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CROTONALDEHYDE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Crotonaldehyde is an acrolein-like compound. More specifically, it is an enal (alpha, beta-unsaturated aldehyde).

Specific Substances

    A) No Synonyms were found in group or single elements
    1.2.1) MOLECULAR FORMULA
    1) C4-H6-O

Available Forms Sources

    A) FORMS
    1) Crotonaldehyde is a flammable liquid (Budavari, 1989).
    2) The crotonaldehyde of commerce has the "trans" configuration (Budavari, 1989; Lewis, 1993).
    a) Crotonaldehyde is available commercially as a technical grade of 87% purity and a liquid assay grade of 92.5% purity (Lewis, 1993; HSDB , 1995). Commercial crotonaldehyde (93%) is stabilized with water (a solid phase separates out at minus 5 degrees C) (Budavari, 1989).
    B) SOURCES
    1) Crotonaldehyde is found in smoke from burning wood, tobacco, polymers, and in the exhaust of gasoline, diesel, and turbine engines, and volcanoes (HSDB , 1995). It is a ubiquitous environmental pollutant (Eder & Hoffman, 1992). It is a minor component of chewing tobacco (Chou & Hee, 1994).
    2) Crotonaldehyde is a metabolite of 1,3-butadiene (Cheng & Ruth, 1993).
    3) Crotonaldehyde is a suspected metabolite of the probable human carcinogen, N-nitrosopyrrolidine (Gray & Barnsky, 1971).
    C) USES
    1) It is utilized in the manufacture of n-butyl alcohol, butyraldehyde, and quinaldine; as a warning agent in fuel gases; as solvent in purification of mineral oils; in the manufacture of resins, rubber antioxidants, and insecticides; in chemical warfare as a tear gas; as an alcohol denaturant; in leather tanning; and in locating breaks and leaks in pipes (ITI, 1985; ACGIH, 1983; Hathaway et al, 1991; Budavari, 1989).
    2) Minor amounts are used in the manufacture of maleic acid, crotyl alcohol, butyl chloral hydrate, and in rubber accelerators (Budavari, 1989).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) There is little experience with acute overexposures in humans. It is highly toxic by the inhalation, dermal, and oral routes. Crotonaldehyde is very irritating to eyes, skin, and mucous membranes. Corneal damage may occur. Respiratory irritation and delayed pulmonary edema are possible. Allergic contact dermatitis may be seen. Crotonaldehyde is a genotoxin and animal carcinogen. Seizures have been seen in experimental animals only.
    0.2.4) HEENT
    A) Eye irritation is common. Corneal injury may occur from direct eye contact. Irritation of nose and throat may occur.
    0.2.6) RESPIRATORY
    A) Upper respiratory irritation frequently occurs with crotonaldehyde inhalation. Acute respiratory distress syndrome and delayed onset of pulmonary edema is possible with inhalation.
    0.2.7) NEUROLOGIC
    A) Seizures have been observed as a terminal event in exposed rats.
    0.2.9) HEPATIC
    A) Experimental animals have had spleen and liver injury after exposure.
    0.2.14) DERMATOLOGIC
    A) Crotonaldehyde is highly irritating to exposed skin. Allergic contact dermatitis has been described.
    0.2.16) ENDOCRINE
    A) Damage to thymus and adrenal glands has been described in exposed experimental animals.
    0.2.20) REPRODUCTIVE
    A) Crotonaldehyde has been detected in human breast milk. It can cause degeneration of spermatocytes in mice.

Laboratory Monitoring

    A) Baseline arterial blood gases and chest x-ray should be obtained in patients with significant respiratory exposure. Baseline liver and renal function tests and complete blood count with differential are suggested in substantial exposures.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) Because of the irritant properties of this substance, EMESIS SHOULD NOT BE INDUCED.
    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) 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.
    D) 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.
    E) Obtain baseline liver and renal function tests and complete blood count.
    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.
    B) ACUTE LUNG INJURY: Maintain ventilation and oxygenation and evaluate with frequent arterial blood gases and/or pulse oximetry monitoring. Early use of PEEP and mechanical ventilation may be needed.
    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).
    2) Allergic contact dermatitis may respond to antihistamine or corticosteroid therapy.

