Dacarbazine

182.18

182.18

224-396-1

7GR28W0FJI

759610|45388

DTXSID0020369

C411

IVORY MICROCRYSTALINE SUBSTANCE

L - Antineoplastic and immunomodulating agents

2934999090

99.73000

-0.24

Dacarbazine appears as white to ivory microcrystals or off-white crystalline solid. (NTP, 1992)

1.5±0.1 g/cm3

205 °C

456.3±55.0 °C at 760 mmHg

229.7±31.5 °C

1.678

Slightly soluble in water, DMSO and ethanol/n

2-8°C

pKa= 4.42

Sensitive to oxidation; stable in neutral solutions in absence of light. Extremely light-sensitive: rapidly undergoes chemical decomposition to form 4-diazoimidazole-5-carboxamide ... .

Insoluble in water.

Amides and Imides

DACARBAZINE decomposes explosively at its melting point (250°C). Decomposes in the presence of light. Sensitive to oxidation.

NONH for all modes of transport

3

45-46-20/21/22-36/37/38

53-36/37/39-45-37/39-36-26

NI3950000

T,Xi,Xn

Dacarbazine is extremely light sensitive and rapidly undergoes photodecomposition. Dacarbazine is sensitive to oxidation but is stable in neutral solutions in the absence of light.

P201-P261-P280-P305 + P351 + P338-P308 + P313

H302 + H312 + H332-H315-H319-H335-H340-H350

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/|PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/|For more Disposal Methods (Complete) data for DACARBAZINE (13 total), please visit the HSDB record page.

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

Weisburger EK; Bioassay Program for Carcinogenic Hazards of Cancer Chemotherapeutic Agents; Cancer 40: 1935-49 (1977). Route: intraperitoneal injection; Species: rats and mice.|National Toxicology Program. Eleventh Report on Carcinogens (2005). The Report on Carcinogens is an informational scientific and public health document that identifies and discusses substances (including agents, mixtures, or exposure circumstances) that may pose a carcinogenic hazard to human health. Dacarbazine (4342-03-4) is listed as reasonably anticipated to be a human carcinogen.[Available from, as of July 31, 2009: http://ntp.niehs.nih.gov/ntp/roc/eleventh/profiles/s054daca.pdf]|Reichman BS, Green KB; Breast Cancer in Young Women: Effect of Chemotherapy on Ovarian Function, Fertility, and Birth Defects; Monogr Natl Cancer Inst 16:125-9 (1994). A comprehensive review of the literature was done to assess the effect of adjuvant chemotherapy for operable breast cancer on ovarian function, fertility, and birth defects.

Flash point data for this chemical are not available. It is probably combustible. (NTP, 1992)

|Danger|H302+H312+H332 (90.48%): Harmful if swallowed, in contact with skin or if inhaled [Warning Acute toxicity, oral; acute toxicity, dermal; acute toxicity, inhalation]|P201, P202, P261, P264, P270, P271, P280, P281, P301+P312, P302+P352, P304+P312, P304+P340, P305+P351+P338, P308+P313, P312, P321, P322, P330, P332+P313, P337+P313, P362, P363, P403+P233, P405, and P501|Aggregated GHS information provided by 42 companies from 5 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Fires involving this material can be controlled with a dry chemical, carbon dioxide or Halon extinguisher. A water fog may also be used. (NTP, 1992)

SMALL SPILLS AND LEAKAGE: If you spill this chemical, you should dampen the solid spill material with water, then transfer the dampened material to a suitable container. Use absorbent paper dampened with water to pick up any remaining material. Seal your contaminated clothing and the absorbent paper in a vapor-tight plastic bag for eventual disposal. Wash all contaminated surfaces with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned. STORAGE PRECAUTIONS: You should protect this chemical from exposure to light. Keep the container tightly closed under an inert atmosphere, and store under refrigerated temperatures. (NTP, 1992)

