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CHLOROPICRIN

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Chloropicrin is an SN2 alkylating agent with an activated halogen group. The major action is combination with sulfhydryl groups, inactivating enzymes. Chloropicrin has the additional toxic effect of interfering with oxygen transport by its reaction with SH-groups in hemoglobin. It is possible that there may also be a photochemical transformation of chloropicrin into phosgene.
    B) Chloropicrin is classified by the military as a "choking agent". It was initially synthesized in 1848 (synonyms: PS and G 25). Common slang terms include vomiting gas and war gas. The chemical name for chloropicrin is trichloronitromethane. It is a slightly oily colorless or pale yellow liquid with an intense odor. It produces a poisonous vapor, is a lacrimator, and is intensely irritating to the skin and mucous membranes. It is poisonous when taken orally.

Specific Substances

    1) Acquinite
    2) Chloroform, nitro-
    3) Dojyopicrin
    4) Dolochlor
    5) G 25
    6) KLOP
    7) Nitrochloroform
    8) Nitrotrichloromethane
    9) Picfume
    10) Picride
    11) Profume A
    12) PS
    13) Tri-clor
    14) Trichloronitromethane
    15) Molecular formula: C-Cl3-N-O2
    16) CAS 76-06-2
    1.2.1) MOLECULAR FORMULA
    1) C-Cl3-N-O2

Available Forms Sources

    A) FORMS
    1) Chloropicrin is a nonflammable liquid, however, it is sometimes in the form of a mixture with other flammable solution (AAR, 2000; (Lewis, 1997).
    2) It may be mixed with xylene, carbon tetrachloride, or ethylene dichloride (to help distribute gas) when injected in soil (HSDB , 2001). It may also be mixed with trichlorethylene (OHM/TADS, 2001).
    B) SOURCES
    1) Chloropicrin was originally synthesized in 1848 by action of hypochlorites (bleach powder) and steam on calcium picrate (Budavari, 2000; HSDB , 2001).
    2) Currently, it is manufactured from alpha chlorination of nitromethane by alkaline hypochlorite (Ashford, 1994; Budavari, 2000).
    C) USES
    1) Chloropicrin was historically used, as early as World War I, as a tear gas. It was also referred to as "war gas" or "vomiting gas" (Prudhomme et al, 1999).
    2) It has been used in grenades (Lewis, 1998).
    3) It has been used in personal protective devices to repel prospective assailants, referred to as "Chemical Mace" (Lewis, 1998).
    4) In 1917, it was discovered that chloropicrin was effective as an insecticide. It has since been used as a soil disinfectant (to control nematodes, soil insects, soil fungi, and weed seeds); as an insecticidal fumigant (especially for grain elevator); and as a rodent exterminator (for stored grain) (Gonmori et al, 1987; Hartley & Kidd, 1990; HSDB , 2001; Lewis, 2000).
    a) It is most intensively used as a fumigant for glasshouse and mushroom-house soil (Hartley & Kidd, 1990; ILO, 1998).
    5) Other uses of chloropicrin have included: dyestuffs (crystal violet) and organic syntheses (HSDB , 2001; ILO, 1998).
    6) It can also be added as a warning agent (because of its strong odor and lacrimation action) and to reduce fire hazard (because it is non-flammable) for use with other fumigants (such as methyl bromide) (Hartley & Kidd, 1990; HSDB , 2001).

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: Chloropicrin, classified by the military as a "choking agent", is a lacrimator and is intensely irritating to the skin and mucous membranes. It has been used in grenades and in protective personal devices. It has also been used as a soil disinfectant, insecticidal fumigant, and as a rodent exterminator for stored grain.
    B) PHARMACOLOGY: Chloropicrin may cause liquefaction necrosis. It can saponify the fats in the cell membrane, destroying the cell and allowing deep penetration into mucosal tissue. In gastrointestinal tissue, an initial inflammatory phase may be followed by tissue necrosis (sometimes resulting in perforation), then granulation and finally stricture formation.
    C) EPIDEMIOLOGY: Exposure has been rarely reported.
    D) WITH POISONING/EXPOSURE
    1) Limited data regarding specific human toxicity following chloropicrin exposure is available. The following effects could be expected to occur, based on exposure data of other alkaline corrosives.
    2) MILD TO MODERATE ORAL TOXICITY: Patients with mild ingestions may only develop irritation or grade I (superficial hyperemia and edema) burns of the oropharynx, esophagus or stomach; acute or chronic complications are unlikely. Patients with moderate toxicity may develop grade II burns (superficial blisters, erosions and ulcerations) and are at risk for subsequent stricture formation, particularly esophageal. Some patients (particularly young children) may develop upper airway edema.
    a) Alkaline corrosive ingestion may produce burns to the oropharynx, upper airway, esophagus and occasionally stomach. Spontaneous vomiting may occur. The absence of visible oral burns does NOT reliably exclude the presence of esophageal burns. The presence of stridor, vomiting, drooling, and abdominal pain are associated with serious esophageal injury in most cases.
    b) PREDICTIVE: The grade of mucosal injury at endoscopy is the strongest predictive factor for the occurrence of systemic and GI complications and mortality.
    3) SEVERE ORAL TOXICITY: May develop deep burns and necrosis of the gastrointestinal mucosa. Complications often include perforation (esophageal, gastric, rarely duodenal), fistula formation (tracheoesophageal, aortoesophageal), and gastrointestinal bleeding. Hypotension, tachycardia, tachypnea and, rarely, fever may develop. Stricture formation (esophageal, less often oral or gastric) is likely to develop long term. Esophageal carcinoma is another long term complication. Upper airway edema is common and often life threatening. Severe toxicity is generally limited to deliberate ingestions in adults in the US, because alkaline products available in the home are generally of low concentration.
    4) INHALATION EXPOSURE: Mild exposure may cause cough and bronchospasm. Severe inhalation may cause upper airway edema and burns, stridor, and rarely acute lung injury.
    5) OCULAR EXPOSURE: Ocular exposure can produce severe conjunctival irritation and chemosis, corneal epithelial defects, limbal ischemia, permanent visual loss and in severe cases perforation.
    6) DERMAL EXPOSURE: Mild exposure causes irritation and partial thickness burns. Prolonged exposure or high concentration products can cause full thickness burns.
    0.2.20) REPRODUCTIVE
    A) Studies on reproductive effects of chloropicrin in humans are not yet available.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no studies on the potential carcinogenic activity of chloropicrin in humans were found.

