-H15-Cl-N4-O2
    7) CAS 150824-47-8
    NITHIAZINE (first generation)
    1) Nithiazine
    THIACLOPRID (second generation)
    1) (3-((6-Chloro-3-pyridinyl)methyl)-2-
    2) thiazolidinylidene)cyanamide
    3) Cyanamide, (3-((6-chloro-3-pyridinyl)methyl)-2-
    4) thiazolidinylidene)-
    5) NTN 33894
    6) YRC 2894
    7) Molecular Formula: C10-H9-Cl-N4-S
    8) CAS 111988-49-9
    THIAMETHOXAM (second generation)
    1) Actara(R)
    2) Cruiser(R)
    3) Flagship(R)
    4) Platinum(R)
    5) CAS 153719-23-4

Available Forms Sources

    A) SOURCES
    1) In 1972 the first lead neonicotinoid, nithiazine, was developed, but never commercialized. The next neonicotinoid, imidacloprid, was developed in 1985 by introducing a 6-chloropyridin-3-ylmethyl group as a substituent of the nitromethylene heterocycle, with an enhancement of more than 100 against rice leafhoppers. The 6-chloropyridin-3-ylmethyl moiety as a heterocyclic group is a common characteristic of the first-generation neonicotinoids. Later, second generation neonicotinoids, a subclass of thianicotinyl compounds, were developed. The second generation insecticide group is synthesized from nitroimino heterocycles of imidacloprid (Maienfisch et al, 2001).
    2) Maienfisch et al (2000) describe a method for the synthesis of N,N-disubstituted-N-nitroguanidines from S-methyl-N-nitroisothiourea, as well as a practical method of synthesis for the neonicotinoid, clothianidin (Maienfisch et al, 2000).
    B) USES
    1) The neonicotinoid insecticides are used both as insecticides in agriculture and as topical ectoparasiticides in veterinary practice (S Sweetman , 2001).
    2) Imidacloprid was introduced in Europe and Japan in 1990 and first registered in the U.S. in 1992. Imidacloprid, the most widely used of this class of insecticides, is used as a soil, seed or foliar treatment in cotton, rice cereals, peanuts, potatoes, vegetables, pome fruits, pecans and turf, for the control of sucking insects, soil insects, whiteflies, termites, turf insects and the Colorado potato beetle, with long residual control. Imidacloprid has no effect on mites or nematodes (Zheng & Liu, 1999). Both imidacloprid and thiamethoxam are effective against white grubs when applied during or immediately after egg laying (Grewal et al, 2001).
    3) The second generation neonicotinoids, such as thiamethoxam, have broad-spectrum insecticidal activity and offer excellent control of a wide variety of crop pests. These compounds exhibit contact, stomach and systemic activity. They are used for foliar, granular and seed treatment application, with long-lasting residual effects (Maienfisch et al, 2001).
    4) Imidacloprid is used as a topical ectoparasiticide (flea adulticide), but with no activity against ticks, in dogs, cats and rabbits. When used as a topical solution, it kills 98% to 100% of existing fleas on cats and dogs within 24 hours (>90% within 12 hours). It is applied as a spot between the shoulder blades (10 mg/kg) on dogs and as a streak on the back of the neck on cats. A 10% spot-on formulation has been used on rabbits infected with cat fleas. When petting animals shortly following administration, no significant exposure effects have been reported in humans (Hutchinson et al, 2001; Jacobs et al, 2001; Jacobs et al, 2001a; Dryden et al, 1999; (Coppoc, 1997)).

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: Neonicotinoids are a class of insecticides. Examples include nithiazine, imidacloprid, thiacloprid, thiamethoxam, nitenpyram, accetamiprid, clothianidin, and dinotefuran.
    B) TOXICOLOGY: The insecticidal action is due to activation of nicotinic acetylcholine receptors. These insecticides are theoretically less toxic to mammals due to a lower affinity for vertebrate nicotinic receptors. Toxicity may be due to activation of nicotinic receptors outside the CNS. Caustic injury is due to solvent N-methyl-2-pyrrolidone (NMP).
    C) EPIDEMIOLOGY: Based on a literature review, 12 cases of neonicotinoid insecticide poisoning were reported between 2007 and 2011.
    D) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE POISONING: Mild to moderate poisoning can cause nausea, vomiting, diarrhea, abdominal pain, dizziness, headache, and mild sedation. These substances can also cause eye irritation.
    2) SEVERE POISONING: Large deliberate ingestions have caused agitation, seizures, metabolic acidosis, coma, hypothermia, pneumonitis, respiratory failure, hypotension, ventricular dysrhythmias, and death. Rare caustic injury to the esophagus has been reported. This is likely due to the solvent component (N-methyl-2-pyrrolidone (NMP)) of the insecticide as opposed to the neonicotinoid itself.
    0.2.20) REPRODUCTIVE
    A) Human reproductive and developmental toxicity data are not available.

Laboratory Monitoring

    A) Monitor vital signs and mental status.
    B) Monitor serum electrolytes.
    C) Institute continuous cardiac monitoring and obtain an ECG in symptomatic patients.
    D) Serum concentrations of neonicotinoid insecticides are not clinically useful in guiding management following exposure.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Administer IV fluids for hypotension.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat hypotension with IV fluids; add vasopressors if hypotension persists. Treat dysrhythmias per ACLS guidelines. Consult a gastroenterologist for patients with pain on swallowing, drooling, or other evidence of caustic injury to evaluate for esophageal damage. Atropine should be considered if a patient is bradycardic or experiencing cholinergic symptoms because these insecticides are frequently mixed with organophosphate and carbamate pesticides.
    C) DECONTAMINATION
    1) PREHOSPITAL: Remove contaminated clothing and wash skin with soap and water. Irrigate exposed eyes. HOSPITAL: Remove contaminated clothing and wash skin with soap and water. Irrigate exposed eyes. Activated charcoal is not recommended in small ingestions. It can be considered, along with aspiration of gastric contents, in massive ingestions after the airway is protected.
    D) AIRWAY MANAGEMENT
    1) Consider intubation if CNS or respiratory depression develops.
    E) ANTIDOTE
    1) No specific antidote is available; symptomatic and supportive care is the mainstay of treatment.
    F) HYPOTENSIVE EPISODE
    1) Administer IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids.
    G) BRADYCARDIA
    1) Usually does not require treatment. Treat bradycardia with atropine; if unresponsive, use beta adrenergic agonists (eg, isoproterenol).
    H) SEIZURE
    1) Administer IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur.
    I) ENHANCED ELIMINATION
    1) There is no data suggesting the use of enhanced elimination. Supportive care is the mainstay of treatment.
    J) PATIENT DISPOSITION
    1) HOME CRITERIA: Patients with inadvertent exposures who are not symptomatic (ie, without gastrointestinal symptoms, respiratory symptoms, or altered mental status) may be observed at home. OBSERVATION CRITERIA: Symptomatic patients and those with deliberate or large ingestions should be referred to a healthcare facility. Observe symptomatic patients until symptoms are resolved. ADMIT CRITERIA: Patients with severe gastrointestinal symptoms, CNS depression, or respiratory symptoms should be admitted. CONSULT CRITERIA: Consult a medical toxicologist or poison center for all intentional ingestions or symptomatic inadvertent ingestions.
    K) PITFALLS
    1) Consider ingestion of multiple pesticides.
    L) TOXICOKINETICS
    1) Some dermal absorption does occur. Toxicity after inhalational exposure has been reported. In rats, imidacloprid is rapidly and almost completely absorbed from the gastrointestinal tract. Peak plasma concentrations were observed within 2.5 hours. Concentrations in human patients generally remain elevated for 10 to 15 hours postingestion. Many patients are asymptomatic despite high levels. This suggests there is little correlation between serum levels and clinical effects. Little penetration of the blood brain barrier occurs in humans.
    M) PREDISPOSING CONDITIONS
    1) Older age has been associated with more severe or fatal toxicity.
    N) DIFFERENTIAL DIAGNOSIS
    1) Poisoning with other pesticides should be considered. This poisoning can mimic mild organophosphate or carbamate poisoning. Also, many reported cases involved coingestion of multiple pesticides and ethanol.

Range Of Toxicity

    A) TOXICITY: A toxic dose is not well established. A median dose of 90 mL of imidacloprid was noted in patients with caustic injuries. A median dose of 75 mL (range 30 to 200 mL) was noted in severely poisoned patients in the largest case series. An adult died after ingesting 200 mL of imidacloprid 9.6% (19.2 g) in N-methyl pyrrolide. In another case, an adult died after ingesting 100 mL of thiacloprid 21.7% of profound shock and cardiac arrest. In a review of the literature, 4 fatalities were reported out of 152 (2.6%) cases of acute neonicotinoid poisoning.