Range Of Toxicity

    A) The minimum lethal exposure to crotonaldehyde is not well established. Its extreme irritant properties prevent voluntary exposure to dangerous concentrations. Lacrimation occurs within 30 seconds at 4.1 ppm. Eye and upper respiratory tract irritation occur after 10 minutes of exposure to 10 ppm and within seconds to 45 ppm. Skin irritation occurs at concentrations greater than 0.12%.

Clinical Effects

Summary Of Exposure

    A) There is little experience with acute overexposures in humans. It is highly toxic by the inhalation, dermal, and oral routes. Crotonaldehyde is very irritating to eyes, skin, and mucous membranes. Corneal damage may occur. Respiratory irritation and delayed pulmonary edema are possible. Allergic contact dermatitis may be seen. Crotonaldehyde is a genotoxin and animal carcinogen. Seizures have been seen in experimental animals only.

Heent

    3.4.1) SUMMARY
    A) Eye irritation is common. Corneal injury may occur from direct eye contact. Irritation of nose and throat may occur.
    3.4.3) EYES
    A) CONJUNCTIVITIS - Lacrimation and eye irritation occur with exposure to vapor from crotonaldehyde (Hathaway et al, 1991; Pattle & Cullumbine, 1956).
    B) CORNEAL DAMAGE - Corneal injury has been reported from direct contact, but healing was complete in 48 hours (Hathaway et al, 1991; Grant, 1986).
    3.4.5) NOSE
    A) NASAL IRRITATION - Upper respiratory irritation occurs with inhalation exposure (Hathaway et al, 1991). The most pronounced effect is irritation of the nose, pharynx, and larynx (HSDB , 1995).
    3.4.6) THROAT
    A) THROAT IRRITATION - Irritation of the upper respiratory tract occurs with inhalation exposure (Hathaway et al, 1991). The most pronounced effect is irritation of the nose, pharynx, and larynx (HSDB , 1995).

Respiratory

    3.6.1) SUMMARY
    A) Upper respiratory irritation frequently occurs with crotonaldehyde inhalation. Acute respiratory distress syndrome and delayed onset of pulmonary edema is possible with inhalation.
    3.6.2) CLINICAL EFFECTS
    A) IRRITATION SYMPTOM
    1) Upper respiratory tract irritation is seen in inhalation exposures (Hathaway et al, 1991).
    B) ADULT RESPIRATORY DISTRESS SYNDROME
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Sudden onset of cough and mild dyspnea occurred in a 55-year-old man following occupational exposure to a highly concentrated mixture of ethenone and crotonaldehyde. Despite symptoms, he continued to work in the contaminated area for the next 12 hours without any protective equipment. At presentation to the emergency department, the patient had developed respiratory failure, requiring intubation and mechanical ventilation. Vital signs indicated hypertension (151/91 mmHg), tachycardia (107 beats/min), and tachypnea (30 breaths/min). His O2 saturation via mask was 92%, his arterial blood gases indicated a P/F ratio of less than 200, and a chest CT revealed bilateral nonsegmental ground glass opacities in his lungs, all of which was consistent with a diagnosis of acute respiratory distress syndrome. With 4 days of supportive therapy, including oxygen and corticosteroids, the patient gradually recovered with regression of his bilateral infiltrates, normalization of his arterial blood gases, and a pulse oxygen saturation of 99%, following extubation. On hospital day 9, the patient was discharged with progressive lung improvement, according to a repeat chest CT, and normal pulmonary function tests at his follow-up 1 month later (Huang et al, 2015).
    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    a) Rats exposed to high concentrations developed an excitatory phase and then severe respiratory distress with bronchiolar injury found at autopsy (Hathaway et al, 1991; Rinehart, 1967).
    b) Changes in pulmonary function were seen in rats exposed to 10 ppm for 200 minutes (ACGIH, 1991).
    2) PULMONARY EDEMA
    a) Pulmonary edema has been observed in laboratory animals after exposure to a fatal level of 1500 ppm for 30 minutes (Hathaway et al, 1991; Rinehart, 1967).

Neurologic

    3.7.1) SUMMARY
    A) Seizures have been observed as a terminal event in exposed rats.
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    a) Seizures have been observed in rats exposed to high concentrations by inhalation, but occurred as a terminal event (Hathaway et al, 1991).

