National Toxicology Program

Commercial Availability

Production and Producers: MVK and its analogs can be produced commercially by an Oppenhauer-type oxidation of the corresponding secondary alcohol. Numerous publications describe various catalysts which can be used to achieve the synthesis of MVK in reasonable yields (Nakano et al., 1987). The precursor, 3-ketobutanol can be formed by condensation of acetone with formaldehyde (HSDB, 1991). Another route involves catalyzed oxidation from 1-butene, used as the starting material (Sinfelt & Barnett, 1976).

Two pharmaceutical manufacturers reported manufacture of this chemical to the EPA's TSCA plant and production database (TSCAPP, 1991). Pfizer, Inc., Groton, CT, reported annual production of 10,000 to 100,000 lbs, and Hoffmann-LaRoche, Inc., Nutley, NJ, declared no production volume (according to a company spokesman, they import MVK stocks from Switzerland). No companies specifically reported imports to the EPA for their TSCAPP data gathering effort. No other data on annual production volumes were found in the available literature. Recent press reports mention several additional companies currently using MVK in the manufacture of copolymers, including Ecolyte Atlantic, Inc. of Baltimore and EcoPlastics Ltd. of Ontario (Anon., 1988a; Anon. 1988b). MVK is also available in research quantifies from CTC Organics, Monomer-Polymer & Dajac Labs (MTM Chemicals), and Pharmaglobe Laboratories, Ltd. Aldrich Chemical Co., Alfa Products, American Tokyo Kasei, Inc., Chem Service,Inc., Fluka Chemical Corp., GFS Chemical Co., Janssen Chimica, Lancaster Synthesis, Ltd., Pfaltz & Bauer, Inc., Riedel-De Haen AG, and Sigma Chemical Co. (FCD, 1991). Exxon Chemical Co. included MVK in a 1968 TSCA §8d submission to EPA on a series of ketones.

Aristech Chemical Corp., Eastman Kodak Co., Exxon Research & Engineering Co. and Mitsui Petrochemical Industries, Ltd. have been issued patents for syntheses of MVK and other unsaturated ketones and other pharmaceutical companies have had an interest in the use of this compound, including Hoffmann-LaRoche and Co. A.-G., Lilly Industries Ltd., Merck & Co., Squibb & Sons, Inc. and SmithKline Beckman Corp. (McMahon et al., 1979; Lukac & Soukup, 1988; Woltersdorf et al., 1989; Badger et al., 1989; Biller & Misra, 1989; Hotten et al., 1990).

Use Pattern: MVK is an important monomer used in many polymer systems to produce plastics and resins. It is offered as a unique ketone monomer with good reactivity toward acrylates, methacrylates, vinyls and itaconates. It serves as a UV-sensitive comonomer which can be grafted to polyethylene, polypropylene, polyethylene terephthalate, polyvinyl chloride, nylon and polystyrene for improved degradability of such products as packaging materials. Styrene-MVK copolymers, for example, are useful as photodegradable polymers in packaging applications (Papa & Sherman, 1981). It has also been reported to be a component of a chain transfer agent used in the manufacture of low density polyethylene (LDPE). MVK dimerizes catalytically to form 3-methylene-2,6-heptadione which is also useful as a polymer precursor (Basavaiah et al., 1987). Various homopolymers of MVK, which can be induced by imidazole in water-ethanol mixtures, are also useful in further polymerization reactions (Ozu et al., 1989).

