Medical Management Guidelines
Nitrogen Mustard (HN-1)
Nitrogen Mustard (HN-2)
Nitrogen Mustard (HN-3)
CAS#: Nitrogen Mustard (HN-1) 538-07-8, Nitrogen Mustard (HN-2) 51-75-2, Nitrogen Mustard (HN-3) 555-77-1
UN#: Nitrogen Mustard (HN-1) 2810, Nitrogen Mustard (HN-2) 2927, Nitrogen Mustard (HN-3) 2810
HN-1: Bis(2-chloroethyl)ethylamine; 2-chloro-N-(2-chloroethyl)-N-ethylethanamine; 2,2'-dichlorotriethylamine; ethylbis(2-chloroethyl)amine; ethyl-S
HN-2: MBA; mechlorethamine; mustine; 2,2'-dichloro-N-methyldiethylamine; dichloren; caryolysin; mechlorethanamine; chlormethine; bis(2-chloroethyl)methylamine
HN-3: Tris(2-chloroethyl)amine; 2-chloro-N,N-bis(2-chloroethyl)ethanamine; 2,2',2"-trichlorotriethylamine
- People whose skin or clothing is contaminated with nitrogen mustard can contaminate rescuers by direct contact or through off-gassing vapor.
- Nitrogen mustards are colorless to yellow, oily liquids with variable odors.
- Nitrogen mustards are absorbed by the skin causing erythema and blisters. Ocular exposure to these agents may cause incapacitating injury to the cornea and conjunctiva. When inhaled, nitrogen mustard damages the respiratory tract epithelium and may cause death.
Nitrogen mustards are vesicants and alkylating agents. They are colorless to pale yellow, oily liquids that evaporate slowly. HN-1 has a faint, fishy or musty odor. It is sparingly soluble in water but miscible with acetone and other organic solvents. At temperatures greater than 194ºC, it decomposes.
HN-2 has a fruity odor at high concentrations and a soapy odor at low concentrations. Its solubility is similar to HN-1.
HN-3 is odorless when pure but has been reported to have a butter almond odor. It is the most stable of the nitrogen mustards but decomposes at temperatures greater than 256ºC. It has a much lower vapor pressure than HN-1 or HN-2 and is insoluble in water.
Routes of Exposure
Inhalation is an important route of exposure. Nitrogen mustard vapors are heavier than air. The LCt50 (the product of concentration times time that is lethal to 50% of the exposed population by inhalation) is approximately 1,500 mg-min/m³ for HN-1 and HN-3, and 3,000 mg-min/m³ for HN-2.
Exposure to nitrogen mustard vapor can cause injury to the eyes, skin, and mucous membranes at low concentrations. Direct contact with the liquid can cause skin and eye burns. The median incapacitating dose for the eyes is 100 mg-min/m³ for HN-2 and 200 mg-min/m³ for HN-1 and HN-3. Absorption may occur after skin or eye exposure to liquid or vapor nitrogen mustard and may cause systemic toxicity.
Ingestion is an uncommon route for exposure but can lead to local effects such as esophageal or gastrointestinal burns and systemic absorption.
Nitrogen mustards were first developed in the late 1920s and early 1930s. HN-1 was originally designed to remove warts but was later identified as a potential chemical warfare agent; HN-2 was designed as a military agent but was later used in chemotherapy; HN-3 was developed as a military agent. None of the nitrogen mustards have been used on the battlefield, and none are included in U.S. stockpiles.
Standards and Guidelines
HN-1: Airborne Exposure Limit (as recommended by the Surgeon General's Working Group, U.S. Department of Health and Human Services) = 0.003 mg/m³ as a time-weighted average (TWA) for the workplace. No standards exist for HN-2 or HN-3.
HN-1 is corrosive to ferrous alloys at temperatures of 149ºF (68ºC) and higher. HN-2 and HN-3 do not have any incompatible actions on metals or other materials.
- Nitrogen mustards are vesicants causing skin, eye, and respiratory tract injury. Although these agents cause cellular changes within several minutes of contact, the onset of pain and other clinical effects is delayed for hours.
- Nitrogen mustards are alkylating agents that may cause bone marrow suppression and neurologic toxicity.
