Mechlorethamine

Toxic Gases & Vapors -> Chemical Weapons

Carcinogens

-> NIOSH Emergency Response Categories

log Kow = 0.91

1.6

0.91

1.118 at 77 °F (EPA, 1998) - Denser than water; will sink

1.118 @ 25 °C/4 °C

1.118 @25 °C

Mobile liquid

Dark liquid

Liquid, colorless/pale yellow when fresh

Very soluble

Very slightly soluble in water; miscible with dimethyl formamide, carbon disulfide, carbon tetrachloride, many organic solvents and oils

3.34e+01 g/L

Breast Feeding; Lactation; Milk, Human; Antineoplastic Agents; Alkylating Agents; Irritants

EMA approved medicines: Human medicine (Orphan designations)

189 °F at 18 mmHg (EPA, 1998)

87°C at 1.80E+01 mm Hg

87 °C @ 18 mm Hg

-76 °F (EPA, 1998)

-60 °C

108 - 111 °C

-60 °C

Danger

H300: Fatal if swallowed [Danger Acute toxicity, oral]

P203, P260, P262, P264, P264+P265, P270, P271, P280, P284, P301+P316, P301+P330+P331, P302+P352, P302+P361+P354, P304+P340, P305+P354+P338, P308+P316, P316, P317, P318, P320, P321, P330, P361+P364, P363, P403+P233, P405, and P501 (click each P-code to see the statement)

Hazard Traits - Carcinogenicity; Developmental Toxicity

The New Jersey Worker and Community Right to Know Act requires public and private employers to provide information about hazardous substances at their workplaces. (N.J.S.A. 34:5A-1 et. seq.)

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 may decrease fertility. [ATSDR MMG] Danger of skin sensitization; Germ cell mutagens that have shown to increase the mutant frequency in the progeny of exposed mammals. [MAK]

MECHLORETHAMINE is a chlorinated amine. Amines are chemical bases. They neutralize acids to form salts plus water. These acid-base reactions are exothermic. The amount of heat that is evolved per mole of amine in a neutralization is largely independent of the strength of the amine as a base. Amines may be incompatible with isocyanates, halogenated organics, peroxides, phenols (acidic), epoxides, anhydrides, and acid halides. Flammable gaseous hydrogen is generated by amines in combination with strong reducing agents, such as hydrides.

If ... THERE IS NO FIRE, go directly to the Table of Initial Isolation and Protective Action Distances /(see table below)/ ... to obtain initial isolation and protective action distances. IF THERE IS A FIRE, or IF A FIRE IS INVOLVED, go directly to the appropriate guide /(see guide(s) below)/ and use the evacuation information shown under PUBLIC SAFETY. /HN-2 (when used as a weapon)/

/GUIDE 153: SUBSTANCES - TOXIC AND/OR CORROSIVE (COMBUSTIBLE)/ Health: TOXIC; inhalation, ingestion, or skin contact with material may cause severe injury or death. Contact with molten substance may cause severe burns to skin and eyes. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution.

/GUIDE 153: SUBSTANCES - TOXIC AND/OR CORROSIVE (COMBUSTIBLE)/ Fire or Explosion: Combustible material: may burn but does not ignite readily. When heated, vapors may form explosive mixtures with air: indoors, outdoors, and sewers explosion hazards. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Contact with metals may evolve flammable hydrogen gas. Containers may explode when heated. Runoff may pollute waterways. Substance may be transported in a molten form.

/GUIDE 153: SUBSTANCES - TOXIC AND/OR CORROSIVE (COMBUSTIBLE)/ Public Safety: CALL Emergency Response Telephone Number ... As an immediate precautionary measure, isolate spill or leak area in all directions for at least 50 meters (150 feet) for liquids and at least 25 meters (75 feet) for solids. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate enclosed areas.

For more DOT Emergency Guidelines (Complete) data for MECHLORETHAMINE (9 total), please visit the HSDB record page.

For information on chemical warfare blister agents see the ERG Criminal or Terrorist Use of CBR Agents. (ERG, 2024)

- HN-2 is combustible.

