Hexamethylphosphoramide

Hazardous Air Pollutants (HAPs)

Other Classes -> Phosphorus Compounds

Carcinogens

AROMATIC ODOR

SPICY ODOR

Aromatic or mild, amine-like odor.

1.024 at 77 °F (NTP, 1992) - Denser than water; will sink

1.03 @ 20 °C

Relative density (water = 1): 1.03

1.024

1.03 @ 20°C

1.03

COLORLESS, MOBILE LIQUID

Clear, colorless liquid [Note: A solid below 43 degrees F].

greater than or equal to 100 mg/mL at 64 °F (NTP, 1992)

MISCIBLE WITH WATER & WITH MOST ORG LIQ; IMMISCIBLE WITH HIGH-BOILING SATURATED HYDROCARBONS

Solubility in water: very good

Miscible

222 °F (NTP, 1992)

NIOSH REL = lowest feasible conc. 222 °F

105 °C

220 °F

220 °F

451 °F at 760 mmHg (NTP, 1992)

233 °C @ 760 MM HG

232 °C

451 °F

232.5 °C @760 [mm Hg]

451 °F

41 to 45 °F (NTP, 1992)

FP: 5-7 °C

7.2 °C

43 °F

7.2 °C

43 °F

6.18 (NTP, 1992) - Heavier than air; will sink (Relative to Air)

6.18 (Air= 1)

Relative vapor density (air = 1): 6.18

6.18

Danger

H340: May cause genetic defects [Danger Germ cell mutagenicity]

P203, P280, P318, P405, and P501 (click each P-code to see the statement)

Danger

H340 (100%): May cause genetic defects [Danger Germ cell mutagenicity]

P203, P280, P318, P405, and P501 (click each P-code to see the statement)

Chemical: Phosphoric triamide, hexamethyl-

Hazard Traits - Carcinogenicity; Genotoxicity; Nephrotoxicity and Other Toxicity to the Urinary System; Reproductive Toxicity; Respiratory Toxicity

S - indicates a substance that is identified in a final Significant New Use Rule.

Hexamethylphosphoramide: Does not have an individual approval but may be used under an appropriate group standard

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.)

This chemical is combustible. (NTP, 1992)

Combustible. Gives off irritating or toxic fumes (or gases) in a fire.

Hexamethylphosphoramide is no longer used in large quantities in the United States. No information is available on the acute (short-term), chronic (long-term), reproductive, developmental, or carcinogenic effects of hexamethylphosphoramide in humans. Acute animal studies have reported effects on the kidneys and lungs from oral exposure to hexamethylphosphoramide, while chronic oral studies in animals have reported an increased incidence of lung disease. An increased incidence of nasal tumors from inhalation exposure to hexamethylphosphoramide was reported in rats. EPA has not classified hexamethylphosphoramide for carcinogenicity; however, the International Agency for Research on Cancer (IARC) has classified it as a Group 2B, possible human carcinogen.

A TLV is not recommended because the absence of data. Rats suffer kidney injury and death after repeated inhalation exposures. HMPA is carcinogenic in animals. The TLV Basis is upper respiratory tract cancer. [ACGIH] May have effects on the lungs, kidneys, and bone marrow; [ICSC]

LLOYD JW; J AM IND HYG ASSOC 36 (12): 917-19 (1975). A REVIEW OF TOXICITY, CARCINOGENICITY, & DISTRIBUTORS OF HEXAMETHYLPHOSPHORIC TRIAMIDE IS PRESENTED.

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. Hexamethylphosphoramide (680-31-9) 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/s095hexa.pdf]

HEXAMETHYLPHOSPHORAMIDE may react with strong oxidizing agents and strong acids (NTP, 1992). Susceptible to formation of highly toxic and flammable phosphine gas in the presence of strong reducing agents such as hydrides. Partial oxidation by oxidizing agents may result in the release of toxic phosphorus oxides.

Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Hexamethylphosphoramine is included on this list.

Fires involving this compound should be controlled using a dry chemical, carbon dioxide or Halon extinguisher. (NTP, 1992)

Use water spray, powder, alcohol-resistant foam, carbon dioxide.

Refer for medical attention.

Wear protective gloves when administering first aid. Remove contaminated clothes. Rinse and then wash skin with water and soap. Refer for medical attention .

