Melphalan

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.

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.

Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary.

Keep container tightly closed in a dry and well-ventilated place.

Melphalan tablets should be stored in well-closed, light-resistant, glass containers at temp less than 40 °C, preferably between 15-30 °C.

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/

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Wear respiratory protection. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal.

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/

SMALL SPILLS AND LEAKAGE: If you spill this chemical, FIRST REMOVE ALL SOURCES OF IGNITION. You should then dampen the solid spill material with 60-70% methanol, then transfer the dampened material to a suitable container. Use absorbent paper dampened with methanol to pick up any remaining material. Your contaminated clothing and absorbent paper should be sealed in a vapor-tight plastic bag for eventual disposal. Solvent-wash contaminated surfaces with 60-70% methanol followed by washing 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.

Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U150, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste.

SRP: Wastewater from contaminant suppression, cleaning of protective clothing/equipment, or contaminated sites should be contained and evaluated for subject chemical or decomposition product concentrations. Concentrations shall be lower than applicable environmental discharge or disposal criteria. Alternatively, pretreatment and/or discharge to a permitted wastewater treatment facility is acceptable only after review by the governing authority and assurance that "pass through" violations will not occur. Due consideration shall be given to remediation worker exposure (inhalation, dermal and ingestion) as well as fate during treatment, transfer and disposal. If it is not practicable to manage the chemical in this fashion, it must be evaluated in accordance with EPA 40 CFR Part 261, specifically Subpart B, in order to determine the appropriate local, state and federal requirements for disposal.

Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber; Contaminated packaging: Dispose of as unused product.

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/

For more Disposal Methods (Complete) data for Melphalan (8 total), please visit the HSDB record page.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Wear respiratory protection. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains.

Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Further processing of solid materials may result in the formation of combustible dusts. The potential for combustible dust formation should be taken into consideration before additional processing occurs. Provide appropriate exhaust ventilation at places where dust is formed.

Appropriate engineering controls: Avoid contact with skin, eyes and clothing. Wash hands before breaks and immediately after handling the product.

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.

For more Preventive Measures (Complete) data for Melphalan (16 total), please visit the HSDB record page.

MINIMUM PROTECTIVE CLOTHING: If Tyvek-type disposable protective clothing is not worn during handling of this chemical, wear disposable Tyvek-type sleeves taped to your gloves.

Eye/face protection: Face shield and safety glasses. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).

Skin protection: Handle with gloves.

Body Protection: Complete suit protecting against chemicals. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.

Respiratory protection: Where risk assessment shows air-purifying respirators are appropriate use a full-face particle respirator type N100 (US) or type P3 (EN 143) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).

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/

Additive bone marrow suppression can be expected when melphalan is admin with other cancer chemotherapeutic agents.

Renal failure occurred in 13 of 17 patients who received cyclosporine and high-dose melphalan therapy ... felt reaction resulted from drug interaction between cyclosporine and melphalan.

The effects of the vasoactive agents hydralazine, nifedipine, and verapamil on the tumor cytotoxicity of melphalan were studied in mice with experimental tumors. Treatment with hydralazine (5 mg/kg) 15 min after melphalan dosing (up to about 12 mg/kg) increased the melphalan induced delay of growth in either RIF-1 or KHT tumors by a factor of about 2.5. Similar enhancements were obtained with measurement of the surviving fraction of tumor cells in vitro following treatment in vivo with hydralazine and melphalan. Tumor cell kill was also increased when nifedipine was administered with melphalan compared to melphalan alone. These enhanced effects were seen when the vasoactive agents were given before or after melphalan. Hydralazine (5 mg/kg) induced nearly 100% radiobiological hypoxia in the tumors. Nifedipine had no effect on tumor hypoxic fraction at a dose of 10 mg/kg, although the antitumor effect of melphalan was substantially increased. A dose of 50 mg/kg nifedipine produced a large increase in tumor hypoxic fraction which persisted for several hours. Verapamil did not change the fraction of hypoxic cells in the KHT tumor and produced only slightly enhanced the antitumor effect of melphalan.