Laboratory Monitoring

    A) Obtain a complete blood count in symptomatic patients following chloropicrin exposure.
    B) In patients with signs and symptoms suggesting severe burns, perforation, or bleeding (or adults with deliberate, high volume or high concentration ingestions), obtain renal function tests, serum electrolytes, INR, PTT, type and crossmatch for blood, and monitor urine output. Serum lactate and base deficit may also be useful in these patients.
    C) Monitor pulse oximetry or arterial blood gases in patients with signs and symptoms suggestive of upper airway edema or burns.
    D) Obtain an upright chest x-ray in patients with signs and symptoms suggesting severe burns, perforation, or bleeding (or adults with deliberate, high volume or high concentration ingestions) to evaluate for pneumomediastinum or free air under the diaphragm. The absence of these findings DOES NOT rule out the possibility of necrosis or perforation of the esophagus or stomach. Obtain a chest radiograph in patients with pulmonary signs or symptoms.
    E) Several weeks after ingestion, barium contrast radiographs of the upper GI tract are useful in patients who sustained grade II or III burns, to evaluate for strictures.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) As there is little data on exposure to chloropicrin, the following treatment information is based on experience with other alkaline corrosive agents.
    B) MANAGEMENT OF MILD TO MODERATE ORAL TOXICITY
    1) Perform early (within 12 hours) endoscopy in patients with stridor, drooling, vomiting, significant oral burns, difficulty swallowing or abdominal pain, and in all patients with deliberate ingestion. If burns are absent or grade I severity, patient may be discharged when able to tolerate liquids and soft foods by mouth. If mild grade II burns, admit for intravenous fluids, slowly advance diet as tolerated. Perform barium swallow or repeat endoscopy several weeks after ingestion (sooner if difficulty swallowing) to evaluate for stricture formation.
    C) SEVERE ORAL TOXICITY
    1) Resuscitate with 0.9% saline; blood products may be necessary. Early airway management in patients with upper airway edema or respiratory distress. Early (within 12 hours) gastrointestinal endoscopy to evaluate for burns. Early bronchoscopy in patients with respiratory distress or upper airway edema. Early surgical consultation for patients with severe grade II or grade III burns, large deliberate ingestions, or signs, symptoms or laboratory findings concerning for tissue necrosis or perforation.
    D) DILUTION
    1) Dilute with 4 to 8 ounces of water may be useful if it can be performed shortly after ingestion in patients who are able to swallow, with no vomiting or respiratory distress; then the patient should be NPO until assessed for the need for endoscopy. Neutralization, activated charcoal, and gastric lavage are all contraindicated.
    E) AIRWAY MANAGEMENT
    1) Aggressive airway management in patients with deliberate ingestions or any indication of upper airway injury.
    F) ENDOSCOPY
    1) Should be performed as soon as possible (preferably within 12 hours, not more than 24 hours) in any patient with deliberate ingestion, adults with any signs or symptoms attributable to inadvertent ingestion, and in children with stridor, vomiting, or drooling after inadvertent ingestion. Endoscopy should also be considered in children with dysphagia or refusal to swallow, significant oral burns, or abdominal pain after unintentional ingestion. Children and adults who are asymptomatic after inadvertent ingestion do not require endoscopy. The grade of mucosal injury at endoscopy is the strongest predictive factor for the occurrence of systemic and GI complications and mortality. The absence of visible oral burns does NOT reliably exclude the presence of esophageal burns.
    G) CORTICOSTEROIDS
    1) The use of corticosteroids to prevent stricture formation is controversial. Corticosteroids should not be used in patients with grade I or grade III injury, as there is no evidence that it is effective. Evidence for grade II burns is conflicting, and the risk of perforation and infection is increased with steroid use.
    H) STRICTURE
    1) A barium swallow or repeat endoscopy should be performed several weeks after ingestion in any patient with grade II or III burns or with difficulty swallowing to evaluate for stricture formation. Recurrent dilation may be required. Some authors advocate early stent placement in these patients to prevent stricture formation.
    I) SURGICAL MANAGEMENT
    1) Immediate surgical consultation should be obtained on any patient with grade III or severe grade II burns on endoscopy, significant abdominal pain, metabolic acidosis, hypotension, coagulopathy, or a history of large ingestion. Early laparotomy can identify tissue necrosis and impending or unrecognized perforation, early resection and repair in these patients is associated with improved outcome.
    J) PATIENT DISPOSITION
    1) OBSERVATION CRITERIA: Patients with alkaline corrosive ingestion should be sent to a health care facility for evaluation. Patients who remain asymptomatic over 4 to 6 hours of observation, and those with endoscopic evaluation that demonstrates no burns or only minor grade I burns and who can tolerate oral intake can be discharged home.
    2) ADMISSION CRITERIA: Symptomatic patients, and those with endoscopically demonstrated grade II or higher burns should be admitted. Patients with respiratory distress, grade III burns, acidosis, hemodynamic instability, gastrointestinal bleeding, or large ingestions should be admitted to an intensive care setting.
    K) PITFALLS
    1) The absence of oral burns does NOT reliably exclude the possibility of significant esophageal burns.
    2) Patients may have severe tissue necrosis and impending perforation requiring early surgical intervention without having severe hypotension, rigid abdomen, or radiographic evidence of intraperitoneal air.
    3) Patients with any evidence of upper airway involvement require early airway management before airway edema progresses.
    4) The extent of eye injury (degree of corneal opacification and perilimbal whitening) may not be apparent for 48 to 72 hours after the burn. All patients with corrosive eye injury should be evaluated by an ophthalmologist.
    L) DIFFERENTIAL DIAGNOSIS
    1) Acid ingestion, gastrointestinal hemorrhage, or perforated viscus.
    0.4.3) INHALATION EXPOSURE
    A) DECONTAMINATION
    1) Administer oxygen as necessary. Monitor for respiratory distress.
    B) AIRWAY MANAGEMENT
    1) Manage airway aggressively in patients with significant respiratory distress, stridor or any evidence of upper airway edema. Monitor for hypoxia or respiratory distress.
    C) BRONCHOSPASM
    1) Treat with oxygen, inhaled beta agonists and consider systemic corticosteroids.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION
    1) Exposed eyes should be irrigated with copious amounts of 0.9% saline for at least 30 minutes, until pH is neutral and the cul de sacs are free of particulate material.
    2) An eye examination should always be performed, including slit lamp examination. Ophthalmologic consultation should be obtained. Antibiotics and mydriatics may be indicated.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION
    a) Remove contaminated clothes and any particulate matter adherent to skin. Irrigate exposed skin with copious amounts of water for at least 15 minutes or longer, depending on concentration, amount and duration of exposure to the chemical. A physician may need to examine the area if irritation or pain persist.

Range Of Toxicity

    A) Serious burns less likely if pH <11.5. Injury greater with either large ingestion (usually deliberate) or high concentration alkali. With highly concentrated liquids, esophageal burns may occur in up to 100% of patients, even after accidental ingestion.
    B) Inhalation of 1 ppm causes eye irritation and constitutes a good warning of exposure. An odor threshold of 1.1 ppm has been reported.
    C) Inhalation of 20 ppm for 1 to 2 minutes causes bronchial or pulmonary lesions.
    D) Inhalation of 2 mg/L (297.6 ppm) for 10 minutes has been fatal to humans.
    E) Inhalation of 0.8 mg/L (119 ppm) for 30 minutes has been fatal to humans.

Clinical Effects

Summary Of Exposure

    A) USES: Chloropicrin, classified by the military as a "choking agent", is a lacrimator and is intensely irritating to the skin and mucous membranes. It has been used in grenades and in protective personal devices. It has also been used as a soil disinfectant, insecticidal fumigant, and as a rodent exterminator for stored grain.
    B) PHARMACOLOGY: Chloropicrin may cause liquefaction necrosis. It can saponify the fats in the cell membrane, destroying the cell and allowing deep penetration into mucosal tissue. In gastrointestinal tissue, an initial inflammatory phase may be followed by tissue necrosis (sometimes resulting in perforation), then granulation and finally stricture formation.
    C) EPIDEMIOLOGY: Exposure has been rarely reported.
    D) WITH POISONING/EXPOSURE
    1) Limited data regarding specific human toxicity following chloropicrin exposure is available. The following effects could be expected to occur, based on exposure data of other alkaline corrosives.
    2) MILD TO MODERATE ORAL TOXICITY: Patients with mild ingestions may only develop irritation or grade I (superficial hyperemia and edema) burns of the oropharynx, esophagus or stomach; acute or chronic complications are unlikely. Patients with moderate toxicity may develop grade II burns (superficial blisters, erosions and ulcerations) and are at risk for subsequent stricture formation, particularly esophageal. Some patients (particularly young children) may develop upper airway edema.
    a) Alkaline corrosive ingestion may produce burns to the oropharynx, upper airway, esophagus and occasionally stomach. Spontaneous vomiting may occur. The absence of visible oral burns does NOT reliably exclude the presence of esophageal burns. The presence of stridor, vomiting, drooling, and abdominal pain are associated with serious esophageal injury in most cases.
    b) PREDICTIVE: The grade of mucosal injury at endoscopy is the strongest predictive factor for the occurrence of systemic and GI complications and mortality.
    3) SEVERE ORAL TOXICITY: May develop deep burns and necrosis of the gastrointestinal mucosa. Complications often include perforation (esophageal, gastric, rarely duodenal), fistula formation (tracheoesophageal, aortoesophageal), and gastrointestinal bleeding. Hypotension, tachycardia, tachypnea and, rarely, fever may develop. Stricture formation (esophageal, less often oral or gastric) is likely to develop long term. Esophageal carcinoma is another long term complication. Upper airway edema is common and often life threatening. Severe toxicity is generally limited to deliberate ingestions in adults in the US, because alkaline products available in the home are generally of low concentration.
    4) INHALATION EXPOSURE: Mild exposure may cause cough and bronchospasm. Severe inhalation may cause upper airway edema and burns, stridor, and rarely acute lung injury.
    5) OCULAR EXPOSURE: Ocular exposure can produce severe conjunctival irritation and chemosis, corneal epithelial defects, limbal ischemia, permanent visual loss and in severe cases perforation.
    6) DERMAL EXPOSURE: Mild exposure causes irritation and partial thickness burns. Prolonged exposure or high concentration products can cause full thickness burns.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH POISONING/EXPOSURE
    1) Fever is NOT seen following chloropicrin exposures (Goldman et al, 1987).

