### Report on Carcinogens, Thirteenth Edition

National Toxicology Program, Department of Health and Human Services 

### For Table of Contents, see home page: http://ntp.niehs.nih.gov/go/roc13 

## 1,3-Butadiene CAS No. 106-99-0 Known to be a human carcinogen First listed in theFifth Annual Report on Carcinogens (1989) H 2 C C H H C CH 2 

### Carcinogenicity 1,3-Butadiene is known to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in humans, including epide miological and mechanistic studies. 1,3 - Butadiene was first listed in the Fifth Annual Report on Carcinogensin 1989 as reasonably antic ipated to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in experimental animals. The listing was revised to known to be a human carcinogen in the Ninth Report on Carcinogensin 2000. Cancer Studies in Humans A number of epidemiological studies have shown an association be tween occupational exposure to 1,3 - butadiene and excess mortality from cancer of the lymphatic and hematopoietic systems. These in clude (1) a cohort study showing increased risk of lymphosarcoma and reticulosarcoma in workers who manufactured 1,3 - butadiene monomer, (2) a study of styrene-butadiene rubber workers in eight plants in the United States and Canada showing increased risk of leukemia among production workers, and (3) a case-control study within the cohort of styrene-butadiene rubber workers showing a large excess of leukemia associated with exposure to 1,3 - butadiene and not to styrene (IARC 1992). In addition, an excess of lymphosarcoma and reticulosarcoma was found among 1,3 - butadiene produc tion workers in a previously unstudied chemical plant (Ward et al. 1996). Excess deaths from leukemia were observed among long-term workers who were hired before 1960 and had worked in the three (of eight studied) styrene-butadiene rubber plants with the highest expo sure to butadiene (standardized mortality ratio = 1.8 in comparisonwith the U.S. population). A second case-control study of styrenebutadiene rubber workers with lymphopoietic cancer (with a new set of controls for each case) confirmed the strong association and significant dose-response relationship between 1,3 - butadiene expo sure score and risk of leukemia (Matanoski et al. 1993). Finally, a fol low-up study of styrene-butadiene rubber workers in the synthetic rubber industry also found a dose-response relationship between 1,3 - butadiene exposure level and the occurrence of leukemia (Del zell et al. 1996, 2006, Macaluso et al. 1996). Studies on Mechanisms of Carcinogenesis 1,3 - Butadiene appears to cause tumors in humans and rodents through its metabolism to DNA-reactive epoxide intermediates, which cause genetic alterations in proto-oncogenes or tumor-sup pressor genes (Melnick and Kohn 1995). Mouse, rat, and human liver microsomes have been shown to oxidize 1,3 - butadiene to epoxy butene (Csadany et al. 1992) and to further oxidize the monoepox ide to diepoxybut ane (Seaton et al. 1995). These metabolites form N

′ -alkylguanine adducts that have been detected in liver DNA of mice exposed to 1,3 - buta diene and in the urine of a worker exposed to 1,3 - butadiene. Activated K- ras oncogenes and inactivated tumorsuppressor genes observed in 1,3 - b utadiene-induced tumors in mice are analogous to genetic alterations frequently observed in a wide variety of human cancers. Dose-related increases in hprt mutations have been observed in lymphocytes isolated from mice exposed to 1,3 - butadiene or its epoxide metabolites and in occupationally ex posed workers. The mutational spectra for 1,3 - b utadiene and its epox ide metabolites at the hprt locus in mouse lymphocytes are similar to the mutational spectrum for ethylene oxide, an alkylating agent listed in the Report on Carcinogens as known to be a human carcinogen. Cancer Studies in Experimental Animals There is sufficient evidence for the carcinogenicity of 1,3 - buta diene from studies in experimental animals. Inhalation exposure to 1,3 - buta diene caused benign or malignant tumors at several different tissue sites in rodents, including the hematopoietic system, heart (hemangiosarcoma), lung, forestomach, Harderian gland, preputial gland, liver, mammary gland, ovary, and kidney in mice (NTP 1984, Huff et al. 1985, Melnick et al. 1990) and the pancreas, testis, thyroid gland, mammary gland, uterus, and Zymbal gland in rats (Owen et al. 1987). 

### Properties 1,3 - Butadiene is an olefin which at room temperature is a colorless gas with a mild aromatic or gasoline odor. It is insoluble in water but soluble in ether, ethanol, acetone, and other organic solvents. It poly merizes readily, especially in the presence of oxygen; therefore, it is shipped and stored with an inhibitor to prevent this reaction (Akron 2009). It is also a dangerous fire hazard. Physical and chemical prop erties of 1,3 - butadiene are listed in the following table. Property Information Molecular weight 54.1 a Density 0.6149 g/cm 3 at 25°C a Melting point –108.966°C a Boiling point –4.5°C at 760 mm Hg a Log K ow 1.99 b Water solubility 0.735 g/L at 20°C a Vapor pressure 2,110 mm Hg at 25°C a Vapor density relative to air 1.87 a Sources: a HSDB 2009, b ChemIDplus 2009. 