Clinical Effects

Summary Of Exposure

    A) USES: Neonicotinoids are a class of insecticides. Examples include nithiazine, imidacloprid, thiacloprid, thiamethoxam, nitenpyram, accetamiprid, clothianidin, and dinotefuran.
    B) TOXICOLOGY: The insecticidal action is due to activation of nicotinic acetylcholine receptors. These insecticides are theoretically less toxic to mammals due to a lower affinity for vertebrate nicotinic receptors. Toxicity may be due to activation of nicotinic receptors outside the CNS. Caustic injury is due to solvent N-methyl-2-pyrrolidone (NMP).
    C) EPIDEMIOLOGY: Based on a literature review, 12 cases of neonicotinoid insecticide poisoning were reported between 2007 and 2011.
    D) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE POISONING: Mild to moderate poisoning can cause nausea, vomiting, diarrhea, abdominal pain, dizziness, headache, and mild sedation. These substances can also cause eye irritation.
    2) SEVERE POISONING: Large deliberate ingestions have caused agitation, seizures, metabolic acidosis, coma, hypothermia, pneumonitis, respiratory failure, hypotension, ventricular dysrhythmias, and death. Rare caustic injury to the esophagus has been reported. This is likely due to the solvent component (N-methyl-2-pyrrolidone (NMP)) of the insecticide as opposed to the neonicotinoid itself.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH POISONING/EXPOSURE
    1) ACETAMIPRID: CASE REPORT: Hypothermia was reported in 2 cases of acetamiprid exposure. In one case, a 58-year-old man intentionally injected and ingested an insecticide containing 18% acetamiprid and presented with a temperature of 33.7 C (92.6 F). In a second case, a 74-year-old woman presented with a temperature of 34.4 degrees C (93.2 degrees F) after ingesting approximately 100 mL of an insecticide containing 2% acetamiprid. Both patients recovered (Imamura et al, 2010).
    2) IMIDACLOPRID: CASE REPORT: Hypothermia (35.3 degrees C; 95.5 degrees F) was reported in a patient after he intentionally ingested an unknown amount of insecticide containing 18.2% imidacloprid combined with liquor. The patient died later after leaving the hospital against medical advice (Yeh et al, 2010).
    3) RATS: Hypothermia has been reported in acute oral rat toxicity studies of imidacloprid, with an average body temperature reduction of 2.0 degrees C and 5.5 degrees C in males and females, respectively, at doses of 307 mg/kg (Sheets, 2001).