TIH (Toxic Inhalation Hazard) - Term used to describe gases and volatile liquids that are toxic when inhaled. Some are TIH materials themselves, e.g., chlorine, and some release TIH gases when spilled in water, e.g., chlorosilanes. [ERG 2016].

PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practicable to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen & date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured & the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed & labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Spill kits containing all materials needed to clean up spills of hazardous drugs should be assembled or purchased. These kits should be readily available in all areas where hazardous drugs are routinely handled. If hazardous drugs are being prepared or administered in a nonroutine area (home setting or unusual patient-care area), a spill kit should be obtained by the drug handler. The kit should include two pairs of disposable gloves (one outer pair of utility gloves and one inner latex pair); low-permeability, disposable protective garments (coveralls or gown and shoe covers); safety glasses or splash goggles; respirator; absorbent, plastic-backed sheets or spill pads; disposable toweling; at least 2 sealable thick plastic hazardous waste disposal bags (prelabeled with an appropriate warning label); a disposable scoop for collecting glass fragments; and a puncture-resistant container for glass fragments. All individuals who routinely handle hazardous drugs must be trained in proper spill management and cleanup procedures. Spills and breakages must be cleaned up immediately according to the following procedures. If the spill is not located in a confined space, the spill area should be identified and other people should be prevented from approaching and spreading the contamination. Wearing protective apparel from the spill kit, workers should remove any broken glass fragments and place them in the puncture-resistant container. Liquids should be absorbed with a spill pad; powder should be removed with damp disposable gauze pads or soft toweling. The hazardous material should be completely removed and the area rinsed with water and then cleaned with detergent. The spill cleanup should proceed progressively from areas of lesser to greater contamination. The detergent should be thoroughly rinsed and removed. All contaminated materials should be placed in the disposal bags provided and sealed and transported to a designated containment receptacle. Spills occurring in the biohazard cabinet should be cleaned up immediately; a spill kit should be used if the volume exceeds 150 ml or the contents of one drug vial or ampule. If there is broken glass, utility gloves should be worn to remove it and place it in the puncture-resistant container located in the biohazard cabinet. The biological safety cabinet, including the drain spillage trough, should be thoroughly cleaned. If the spill is not easily and thoroughly contained, the biological safety cabinet should be decontaminated after cleanup. If the spill contaminates the high efficiency particulate air filter, use of the biological safety cabinet should be suspended until the cabinet has been decontaminated and the high efficiency particulate air filter replaced. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ If hazardous drugs are routinely prepared or administered in carpeted areas, special equipment is necessary to remove the spill. Absorbent powder should be substituted for pads or sheets and left in place on the spill for the time recommended by the manufacturer. The powder should then be picked up with a small vacuum unit reserved for hazardous drug cleanup. The carpet should then be cleaned according to usual procedures. The vacuum bag should be removed and discarded or cleaned, and the exterior of the vacuum cleaner should be washed with detergent and rinsed before being covered and stored. The contaminated powder should be discarded into a sealable plastic bag and segregated with other contaminated waste materials. Alternatively, inexpensive wet or dry vacuum units may be purchased for this express use and used with appropriate cleaners. All such units are contaminated, once used, and must be cleaned, stored, and ultimately discarded /properly/ ... The circumstances and handling of spills should be documented. Health-care personnel exposed during spill management should also complete an incident report or exposure form. /Antineoplastic agents/

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds & specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods & recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous & organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp & carcinogenic wastes generated by this treatment conducted to & burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter & misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/

For more Disposal Methods (Complete) data for MECHLORETHAMINE (6 total), please visit the HSDB record page.

PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food & beverage containers or utensils, & the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, & rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes & wear protective suits (preferably disposable, one-piece & close-fitting at ankles & wrists), gloves, hair covering & overshoes. ... clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves & gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, & disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": ... operations connected with synth & purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care & vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... & when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, & contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) & label fixed to it, giving date of test & avg air-flow measured. This test should be repeated periodically & after any structural changes. /Chemical Carcinogens/

For more Preventive Measures (Complete) data for MECHLORETHAMINE (10 total), please visit the HSDB record page.