Hepatic

    3.9.1) SUMMARY
    A) Experimental animals have had spleen and liver injury after exposure.
    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    a) Crotonaldehyde produced moderate to severe liver injury in 10 of 23 rats with chronic exposure to 6 mM in the drinking water (Chung et al, 1986). Injection of crotonaldehyde intraperitoneally to mice produced elevations of lactate dehydrogenase (Warholm et al, 1984).
    2) SPLEEN DISORDER
    a) Intraperitoneal injection of crotonaldehyde to mice has produced injury to the spleen (Warholm et al, 1984).

Dermatologic

    3.14.1) SUMMARY
    A) Crotonaldehyde is highly irritating to exposed skin. Allergic contact dermatitis has been described.
    3.14.2) CLINICAL EFFECTS
    A) DERMATITIS
    1) Crotonaldehyde is a skin irritant with dermal contact (Hathaway et al, 1991).
    B) CONTACT DERMATITIS
    1) One case of a textile worker with allergic contact dermatitis to dimethoxane in an aqueous phase spin finish demonstrated sensitization to crotonaldehyde (Shmunes & Kempton, 1980).

Endocrine

    3.16.1) SUMMARY
    A) Damage to thymus and adrenal glands has been described in exposed experimental animals.
    3.16.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    a) Intraperitoneal injection to mice has caused thymic injury (Warholm et al, 1984).
    2) ADRENAL INSUFFICIENCY
    a) Intraperitoneal injection to mice has caused adrenal injury (Warholm et al, 1984).

Reproductive

    3.20.1) SUMMARY
    A) Crotonaldehyde has been detected in human breast milk. It can cause degeneration of spermatocytes in mice.
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Crotonaldehyde was detected in 1 of 12 human breast milk samples from the US (Pellizzari, 1982).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS4170-30-3 (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) IARC Classification
    a) Listed as: Crotonaldehyde
    b) Carcinogen Rating: 3
    1) The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.
    3.21.4) ANIMAL STUDIES
    A) HEPATIC CARCINOMA
    1) Chronic oral administration of 0.6 mM in the drinking water produced liver neoplasms in 9 of 27 male F344 rats (Chung et al, 1986).

Genotoxicity

    A) Crotonaldehyde can form DNA adducts and is mutagenic and clastogenic.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Baseline arterial blood gases and chest x-ray should be obtained in patients with significant respiratory exposure. Baseline liver and renal function tests and complete blood count with differential are suggested in substantial exposures.
    4.1.2) SERUM/BLOOD
    A) ACID/BASE
    1) Baseline arterial blood gases should be obtained in patients with significant inhalation exposure and respiratory irritation.
    B) BLOOD/SERUM CHEMISTRY
    1) Patients with significant ingestions should have monitoring of liver function tests, particularly lactate dehydrogenase (LDH).
    C) HEMATOLOGIC
    1) WHITE BLOOD COUNT WITH DIFFERENTIAL - Patients with significant exposure could theoretically have decreased T-lymphocyte counts from thymic injury.

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) Baseline chest x-ray should be obtained in patients with significant inhalation exposure and respiratory irritation.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Baseline arterial blood gases and chest x-ray should be obtained in patients with significant respiratory exposure. Baseline liver and renal function tests and complete blood count with differential are suggested in substantial exposures.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) INHALATION EXPOSURE -
    1) 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.
    B) DERMAL EXPOSURE -
    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).
    2) Allergic contact dermatitis may respond to antihistamine or corticosteroid therapy.
    C) EYE EXPOSURE-
    1) 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.
    D) ORAL EXPOSURE -
    1) DILUTION: If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. Dilution may only be helpful if performed in the first seconds to minutes after ingestion. The ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting (Caravati, 2004).
    2) Because of potential gastrointestinal tract irritation and seizures, emesis should not be induced.
    3) Significant esophageal or gastrointestinal tract irritation or burns may occur following ingestion. The possible benefit of early removal of some ingested material by cautious gastric lavage must be weighed against potential complications of bleeding or perforation.
    4) 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).
    5) 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.
    6.5.2) PREVENTION OF ABSORPTION
    A) EMESIS/NOT RECOMMENDED
    1) Because of the irritant properties of this substance, EMESIS SHOULD NOT BE INDUCED.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    C) GASTRIC LAVAGE
    1) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).
    a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.
    2) PRECAUTIONS:
    a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
    b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.
    3) LAVAGE FLUID:
    a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
    b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
    c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.
    4) COMPLICATIONS:
    a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
    b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).
    5) CONTRAINDICATIONS:
    a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Human oral exposures have not been reported. Based on experimental animal data (Warholm et al, 1984), injury to liver, spleen, adrenal glands, and thymus might occur.
    2) Baseline liver and renal function tests and complete blood count with differential are suggested.
    3) Patients with ingestions should be followed clinically for injury to the above organs.
    B) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 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).
    C) IRRITATION SYMPTOM
    1) Observe patients with ingestion carefully for the possible development of esophageal or gastrointestinal tract irritation or burns. If signs or symptoms of esophageal irritation or burns are present, consider endoscopy to determine the extent of injury.

