The Risk Assessment Information System

Toxicity Summary for BENZO[B]FLUORANTHENE

NOTE: Although the toxicity values presented in these toxicity profiles were correct at the time they were produced, these values are subject to change. Users should always refer to the Toxicity Value Database for the current toxicity values.

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EXECUTIVE SUMMARY

1. INTRODUCTION

2. METABOLISM AND DISPOSITION

2.1 ABSORPTION
2.2 DISTRIBUTION
2.3 METABOLISM
2.4 EXCRETION

3. NONCARCINOGENIC HEALTH EFFECTS

3.1 ORAL EXPOSURES
3.2 INHALATION EXPOSURES
3.3 OTHER ROUTES OF EXPOSURE
3.4 TARGET ORGANS/CRITICAL EFFECTS

4. CARCINOGENICITY

4.1 ORAL EXPOSURES
4.2 INHALATION EXPOSURES
4.3 OTHER ROUTES OF EXPOSURE
4.4 EPA WEIGHT-OF-EVIDENCE
4.5 CARCINOGENICITY SLOPE FACTORS

5. REFERENCES

May 1994

Prepared by: Rosmarie A. Faust, Ph.D., Chemical Hazard Evaluation and Communication Group, Biomedical and Environmental Information Analysis Section, Health and Safety Research Division, *, Oak Ridge, Tennessee.

Prepared for OAK RIDGE RESERVATION ENVIRONMENTAL RESTORATION PROGRAM.

*Managed by Martin Marietta Energy Systems, Inc., for the U.S. Department of Energy under Contract No. DE-AC05-84OR21400.

EXECUTIVE SUMMARY

Benzo[b]fluoranthene, a crystalline solid with a chemical formula of C₂₀H₁₂ and a molecular weight of 252.32 (Lide, 1991), is a polycyclic aromatic hydrocarbon (PAH) with one five-membered ring and four six-membered rings. There is no commercial production or known use of this compound (IARC, 1983). Benzo[b]fluoranthene is found in fossil fuels and occurs ubiquitously in products of incomplete combustion. It has been detected in mainstream cigarette smoke; urban air; gasoline engine exhaust; emissions from burning coal and from oil-fired heating; broiled and smoked food; oils and margarine (IARC, 1983); and in soils, groundwater, and surface waters at hazardous waste sites (ATSDR, 1990).

No absorption data were available for benzo[b]fluoranthene; however, by analogy to structurally-related PAHs, primarily benzo[a]pyrene, it would be expected to be absorbed from the gastrointestinal tract, lungs, and skin (EPA, 1991). Major metabolites of benzo[b]fluoranthene formed in vitro in rat liver include dihydrodiols and monohydroxy derivatives (Amin et al., 1982) and monohydroxy derivatives in mouse epidermis (Geddie et al., 1987).

No data were found concerning the acute, subchronic, chronic, developmental, or reproductive toxicity of benzo[b]fluoranthene. No data were available for the derivation of an oral reference dose (RfD) or inhalation reference concentration (RfC) (EPA, 1994).

No long-term oral or inhalation bioassays were available to assess the carcinogenicity of benzo[b]fluoranthene. Benzo[b]fluoranthene was tested for carcinogenicity in dermal application, lung implantation, subcutaneous (s.c.) injection, and intraperitoneal (i.p.) injection studies. Dermal applications of 0.01-0.5% solutions of benzo[b]fluoranthene for life produced a high incidence of skin papillomas and carcinomas in mice (Wynder and Hoffmann, 1959). In initiation-promotion assays, the compound was active as an initiator of skin carcinogenesis in mice (LaVoie et al., 1982; Amin et al., 1985). Sarcomas and carcinomas of the lungs and thorax were seen in rats receiving single lung implants of 0.1-1 mg benzo[b]fluoranthene (Deutsch-Wenzel et al., 1983). Newborn mice receiving 0.5 umol benzo[b]fluoranthene via i.p. injection developed liver and lung tumors (LaVoie et al., 1987), and mice administered three s.c. injections of 0.6 mg benzo[b]fluoranthene developed injection site sarcomas (IARC, 1993).

Based on no human data and sufficient evidence for carcinogenicity in animals, EPA has assigned a weight-of-evidence classification of B2, probable human carcinogen, to benzo[b]fluoranthene (EPA, 1994).

