Chlormethine

Absorption

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

Toxicity

Symptoms of overexposure include severe leukopenia, anemia, thrombocytopenia, and a hemorrhagic diathesis with subsequent delayed bleeding may develop. Death may follow. The most common adverse reactions (≥5%) of the topical formulation are dermatitis, pruritus, bacterial skin infection, skin ulceration or blistering, and hyperpigmentation. The oral LD50 for a rat is 10 mg/kg.

Description

Nitrogen mustards are very potential chemical substances of yesteryears and produced during the 1920s and 1930s as chemical warfare weapons. They are vesicants (or blister agents) similar to the sulphur mustards. They smell fishy, musty, soapy, or fruity and are either in the form of an oily textured liquid or a vapour (the gaseous form of a liquid) or a solid. It is in liquid form at normal room temperature (70 F) with a clear, pale amber, or yellow colour. HN-1, HN-2, and HN-3 are the military designations of nitrogen mustard (for more data, refer to Muatars gas). Nitrogen mustards (HN-1, HN-2, HN-3) are colourless to yellow, oily liquids that evaporate very slowly. HN-1 has a faint fishy or musty odour. HN-2 has a soapy odour at low concentrations and a fruity odour at higher concentrations. HN-3 may smell like butter almond. Use of nitrogen mustards is very much restricted other than for chemical warfare. In fact, presently, its use has no records. HN-1 has been used to remove warts in the past, and HN-2 has been used sparingly in chemotherapy.

Chemical properties

Nitrogen mustard is a pale yellow, oily, mobile liquid with a faint odor of herring. Nitrogen mustards are colorless when pure but are typically a yellow to brown oily substance. Odors are variably described as; sweet, agreeable, slightly garlic- or mustard-like. NIOSH reports HN-2 as having “a fruity odor at high concentrations, and a soapy or fishy odor at low concentrations.

The Uses of Chlormethine

Antineoplastic.

The Uses of Chlormethine

HN-2 has been used sparingly in chemotherapy.

Production Methods

The nitrogen mustards are tertiary amines in which the halogen atom and the amine portion have reactivities similar to those of alkyl halides and alkyl amines. They are oily liquids that have limited water solubility but form readily soluble hydrochlorides. They are prepared by the action of thionyl chloride on the appropriate alkanolamine. Many of the actions of the nitrogen mustards resemble those of ethyleneimine derivatives because they are transformed in aqueous solutions into the highly reactive ethylenimonium intermediates: these ions can readily react with a variety of organic compounds in vitro, especially with amino, sulfhydro, and carboxyl groups of proteins and phosphate groups in nucleic acid, and therefore can alkylate biologically important macromolecules.

Definition

A class of compounds with fishy odor and lachrymatory properties. They are named from their similarity in structure to mustard gas (dichlorodiethyl sulfide). The sulfur of the mustard gas is replaced by an amino nitrogen.Typical nitrogen mustards are halogenated alkylamines, such as methyl bis(2-chloroethyl)amine: (ClCH2CH2)2NCH3. Other examples are triethylene melamine, triethylene thiophosphoramide, and triethylene phosphoramide.

Indications

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.

Background

A vesicant and necrotizing irritant destructive to mucous membranes, mechlorethamine is an alkylating drug. It was formerly used as a war gas. The hydrochloride is used as an antineoplastic in Hodgkin's disease and lymphomas. It causes severe gastrointestinal and bone marrow damage.
The FDA granted marketing approval for the orphan drug Valchlor (mechlorethamine) gel on August 23, 2013 for the topical treatment of stage IA and IB mycosis fungoides-type cutaneous T-cell lymphoma (CTCL) in patients who have received prior skin-directed therapy. Each tube of Valchlor contains 0.016% of mechlorethamine which is equivalent to 0.02% mechlorethamine HCl.

brand name

Mustargen (Ovation).

General Description

Mobile liquid; faint odor of herring. Used as a drug for the treatment of cancer. Formerly used as a gas warfare agent.

Reactivity Profile

Chlormethine 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.

Hazard

Strong irritant to tissues, lachrymatory. Probable carcinogen.