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.
    6.7.2) TREATMENT
    A) ACUTE LUNG INJURY
    1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
    2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).
    a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)
    3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
    4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
    5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
    6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
    7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Eye Exposure

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

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) 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).
    6.9.2) TREATMENT
    A) ACUTE ALLERGIC REACTION
    1) Allergic contact dermatitis may occur and may respond to treatment with antihistamines or corticosteroids. Further exposure should be prevented.
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Range Of Toxicity

Summary

    A) The minimum lethal exposure to crotonaldehyde is not well established. Its extreme irritant properties prevent voluntary exposure to dangerous concentrations. Lacrimation occurs within 30 seconds at 4.1 ppm. Eye and upper respiratory tract irritation occur after 10 minutes of exposure to 10 ppm and within seconds to 45 ppm. Skin irritation occurs at concentrations greater than 0.12%.

Minimum Lethal Exposure

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

Maximum Tolerated Exposure

    A) CONCENTRATION LEVEL
    1) Lacrimation can occur within 30 seconds at 4 ppm (HSDB , 1995; ACGIH, 1991). Exposure of humans to crotonaldehyde at 4 ppm for 10 minutes caused lacrimation and upper respiratory irritation. At 45 ppm, there was conjunctival irritation after a few seconds (Hathaway et al, 1991; Grant, 1986).
    2) The highly irritating odor of crotonaldehyde precludes voluntary exposure to dangerous concentrations (Grant, 1986).
    3) Immediately Dangerous to Life or Death - 50 ppm (NIOSH, 1995).
    4) The minimum concentration for skin irritation is 0.12% in vegetable oil (Bainova & Madzhunov, 1984).

Workplace Standards

    A) ACGIH TLV Values for CAS4170-30-3 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Editor's Note: The listed values are recommendations or guidelines developed by ACGIH(R) to assist in the control of health hazards. They should only be used, interpreted and applied by individuals trained in industrial hygiene. Before applying these values, it is imperative to read the introduction to each section in the current TLVs(R) and BEI(R) Book and become familiar with the constraints and limitations to their use. Always consult the Documentation of the TLVs(R) and BEIs(R) before applying these recommendations and guidelines.
    a) Adopted Value
    1) Crotonaldehyde
    a) TLV:
    1) TLV-TWA:
    2) TLV-STEL:
    3) TLV-Ceiling: 0.3 ppm
    b) Notations and Endnotes:
    1) Carcinogenicity Category: A3
    2) Codes: Skin
    3) Definitions:
    a) A3: Confirmed Animal Carcinogen with Unknown Relevance to Humans: The agent is carcinogenic in experimental animals at a relatively high dose, by route(s) of administration, at site(s), of histologic type(s), or by mechanism(s) that may not be relevant to worker exposure. Available epidemiologic studies do not confirm an increased risk of cancer in exposed humans. Available evidence does not suggest that the agent is likely to cause cancer in humans except under uncommon or unlikely routes or levels of exposure.
    b) Skin: This refers to the potential significant contribution to the overall exposure by the cutaneous route, including mucous membranes and the eyes, either by contact with vapors or, of likely greater significance, by direct skin contact with the substance. It should be noted that although some materials are capable of causing irritation, dermatitis, and sensitization in workers, these properties are not considered relevant when assigning a skin notation. Rather, data from acute dermal studies and repeated dose dermal studies in animals or humans, along with the ability of the chemical to be absorbed, are integrated in the decision-making toward assignment of the skin designation. Use of the skin designation provides an alert that air sampling would not be sufficient by itself in quantifying exposure from the substance and that measures to prevent significant cutaneous absorption may be warranted. Please see "Definitions and Notations" (in TLV booklet) for full definition.
    c) TLV Basis - Critical Effect(s): Eye and URT irr
    d) Molecular Weight: 70.09
    1) For gases and vapors, to convert the TLV from ppm to mg/m(3):
    a) [(TLV in ppm)(gram molecular weight of substance)]/24.45
    2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:
    a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance
    e) Additional information:

