Phosgene Toxicity



Phosgene (COCl2) is a highly toxic gas or liquid that is classified as a pulmonary irritant. Synonyms for phosgene include carbonic dichloride, carbon oxychloride, carbonyl dichloride, chloroformyl chloride, d-stoff, and green cross. The military symbol for phosgene is CG, and its United Nations/Department of Transportation number is UN#1076. The American Chemical Society's Chemical Abstracts Service (CAS) registry number for phosgene is #75-44-5. Phosgene's structure is depicted in the image below.

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Phosgene structure.

Sir Humphrey Davy first synthesized phosgene in 1812 by passing carbon monoxide and chloride through charcoal. During World War I, it was used in combination with chlorine gas for combat purposes by the German army. This combination allowed phosgene emission to be hastened in cold weather. The German army switched to mustard gas in 1917 because of the development of effective gas masks. More effective agents and improved personal protective equipment make phosgene an unlikely agent to be used in future battles.

Present day exposure occurs during the manufacture of aniline dyes, polycarbonate resins, coal tar, pesticides, isocyanates, polyurethane, and pharmaceuticals. Phosgene exposure also occurs in the uranium enrichment process and during the bleaching of sand for glass production. Exposures related to the heating or combustion of chlorinated organic compounds, such as carbon tetrachloride, chloroform, and methylene chloride, also occur.[1] These products are found in common household solvents, paint removers, and dry cleaning fluids.[2] Occupational exposure can occur when welders heat metals treated with these chemicals and in organic chemistry laboratories that use chloroform.[3, 4] Similarly, vehicle crashes involving trains or trucks transporting phosgene (or chlorinated hydrocarbons, such as methylene chloride, that could combust to form phosgene) could expose numerous individuals to this toxin.[1]


Phosgene is a colorless gas with the odor of newly mown hay or green corn. Olfactory fatigue may occur with a large exposure. Exposure to concentrations of 3 ppm may not cause noticeable symptoms for 12-24 hours. Exposures to 50 ppm may be rapidly fatal. While an odor threshold of 1.5 ppm has been reported in some humans, this does not protect against toxic inhalation effects.[5, 6, 7]

Phosgene is considered to have poor warning properties and, hence, may reach the lower airways before it is noticed. It is 4 times heavier than air and is a gas above 47°F (8°C). Because of hydrolysis from atmospheric water, it appears as a white cloud in an outside environment.

There are 2 mechanisms of injury, hydrolysis and acylation.[8] In hydrolysis, damage caused by phosgene is due to the presence of a highly reactive carbonyl group attached to 2 chloride atoms. The gas dissolves slowly in water, but when this occurs, it hydrolyses to form carbon dioxide and hydrochloric acid. This slow dissolution allows phosgene to enter the pulmonary system without significant damage to the upper airways. However, in the lower airways and alveoli, the tissue undergoes necrosis and inflammation. After the first few hours of exposure, the carbonyl group attacks the surface of the alveolar capillaries, causing leakage of serum into the alveolar septa. The tissue fills with fluid, causing hypoxia and apnea. Massive amounts of fluid (up to 1 L/h) leak out of the circulation, leading to a noncardiogenic pulmonary edema, with associated hypoxemia and volume depletion.

Acylation involves the reaction of phosgene with nucleophilic moieties causing denaturation of proteins, changes in cell membranes, and disruption of enzymes. The permeability of the blood-air barrier is altered, leading to interstitial edema, and the inflammatory cascade is activated. This primarily occurs in the bronchioli and alveoli since they are not protected by a mucous layer.

Researchers in the past decade have discovered 2 important facts that may lead to improved therapy. First, phosgene stimulates the synthesis of lipoxygenase-derived leukotrienes. Second, phosgene combines with glutathione to form diglutathionyl dithiocarbonate. When the glutathione stores become depleted, phosgene binds to the cellular macromolecules, causing cell necrosis in the renal and hepatic tissues.



United States

Clinically significant phosgene exposure occurs infrequently. Sporadic exposures in recent years are related to industrial accidents or isolated.[9]


In view of currently available war gases, which are much more lethal than phosgene, and improved respiratory protection, phosgene is no longer considered a significant threat.


