### 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


## Benzene
CAS No. 71-43-2 Known to be a human carcinogen First listed in the First Annual Report on Carcinogens (1980)



### Carcinogenicity
Benzene is known to be a human carcinogen based on sufficient evi

dence of carcinogenicity from studies in humans.
Cancer Studies in Humans Case reports and case series have reported leukemia (mostly acute myelogenous leukemia, also known as acute myeloid or myelocytic leukemia) in individuals exposed to benzene. The strongest epide

miological evidence that benzene causes cancer is from several co

hort studies in various industries and geographical locations, which found that occupational exposure to benzene increased the risk ofmortality from leukemia (mainly acute myelogenous leukemia). Casecontrol studies also reported that exposure to benzene increased the risk of leukemia, but the usefulness of these studies was limited by poorly defined exposures and mixed exposure patterns (IARC 1974, 1982, 1987). Since benzene was reviewed for listing in the First Annual Report on Carcinogens, numerous epidemiological studies of benzene expo

sure and cancer have been published. The International Agency for Research on Cancer (IARC) evaluated benzene in 2012 and concluded that there was sufficient evidence for the carcinogenicity of benzene in humans, based on a causal relationship with myeloid leukemia/ acute non-lymphocytic leukemia (IARC 2012). IARC also concluded that there was limited evidence of carcinogenicity based on a pos

itive association between exposure to benzene and acute lympho

cytic leukemia, chronic lymphocytic leukemia, multiple myeloma, and non-Hodgkin lymphoma. Cancer Studies in Experimental Animals Studies in experimental animals, including many published after benzene was listed in the First Annual Report on Carcinogens, have demonstrated that benzene causes cancer at numerous tissue sites in rodents. Oral exposure to benzene caused cancer of the Zymbal gland (carcinoma) in rats and mice of both sexes, cancer of the oral cav

ity (squamous-cell carcinoma) in rats of both sexes, malignant lym

phoma and lung cancer (alveolar/bronchiolar carcinoma) in mice of both sexes, skin cancer (squamous-cell carcinoma) in male rats, be

nign tumors of the Harderian gland (adenoma) and cancer of the pre

putial gland (carcinoma) in male mice, and benign ovarian tumors and cancer of the mammary gland (carcinoma and carcinosarcoma) in female mice (NTP 1986, Huff et al. 1989). Inhalation exposure to benzene caused tumors at many tissue sites in rats and a tendency towards induction of lymphoid tumors in mice. Benzene adminis

tered by intraperitoneal injection caused benign lung tumors in male mice (IARC 1982, 1987). Dermal application of benzene caused be

nign skin tumors in transgenic mice carrying the v

- H a - ras onco gene, which increases their susceptibility to carcinogens (Blanchard et al. 1998, Spaldinget al. 1999, French and Saulnier 2000). In het

erozygous p53

- deficient mice (with only one functional copy of the p53 tumor-suppressor gene), benzene administered by stomach tube caused cancer (sarcoma) of head and neck, thoracic cavity, and sub

cutaneous tissue (French et al. 2001, Hulla et al. 2001). 

### Properties Benzene is the primary aromatic compound. It exists at room tem

perature as a clear, colorless-to-yellow liquid with an aromatic odor. It is only slightly soluble in water, but it is miscible with alcohol, ether, chloroform, carbon disulfide, acetone, oils, carbon tetrachloride, gla

cial acetic acid, and most other organic solvents. Benzene is highly flammable (Akron 2009). Physical and chemical properties of ben

zene are listed in the following table.
Property Information Molecular weight 78.1 Specific gravity 0.8787 at 15°C/4°C Melting point 5.5°C Boiling point 80.1°C Log K ow 2.13 Water solubility 1.79 g/L at 25°C Vapor pressure 94.8 mm Hg at 25°C Vapor density relative to air 2.8
Source: HSDB 2009.


### Use Benzene is used primarily as a solvent in the chemical and pharma

ceutical industries, as a starting material and intermediate in the syn

thesis of numerous chemicals, and in gasoline. As a raw material, it is used in the synthesis of ethylbenzene (used to produce styrene) (53%), cumene (used to produce phenol and acetone) (22%), cyclohexane (12%), nitrobenzene (used to produce aniline and other chemicals) (5%), detergent alkylate (linear alkylbenzene sulfonates) (3%), and chlorobenzenes and other products (5%). Benzene is used as an ad

ditive in gasoline, but it also is present naturally in gasoline, because it occurs naturally in crude oil and is a by-product of oil-refining pro

cesses. The percentage of benzene in unleaded gasoline is approxi

mately 1% to 2% by volume (ATSDR 1997, HSDB 2009). 