HN-2 is a suspected carcinogen, developmental toxin, and reproductive toxin. Chronic or repeated exposure to HN-2 may cause bone marrow suppression, lymph node damage, weakening of the immune system, kidney damage, and reproductive system damage. Chronic or repeated exposure to HN-2 may cause genotoxicity.

0.002 [mg/m3]

0.022 [mg/m3]

0.37 [mg/m3]

For information on chemical warfare blister agents see the ERG Criminal or Terrorist Use of CBR Agents. (ERG, 2024)

PRECAUTIONS FOR "CARCINOGENS": ... dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece & close-fitting at ankles & wrists), gloves, hair covering & overshoes. ... In chemical laboratory, gloves & gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, & disposable plastic aprons might provide addnl protection. ... gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/

GENERAL INFORMATION

The aim of this study was to test the efficacy of several candidate molecules against sulfur mustard (SM) and nitrogen mustard (HN2) using a human bronchial-epithelial cell line (16HBE14o-). Candidate molecules were chosen on the basis of the known cytotoxicity mechanisms of mustards or their efficacy previously observed on other cellular models. It included the sulfhydryl-containing molecules N-acetyl-cysteine (NAC) and WR-1065, the nucleophile hexamethylenetetramine (HMT), the energy-level stabilizer niacinamide (NC), the antioxidant dimethylthiourea (DMTU), L-arginine analogues such as L-thiocitrulline (L-TC) and L-nitroarginine methyl ester (L-NAME), and the anti-gelatinase doxycycline (DOX). Their efficacy was determined using 2-(4-[3-iodophenyl)-3-(4-nitrophenyl)-5-(2, 4-disulfophenyl)-2Htetrazolium (WST-1) reduction by viable cells 24 h after initial exposure to 100 microM HN2 or SM. On individual immediate cotreatment, some molecules exhibited selective protection against only one mustard, such as DMTU and WR-1065 against HN2 and DOX against SM, whereas NAC and L-TC were effective against both SM and HN2 cytotoxicity. However, as the level of protection against SM was always weak compared to HN2, several combinations were investigated against SM to improve the protection. The effective combinations (L-TC + DOX, NAC + DOX, NAC + DMTU, NAC + HMT, NC + DOX) combined agents, reducing the bioavailability of the mustard with compounds possibly acting on the consequences of alkylation. One of these combinations, NAC + DOX, appeared to be the most interesting, as these agents are already used in human therapy. It exhibited good efficacy in delayed cotreatment (up to 90 min) against SM.

The present study was undertaken to find potent molecules against the toxicity of nitrogen mustard mechlorethamine (HN2) on respiratory epithelial cells, using a human bronchial epithelial cell line (16HBE14o-) as an in vitro model. The compounds examined included inhibitors of poly(ADP-ribose) polymerase (PARP), sulfhydryl-group donors as nucleophiles, and iron chelators and inhibitors of lipid peroxidation as antioxidants. Their effectiveness was determined upon observance of metabolic dysfunction induced by HN2 following a 4-hr exposure, using (3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) reduction and ATP-level assays as indicators. Moreover, the fluorescent probe, monobromobimane (mBBr), and 2',7'-dichlorofluorescin-diacetate (H2DCF-DA) were used to assess intracellular sulfhydryl and peroxide level modifications by flow cytometry, respectively, following a 3-h exposure. Cell death was assessed by flow cytometry using the propidium iodide (PI)-dye-exclusion assay following 24-hr exposure. PARP inhibitors (niacinamide, 3-aminobenzamide, 6(5H)-phenanthridinone), and two sulfhydryl-group donors (N-acetylcysteine, WR-1065) were found to be effective in preventing HN2-induced metabolic dysfunction when added in immediate or delayed treatment with HN2. Only N-acetylcysteine, however, was found to prevent cell death induced by HN2, though it must be present at the time of the HN2 challenge.