Heent

    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) MYDRIASIS: In a literature review of neonicotinoid pesticide exposures, mydriasis was reported in 0% of nonsevere cases and in 23% of severe cases (nonsevere cases n=44; severe cases n=22) (Lin et al, 2013).
    2) IRRITATION: Following eye contact, minimal redness may occur ((Anon, 1998)) which is reversible within 72 hours (MSDS, 1994). In the standard Draize test, mild irritation was reported following nitenpryam application in rabbits (RTECS , 2001).
    a) CASE SERIES: In a series of 1142 neonicotinoid insecticide exposures (predominantly imidacloprid (77%) or dinotefuran (17%)), ingestion (51%) was the most common route of exposure followed by dermal (44%) and ocular (11%) routes. Ocular irritation was the most common adverse event reported with a total of 74 (6.5%) events reported. Serious exposures occurred in 6 (18,8%) cases (Forrester, 2014).
    3) ANIMALS: PUPIL SIZE: In comparative acute toxicity animal studies of the various neonicotinoid insecticides, impaired pupil function (either dilated or pin-point pupils) was noted at higher dose levels (Sheets, 2001).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) INCIDENCE: In a literature review of neonicotinoid insecticide exposures, hypotension was reported in 0% of nonsevere cases and in 45% of severe cases (nonsevere cases n=44; severe cases n=22) (Lin et al, 2013).
    b) ACETAMIPRID: CASE REPORT: A 74-year-old woman with chronic hypertension treated with cilnidipine and candesartan developed hypotension (82/40 mmHg) after intentionally ingesting approximately 100 mL of an insecticide containing 2% acetamiprid and 97% diethylene glycol (DEG) with 1% surface-active agent. She presented to the emergency department 90 minutes after ingestion. She underwent decontamination and received supportive treatment including vasopressors. The hypotension improved within 11 hours. She recovered fully and was discharged the day after ingestion (Imamura et al, 2010).
    c) FLONICAMID AND SPINOSAD: CASE REPORT: An 80-year-old woman with depression intentionally ingested a mixture of pesticides containing 80 mL of Conserve (R) (spinosad; 11.6% spinosyn) and 2 to 3 g of powdered flonicamid. She presented to the emergency department unconscious approximately 3 hours after ingestion. At presentation her blood pressure was 70/50 mmHg, heart rate 81 beats/min, and respiratory rate was irregular at 20 breaths/min. She was intubated immediately. IV hydration and dopamine were initiated. She regained consciousness within a couple of days and was extubated. She was discharged without residual complications following 5 weeks of hospitalization with supportive care (Su et al, 2011).
    d) IMIDACLOPRID: CASE REPORT: A 56-year-old man developed hypotension (87/56 mmHg) after he intentionally ingested 40 mL of a pesticide containing 9.6% imidacloprid in a solvent of N-methyl-2-pyrrolidone. He presented to the emergency department 20 minutes after ingestion. Upon examination his heart rate was 79 beats/minute. He was drowsy, dyspneic (24 breaths/minute), and diaphoretic. He was intubated 8 hours after arrival and transferred to the ICU. He received supportive treatment including antibiotics and was extubated 8 days after admission. Four days later he was discharged (Lin et al, 2013).
    B) CONDUCTION DISORDER OF THE HEART
    1) WITH POISONING/EXPOSURE
    a) ACETAMIPRID
    1) CASE REPORT: A 74-year-old woman with chronic hypertension treated with cilnidipine and candesartan presented to the emergency department 90 minutes after intentionally ingesting approximately 100 mL of an insecticide containing 2% acetamiprid and 97% diethylene glycol (DEG) with 1% surface-active agent. Upon arrival to the emergency department, her blood pressure was 82/40 mmHg, heart rate 104 beats/minute, O2 saturation 84% on room air, and temperature 34.4 degrees C (93.2 degrees F). Initial ECG showed multiple ventricular extrasystoles and a 3 mm ST segment depression. She underwent decontamination using gastric lavage, activated charcoal, cathartics, and antiemetics. This was followed by supportive therapy including H2 blockers and antibiotics. Hypotension and tachycardia improved within 11 hours. The day after ingestion she recovered fully and was discharged (Imamura et al, 2010).
    b) IMIDACLOPRID
    1) CASE REPORT: A 67-year-old man who had been consuming 200 mL of 58% alcohol daily for 1 week presented to the emergency department after intentionally ingesting an unknown amount of insecticide containing 18.2% imidacloprid combined with liquor. Upon arrival he was drowsy, irritable, hypotensive (117/56 mmHg), and hypothermic but responsive to his name. Chest xray showed cardiomegaly and right lower lung infiltration. Laboratory analysis showed slightly elevated creatine kinase (270 U/L) and troponin I (2.2 mcg/L). He received supportive treatment and was stabilizing but 3 hours after arrival he lost consciousness and became cyanotic. He received CPR and cardioversion, which was followed by return of spontaneous circulation. Within 24 hours of arrival, he received additional aggressive treatment for shock and multiorgan failure followed by admission to the ICU. However, after admission to the ICU, he discharged against medical advice and later died (Yeh et al, 2010).
    2) CASE REPORT: A 69-year-old woman developed severe hypotension and dysrhythmias after ingesting 200 mL of imidacloprid 9.6% (19.2 g) in N-methyl pyrrolide. She was found drowsy, vomiting, and diaphoretic 30 minutes after ingestion. Upon presentation to the emergency department her blood pressure was 170/73 mm Hg, heart rate of 117 beats per minute, respiratory rate of 24, and temperature of 95 F. Past medical history included hypertension, treated with terazosin and irbesartan, and a lacunar infarction 8 months prior. Approximately one hour after receiving fluids, gastric lavage, and activated charcoal she became cyanotic, apneic, and unconscious. The ECG showed intermittent ventricular fibrillation and ventricular tachycardia. The patient's condition quickly deteriorated despite aggressive resuscitation and supportive efforts. She expired 12 hours post ingestion from intractable hypotension and dysrhythmias (Huang et al, 2006).
    C) CARDIAC ARREST
    1) WITH POISONING/EXPOSURE
    a) THIACLOPRID
    1) CASE REPORT: A 23-year-old man intentionally ingested 100 mL of thiacloprid suspension (21.7% thacloprid w/w) and initially developed nausea, vomiting, and agitation. Approximately, 2 hours later he had multiple tonic-clonic seizures and remained unconscious. His initial vitals signs included sinus tachycardia (130 to 150 beats/min) and a slightly elevated blood pressure. However, over the next 30 hours he developed progressive hypotension and oliguria. Neurologically he remained comatose and did not respond to painful stimuli. A short time later he developed shock that was refractory to vasopressors and sustained cardiac arrest occurred. He died 36 hours after ingestion (Vinod et al, 2015).
    D) TACHYCARDIA
    1) WITH POISONING/EXPOSURE
    a) INCIDENCE: In a literature review of neonicotinoid insecticide exposures, tachycardia was reported in 5% of nonsevere cases and in 50% of severe cases (nonsevere cases n=44; severe cases n=22) (Lin et al, 2013).
    E) BRADYCARDIA
    1) WITH POISONING/EXPOSURE
    a) INCIDENCE: In a literature review of neonicotinoid insecticide exposures, bradycardia was reported in 2% of nonsevere cases and in 18% of severe cases (nonsevere cases n=44; severe cases n=22) (Lin et al, 2013).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) CYANOSIS
    1) WITH POISONING/EXPOSURE
    a) IMIDACLOPRID
    1) CASE REPORT: A 69 year old woman developed cyanosis and apnea, requiring intubation and ventilation after ingesting 200 mL of imidacloprid 9.6% (19.2 g) in N-methyl pyrrolide. Despite supportive care, she expired 12 hours postingestion from severe hypotension and dysrhythmias (Huang et al, 2006).
    2) CASE REPORT: A 24-year-old male farmer became unconscious after inhaling 17.8% imidacloprid after spraying the compound and was breathless with severe agitation and disorientation at presentation. Physical exam revealed frothy secretions, cyanosis, and diaphoresis. Breath sounds were clear bilaterally with a normal chest x-ray. ABGs were suggestive of type II respiratory failure. The patient required intubation and mechanical ventilation. By day 6, weakness and delirium resolved and the patient was discharged with no permanent sequelae. At 2 month follow-up, the patient was well with no deficits (Agarwal & Srinivas, 2007).
    B) RESPIRATORY INSUFFICIENCY
    1) WITH POISONING/EXPOSURE
    a) INCIDENCE: In a literature review of neonicotinoid insecticide exposures, dyspnea or apnea were reported in 2% of nonsevere cases and in 73% of severe cases (nonsevere cases n=44; severe cases n=22) (Lin et al, 2013).
    b) CASE SERIES: In a retrospective analysis of neonicotinoid exposure reported to the Taiwan National Poison Center from 1987 through 2007, 70 patients with acute neonicotinoid insecticide poisoning were analyzed. Of these patients, 57 cases of oral exposure were identified and included: 53 imidacloprid only ingestions, 2 acetamiprid ingestions, 2 clothianidin ingestions, and 7 were exposed to other substances. Most patients developed mild (n=30) to moderate (n=10) clinical effects; 7 patients were asymptomatic following ingestion. Eight patients developed severe toxicity (ie, respiratory failure, aspiration pneumonia, or coma) and 2 deaths occurred which were attributable to imidacloprid (Phua et al, 2009).
    c) FLONICAMID AND SPINOSAD: CASE REPORT: An 80-year-old woman with depression developed respiratory complications after intentionally ingesting a mixture of pesticides containing 80 mL of Conserve (spinosad; 11.6% spinosyn) and 2 to 3 g of powdered flonicamid. She presented to the emergency department approximately 3 hours after ingestion unconscious, hypotensive along with irregular respirations. She required intubation and ventilation for several days. Over the course of a 5-week hospitalization, bilateral infiltrates were observed on chest x-ray, pneumonitis was diagnosed, and she developed restrictive lung disease. She was discharged without residual complications after 5 weeks of supportive care (Su et al, 2011).
    d) IMIDACLOPRID
    1) CASE REPORT: A 56-year-old man developed respiratory depression after he intentionally ingested 40 mL of a pesticide containing 9.6% imidacloprid in a solvent of N-methyl-2-pyrrolidone. He presented to the emergency department 20 minutes after ingestion. Upon examination he was found to be hypotensive, drowsy, dyspneic (24 breaths/minute), and diaphoretic. He was intubated 8 hours after arrival and transferred to the ICU. He received supportive treatment including antibiotics and was extubated 8 days after admission. He was discharged 4 days later (Lin et al, 2013).
    2) CASE REPORT: A 67-year-old healthy man intentionally ingested an unknown amount of imidacloprid (insecticide formulation (Confidor SC-350)) and became disoriented, drowsy, and developed increased salivation one hour after ingestion, which initially suggested organophosphate exposure. Upon admission, the patient's mental status (Glasgow Coma Scale (GCS): 3/15) and respiratory function were decreased with a blood pressure of 80/60 mm Hg. Intubation and mechanical ventilation were required for approximately 24 hours. The patient was successfully extubated the following day along with neurologic improvement (GCS: 11/15). The patient was discharged on day 4 with no permanent sequelae (Karatas, 2009).
    3) CASE REPORT: A 35 year-old woman developed agitation and respiratory insufficiency (ie, suspected pulmonary aspiration, respiratory arrest) after ingesting an unknown amount of imidacloprid. The patient recovered completely with intensive supportive care (Mohamed et al, 2009).
    4) CASE REPORT: A 37-year-old man who intentionally ingested 50 mL of a 17.8% solution of imidacloprid, initially developed weakness of the neck muscles, followed by labored breathing and a decrease in oxygen saturation (SaO2 dropped to 86%) approximately 20 hours after exposure. Mechanical ventilation was required for 4 days. Chest x-ray was negative. Although the patient was febrile (peak 104 degrees F) for 7 days, laboratory parameters remained within normal limits. The patient was discharged on day 9 with no permanent sequelae (Panigrahi et al, 2009).
    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) RESPIRATORY DISORDER
    a) In rat studies, signs of imidacloprid poisoning included respiratory disturbances ((Anon, 1998)). Labored breathing is reported following oral acute (single) lethal doses given to rats (Felsot, 2001).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM DEFICIT