### Production Benzene has been produced commercially from coal since 1849 and from petroleum since 1941. Since 1959, the major U.S. source of benzene has been petroleum (IARC 1989). In 1994, benzene ranked 17th in production volume among chemicals produced in the United States. U.S. production of benzene increased from 5.4 million met

ric tons (12.0 billion pounds) in 1992 to 7.2 million metric tons (15.8 billion pounds) in 2002, an average increase of 2.8% per year (CEN 2003). Annual production during this period was highest in 2000, at 8.1 million metric tons (17.8 billion pounds). In 2009, 59 U.S. man

ufacturers (SRI 2009) and 24 U.S. suppliers of benzene were identi

fied (ChemSources 2009). In 2002, U.S. imports of benzene totaled over 4 billion liters (1.1 billion gallons), which greatly exceeded ex

ports of 6 million liters (1.6 million gallons). This trend continued in 2008, when 3.9 billion liters (1.03 billion gallons) was imported and 49.6 million liters (13.1 million gallons) was exported (USITC 2009). 

### Exposure The primary route of human exposure to benzene is inhalation of ambient air. Benzene is present in the atmosphere both from nat

ural sources, which include forest fires and oil seeps, and from in

dustrial sources, which include automobile exhaust, industrial emissions, and fuel evaporation from gasoline filling stations. Ben

zene has been measured in outdoor air at various U.S. locations at concentrations ranging from 0.02 ppb (0.06 μg/m 3 ) in a rural area to 112 ppb (356 μg/m 3 ) in an urban area. The maximum 24-hour aver

age concentrations of benzene reported for four U.S. cities in 2004 were 1.1 ppb (3.5 μg/m 3 ) for St. Louis, Missouri, 2.7 ppb (8.6 μg/m 3 )

### Report on Carcinogens, Thirteenth Edition

National Toxicology Program, Department of Health and Human Services 2 for Chicago, Illinois, 2.9 ppb (9.3 μg/m 3 ) for Los Angeles, Califor

nia, and 73.5 ppb (234.8 μg/m 3 ) for Houston, Texas (Clements et al. 2006). Exposure to benzene is highest in areas of heavy motor vehi

cle traffic and around gasoline filling stations. Based on an average benzene concentration of 12.5 ppb (40 μg/m 3 ) in the air and expo

sure of 1 hour per day, daily benzene intake from driving or riding in a motor vehicle is estimated to be 40 μg. Exposure is greater among people who spend significant time in motor vehicles in areas of con

gested traffic. In addition, pumping of gasoline can be a significant source of benzene exposure; for an individual spending 70 minutes per year pumping gasoline, daily benzene intake is estimated to be 10 μg (ATSDR 1997). The general population can also be exposed to benzene by inhal

ing air containing tobacco smoke, drinking contaminated water, or eating contaminated food. About half of the total national exposure to benzene comes from cigarette smoke. The median level of benzene was 2.2 ppb (7 μg/m 3 ) in 185 homes without smokers and 3.3 ppb (10.5 μg/m 3 ) in 343 homes with one or more smokers. Amounts of benzene measured per cigarette ranged from 5.9 to 75 μg in main

stream smoke and from 345 to 653 μg in sidestream smoke. Benzene has been detected in fruits, vegetables, nuts, dairy products, eggs, and fish. In a 1992 survey of more than 50 foods, benzene concen

trations in foods containing both benzoate and ascorbate food addi

tives ranged from less than 1 to 38 ppb (< 3 to 120 μg/m 3 ) (ATSDR, 1997). According to the U.S. Environmental Protection Agency’s Tox

ics Release Inventory, environmental releases of benzene decreased from 34 million pounds in 1988 to 6 million pounds in 2001, when 5 million pounds was released to air and 19,000 lb to water. In 2007, 775 facilities released 6.3 million pounds of benzene (TRI 2009). Ben

zene levels in water in the vicinity of four manufacturing facilities us

ing or producing benzene ranged from less than 1 to 179 ppb (< 3 to 569 μg/m 3 ) (ATSDR, 1997). Occupational exposure may occur during production of benzene or use of substances containing it. In the vulcanization step of tire manufacturing, benzene was measured at concentrations of up to 27.2 mg/m 3 , resulting in an estimated daily intake of 0.0045 mg/kg of body weight for workers (Durmusoglu 2007). The National Occupa

tional Health Survey (conducted from 1972 to 1974) estimated that 147,600 U.S. workers potentially were exposed to benzene (NIOSH 1976), and the National Occupational Exposure Survey (conducted from 1981 to 1983) estimated that about 272,000 workers, including 143,000 women, potentially were exposed to benzene (NIOSH 1990). 