1. INTRODUCTION

Benzo[b]fluoranthene (CAS Reg. No. 205-99-2), also known as benz(e)acephenanthrylene, 3,4-benz(e)acephenanthrylene, 2,3-benzofluoranthene, 3,4-benzofluoranthene, and benzo(e)fluoranthene (IARC, 1983) is a polycyclic aromatic hydrocarbon (PAH) with one five-membered ring and four six-membered rings. It is a crystalline solid with a chemical formula of C₂₀H₁₂, a molecular weight of 252.32, and a melting point of 168C (Lide, 1991). Benzo[b]fluoranthene is virtually insoluble in water and is slightly soluble in benzene and acetone (IARC, 1983). It has a vapor pressure of 10^-11 to 10^-6 torr at 20C, an octanol/water partition coefficient of 1.1x10⁶, and a Henry's Law constant of 1.22x10^-5 (ATSDR, 1990). There is no commercial production or known use of this compound (IARC, 1983).

Benzo[b]fluoranthene is found in fossil fuels and occurs ubiquitously in products of incomplete combustion. It has been detected in mainstream cigarette smoke; urban air; gasoline engine exhaust; emissions from burning coal and from oil-fired heating; broiled and smoked food; oils and margarine (IARC, 1973); and in soils, groundwater, and surface waters at hazardous waste sites (ATSDR, 1990). Benzo[b]fluoranthene is one of a number of PAHs on the United States Environmental Protection Agency's (EPA's) priority pollutant list (ATSDR, 1990).

2. METABOLISM AND DISPOSITION

2.1 ABSORPTION

Data regarding the gastrointestinal or pulmonary absorption of benzo[b]fluoranthene in humans or animals were not available. However, data from structurally-related PAHs, primarily benzo[a]pyrene, suggest that benzo[b]fluoranthene would be absorbed from the gastrointestinal tract, lungs, and skin (EPA, 1991).

2.2 DISTRIBUTION

No human or animal data were available concerning the tissue distribution of benzo[b]fluoranthene.

2.3 METABOLISM

Amin et al. (1982) investigated the in vitro metabolism of benzo[b]fluoranthene by rat liver microsomes and identified 5- and 6-hydroxybenzo[b]fluoranthene and 4- or 7-hydroxybenzo[b]fluoranthene as major metabolites. The principal dihydrodiol metabolite formed was trans-11,12-dihydro-11,12-dihydroxybenzo[b]fluoranthene. Geddie et al. (1987) investigated the metabolism of benzo[b]fluoranthene in mouse epidermis. Following dermal application of benzo[b]fluoranthene, 4-, 5-, and 6-hydroxybenzo[b]fluoranthene were identified as major metabolites. Sulfate and glucuronide conjugates of these hydroxy compounds were also detected.

2.4 EXCRETION

No human or animal data were available concerning the excretion of benzo[b]fluoranthene.

3. NONCARCINOGENIC HEALTH EFFECTS

3.1 ORAL EXPOSURES

Information on the acute, subchronic, chronic, developmental, or reproductive oral toxicity of benzo[b]fluoranthene in humans or animals was not available. Because of a lack of toxicity data, an oral reference dose (RfD) for benzo[b]fluoranthene has not been derived (EPA, 1994).

3.2 INHALATION EXPOSURES

Information on the acute, subchronic, chronic, developmental, or reproductive toxicity of benzo[b]fluoranthene in humans or animals following inhalation exposure was not available. Because of a lack of toxicity data, an inhalation reference concentration (RfC) for benzo[b]fluoranthene has not been derived (EPA, 1994).

3.3 OTHER ROUTES OF EXPOSURE

Information on the acute, subchronic, chronic, developmental, or reproductive toxicity of benzo[b]fluoranthene in humans or animals by other routes of exposure was not available.

3.4 TARGET ORGANS/CRITICAL EFFECTS

No data were available to determine target organs/critical effects for oral, inhalation, or other routes of exposure to benzo[b]fluoranthene.

4. CARCINOGENICITY

4.1 ORAL EXPOSURES

Information on the carcinogenicity of benzo[b]fluoranthene in humans or animals following oral exposure was not available.