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with a combination filter cartridge, i.e. organic vapor/acid gas/HEPA (specific for organic vapors, HCl, acid gas, SO2 and a high efficiency particulate filter). (NTP, 1992)|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/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Protective apparel: Disposable closed-front gown or coveralls, disposable utility gloves over disposable latex gloves, NIOSH-approved air-purifying half-mask respirator equipped with a high efficiency filter, and eye protection should be worn. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Class 100 clean-air work stations, both horizontal and vertical airflow (with no containment characteristics), are inappropriate engineering controls for handling hazardous drugs because they provide no personnel protection and permit environmental contamination. Although there are no engineering controls designed specifically for the safe handling of hazardous chemicals as sterile products, Class II contained vertical-flow biological safety cabinets (biohazard cabinets) have been adopted for this use. Biohazard cabinetry is, however, designed for the handling of infectious agents, not hazardous chemicals. ... Based on design, ease of use, and cost considerations, Class II contained-vertical-flow biohazard cabinetry is currently recommended for use in preparing sterile doses of hazardous drugs. Class II cabinetry design and performance specifications are defined in NSF Standard 49. Biological safety cabinets selected for use with hazardous drugs should meet NSF Standard 49 specifications to ensure the maximum protection from these engineering controls. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Workers should wear powder free, disposable surgical latex gloves of good quality when preparing hazardous drugs. Selection criteria for gloves should include thickness (especially at the fingertips where stress is the greatest), fit, length, and tactile sensation. ... The practice of double gloving is supported by research that indicates that many glove materials vary in drug permeability even within lots; therefore, double gloving is recommended. ... In general, surgical latex gloves fit better, have appropriate elasticity for double gloving and maintaining the integrity of the glove-gown interface, and have sufficient tactile sensation (even during double gloving) for stringent aseptic procedures. ... Powdered gloves should be avoided. /Antineoplastic agents/|For more Personal Protective Equipment (PPE) (Complete) data for DACARBAZINE (6 total), please visit the HSDB record page.

EXPLOSIVE DECOMP AT 250-255 °C.

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/

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 DACARBAZINE (28 total), please visit the HSDB record page.

PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped & will resist attack from the carcinogen. Both bottle & the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies & airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/|PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary & secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen & is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container & the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest & most secure form of transport & notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/

LD50=350mg/kg (orally in mice)

Mild and transient elevations in serum aminotransferase levels are not uncommon during courses of systemic combination chemotherapy and the role of dacarbazine in these abnormalities is not clear. However, dose modification for serum enzyme elevations is rarely necessary. More importantly, dacarbazine is associated with a severe and distinctive liver injury which typically arises during the second or third cycle of therapy and most likely represents severe acute sinusoidal obstruction syndrome. Patients typically develop the sudden onset of severe abdominal pain, hemodynamic instability and rapidly rising levels of serum aminotransferase levels and prothrombin time, with death within 1 to 10 days (Cases 1 and 2). Liver biopsy and necropsy findings indicate centrolobular necrosis with occlusion of sinusoids and small and large hepatic veins. In some cases, hepatic infarcts are found as well. Eosinophilic infiltrations are common and peripheral eosinophilia may also be present. Unlike with other alkylating agents, sinusoidal obstruction syndrome caused by dacarbazine is associated with the usual chemotherapy doses, not the higher doses used in myeloablation in preparation for bone marrow transplantation. This syndrome is now rarely reported, probably because of use of dacarbazine in somewhat lower doses.

Dacarbazine-induced inhibition of xanthine oxidase may cause additive hypouricemic effects when use concurrently with allopurinol.|Leukopenic and/or thrombocytopenic effects of dacarbazine may be increased with concurrent or recent therapy /with blood dyscrasia-causing medications/ if these medications cause the same effects; dosage adjustment of dacarbazine, if necessary, should be based on blood counts.|Additive bone marrow depression may occur; dosage reduction may be required when two or more bone marrow depressants, including radiation, are used concurrently or consecutively /with dacarbazine/.

Less than 5%

The primary routes of potential human exposure to dacarbazine are ... inhalation, and dermal contact ... Potential exposure of health professionals who handle this drug (eg, pharmacists, nurses, and physicians) may occur during drug preparation, administration, or cleanup ... Potential occupational exposure may also occur for workers involved in the formulation or packaging of the pharmaceuticals.|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The danger to health-care personnel from handling a hazardous drug stems from a combination of its inherent toxicity and the extent to which workers are exposed to the drug in the course of carrying out their duties. This exposure may be through inadvertent ingestion of the drug on foodstuffs (eg, workers' lunches), inhalation of drug dusts or droplets or direct skin contact. /Antineoplastic agents/

For the treatment of metastatic malignant melanoma. In addition, dacarbazine is also indicated for Hodgkin's disease as a secondary-line therapy when used in combination with other antineoplastic agents.|Drug: Abvd|Drug: Copdac|Drug: Dacarbazine

Dacarbazine (also known as DTIC) is an intravenously administered alkylating agent used in the therapy of Hodgkin disease and malignant melanoma. Dacarbazine therapy has been associated with serum enzyme elevations during therapy and occasional cases of severe and distinctive acute hepatic failure, probably caused by acute sinusoidal obstruction syndrome.