Health Hazard

Toxic doses as low as 400 mg/kg have been reported in humans. Blood clots may occur at site of intravenous injection and tissue damage if outside vein. Powerful vesicant (causes blisters) when it contacts skin, mucous membranes, or eyes. Delayed toxicity -- missed menstrual periods, alopecia (hair loss), hearing loss, tinnitus (ringing in ears), jaundice, impaired spermatogenesis and germinal aplasia, swelling, and hypersensitivity. May damage fetus in pregnant women.

Fire Hazard

Undiluted liquid decomposes on standing.

Pharmacokinetics

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.

Safety Profile

Confirmed human carcinogenproducing skin tumors by skin contact. Experimentalcarcinogenic, tumorigenic, and neoplastigenic data. Adeadly poison by inhalation, ingestion, skin contact, andmost other routes. Experimental teratogenic andreproductive eff

Potential Exposure

Drug used in treatment of cancer. 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. Sulfur mustards were formerly used as a gas warfare agent. Nitrogen mustards have not previously been used in warfare

First aid

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.[NIOSH] Because health effects due to nitrogen mustard may not occur until several hours after exposure, patients/victims should be observed in a hospital setting for at least 24 h. Gastric lavage is contraindicated following ingestion of this agent due to the risk of perforation of the esophagus or upper airway. If this chemical gets into the eyes, remove any contact lenses at once and irrigate immediately for at least 15 min, occasionally lifting upper and lower lids. Seek medical attention immediately. If this chemical contacts the skin, remove contaminated clothing and wash immediately with soap and water. Speed in removing material from skin is of extreme importance. Seek medical attention immediately. If this chemical has been inhaled, remove from exposure, begin rescue breathing (using universal precautions, including resuscitation mask) if breathing has stopped and CPR if heart action has stopped. Transfer promptly to a medical facility. When this chemical has been swallowed, get medical attention. Give large quantities of water and induce vomiting. Do not make an unconscious person vomit. Keep victim quiet and maintain normal body temperature. Effects may be delayed; keep victim under observation.

Metabolism

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.

storage

Color Code—Blue: Health Hazard/Poison: Store in a secure poison location. Prior to working with this chemical you should be trained on its proper handling and storage. A regulated, marked area should be established where this chemical is handled, used, or stored. Store in 1674 Mechlorethamine (Agent HN-2, WMD) tightly closed containers in a cool, well-ventilated area. Where possible, automatically pump liquid from drums or other storage containers to process containers.

Shipping

UN2810 Toxic liquids, organic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials, Technical Name Required. Military driver shall be given full and complete information regarding shipment and conditions in case of emergency. AR 50-6 deals specifically with the shipment of chemical agents. Shipments of agent will be escorted in accordance with AR 740-32

Incompatibilities

HN-2 is not stable except as dry crystals. Polymerization of HN-2 results in components that present an explosion hazard in open air. Avoid contact or contamination with oxidizers e.g., nitrates, oxidizing acids; chlorine bleaches pool chlorine); which may result in ignition. Unstable in the presence of light and heat and forms dimers at temperatures above 50C. Corrosive to ferrous alloys beginning @ 65C. Polymerizes slowly, so munitions would be effective for several years. Heated to decomposition emits hydrogen chloride and nitrogen oxide. Contact with metals may evolve flammable hydrogen gas. Note: Chlorinating agents destroy nitrogen mustards. Dry chlorinated lime and chloramines with a high content of active chlorine vigorously chlorinate nitrogen mustards to the carbon chain, giving low toxicity products. In the presence of water this interaction proceeds less actively. They are rapidly oxidized by peracids in aqueous solution at weakly alkaline pH. In acid solution the oxidation is much slower.
An amine and a chemical base: will neutralize acids to form salts plus water with an exothermic reaction. 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, nitrides, alkali metals, and sulfides

Waste Disposal

It is inappropriate and possibly dangerous to the environment to dispose of expired or waste drugs and pharmaceuticals by flushing them down the toilet or discarding them to the trash. Household quantities of expired or waste pharmaceuticals may be mixed with wet cat litter or coffee grounds, double-bagged in plastic, discard in trash. Larger quantities shall carefully take into consideration applicable DEA, EPA, and FDA regulations. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged, and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator