MOBILE VIEW  | 

FIPRONIL

Classification   |    Detailed evidence-based information

Therapeutic Toxic Class

    A) Fipronil, an N-phenylpyrazole with a trifluoromethylsulfinyl moiety, is unique and represents a new chemical class of insecticides which acts on the gamma-aminobutyric acid receptor (GABA) as a non-competitive blocker of the GABA-gated chloride channel.

Specific Substances

    1) 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]
    2) -4-[(1R,S)-(trifluoromethyl)sulfinyl]-1H-pyrazole
    3) -3-carbonitrile
    4) Frontline(R)
    5) Pyrazole-3-carbonitrile, 5-amino-1-(2,6-dichloro-4-
    6) (trifluoromethyl)phenyl)-4-(trifluoromethyl)sulfinyl-
    7) (9ci)
    8) IS: MB 46030
    9) IS: RM 1601
    10) Molecular Formula: C12-H4-Cl2-F6-N4-OS
    11) CAS 120068-37-3
    1.2.1) MOLECULAR FORMULA
    1) C12-H4-C12-F6-N4-O-S

Available Forms Sources

    A) FORMS
    1) Fipronil is a clear, colorless to slightly yellow liquid with the odor of almond or ester (Tech Info Frontline(R) Top Spot(TM), 1997).
    2) Technical grade fipronil is a white powder with a moldy odor (Budavari, 1996; EPA, 1996).
    B) SOURCES
    1) Fipronil is available as Frontline(R) Top Spot(TM) a liquid containing 9.7% fipronil w/w and Frontline(R), Spray Treatment containing fipronil 0.29% w/w from Rhone Merieux, Inc., Athens, GA, USA (Tech Info {Spot & Spray Treatment}, 1997).
    2) Fipronil 1.5% granular soil insecticide ((Anon, 2000))
    C) USES
    1) Fipronil is an insecticide used for a wide range of pests which can include the boll weevil, plant insects, mole cricket, cockroaches, and grasshoppers. The granular formula has been applied to golf courses and commercial turf (EPA, 1996). It is also available as a concentrated liquid and spray for the treatment of fleas and ticks for dogs and cats (Tech Info {Spot & Spray Treatment}, 1997).

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) Based on animal data, the central nervous system would be the expected target organ for toxicity. A woman experienced only mild subjective impairment of sensorium after the accidental ingestion of fipronil ant bait.
    B) PHARMACOLOGICAL EFFECT - Fipronil appears to have selective GABA receptor sensitivity which makes it much more toxic to insects than to vertebrates. In animal studies, the end-use product of fipronil has a low order of toxicity following oral, dermal or inhalation exposure. It is not a sensitizer.
    C) ANIMAL DATA - Chronic feeding studies in rats produced the following effects: seizures (sometimes resulting in death), decreased body weight, decreased blood counts, and an alteration in biochemistry values (e.g., cholesterol, calcium, protein, thyroid hormone).
    0.2.4) HEENT
    A) Fipronil may cause eye irritation.
    0.2.6) RESPIRATORY
    A) Findings from animal studies suggested a low order of toxicity for inhalation exposure to fipronil as a commercially available product.
    0.2.7) NEUROLOGIC
    A) In animal studies the central nervous system appears to be the target organ of toxicity. Seizures have occurred in animals and may be expected in humans following toxic exposures.
    0.2.8) GASTROINTESTINAL
    A) Findings from animal studies suggested a low order of toxicity for oral exposure to fipronil as a commercially available product. However, the technical product has a high order of toxicity to mammals.
    0.2.9) HEPATIC
    A) Changes in liver weight have been reported during chronic feeding studies in animals.
    0.2.14) DERMATOLOGIC
    A) Skin irritation may occur following exposure.
    0.2.20) REPRODUCTIVE
    A) In rat studies, fipronil was associated with reproductive effects including decreased litter sizes, decreased body weights, decrease in the percent of animals mating, reduced post-implantation survival and offspring survival postnatal, and delay in physical development. Teratogenic effects have not been reported.

Laboratory Monitoring

    A) Monitor neurological function following significant exposure.
    B) Monitor liver function tests following significant ingestions.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) GASTRIC LAVAGE: Consider after ingestion of a potentially life-threatening amount of poison if it can be performed soon after ingestion (generally within 1 hour). Protect airway by placement in the head down left lateral decubitus position or by endotracheal intubation. Control any seizures first.
    1) CONTRAINDICATIONS: Loss of airway protective reflexes or decreased level of consciousness in unintubated patients; following ingestion of corrosives; hydrocarbons (high aspiration potential); patients at risk of hemorrhage or gastrointestinal perforation; and trivial or non-toxic ingestion.
    B) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    C) Treatment is symptomatic and supportive, there is NO specific antidote for fipronil.
    D) Monitor neurological function; seizures have been reported following oral exposure in mice and rat studies.
    E) SEIZURES: Administer a benzodiazepine; DIAZEPAM (ADULT: 5 to 10 mg IV initially; repeat every 5 to 20 minutes as needed. CHILD: 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) or LORAZEPAM (ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist. CHILD: 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).
    1) Consider phenobarbital or propofol if seizures recur after diazepam 30 mg (adults) or 10 mg (children greater than 5 years).
    2) Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.
    0.4.3) INHALATION EXPOSURE
    A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