The effect of both hyperthermia and verapamil on cytotoxicity and transport of melphalan was studied in a pleiotropic drug-resistant Chinese hamster ovary cell line (CHRC5) and in the drug-sensitive parent line (AuxB1). The CHRC5 cell line was selected for resistance to colchicine but is also cross-resistant to other drugs including melphalan. Verapamil (10 uM) incr melphalan cytotoxicity in drug-resistant cells but not in drug-sensitive cells. Hyperthermia (40 to 45 degrees C) incr melphalan cytotoxicity in both cell lines ... melphalan cytotoxicity was incr further when verapamil was combined with hyperthermia (40 to 45 degrees C). The incr cytotoxicity caused by verapamil in drug-resistant cells was accompanied by alterations in membrane permeability to melphalan. The cellular uptake of melphalan after 14 min incr in the presence of verapamil (7 to 30 uM) at 37 and 42 degrees C. When verapamil (10 uM) was present, the rate of efflux of melphalan from CHRC5 cells decr by almost 40% at 37 degrees C. The rate of efflux was incr at 42 degrees C relative to 37 degrees C, but with verapamil the rate decr to that obtained at 37 degrees C in CHRC5 cells. In drug-sensitive cells, verapamil (< or = 50 uM) did not affect either uptake or efflux of melphalan. These findings suggest that verapamil could be beneficial by incr the effectiveness of melphalan in the elimination of multidrug-resistant cells the combo of hyperthermia and verapamil could be especially advantageous by incr melphalan cytotoxicity in a localized target region.

For more Interactions (Complete) data for Melphalan (15 total), please visit the HSDB record page.

Mild and transient elevations in serum aminotransferase levels are uncommon with standard doses of melphalan, but occur more commonly with high dose intravenous regimens. The enzyme elevations are usually mild and asymptomatic and do not require dose modification. Clinically apparent liver disease has not been reported with standard doses of melphalan in chemotherapeutic regimens. However, use of high doses of melphalan in preparation for hematopoietic cell (bone marrow and stem cell) transplantation or in local-regional therapy has been associated with sinusoidal obstruction syndrome that can be severe, leading to acute liver failure and death. Onset of sinusoidal obstruction syndrome is usually within 1 to 3 weeks of the myeloablative or high dose therapy, and is characterized by the onset of abdominal pain, hepatomegaly, weight gain and ascites followed by jaundice. The pattern of serum enzyme elevations is usually hepatocellular, with marked increases in serum aminotransferase and lactic dehydrogenase levels and minimal increase in alkaline phosphatase. The severity of injury varies considerably. In mild forms there is serum enzyme elevations without jaundice and with few or no symptoms. In severe instances, there are elevations in prothrombin time and progressive jaundice and hepatic failure. Immunoallergic and autoimmune features are uncommon. The fatality rate is high. Liver biopsy shows centrolobular necrosis and congestion with occlusion of small veins and red cells in sinusoids.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 350(SRC), determined from a structure estimation method(2), indicates that melphalan is expected to have moderate mobility in soil(SRC). The estimated pKa values of melphalan are 4.3, 6.5 and 12.3(3), indicating that this compound will exist as a zwitterion in the environment and zwitterions generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization from moist soil is not expected because the compound exists as a zwitterion and ions do not volatilize. Melphalan is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.0X10-10 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2016).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 350(SRC), determined from a structure estimation method(2), indicates that melphalan is expected to adsorb to suspended solids and sediment(SRC). The estimated pKa values of melphalan are 4.3, 6.5 and 12.3(3), indicating that melphalan will exist almost entirely in the zwitterion form at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process(SRC). According to a classification scheme(4), an estimated BCF of 3(SRC), from its log Kow of -0.52(5) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). At 25 °C, the neutral aqueous hydrolysis rate constant for melphalan has been experimentally determined to be 0.15/hr which corresponds to a half-life of 4.6 hrs at pH 7(6). Biodegradation data in water were not available(SRC, 2016).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), melphalan, which has an estimated vapor pressure of 3.0X10-10 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase melphalan may be removed from the air by wet and dry deposition(SRC). Melphalan does not absorb UV light at wavelengths >290 nm(3) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).