MVK is a versatile reactive chemical, alkylating agent, and important Michael acceptor used as a starting material in numerous commercial- and research-scale organic syntheses. This conjugated ketone is a starting material in a Skraup synthesis of 4-methylquinoline (Holter, 1982) and in a Michael reaction to yield the indole derivative, 1-(3'-indolyl)-butan-3-one (Bannister, 1981). It has been reportedly used in the pharmaceutical, agricultural chemical, cosmetic, coatings, and adhesives industries and in bioengineering. For example, Chapman et al. (1990) reported that the synthesis of potent hypolipidemic agents (anticholesteremics) started with the Michael addition of MVK to appropriately substituted phthalimides. MVK is used as a pharmaceutical intermediate in the synthesis of steroids and vitamin A and pyrazole derivatives as inhibitors of blood platelet aggregation (Ferroni, et al., 1989; Matsuda, 1987; Nakayana et al., 1985; Sax & Lewis, 1987; Tanaka, et al., 1982). The U.S. Department of Agriculture was granted a patent in 1989 to use MVK as a chemical intermediate in the production of natural pesticides (Chuman et al., 1989). Firmenich S.A. was granted a patent in 1990 for the preparation of tricyclic spiroketone perfume ingredients using MVK as a starting material (Giersch & Schulte-Elte, 1990).

Human Exposure: Human exposure to mutagenic a,b-unsaturated carbonyl compounds, including MVK, is said to be widespread by both exogenous and endogenous routes (Chung et al., 1986). The odor threshold concentration for olfactory recognition of MVK is 0.5720 mg/m³ (Ruth, 1986) or is approximately 200 ppb (Waritz, 1988).

Occupational exposure may occur by inhalation or contact as a result of use of MVK as an alkylating agent, chemical intermediate and monomer in polymer manufacture. MVK can be readily absorbed dermally and is considered extremely hazardous and toxic by all routes of exposure (HSDB, 1991).

Hercules, Inc., in a 1988 FYI submission to the EPA, reported the formation of small amounts of MVK in the combustion zone of a plant incinerator burning waste methyl ethyl ketone from a plant process (Waritz, 1988). They reported an approximately 25 ppm concentration of MVK exiting the incinerator combustion area which was reduced to approximately 2 ppm by a secondary catalytic combustion unit. A computer model downwash prediction, taking into consideration the locale of the plant, estimated an 8-hour average ground level concentration of 1 ppb MVK at the point of nearest human habitation.

MVK has been documented as one of the many combustion products found in cigarette/tobacco smoke (Curvall et al., 1984; Florin et al., 1980). Kusama et al. (1978) reported a semi-quantitative estimate of this low-boiling compound in cellulose cigarette smoke of 0.13 mg/cigarette.

Niemand et al. (1983) investigated the effects of g-radiolysis on major sugars in subtropical fruits in connection with the safety of food irradiation. They identified MVK as one of the radiolytic products.

Sheiseido Laboratories has reported that MVK arises as one of several oxidation products resulting from the reaction of linalool, a common ingredient of perfumes, with cosmetic pigments in the presence of air (Sheiseido Laboratories, 1988).

Ase et al. (1985) reported MVK to be among a number of trace gaseous species identified in the combustion products obtained from firings of an M16 rifle.

Environmental Occurrence: MVK has been reported to be a naturally occurring compound. Shimizu (1982) identified MVK as a volatile component of grape musts of the Muscat of Alexandria variety. Isidorov et al. (1985) found this substance in the volatile organic compound (VOC) emissions characteristic of northern hemisphere forests. They identified two arboreous plant sources of MVK as aspen and European oak. MVK has also been identified in the underground environment of mines as a component of toxic fumes resulting from pyrolysis of virgin red oak and virgin and fire and rot retardant-treated Douglas fir (Christos & Hay, 1986).

Kallio (1989) described MVK as a component of natural birch syrup derived from birch sap by dehydrogenation. Jackson et al. (1990) identified MVK as a component of Dufour gland secretion in Manica rubida worker ants.

According to Herrington et al. (1987), MVK is a natural soil fungistatic agent. It is a volatile compound produced by the microorganism, Streptomyces griseoruber, and acts as a strong inhibitor of the spore germination of Cladosporium cladosporioides.

MVK has been reported to be one of several oxygen-containing impurities in crude isoprene used in the production of rubber, butadiene, 3-buten-2-ol and methyl ethyl ketone. Noguchi et al., (1983) reported a 9.7% by-product yield of MVK in the synthesis of vinyl ether monomers. It has also been identified as a breakdown product in the autoxidation of isoprene and as a by-product of whiskey manufacture and biomass combustion.