The Occupational Safety and Health Administration permissible exposure limit (OSHA PEL) for the workplace is 0.1 ppm (0.4 mg/m) as an 8-hour time weighted average. The level immediately dangerous to life or health (IDLH) is 2 ppm. Even a short exposure to 50 ppm may result in rapid fatality.

Another means to assess exposure and potential complications is using the inhaled dose instead of concentration alone. An inhaled dose of greater than 25 ppm-min leads to subclinical biochemical lung alterations, greater than 150 ppm-min causes overt alveolar edema, greater than 300 ppm-min is possibly lethal, and the level with 50% mortality is about 500 ppm-min.[5, 6, 7]


No evidence has demonstrated that outcome of phosgene toxicity is dependent on race.


No sex predilection exists. Historically, most exposures have occurred in men because of their military roles. Women were exposed during World War I from developing and testing gas masks at the home front.


Diagnosis of phosgene toxicity depends largely on history of exposure.[9] Consider phosgene toxicity in patients involved in the manufacture of dyes, resins, coal tar, and pesticides. Query patients regarding occupation and any exposure to chemicals, especially around sources of heat.[10] In the work setting and at home, phosgene can be produced by the combustion of methylene chloride (paint remover) or trichloroethylene (a degreasing solvent). Patients typically have an asymptomatic period of 30 minutes to 72 hours, but most significant exposures have a latent period less than 24 hours. The duration and concentration of exposure determine the time to symptom onset.


Head, ears, eyes, nose, and throat

Cardiovascular (caused by volume depletion or hypoxemia)



Physical examination is useful with patients with active symptoms. Patients who relate a recent exposure may be in the latent phase and have no specific findings related to the exposure.


Head, ears, eyes, nose, and throat

Upper airway findings are not good prognostic indicators because significant injury may occur to the lower airways without upper airway involvement.




The major risks are occupational exposure and close proximity to an industrial incident.[11]

Laboratory Studies

ABG demonstrates the degree of hypoxemia. A partial pressure of oxygen (pO2) as low as 23 mm Hg on 8 L/min of oxygen by face mask has been reported. Typical presenting pO2 levels are 50-60 mm Hg while breathing room air. The carboxyhemoglobin level is important for cases involving exposure to methylene chloride or when carbon monoxide exposure is suspected. Methemoglobinemia may suggest other causes.

CBC may be obtained as a baseline level or if pneumonia is high on the differential diagnosis list. An elevated WBC count is not specific because it may result from hypoxemic stress or an infectious process. CBC may reveal hemoconcentration late in the disease process.

Electrolytes may be obtained as baseline studies because of the anticipated large fluid shifts that occur.

Cardiac enzymes (eg, creatine kinase-MB [CK-MB], troponin T, troponin I) may be obtained if cardiogenic pulmonary edema is high on the differential.

Continue pulse oximetry and cardiac monitoring in patients suspected of phosgene toxicity.

Investigation on a blood test that measures exposure to phosgene is being pursued. Most likely, this test will be used in laboratory settings.

Imaging Studies

Chest x-ray

Initial findings may be normal; however, as the disease progresses, the chest x-ray (CXR) may demonstrate bilateral, diffuse interstitial infiltrates, as in the images below.

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The chest radiograph of a 42-year-old woman chemical worker 2 hours postexposure to phosgene. Dyspnea progressed rapidly over the second hour; PO2 was....

View Image

An anteroposterior (AP) portable chest radiograph of a male patient, who developed phosgene-induced adult respiratory distress syndrome. Notice the bi....

Heart and pulmonary vessel sizes are usually normal unless the patient has baseline cardiomegaly.

CXR findings may precede the clinical presentation.


Prehospital Care

To avoid further exposures, hazardous materials (Hazmat) prehospital providers should always ensure that the environment is safe.[8] A self-contained breathing apparatus (SCBA) should be worn at the exposure site.[13] Remove the patient's clothes to prevent further contamination. If the eyes and skin are exposed, begin irrigation on site.