### Regulations Coast Guard, Department of Homeland Security Comprehensive regulations have been established for safe transport of benzene on ships and barges. Consumer Product Safety Commission (CPSC) Products containing 5% or more by weight of benzene are considered hazardous and require special labeling. Solvents for paints or other surface-coating materials containing 10% or more by weight of benzene require special packaging. Department of Transportation (DOT) Benzene is considered a hazardous material, and special requirements have been set for marking, labeling, and transporting this material. Environmental Protection Agency (EPA) Clean Air Act Comprehensive regulations have been developed to control benzene levels in gasoline and benzene emissions from motor vehicles. Mobile Source Air Toxics:Beginning in 2011, refiners must meet an annual average gasoline benzene content standard of 0.62% by volume (vol%) on all gasoline; by 2012, a maximum benzene content of 1.3 vol% may not be exceeded. National Emission Standards for Hazardous Air Pollutants:Listed as a hazardous air pollutant. New Source Performance Standards:Manufacture is subject to certain provisions for the control of volatile organic compound emissions. Urban Air Toxics Strategy:Identified as one of 33 hazardous air pollutants that present the greatest threat to public health in urban areas. Clean Water Act Designated a hazardous substance. Effluent Guidelines:Listed as a toxic pollutant. Water Quality Criteria:Based on fish or shellfish and water consumption = 2.2 μg/L; based on fish or shellfish consumption only = 51 μg/L. 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. Resource Conservation and Recovery Act Characteristic Hazardous Waste:Toxicity characteristic leaching procedure (TCLP) threshold = 0.5 mg/L. Listed Hazardous Waste:Waste codes for which the listing is based wholly or partly on the presence of benzene = U019, F005, F024, F025, F037, F038, K085, K104, K105, K141, K142, K143, K144, K145, K147, K151, K159, K169, K171, K172. Listed as a hazardous constituent of waste. Safe Drinking Water Act Maximum contaminant level (MCL) = 0.005 mg/L. Food and Drug Administration (FDA) Maximum permissible level in bottled water = 0.005 mg/L. Residues of benzene used as a solvent in producing modified hop extract shall not exceed 1.0 ppm. 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. Acceptable peak exposure = 50 ppm (maximum duration = 10 min) for select industries. Ceiling concentration = 25 ppm for select industries. Permissible exposure limit (PEL) = 1 ppm; = 10 ppm for select industries. Short-term exposure limit (STEL) = 5 ppm. Comprehensive standards for occupational exposure to benzene have been developed. 

### Guidelines American Conference of Governmental Industrial Hygienists (ACGIH) Threshold limit value – time-weighted average (TLV-TWA) = 0.5 ppm. Threshold limit value – short-term exposure limit (TLV-STEL) = 2.5 ppm. Potential for dermal absorption. National Institute for Occupational Safety and Health (NIOSH) Immediately dangerous to life and health (IDLH) limit = 500 ppm. Short-term exposure limit (STEL) = 1 ppm. Recommended exposure limit (time-weighted-average workday) = 0.1 ppm. Listed as a potential occupational carcinogen. 