### Use 1,3 - Butadiene is used primarily as a monomer to manufacture many different types of polymers and copolymers and as a chemical in termediate to produce a number of important industrial chemicals. More than 75% of the 1,3 - butadiene produced goes into synthetic rubber products (CEN 1986). The major uses include production of styrene-butadiene rubber (30% to 35%), polybutadiene rubber (20% to 22%), adiponitrile (12% to 15%), styrene-butadiene latex (10%), neo prene rubber (5% to 6%), acrylonitrile-butadiene-styrene resins (5% to 6%), and nitrile rubber (3%), exports (4%), and other uses, includ ing production of specialty polymers (2% to 8%) (IARC 1992, ATSDR 1993). The major end-use products containing styrene-butadiene and polybutadiene are tires. Other products include latex adhesives, seals, hoses, gaskets, various rubber products, nylon carpet backings, paper coatings, paints, pipes, conduits, appliance and electrical equipment components, automotive parts, and luggage. The only major nonpoly mer use is in the manufacture of adiponitrile, a nylon intermediate. Butadiene is also used in the manufacture of the fungicides captan and captafol (Morrow 1990, IARC 1992, Kirschner 1996). 

### Production 1,3 - Butadiene is isolated by distillation or extraction from crude butadiene, which is a by-product of ethylene production. Commer cial production began in the 1930s (IARC 1992). Between 1980 and 2002, annual U.S. production of rubber-grade 1,3 - butadiene ranged

### Report on Carcinogens, Thirteenth Edition

National Toxicology Program, Department of Health and Human Services 2 from a low of 869,000 metric tons (1.9 billion pounds) in 1982 to a high of 2,009,000 metric tons (4.4 billion pounds) in 2000 (IARC 1992, CEN 1999, 2003). The average annual change was about 2.5% from 1992 to 2002 compared with about 1.2% from 1980 to 1990. 1,3 - B uta diene ranked 34th among the top 50 chemical commodities produced in the United States in 1987, falling to 36th by the mid 1990s (Morrow 1990, Kirschner 1996, CEN 1997). In 1990, 30 ethylene plants in the United States produced crude butadiene streams that were processed in 11 extraction plants (Morrow 1990). In 2009, 11 U.S. producers and 12 U.S. suppliers of 1,3 - b utadiene were identified (ChemSources 2009, SRI 2009). Because U.S. demand for 1,3 - b utadiene has exceeded the domestic supply in most years, imports have greatly exceeded ex ports. Annual U.S. imports ranged from 500 million to 900 million pounds from the late 1970s to the mid 1980s and from 1.2 billion to 1.4 billion pounds from 1998 to 2000, decreasing to 200 million pounds in 2002 (ATSDR 1993, USITC 2009). In 2008, imports were 1.7 billion pounds. Annual U.S. exports ranged from 94 million to 145 million pounds from the late 1970s through the mid 1980s, de creasing to 37.6 million pounds in 2000 and 15.2 million pounds in 2002. In 2008, exports were 217.6 million pounds. 