Antineoplastic Agents, Alkylating Agents

Antineoplastic Agents, Alkylating|AT PRESENT DACARBAZINE IS EMPLOYED PRINCIPALLY FOR THE TREATMENT OF MALIGNANT MELANOMA; THE OVERALL RESPONSE RATE IS ABOUT 20%. BENEFICIAL RESPONSES HAVE ALSO BEEN REPORTED IN PATIENTS WITH HODGKIN'S DISEASE, PARTICULARLY WHEN THE DRUG IS USED CONCURRENTLY WITH DOXORUBICIN, BLEOMYCIN, AND VINBLASTINE ..., AS WELL AS IN VARIOUS SARCOMAS WHEN USED WITH DOXORUBICIN ... .|...STATUS AS ANTINEOPLASTIC AGENT IS STILL UNDER EVALUATION. CLINICAL REPORTS INDICATE THAT AGENT MAY HAVE SIGNIFICANT ACTIVITY IN SOME CASES OF MALIGNANT MELANOMA & HODGKIN'S DISEASE. STILL TO BE ASSESSED IS POSSIBLE USE...IN COMBINATION WITH OTHER ANTINEOPLASTIC AGENTS.|Dacarbazine is used as an antineoplastic agent in the treatment of diseases such as malignant melanomas, Hodgkin's disease, soft-tissue sarcomas, osteogenic sarcomas, and neuroblastomas. It is occasionally used in the therapy of other neoplastic diseases that have become resistant to alternative treatment ... the usual initial dose is 2-4.5 mg/kg body weight intravenously or intra-arterially daily for 10 days and repeated after intervals of 4 weeks, or 100-250 mg/sq m of body surface for 5 days and repeated after intervals of 3 weeks.|For more Therapeutic Uses (Complete) data for DACARBAZINE (8 total), please visit the HSDB record page.

GI REACTIONS & HEMATOPOIETIC DEPRESSION ARE MOST PROMINENT. ... IF HEMATOPOIETIC ACTIVITY IS CAREFULLY MONITORED, DACARBAZINE USUALLY CAN BE ADMIN WITHOUT SERIOUS MYELOSUPPRESSIVE CONSEQUENCES.|ACUTE ADVERSE EFFECTS /OF DACARBAZINE/ ARE MOST PROMINENT DURING FIRST FEW DAYS OF TREATMENT & TEND TO SUBSIDE WITH CONTINUED ADMIN.|The bone marrow depressant effects of dacarbazine may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. Dental work, whenever possible should be completed prior to initiation of therapy or deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene during treatment, including caution in use of regular tooth brushes, dental floss, and toothpicks. Dacarbazine may also rarely cause stomatitis associated with considerable discomfort.|Because normal defense mechanisms may be suppressed by dacarbazine therapy, the patient's antibody response to the vaccine may be decreased. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year.|For more Drug Warnings (Complete) data for DACARBAZINE (9 total), please visit the HSDB record page.

Dacarbazine is a synthetic analog of naturally occurring purine precursor 5-amino-1H-imidazole-4-carboxamide (AIC). After intravenous administration of dacarbazine, the volume of distribution exceeds total body water content suggesting localization in some body tissue, probably the liver. Its disappearance from the plasma is biphasic with initial half-life of 19 minutes and a terminal half-life of 5 hours. 1 In a patient with renal and hepatic dysfunctions, the half-lives were lengthened to 55 minutes and 7.2 hours. 1 The average cumulative excretion of unchanged DTIC in the urine is 40% of the injected dose in 6 hours. 1 DTIC is subject to renal tubular secretion rather than glomerular filtration. At therapeutic concentrations dacarbazine is not appreciably bound to human plasma protein.

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) (See all compounds classified as Antineoplastic Agents, Alkylating.)