    A) No minimal or lethal toxic dose for fipronil has been established.
    B) In animal studies, neurotoxicity appears to be the acute dietary endpoint of concern. Seizures have developed in rats following chronic oral exposure to fipronil.
    C) A woman experienced mild subjective impairment of sensorium after the accidental ingestion of fipronil ant bait (each piece ant bait weighed 1.4 g with 0.01% (0.14 mg) fipronil). She was discharged following a short period of observation.

Summary Of Exposure

    A) Based on animal data, the central nervous system would be the expected target organ for toxicity. A woman experienced only mild subjective impairment of sensorium after the accidental ingestion of fipronil ant bait.
    B) PHARMACOLOGICAL EFFECT - Fipronil appears to have selective GABA receptor sensitivity which makes it much more toxic to insects than to vertebrates. In animal studies, the end-use product of fipronil has a low order of toxicity following oral, dermal or inhalation exposure. It is not a sensitizer.
    C) ANIMAL DATA - Chronic feeding studies in rats produced the following effects: seizures (sometimes resulting in death), decreased body weight, decreased blood counts, and an alteration in biochemistry values (e.g., cholesterol, calcium, protein, thyroid hormone).

Heent

    3.4.1) SUMMARY
    A) Fipronil may cause eye irritation.
    3.4.3) EYES
    A) ANIMAL DATA - A commercial insecticide containing fipronil caused eye irritation in rabbits following ocular exposure which resolved within 3 days (EPA, 1996).
    B) Fipronil may cause eye irritation following human exposure (Tech Info {Spot & Spray Treatment}, 1997).

Respiratory

    3.6.1) SUMMARY
    A) Findings from animal studies suggested a low order of toxicity for inhalation exposure to fipronil as a commercially available product.
    3.6.2) CLINICAL EFFECTS
    A) RESPIRATORY FINDING
    1) LACK OF EFFECT
    a) Findings from animal studies suggested a low order of toxicity for inhalation exposure to fipronil as a commercially (Chipco Choice Insecticide(R)) available product (EPA, 1996).
    b) Avoidance of inhalation is recommended by the manufacturer (Tech Info {Spot & Spray Treatment}, 1997).

Neurologic

    3.7.1) SUMMARY
    A) In animal studies the central nervous system appears to be the target organ of toxicity. Seizures have occurred in animals and may be expected in humans following toxic exposures.
    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT - A 77-year-old female experienced mild subjective impairment of sensorium after the accidental ingestion of fipronil ant bait (each piece ant bait weighed 1.4 g with 0.01% (0.14 mg) fipronil). She was discharged following a short period of observation (Fung et al, 2003).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) SEIZURE
    a) CHRONIC TOXICITY
    1) Seizures, including seizures resulting in death, were reported in rats following chronic oral exposure (EPA, 1996). The USEPA, has established that the acute dietary endpoint of concern is neurotoxicity.

Gastrointestinal

    3.8.1) SUMMARY
    A) Findings from animal studies suggested a low order of toxicity for oral exposure to fipronil as a commercially available product. However, the technical product has a high order of toxicity to mammals.
    3.8.2) CLINICAL EFFECTS
    A) DRUG-INDUCED GASTROINTESTINAL DISTURBANCE
    1) LACK OF EFFECT
    a) Findings from animal studies suggested a low order of toxicity for oral exposure to fipronil as a commercially (Chipco Choice Insecticide(R)) available product (EPA, 1996). However, the technical product has a high order of toxicity to mammals.
    3.8.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) WEIGHT DECREASE
    a) In rat studies, loss of appetite accompanied by weight loss was observed at continuous oral doses of 420 mg/kg/2 weeks (RTECS , 2000).

Hepatic

    3.9.1) SUMMARY
    A) Changes in liver weight have been reported during chronic feeding studies in animals.
    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEPATIC FUNCTION ABNORMAL
    a) In rat studies, an increased liver weight occurred following continuous oral doses of fipronil at 336 mg/kg/4 weeks (RTECS , 2001; EPA, 1996). Alterations in total protein and bilirubin levels were also observed.