Nitrogen mustards are vesicants and alkylating agents; however, the mechanisms of action are not clearly understood. They are highly reactive and combine rapidly with proteins, DNA, or other molecules. Therefore, within minutes following exposure intact mustard or its reactive metabolites are not found in tissue or biological fluids.
High doses of nitrogen mustards have caused tremors, seizures, incoordination, ataxia, and coma in laboratory animals.
Damage to the mucosa of the airways begins within hours and may progress over several days. Nasal and sinus pain or discomfort, pharyngitis, laryngitis, cough, and dyspnea may occur. Pulmonary edema is uncommon.
Ingestion may cause chemical burns of the GI tract and hemorrhagic diarrhea. Nausea and vomiting may occur following ingestion, dermal, or inhalation exposure.
Exposure to nitrogen mustard vapor or liquid may cause intense conjunctival and scleral inflammation, pain, swelling, lacrimation, photophobia, and corneal damage. High concentrations can cause burns and blindness.
Direct skin exposure to nitrogen mustards causes erythema and blistering. Generally, a rash will develop within several hours, followed by blistering within 6 to 12 hours. Prolonged contact, or short contact with large amounts, may result in second- and third-degree chemical burns.
Systemic absorption of nitrogen mustard may induce bone marrow suppression and an increased risk for fatal complicating infections, hemorrhage, and anemia.
Chemotherapeutic doses of HN-2 have been associated with menstrual irregularities, alopecia, hearing loss, tinnitus, jaundice, impaired spermatogenesis, generalized swelling, and hyperpigmentation.
Chronic respiratory and eye conditions may persist following exposure to large amounts of nitrogen mustards. Narrowing of the esophagus and severe corrosive damage to the stomach lining can result from ingesting formalin.
In laboratory animal studies, prolonged or repeated exposures to nitrogen mustards have caused cancer, developmental and reproductive effects, and hepatic toxicity. Repeated exposures result in cumulative effects because mustards are not naturally detoxified by the body.
The International Agency for Research on Cancer (IARC) has classified nitrogen mustard as probably carcinogenic to humans (Group 2A). There is some evidence that it causes leukemia in humans, and it has been shown to cause leukemia and cancers of the lung, liver, uterus, and large intestine in animals.
Reproductive and Developmental Effects
Nitrogen mustards may decrease fertility. A few case reports have linked treatment with HN-2 to fetal abnormalities in humans. Nitrogen mustards have produced developmental effects in animals.
- Victims whose skin or clothing is contaminated with liquid nitrogen mustard can contaminate rescuers by direct contact or through off-gassing vapor.
- Nitrogen mustards are extremely toxic and may damage the eyes, skin, and respiratory tract and suppress the immune system. Although these agents cause cellular changes within minutes of contact, the onset of pain and other symptoms is delayed.
- There is no antidote for nitrogen mustard toxicity. Decontamination of all potentially exposed areas within minutes after exposure is the only effective means of decreasing tissue damage.
Rescuers should be trained and appropriately attired before entering the Hot Zone. If the proper equipment is not available, or if the rescuers have not been trained in its use, call for assistance from the U.S. Soldier and Biological Chemical Command-Edgewood Research Development and Engineering Center (from 0700-1630 EST call 410-671-4411, and from 1630-0700 EST call 410-278-5201; ask for the Staff Duty Officer).
Nitrogen mustard vapor and liquid are readily absorbed by inhalation and ocular and dermal contact.
Respiratory Protection: Pressure-demand, self-contained breathing apparatus (SCBA) is recommended in response situations that involve exposure to any amount of nitrogen mustard.
Skin/Ocular Protection: Personal protective equipment (PPE) and butyl rubber chemical protective gloves are recommended at all times when these chemicals are suspected to be involved.
Chemical casualty triage is based on walking feasibility, respiratory status, age, and additional conventional injuries. The triage officer must know the natural course of a given injury, the medical resources immediately available, the current and likely casualty flow, and the medical evacuation capabilities. General principles of triage for chemical exposures are presented in the box on the following page. There are four triage categories: immediate (priority 1), delayed (priority 2), minimal (priority 3), and expectant (priority 4).