4.2 INHALATION EXPOSURES

4.2.1 Human

Although there are no human data that specifically link exposure to benzo[b]fluoranthene to human cancers, benzo[b]fluoranthene is a component of mixtures that have been associated with human cancer. These mixtures include coal tar, soots, coke oven emissions, and cigarette smoke (EPA, 1994).

4.2.2 Animal

Information on the carcinogenicity of benzo[b]fluoranthene in animals following inhalation exposure was not available.

4.3 OTHER ROUTES OF EXPOSURE

4.3.1 Human

Information on the carcinogenicity of benzo[b]fluoranthene in humans by other routes of exposure was not available.

4.3.2 Animal

Benzo[b]fluoranthene was tested for carcinogenicity in dermal application, lung implantation, subcutaneous (s.c.) injection, and intraperitoneal (i.p.) injection bioassays.

Wynder and Hoffmann (1959) applied 0.01, 0.1, or 0.5% solutions of benzo[b]fluoranthene in acetone three times weekly to the skin of three groups of 20 Swiss mice for life; there were no untreated or vehicle controls. The highest dose produced skin papillomas in 100% and carcinomas in 90% of treated mice within 8 months; the intermediate dose produced papillomas in 65% and carcinomas in 85% of treated mice within 12 months. Of 10 surviving mice that received the lowest dose, only one animal developed a papilloma after 14 months.

A single dermal application of 1 mg benzo[b]fluoranthene in acetone produced no tumors in 20 Swiss mice during a 63-week observation period (Van Duuren et al., 1966). However, the same protocol followed by repeated applications of croton resin produced papillomas in 18/20 and carcinomas in 5/20 treated mice.

LaVoie et al. (1982) evaluated the tumor-initiating activity of benzo[b]fluoranthene by applying initiation doses of 0, 10, 30, or 100 ug benzo[b]fluoranthene in acetone (10 doses, every other day) to the skin of Crl:CD-1 mice (20/group). This procedure was followed by treatment with 12-o-tetradecanoyl-phorbol-13-acetate (TPA), 3 times weekly for 20 weeks. There was a dose-related increased incidence of skin tumors, predominantly squamous cell papillomas. Skin tumors were seen in 0, 45, 60, and 80% of mice treated with 0, 10, 30, or 100 ug benzo[b]fluoranthene, respectively. A similar initiation/protocol by Amin et al. (1985) resulted in a comparable increased incidence of skin tumors in female Swiss albino mice.

Sixteen male and 14 female XVII nc/Z mice were given three s.c. injections of 0.6 mg benzo[b]fluoranthene in olive oil over a period of 2 months (IARC, 1973). Injection site sarcomas developed in 18/24 surviving mice, with an average latent period of 4.5 months.

Female Osborne-Mendel rats (35/group) received single lung implants of 0.1, 0.3, or 1 mg benzo[b]fluoranthene in a mixture of beeswax and trioctanoin (Deutsch-Wenzel et al., 1983). An untreated group and a group receiving the vehicle served as controls. Granulomatous inflammatory lesions developed at the injection sites. After a lifetime of observation, there was a dose-related increased incidence of epidermoid carcinomas and pleomorphic sarcomas in the lung and thorax (combined). The observed incidences were 1/35, 3/35, and 13/35, respectively, in the low-, mid-, and high-dose groups. No lung tumors were reported in untreated and vehicle controls. In contrast, multiple intratracheal instillations of benzo[b]fluoranthene, administered as 30 weekly doses of 0.05 or 0.5 mg, did not induce a significant number of respiratory tract tumors in male Syrian golden hamsters (Sellakumar and Shubik, 1974). The group receiving the higher dose had one papilloma of the trachea at week 99.

LaVoie et al. (1987) administered i.p. injections of benzo[b]fluoranthene in dimethyl sulfoxide to newborn CD-1 mice (15 males and 17 females) on days 1, 8, and 15 of age at a total dose of 0.5 umol/mouse. The animals were sacrificed at 52 weeks of age. Treatment with benzo[b]fluoranthene induced hepatic tumors (adenomas and hepatomas combined) in eight male mice. One hepatoma developed in 1/17 male controls; no hepatic tumors were seen in female treated mice or in female controls. Lung adenomas were found in two male and in three female mice; no lung tumors occurred in controls.