Heent

    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) Following aerosol exposures, lacrimation and conjunctiva irritation have been reported to occur with concentrations of 0.3 to 0.37 ppm in 3 to 30 seconds, depending on individual susceptibility (Davis, 1993; Lewis, 1996). Eye redness and irritation is common (Brewer & Amick, 1999; Goldman et al, 1987; Okada et al, 1970).
    2) Lacrimation and eye pain and burning were reported following an off-site drift of chloropicrin into a residential area (MMWR, 2004).
    3) Eye pain, conjunctival injection and corneal abrasions were reported in a 52-year-old tobacco farmer who unintentionally sprayed his face with a 99.7% solution of chloropicrin (Menkin et al, 2015).
    3.4.5) NOSE
    A) WITH POISONING/EXPOSURE
    1) Signs and symptoms following inhalation include nasal and pharyngeal mucosal edema, irritation and erythema, and a strong odor (Brewer & Amick, 1999) (MSDS, 1998) (HSDB , 1999; TeSlaa et al, 1986).
    2) In animal studies, inhalations appeared to cause ulcerations of the olfactory epithelium and necrosis of lung tissues (HSDB , 1999; TeSlaa et al, 1986).
    3.4.6) THROAT
    A) WITH POISONING/EXPOSURE
    1) Signs and symptoms following inhalation include dry or productive coughing (often extreme), nasal and pharyngeal mucosal edema and erythema, lacrimation, rhinorrhea and an unusual taste (Brewer & Amick, 1999) MSDS, 1998; (HSDB , 1999; Goldman et al, 1987; TeSlaa et al, 1986; Okada et al, 1970).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) ORTHOSTATIC HYPOTENSION
    1) WITH POISONING/EXPOSURE
    a) Orthostatic hypotension, described as significant in some cases, has been reported as an acute effect of chloropicrin aerosol exposure (Goldman et al, 1987; Okada et al, 1970).
    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) VASODILATATION
    a) Results of chronic toxicity studies in rats showed congestion and dilatation of capillary vessels, increased Aschoff-like cells, and degeneration of myocardial fibers (Okada et al, 1970).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) ACUTE LUNG INJURY
    1) WITH POISONING/EXPOSURE
    a) Chloropicrin is a non-water soluble corrosive which produces more injury to medium and small bronchi (causing bronchitis) than the trachea and large bronchi when inhaled or aspirated. Pulmonary edema occurs in severe cases and is the most frequent cause of early deaths (Davis, 1993). It is a strong irritant causing intense irritation of the respiratory tract (TeSlaa et al, 1986; Okada et al, 1970). Fatal pulmonary edema was reported 3 hours after exposure to chloropicrin (Gonmori et al, 1987).
    b) CASE REPORT: An 18-year-old girl died due to pulmonary edema, approximately 4 hours postexposure to a direct spraying of a soil fumigant containing chloropicrin. The dose of chloropicrin was difficult to determine, but the postmortem lung concentration was measured as 1.6 ng/g of wet lung (Gonmori et al, 1987).
    B) PNEUMONITIS
    1) WITH POISONING/EXPOSURE
    a) Secondary infections, bronchopneumonia, or bronchiolitis obliterans have been reported to cause later sickness or deaths following chloropicrin inhalation or aspiration (Davis, 1993; TeSlaa et al, 1986).
    C) RESPIRATORY CONDITION DUE TO CHEMICAL FUMES AND/OR VAPORS
    1) WITH POISONING/EXPOSURE
    a) Cough, dyspnea, upper respiratory irritation, chest pain, and exacerbation of asthma have been reported following off-site drift of chloropicrin into a residential area (MMWR, 2004).
    D) ADULT RESPIRATORY DISTRESS SYNDROME
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 52-year-old tobacco farmer reported eye pain, chest tightness, and dyspnea approximately 3 hours after unintentionally spraying his face with a 99.7% solution of chloropicrin. His respiratory rate was 23/minute and his oxygen saturation was 89% on room air, which improved to 98% with 2 liters of oxygen via nasal cannula. A chest CT scan revealed ground glass and solid airspace consolidations. Treatment included erythromycin eye ointment, nebulized bronchodilators, methylprednisolone, and N-acetylcysteine. He developed hypoxia, requiring intubation, and his chest X-ray showed interstitial edema, all of which was consistent with acute respiratory distress syndrome (ARDS). Venovenous extracorporeal membrane oxygenation (ECMO) was started on hospital day 2, resulting in sustained improvement in oxygenation. ECMO was stopped on hospital day 6 and the patient was extubated 2 days later (Menkin et al, 2015).
    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) PNEUMONITIS
    a) A dog exposed to chloropicrin developed lacrimation, dyspnea and repeated coughing, which was diagnosed as a chemically-induced bronchitis and pneumonia. The dog recovered following therapy with antibiotics and steroids (TeSlaa et al, 1986).
    b) Okada et al (1970) reported in chloropicrin rat toxicity studies pulmonary congestion, pulmonary edema, pulmonary hemorrhage and pneumonia (Okada et al, 1970a).
    2) RESPIRATORY DISORDER
    a) Serious exudation, exfoliation, erosion, ulceration and necrosis of the respiratory epithelium has been reported in animal toxicity studies (TeSlaa et al, 1986; Okada et al, 1970).
    3) BRONCHITIS
    a) RESPIRATORY TRACT INJURY: Experimental animal studies have shown that lower respiratory tract injury (fibrosing peribronchitis and peribronchiolitis) can be produced by chloropicrin (Buckley et al, 1984).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DIZZINESS
    1) WITH POISONING/EXPOSURE
    a) Following aerosol exposures, autonomic nervous system symptoms of dizziness, weakness and lethargy have been reported (Brewer & Amick, 1999; Prudhomme et al, 1999; Goldman et al, 1987; Okada et al, 1970; MMWR, 2004).
    B) HEADACHE
    1) WITH POISONING/EXPOSURE
    a) Headache and anxiety are consistent with chloropicrin exposures (Brewer & Amick, 1999; Goldman et al, 1987; Okada et al, 1970; MMWR, 2004).
    C) SYNCOPE
    1) WITH POISONING/EXPOSURE
    a) Syncope has been reported, probably secondary to orthostatic hypotension (Goldman et al, 1987; Okada et al, 1970).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH POISONING/EXPOSURE
    a) Nausea, vomiting and loss of appetite are common effects following ingestions and inhalations (probably due to swallowing saliva in which small amounts of chloropicrin have dissolved) (Lewis, 1996; Davis, 1993; Goldman et al, 1987; Okada et al, 1970). Nausea, vomiting, coughing, colic, and diarrhea have been reported following ingestions due to its toxic effect on the gastrointestinal tract. In the military, chloropicrin has been referred to as vomiting gas or war gas.
    b) Nausea, vomiting, abdominal pain, diarrhea, and hematochezia were reported following an offsite drift of chloropicrin into a residential area (MMWR, 2004).
    3.8.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) CHEMICAL BURNS
    a) RATS - Oral toxicity was studied in rats, with major histological changes seen in the stomach. Forestomach inflammation, necrosis, acantholysis, hyperkeratosis, and ulceration were all reported at histological examination, and severity appeared to be dose related (Condie et al, 1994). The primary target organ for oral toxicity appears to be the stomach, with corrosive actions on the forestomach tissue.

Hepatic

    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEPATOCELLULAR DAMAGE
    a) Okada et al (1970) reported on chronic chloropicrin toxicity in rats. Dilatation of sinusoids was reported. The degree of turbid centrilobular swelling of hepatic cells increased in the chronic phase of the study.

Genitourinary

    3.10.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) RENAL TUBULAR NECROSIS
    a) Okada et al (1970) reported a chronic chloropicrin toxicity study in rats. On day 7, one rat exhibited remarkable capillary vessel dilatation, turbid swelling of the main tubules and epithelial necrosis and breakdown. Other rats displayed similar renal toxicities.

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) METHEMOGLOBINEMIA
    1) WITH POISONING/EXPOSURE
    a) Chloropicrin reacts with SH-groups in hemoglobin, thus interfering with oxygen transport, which may theoretically cause mild to moderate methemoglobinemia in severe, acute exposures (Lewis, 1996). This has not yet been reported in human cases.