MVK is an ubiquitous low-molecular weight oxygenated organic air pollutant. Jonsson and Berg (1983) identified MVK in city air and stressed the need to determine details of the occurrence and distribution of such oxygenates in ambient atmospheres, their possible role in photochemical smog formation, and their toxic and potentially carcinogenic properties. Jonsson et al. (1985) found this chemical in five sites of ambient air sampling in a one-year study of Stockholm air. These researchers documented higher concentration of MVK at two urban sites than at sites outside the city and reported a strong correlation of ambient air MVK concentrations at these two sites with vehicle exhaust concentrations. Westerholm et al. (1990) identified MVK in passenger car exhausts measured under different driving conditions; and Westerholm et al. (1991) determined that levels of MVK in exhaust emissions from a heavy duty diesel vehicle during transient driving conditions were in the range of 12 +5.9 mg/km.

Dumdel and Kenny (1988) identified MVK as a breakdown product resulting from the photooxidation of toluene in polluted urban atmospheres. They reported a determination of 6 ppb effluent concentration of the ring fragmentation product, MVK. In order to correlate ambient environmental pollutant levels with human body burden, Pellizzari et al. (1982) identified MVK in human milk in one of 12 samples from four urban areas studied. The atmospheric photochemical degradation of MVK by hydroxyl radicals was reported to be relatively rapid (half-life in air: ~20.8 hr.). MVK's fate in soil was reported to be less well documented, but leaching was considered likely based on an estimated Koc value of 28.

MVK is a pollutant frequently found in industrial wastewaters (Levec, 1990). Several citations have identified MVK as a wastewater component resulting, for example, from the oxidative dehydrogenation of butenes (Chen et al., 1983). Hall et al. (1986) studied the thermal decomposition characteristics of a 12-component mixture of organic solvents, including methyl ethyl ketone (MEK), devised to simulate an actual waste stream subjected to incineration in a liquid-injection incineration unit. MVK was among the stable thermal reaction products reported to occur at 650oC with a decomposition dependence observed relative to time-at-temperature and O2 concentration in the decomposition atmosphere. MVK was classified as a major product of incomplete combustion (PIC) in this system. The authors raised concern that products may be more toxic than input materials in full scale thermal destruction of VOC input materials and warrant attention as potential hazards. In fact, as reported above in the Human Exposure section, Hercules, Inc., identified MVK as a combustion zone PIC resulting from incineration of plant process MEK (Waritz, 1988).

Regulatory Status: MVK is listed as a hazardous chemical subject to transportation restrictions for labeling and handling (49 CFR 171-177). MTM Research Chemicals, Inc. (1991) recommends disposal by incineration and advises that MVK will not degrade microbiologically in wastewater treatment plants and should never be discarded by drain.

MVK is listed in the TSCA inventory and is subject to several rules under SARA. The following information is summarized based on a search of the CHEMLIST database (CHEMLIST, 1991).

TSCA/FYI: Toxicity/Exposure study and environmental fate monitoring information (Hercules study cited above), 12/30/88

SARA/Title III: Extremely hazardous substance under Section 302, proposed in FR 52 #77:13378, 4/22/87.

CERCLA: Hazardous substance under Section 102(a), proposed in FR 54 #13:3388, 1/23/89.

SARA/Title III: Final rule on reporting requirements under Section 313 (Toxics Release Inventory) revising reporting under Sections 311 & 312; proposed reduction from a reporting threshold (RT) of 10,000 lbs. to 500 lbs., 3/29/89.

EPA reported the following regulatory information in Anon. (1987):

Toxicity Value Used for Listing Under Section 302: LC50 inhalation (rat) = 0.007 mg/liter/4 hours

TPQ: 10 (lbs)

RQ: 1 (lb) (statutory, for notification under SARA Section 304(a)(2))