Before transport, all casualties must be decontaminated. If needed, consult with the base station physician or the regional poison control center for advise concerning management of multiple casualties.
Because most signs and symptoms of nitrogen mustard exposure do not occur for several hours postexposure, patients should be observed for at least 6 hours or sent home with instructions to return immediately if symptoms develop. Patients who develop significant dermal, ocular, or airway injury and patients who have ingested nitrogen mustard should be transported to a medical facility for evaluation.
Symptoms may not develop for 24 hours. Patients with mild symptoms who are seen long enough after exposure to minimize the likelihood that the lesions will worsen may be sent home after their names, addresses, and telephone numbers have been recorded. They should be advised to rest and to seek medical care promptly if additional symptoms develop (see Follow-up Instructions included with the Nitrogen Mustard Patient Information Sheet).
Consult with the base station physician or closest Metropolitan Medical Response System, or the regional poison control center for advice regarding triage of multiple victims.
General principles of triage for chemical exposures are as follows:
- Check triage tag/card for any previous treatment or triage.
- Survey for evidence of associated traumatic/blast injuries.
- Observe for sweating, labored breathing, coughing/vomiting, secretions.
- Severe casualty triaged as immediate if assisted breathing is required.
- Blast injuries or other trauma, where there is question whether there is chemical exposure, victims must be tagged as immediate in most cases. Blast victims evidence delayed effects such as ARDS, etc.
- Mild/moderate casualty: self/buddy aid, triaged as delayed or minimal and release is based on strict follow up and instructions.
- If there are chemical exposure situations which may cause delayed but serious signs and symptoms, then overtriage is considered appropriate to the proper facilities that can observe and manage any delayed onset symptoms. For nitrogen mustards, potentially exposed individuals should be observed for 6 - 8 hours and, if signs or symptoms appear, be sent to the hospital.
- Expectant categories in multi-casualty events are those victims who have experienced a cardiac arrest, respiratory arrest, or continued seizures immediately. Resources should not be expended on these casualties if there are large numbers of casualties requiring care and transport with minimal or scant resources available.
- Immediate: casualties who require lifesaving care within a short time, when that care is available and of short duration. This care may be a procedure that can be done within minutes at an emergency treatment station (e.g., relief of an airway obstruction, administering antidotes) or may be acute lifesaving surgery.
- Delayed: casualties with severe injuries who are in need of major or prolonged surgery or other care and who will require hospitalization, but delay of this care will not adversely affect the outcome of the injury (e.g., fixation of a stable fracture).
- Minimal: casualties who have minor injuries, can be helped by nonphysician medical personnel, and will not require hospitalization.
- Expectant: casualties with severe life-threatening injuries who would not survive with optimal medical care, or casualties whose injuries are so severe that their chance of survival does not justify expenditure of limited resources. As circumstances permit, casualties in this category may be reexamined and possibly be retriaged to a higher category.
Quickly ensure that the victim has a patent airway. Maintain adequate circulation. If trauma is suspected, maintain cervical immobilization manually and apply a cervical collar and a backboard when feasible. Apply direct pressure to stop arterial bleeding, if present.
If victims can walk, lead them out of the Hot Zone to the Decontamination Zone. Victims who are unable to walk may be removed on backboards or gurneys. If these are not available, carefully carry or drag victims to safety.
Decontamination within 1 or 2 minutes following exposure is the only effective means for decreasing tissue damage. Later decontamination is not likely to improve the victim's condition but will protect other personnel from exposure. Decontaminable gurneys and back boards should be used if available when managing casualties in a contaminated area. Decontaminable gurneys are made of a monofilament polypropylene fabric that allows drainage of liquids, does not absorb chemical agents, and is easily decontaminated. Fiberglass back boards have been developed specifically for use in HAZMAT incidents. These are nonpermeable and readily decontaminated. The Chemical Resuscitation Device is a bag-valve mask equipped with a chemical agent cannister that can be used to ventilate casualties in a contaminated environment.
Personnel should continue to wear the same level of protection as required in the Hot Zone (see Rescuer Protection under Hot Zone, above).