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) SKIN IRRITATION
    1) WITH POISONING/EXPOSURE
    a) Short term dermal exposure to aerosol or liquid has resulted in skin irritation, sometimes severe, as well as a bluish skin color, or cyanosis (MSDS, 1998).
    B) ERUPTION
    1) WITH POISONING/EXPOSURE
    a) Rash and pruritus were reported following an off-site drift of chloropicrin into a residential area (MMWR, 2004).
    C) CYANOSIS
    1) WITH POISONING/EXPOSURE
    a) Inhalation or dermal contact of aerosols may result in cyanosis with a bluish skin discoloration (MSDS, 1998; (HSDB , 1999; Gonmori et al, 1987). The main postmortem findings in a homicidal case of chloropicrin spraying was reported to be spotty dark purple discoloration of the skin and severe pulmonary edema (Gonmori et al, 1987).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) RHABDOMYOLYSIS
    1) WITH POISONING/EXPOSURE
    a) Three cases of increased levels of creatine phosphokinase, suggesting possible low-grade rhabdomyolysis, and persistent chest wall pain have been documented following chloropicrin vapor exposure in an agricultural chemicals facility. The 3 workers presented approximately 6 weeks after accidental exposure, with duration of exposure ranging from more than 1 minute in case 1, to under 15 seconds in case 3. Myoglobinuria was not found. Effects appeared to follow a dose-response relationship.
    1) Case 1, the most severe, developed burning in the chest and skeletal muscle cramping associated with increased levels of the MM subfraction of creatine phosphokinase (CK-MM). Symptoms persisted as pleuritic chest pain, chest wall pain, and generalized myalgia (Prudhomme et al, 1999).
    3.15.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) MUSCLE NECROSIS
    a) In a chronic chloropicrin rat study, necrosis of muscle fibers with infiltration of histiocytes was reported, but was mild throughout the entire study (Okada et al, 1970).

Reproductive

    3.20.1) SUMMARY
    A) Studies on reproductive effects of chloropicrin in humans are not yet available.
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) Studies on lactation effects of chloropicrin are not yet available.

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS76-06-2 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no studies on the potential carcinogenic activity of chloropicrin in humans were found.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, no studies on the potential carcinogenic activity of chloropicrin in humans were found.
    3.21.4) ANIMAL STUDIES
    A) NEOPLASM
    1) MOUSE - In mouse studies, a TDLo (oral route) of 400 mg/kg/10 days, intermittent, produced gastrointestinal tumors, and is considered an equivocal tumorigenic agent (RTECS , 1999).
    2) RATS AND MICE - Chloropicrin was not carcinogenic in rats and mice when administered by the oral route in corn oil at 22 and 26 mg/kg/day in females and males, respectively, on an irregular dosing schedule. This rat assay could not be fully evaluated, however, because of early deaths (Anon, 1978).

Genotoxicity

    A) Chloropicrin has been reported to be mutagenic in the Ames test and produced sister chromatid exchanges, but not chromosomal aberrations in in-vitro human lymphocytes. It did not induce mutations in the Drosophila sex-linked recessive lethal test.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Obtain a complete blood count in symptomatic patients following chloropicrin exposure.
    B) In patients with signs and symptoms suggesting severe burns, perforation, or bleeding (or adults with deliberate, high volume or high concentration ingestions), obtain renal function tests, serum electrolytes, INR, PTT, type and crossmatch for blood, and monitor urine output. Serum lactate and base deficit may also be useful in these patients.
    C) Monitor pulse oximetry or arterial blood gases in patients with signs and symptoms suggestive of upper airway edema or burns.
    D) Obtain an upright chest x-ray in patients with signs and symptoms suggesting severe burns, perforation, or bleeding (or adults with deliberate, high volume or high concentration ingestions) to evaluate for pneumomediastinum or free air under the diaphragm. The absence of these findings DOES NOT rule out the possibility of necrosis or perforation of the esophagus or stomach. Obtain a chest radiograph in patients with pulmonary signs or symptoms.
    E) Several weeks after ingestion, barium contrast radiographs of the upper GI tract are useful in patients who sustained grade II or III burns, to evaluate for strictures.
    4.1.2) SERUM/BLOOD
    A) HEMATOLOGIC
    1) Obtain a complete blood count in patients with symptomatic chloropicrin exposure.
    B) COAGULATION STUDIES
    1) In patients with signs and symptoms suggesting severe burns, perforation, or bleeding, obtain renal function tests, PT or INR, PTT, and type and crossmatch for blood.
    4.1.3) URINE
    A) OTHER
    1) Monitor urine output in patients with significant gastrointestinal burns, perforation, or bleeding.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Monitor pulse oximetry or arterial blood gases in patients with signs and symptoms suggestive of upper airway burns.

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) Obtain an upright chest x-ray in patients with significant signs and symptoms to evaluate for pneumomediastinum or free air under the diaphragm.
    2) The absence of these findings does not rule out the possibility of necrosis or perforation of the esophagus or stomach (Davis et al, 1972; Allen et al, 1970).
    3) Obtain a chest x-ray in patients with significant pulmonary signs or symptoms
    4) A water-soluble contrast material should be used initially to exclude esophageal perforation in patients with GI burns associated with alkaline ingestions, as water soluble contrast causes less injury than barium if it extravasates into tissue (Kirsh & Ritter, 1976; Chen et al, 1988).
    5) Barium esophagogram performed once perforation has been excluded may be useful to evaluate extent of injury or presence of strictures (Leape et al, 1971; Lowe et al, 1979; Chen et al, 1988).

Methods

    A) CHROMATOGRAPHY
    1) Gonmori et al (1987) reported a gas-liquid chromatography (GC) method for the quantitative determination of chloropicrin in the lungs (Gonmori et al, 1987).
    2) Shuali & Aharoni (1974) developed a highly sensitive method based on gas chromatography with electron capture detection to test filters used in chloropicrin exposures (Shuali & Aharoni, 1974).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Symptomatic patients, and those with endoscopically demonstrated grade II or higher burns should be admitted. Patients with respiratory distress, grade III burns, acidosis, hemodynamic instability, gastrointestinal bleeding, or large ingestions should be admitted to an intensive care setting.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with alkaline corrosive ingestion should be sent to a health care facility for evaluation. Patients who remain asymptomatic over 4 to 6 hours of observation, and those with endoscopic evaluation that demonstrates no burns or only minor grade I burns and who can tolerate oral intake can be discharged home.
    6.3.3) DISPOSITION/INHALATION EXPOSURE
    6.3.3.1) ADMISSION CRITERIA/INHALATION
    A) Patients with severe respiratory distress, those with hypoxia, evidence of pulmonary edema, hemodynamic instability or severe burns should be admitted.
    6.3.3.5) OBSERVATION CRITERIA/INHALATION
    A) Patients who experience only minor sensations of burning on the mucous membranes of the nose, throat, eyes and respiratory tract (with perhaps a slight cough) require no treatment beyond removal from chloropicrin atmosphere. In most instances, these patients will be free of symptoms within an hour or less.
    B) Patients experiencing more severe symptoms (tightness in the chest, dyspnea, distressing cough, anxiety, etc) must be treated accordingly with oxygen and other supportive measures.