In the field, standard management of ABCs usually is sufficient. Severe exposures may require ET intubation and suctioning. If a significant bronchospastic component is present, bronchodilators may be used with caution.[8, 14]

Past wartime experience has demonstrated that, in a mass casualty situation, phosgene exposures should be classified as immediate because of the impending need for intubation and positive end-expiratory pressure (PEEP) to maintain distal airway opening.[15]

Emergency Department Care

Always consider the need for decontamination in any toxic exposure to minimize the risk of poisoning hospital personnel. Inhalational exposure of phosgene should not occur unless in the proximity of the gas. If external decontamination has not been performed in the field, use personal protective equipment, as necessary, including dermal, eye, and facial protection. A decontamination shower unit may be used.[8, 13]

Initiate humidified oxygen supplementation. Intubation with continuous positive airway pressure (CPAP) ventilation and pressure support is usually required to improve oxygenation. Frequent suctioning may improve conditions.

Bronchodilators may improve existing bronchospasm. In animal studies, beneficial effect has been shown with the administration of numerous drugs, including leukotriene antagonists, ibuprofen, colchicine, cyclophosphamide, terbutaline, aminophylline, and N -acetylcysteine.[16, 17] Nebulized sodium bicarbonate treatment theoretically may be beneficial; however, consider it as second line after the drugs noted above.

Avoid excessive fluid administration. Pulmonary artery catheter monitoring may be required to maintain appropriate fluid balance while treating hypotension caused by fluid shifts.

In severe cases, extracorporeal membrane oxygenation (ECMO) may be considered refractory to supportive care.

Minimize fluid administration except when it is needed to correct hypotension. Avoid diuretics because the patient typically is volume-depleted from fluid shifts.

Avoid exertion during treatment and for several weeks after recovery.

Prophylactic antibiotics have been recommended by some authors based on the findings of pneumonia and bronchitis in virtually all autopsy specimens.

Corticosteroid administration postexposure has been recommended to reduce the degree of pulmonary edema by reducing the inflammatory response. Some sources recommend administration begin within 15 minutes or as soon as possible after exposure.

No specific antidote or effective elimination process exists. During both world wars, the Germans and Russians believed that hexamethylene tetramine was the antidote. Subsequent studies have shown some preexposure benefit but no definite postexposure benefit.

Tomelukast, a leukotriene receptor antagonist, prevents pulmonary edema in phosgene-exposed rabbits. Experimentally, ibuprofen has been shown to reduce phosgene-induced pulmonary edema.[18] Colchicine and cyclophosphamide reduce neutrophil influx when administered to mice 30 minutes following phosgene exposure. These drugs reduce lung injury and mortality in mice.[19]

Intratracheal dibutyryl cyclic adenosine monophosphate (DBcAMP), a cyclic adenosine monophosphate (cAMP) analogue, inhibits the release of leukotrienes that contribute to the disease process.[20, 21] In phosgene-exposed rabbits, terbutaline and aminophylline (cAMP enhancers) limit the pulmonary capillary leakage. Also, intratracheal N -acetylcysteine (NAC), administered to rabbits 45 minutes postexposure, reduces leukotriene formation and pulmonary edema.[22] Theoretically, nebulized NAC also should be effective.


Medication Summary

Management of phosgene toxicity is supportive. Oxygen, corticosteroids (inhaled, systemic), leukotriene inhibitors, IV fluids, and prophylactic antibiotics are recommended. The recommended steroid dose is much higher than the dose conventionally used in asthma. Prophylactic antibiotics and antifungals may be required because of the risk of superinfection. Pressor agents may be required to treat hypotension, bradycardia, and renal failure.

Beclomethasone (Beclovent, Vanceril)

Clinical Context:  Inhibits bronchoconstriction mechanisms, producing direct smooth muscle relaxation; may decrease number and activity of inflammatory cells, in turn decreasing airway hyperresponsiveness.

Methylprednisolone (Solu-Medrol)

Clinical Context:  Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability.

Betamethasone (Celestone, Soluspan)

Clinical Context:  Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability.

Class Summary

Reduce inflammatory response. Whether early administration of corticosteroids can prevent development of noncardiogenic pulmonary edema is unknown. The decision to administer corticosteroids must be made on clinical grounds.

Treatments lasting more than 1 week may require a taper to prevent abrupt steroid withdrawal.

Dopamine (Intropin)

Clinical Context:  Stimulates adrenergic and dopaminergic receptors. Hemodynamic effect is dependent on the dose. Lower doses predominantly stimulate dopaminergic receptors that, in turn, produce renal and mesenteric vasodilation. Use low dose to protect renal function; use high dose to combat severe hypotension unresponsive to fluid administration.