Cycloheximide is reported to protect rat intestinal crypt cells from mitotic inhibition by mechlorethamine as it is an inhibitor of protein synthesis.

Caffeine potentiates the cytotoxic action of mechlorethamine against cultured P388 mouse lymphoma cells. Caffeine did not potentiate the cytotoxic action of the /mechlorethamine/ against W256 rat mammary carcinosarcoma cells, which were 5 to 7 times more sensitive than P388 cells to the cytotoxic action of /mechlorethamine/. Potentiation was observed ... When caffeine was present during ... 12 to 100 hr after a 1 hr exposure of P388 cells to /mechlorethamine/ caffeine ... At concentrations <0.1 m/m increased the mean population doubling times of the two types of cells.

For more Interactions (Complete) data for MECHLORETHAMINE (12 total), please visit the HSDB record page.

Mild and transient elevations in serum aminotransferase levels were not uncommon during cycles of cancer chemotherapy regimens that included mechlorethamine, but its role in causing these abnormalities was never entirely clear. The enzyme elevations were usually mild, transient and without symptoms, so that dose modifications of mechlorethamine were rarely needed. Mechlorethamine has not been associated specifically with clinically apparent liver injury. Sinusoidal obstruction syndrome has been reported after MOPP therapy, but largely in patients with other risk factors for this complication, such as total body irradiation or previous courses of antineoplastic therapy. Topical mechlorethamine has not been associated with liver injury, although the possibility of systemic absorption continues to make hepatic adverse events mentioned as a concern. Careful analysis for bone marrow toxicity and plasma concentrations of the drug, however, have failed to demonstrate any evidence for significant absorption with proper use of the cutaneous gel.

TERRESTRIAL FATE: The hydrolysis of mechlorethamine is generally described as rapid(1,2). A hydrolysis half-life of 11 hours was reported for mechlorethamine in a 66.7% acetone-water solution at 25 °C(3), and would be expected to be more rapid in a solution with just water as the solvent (SRC). The predominate environmental fate of mechlorethamine is expected to be hydrolysis, and it will not be expected to leach in soil(SRC). Mechlorethamine is not expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 0.17 mm Hg at 25 °C(1).

AQUATIC FATE: The hydrolysis of mechlorethamine is generally described as rapid(1,2). A hydrolysis half-life of 11 hours was reported for mechlorethamine in a 66.7% acetone-water solution at 25 °C(3), and would be expected to be more rapid in a solution with just water as the solvent(SRC). The predominate environmental fate of mechlorethamine is expected to be hydrolysis and therefore bioconcentration is not expected to be an important environmental fate process(SRC). The hydrolysis of mechlorethamine may be limited by its rate of dissolution(SRC) as is seen for a related compound, bis(2-chloroethyl)sulfide (mustard gas)(4).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), mechlorethamine, which has a vapor pressure of 0.17 mm Hg at 25 °C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase mechlorethamine is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 2 days(SRC), calculated from its rate constant of 8.4X10-12 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Mechlorethamine does not contain any functional groups that would be expected to absorb light with wavelengths >290 nm, and it would not be expected to be susceptible to direct photolysis by sunlight(SRC).

HN-2 can be absorbed into the body by inhalation, ingestion, eye contact, and skin contact. Inhalation is an important route of exposure. Ingestion is an uncommon route of exposure. Tender skin, the moist lining of body passages and cavities (mucous membranes) and perspiration-covered skin are more sensitive to the effects of this agent.

Partially absorbed following intracavitary administration, most likely due to rapid deactivation by body fluids. When it is topically administered, systemic exposure was undetectable.

Alkylating agents work by three different mechanisms: 1) attachment of alkyl groups to DNA bases, resulting in the DNA being fragmented by repair enzymes in their attempts to replace the alkylated bases, preventing DNA synthesis and RNA transcription from the affected DNA, 2) DNA damage via the formation of cross-links (bonds between atoms in the DNA) which prevents DNA from being separated for synthesis or transcription, and 3) the induction of mispairing of the nucleotides leading to mutations. Mechlorethamine is cell cycle phase-nonspecific.