Monitoring

    A) Obtain a complete blood count in symptomatic patients following chloropicrin exposure.
    B) In patients with signs and symptoms suggesting severe burns, perforation, or bleeding (or adults with deliberate, high volume or high concentration ingestions), obtain renal function tests, serum electrolytes, INR, PTT, type and crossmatch for blood, and monitor urine output. Serum lactate and base deficit may also be useful in these patients.
    C) Monitor pulse oximetry or arterial blood gases in patients with signs and symptoms suggestive of upper airway edema or burns.
    D) Obtain an upright chest x-ray in patients with signs and symptoms suggesting severe burns, perforation, or bleeding (or adults with deliberate, high volume or high concentration ingestions) to evaluate for pneumomediastinum or free air under the diaphragm. The absence of these findings DOES NOT rule out the possibility of necrosis or perforation of the esophagus or stomach. Obtain a chest radiograph in patients with pulmonary signs or symptoms.
    E) Several weeks after ingestion, barium contrast radiographs of the upper GI tract are useful in patients who sustained grade II or III burns, to evaluate for strictures.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Severe gastrointestinal tract irritation or burns may occur. The role of gastrointestinal decontamination is unclear.
    B) DILUTION
    1) If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. The exact 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) USE OF DILUENTS IS CONTROVERSIAL: While experimental models have suggested that immediate dilution may lessen caustic injury (Homan et al, 1993; Homan et al, 1994; Homan et al, 1995), this has not been adequately studied in humans.
    3) DILUENT TYPE: Use any readily available nontoxic, cool liquid. Both milk and water have been shown to be effective in experimental studies of caustic ingestion (Maull et al, 1985; Rumack & Burrington, 1977; Homan et al, 1995; Homan et al, 1994; Homan et al, 1993).
    4) ADVERSE EFFECTS: Potential adverse effects include vomiting and airway compromise (Caravati, 2004).
    5) CONTRAINDICATIONS: Do NOT attempt dilution in patients with respiratory distress, altered mental status, severe abdominal pain, nausea or vomiting, or patients who are unable to swallow or protect their airway. Diluents should not be force fed to any patient who refuses to swallow (Rao & Hoffman, 2002).
    C) ACTIVATED CHARCOAL/NOT RECOMMENDED
    1) Charcoal administration may worsen injury by causing vomiting and may interfere with the ability to visualize burns at endoscopy. The use of activated charcoal is generally not recommended.
    6.5.2) PREVENTION OF ABSORPTION
    A) DILUTION
    1) If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. The exact 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) USE OF DILUENTS IS CONTROVERSIAL: While experimental models have suggested that immediate dilution may lessen caustic injury (Homan et al, 1993; Homan et al, 1994; Homan et al, 1995), this has not been adequately studied in humans.
    3) DILUENT TYPE: Use any readily available nontoxic, cool liquid. Both milk and water have been shown to be effective in experimental studies of caustic ingestion (Maull et al, 1985; Rumack & Burrington, 1977; Homan et al, 1995; Homan et al, 1994; Homan et al, 1993).
    4) ADVERSE EFFECTS: Potential adverse effects include vomiting and airway compromise (Caravati, 2004).
    5) CONTRAINDICATIONS: Do NOT attempt dilution in patients with respiratory distress, altered mental status, severe abdominal pain, nausea or vomiting, or patients who are unable to swallow or protect their airway. Diluents should not be force fed to any patient who refuses to swallow (Rao & Hoffman, 2002).
    B) GASTRIC EMPTYING
    1) Should be avoided to prevent re-exposure of the esophagus to the corrosive properties of chloropicrin.
    C) NASOGASTRIC SUCTION
    1) Some clinicians may choose to insert a small, flexible nasogastric tube through the mouth, if the patient is alert and cooperative, in an attempt to remove the chloropicrin following a recent ingestion.
    2) The decision should be based on the amount of the ingestion, the concentration of chloropicrin, and the risk and potential benefit to the patient. In suicidal ingestions involving large quantities of material and an increased likelihood of severe mucosal burns, the risk of causing perforation may outweigh the potential benefit of removing this corrosive material.
    D) ACTIVATED CHARCOAL
    1) Since the hazard of chloropicrin ingestion stems primarily from local tissue injury and not from systemic absorption of toxicant, activated charcoal is not likely to be of benefit. Charcoal administration may worsen injury by causing vomiting and may interfere with the ability to visualize burns at endoscopy.
    6.5.3) TREATMENT
    A) DILUTION
    1) Do not exceed 8 ounces in adults and 4 ounces in children, as vomiting may occur with excessive fluid. Contraindications include perforations and patients at risk of vomiting. Keep patient NPO following initial dilution until after medical/surgical evaluation.
    B) ENDOSCOPIC PROCEDURE
    1) SUMMARY: Obtain consultation concerning endoscopy as soon as possible, and perform endoscopy within the first 24 hours when indicated.
    2) INDICATIONS: Endoscopy should be performed in adults with a history of deliberate ingestion, adults with any signs or symptoms attributable to inadvertent ingestion, and in children with stridor, vomiting, or drooling after unintentional ingestion (Crain et al, 1984). Endoscopy should also be performed in children with dysphagia or refusal to swallow, significant oral burns, or abdominal pain after unintentional ingestion (Gaudreault et al, 1983; Nuutinen et al, 1994). Children and adults who are asymptomatic after accidental ingestion do not require endoscopy (Gupta et al, 2001; Lamireau et al, 2001; Gorman et al, 1992).
    3) RISKS: Numerous large case series attest to the relative safety and utility of early endoscopy in the management of caustic ingestion.
    a) REFERENCES: (Dogan et al, 2006; Symbas et al, 1983; Crain et al, 1984a; Gaudreault et al, 1983a; Schild, 1985; Moazam et al, 1987; Sugawa & Lucas, 1989; Previtera et al, 1990; Zargar et al, 1991; Vergauwen et al, 1991; Gorman et al, 1992)
    4) The risk of perforation during endoscopy is minimized by (Zargar et al, 1991):
    a) Advancing across the cricopharynx under direct vision
    b) Gently advancing with minimal air insufflation
    c) Never retroverting or retroflexing the endoscope
    d) Using a pediatric flexible endoscope
    e) Using extreme caution in advancing beyond burn lesion areas
    f) Most authors recommend endoscopy within the first 24 hours of injury, not advancing the endoscope beyond areas of severe esophageal burns, and avoiding endoscopy during the subacute phase of healing when tissue slough increases the risk of perforation (5 to 15 days after ingestion) (Zargar et al, 1991).
    5) GRADING
    a) Several scales for grading caustic injury exist. The likelihood of complications such as strictures, obstruction, bleeding, and perforation is related to the severity of the initial burn (Zargar et al, 1991):
    b) Grade 0 - Normal examination
    c) Grade 1 - Edema and hyperemia of the mucosa; strictures unlikely.
    d) Grade 2A - Friability, hemorrhages, erosions, blisters, whitish membranes, exudates and superficial ulcerations; strictures unlikely.
    e) Grade 2B - Grade 2A plus deep discreet or circumferential ulceration; strictures may develop.
    f) Grade 3A - Multiple ulcerations and small scattered areas of necrosis; strictures are common, complications such as perforation, fistula formation or gastrointestinal bleeding may occur.
    g) Grade 3B - Extensive necrosis through visceral wall; strictures are common, complications such as perforation, fistula formation, or gastrointestinal bleeding are more likely than with 3A.
    6) FOLLOW UP - If burns are found, follow 10 to 20 days later with barium swallow or esophagram.
    7) SCINTIGRAPHY - Scans utilizing radioisotope labelled sucralfate (technetium 99m) were performed in 22 patients with caustic ingestion and compared with endoscopy for the detection of esophageal burns. Two patients had minimal residual isotope activity on scanning but normal endoscopy and two patients had normal activity on scan but very mild erythema on endoscopy. Overall the radiolabeled sucralfate scan had a sensitivity of 100%, specificity of 81%, positive predictive value of 84% and negative predictive value of 100% for detecting clinically significant burns in this population (Millar et al, 2001). This may represent an alternative to endoscopy, particularly in young children, as no sedation is required for this procedure. Further study is required.
    8) MINIPROBE ULTRASONOGRAPHY - was performed in 11 patients with corrosive ingestion . Findings were categorized as grade 0 (distinct muscular layers without thickening, grade I (distinct muscular layers with thickening), grade II (obscured muscular layers with indistinct margins) and grade III (muscular layers that could not be differentiated). Findings were further categorized as to whether the worst appearing image involved part of the circumference (type a) or the whole circumference (type b). Strictures did not develop in patients with grade 0 (5 patients) or grade I (4 patients) lesions. Transient stricture formation developed in the only patient with grade IIa lesions, and stricture requiring repeated dilatation developed in the only patient with grade IIIb lesions (Kamijo et al, 2004).
    C) CORTICOSTEROID
    1) CORROSIVE INGESTION/SUMMARY: The use of corticosteroids for the treatment of caustic ingestion is controversial. Most animal studies have involved alkali-induced injury (Haller & Bachman, 1964; Saedi et al, 1973). Most human studies have been retrospective and generally involve more alkali than acid-induced injury and small numbers of patients with documented second or third degree mucosal injury.
    2) FIRST DEGREE BURNS: These burns generally heal well and rarely result in stricture formation (Zargar et al, 1989; Howell et al, 1992). Corticosteroids are generally not beneficial in these patients (Howell et al, 1992).
    3) SECOND DEGREE BURNS: Some authors recommend corticosteroid treatment to prevent stricture formation in patients with a second degree, deep-partial thickness burn (Howell et al, 1992). However, no well controlled human study has documented efficacy. Corticosteroids are generally not beneficial in patients with a second degree, superficial-partial thickness burn (Caravati, 2004; Howell et al, 1992).
    4) THIRD DEGREE BURNS: Some authors have recommended steroids in this group as well (Howell et al, 1992). A high percentage of patients with third degree burns go on to develop strictures with or without corticosteroid therapy and the risk of infection and perforation may be increased by corticosteroid use. Most authors feel that the risk outweighs any potential benefit and routine use is not recommended (Boukthir et al, 2004; Oakes et al, 1982; Pelclova & Navratil, 2005).
    5) CONTRAINDICATIONS: Include active gastrointestinal bleeding and evidence of gastric or esophageal perforation. Corticosteroids are thought to be ineffective if initiated more than 48 hours after a burn (Howell, 1987).
    6) DOSE: Administer daily oral doses of 0.1 milligram/kilogram of dexamethasone or 1 to 2 milligrams/kilogram of prednisone. Continue therapy for a total of 3 weeks and then taper (Haller et al, 1971; Marshall, 1979). An alternative regimen in children is intravenous prednisolone 2 milligrams/kilogram/day followed by 2.5 milligrams/kilogram/day of oral prednisone for a total of 3 weeks then tapered (Anderson et al, 1990).
    7) ANTIBIOTICS: Animal studies suggest that the addition of antibiotics can prevent the infectious complications associated with corticosteroid use in the setting of caustic burns. Antibiotics are recommended if corticosteroids are used or if perforation or infection is suspected. Agents that cover anaerobes and oral flora such as penicillin, ampicillin, or clindamycin are appropriate (Rosenberg et al, 1953).
    8) STUDIES
    a) ANIMAL
    1) Some animal studies have suggested that corticosteroid therapy may reduce the incidence of stricture formation after severe alkaline corrosive injury (Haller & Bachman, 1964; Saedi et al, 1973a).
    2) Animals treated with steroids and antibiotics appear to do better than animals treated with steroids alone (Haller & Bachman, 1964).
    3) Other studies have shown no evidence of reduced stricture formation in steroid treated animals (Reyes et al, 1974). An increased rate of esophageal perforation related to steroid treatment has been found in animal studies (Knox et al, 1967).
    b) HUMAN
    1) Most human studies have been retrospective and/or uncontrolled and generally involve small numbers of patients with documented second or third degree mucosal injury. No study has proven a reduced incidence of stricture formation from steroid use in human caustic ingestions (Haller et al, 1971; Hawkins et al, 1980; Yarington & Heatly, 1963; Adam & Brick, 1982).
    2) META ANALYSIS
    a) Howell et al (1992), analyzed reports concerning 361 patients with corrosive esophageal injury published in the English language literature since 1956 (10 retrospective and 3 prospective studies). No patients with first degree burns developed strictures. Of 228 patients with second or third degree burns treated with corticosteroids and antibiotics, 54 (24%) developed strictures. Of 25 patients with similar burn severity treated without steroids or antibiotics, 13 (52%) developed strictures (Howell et al, 1992).
    b) Another meta-analysis of 10 studies found that in patients with second degree esophageal burns from caustics, the overall rate of stricture formation was 14.8% in patients who received corticosteroids compared with 36% in patients who did not receive corticosteroids (LoVecchio et al, 1996).
    c) Another study combined results of 10 papers evaluating therapy for corrosive esophageal injury in humans published between January 1991 and June 2004. There were a total of 572 patients, all patients received corticosteroids in 6 studies, in 2 studies no patients received steroids, and in 2 studies, treatment with and without corticosteroids was compared. Of 109 patients with grade 2 esophageal burns who were treated with corticosteroids, 15 (13.8%) developed strictures, compared with 2 of 32 (6.3%) patients with second degree burns who did not receive steroids (Pelclova & Navratil, 2005).
    3) Smaller studies have questioned the value of steroids (Ferguson et al, 1989; Anderson et al, 1990), thus they should be used with caution.
    4) Ferguson et al (1989) retrospectively compared 10 patients who did not receive antibiotics or steroids with 31 patients who received both antibiotics and steroids in a study of caustic ingestion and found no difference in the incidence of esophageal stricture between the two groups (Ferguson et al, 1989).
    5) A randomized, controlled, prospective clinical trial involving 60 children with lye or acid induced esophageal injury did not find an effect of corticosteroids on the incidence of stricture formation (Anderson et al, 1990).
    a) These 60 children were among 131 patients who were managed and followed-up for ingestion of caustic material from 1971 through 1988; 88% of them were between 1 and 3 years old (Anderson et al, 1990).
    b) All patients underwent rigid esophagoscopy after being randomized to receive either no steroids or a course consisting initially of intravenous prednisolone (2 milligrams/kilogram per day) followed by 2.5 milligrams/kilogram/day of oral prednisone for a total of 3 weeks prior to tapering and discontinuation (Anderson et al, 1990).
    c) Six (19%), 15 (48%), and 10 (32%) of those in the treatment group had first, second and third degree esophageal burns, respectively. In contrast, 13 (45%), 5 (17%), and 11 (38%) of the control group had the same levels of injury (Anderson et al, 1990).
    d) Ten (32%) of those receiving steroids and 11 (38%) of the control group developed strictures. Four (13%) of those receiving steroids and 7 (24%) of the control group required esophageal replacement. All but 1 of the 21 children who developed strictures had severe circumferential burns on initial esophagoscopy (Anderson et al, 1990).
    e) Because of the small numbers of patients in this study, it lacked the power to reliably detect meaningful differences in outcome between the treatment groups (Anderson et al, 1990).
    6) ADVERSE EFFECTS
    a) The use of corticosteroids in the treatment of caustic ingestion in humans has been associated with gastric perforation (Cleveland et al, 1963) and fatal pulmonary embolism (Aceto et al, 1970).
    D) SURGICAL PROCEDURE
    1) SUMMARY: Initially if severe esophageal burns are found a string may be placed in the stomach to facilitate later dilation. Insertion of a specialized nasogastric tube after confirmation of a circumferential burn may prevent strictures. Dilation is indicated after 2 to 4 weeks if strictures are confirmed. If dilation is unsuccessful colonic intraposition or gastric tube placement may be needed. Early laparotomy should be considered in patients with evidence of severe esophageal or gastric burns on endoscopy.
    2) STRING - If a second degree or circumferential burn of the esophagus is found a string may be placed in the stomach to avoid false channel and to provide a guide for later dilation procedures (Gandhi et al, 1989).
    3) STENT - The insertion of a specialized nasogastric tube or stent immediately after endoscopically proven deep circumferential burns is preferred by some surgeons to prevent stricture formation (Mills et al, 1978; (Wijburg et al, 1985; Coln & Chang, 1986).
    a) STUDY - In a study of 11 children with deep circumferential esophageal burns after caustic ingestion, insertion of a silicone rubber nasogastric tube for 5 to 6 weeks without steroids or antibiotics was associated with stricture formation in only one case (Wijburg et al, 1989).
    4) DILATION - Dilation should be performed at 1 to 4 week intervals when stricture is present(Gundogdu et al, 1992). Repeated dilation may be required over many months to years in some patients. Successful dilation of gastric antral strictures has also been reported (Hogan & Polter, 1986; Treem et al, 1987).
    5) COLONIC REPLACEMENT - Intraposition of colon may be necessary if dilation fails to provide an adequate sized esophagus (Chiene et al, 1974; Little et al, 1988; Huy & Celerier, 1988).
    6) LAPAROTOMY/LAPAROSCOPY - Several authors advocate laparotomy or laparoscopy in patients with endoscopic evidence of severe esophageal or gastric burns to evaluate for the presence of transmural gastric or esophageal necrosis (Cattan et al, 2000; Estrera et al, 1986; Meredith et al, 1988; Wu & Lai, 1993).
    a) STUDY - In a retrospective study of patients with extensive transmural esophageal necrosis after caustic ingestion, all 4 patients treated in the conventional manner (esophagoscopy, steroids, antibiotics, and repeated evaluation for the occurrence of esophagogastric necrosis and perforation) died while all 3 patients treated with early laparotomy and immediate esophagogastric resection survived (Estrera et al, 1986).
    E) 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).
    F) GENERAL TREATMENT
    1) Treatment should include recommendations listed in the INHALATION EXPOSURE section when appropriate.