First rinse with plenty of water for several minutes (remove contact lenses if easily possible), then refer for medical attention.

Rinse mouth. Refer for medical attention .

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.

(General first aid procedures)

PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical 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/

SMALL SPILLS AND LEAKAGE: If you spill this chemical, FIRST REMOVE ALL SOURCES OF IGNITION. Then, use absorbent paper to pick up all liquid spill material. Seal the absorbent paper, as well as any of your clothing which may be contaminated, in a vapor-tight plastic bag for eventual disposal. Wash any surfaces you may have contaminated 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.

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/

PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols & thiosulfate. The reactivity of various alkylating agents varies greatly ... & is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness & safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/

Personal protection: filter respirator for organic gases and vapours adapted to the airborne concentration of the substance. Collect leaking and spilled liquid in sealable containers as far as possible. Absorb liquid in sand or inert absorbent. Then store and dispose of according to local regulations.

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 HEXAMETHYLPHOSPHORAMIDE (11 total), please visit the HSDB record page.

A series of six alkyl-substituted dioxolanes were studied for their inhibitory effects on mono-oxygenase activities in vitro with nasal and hepatic microsomes from rats and rabbits. Carbon monoxide binding and hexamethylphosphoramide (HMPA) N-demethyase activity were most susceptible to inhibition by the test compounds. Inhibition of HMPA N-demethylase activity in both nasal and liver microsomes increased with lipophilicity of the inhibiting compound. In olfactory mucosa, the bulk of the substiturent at the 4-position also seemed to have an effect on inhibition. Mono-oxygenase activity in the nasal mucosa was inhibited more readily than that in the liver.

Eighteen methylenedioxyphenyl compounds, including some commonly inhaled by people, were tested for the ability to inhibit rabbit nasal microsomal cytochrome p450 dependent hexamethylphosphoramide (HMPA) N-demethylase. For comparison, liver microsomes were also used. Nasal cytochrome p450 from rabbits metabolized methylenedioxyphenyl compounds to form cytochrome p450 metabolite (P-450-MI) complexes as indicated by differences spectra in the Soret region. Several of the methylenedioxyphenyl compounds were potent inhibitors of nasal p450 dependent -N-demethylase. If inhibition of nasal p450 also occurs in vivo after inhibiting MDP compounds are inhaled, the metabolism of concurrently or subsequently inhaled comppounds may be altered.

TERRESTRIAL FATE: Based on an estimated Koc of 34(1,2,SRC), hexamethylphosphoramide is expected to be very highly mobile in soil and may leach(3). Based upon an estimated Henry's Law constant of 2X10-8 atm cu-m/mole at 25 °C(1,2,4,SRC), volatilization from moist soils is not expected to be an important fate process for hexamethylphosphoramide. (SRC)

AQUATIC FATE: Volatilization (based upon an estimated Henry's Law constant of 2X10-8 atm cu-m/mole at 25 °C(1,2,4,SRC)), bioconcentration (based upon an estimated BCF of 0.96(1,2,SRC)), and adsorption to sediment (based upon an estimated Koc of 34(1,2,SRC)) are not expected to be important fate process of hexamethylphosphoramide in water(SRC).

ATMOSPHERIC FATE: Based upon a measured vapor pressure of 0.046 mm Hg at 25 °C(2), hexamethylphosphoramide is expected to exist almost entirely in the vapor-phase in the ambient atmosphere(1). It is expected to degrade relatively rapidly in an average ambient atmosphere (estimated half-life of about 2 hr) by reaction with photochemically produced hydroxyl radicals(3). Since hexamethylphosphoramide is miscible in water(4), physical removal via wet deposition is likely to occur.

The substance can be absorbed into the body by inhalation and through the skin.

inhalation, skin absorption, ingestion, skin and/or eye contact

MAY BE ABSORBED!

irritation eyes, skin, respiratory system; dyspnea (breathing difficulty); abdominal pain; [potential occupational carcinogen]

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/

Based on a measured log Kow of 0.28(2), the Koc for hexamethylphosphoramide can be estimated to be 34 using a recommended regression derived equation(1,SRC). This Koc value suggests that hexamethylphosphoramide has very high mobility in soil and may leach(3).