- Mild (onset within 4 to 12 hours): Tear production (lacrimation), irritation, itching, burning, spasmodic blinking (blepharospasm), dryness or gritty feeling, and possible pinpoint pupils (miosis).

- Nausea, vomiting (emesis), pain, hemorrhagic diarrhea, and chemical burns of the gastrointestinal (GI) tract.

- Mild (onset within 2 to 24 hours): Runny nose (rhinorrhea), sneezing, nosebleed (epistaxis), hoarseness progressing to “toneless” voice, barking cough, loss of taste and smell, wheezing and difficulty breathing or shortness of breath (dyspnea) in smokers and asthmatics, and nasal and sinus pain (occurring later).

- Tender skin, the moist lining of body passages and cavities (mucous membranes), and perspiration-covered skin are more sensitive to the effects of nitrogen mustard.

PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/

A hydrolysis half-life of 11 hours was reported for mechlorethamine in a 66.7% acetone-water solution at 25 °C(1) and would be expected to be more rapid in a solution with just water as the solvent (SRC). The predominant environmental fate of mechlorethamine is expected to be hydrolysis, and it will not be expected to leach in soil(SRC).

/HUMAN EXPOSURE STUDIES/ During the Iraq-Iran war (1980-1988), a group of patients exposed to mustard gas (one of the chemical warfare agents used by Iraq) were referred to our dermatology department. ... A group of patients, including 14 children and teenagers, exposed to mustard gas were studied. Laboratory tests including blood cell counts, hemoglobin, hematocrit, urine analysis, etc., were determined. Among the most frequent disorders were facial involvement (78%), which dominated the clinical picture, followed by genital (42%), truncal, and axillary lesions (both 14%). Eosinophilia was the most prominent laboratory disorder seen in 12% of the patients. Skin lesions started 4-18 hours after exposure. Erythema developed within 20-30 hours after exposure, followed by blisters. The time of onset of manifestations had been shorter and severity of the lesions higher in children and teenagers compared with adults. Both phenomena could be attributed to the more delicate skin of the young patients. Genital manifestations were less frequent in this subgroup while ophthalmic, pulmonary, and gastrointestinal lesions were more frequently encountered in children than in adults. /Unspecified mustard gas/

/SIGNS AND SYMPTOMS/ Nitrogen mustard exposure following absorption from the skin or respiratory or gastrointestinal tracts may exert profound effects on the hematopoietic and lymphoid tissue. Degenerative bone marrow changes may be detected within 12 hours and may progress to severe aplasia. There may be a transient leukocytosis for a few hours, followed by severe lymphopenia, granulocytopenia, thrombocytopenia, and a moderate anemia. /Nitrogen mustard/

/CASE REPORTS/ A 55-year-old man with chronic, active diffuse psoriasis was accidentally given 30 mg of mechlorethmine deep into the buttock muscles. About 5 hours after the intramuscular (IM) mechlorethamine injection, 1/6 M sodium thiosulfate was infused around the intramuscular site. Although systemic responses to the mechlorethamine developed, the expected muscular and adjacent skin destruction did not occur. Instead, IM mechlorethamine induced only minimal local tenderness.