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) SUMMARY: Remove the patient from the contaminated environment as rapidly as possible. Make sure that rescuers are wearing self-contained breathing apparatus and have protective clothing. No specific antidotes are available.
    B) DECONTAMINATION: Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis.
    C) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    D) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen with assisted ventilation as required. Exposed skin and eyes should be copiously flushed with water.
    E) CLOTHING: If clothing is contaminated with chloropicrin, remove and wash skin with copious amounts of water.
    6.7.2) TREATMENT
    A) OXYGEN
    1) Initially, administer 100 percent humidified oxygen for as long as needed to assure adequate oxygenation, then adjust oxygen concentration to the comfort of the patient.
    B) BRONCHOSPASM
    1) BRONCHOSPASM SUMMARY
    a) Administer beta2 adrenergic agonists. Consider use of inhaled ipratropium and systemic corticosteroids. Monitor peak expiratory flow rate, monitor for hypoxia and respiratory failure, and administer oxygen as necessary.
    2) ALBUTEROL/ADULT DOSE
    a) 2.5 to 5 milligrams diluted with 4 milliliters of 0.9% saline by nebulizer every 20 minutes for three doses. If incomplete response, administer 2.5 to 10 milligrams every 1 to 4 hours as needed OR administer 10 to 15 milligrams every hour by continuous nebulizer as needed. Consider adding ipratropium to the nebulized albuterol; DOSE: 0.5 milligram by nebulizer every 30 minutes for three doses then every 2 to 4 hours as needed, NOT administered as a single agent (National Heart,Lung,and Blood Institute, 2007).
    3) ALBUTEROL/PEDIATRIC DOSE
    a) 0.15 milligram/kilogram (minimum 2.5 milligrams) diluted with 4 milliliters of 0.9% saline by nebulizer every 20 minutes for three doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulizer as needed. Consider adding ipratropium to the nebulized albuterol; DOSE: 0.25 to 0.5 milligram by nebulizer every 20 minutes for three doses then every 2 to 4 hours as needed, NOT administered as a single agent (National Heart,Lung,and Blood Institute, 2007).
    4) ALBUTEROL/CAUTIONS
    a) The incidence of adverse effects of beta2-agonists may be increased in older patients, particularly those with pre-existing ischemic heart disease (National Asthma Education and Prevention Program, 2007). Monitor for tachycardia, tremors.
    5) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm. PREDNISONE: ADULT: 40 to 80 milligrams/day in 1 or 2 divided doses. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 or 2 divided doses (National Heart,Lung,and Blood Institute, 2007).
    C) MONITORING OF PATIENT
    1) Monitor respiratory function for several hours to assure that pulmonary edema does not develop. Respiratory findings may be delayed up to a few hours.
    2) Respiratory failure which requires mechanical ventilation indicates a poorer prognosis.
    3) Respiratory monitoring is recommended until the patient is symptom-free. Patients with pre-existing pulmonary disease, such as asthma, should be observed for possible exacerbation.
    D) IRRITATION SYMPTOM
    1) Respiratory tract irritation, if severe, can progress to noncardiogenic pulmonary edema which may be delayed in onset up to 24 to 72 hours after exposure in some cases.
    2) There are no controlled studies indicating that early administration of corticosteroids can prevent the development of noncardiogenic pulmonary edema in patients with inhalation exposure to respiratory irritant substances, and long-term use may cause adverse effects (Boysen & Modell, 1989).
    a) However, based on anecdotal experience, some clinicians do recommend early administration of corticosteroids (such as methylprednisolone 1 gram intravenously as a single dose) in an attempt to prevent the later development of pulmonary edema.
    1) Anecdotal experience with dimethyl sulfate inhalation showed possible benefit of methylprednisolone in the TREATMENT of noncardiogenic pulmonary edema (Ip et al, 1989).
    3) Anecdotal experience also indicated that systemic corticosteroids may have possible efficacy in the TREATMENT of drug-induced noncardiogenic pulmonary edema (Zitnik & Cooper, 1990; Stentoft, 1990; Chudnofsky & Otten, 1989) or noncardiogenic pulmonary edema developing after cardiopulmonary bypass (Maggart & Stewart, 1987).
    4) It is not clear from the published literature that administration of systemic corticosteroids early following inhalation exposure to respiratory irritant substances can PREVENT the development of noncardiogenic pulmonary edema. The decision to administer or withhold corticosteroids in this setting must currently be made on clinical grounds.
    E) 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).
    F) BURN OF SKIN OF BODY REGION
    1) Examination of mucous membranes, eyes and skin should be performed to be sure that corrosive effects have not occurred.
    G) VENTRICULAR ARRHYTHMIA
    1) Except for severe cases, dysrhythmias are rare. Antiarrhythmics should be considered, however, if cardiac monitoring exposes a serious dysrhythmia.
    H) EXTRACORPOREAL MEMBRANE OXYGENATION
    1) CASE REPORT: A 52-year-old tobacco farmer reported eye pain, chest tightness, and dyspnea approximately 3 hours after unintentionally spraying his face with a 99.7% solution of chloropicrin. His respiratory rate was 23/minute and his oxygen saturation was 89% on room air, which improved to 98% with 2 liters of oxygen via nasal cannula. A chest CT scan revealed ground glass and solid airspace consolidations. Treatment included erythromycin eye ointment, nebulized bronchodilators, methylprednisolone, and N-acetylcysteine. He developed hypoxia, requiring intubation, and his chest X-ray showed interstitial edema, all of which was consistent with acute respiratory distress syndrome (ARDS). Venovenous extracorporeal membrane oxygenation (ECMO) was started on hospital day 2, resulting in sustained improvement in oxygenation. ECMO was stopped on hospital day 6 and the patient was extubated 2 days later (Menkin et al, 2015).
    I) 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).
    6.8.2) TREATMENT
    A) IRRITATION SYMPTOM
    1) Conjunctival irritation should be evaluated with an examination with fluorescein for cornea defects.
    2) Immediate ophthalmology consultation is recommended in patients with evidence of corneal burns or other ocular injury.
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