Quickly ensure that the victim has a patent airway. Maintain adequate circulation. Stabilize the cervical spine with a decontaminable collar and a backboard if trauma is suspected. Administer supplemental oxygen if cardiopulmonary compromise is suspected. Assist ventilation with a bag-valve-mask device equipped with a cannister or air filter if necessary. Direct pressure should be applied to control heavy bleeding, if present.
The eyes and skin must be decontaminated within 1 or 2 minutes after exposure to reduce tissue damage. Flush the eyes immediately with water for about 5 to 10 minutes by tilting the head to the side, pulling eyelids apart with fingers, and pouring water slowly into eyes. Do not cover eyes with bandages.
If exposure to liquid agent is suspected, cut and remove all clothing and wash skin immediately with soap and water. If shower areas are available, showering with water alone will be adequate. However, in those cases where water is in short supply, and showers are not available, an alternative form of decontamination is to use 0.5% sodium hypochlorite solution or absorbent powders such as flour, talcum powder, or Fuller's earth. If exposure to vapor only is certain, remove outer clothing and wash exposed areas with soap and water or 0.5% solution of sodium hypochlorite. Place contaminated clothes and personal belongings in a sealed double bag.
In cases of ingestion, do not induce emesis. There is no evidence that administration of activated charcoal is beneficial.
Transfer to Support Zone
As soon as basic decontamination is complete, move the victim to the Support Zone.
Be certain that victims have been decontaminated properly (see Decontamination Zone, above). Victims who have undergone decontamination pose no serious risk of secondary contamination to rescuers. In such cases, Support Zone personnel require no specialized protective gear.
Quickly ensure that the victim has a patent airway. If trauma is suspected, maintain cervical immobilization manually and apply a cervical collar and a backboard when feasible. Ensure adequate respiration; administer supplemental oxygen if cardiopulmonary compromise is suspected. Maintain adequate circulation. Establish intravenous access if necessary. Attach a cardiac monitor, as needed. Direct pressure should be applied to stop bleeding, if present.
In cases of ingestion, do not induce emesis. If the victim is alert and able to swallow, give 4 to 8 ounces of milk or water to drink. There is no evidence that administration of activated charcoal is beneficial.
Intubate the trachea in cases of respiratory compromise. When the patient's condition precludes endotracheal intubation, perform cricothyrotomy if equipped and trained to do so.
Treat patients who have bronchospasm with bronchodilators. Trauma patients who are comatose, hypotensive, or have seizures or cardiac dysrhythmias should be treated according to advanced life support (ALS) protocols.
Transport to Medical Facility
Report the condition of the patient, treatment given, and estimated time of arrival at the medical facility to the base station and the receiving medical facility.
Emergency Department Management
- Patients whose skin or clothing is contaminated with liquid nitrogen mustard can contaminate rescuers by direct contact or through off-gassing vapor.
- Nitrogen mustards are extremely toxic and may damage eyes, skin, and respiratory tract and suppress the immune system. Although these agents cause cellular changes within minutes of contact, the onset of pain and other symptoms is delayed. Thus, patients arriving immediately from the scene of exposure are not likely to have signs and symptoms.
- There is no antidote for nitrogen mustard toxicity. Decontamination of all potentially exposed areas within minutes after exposure is the only effective means of decreasing tissue damage. Thus, by the time a patient arrives in the emergency department, decontamination can only prevent secondary exposure to medical staff; it does not limit the patient's injury. Medical treatment is supportive.
Previously decontaminated patients may be treated or held for observation. Others require decontamination as described below.
Evaluate and support the airway, breathing, and circulation. Intubate the trachea in cases of respiratory compromise. If the patient's condition precludes intubation, surgically create an airway.
Treat patients who have bronchospasm with bronchodilators. Patients who are comatose or hypotensive, or who have seizures or ventricular dysrhythmias due to other exposures or trauma, should be treated in the conventional manner.
If contaminated patients are expected to arrive at the Emergency Department, they must be decontaminated before being allowed to enter the facility. Decontamination can take place inside the hospital only if there is a decontamination facility with negative air pressure and floor drains to contain contamination. Personnel should wear the same level of protection required in the Hot Zone (see Rescuer Protection under Hot Zone, above).
Flush the eyes with water for about 5 to 10 minutes. Do not cover eyes with bandages; if necessary, use dark or opaque goggles to relieve discomfort from photophobia.