/SPECIAL STUDIES/ The temporal regulation, of cyclin A- and B1-dependent kinases /were investigated/ in human lymphoma cells treated with nitrogen mustard and pentoxifylline, to determine whether the activity of these complexes correlated with cell cycle arrest induced by DNA damage. Cells were synchronized in Gl/S, treated with nitrogen mustard, and then postincubated with pentoxifylline. Nitrogen mustard-induced a protracted delay in G2 phase. This delay correlated with suppression of cyclin Bl- and cdc2-kinase activities, and stabilization of hyperphosphorylated-cdc2 in the presence of similar cyclin Bl levels to those found in mitosis. Nitrogen mustard had no discernible effect on the S phase activity of cyclin A- or cdk2-immune complexes. Entry of control cells into mitosis correlated with destruction of cyclin A, disappearance of cyclin A-bound cdk2 and decreased cdk2 kinase activity. G2 delay induced by nitrogen mustard was associated with stabilization of cyclin A, increased abundance of cyclin A-bound cdk2, and increased cdk2 activity. Cyclin A was also associated with cdc2, which, contrary to complexes containing cdk2, were only activated upon entry into mitosis. Pentoxifylline abrogated cell cycle arrest induced by aphidicolin and nitrogen mustard in human lymphoma cells. Pentoxifylline also reverted the activity of cyclin A- and Bl-kinases in nitrogen mustard-treated cells to approximately that observed in controls. Delayed entry into mitosis following DNA damage correlates with suppression of cyclin B1/cdc2 and cyclin A/cdc2 complexes, while maintaining cyclin A/cdc2 complexes in an active state. Furthermore, pentoxifylline disrupts the signal transduction pathway that regulates these complexes when damaged DNA is present, resulting ln abrogation of cell cycle arrest.

For more Human Toxicity Excerpts (Complete) data for MECHLORETHAMINE (6 total), please visit the HSDB record page.

Mechlorethamine as its hydrochloride salt is used as an antineoplastic agent(1,2). Mechlorethamine hydrochloride's production and use may result in the release of mechloroethamine to the environment through various waste streams(SRC). Mechlorethamine was produced as a vesicant in chemical warfare(2). While mechlorethamine was not used for military purposes, stockpiles may have existed in the US as recently as 1974(2). Mechlorethamine production and storage may result in its release to the environment through various waste streams(SRC), although it is not manufactured in commercial quantities in the US(2).

Releases of CERCLA hazardous substances are subject to the release reporting requirement of CERCLA section 103, codified at 40 CFR part 302, in addition to the requirements of 40 CFR part 355. Mechlorethamine is an extremely hazardous substance (EHS) subject to reporting requirements when stored in amounts in excess of its threshold planning quantity (TPQ) of 10 lbs.

HN2 (nitrogen mustard-2)

CUM 100g

CUM 100g

Chemical Weapons/Chemical Weapons Precursors chemical material that, if stolen or diverted, can be converted into weapons using simple chemistry, equipment, or techniques.

L - Antineoplastic and immunomodulating agents

QL - Antineoplastic and immunomodulating agents

Mechlorethamine also known as mustine, nitrogen mustard, and HN2, is the prototype anticancer chemotherapeutic drug. Successful clinical use of mechlorethamine gave birth to the field of anticancer chemotherapy. The drug is an analogue of mustard gas and was derived from toxic gas warfare research. Mechlorethamine is a nitrogen mustard alkylating agent. Alkylating agents work by three different mechanisms all of which achieve the same end result - disruption of DNA function and cell death.

Alkylating agents work by three different mechanisms: 1) attachment of alkyl groups to DNA bases, resulting in the DNA being fragmented by repair enzymes in their attempts to replace the alkylated bases, preventing DNA synthesis and RNA transcription from the affected DNA, 2) DNA damage via the formation of cross-links (bonds between atoms in the DNA) which prevents DNA from being separated for synthesis or transcription, and 3) the induction of mispairing of the nucleotides leading to mutations. Mechlorethamine is cell cycle phase-nonspecific.

Mechlorethamine, as an alkylating agent, interferes with DNA replication and transcription of RNA, and ultimately results in the disruption of nucleic acid function.