    1) WITH POISONING/EXPOSURE
    a) INCIDENCE: In a literature review of neonicotinoid insecticide exposures, coma, defined as Glasgow Coma Scale score of 3/15, was reported in 2% of nonsevere cases and in 64% of severe cases (nonsevere cases n=44; severe cases n=22) (Lin et al, 2013).
    b) IMIDACLOPRID
    1) CASE SERIES: In a series of 1142 neonicotinoid insecticide exposures (predominantly imidacloprid (77%) or dinotefuran (17%)), ingestion (51%) was the most common route of exposure followed by dermal (44%) and ocular (11%) routes. Dizziness was reported in 13 (1.1%) cases of all exposures with only 2 cases considered serious (Forrester, 2014).
    2) CASE SERIES: In a study of 56 patients with an intentional imidacloprid exposure, 54 patients developed only mild symptoms of toxicity, which included dizziness and headache (Mohamed et al, 2009).
    3) CASE REPORT: A 67-year-old healthy man intentionally ingested an unknown amount of imidacloprid (insecticide formulation (Confidor SC-350)) and became disoriented, drowsy, and developed increased salivation one hour after ingestion, which initially suggested organophosphate exposure. Upon admission, the patient was comatose (Glasgow Coma Scale (GCS): 3/15) with respiratory insufficiency and a blood pressure of 80/60 mm Hg. Intubation and mechanical ventilation were required for approximately 24 hours. The patient was successfully extubated the following day along with neurologic improvement (GCS: 11/15). The patient was discharged on day 4 with no permanent sequelae (Karatas, 2009).
    4) CASE REPORT: A 69 year old woman experienced dizziness and disorientation after ingesting 200 mL of imidacloprid 9.6% (19.2 g) in N-methyl pyrrolide. Despite supportive care, she expired 12 hours postingestion from severe hypotension and dysrhythmias (Huang et al, 2006).
    5) CASE REPORT: In a case of acute ingestion (about 100 mL) of an insecticide formulation containing 9.6% imidacloprid, less than 2% surfactant and the balance as solvent (N-methyl pyrrolidone), a 64-year-old man was reported to be disoriented, drowsy, and dizzy. His mild CNS depression was likely a result of the solvent effects rather than the imidacloprid (Wu et al, 2001).
    c) FLONICAMID AND SPINOSAD: CASE REPORT: An 80-year-old woman was found unconscious approximately 3 hours after intentionally ingesting a mixture of pesticides containing 80 mL of Conserve (spinosad; 11.6% spinosyn) and 2 to 3 g of powdered flonicamid. She presented to the emergency department unconscious and hypotensive and was immediately intubated. Her clinical course included shock, metabolic acidosis, respiratory failure, pneumonitis and urinary retention. The patient was successfully extubated and symptoms resolved. She was discharged without residual complications after 5 weeks of supportive care (Su et al, 2011).
    B) FEELING AGITATED
    1) WITH POISONING/EXPOSURE
    a) IMIDACLOPRID
    1) CASE REPORT: A 35 year-old woman developed agitation and respiratory insufficiency (i.e., suspected pulmonary aspiration, respiratory arrest) after ingesting an unknown amount of imidacloprid. The patient recovered completely with intensive supportive care (Mohamed et al, 2009).
    2) CASE REPORT: A 24-year-old male farmer became unconscious after inhaling 17.8% imidacloprid after spraying the compound and developed severe agitation and disorientation. The patient was initially treated with lorazepam, but a continuous propofol infusion was required for extreme agitation. No seizure activity was observed. The patient gradually improved and was discharged to home on day 6. At 2 month follow-up, the patient was well with no neurologic deficits (Agarwal & Srinivas, 2007).
    C) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) INCIDENCE: In a literature review of neonicotinoid insecticide exposures, seizure was reported in 2% of nonsevere cases and in 5% of severe cases (nonsevere cases n=44; severe cases n=22) (Lin et al, 2013).
    b) ACETAMIPRID: CASE REPORT: A 58-year-old man with diabetic gangrene developed a seizure after intentionally injecting and ingesting an insecticide containing 18% acetamiprid. The insecticide was formulated with 31% N-methyl-2-pyrrolidone and 48% dimethylsulfoxide (including 3% surface-active agent). He subcutaneously injected 8 mL of the formulation and then ingested approximately 10 mL. He immediately experienced nausea, muscle weakness, and a self-limited seizure. Upon arrival at the emergency department, examination was unremarkable other than a temperature of 33.7 C (92.66 F). Laboratory analysis showed acidosis. He was treated with gastric lavage, activated charcoal, cathartics, and antiemetics. He developed no other symptoms and was transferred to a hospital for treatment of diabetic gangrene 2 days after admission (Imamura et al, 2010).
    c) ACETAMIPRID: CASE REPORT: A 74-year-old woman with chronic hypertension treated with cilnidipine and candesartan developed a seizure after intentionally ingesting approximately 100 mL of an insecticide containing 2% acetamiprid and 97% diethylene glycol (DEG) with 1% surface-active agent. She presented to the emergency department 90 minutes after ingestion. Upon arrival she was hypotensive, hypoxic, and hypothermic. Decontamination was performed using gastric lavage, activated charcoal, cathartics, and antiemetics followed by supportive therapy. She recovered fully and was discharged one day after ingestion (Imamura et al, 2010).
    d) THIACLOPRID: CASE REPORT: A 23-year-old man intentionally ingested 100 mL of thiacloprid suspension (21.7% thacloprid w/w) and initially developed nausea, vomiting, and agitation. Approximately, 2 hours later he had multiple tonic-clonic seizures and remained unconscious. His initial vitals signs included sinus tachycardia (130 to 150 beats/min) and a slightly elevated blood pressure. However, over the next 30 hours he developed progressive hypotension and oliguria. Neurologically he remained comatose and did not respond to painful stimuli. A short time later he developed shock refractory to vasopressors and sustained cardiac arrest occurred. He died 36 hours after ingestion (Vinod et al, 2015).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) CNS EFFECTS
    a) In comparative acute animal toxicity studies of imidacloprid, acetamiprid, clothianidin, thiacloprid, and thiamethoxam, the most consistent finding at a lower dose was decreased activity. At higher doses, the most common effects were tremor, impaired pupillary function, gait incoordination, and hypothermia. Following a lethal dose, deaths occurred within 4 to 24 hours (Sheets, 2001).
    b) In mouse studies, tremor was reported in mice that had been treated with an acute oral dose of imidacloprid or one of several other neonicotinoids. This study provided evidence of nicotinic stimulation at near-lethal or lethal dose levels (Chao & Casida, 1997).
    c) In rat studies, signs of imidacloprid poisoning included lethargy, decreased movement, staggering gait, occasional tremors, and spasms ((Anon, 1998)). Acute oral neurotoxicity studies in rodents showed gait abnormalities and decreased rearing behavior, grip strength, response to stimuli, and motor activity (Felsot, 2001). Acute single lethal doses showed typical CNS poisoning symptoms, similar to those of organophosphate poisoning, including lethargy, dyspnea, lack of coordination, staggering, trembling, and spasms (Felsot, 2001).
    d) Clinical signs were not seen in rats until an acute imidacloprid dose of 315 mg/kg was exceeded. At that dose, the incidence of mortality increased abruptly, with 20% mortality at a dose of 400 mg/kg and 100% mortality at 500 mg/kg body weight. Clinical signs prior to death included tremor, gait incoordination, evidence of decreased motility and activity, and nasal and urine staining. Symptoms occurred within 15 to 40 minutes, and were reversible within 8 to 24 hours following treatment (Sheets, 2001).
    e) DOGS: In a 13-week subchronic toxicity study of imidacloprid, tremor occurred and was more severe in the higher doses (up to 1800 ppm dietary groups). No evidence of tissue damage by clinical chemistry, gross necropsy examination or microscopic examination was noted at any dietary level (Sheets, 2001).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA, VOMITING AND DIARRHEA
    1) WITH POISONING/EXPOSURE
    a) After a massive ingestion of a neonicotinoid insecticide formulation, nausea, vomiting and diarrhea may be expected (Forrester, 2014; Vinod et al, 2015; Huang et al, 2006).
    b) INCIDENCE: In a literature review of neonicotinoid insecticide exposures, nausea and vomiting were reported in 68% of nonsevere cases and in 41% of severe cases (nonsevere cases n=44; severe cases n=22) (Lin et al, 2013).
    c) CASE SERIES: In a series of 1142 neonicotinoid insecticide exposures (predominantly imidacloprid (77%) or dinotefuran (17%)), ingestion (51%) was the most common route of exposure followed by dermal (44%) and ocular (11%) routes. Nausea was reported in 32 (2.8%) cases of all exposures with only 5 cases considered serious. Vomiting was reported in 27 (2.4%) cases of all exposures with only 2 (6.3%) cases considered serious (Forrester, 2014).
    d) IMIDACLOPRID: CASE SERIES: Out of 56 patients with an intentional imidacloprid exposure, 54 patients developed only mild symptoms of toxicity which included nausea, vomiting, diarrhea, and abdominal pain (Mohamed et al, 2009).
    e) ACETAMIPRID: CASE REPORT: A 58-year-old man with diabetic gangrene developed nausea after intentionally injecting and ingesting an insecticide containing 18% acetamiprid, 31% N-methyl-2-pyrrolidone, and 48% dimethylsulfoxide (including 3% surface-active agent). He subcutaneously injected 8 mL of the formulation and then ingested approximately 10 mL. He underwent decontamination using gastric lavage, activated charcoal, cathartics and antiemetics. He recovered within 2 days and was transferred to a hospital for treatment of diabetic gangrene (Imamura et al, 2010).
    f) ACETAMIPRID: CASE REPORT: A 74-year-old woman with chronic hypertension treated with cilnidipine and candesartan developed nausea, dyspnea, and thirst, after intentionally ingesting approximately 100 mL of an insecticide containing 2% acetamiprid and 97% diethylene glycol (DEG) with 1% surface-active agent. Upon arrival to the emergency department 90 minutes after ingestion, she was hypotensive, hypoxic, and hypothermic. She underwent decontamination with gastric lavage, activated charcoal, cathartics, and antiemetics followed by supportive therapy. The nausea resolved within 7 hours. She recovered fully and was discharged one day after ingestion (Imamura et al, 2010).
    B) ULCER OF MOUTH
    1) WITH POISONING/EXPOSURE
    a) INCIDENCE: In a literature review of neonicotinoid insecticide exposures, oral ulcers were reported in 7% of nonsevere cases and in 9% of severe cases (nonsevere cases n=44; severe cases n=22) (Lin et al, 2013).
    b) CASE SERIES: In a series of 1142 neonicotinoid insecticide exposures (predominantly imidacloprid (77%) or dinotefuran (17%)), ingestion (51%) was the most common route of exposure followed by dermal (44%) and ocular (11%) routes. Oral irritation was reported in 25 (2.2%) cases of all exposures with only 1 case considered to be serious (Forrester, 2014).
    c) FLONICAMID AND SPINOSAD: CASE REPORT: An 80-year-old woman developed oral ulcerations and corrosive esophageal injury (grade 2a) after intentionally ingesting a mixture of pesticides containing 80 mL of Conserve (spinosad; 11.6% spinosyn) and 2 to 3 g of powdered flonicamid. She presented to the emergency department unconscious and hypotensive and was immediately intubated. Multiple oral ulcerations were noted after she was extubated. She was discharged without residual complications after 5 weeks of supportive care (Su et al, 2011).
    d) IMIDACLOPRID: CASE REPORT: A 56-year-old man developed multiple oral ulcers after he intentionally ingested 40 mL of a pesticide containing 9.6% imidacloprid in a solvent of N-methyl-2-pyrrolidone. He presented to the emergency department 20 minutes after ingestion. His condition deteriorated and he was intubated 8 hours after arrival. He received supportive treatment including antibiotics in the ICU and was extubated 8 days after admission. He was discharged 4 days after being extubated (Lin et al, 2013).
    3.8.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) DIARRHEA
    a) In rat studies, acute (single) oral lethal doses showed typical CNS poisoning similar to that of organophosphate poisoning, including diarrhea and emaciation (Felsot, 2001).