IDENTIFICATION AND USE: Melphalan is an alkylating agent that is a white to buff odorless powder at room temperature. Melphalan is used as a drug to treat cancer and other medical conditions, including ovarian cancer, malignant melanoma, multiple myeloma, breast cancer, advanced prostate cancer, testicular cancer, chronic myelogenous leukemia, osteogenic sarcoma, polycythemia vera, amyloidosis, and scleromyxedema (a rare skin disease). It is also used as an insect chemosterilant. HUMAN EXPOSURE AND TOXICITY: Epidemiological studies found that patients treated with melphalan for breast cancer, ovarian cancer, and bone-marrow cancer (multiple myeloma) had an increased risk of leukemia. The risk of leukemia increased with increasing dose of melphalan but was not affected by co-exposure to radiation therapy. Melphalan produces chromatid-type aberrations in peripheral blood lymphocytes taken from cancer patients. ANIMAL STUDIES: There is sufficient evidence for the carcinogenicity of melphalan from studies in experimental animals. When administered by intraperitoneal injection, melphalan caused cancer of lymphatic tissue (lymphosarcoma) in male mice, lung tumors in mice of both sexes, and cancer of the abdominal cavity (sarcoma of the peritoneum) in rats of both sexes. Melphalan produces structural aberrations of chromatid and chromosome types in bone marrow cells of treated rats.

Alkylating agents work by three different mechanisms: 1) attachment of alkyl groups to DNA bases (primarily at the N-7 position of guanine and to a lesser extent, at the N-3 position of adenine), forming monoadducts and 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.

EPA has released the Interactive Chemical Safety for Sustainability (iCSS) Dashboard. The iCSS Dashboard provides an interactive tool to explore rapid, automated (or in vitro high-throughput) chemical screening data generated by the Toxicity Forecaster (ToxCast) project and the federal Toxicity Testing in the 21st century (Tox21) collaboration. /The title compound was tested by ToxCast and/or Tox21 assays/[USEPA; ICSS Dashboard Application; Available from, as of December 8, 2016: http://actor.epa.gov/dashboard/]

The following link will take the user to the National Toxicology Program (NTP) Test Status of Agents Search page, which tabulates the results and current status of tests such as "Short-Term Toxicity Studies", "Long-term Carcinogenicity Studies", "Developmental Studies", "Genetic Toxicology Studies", etc., performed with this chemical. Testing status for melphalan is available.[Available from, as of March 24, 2017: https://ntpsearch.niehs.nih.gov/?e=True&ContentType=Testing+Status]

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/

Using a structure estimation method based on molecular connectivity indices(1), the Koc of melphalan can be estimated to be 350(SRC). According to a classification scheme(2), this estimated Koc value suggests that melphalan is expected to have moderate mobility in soil. The estimated pKa values of melphalan are 4.3, 6.5 and 12.3(3), indicating that this compound will exist almost entirely in the zwitterion form in the environment and zwtterions generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).

/HUMAN EXPOSURE STUDIES/ Twenty-one previously untreated multiple myeloma (MM) patients and 10 previously treated patients with refractory or relapsed disease received two or three cycles of intermediate-dose melphalan (70 mg/sq m), admin iv every 6 wk. Seven previously untreated patients received three and all other patients received two courses of intermediate-dose melphalan. the objective of the study was to reduce the toxicity of high-dose melphalan (140 mg/sq m) while maintaining its cytotoxic efficacy and secondly to ensure the possibility of collecting sufficient numbers of peripheral blood stem cells (PBSC) for transplantation. Eighteen (85%) previously untreated patients responded, of whom four achieved CR (18%). In addition five out of 10 previously treated patients with refractory or relapsed disease responded although bone marrow toxicity in this category was a major drawback. Toxicity was moderate, consisting of alopecia and moderate bone marrow suppression: the granulocyte count dropped below 0.5 X 10+9/L and platelets below 25 X 10+9/L for a median of 8 and 6d, respectively. No serious infections occurred and the majority of patients attended the out-patient clinic. In 12/14 previously untreated patients sufficient peripheral blood CD34+ cells for harvest were present in the repopulation phase after the first intermediate-dose melphalan. In nine patients peripheral blood stem cells were collected and eight patients have undergone successful transplantation. Repeated intermediate-dose melphalan followed by filgrastim is highly effective in untreated MM and may be safely admin to reduce tumor load prior to PBSC collection.