The alkylating agent, nitrogen mustard (HN2), is thought to cause apoptosis through production of free oxygen radicals. To explore the mechanism of HN2-induced apoptosis, we utilized ebselen, a selenoorganic compound with potent antioxidant activity. We examined whether ebselen would inhibit apoptosis in BALB/c mouse spleen lymphocytes and human MOLT-4 leukemia cells treated with HN2 (2.5 microM) in vitro. Non-toxic concentrations (<50 microM) of ebselen were found to prevent HN2-induced apoptosis of murine lymphocytes in a dose-dependent manner, as measured by cell viability, hypodiploid DNA formation, and phosphatidylserine externalization. However, ebselen was ineffective at preventing spontaneous apoptosis in these cells, pointing to the selectivity of its action. Furthermore, pretreatment with ebselen at 1-10 microM for 72 hr protected MOLT-4 cells from HN2-induced apoptosis and maintained cell viability and proliferation as monitored by the above-mentioned parameters. This was accompanied by the preservation of mitochondrial transmembrane potential and elevated glutathione levels and by a blockage of caspase-3 and -9 activation. In vivo, ebselen also had a marked protective effect against spleen weight loss associated with lymphocyte apoptosis in mice treated by HN2. Therefore, ebselen provides an efficient protection against HN2-induced cell death in normal and tumoral lymphocytes and might prove useful as an antidote against alkylating agents.

Nitrogen mustard (bis(2-chloroethyl) methylamine, HN2) inhibited the binding of upstream factors Sp1 and AP2 to their consensus sequences. At concentrations where 50% of the consensus sequence DNA contained at least one lesion, HN2 inhibited formation of the Sp1 complex by 37% (40 microM HN2) and the AP2 complex by 40% (50 microM HN2). The binding of the TATA binding protein (TBP) to the TATA element was also inhibited by HN2, whereas sulphur mustard and the monofunctional sulphur mustard 2-chloroethyl ethyl sulphide (CEES) resulted in a disproportional extent of inhibition with respect to the level of alkylation. The level of alkylation of the TBP oligonucleotide varied significantly at 100 microM drug, with 80, 42 and 15% of HN2, sulphur mustard and CEES, respectively. However, this level of alkylation inhibited formation of the TBP-DNA complex by 70, 70 and 45%, respectively. This differential sensitivity of transcription factors to mustard-induced DNA damage therefore appears to reside dominantly in the stereochemical differences between the specific mustard lesions.

The ability of the antioxidant N-acetylcysteine to prevent apoptosis induced in lymphocytes by nitrogen mustard (HN2) was investigated. HN2 caused a concentration-dependent induction of apoptosis on C3H murine spleen cells, as identified by two criteria: morphological features revealed by microscopical observations and DNA fragmentation visualized by the characteristic "ladder" pattern observed upon agarose gel electrophoresis, as well as by hypodiploid DNA-containing cells revealed by the flow cytometric analysis of propidium iodide labelled cells. The antioxidant N-acetylcysteine (NAC) was found to markedly reduce the occurrence of HN2-induced apoptosis in these cells. This protective effect will still obtained when NAC was added 30 min after HN2. In contrast, the pretreatment of spleen cells with this antioxidant did not provide any significant protection. We also showed that lymphocytes protected by NAC are still able to respond to a mitogenic stimulation. To gain some insight into the mechanisms underlying the cytoprotective action of NAC against HN2, we tested whether or not poly(ADP-ribose) polymerase (PARP, EC 2.4.2.30), a nuclear enzyme that participates in the triggering of apoptosis induced by alkylating agents, is involved. We report that 6(5H)-phenanthridinone, a potent PARP inhibitor, did not affect the ability of NAC to prevent HN2-induced apoptosis under our experimental conditions. Thus, the exact mechanism by which NAC protects lymphocytes from HN2 cytotoxicity has yet to be determined.

Undergoes rapid chemical transformation and combines with water or reactive compounds of cells, so that the drug is no longer present in active form a few minutes after administration.

Following its in vivo admin, mechlorethamine or its hydrochloride is probably converted into ethyleneimmonium ion which reacts with guanine residues in /either the same or/ adjacent strands of DNA as well as with SH groups.

In vivo hydrolytic splitting of quaternary nitrogen mustard compound gives rise to n-methyl mustard a potent inducer of chromatid aberrations in Vicia faba root meristems and ascites tumors of mouse. In Vicia faba, nitromin was much less effective inducer than nitrogen mustard.