Hepatic

    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEPATOCELLULAR DAMAGE
    a) BIRDS: Experimental poisoning of quails with imidacloprid-coated seeds showed the liver as the main target organ. The liver and kidney contained the highest concentrations of imidacloprid (Berny et al, 1999).
    b) RATS: In subchronic inhalation studies, rats exposed to imidacloprid developed increased liver weights and induction of liver enzymes (Felsot, 2001).
    c) RATS: Subchronic toxicity studies of imidacloprid in rats fed the insecticide in their diets over a 13-week period revealed no inhibition of cholinesterase activity at any dietary level. The liver was the principal target organ, with hypertrophy of hepatocytes and sporadic cell necrosis in high-dose males. Liver pathology was fully reversible at the end of the study (Sheets, 2001).
    d) DOGS: Chronic imidacloprid toxicity studies in dogs fed the insecticide in their diets for 52 weeks showed the liver to be the principal target organ, with an induction of cytochrome P-450 enzymes associated with a slight increase in liver weight (Sheets, 2001).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) SERUM CREATININE RAISED
    1) WITH POISONING/EXPOSURE
    a) IMIDACLOPRID: CASE REPORT: Raised serum creatinine (1.6 mg/dL) and BUN (17 mg/dL) levels were reported after a 56-year-old man intentionally ingested 40 mL of a pesticide containing 9.6% imidacloprid in a solvent of N-methyl-2-pyrrolidone. He presented to the emergency department 20 minutes after ingestion. He was intubated 8 hours after arrival and transferred to the ICU. He received supportive treatment including antibiotics and was extubated 8 days after admission. He was discharged 4 days later (Lin et al, 2013).
    B) RETENTION OF URINE
    1) WITH POISONING/EXPOSURE
    a) FLONICAMID AND SPINOSAD: An 80-year-old woman developed urinary retention after intentionally ingesting a mixture of pesticides containing 80 mL of Conserve (spinosad; 11.6% spinosyn) and 2 to 3 g of powdered flonicamid. She presented to the emergency department unconscious and hypotensive and was immediately intubated. Following extubation it was noted that she had developed urinary retention. A urodynamics study detected detrusor hyperactivity with impaired contractility with an incomplete relaxing sphincter and a normal urethral closing pressure suggesting neurogenic bladder. Symptoms resolved and she was discharged without residual complications after 5 weeks of supportive care (Su et al, 2011).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) WITH POISONING/EXPOSURE
    a) ACETAMIPRID: CASE REPORT: A 58-year-old man with diabetic gangrene developed acidosis after intentionally injecting and ingesting an insecticide containing 18% acetamiprid, 31% N-methyl-2-pyrrolidone, and 48% dimethylsulfoxide (including 3% surface-active agent). He subcutaneously injected 8 mL of the formulation and then ingested approximately 10 mL. Laboratory analysis at the emergency department showed acidosis (pH, 7.36; PaCO2 , 31.7 mmHg; PaO2, 96.2 mmHg; HCO3, 18.1 mm/L; base excess, -7.6 mm/L). He was decontaminated using gastric lavage, activated charcoal, cathartics, and antiemetics. He recovered within 2 days and was transferred to a hospital for treatment of diabetic gangrene (Imamura et al, 2010).
    b) ACETAMIPRID: CASE REPORT: A 74-year-old woman with chronic hypertension treated with cilnidipine and candesartan developed metabolic acidosis after intentionally ingesting approximately 100 mL of an insecticide containing 2% acetamiprid and 97% diethylene glycol (DEG) with 1% surface-active agent. She presented to the emergency department 90 minutes after ingestion. Blood gas analysis showed pH 7.28, CO2 35.2 mmHg, PaO2 134.3 mmHg, HCO3 17 mm/L, and base excess 11 mm/L. Following decontamination and supportive care, she recovered fully and was discharged the day after ingestion (Imamura et al, 2010).
    c) FLONICAMID AND SPINOSAD: CASE REPORT: An 80-year-old woman with depression developed metabolic acidosis after intentionally ingesting a mixture of pesticides containing 80 mL of Conserve (spinosad; 11.6% spinosyn) and 2 to 3 g of powdered flonicamid. She presented to the emergency department unconscious approximately 3 hours after ingestion. She was intubated immediately. Arterial blood gases indicated metabolic acidosis (after intubation) with pH 7.41, pCO2 23.4 mmHg, pO2 310.6 mmHg, HCO3 14.6 mm/L, and SaO2 99.9%. She regained consciousness within a couple of days and was extubated. She was discharged without residual complications after 5 weeks of supportive care (Su et al, 2011).
    d) IMIDACLOPRID: CASE REPORT: A 56-year-old man developed lactic acidosis (lactate 9.5 m/mole) after he intentionally ingested 40 mL of a pesticide containing 9.6% imidacloprid in a solvent of N-methyl-2-pyrrolidone. He presented to the emergency department 20 minutes after ingestion and was intubated 8 hours after arrival. In ICU he received supportive treatment including antibiotics. Eight days after admission he was extubated. He was discharged 4 days later (Lin et al, 2013).
    e) THIACLOPRID: CASE REPORT: A 23-year-old man intentionally ingested 100 mL of thiacloprid suspension (21.7% thacloprid w/w) and initially developed nausea, vomiting, and agitation. Approximately, 2 hours later he had multiple tonic-clonic seizures and remained unconscious. His initial vitals signs included sinus tachycardia (130 to 150 beats/min) and a slightly elevated blood pressure. However, over the next 30 hours he developed progressive hypotension and oliguria. occurred. Neurologically he remained comatose and did not respond to painful stimuli. Metabolic acidosis was noted with a pH of 7.20 and bicarbonate of 12 mmol/L. A short time later he developed shock refractory to vasopressors and sustained cardiac arrest occurred. He died 36 hours after ingestion (Vinod et al, 2015).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LEUKOCYTOSIS
    1) WITH POISONING/EXPOSURE
    a) FLONICAMID AND SPINOSAD: CASE REPORT: An 80-year-old woman with depression developed leukocytosis with left shift after intentionally ingesting a mixture of pesticides containing 80 mL of Conserve (spinosad; 11.6% spinosyn) and 2 to 3 g of powdered flonicamid. She presented to the emergency department approximately 3 hours after ingestion unconscious and hypotensive and was immediately intubated. Laboratory analysis at presentation showed leukocytosis (WBC 11,500/mcL; neutrophils 74%). She was discharged without residual complications after 5 weeks of supportive care (Su et al, 2011).
    b) IMIDACLOPRID: CASE REPORT: A 56-year-old man developed leukocytosis (WBC 13,900/mcL) after he intentionally ingested 40 mL of a pesticide containing 9.6% imidacloprid in a solvent of N-methyl-2-pyrrolidone. He presented to the emergency department 20 minutes after ingestion. He was intubated 8 hours after arrival and transferred to the ICU. He received supportive treatment including antibiotics and was extubated 8 days after admission. He was discharged 4 days later (Lin et al, 2013).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) SKIN IRRITATION
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES
    1) In a series of 1142 neonicotinoid insecticide exposures (predominantly imidacloprid (77%) or dinotefuran (17%)), ingestion (51%) was the most common route of exposure followed by dermal (44%) and ocular (11%) routes. Dermal irritation was a common adverse event. It was reported in a total of 61 (5.3%) events. Serious exposures occurred in 2 (6.3%) cases. Erythema also occurred in a total of 20 (1.8%) exposures with 3 of those cases reported as serious (Forrester, 2014).
    b) LACK OF EFFECT
    1) These compounds are nonirritating to the skin. They are not skin sensitizers (Felsot, 2001; (Anon, 1998)). Exposure to formulations may result in irritation due to the surfactants or other ingredients.
    c) Thiamethoxam is listed as a slight skin irritant (MSDS, 2001).
    B) ERUPTION
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: In a series of 1142 neonicotinoid insecticide exposures (predominantly imidacloprid (77%) or dinotefuran (17%)), ingestion (51%) was the most common route of exposure followed by dermal (44%) and ocular (11%) routes. Rash was reported in 17 (1.5%) cases with 3 cases considered to be serious (Forrester, 2014).
    3.14.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) DERMATITIS
    a) CAT: Acute-onset exfoliative erythroderma, with gross and histopathological lesions of erythema multiforme, was reported in a cat 5 days after application of imidacloprid (80 mg) for treatment of flea infestation. The dermatosis may have been a reaction to the insecticide or it may have been a paraneoplastic disease associated with a thymoma (Godfrey, 1999).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) RHABDOMYOLYSIS
    1) WITH POISONING/EXPOSURE
    a) IMIDACLOPRID: CASE REPORT: Mild rhabdomyolysis was observed in a 24-year-old man following inhalation exposure to 17.8% imidacloprid. The patient was treated with hydration and forced alkaline diuresis. The patient recovered with no permanent sequelae (Agarwal & Srinivas, 2007)
    B) MUSCLE WEAKNESS
    1) WITH POISONING/EXPOSURE
    a) ACETAMIPRID: CASE REPORT: A 58-year-old man with diabetic gangrene developed muscle weakness after intentionally injecting and ingesting an insecticide containing 18% acetamiprid, 31% N-methyl-2-pyrrolidone, and 48% dimethylsulfoxide (including 3% surface-active agent). He subcutaneously injected 8 mL of the formulation and then ingested approximately 10 mL. He underwent decontamination using gastric lavage, activated charcoal, cathartics, and antiemetics. He recovered within 2 days and was transferred to a hospital to treat diabetic gangrene (Imamura et al, 2010).
    b) ACETAMIPRID: CASE REPORT: A 74-year-old woman with chronic hypertension treated with cilnidipine and candesartan developed muscle weakness after intentionally ingesting approximately 100 mL of an insecticide containing 2% acetamiprid and 97% diethylene glycol (DEG) with 1% surface-active agent. Upon arrival to the emergency department 90 minutes after ingestion, she was hypotensive, hypoxic, and hypothermic. She underwent decontamination using gastric lavage, activated charcoal, cathartics, and antiemetics followed by supportive therapy. She recovered fully and was discharged one day after ingestion (Imamura et al, 2010).