/SIGNS AND SYMPTOMS/ Hematologic toxicity is the major and dose-limiting adverse effect of both oral and iv melphalan and is manifested principally by leukopenia and thrombocytopenia. Anemia, hemolytic anemia, pancytopenia, and agranulocytosis may also occur.

/SIGNS AND SYMPTOMS/ Melphalan is most widely used for treatment of mammary carcinoma, malignant malinoma, multiple myeloma, ovarian carcinoma, and testicular seminoma. It produces anorexia, nausea, and vomiting. Leukopenia, thrombocytopenia, and anemia are the dose limiting toxicities.

/SIGNS AND SYMPTOMS/ Overdosage with melphalan doses up to 290 mg/sq m was associated with severe nausea, vomiting, ulceration of the mouth, decreased consciousness, seizures, muscular paralysis, and cholinomimetic effects. ... Several fatalities following melphalan overdosage have been reported to date. One child who received standard supportive care survived a single melphalan dose of 254 mg/sq m. In patients receiving high doses of melphalan (i.e., greater than 100 mg/sq m), severe mucositis, stomatitis, colitis, diarrhea, and GI bleeding have been reported. Elevations in liver enzymes, hepatic veno-occlusive disease, nephrotoxicity, and adult respiratory distress syndrome have occurred rarely. In some patients, severe hyponatremia caused by inappropriate antidiuretic hormone secretion (SIADH) has been reported. The principal toxic effect of melphalan is bone marrow suppression. The patients's hematologic status should be monitored carefully for 3-6 weeks following melphalan overdosage.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including melphalan, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including melphalan hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Melphalan hydrochloride/

U150; As stipulated in 40 CFR 261.33, when melphalan, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5).

Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 1 lb or 0.454 kg. The toll free number of the NRC is (800) 424-8802. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b).

Insect chemosterilant

MEDICATION

Antineoplastic Agents, Alkylating; Myeloablative Agonists

Used as a poison gas.

For the palliative treatment of multiple myeloma and for the palliation of non-resectable epithelial carcinoma of the ovary. Has also been used alone or as part of various chemotherapeutic regimens as an adjunct to surgery in the treatment of breast cancer, alone or in combination regimens for palliative treatment of locally recurrent or unresectable in-transit metastatic melanoma of the extremities, as well as for the treatment of amyloidosis with prednisone.

L-3-Phenylalanine is nitrated and the p-nitro compound is reduced to L-3-(p-aminophenyl)alanine. This is reacted with ethylene oxide to form the corresponding bis(2-hydroxy-ethyl)-amino compound that then is treated with phosphoryl chloride to yield the drug.

Melphalan can be synthesized by treating p-nitro-L-phenylalanine ethyl ester ... with phthalic anhydride and then with hydrochloric acid to yield p-nitro-N-phthaloyl-L-phenylalanine ethyl ester. This product is then hydrogenated and treated with ammonia and ethylene oxide to give p-di-(2-hydroxyethyl)amino-N-alpha-phthaloyl-L-phenylalanine ethyl ester. Chlorination with phosphorus oxychloride followed by hydrolysis yields melphalan.

Melphalan is available in US as USP grade in form of tablets containing 2 mg active ingredient. Melphalan powder USP, used to formulate tablets, contains 93.0-100.5% melphalan ... in Western Europe ... available in tablets containing 2 & 5 mg & as injections equiv to 100 mg anhydride active ingredient.

Alkeran: Parenteral for injection, 50 mg (of melphalan) /Melphalan Hydrochloride/

Alkeran: oral tablets, film-coated 2 mg /Melphalan/