### Exposure The primary route of potential exposure to 1,3 - b utadiene for the gen eral population is inhalation. Some exposure may occur through in gestion of contaminated food or water or dermal contact; however, these routes of exposure are unlikely under most circumstances. 1,3 - Butadiene is not a common contaminant of water supplies. Al though some food packaging contains residual 1,3 - butadiene, the available data indicate that it does not usually migrate to the food. Certain cooking oils, such as rapeseed oil (canola), release 1,3 - buta diene when heated (Shieldset al. 1995). Most people are exposed to low levels of 1,3 - butadiene in the air, because it is released to the environment during its production, use, storage, and disposal and is present in gasoline, automobile exhausts, and cigarette smoke. 1,3 - Butadiene is emitted from petroleum refin eries and from furnaces at secondary lead smelting facilities handling automotive lead-acid batteries that contain plastic battery separators or that have hard rubber casings (EPA 1996). Incomplete combustion of a variety of fuels forms 1,3 - butadiene as a product. 1,3 - Butadiene makes up 0.5% to 2% of the total organic gas emissions from most types of combustion (Ligockiet al. 1994). It can also be found in mo tor-vehicle exhaust emissions as a product of incomplete combustion of gasoline and diesel oil and from the thermal breakdown of plastics (ATSDR 1993, EPA 1996). Through modeling of dispersion from atypical freeway source in California, it was estimated that gasolinefueled vehicles emit 0.011 g of 1,3 - butadiene per mile (Cooper and Reisman 1992). 1,3 - Butadiene also is formed naturally as a by-prod uct of forest fires (HSDB 2009). Releases of 1,3 - butadiene in side stream cigarette smoke into the air have been variously estimated at 152 to 400 μg per cigarette (Ligockiet al. 1995). Calculations based on 400 μg per cigarette indicate that 1,3 - b utadiene concentrations in the homes of smokers would be increased by approximately 4 μg/m 3 , and concentrations in air at workplaces allowing smoking would be increased by 13 μg/m 3(Wallace 1991). According to the U.S. Environmental Protection Agency’s Toxics Release Inventory, total industrial environmental releases of 1,3 - b uta diene declined from more than 7.7 million pounds in 1988 to about 1.8 million pounds in 2007, of which over 90% was released to air (TRI 2009). However, a nationwide 1,3 - butadiene inventory (includ ing vehicle emissions and emissions from manufacturing and produc ing facilities) calculated annual butadiene emissions to air to be 102 million kilograms (225 million pounds) in 1990 (Ligockiet al. 1994), considerably higher than EPA’s estimate of about 5.2 million pounds (2.4 million kilograms) for industrial emissions in the same year. The median daily concentrations of 1,3 - butadiene in U.S. ambi ent air samples collected from 1970 to 1987 were 0.29 ppb in urban areas (385 samples), 0.32 ppb in suburban areas (196 samples), and 0.1 ppb in rural areas (2 samples). The maximum 24-hour average concentrations of 1,3-butadiene reported for four U.S. cities in 2004 were 0.3 ppb for St. Louis, Missouri, 0.5 ppb for Chicago, Illinois, and Los Angeles, California, and 37.4 ppb for Houston, Texas (Cle ments et al. 2006). However, reported average daily concentrations of 1,3 - buta diene in ambient air within a mile of petrochemical fa cilities have exceeded 100 ppb, and the highest hourly average con centrations have exceeded 900 ppb (ATSDR 1993). Volatilization of 1,3 - b utadiene from wastewaters of styrene-1,3-butadiene copolymer production at publicly owned treatment works has been calculated to be 21 tons per year (EPA 1996). Occupational exposure to 1,3 - butadiene may occur through in halation and, to a lesser extent, dermal contact (NTP 1984). The National Occupational Exposure Survey (conducted from 1981 to 1983) estimated that about 52,000 workers at 2,201 facilities, includ ing 1,410 women, potentially were exposed to 1,3 - b utadiene (NIOSH 1990). This estimate does not include workers exposed to butadiene polymers and copolymers and is consistent with an earlier estimate of about 66,000 to 70,000 workers at 3,086 facilities reported in the National Occupational Hazard Survey (conducted from 1972 to 1974) (NIOSH 1976). Health hazard evaluation surveys conducted by the National Institute for Occupational Safety and Health at six facili ties found air concentrations of 1,3 - butadiene ranging from 0.06 to 39 ppm. Surveys conducted at many monomer, polymer, and end-user plants have reported concentrations ranging from below detection to 374 ppm (827 mg/m 3 ). In most cases, 8 - h our time-weighted-average concentrations were less than 10  ppm (<  22  mg/m 3 ) (IARC 1992, ATSDR 1993). For the monomer industry as a whole, 1,3 - butadiene concentrations were greater than 10 ppm (> 22 mg/m 3 ) in 7.1% of the samples, 2 to 10 ppm (4 to 22 mg/m 3 ) in 12.8%, 1 to 2 ppm (2 to 4 mg/m 3 ) in 12.3% and less than 1 ppm (< 2 mg/m 3 ) in 67.8%. The Occupational Safety and Health Administration permissible expo sure limit is 1 ppm. For the polymer industry as a whole, the corre sponding percentages for these four ranges were 3.3%, 7.7%, 3.3%, and 85.8%, respectively. The arithmetic mean exposure for personal full-shift exposures in the polymer plants was 1.14 ppm (2.57 mg/m 3 ) (Fajenet al. 1993). 

### Regulations Department of Transportation (DOT) Butadienes are considered hazardous materials, and special requirements have been set for marking, labeling, and transporting these materials. Environmental Protection Agency (EPA) Clean Air Act Mobile Source Air Toxics:Listed as a mobile source air toxic for which regulations are to be developed. National Emission Standards for Hazardous Air Pollutants:Listed as a hazardous air pollutant. New Source Performance Standards:Manufacture of 1,3‐butadiene is subject to certain provisions for the control of volatile organic compound emissions. Prevention of Accidental Release:Threshold quantity (TQ) = 10,000 lb. Urban Air Toxics Strategy:Identified as one of 33 hazardous air pollutants that present the greatest threat to public health in urban areas. Standards have been established for emissions of 1,3‐butadiene from reformulated gasoline and motor vehicles. Comprehensive Environmental Response, Compensation, and Liability Act Reportable quantity (RQ) = 10 lb. Emergency Planning and Community Right-To-Know Act Toxics Release Inventory:Listed substance subject to reporting requirements.

### Report on Carcinogens, Thirteenth Edition

National Toxicology Program, Department of Health and Human Services 3 Occupational Safety and Health Administration (OSHA) While this section accurately identifies OSHA’s legally enforceable PELs for this substance in 2010, specific PELs may not reflect the more current studies and may not adequately protect workers. Permissible exposure limit (PEL) = 1 ppm. Short - term exposure limit (STEL) = 5 ppm. Comprehensive standards for occupational exposure to 1,3‐butadiene have been developed. 

### Guidelines American Conference of Governmental Industrial Hygienists (ACGIH) Threshold limit value – time - weighted average (TLV-T WA) = 2 ppm. National Institute for Occupational Safety and Health (NIOSH) Immediately dangerous to life and health (IDLH) limit = 2,000 ppm. Listed as a potential occupational carcinogen. 

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