Reproductive

    3.20.1) SUMMARY
    A) Human reproductive and developmental toxicity data are not available.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) IMIDACLOPRID - An increase in skeletal abnormalities and reduced body weights was reported in fetal rats and rabbits at higher doses tested ((Anon, 1998)).
    2) IMIDACLOPRID - In rat and rabbit studies, imidacloprid was shown not to be a primary embryotoxicant and not teratogenic (Sheets, 2001).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) IMIDACLOPRID - No evidence of cancer effects was reported in long-term animal studies (Sheets, 2001; (Anon, 1998)).
    2) THIAMETHOXAM - No evidence of carcinogenicity was noted in chronic toxicity studies in rats (MSDS, 2001).

Genotoxicity

    A) Using a full complement of in vitro and in vivo tests, imidacloprid was not shown to be mutagenic.
    B) No genotoxicity was observed with imidacloprid using the micronucleus tests, but results of the comet assay showed significant DNA damage in earthworms and a dose-effect relationship. Results of a mouse bone-marrow micronuclei test indicated no significant effects on micronuclei frequency in mice bone marrow cells until an imidacloprid dose of 100 mg/kg was reached.
    C) In 8 of 9 tests following chronic exposure over 2 years, imidacloprid caused no mutations or chromosomal breakage. One in-vitro study showed chromosomal aberrations.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and mental status.
    B) Monitor serum electrolytes.
    C) Institute continuous cardiac monitoring and obtain an ECG in symptomatic patients.
    D) Serum concentrations of neonicotinoid insecticides are not clinically useful in guiding management following exposure.
    4.1.2) SERUM/BLOOD
    A) Monitor serum electrolytes.
    B) Serum concentrations are not clinically useful in guiding management following exposure.
    4.1.3) URINE
    A) URINALYSIS
    1) Following exposure of workers to imidacloprid, monitoring of the metabolite, 6-chloronicotinic acid, in urine has been used as an indicator of exposure. The metabolite is extracted from urine using solid phase extraction and analyzed via gas chromatography-tandem mass spectrometric (GC-MS-MS) determination. Limits of detection and determination of the method were 16 and 56 pg/mL, respectively (Uroz et al, 2001).
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) Institute continuous cardiac monitoring and obtain an ECG in symptomatic patients.
    2) MONITORING
    a) Monitor vital signs and mental status.

Methods

    A) CHROMATOGRAPHY
    1) High performance liquid chromatography (HPLC) with UV detection or high performance thin layer chromatography (HPTLC) are commonly used to analyze residues of imidacloprid in animal tissue. HPLC with diode-array detection is described for the determination of imidacloprid and its metabolite, 6-chloronicotinic acid, in greenhouse air (Frenich et al, 2000) Zheng & Liu, 1999; (Berny et al, 1999).
    2) Reversed-phase liquid chromatography, with propiophenone as internal standard, has been described for the quantitation of imidacloprid in liquid and solid formulations. This method has been adopted first action by AOAC International (Macke, 1998).
    3) Following exposure of workers to imidacloprid, monitoring of the metabolite, 6-chloronicotinic acid, in human urine has been used as an indicator of exposure. The metabolite is extracted from urine using solid phase extraction and analyzed via gas chromatography-tandem mass spectrometric (GC-MS-MS) determination. Limits of detection and determination of the method were 16 and 56 pg/mL, respectively (Uroz et al, 2001).
    4) In two fatal poisoning cases with imidacloprid, an LC/MS with electrospray method was used to measure imidacloprid and its metabolites in post-mortem samples (Proenca et al, 2005).
    B) IMMUNOASSAY
    1) An enzyme-linked immunosorbent assay (ELISA), using polyclonal antibodies, was developed for the measurement of imidacloprid in fortified water, coffee cherry, bean extracts and agricultural and environmental samples. It is expected that this method may be extended to human fluids (Lee et al, 2001; Li & Li, 2000).

Treatment

Monitoring

    A) Monitor vital signs and mental status.
    B) Monitor serum electrolytes.
    C) Institute continuous cardiac monitoring and obtain an ECG in symptomatic patients.
    D) Serum concentrations of neonicotinoid insecticides are not clinically useful in guiding management following exposure.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Remove contaminated clothing and wash skin with soap and water. Irrigate exposed eyes.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) Activated charcoal may be considered and used cautiously with massive ingestions. Vomiting is a frequent effect of neonicotinoid exposure and emesis of charcoal may impair endoscopic evaluation in patients with corrosive injuries (Phua et al, 2009). Activated charcoal is not recommended in small ingestions or in the presence of corrosive injuries to oral or gastrointestinal mucosa (Lin et al, 2013).
    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).
    B) GASTRIC LAVAGE
    1) Gastric lavage may be considered in massive ingestions if the patient presents early, the airway is protected, and the patient is not vomiting (Phua et al, 2009). Gastric lavage is not recommended in the presence of corrosive injuries to oral or gastrointestinal mucosa (Lin et al, 2013).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive. (Lin et al, 2013). Administer IV fluids for hypotension.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive (Lin et al, 2013). Treat hypotension with IV fluids; add vasopressors if hypotension persists. Treat dysrhythmias per ACLS guidelines. Consult a gastroenterologist for patients with pain on swallowing, drooling, or other evidence of caustic injury to evaluate for esophageal damage. Atropine should be considered if a patient is bradycardic or experiencing cholinergic symptoms because these insecticides are frequently mixed with organophosphate and carbamate pesticides.
    B) MONITORING OF PATIENT
    1) Monitor vital signs and mental status.
    2) Monitor serum electrolytes.
    3) Institute continuous cardiac monitoring and obtain an ECG in symptomatic patients.
    4) Serum concentrations of neonicotinoid insecticides are not clinically useful in guiding management following exposure.
    C) IRRIGATION
    1) Irrigate the mouth with water rinses.
    D) ENDOSCOPIC PROCEDURE
    1) Consider endoscopy in patients with signs or symptoms of mucous membrane irritation, including hoarseness and stridor, following ingestion of formulations containing corrosive solvents or irritants (Phua et al, 2009).
    E) 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).
    F) FLUID/ELECTROLYTE BALANCE REGULATION
    1) Vomiting and diarrhea may be prolonged with large ingestions of insecticide formulations containing solvents, resulting in fluid and electrolyte loss. Monitor and replace as necessary.
    G) BRADYCARDIA
    1) ATROPINE/DOSE
    a) ADULT BRADYCARDIA: BOLUS: Give 0.5 milligram IV, repeat every 3 to 5 minutes, if bradycardia persists. Maximum: 3 milligrams (0.04 milligram/kilogram) intravenously is a fully vagolytic dose in most adults. Doses less than 0.5 milligram may cause paradoxical bradycardia in adults (Neumar et al, 2010).
    b) PEDIATRIC DOSE: As premedication for emergency intubation in specific situations (eg, giving succinylchoine to facilitate intubation), give 0.02 milligram/kilogram intravenously or intraosseously (0.04 to 0.06 mg/kg via endotracheal tube followed by several positive pressure breaths) repeat once, if needed (de Caen et al, 2015; Kleinman et al, 2010). MAXIMUM SINGLE DOSE: Children: 0.5 milligram; adolescent: 1 mg.
    1) There is no minimum dose (de Caen et al, 2015).
    2) MAXIMUM TOTAL DOSE: Children: 1 milligram; adolescents: 2 milligrams (Kleinman et al, 2010).
    2) ISOPROTERENOL INDICATIONS
    a) Used for temporary control of hemodynamically significant bradycardia in a patient with a pulse; generally other modalities (atropine, dopamine, epinephrine, dobutamine, pacing) should be used first because of the tendency to develop ischemia and dysrhythmias with isoproterenol (Neumar et al, 2010).
    b) ADULT DOSE: Infuse 2 micrograms per minute, gradually titrating to 10 micrograms per minute as needed to desired response (Neumar et al, 2010).
    c) CAUTION: Decrease infusion rate or discontinue infusion if ventricular dysrhythmias develop(Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    d) PEDIATRIC DOSE: Not well studied. Initial infusion of 0.1 mcg/kg/min titrated as needed, usual range is 0.1 mcg/kg/min to 1 mcg/kg/min (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    H) 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, 2009; 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.

Eye Exposure

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

Dermal Exposure

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

Enhanced Elimination

    A) LACK OF EFFECT
    1) There is currently no role for hemoperfusion in the treatment of neonicotinoid pesticide poisoning (Lin et al, 2013). There is no data suggesting the use of enhanced elimination.