    B) NIOSH REL and IDLH Values for CAS4170-30-3 (National Institute for Occupational Safety and Health, 2007):
    1) Listed as: Crotonaldehyde
    2) REL:
    a) TWA: 2 ppm (6 mg/m(3))
    b) STEL:
    c) Ceiling:
    d) Carcinogen Listing: (Not Listed) Not Listed
    e) Skin Designation: Not Listed
    f) Note(s): See Appendix C (Aldehydes)
    3) IDLH:
    a) IDLH: 50 ppm
    b) Note(s): Not Listed

    C) Carcinogenicity Ratings for CAS4170-30-3 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A3 ; Listed as: Crotonaldehyde
    a) A3 :Confirmed Animal Carcinogen with Unknown Relevance to Humans: The agent is carcinogenic in experimental animals at a relatively high dose, by route(s) of administration, at site(s), of histologic type(s), or by mechanism(s) that may not be relevant to worker exposure. Available epidemiologic studies do not confirm an increased risk of cancer in exposed humans. Available evidence does not suggest that the agent is likely to cause cancer in humans except under uncommon or unlikely routes or levels of exposure.
    2) EPA (U.S. Environmental Protection Agency, 2011): Not 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): 3 ; Listed as: Crotonaldehyde
    a) 3 : The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed ; Listed as: Crotonaldehyde
    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 CAS4170-30-3 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Listed as: Crotonaldehyde
    2) Table Z-1 for Crotonaldehyde:
    a) 8-hour TWA:
    1) ppm: 2
    a) Parts of vapor or gas per million parts of contaminated air by volume at 25 degrees C and 760 torr.
    2) mg/m3: 6
    a) Milligrams of substances per cubic meter of air. When entry is in this column only, the value is exact; when listed with a ppm entry, it is approximate.
    3) Ceiling Value:
    4) Skin Designation: No
    5) Notation(s): Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) References: (ITI, 1988; Lewis, 1992; RTECS, 1995
    1) LD50- (ORAL)MOUSE:
    a) 104 mg/kg
    2) LD50- (SUBCUTANEOUS)MOUSE:
    a) 160 mg/kg
    3) LD50- (ORAL)RAT:
    a) 206 mg/kg
    b) 300 mg/kg
    4) LD50- (SUBCUTANEOUS)RAT:
    a) 140 mg/kg
    5) TCLo- (INHALATION)HUMAN:
    a) 4.1 ppm -- TFX,IRR

Pharmacology Toxicology

Toxicologic Mechanism

    A) Crotonaldehyde is a primary irritant of the eyes, skin, and mucous membranes (Hathaway et al, 1991; Coenraads et al, 1975).
    B) Pulmonary edema may be the result of hydrolysis in the lower respiratory tract (Raffle, 1987).
    C) Crotonaldehyde can form 1,N2-cyclic guanine adducts in DNA and is a mutagen. This may be the mechanism of its carcinogenic activity (Chung F, 1992).
    D) Enals, a class of aldehydes including crotonaldehyde, can deplete glutathione and react with proteins by forming conjugates with thiol groups (Chung F, 1992).

Physicochemical

Physical Characteristics

    A) Crotonaldehyde is a water-white (colorless), flammable liquid, with a pungent, suffocating (tar-like) odor (ACGIH, 1991; Budavari, 1989; Lewis, 1993).
    1) Turns to a pale yellow color in contact with light and air (Lewis, 1993).

Molecular Weight

    A) 70.09

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