Chronic toxicity and oncogenicity were evaluated in two separate experiments in male and female Charles River-CD rats exposed to hexamethylphosphoramide (HMPA) via inhalation. In experiment No. 1, 120 rats/sex/group were exposed to 0, 50, 400 or 4000 ppb HMPA for 9-24 months, and in experiment No. 2, 100 rats/sex/group were exposed to 0, 10, 50 or 100 ppb HMPA for 6-24 months. There were significant increases between treated and control animals in the following: rhinitis and squamous metaplasia in the nasal cavity with formation of excessive keratin material which occasionally almost occluded the entire nasal cavity (all treatment levels except 10 ppb), keratinized squamous metaplasia of the trachea (4000 ppb), dose-related increase in tracheitis and desquamation of the tracheal epithelium, and bronchitis, desquamation and regeneration of the bronchial epithelium (100, 400 and 4000 ppb), murine pneumonia (dose related pulmonary lesions at 100, 400 and 4000 ppb), bone marrow erythropoietic hyperplasia (males at 4000 ppb), and testicular atrophy (males at 4000 ppb). Exposures at 400 and 4000 ppb HMPA were stopped at 9 and 10 months, respectively, due to the high incidence of nasal tumors and mortality. HMPA lesions were confined to the bronchial air passages of the lungs and there were no changes in alveoli adjacent to respiratory bronchioles.

... NO SIGNIFICANT INCR IN CHROMOSOME ABERRATIONS /WAS REPORTED/ WHEN CULTURED HUMAN LEUKOCYTES WERE TREATED WITH 5X10-3 MOLAR HEXAMETHYLPHOSPHORAMIDE.

A POTENTIAL CARCINOGEN.

Since hexamethylphosphoramide is used as a UV inhibitor in polyvinyl chloride, in promoting stereo specific reactions and as a specialty solvent(1), it may be released to the environment in waste streams generated at sites of its commercial production and use(1,SRC).

Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Hexamethylphosphoramine is included on this list.

IN RATS & MICE, HEXAMETHYLPHOSPHORAMIDE UNDERGOES A SEQUENCE OF N-DEMETHYLATION REACTIONS TO YIELD PENTAMETHYLPHOSPHORAMIDE, N',N',N'',N'''-TETRAMETHYLPHOSPHORAMIDE & N', N'',N''-TRIMETHYLPHOSPHORAMIDE. IN VITRO STUDIES WITH RAT LIVER SLICES INDICATED OXIDATIVE DEMETHYLATION, WITH SIMULTANEOUS FORMATION OF FORMALDEHYDE.

The metabolism of hexamethylphosphoramide (HMPA), aminopyrine, ethoxycoumarin, ethoxyrsorufin, and pentoxyresorufin, by the monooxygenase cytochrome p450 dependent system, was studied in microsomes from nasal epithelial membranes and liver tissue of Sprague-Dawley rats. Nasal metabolism rates for the different substrates ranged from 9% of liver values for aminopyrine to 83% for ethoxycoumarin. HMPA-demethylase activity followed Michaelis-Menten kinetics in nasal mucosa microsomes but was biphasic in those from liver. SKF 525A, metyrapone, dioxolane and alpha-naphthoflavone (ANF), inhibitors of various p450 monoxygenase, were examined with regard to inhibition of nasal and liver ethoxycoumarin deethylase. In addition, activity of epoxide hydrolase, glutathione S-transferase, DT-diaphorase and UDP-glucuronyltransferase (UDP-GT) in nasal tissue homogenates were investigated. These activities were lower than those present in the liver. Various attempts to increase the activity of oxidative enzymes in nasal tissue by PB, 3-MC and ethanol failed, 3-MC and PB doubled the microsomal UDP-GT and the epoxide hydrolase activities. The results together with data from the literature sugggest that the balance between p450 isozymes and detoxifying enzymes differs in the nose compared with the liver. The activities of these enzymes in nasal tissue of different strains of rats also varies substantially with implications regarding the metabolic fate and activation of inhaled xenobiotics.