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) IRRITATION SYMPTOM
    1) If dermatitis persists for more than one hour, topical treatment with wet dressings of Burow's solution 1:40, followed by corticosteroid creams or calamine lotion may be applied. Secondary infections may necessitate antibiotic therapy. Oral antihistamines may be useful for pruritus.
    B) GENERAL TREATMENT
    1) Treatment should include recommendations listed in the INHALATION EXPOSURE section when appropriate.
    C) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Abstracts

Case Reports

    A) ADULT
    1) CHRONIC EFFECTS
    a) A 33-year-old man developed coughing, nasal and pharyngeal mucosal edema, and erythema, lacrimation, and rhinorrhea after exposure to a chloropicrin-fumigated house for one week. One week later symptoms had subsided except for nasal mucosa edema.
    1) Chloropicrin levels measured in the house were 30 to 48.3 ppb at 6 weeks after application, and 0.22 ppb at 18 weeks after application (TeSlaa et al, 1986).
    b) MMWR weekly reported in 2003 that 165 individuals in Kern County, California, experienced irritant symptoms (eye 99%, respiratory 51%, gastrointestinal 47%, neurologic including headache 24%, and skin 2%) after chloropicrin was sprayed as a fumigant over a 24 hour period. Seven patients had persistent respiratory symptoms 11 days postexposure (Centers for Disease Control and Prevention, 2004).

Range Of Toxicity

Summary

    A) Serious burns less likely if pH <11.5. Injury greater with either large ingestion (usually deliberate) or high concentration alkali. With highly concentrated liquids, esophageal burns may occur in up to 100% of patients, even after accidental ingestion.
    B) Inhalation of 1 ppm causes eye irritation and constitutes a good warning of exposure. An odor threshold of 1.1 ppm has been reported.
    C) Inhalation of 20 ppm for 1 to 2 minutes causes bronchial or pulmonary lesions.
    D) Inhalation of 2 mg/L (297.6 ppm) for 10 minutes has been fatal to humans.
    E) Inhalation of 0.8 mg/L (119 ppm) for 30 minutes has been fatal to humans.

Minimum Lethal Exposure

    A) ADULT
    1) Data from World War I have shown lethal human inhalation exposures, with death due to pulmonary edema (Bingham et al, 2001):
    1) 2 milligrams/liter (297.6 parts per million) for 10 minutes
    2) 0.8 milligrams/liter (119.0 parts per million) for 30 minutes
    2) At the concentration of 2000 mg/m(3), chloropicrin is lethal in 10 minutes (HSDB , 2001).
    3) At 0.12 mg/L, it is fatal in 30 to 60 minutes (Hartley & Kidd, 1990).
    4) CASE REPORT - The intentional ingestion of 100 mL chloropicrine sodium resulted in severe metabolic acidosis, acute cardiac failure, and death 7 hours post-exposure in an adult (Honda et al, 2002).
    B) ANIMAL STUDIES
    1) "Concentrations of 340 parts per million of chloropicrin in air are lethal to rats in one minute" (ACGIH, 1991).
    2) The lethal concentration was 119 ppm in air for guinea pigs, rabbits, and cats (OHM/TADS, 2001).