Undergoes rapid chemical transformation and combines with water or reactive compounds of cells, so that the drug is no longer present in active form a few minutes after administration. Half Life: 15 minutes

50D9XSG0VR

MECHLORETHAMINE

Mechanisms of Action [MoA] - Alkylating Activity

Established Pharmacologic Class [EPC] - Alkylating Drug

Mechlorethamine is an Alkylating Drug. The mechanism of action of mechlorethamine is as an Alkylating Activity.

Highly reactive chemicals that introduce alkyl radicals into biologically active molecules and thereby prevent their proper functioning. Many are used as antineoplastic agents, but most are very toxic, with carcinogenic, mutagenic, teratogenic, and immunosuppressant actions. They have also been used as components in poison gases.

Chemicals that are used to cause the disturbance, disease, or death of humans during WARFARE.

Drugs that act locally on cutaneous or mucosal surfaces to produce inflammation; those that cause redness due to hyperemia are rubefacients; those that raise blisters are vesicants and those that penetrate sebaceous glands and cause abscesses are pustulants; tear gases and mustard gases are also irritants.

A class of drugs that differs from other alkylating agents used clinically in that they are monofunctional and thus unable to cross-link cellular macromolecules. Among their common properties are a requirement for metabolic activation to intermediates with antitumor efficacy and the presence in their chemical structures of N-methyl groups, that after metabolism, can covalently modify cellular DNA. The precise mechanisms by which each of these drugs acts to kill tumor cells are not completely understood. (From AMA, Drug Evaluations Annual, 1994, p2026)

Partially absorbed following intracavitary administration, most likely due to rapid deactivation by body fluids. When it is topically administered, systemic exposure was undetectable.

Iv dose of 3 mg/kg body wt /mechlorethamine/ administered to dogs rapidly disappeared from blood: 0.01% was found in urine, and low levels were found in tissues, highest concentration being in bone marrow. 90% breakdown ... Occurred within 4 min of incubation with whole blood.

... Immediate disappearance of (14)CH3-labeled mechlorethamine from blood of dogs given 0.5 mg/kg iv over 5 sec or 60 min, and low urinary excretion of HN2. ... In rats, 16% of injected dose of mechlorethamine was found present in spleen, lung, kidneys, liver and blood, and 17% was excreted in urine.

Absorption may occur after skin or eye exposure to liquid or vapor nitrogen mustard and may cause systemic toxicity. .../Nitrogen mustards/ ...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. /Nitrogen mustards/

Used as an antineoplastic drug and formerly used as a gas warfare agent; [HSDB]

Antineoplastic agent /Hydrochloride/

As a former gas warfare agent.

Lab experiments ... conducted ... for use as cross linking agent in textiles. In USSR ... tested for use in sizing agents for cotton yarn, in grease for metal cutting, as fungicide and as antiviral aerosol disinfectant.

HN-2 is one of three nitrogen mustard blister agents (vesicants). Nitrogen mustards have not previously been used in warfare. The properties of nitrogen mustards are only slightly different from those of sulfur mustards, another major class of blister agents. However, exposure to nitrogen mustards may be more immediately toxic than exposure to sulfur mustard. Nitrogen mustards are alkylating agents that affect DNA and other molecules in the body. Exposure to nitrogen mustard damages the eyes, skin, and respiratory tract and suppresses the immune system. Although the nitrogen mustards cause cellular changes within minutes of contact, the onset of pain and other symptoms is delayed. Exposure to large amounts can be fatal. HN-2 has a fruity odor at high concentrations, and a soapy or fishy odor at low concentrations.

For the palliative treatment of Hodgkin's disease (Stages III and IV), lymphosarcoma, chronic myelocytic or chronic lymphocytic leukemia, polycythemia vera, mycosis fungoides, and bronchogenic carcinoma. Also for the palliative treatment of metastatic carcinoma resulting in effusion.

Ethanamine, 2-chloro-N-(2-chloroethyl)-N-methyl-: ACTIVE

Only known commercial deriv of mechlorethamine is its hydrochloride ...

Bis(2-chloroethyl)methylamine is listed as a Schedule 1 chemical.

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.