Erratic, slow and incomplete.|Dacarbazine is subject to renal tubular secretion rather than glomerular filtration. In man, dacarbazine is extensively degraded. Besides unchanged dacarbazine, 5-aminoimidazole -4 carboxamide (AIC) is a major metabolite of dacarbazine excreted in the urine.|15 MIN AFTER IP INJECTION OF [(14)C]-5-(3,3-DIMETHYL-1- TRIAZENO)-IMIDAZOLE-4-CARBOXAMIDE TO MICE, LEVELS OF (14)C WERE RELATIVELY HIGH IN GI TRACT (13%) & KIDNEYS (4%), INDICATING RAPID HEPATIC & RENAL ELIMINATION OF (14)C.|IN MAN, N-DEMETHYLATION WAS MAJOR METABOLIC PATHWAY, & 21% OF ORAL DOSE...WAS EXCRETED IN EXPIRED AIR IN 6 HR. THAT ORAL DOSE...WAS READILY ABSORBED IN HUMAN PT WAS INDICATED BY PEAK PLASMA LEVELS OF DRUG IN 30 MIN & URINARY EXCRETION OF UP TO 46% IN 6 HR, WHEN PLASMA DRUG LEVELS WERE NEGLIGIBLE.|PRETREATMENT OF ANIMALS WITH INDUCERS OF DRUG-METABOLIZING ENZYMES INCR AMT OF (14)C /FROM LABELED DACARBAZINE/ EXCRETED IN EXPIRED AIR, OWING TO INCR N-DEMETHYLASE ACTIVITY.|In mice, ((14)C-2)-labelled dacarbazine (50 mg/kg bw) is rapidly absorbed from the site of its ip injection and distributed to tissues; and more than 90% of the dose is eliminated in the urine within 24 hours. The plasma half-life was 20 min. Studies with dacarbazine labelled at the methyl group gave similar results, except that 9% of the radioactivity was recovered in the expired air within 24 hours, and only 44% was found in the urine ... .|For more Absorption, Distribution and Excretion (Complete) data for DACARBAZINE (11 total), please visit the HSDB record page.

Hepatic|Elevated urinary concn of 5-aminoimidazole-4-carboxamide (AIC) are derived from the catabolism of dacarbazine, rather than by inhibition of de-novo purine biosynthesis.|RATS EXCRETED 4% OF (METHYL-(14)C)-5-(3,3-DIMETHYL-1-TRIAZENO)-IMIDAZOLE-4-CARBOXAMIDE IN EXPIRED AIR IN 6 HR & 60% IN URINE IN 24 HR.|IN MAN & IN RODENTS, MAJOR METABOLITE IS AMINO DERIV /OF 5-(3,3-DIMETHYL-1-TRIAZENO)IMIDAZOLE-4-CARBOXAMIDE/. IT IS BELIEVED THAT FIRST STEP IS OXIDATIVE N-DEMETHYLATION, FOLLOWED BY SPONTANEOUS REARRANGEMENT TO YIELD...DIAZOMETHANE

5 hours|Dacarbazine is administered iv; after an initial rapid phase of disappearance (t/2 of about 20 minutes) the drug is removed from plasma with a half-time of about 5 hours ... The half-life is prolonged in the presence of hepatic or renal disease.|...AFTER IP INJECTION...TO MICE... BILIARY-SECRETED MATERIAL WAS REABSORBED, SINCE 92% WAS EXCRETED IN 24-HR URINE & ONLY 0.3% IN FECES; 9% WAS RETAINED IN BODY. PLASMA T/2 OF (14)C /IN LABELED DACARBAZINE/ WAS 20 MIN.

The mechanism of action is not known, but appears to exert cytotoxic effects via its action as an alkylating agent. Other theories include DNA synthesis inhibition by its action as a purine analog, and interaction with SH groups. Dacarbazine is not cell cycle-phase specific.|Dacarbazine functions as an alkylating agent after metabolic activation in the liver. It appears to inhibit the synthesis of RNA and protein more than it inhibits the synthesis of DNA. It kills cells slowly, and there appears to be no phase of the cell cycle in which sensitivity is increased ... .|...FOR CHEMOTHERAPEUTIC EFFECTIVENESS, DACARBAZINE REQUIRES INITIAL ACTIVATION BY CYTOCHROME P450 SYSTEM OF LIVER THROUGH N-DEMETHYLATION REACTION. IN TARGET CELL...OCCURS SPONTANEOUS CLEAVAGE LIBERATING AIC /5-AMINOIMIDAZOLE-4-CARBOXAMIDE/ & ALKYLATING MOIETY, PRESUMABLY DIAZOMETHANE...|Although the mechanism of action of dacarbazine is not known in detail, it is demethylated by liver microsomal enzymes to form an unstable monoalkyl derivative which can decompose spontaneously into alkylating moieties. In light, dacarbazine can also rapidly undergo chemical decomposition to form 4-diazoimidazole-5-carboxamide, which is highly toxic but which has no antitumor activity in vivo ... .