Dermatologic

    3.14.1) SUMMARY
    A) Skin irritation may occur following exposure.
    3.14.2) CLINICAL EFFECTS
    A) SKIN IRRITATION
    1) Fipronil may cause skin irritation following human exposure (Tech Info {Spot & Spray Treatment}, 1997).
    B) LACK OF EFFECT
    1) Findings from animal studies suggested a low order of toxicity for skin irritation to fipronil as a commercially (Chipco Choice Insecticide(R)) available product (EPA, 1996).
    3.14.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) IRRITATION
    a) In rabbits, a commercial product containing fipronil caused slight irritation following dermal exposure that resolved within 72 hours (EPA, 1996).
    2) LACK OF EFFECT
    a) Fipronil was NOT found to be a sensitizer during animal (guinea pig) studies of a commercially prepared product (EPA, 1996).

Reproductive

    3.20.1) SUMMARY
    A) In rat studies, fipronil was associated with reproductive effects including decreased litter sizes, decreased body weights, decrease in the percent of animals mating, reduced post-implantation survival and offspring survival postnatal, and delay in physical development. Teratogenic effects have not been reported.
    3.20.2) TERATOGENICITY
    A) LACK OF EFFECT
    1) Teratogenic effects have not been reported (Tech Info {Spot & Spray Treatment}, 1997).
    3.20.3) EFFECTS IN PREGNANCY
    A) ANIMAL STUDIES
    1) In rat studies, fipronil was associated with reproductive effects (EPA, 1996). The lowest observable effect level (LOEL) for reproductive toxicity was 300 ppm (26.03 mg/kg/day for males, 28.4 mg/kg/day females) which resulted in the following: decreased litter sizes, decreased body weights, decrease in the percent of animals mating, reduced post-implantation survival and offspring survival, and delay in physical development.

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS120068-37-3 (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
    3.21.4) ANIMAL STUDIES
    A) THYROID ADENOMA
    1) Fipronil has been classified as a Group C (possible human) carcinogen, based on rat studies in which an increase in thyroid follicular cell tumors were produced in both sexes (EPA, 1996). Statistical significance was observed in pair wise and trend analyses.
    B) CARCINOMA
    1) Based on alterations in clinical chemistry, thyroid parameters, and an increased incidence of clinical signs, fipronil was carcinogenic in rats at doses of 300 ppm in males (12.68 mg/kg/day) and females (16.75 mg/kg/day) (EPA, 1996).
    C) LACK OF EFFECT
    1) Based on decreased food conversion efficiency, decreased body weight gain, increased liver weights, and increased incidence of hepatic histopathological changes, technical fipronil was not carcinogenic in mice when administered at doses of 30 ppm or greater (EPA, 1996).

Genotoxicity

    A) At the time of this review, several mutagenicity studies (Ames, cytogenic and mouse micronucleus assays) have been negative.

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor neurological function following significant exposure.
    B) Monitor liver function tests following significant ingestions.

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Monitor neurological function following significant exposure.
    B) Monitor liver function tests following significant ingestions.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) EMESIS/NOT RECOMMENDED -
    1) EMESIS: Ipecac-induced emesis is not recommended because of the potential for seizures.
    B) ACTIVATED CHARCOAL -
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    B) GASTRIC LAVAGE
    1) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).
    a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.
    2) PRECAUTIONS:
    a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
    b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.
    3) LAVAGE FLUID:
    a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
    b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
    c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.
    4) COMPLICATIONS:
    a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
    b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).
    5) CONTRAINDICATIONS:
    a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is symptomatic and supportive. There is NO specific antidote for fipronil.
    B) MONITORING OF PATIENT
    1) Monitor neurological function following significant exposure or as indicated. Based on animal data, the central nervous system would be the anticipated target organ following human exposure (EPA, 1996).
    2) Monitor liver function following large intentional ingestions.
    C) SEIZURE
    1) Seizures have been reported following oral exposure in mice and rat studies (EPA, 1996). Monitor patients following a significant exposure.
    2) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    3) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    4) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    5) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    6) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    7) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

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) 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).

Case Reports

    A) A 50 year-old male developed headache, nausea, vertigo and weakness two hours after spraying with a diluted 20% fipronil solution for five hours. He used no personal protective equipment. Exposure was believed to be by the pulmonary and dermal routes. Symptoms resolved spontaneously without therapeutic intervention approximately five hours after onset(Chodorowski & Anand, 2004) .

Summary

    A) No minimal or lethal toxic dose for fipronil has been established.
    B) In animal studies, neurotoxicity appears to be the acute dietary endpoint of concern. Seizures have developed in rats following chronic oral exposure to fipronil.
    C) A woman experienced mild subjective impairment of sensorium after the accidental ingestion of fipronil ant bait (each piece ant bait weighed 1.4 g with 0.01% (0.14 mg) fipronil). She was discharged following a short period of observation.