If a liquid splash is suspected, clothing must be removed and the patient showered using soap and water. Showering should be accomplished using cool water and enough water pressure to quickly reduce the potential for agent penetration of the skin. If the patient was exposed to vapor only, remove outer clothing and wash exposed skin with soap and water. Place contaminated clothes and personal belongings in a sealed double bag.
In cases of ingestion, do not induce emesis. If the victim is alert and able to swallow, give 4 to 8 ounces of milk or water to drink if not already administered. There is no evidence that administration of activated charcoal is beneficial.
Critical Care Area
Be certain that appropriate decontamination has been carried out (see Decontamination Area above).
Evaluate and support the airway, breathing, and circulation (as in ABC Reminders, above). Establish intravenous access and continuously monitor cardiac rhythm in seriously ill patients.
Patients who are comatose, hypotensive, or who have seizures or ventricular dysrhythmias due to other exposures or trauma should be treated in the conventional manner.
Patients arriving at the emergency department directly from the scene of potential exposure (within 30-60 minutes) will rarely have symptoms. Following decontamination, patients with signs of airway involvement should be admitted directly to the Critical Care Unit. The others should be observed for at least 6 hours. Patients arriving later should be evaluated as described below. The sooner after exposure that symptoms occur, the more likely they are to progress and become severe.
Mild conjunctivitis beginning more than 12 hours after exposure is unlikely to progress to a severe lesion. The patient should have a thorough eye examination (including a test for visual acuity). The patient should be treated with a soothing eye solution, sent home, and told to return if there is worsening. Conjunctivitis beginning earlier and other effects such as lid swelling and signs/symptoms of inflammation indicate a need for inpatient care and observation.
A small area of erythema beginning later than 12 hours after exposure is unlikely to progress to a significant lesion. The patient should be examined, treated with a soothing lotion , sent home, and instructed to return if progression occurs. A patient with a significant area of erythema or one seen earlier with a significant area of erythema with or without blistering should be admitted for further evaluation.
A patient with a mild, non-productive cough, irritation of the nose and sinuses, and/or a sore throat that began later than 12 hours after exposure should be advised to use a cool steam vaporizer and lozenges or cough drops, and sent home with instructions to return if the symptoms worsen. Intubation should be done at the first sign of more severe effects. A patient with more severe effects (laryngitis, shortness of breath, a productive cough, pulmonary edema, pseudomembrane formation) should be provided with oxygen-assisted ventilation as necessary and admitted directly to the Critical Care Unit once decontamination has been assured. Signs of damage to the larynx or lower airway indicate oxygen-assisted ventilation with PEEP. Patients with less severe effects should be admitted to a routine care ward.
Lewisite causes systemic capillary leakage, and hypovolemic shock may occur in severely exposed patients. Closely monitor blood pressure, blood volume, and hepatic and renal function.
A patient with a mild, non-productive cough, irritation of the nose and sinuses, and/or a sore throat that began later than 12 hours after exposure should be told to use a cool steam vaporizer and lozenges or cough drops, and sent home with instructions to return if the symptoms worsen. Patients with more severe effects (laryngitis, shortness of breath, a productive cough) seen at any time postexposure should be admitted directly to the Critical Care Unit once decontamination has been assured. Those with less severe effects should be admitted to a routine care ward.
Do not induce emesis. If a large dose has been ingested and the patient's condition is evaluated within 30 minutes after ingestion, cautious orogastric lavage might remove ingested material. However, the risk of potential bleeding and perforation must be considered. There is no evidence that activated charcoal is beneficial.
Antidotes and Other Treatments
There is no antidote for nitrogen mustard. Treatment is supportive.
Routine laboratory studies should be done for all patients requiring admission. These include CBC, glucose, and serum electrolytes. Chest x-ray and pulse oximetry (or ABG measurements) are recommended for inhalation exposures.
Disposition and Follow-up
As discussed above, consider hospitalizing patients who have had significant exposures.
Significant systemic absorption of nitrogen mustard may produce a fall in the leukocyte count beginning on days 3 to 5. Erythrocytes and thrombocytes may subsequently fall if bone marrow damage is severe and in this case the risk of life-threatening infection rises.