SYMPTOMS: Symptoms of exposure to this compound may include nausea, vomiting, bone marrow suppression, leukopenia, thrombocytopenia, hepatotoxicity, hepatic vein thrombosis and hepatocellular necrosis. Other symptoms may include hemopoietic depression, anemia, anaphylaxis, anorexia, diarrhea, facial paresthesias, death, and rarely, erythematous and urticarial rashes, and photosensitivity reactions. It may cause cardiovascular collapse, burning of the throat, abdominal pain, oliguria, anuria, delirium, fall of blood pressure, convulsions, muscular weakness with respiratory failure and collapse. Large doses may cause gastrointestinal bleeding. Exposure may also result in alopecia, facial flushing, and a flu-like syndrome of fever, myalgias and malaise. It can cause chills, dermatological reactions and neurotoxicity. ACUTE/CHRONIC HAZARDS: There is limited evidence that this compound is carcinogenic in humans. When heated to its melting point it decomposes violently and emits toxic fumes of nitrogen oxides. (NTP, 1992)

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop. SKIN: IMMEDIATELY flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. If symptoms such as redness or irritation develop, IMMEDIATELY call a physician and be prepared to transport the victim to a hospital for treatment. INHALATION: IMMEDIATELY leave the contaminated area; take deep breaths of fresh air. IMMEDIATELY call a physician and be prepared to transport the victim to a hospital even if no symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA) should be used; if not available, use a level of protection greater than or equal to that advised under Protective Clothing. INGESTION: DO NOT INDUCE VOMITING. If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and IMMEDIATELY call a hospital or poison control center. Be prepared to transport the victim to a hospital if advised by a physician. If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the victim on his/her side with the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport the victim to a hospital. OTHER: Since this chemical is a known or suspected carcinogen you should contact a physician for advice regarding the possible long term health effects and potential recommendation for medical monitoring. Recommendations from the physician will depend upon the specific compound, its chemical, physical and toxicity properties, the exposure level, length of exposure, and the route of exposure. (NTP, 1992)

Toxicity includes nausea and vomiting in more than 90% of patients; this usually develops 1 to 3 hours after treatment. Myelosupression, with both leukopenia and thrombocytopenia, is usually mild to moderate. A flu-like syndrome, consisting of chills, fever, malaise, and myalgias, may occur during treatment. Hepatotoxicity, alopecia, facial flushing, neurotoxicity, and dermatological reactions have also been reported.|/IV ADMIN/ GI REACTIONS & HEMATOPOIETIC DEPRESSION ARE MOST PROMINENT. ... MYELOSUPPRESSION IS REVERSED WITHIN 3-6 WK. ... OTHER REACTIONS INCL FEVER, DIARRHEA, ALOPECIA, FACIAL FLUSHING, & PARESTHESIA. ... EXTRAVASATION OF DRUG SC MAY RESULT IN TISSUE DAMAGE & SEVERE PAIN.|... There is inadequate evidence for the carcinogenicity of dacarbazine in humans ... A single case of acute leukemia after treatment with dacarbazine in combination with other cytotoxic agents has been reported ... .|(In view of the extreme light sensitivity of dacarbazine, the data below should be interpreted with caution, since most reports do not describe if steps were taken to protect the compound from light.) In common with most other cytotoxic drugs, the toxic effects of dacarbazine are mainly myelosuppression and gastrointestinal upset. Leucopenia and thrombocytopenia occurred from 5 to 21 days after a dose of 4.5 mg/kg bw per day for up to 10 days; blood counts recovered only after 2-3 weeks. Nausea and vomiting limit the therapeutic dose which can be given either intravenously or orally ... . High doses of dacarbazine also cause gastrointestinal bleeding ... possibly due to a combination of low platelet counts and abnormal platelet function as suggested by coagulation studies in vitro ... .|For more Human Toxicity Excerpts (Complete) data for DACARBAZINE (16 total), please visit the HSDB record page.

5-(3,3-Dimethyl-1-triazeno)imidazole-4-carboxamide

Dacarbazine is available as powder for preparing injections in vials containing 100 and 200 mg with mannitol and citric acid.

Dacarbazine can be analyzed colorimetrically by coupling with N-(1-naphthyl)ethylenediamine. The limits of detection in blood plasma and urine as 2 and 250 ug/ml, respectively ... .|A single reversed phase high performance LC method is described for the separation and determination of dacarbazine 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide) and its metabolites in plasma. The method was used to study the pharmacokinetics of the drug in plasma after systemic administration and in perfusate during regional perfusion of the extremity.

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