Maximum Tolerated Exposure

    A) ADULT
    1) Data from World War I have shown the following effects of various inhaled concentrations (Davis, 1993):
    1) 0.1 milligram/liter (15 parts per million) for 1 minute caused intolerance
    2) 0.050 milligram/liter (7.5 parts per million) for 10 minutes caused intolerance
    3) 0.009 milligram/liter (1.3 parts per million) was lowest irritant concentration
    4) 0.0073 milligram/liter (1.1 parts per million) was lowest concentration for detectable odor
    5) 0.002 to 0.025 milligram/liter (0.3 to 3.7 parts per million) for 3 to 30 seconds caused closing of eyelids
    2) Chloropicrin in concentrations of 0.3 to 0.37 ppm caused painful irritation to the eyes in 3 to 30 seconds (HSDB , 2001).
    3) Chloropicrin in concentration of 4 ppm rendered a man unfit for activity in a few seconds (HSDB , 2001).
    4) Chloropicrin in concentration of 15 ppm resulted in respiratory tract injury in a few seconds (HSDB , 2001).
    5) Exposure to chloropicrin produces more coughing and less delay in onset of pulmonary edema than does phosgene. Additional symptoms include anemia, weak and irregular heartbeat, and recurrent asthmatic attacks. Renal damage cardiac necrosis, hepatic necrosis, and coma can also occur. Overexposure can lead to late death as results of bronchopneumonia, bronchiolitis obliterans, or secondary infections (HSDB , 2001; ILO, 1998).
    6) It is extremely toxic and lachrymatory. At 0.008 mg/L, it can be clearly detected. At 0.016 mg/L, it produces coughing and lacrimation (Hartley & Kidd, 1990).
    B) CASE REPORTS
    1) A man who was accidentally exposed to residual chloropicrin spray of undetermined concentration reportedly had a dry cough with red and edematous nasal and pharyngeal mucosa (ACGIH, 1991).
    2) A splash of chloropicrin in the eye of a 73-year-old man caused severe edema of the eyelid and cornea. The ocular conjunctiva began to partially liquefy with a bulbar adherence at two days after the accident (HSDB , 2001).
    C) ANIMAL DATA
    1) RAT - In a 13-week inhalation study, male Fischer 344 rats were exposed to 0, 0.4, 0.7, 1.6, or 2.9 parts per million chloropicrin for 6 hours/day, 5 days/week. The no-observed-adverse-effect-level (NOAEL) was determined to be 0.7 parts per million (Bingham et al, 2001).
    2) RAT - When Fischer 344 rats were exposed for 30 minutes at 46 parts per million, 100% mortality was reported (Bingham et al, 2001).
    3) RAT - Nose-only exposure of Fischer 344 rats for 4 hours produced an LC50 of 6.6 parts per million, significantly lower than for whole-body exposures (11.9 and 14.4 parts per million) (Bingham et al, 2001).
    4) RAT - Rats exposed daily to 5 parts per million for 6 hours died after 7 to 10 days (Bingham et al, 2001).
    5) MOUSE - The RD50 (concentration of an airborne sensory irritant eliciting a 50% decrease in respiratory rate) of chloropicrin in mice is reported to be 8 parts per million. At this concentration, when mice were treated for 6 hours a day for a total of 5 days, moderate damage in the nasal passages and in lung were reported without any mortality (Bingham et al, 2001).
    6) MOUSE - Exposure to a concentration of 50 parts per million (0.34 mg/L) for 15 minutes produced death in mice after 10 days. Exposure to a concentration of 125 parts per million (0.85 mg/L) for 15 minutes caused death in 3 hours to 1 day (Bingham et al, 2001).
    7) MOUSE - In mice, exposure to 9 parts per million caused a 50% decrease in respiratory rate, placing it among the more potent of inhalational toxins (ACGIH, 1991; Hathaway et al, 1996; TeSlaa et al, 1986). Ulceration and necrosis of the respiratory epithelium and moderate damage to lung tissue were reported (ACGIH, 1991).
    8) MOUSE - Mice tolerated 25 ppm (0.17 mg/L) for 15 minutes (Bingham et al, 2001).
    9) CAT - Exposure to a concentration of 76 parts per million for 25 minutes caused death in cats, usually within 1 day. Exposure to a concentration of 48 parts per million for 20 minutes caused death after 8 to 12 days (Bingham et al, 2001).
    10) DOG - Exposure to concentrations of 117 to 140 parts per million for 30 minutes caused deaths in 43% of exposed dogs (Bingham et al, 2001; HSDB , 2001).
    11) DOG - Dogs tolerated 48 ppm (0.32 mg/L) for 15 minutes (Bingham et al, 2001; HSDB , 2001).

Workplace Standards

    A) ACGIH TLV Values for CAS76-06-2 (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) Chloropicrin
    a) TLV:
    1) TLV-TWA: 0.1 ppm
    2) TLV-STEL:
    3) TLV-Ceiling:
    b) Notations and Endnotes:
    1) Carcinogenicity Category: A4
    2) Codes: Not Listed
    3) Definitions:
    a) A4: Not Classifiable as a Human Carcinogen: Agents which cause concern that they could be carcinogenic for humans but which cannot be assessed conclusively because of a lack of data. In vitro or animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other categories.
    c) TLV Basis - Critical Effect(s): Eye irr; pulm edema
    d) Molecular Weight: 164.39
    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 CAS76-06-2 (National Institute for Occupational Safety and Health, 2007):
    1) Listed as: Chloropicrin
    2) REL:
    a) TWA: 0.1 ppm (0.7 mg/m(3))
    b) STEL:
    c) Ceiling:
    d) Carcinogen Listing: (Not Listed) Not Listed
    e) Skin Designation: Not Listed
    f) Note(s):
    3) IDLH:
    a) IDLH: 2 ppm
    b) Note(s): Not Listed

    C) Carcinogenicity Ratings for CAS76-06-2 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A4 ; Listed as: Chloropicrin
    a) A4 :Not Classifiable as a Human Carcinogen: Agents which cause concern that they could be carcinogenic for humans but which cannot be assessed conclusively because of a lack of data. In vitro or animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other categories.
    2) EPA (U.S. Environmental Protection Agency, 2011): Not 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 ; Listed as: Chloropicrin
    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 CAS76-06-2 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Listed as: Chloropicrin
    2) Table Z-1 for Chloropicrin:
    a) 8-hour TWA:
    1) ppm: 0.1
    a) Parts of vapor or gas per million parts of contaminated air by volume at 25 degrees C and 760 torr.
    2) mg/m3: 0.7
    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: Lewis, 2000 OHM/TADS, 2001 RTECS, 2001
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 25 mg/kg
    2) LD50- (ORAL)RAT:
    a) 250 mg/kg
    3) TCLo- (INHALATION)HUMAN:
    a) 2 mg/m(3) -- caused lacrimation, conjunctive irritation, and changes in respiratory system
    b) 2000 mg/m(3) for 10M (Lewis, 2000)

Pharmacology Toxicology

Toxicologic Mechanism

    A) IRRITATION - Chloropicrin is a strong irritant and corrosive agent, affecting all body surfaces. When inhaled, its powerful corrosive actions affect the lower respiratory tract. It is not water soluble, thus chloropicrin produces more injury to medium and small bronchi (lower respiratory tract) than the trachea and large bronchi (Clayton & Clayton, 1993; Gonmori et al, 1987; Lewis, 1996). Lacrimation, vomiting, bronchitis, pulmonary edema, and irritation to gastrointestinal and respiratory tracts occur following inhalation. Cause of death is from severe respiratory irritation leading to pulmonary edema and respiratory failure.
    B) HEMOGLOBIN - Chloropicrin is an SN2 alkylating agent with an activated halogen group. The major action is combination with sulfhydryl groups, fixing enzymes. Chloropicrin has the additional toxic effect of interfering with oxygen transport by its reaction with SH-groups in hemoglobin. It is possible that there may also be a photochemical transformation of chloropicrin into phosgene (Lewis, 1996).
    C) MUSCLE - Prudhomme et al, (1999) proposed a direct toxic mechanism of chloropicrin on skeletal muscle, with a predilection for intercostal muscles, with serum creatine kinase predominantly of the MM subfraction increasing, in toxicity cases. More studies are required to verify this hypothesis.

Physicochemical

Physical Characteristics

    A) Chloropicrin is a slightly oily, colorless to faint yellow, refractive, and odorous (described as intensely irritating tear gas odor) liquid (AAR, 2000; (HSDB , 2001; Lewis, 1997).
    B) It is heavier than water and sinks in water (AAR, 2000; ((CHRIS, 2001)).
    C) It slowly volatilizes (HSDB , 2001).

Molecular Weight

    A) 164.37

Animal Toxicology

Clinical Effects

    11.1.3) CANINE/DOG
    A) A dog exposed at night to chloropicrin fumes developed lacrimation, dyspnea, and coughing. He recovered after treatment with antibiotics and steroids (TeSlaa et al, 1986).

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