Patients who have sustained mild exposure may be discharged. Discharged patients should be advised to rest and to seek medical care promptly if symptoms develop (see page 22, Follow-up Instructions, included with the Nitrogen Mustard Patient Information Sheet).
Other people may still be at risk in the setting where this incident occurred or away from the setting due to secondary contamination. If a public health risk exists, notify your state or local health department or other responsible public agency.
Patient Information Sheet
This handout provides information and follow-up instructions for people who have been exposed to nitrogen mustards.
Nitrogen mustards are compounds that were initially developed as chemical warfare agents or pharmaceuticals. They have never been used on the battlefield. HN-2 has been used in chemotherapy.What immediate health effects can be caused by exposure to formaldehyde?
Nitrogen mustards cause injury to the skin, eyes, nose and throat. Eye damage may occur within minutes of exposure. Nausea and vomiting also may occur shortly after exposure. Skin rashes, blisters, and lung damage may develop within a few hours of exposure but may take 6 hours or more. Nitrogen mustards can also suppress the immune system.Can formaldehyde poisoning be treated?
There is no antidote for nitrogen mustard, but its effects can be treated and most exposed people recover. Immediate decontamination reduces symptoms. People who have been exposed to large amounts of nitrogen mustard will need to be treated in a hospital.Are any future health effects likely to occur?
Adverse health effects, such as chronic respiratory diseases, may occur from exposure to high levels of these agents. Severe damage to the eye may be present for a long time following the exposure.What tests can be done if a person has been exposed to formaldehyde?
There are no routine tests to confirm exposure.Where can more information about formaldehyde be found?
More information about nitrogen mustards can be obtained from your regional poison control center; the Agency for Toxic Substances and Disease Registry (ATSDR); your doctor; or a clinic in your area that specializes in toxicology or occupational and environmental health. Ask the person who gave you this form for help locating these telephone numbers.
Keep this page and take it with you to your next appointment. Follow only the instructions checked below.
[ ] Call your doctor or the Emergency Department if you develop any unusual signs or symptoms within the next 24 hours, especially:
- coughing, wheezing, shortness of breath, or discolored sputum
- increased pain or discharge from injured eyes
- increased redness, pain, or a pus-like discharge from injured skin
- fever or chills
[ ] No follow-up appointment is necessary unless you develop any of the symptoms listed above.
[ ] Call for an appointment with Dr.____ in the practice of ________.
When you call for your appointment, please say that you were treated in the Emergency Department at _________ Hospital by________and were advised to be seen again in ____days.
[ ] Return to the Emergency Department/Clinic on ____ (date) at _____ AM/PM for a follow-up examination.
[ ] Do not perform vigorous physical activities for 1 to 2 days.
[ ] You may resume everyday activities including driving and operating machinery.
[ ] Do not return to work for _____days.
[ ] You may return to work on a limited basis. See instructions below.
[ ] Avoid exposure to cigarette smoke for 72 hours; smoke may worsen the condition of your lungs.
[ ] Avoid drinking alcoholic beverages for at least 24 hours; alcohol may worsen injury to your stomach or have other effects.
[ ] Avoid taking the following medications: ________________
[ ] You may continue taking the following medication(s) that your doctor(s) prescribed for you: _______________________________
[ ] Other instructions: ____________________________________ _____________________________________________________
- Provide the Emergency Department with the name and the number of your primary care physician so that the ED can send him or her a record of your emergency department visit.
- You or your physician can get more information on the chemical by contacting: ____________ or _____________, or by checking out the following Internet Web sites: ___________;__________.
Signature of patient _______________ Date ____________
Signature of physician _____________ Date ____________
Where can I get more information?
ATSDR can tell you where to find occupational and environmental health clinics. Their specialists can recognize, evaluate, and treat illnesses resulting from exposure to hazardous substances. You can also contact your community or state health or environmental quality department if you have any more questions or concerns.
For more information, contact:
Agency for Toxic Substances and Disease Registry
Division of Toxicology and Environmental Medicine
1600 Clifton Road NE, Mailstop F-32
Atlanta, GA 30333
Phone: 1-800-CDC-INFO • 888-232-6348 (TTY)