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 severe gastrointestinal symptoms, CNS depression, or respiratory symptoms should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Patients with inadvertent exposures who are not symptomatic (ie, without gastrointestinal symptoms, respiratory symptoms, or altered mental status) may be observed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist or poison center for all intentional ingestions or symptomatic inadvertent ingestions.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Symptomatic patients and those with deliberate or large ingestions should be referred to a healthcare facility. Observe symptomatic patients until symptoms are resolved.

Range Of Toxicity

Summary

    A) TOXICITY: A toxic dose is not well established. A median dose of 90 mL of imidacloprid was noted in patients with caustic injuries. A median dose of 75 mL (range 30 to 200 mL) was noted in severely poisoned patients in the largest case series. An adult died after ingesting 200 mL of imidacloprid 9.6% (19.2 g) in N-methyl pyrrolide. In another case, an adult died after ingesting 100 mL of thiacloprid 21.7% of profound shock and cardiac arrest. In a review of the literature, 4 fatalities were reported out of 152 (2.6%) cases of acute neonicotinoid poisoning.

Therapeutic Dose

    7.2.1) ADULT
    A) DISEASE STATE
    1) HEAD LICE - Imidacloprid has been used as an investigational agent to treat head and body lice (Pediculus capitis). It has been found equally effective against both body and head lice at a concentration of 0.2% with 24 hour topical exposure (Downs et al, 2000).

Minimum Lethal Exposure

    A) CASE SERIES
    1) A total of 152 cases of acute neonicotinoid poisoning were analyzed in a literature review including 13 case reports and 2 articles. Out of 152 cases of exposure, 4 fatalities (2.6%) were reported. The 4 fatal cases were attributed to imidacloprid ingestion (Lin et al, 2013).
    B) CASE REPORTS
    1) IMIDACLOPRID
    a) A 69-year-old woman died after ingesting 200 mL of imidacloprid 9.6% (19.2 g) in N-methyl pyrrolide. Past medical history included: hypertension, treated with terazosin and irbesartan, and a lacunar infarction 8 months prior. Approximately one hour after receiving fluids, gastric lavage, and activated charcoal she became cyanotic, apneic and unconscious. The ECG showed intermittent ventricular fibrillation and ventricular tachycardia. The patient's condition quickly deteriorated despite aggressive resuscitation and supportive efforts. She expired 12 hours postingestion from intractable hypotension and dysrhythmias (Huang et al, 2006).
    2) THIACLOPRID
    a) A 23-year-old man intentionally ingested 100 mL of thiacloprid suspension (21.7% thacloprid w/w) and initially developed nausea, vomiting, and agitation. Approximately, 2 hours later he had multiple tonic-clonic seizures and remained unconscious. His initial vitals signs included sinus tachycardia (130 to 150 beats/min) and a slightly elevated blood pressure. However, over the next 30 hours he developed progressive hypotension and oliguria. Neurologically he remained comatose and did not respond to painful stimuli. A short time later he developed shock that was refractory to vasopressors and sustained cardiac arrest occurred. He died 36 hours after ingestion (Vinod et al, 2015).
    C) ANIMAL DATA
    1) IMIDACLOPRID: In rat studies, 100% mortality was reported with an acute imidacloprid dose of 500 mg/kg. Clinical signs prior to death included tremor, gait incoordination, evidence of decreased motility and activity, and nasal and urine staining. Symptoms occurred within 15 to 40 minutes. Deaths generally occurred within 3 to 7 hours (Sheets, 2001).

Maximum Tolerated Exposure

    A) CASE SERIES
    1) NEONICOTINOID INSECTICIDE/CASE SERIES: In a series of 1142 neonicotinoid insecticide exposures (predominantly imidacloprid (77%) or dinotefuran (17%)) reported to 6 poison centers in Texas during 2000 to 2012, ingestion (51%) was the most common route of exposure followed by dermal (44%) and ocular (11%) routes. Most exposures (97%) were unintentional and likely occurred at the patient's home. The outcome of exposure was no effect (22%), minor effect (11%), moderate effect (1%), not followed because of no or minimal effects (60%), unable to follow due to potentially toxic effects (1%) and an unrelated effect (4%). The most common adverse events were as follows: ocular irritation (6.5%), dermal irritation (5.3%), nausea (2.8%), vomiting (2.4%), oral irritation (2.2%), erythema (1.8%), red eye (1.8%), rash (1.5%), numbness (1.2%) and dizziness (1.1%). Most patients (92%) were treated at home with dilution or washing (85%) of the affected area. Other therapies included the administration of antihistamines (1.5%), moving the patient to fresh air (1.1%); no treatment was reported for 123 (10.8%) exposures (Forrester, 2014).
    2) One case of acute neonicotinoid poisoning was described and a literature review was performed on 152 previously reported cases including 13 case reports and 2 original articles. In the present case, a man orally ingested 40 mL of 9.6% imidacloprid in a N-methyl-2-pyrrolidone solvent. He sustained a coma, dyspnea requiring mechanical ventilation, persistent hypotension and severe lactic acidosis. He recovered uneventfully after a 12 day hospitalization. In the literature review, exact ingested amounts were not described. The majority of cases (94%) involved imidacloprid exposures. Seven (5%) exposures involved acetamiprid and 2 (1%) exposures involved clothianidin. Severe toxicity (status epilepticus, respiratory failure, ventricular tachycardia with hypotension, cardiac or respiratory arrest, disseminated intravascular coagulation, massive hematemesis, melena) was reported in 22 cases and 130 cases were nonsevere. Oral ingestion was reported in 21 (95%) severe cases and 110 (84%) nonsevere cases. Inhalation or dermal contact were reported in one (5%) severe case and 20 (15%) nonsevere cases (Lin et al, 2013).
    3) IMIDACLOPRID: In a series of 56 patients with an imidacloprid only ingestion, the median amount ingested was 15 mL (range: 10 to 50 mL). Most patients (54/56) developed only mild symptoms of nausea, vomiting, headache, dizziness and diarrhea. Of the 2 patients that developed severe toxicity (ie, suspected pulmonary aspiration), both recovered without permanent sequelae (Mohamed et al, 2009).
    4) In a retrospective analysis of neonicotinoid exposure reported to the Taiwan National Poison Center from 1987 through 2007, 70 patients with acute neonicotinoid insecticide poisoning were analyzed. Of these patients, 57 cases of oral exposure were identified and included: 53 imidacloprid only ingestions, 2 ingested acetamiprid, 2 ingested clothianidin and 7 were exposed to other substances. Most patients developed mild (n=30) to moderate (n=10) clinical effects; 7 patients were asymptomatic following ingestion. Eight patients developed severe toxicity (ie, respiratory failure, aspiration pneumonia, or coma) and 2 deaths occurred which were attributed to imidacloprid. Six patients suffered caustic injuries including oral ulcers and gastrointestinal bleeding after ingesting a median 90 mL (50 to 200 mL) of imidacloprid. In this study, the estimated amount ingested between severe/fatal toxicity (75 mL (range: 30 to 200 mL)) and non-severe toxicity (90 mL (range: 5 to 300 mL)) were similar (Phua et al, 2009). The authors concluded that there was no significant association between the severity of symptoms and the volume ingested presumably because of the small number of severe/fatal poisonings found in this study.
    B) CASE REPORTS
    1) MIXED INGESTION: An 80-year-old woman intentionally ingested a mixture of pesticides containing 80 mL of Conserve (R) (spinosad; 11.6% spinosyn) and 2 to 3 g of powdered flonicamid. She developed severe toxicity and presented to the emergency department unconscious and in shock. Her clinical course included metabolic acidosis, respiratory failure, pneumonitis and urinary retention. The patient required intensive care and mechanical ventilation for about 2 days. She was discharged following 5 weeks of hospitalization without residual complications (Su et al, 2011).
    2) IMIDACLOPRID INGESTION: An adult intentionally ingested 50 mL of a 17.8% solution of imidacloprid, and developed weakness of the neck muscles, followed by labored breathing and a decrease in oxygen saturation (SaO2 dropped to 86%) approximately 20 hours after exposure. Mechanical ventilation was required for 4 days; the patient recovered completely (Panigrahi et al, 2009).
    3) IMIDACLOPRID INGESTION: Following an intentional ingestion of about 9 g imidacloprid (an insecticide formulation), mild CNS depression was noted. It is likely that the solvent (N-methyl pyrrolidone) was a contributing factor in the CNS depression (Wu et al, 2001).
    4) IMIDACLOPRID INHALATION: A 24-year-old male farmer became unconscious after inhaling 17.8% imidacloprid after spraying the compound, and was breathless, with severe agitation and disorientation at presentation. Physical exam revealed extreme agitation, frothy secretions, cyanosis, and diaphoresis. Supportive care included a propofol infusion and mechanical ventilation for several days. By day 6, weakness and delirium resolved and the patient was discharged with no permanent sequelae. At 2 month follow-up, the patient was well with no deficits (Agarwal & Srinivas, 2007).
    C) ANIMAL DATA
    1) IMIDACLOPRID: Clinical signs were not seen in rats until an acute imidacloprid dose of 315 mg/kg was exceeded. At that dose, the incidence of mortality increased abruptly, with 20% mortality at a dose of 400 mg/kg and 100% mortality at 500 mg/kg body weight. Clinical signs occurring within 15 to 40 minutes included tremor, gait incoordination, evidence of decreased motility and activity, and nasal and urine staining. Symptoms were reversible within 8 to 24 hours following lower dosing (Sheets, 2001).
    2) IMIDACLOPRID: Subchronic toxicity studies of imidacloprid in rats fed the insecticide in their diets over a 13-week period revealed no inhibition of cholinesterase activity at any dietary level. The liver was the principal target organ, with hypertrophy of hepatocytes and sporadic cell necrosis in high-dose males. Liver pathology was fully reversible at the end of the study. A NOEL for this study was reported as 14 mg/kg/day in males and 83 mg/kg/day in females.(Sheets, 2001).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) After exposure to neonicotinoid pesticides, many patients are asymptomatic despite high levels, suggesting there is little correlation between serum levels and clinical effect (Mohamed et al, 2009).
    2) ACUTE INGESTION
    a) CASE SERIES: In a series of intentional exposures with an imidacloprid compound, 33 cases were analyzed with a median admission plasma concentration of 10.58 ng/L (IQR: 3.84 to 15.58 ng/L; range: 0.02 to 51.25 ng/L) in 28 patients; 5 patients had a plasma concentration that could not be quantified (Mohamed et al, 2009). Most patients had only mild symptoms; no fatalities occurred.
    1) CASE REPORT: In the same study, a 35 year-old woman who developed respiratory insufficiency (i.e., suspected pulmonary aspiration, respiratory arrest) had an imidacloprid plasma concentration of 44.6 ng/L five hours after ingesting an unknown amount of imidacloprid; butyryl cholinesterase activity was normal. The patient recovered completely with intensive supportive care (Mohamed et al, 2009).
    b) ACETAMIPRID: CASE REPORT: An acetamiprid serum concentration of 59.83 mcg/mL was detected in a 74-year-old woman 90 minutes after she intentionally ingested approximately 100 mL of an insecticide containing 2% acetamiprid and 97% diethylene glycol (DEG) with 1% surface-active agent. After ingestion, her symptoms included nausea, muscle weakness, tachycardia, hypotension, dyspnea, thirst, hypothermia, ECG changes, and a self-limited seizure. She recovered fully and was discharged the day after ingestion (Imamura et al, 2010).
    3) POSTMORTEM LEVELS
    a) In two fatal intoxication cases with imidacloprid, the following postmortem levels were observed (Proenca et al, 2005):
    SAMPLESCASE 1 LEVELSCASE 2 LEVELS
    BLOOD12.5 mcg/mL2.05 mcg/mL
    URINENot available0.29 mcg/mL
    KIDNEY13.6 mcg/mL2.5 mcg/mL
    LIVER9.9 mcg/mL1.01 mcg/mL
    LUNG20.6 mcg/mL8.8 mcg/mL
    STOMACH CONTENTS70 mg (in 200 mL)37.1 mg (in 150 mL)