Class Summary

Used to treat hypotension, bradycardia, or renal failure.

Zafirlukast (Accolate)

Clinical Context:  No human studies have evaluated the efficacy and safety of zafirlukast in patients exposed to phosgene. Nevertheless, given the known effects of leukotriene stimulation by phosgene, the results from animal studies, and the drug's safety profile, should be considered first line.

In the presence of food, bioavailability of oral zafirlukast is decreased by 40%. Administer on an empty stomach.

Class Summary

Reduce the inflammatory response elicited by the leukotriene cascade. Leukotriene antagonists are approved by the Food and Drug Administration (FDA) only for chronic asthma management.

Further Inpatient Care

Further Outpatient Care






Daniel Noltkamper, MD, FACEP, EMS Medical Director, Department of Emergency Medicine, Naval Hospital of Camp Lejeune

Disclosure: Nothing to disclose.


Stephen W Burgher, MD, FACEP, Medical Director, Emegency Preparedness and Management, Department of Emergency Medicine, Baylor University Medical Center

Disclosure: Nothing to disclose.

Specialty Editors

Miguel C Fernandez, MD, FAAEM, FACEP, FACMT, FACCT, Associate Clinical Professor; Medical and Managing Director, South Texas Poison Center, Department of Surgery/Emergency Medicine and Toxicology, University of Texas Health Science Center at San Antonio

Disclosure: Nothing to disclose.

John T VanDeVoort, PharmD, Regional Director of Pharmacy, Sacred Heart & St. Joseph's Hospitals

Disclosure: Nothing to disclose.

Fred Harchelroad, MD, FACMT, FAAEM, FACEP, Director of Medical Toxicology, Allegheny General Hospital

Disclosure: Nothing to disclose.

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center

Disclosure: Nothing to disclose.

Chief Editor

Asim Tarabar, MD, Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital

Disclosure: Nothing to disclose.


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Phosgene structure.

The chest radiograph of a 42-year-old woman chemical worker 2 hours postexposure to phosgene. Dyspnea progressed rapidly over the second hour; PO2 was 40 mm Hg breathing room air. This radiograph shows bilateral perihilar, fluffy, and diffuse interstitial infiltrates. The patient died 6 hours postexposure. (Used with permission from Medical Aspects of Chemical and Biological Warfare, Textbook of Military Medicine, 1997, p 258)

An anteroposterior (AP) portable chest radiograph of a male patient, who developed phosgene-induced adult respiratory distress syndrome. Notice the bilateral infiltrates and ground-glass appearance. (Image courtesy of Fred P. Harchelroad, MD, and Ferdinando L. Mirarchi, DO)

British machine-gunners in anti-phosgene masks, Somme, 1915. (Photograph courtesy of the Imperial War Museum, London)

Phosgene structure.

The chest radiograph of a 42-year-old woman chemical worker 2 hours postexposure to phosgene. Dyspnea progressed rapidly over the second hour; PO2 was 40 mm Hg breathing room air. This radiograph shows bilateral perihilar, fluffy, and diffuse interstitial infiltrates. The patient died 6 hours postexposure. (Used with permission from Medical Aspects of Chemical and Biological Warfare, Textbook of Military Medicine, 1997, p 258)

A lung section of the patient whose chest radiograph is presented above. This patient died 6 hours following exposure to phosgene; the biopsy section was taken during postmortem examination. The section shows nonhemorrhagic pulmonary edema with few scattered inflammatory cells. Hematoxylin and eosin stain; original magnification X 100. (Used with permission from Medical Aspects of Chemical and Biological Warfare, Textbook of Military Medicine, 1997, p 258)

An anteroposterior (AP) portable chest radiograph of a male patient, who developed phosgene-induced adult respiratory distress syndrome. Notice the bilateral infiltrates and ground-glass appearance. (Image courtesy of Fred P. Harchelroad, MD, and Ferdinando L. Mirarchi, DO)

Chemical Terrorism Agents and Syndromes. Signs and symptoms. Chart courtesy of North Carolina Statewide Program for Infection Control and Epidemiology (SPICE), copyright University of North Carolina at Chapel Hill,