Two unique forms of cytochrome p450 (p450), designated NMa and NMb, were recently isolated in this laboratory from nasal microsomes of rabbits. In the present study, polyclonal antibodies to the pruified nasal cytochrome were prepared. Immunochemical analysis with specific rabbit anti-NMa and sheep anti-NMb antibodies indicated that p450 isozymes identical to or having a high structural homology with NMa are present in both olfactory and respiratory mucosa, as well as in liver, but NMb was detected only in the olfactory mucosa. Neither form was detected in other tissues examined, including brain, esophageal mucosa, heart, intestinal mucosa, kidney, and lung. The specific occurrence of NMb in the olfactory mucosa was further substantiated by the detection and specific inhibition by anti-NMb of the formation of unique NMb-dependent metabolites of testosterone in olfactory microsomes but not in microsomes from liver or respiratory mucosa. Similar experiments with antibody to previously purified rabbit hepatic p450 isozymes indicated that not all of the hepatic cytochromes are expressed in the nasal tissues. Thus, p450 isozymes structurally homologous to hepatic forms 2, 3a, and 4, but not 3b and 6, were found in the olfactory mucosa. On the other hand, only form 2 was detected in the respiratory mucosa. Immunoquantitation experiments revealed that NMa nd NMb are the major p450 forms in olfactory microsomes, whereas NMa and P450 form 2 (or its homolog) constitute the major portion of the respiratory nasal microsomal p450. The level of NMa in the liver is relatively low, accounting for less than 3% of total microsomal p450 in this tissue. In addition, evidence is provided that NMa is the major catalyst in the dealkylation of two nasal carcinogens, hexamethylphosphoramide and phenacetin, in both olfactory and respiratory nasal microsomes.

Possible roles of chtochrome p450 monooxygenases in nasal tissues are discussed. Nasal cytochrome p450 is known to occur in dogs, rats, monkeys mice, guinea pigs, and Syrian hamsters, and possible other species. The concentrations of cytochrome p450 in the olfactory mucosa of monkeys, dogs, and rats is much higher than in the nasal rspiratory mucosa. The substrate specificity of nasal cytochrome p450 is different from that of the liver. For example, whereas liver cytochrome p450 oxidizes benoz(a)pyrene faster than nasal cytochrome, the reverse is true for hexamethylphosphoramide (HMPA). Nasal cytochrome p450 may be involved in producing toxic or carcinogenic metabolites from inhaled compounds. For exampe, HMPA may be demethylated to formaldehyde by nasal cytochrome p450. Nasal cytochrome p450 may have a role in protecting lungs, since nasal metabolism of inhaled organic vapors can reduce the concentration of the vapors reaching the lungs. Nasal cytochrome p450 may help maintain acuity of the sense of smell through removal of odorants by metabolizing them. Without this function, odorants remaining in the mucus covering of the sensory organs might produce an unacceptably high background odor, thereby decreasing acuity. In species that are highly dependent on the sense of smell, the lack of olfactory acuity could have serious debilitating effects.

Hexamethylphosphoramide has known human metabolites that include Pentamethylphosphoramide.

Hexamethylphosphoramide is no longer used in large quantities in the United States. Hexamethylphosphoramide was used in the past as a selective solvent for gases, a polymerization catalyst, a stabilizer against thermal degradation in polystyrene, and an additive to polyvinyl resins.

Used as a solvent for aromatic polyamide fibers; also used as a catalyst, stabilizer, and additive for polymers and resins; [ACGIH]

Textiles (Fiber & Fabric Manufacturing) [Category: Industry]

PROCESSING SOLVENT FOR AROMATIC POLYAMIDE FIBER

DE-ICING ADDITIVE FOR JET FUELS; /EXPERIMENTAL/ CHEMOSTERILANT FOR A NUMBER OF INSECT PESTS; AS A CHEMICAL MUTAGEN

AS A SOLVENT FOR POLYMERS, AS A SELECTIVE SOLVENT FOR GASES, AS A POLYMERIZATION CATALYST, AS A STABILIZER AGAINST THERMAL DEGRADATION IN POLYSTYRENE, AS AN ADDITIVE TO POLYVINYL & POLYOLEFIN RESINS TO PROTECT AGAINST DEGRADATION BY UV LIGHT, & AS A SOLVENT IN ORG & ORGANOMETALLIC REACTIONS IN RESEARCH LAB

(1975) PROBABLY GREATER THAN 4.54X10+5 GRAMS

(1976) PROBABLY GREATER THAN 2.27X10+6 GRAMS