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) IMIDACLOPRID
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 35 mg/kg (RTECS, 2001)
    2) LD50- (ORAL)MOUSE:
    a) 98 mg/kg (RTECS, 2001)
    b) 131-168 mg/kg (Sheets, 2001)
    3) LD50- (ORAL)RAT:
    a) 410 mg/kg (RTECS, 2001)
    b) 424-475 mg/kg (RTECS, 2001)
    4) LD50- (SKIN)RAT:
    a) >5 g/kg (RTECS, 2001)
    B) NITENPYRAM
    1) LD50- (ORAL)MOUSE:
    a) 867 mg/kg (RTECS, 2001)
    2) LD50- (ORAL)RAT:
    a) 1575 mg/kg (RTECS, 2001)
    3) LD50- (SKIN)RAT:
    a) >2 g/kg (RTECS, 2001)
    C) THIACLOPRID
    1) LD50- (ORAL)RAT:
    a) 444 mg/kg (RTECS, 2001)
    D) THIAMETHOXAM
    1) LD50- (ORAL)RAT:
    a) >3000 mg/kg (MSDS, 2001)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) The neonicotinoid insecticides are partial agonists on the nicotinic ACh receptor. Insect exposure is through contact or ingestion. Following plant application, the neonicotinoid insecticides are taken up by developing roots and move rapidly throughout the plant; they are also applied as a foliar insecticide. The primary mode of action following ingestion of the insecticide by the insect from a plant is interference with the nicotinic acetylcholine receptors of the insects' central and peripheral nervous system causing irreversible blockage of postsynaptic nicotinergic acetylcholine receptors. The target insects show effects 15 to 30 minutes after uptake and then stop feeding. The insecticidal potency of these insecticides is dependent on the species of insects (Suchail et al, 2001; Zhang et al, 2000; Nagata et al, 1998). Mortality in bees is induced within 72 hours following onset of intoxication due to imidacloprid (Suchail et al, 2001).
    1) These insecticides have agonist actions which activate, then block the postsynaptic nicotinic acetylcholine receptors (nAChR) (Kiriyama et al, 2001). It has been shown that the negatively charged tip of the nitro group or negatively charged region of the cyano group of nicotinoid insecticides are most important in providing affinity for the insect nAChR (Tomizawa et al, 2000). Selective toxicity of imidacloprid has been shown to be due to electrostatic interactions of the nitroimine group and bridgehead nitrogen with particular nAChR amino acid residues of the insect nervous system as opposed to vertebrates (Matsuda et al, 2001).
    a) These insecticides are partial agonists, with the imidazolidine moiety of the molecule most likely to contribute to the partial agonist activity. The role of loop D of the alpha-7 nicotinic acetylcholine receptor in its interaction with the neonicotinoids appears important to the mechanism of action as insecticides (Matsuda et al, 2000).
    2) Further studies, using biochemical and three dimensional quantitative structure-activity relationship (3D-QSAR) techniques, are required to elucidate the mechanism of molecular recognition of neonicotinoid insecticides by the binding site, nAChR (Sukekawa & Nakayama, 1999).
    B) These insecticides are characterized by their persistent effects, broad activity spectrum, good systemic properties, low toxicity to mammals and aquatic life, and moderate stability in agricultural fields (Okazawa et al, 2000).

Toxicologic Mechanism

    A) In mammals, imidacloprid is metabolized to several metabolites, including a small percent of the desnitro derivative. This metabolite is selective for the mammalian nAChRs and binds with the same affinity as nicotine at the nAChRs in mouse brain (Tonder & Olesen, 2001; Chao & Casida, 1997). However, the desnitro metabolite also detaches (disassociates) from the receptors about 8 times faster than nicotine. Thus, any interactions with the nerve endings would be very transitory compared to nicotine (Felsot, 2001).
    B) Acute toxicity of the various neonicotinoids in mammals is most closely related to potency at the alpha-7 nicotinic receptor subtype, with a decreasing toxicity relationship reported sequentially at alpha-4, beta-2, alpha-3, and alpha-1 nicotinic receptors. Actions at these receptor subtypes involve a combination of agonist and antagonist effects. Toxic effects are expected to vary in vivo among the various neonicotinoids. No systematic assessment of toxicity in vivo under appropriately standardized conditions has been reported (Sheets, 2001; Tomizawa et al, 2000; Nagata et al, 1998).
    1) Tomizawa et al (2000) and Tomizawa & Casida (2000) have shown, in mouse studies, that the neonicotinoid insecticides or their imine metabolites do cross the blood brain barrier (minor amounts), bind to the alpha-4, beta-2 nicotinic acetylcholine receptor subtype and display adverse toxic effects. Chronic 3 day exposure of M10 cells to the insecticides and their imine derivatives elicits approximately a 5- to 8-fold up-regulation of alpha-4 beta-2 nicotinic AchR levels (Tomizawa et al, 2000; Tomizawa et al, 2000).

Physicochemical

Physical Characteristics

    A) IMIDACLOPRID and its main metabolite, 6-chloronicotinic acid, are polar compounds with high solubility in water (Frenich et al, 2000). Imidacloprid is stable in acidic and neutral water, but readily hydrolyzed in alkaline water (Zheng & Liu, 1999). Imidacloprid has high water solubility (510 mg/L) and very low vapor pressure (1.9 x 10(-9) mmHg), making it unlikely to evaporate from soil and plant surfaces (Felsot, 2001).
    B) THIAMETHOXAM - The product, Cruiser 350 FS, which contains 35% thiamethoxam is a red, slightly viscous liquid with a weakly sweetish odor. It is non-flammable and is not combustible. It is dispersible in water (MSDS, 2001).

Molecular Weight

    A) Imidacloprid: 255.69 (RTECS , 2001)
    B) Nitenpyram: 270.75 (RTECS , 2001)
    C) Thiacloprid: 252.74 (RTECS , 2001)

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