### References
Akron. 2009. The Chemical Database . The Department of Chemistry at the University of Akron. http://ull. chemistry.uakron.edu/erd and search on CAS number. Last accessed: 10/20/09. ATSDR. 1997. Toxicological Profile for Benzene. Update (Final Report) . NTIS Accession No. PB98-101157. Atlanta, GA: Agency for Toxic Substances and Disease Registry. 459 pp. Blanchard KT, Ball DJ, Holden HE, Furst SM, Stoltz JH, Stoll RE. 1998. Dermal carcinogenicity in transgenic mice: relative responsiveness of male and female hemizygous and homozygous Tg.AC mice to 12- O -tetradecanoylphorbol 13-acetate (TPA) and benzene. Toxicol Pathol 26(4): 541-547. CEN. 2003. Production inches up in most countries. Chem Eng News81(27): 51-61. ChemSources. 2009. Chem Sources - Chemical Search. Chemical Sources International. http://www. chemsources.com/chemonline.html and search on benzene. Last accessed: 10/20/09. Clements AL, Flatt VB, Fraser MP, Hamilton WJ, Ledvina PS, Mathur SK, Tamhane A, Ward JB. 2006. The Control of Air Toxics: Toxicology Motivation and Houston Implications . Rice University Department of Civil and Environmental Engineering. http://hydrology.rice.edu/ceve/fraser/FINAL%20MASTER.pdf. Durmusoglu E, Aslan S, Can E, Bulut Z. 2007. Health risk assessment of workers’ exposure to organic compounds in a tire factory. Hum Ecol Risk Assess13: 209-222. French JE, Lacks GD, Trempus C, Dunnick JK, Foley J, Mahler J, Tice RR, Tennant RW. 2001. Loss of heterozygosity frequency at the Trp53 locus in p53-deficient (+/–) mouse tumors is carcinogen-and tissue-dependent. Carcinogenesis 22(1): 99-106.French JE, Saulnier M. 2000. Benzene leukemogenesis: an environmental carcinogen-induced tissuespecific model of neoplasia using genetically altered mouse models. J Toxicol Environ Health A 61(5-6): 377-379. HSDB. 2009. Hazardous Substances Data Bank . National Library of Medicine. http://toxnet.nlm.nih.gov/ cgi-bin/sis/htmlgen?HSDB and search on CAS number. Last accessed: 10/20/09.

### Report on Carcinogens, Thirteenth Edition

National Toxicology Program, Department of Health and Human Services 3 Huff JE, Haseman JK, DeMarini DM, Eustis S, Maronpot RR, Peters AC, Persing RL, Chrisp CE, Jacobs AC. 1989. Multiple-site carcinogenicity of benzene in Fischer 344 rats and B6C3F 1 mice. Environ Health Perspect 82: 125-163. Hulla JE, French JE, Dunnick JK. 2001. Chromosome 11 allelotypes reflect a mechanism of chemical carcinogenesis in heterozygous p53-deficient mice. Carcinogenesis 22(1): 89-98. IARC. 1974. Benzene. In Some Anti-Thyroid And Related Substances, Nitrofurans And Industrial Chemicals

. IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Humans, vol. 7. Lyon, France: International Agency for Research on Cancer. pp. 203-221. IARC. 1982. Benzene. In Some Industrial Chemicals and Dyestuffs . IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Humans, vol. 29. Lyon, France: International Agency for Research on Cancer. pp. 93-148. IARC. 1987. Benzene. In Overall Evaluations of Carcinogenicity. IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Humans, suppl 7. Lyon, France: International Agency for Research on Cancer. pp. 120-122. IARC. 1989. Occupational exposures in petroleum refining. In Occupational Exposures in Petroleum Refining; Crude Oil and Major Petroleum Fuels . IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Humans, vol. 45. Lyon, France: International Agency for Research on Cancer. pp. 39-118. NIOSH. 1976. National Occupational Hazard Survey (1972-74) . DHEW (NIOSH) Publication No. 78-114. Cincinnati, OH: National Institute for Occupational Safety and Health. NIOSH. 1990. National Occupational Exposure Survey (1981-83). National Institute for Occupational Safety and Health. Last updated: 7/1/90. http://www.cdc.gov/noes/noes1/09070sic.html. NTP. 1986. Toxicology and Carcinogenesis Studies of Benzene (CAS No. 71-43-2) in F344/N Rats and B6C3F 1 Mice (Gavage Studies) . Technical Report Series no. 289. NIH Publication no. 86-2545. Research Triangle Park, NC, and Bethesda, MD: National Toxicology Program. 277 pp. Spalding JW, French JE, Tice RR, Furedi-Machacek M, Haseman JK, Tennant RW. 1999. Development of a transgenic mouse model for carcinogenesis bioassays: evaluation of chemically induced skin tumors in Tg.AC mice. Toxicol Sci 49(2): 241-254. SRI. 2009. Directory of Chemical Producers . Menlo Park, CA: SRI Consulting. Database edition. Last accessed: 10/20/09. TRI. 2009. TRI Explorer Chemical Report. U.S. Environmental Protection Agency. http://www.epa.gov/ triexplorer and select Benzene. USITC. 2009. USITC Interactive Tariff and Trade DataWeb. United States International Trade Commission. http://dataweb.usitc.gov/scripts/user_set.asp and search on HTS no. 2900220. Last accessed: 10/20/09.