4.4 EPA WEIGHT OF EVIDENCE

Classification--B2; probable human carcinogen (EPA, 1994)

Basis--Based on no human data and sufficient data from animal bioassays.

Benzo[b]fluoranthene produced tumors in mice after lung implantation, i.p. or s.c. injection, or skin painting.

4.5 CARCINOGENICITY SLOPE FACTORS

No carcinogenicity slope factors were calculated.

5. REFERENCES

Amin, S., E.J. LaVoie, and S.S. Hecht. 1982. "Identification of metabolites of benzo[b]fluoranthene." Carcinogenesis 3: 171-174.

Amin, S., K. Huie, and S.S. Hecht. 1985. "Mutagenicity and tumor initiating activity of methylated benzo[b]fluoranthene." Carcinogenesis 6: 1023-1025.

ATSDR (Agency for Toxic Substances and Disease Registry). 1990. Toxicological Profile for Polycyclic Aromatic Hydrocarbons. Acenaphthene, Acenaphthylene, Anthracene, Benzo(a)anthracene, Benzo(a)pyrene, Benzo(b)fluoranthene, Benzo(g,i,h)perylene, Benzo(k)fluoranthene, Chrysene, Dibenzo(a,h)anthracene, Fluoranthene, Fluorene, Indeno(1,2,3-c,d)pyrene, Phenanthrene, Pyrene. Prepared by Clement International Corporation, under Contract No. 205-88-0608. ATSDR/TP-90-20.

Deutsch-Wenzel, R.P., H. Brune, G. Grimmer, et al. 1983. "Experimental studies in rat lungs on the carcinogenicity and dose-response relationships of eight frequently occurring environmental polycyclic aromatic hydrocarbons." J. Natl. Cancer Inst. 71: 539-544.

Geddie, J.E., S. Amin, K. Hui, et al. 1987. "Formation and tumorigenicity of benzo[b]fluoranthene metabolites in mouse epidermis." Carcinogenesis 8: 1579-1584.

IARC (International Agency for Research on Cancer). 1973. "Benzo[b]fluoranthene." In: IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. Certain Polycyclic Aromatic Hydrocarbons and Heterocyclic Compounds, Vol 3. Lyon, France, pp. 69-81.

IARC (International Agency for Research on Cancer). 1983. "Benzo[b]fluoranthene." In: IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Humans. Polycyclic Aromatic Compounds, Part 1, Chemical, Environmental and Experimental Data, Vol 32. Lyon, France, pp. 33-91, 147-153.

LaVoie, E.J., S. Amin, S.S. Hecht, et al. 1982. "Tumor initiating activity of dihydrodiols of benzo[b]fluoranthene, benzo[j]fluoranthene, and benzo[k]fluoranthene." Carcinogenesis 3: 49-52.

LaVoie, E.J., J. Braley, J.E. Rice, et al. 1987. "Tumorigenic activity for non-alternant polynuclear aromatic hydrocarbons in newborn mice." Cancer Lett. 34: 15-20.

Lide, D.R., Ed. 1991. CRC Handbook of Chemistry and Physics, 1991-1992, 72nd ed. Boca Raton, FL, p. 3-96.

Sellakumar, A. and P. Shubik. 1974. "Carcinogenicity of different polycyclic hydrocarbons in the respiratory tract of hamsters." J. Natl. Cancer Inst. 53: 1713-1719.

United States Environmental Protection Agency (EPA). 1991. Drinking Water Criteria Document for Polycyclic Aromatic Hydrocarbons (PAH). Prepared by the Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, U.S. Environmental Protection Agency, Cincinnati, OH, for the Office of Drinking Water. ECAO-CIN-D010.

United States Environmental Protection Agency (EPA). 1994. Integrated Risk Information System (IRIS). Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Cincinnati, OH.

Van Duuren, B.L., A. Sivak, A. Segal, et al. 1966. "The tumor-promoting agents of tobacco leaf and tobacco smoke condensate." J. Natl. Cancer Inst. 37: 519 -526.

Wynder, E.L. and D. Hoffmann. 1959. "The carcinogenicity of benzofluoranthenes." Cancer 12: 1194-1199. Retrieve Toxicity Profiles Condensed Version

Last Updated 8/29/97