Minimum Lethal Exposure

    A) GENERAL/SUMMARY
    1) The minimum lethal human dose to this agent has not been delineated.

Maximum Tolerated Exposure

    A) CASE REPORT - A 77-year-old female experienced mild subjective impairment of sensorium after the accidental ingestion of fipronil ant bait (each piece ant bait weighed 1.4 g with 0.01% (0.14 mg) fipronil). She was discharged following a short period of observation (Fung et al, 2003).
    B) ANIMAL STUDIES
    1) Neurotoxicity has been reported in rats following chronic oral exposure (EPA, 1996).

Workplace Standards

    A) ACGIH TLV Values for CAS120068-37-3 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS120068-37-3 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS120068-37-3 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS120068-37-3 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) References: EPA, 1996 RTECS, 2001
    1) LD50- (ORAL)RAT:
    a) 97 mg/kg
    2) LD50- (SKIN)RAT:
    a) >2000 mg/kg

Pharmacologic Mechanism

    A) Fipronil, an N-phenylpyrazole with a trifluoromethylsulfinyl substituent, is a selective insecticide which acts at the gamma-aminobutyric acid (GABA) receptor as a noncompetitive blocker of the GABA-gated chloride channel (Hainzl & Casida, 1996). It appears to have more selective toxicity for insects than the earlier first generation of insecticidal chloride-channel blockers (i.e., chlorinated cyclodienes, other polychlorocycloalkanes {PCCAs}) (Hainzl et al, 1998).
    B) Hainzl et al (1998) observed that differences in GABA receptor sensitivity, assayed by displacement of 4'-ethynyl-4-n-[2,3-(3)H(2)-propylbicycloorthobenzoate ([(3)H]EBOB) from the noncompetitive blocker site, is the major reason that fipronil is more toxic to insects (housefly and fruit fly) than to vertebrates (humans, dogs, mice, chickens, quail and salmon).
    C) Based on normal use, fipronil degrades photochemically and produces three main toxicants: the parent compound, its major sulfone metabolite, and the desulfinyl photoproduct (Hainzl & Casida, 1996; Hainzl et al, 1998). Desulfinylfipronil is a major photoproduct, but was not found to be a metabolite in mammals. It reportedly has a long duration of environmental persistence, along with high neuroactivity, which may play a role in the effectiveness of fipronil as an insecticide.
    D) In mice, metabolism of fipronil yielded sulfone alone, with no other derivatives (Hainzl & Casida, 1996).

Toxicologic Mechanism

    A) Toxicity of fipronil is dependent on the parent compound, the sulfone metabolite, and the desulfinyl photoproduct (a bioactive component of fipronil-derived residues) (Hainzl et al, 1998). The neurotoxic potential of fipronil, as analyzed in houseflies and mice, was increased or decreased upon photodegradation to the sulfinyl derivative; whereas the detrifluoromethylsulfinyl compounds had minimal effect (Hainzl & Casida, 1996).
    1) PARENT COMPOUND - Fipronil can act as a toxicant for mammals and an insecticide without oxidation to the sulfone (Hainzl et al, 1998). Selective toxicity appears to be due to the higher potency of the parent compound at the insect, as compared to the mammalian GABA receptor. However, the rate of conversion to the longer acting and less selective sulfone metabolite and desulfinyl photoproduct are also factors.
    2) SULFONE METABOLITE - Fipronil sulfone is easily formed from fipronil and has a major role in toxicity to freshwater fish and waterfowl and game birds, but reportedly not more toxic to mice (Hainzl et al, 1998).
    a) At the time of this review, identification of further metabolites has not been found (Hainzl et al, 1998).
    3) PHOTOPRODUCT - The desulfinyl photoproducts are considered less selective and generally more toxic than the parent compound (Hainzl et al, 1998). They have more increased toxicity and potency at the chloride channel than either fipronil or sulfone (major metabolite).
    a) Hainzl & Casida (1996) observed that the desulfinylfipronil compound was 10-fold more potent than fipronil at the mammalian chloride channel, which would reduce the intrinsic selectivity between the insect and mammal. The authors suggested that this degradation product, based on its toxicity and persistence, should be considered during the toxicological evaluation of this agent.

Physical Characteristics

    A) GRANULAR FORMULA - A white powder with a moldy odor (Budavari, 1996; EPA, 1996).
    B) LIQUID FORMULA - clear, colorless to slightly yellow liquid; odor of almond or ester (Tech Info Top Spot(R), 1997).

Ph

    A) GRANULAR FORMULA - 5.9 to 6.1 at 23 degrees Centigrade (1% w/v water) (EPA, 1996).

Molecular Weight

    A) 437.16 (RTECS , 2001)

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