Toxicity Profiles
Formal Toxicity Summary for BENZO[K]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.
- EXECUTIVE SUMMARY
- 1. INTRODUCTION
- 2. METABOLISM AND DISPOSITION
- 1. INTRODUCTION
- 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[k]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 and four six-membered rings. There is no commercial production or known use of this compound (IARC, 1983). Benzo[k]fluoranthene is found in fossil fuels and occurs ubiquitously in products of incomplete combustion (IARC, 1983) and in soils, groundwater, and surface waters at hazardous waste sites (ATSDR, 1990).
No absorption or excretion data were available for benzo[k]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). Rat liver microsomes have been shown to metabolize benzo[k]fluoranthene to the dihydrodiol, 8,9-dihydro-8,9-dihydroxy benzo[k]fluoranthene (LaVoie et al., 1980).
No data were found concerning the acute, subchronic, chronic, developmental, or reproductive toxicity of benzo[k]fluoranthene. Because of a lack of toxicity data, an oral reference dose (RfD) or inhalation reference concentration (RfC) have not been derived (EPA, 1994).
No long-term oral or inhalation bioassays were available to assess the carcinogenicity of benzo[k]fluoranthene. Benzo[k]fluoranthene was tested for carcinogenicity in dermal application, subcutaneous (s.c.) injection, lung implantation, and intraperitoneal (i.p.) injection studies. Dermal applications of 0.5% solutions of benzo[k]fluoranthene for life produced only a few skin papillomas in mice (Wynder and Hoffmann, 1959), but in initiation-promotion assays, benzo[k]fluoranthene was active as an initiator of skin carcinogenesis (LaVoie et al., 1982; Amin et al., 1985). Injection site sarcomas developed in mice given three s.c. injections of 0.6 mg benzo[k]fluoranthene (Lacassagne et al., 1963) and dose-related increases of epidermoid carcinomas of the lungs were reported in rats receiving single lung implants of 0.16-4.15 mg benzo[k]fluoranthene (Deutsch-Wenzel et al., 1983). In a short-term assay, hepatic and lung tumors occurred in newborn mice receiving 2.1 umol benzo[k]fluoranthene via i.p. injection (LaVoie et al., 1987).
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[k]fluoranthene (EPA, 1994).
1. INTRODUCTION
Benzo[k]fluoranthene (CAS Reg. No. 207-08-9), also known as 8,9-benzofluoranthene; 11,12-benzofluoranthene; 2,3,1',8'-binaphthylene; and dibenzo(b,j,k)fluorene (IARC, 1983) is a polycyclic aromatic hydrocarbon (PAH) with one five-membered and four six-membered rings. It is a crystalline solid with a chemical formula of C20H12, a molecular weight of 252.32, a melting point of 217C (Lide, 1991), and a boiling point of 480C (IARC, 1983). Benzo[k]fluoranthene is insoluble in water but is soluble in acetic acid, benzene, and ethanol (IARC, 1983). It has a vapor pressure of 9.59x10-11 mm Hg at 25C, an estimated octanol/water partition coefficient of 6.04-6.44 (EPA, 1987), and a Henry's Law constant of 3.87x10-5 (ATSDR, 1990).
No commercial production or commercial use of benzo[k]fluoranthene is known at this time; small amounts of this compound are used for research (IARC, 1983). Benzo[k]fluoranthene is found in fossil fuels and occurs ubiquitously in products of incomplete combustion. It has been detected in mainstream cigarette smoke; gasoline engine exhaust; emissions from burning coal and from oil-fired heating; lubricating oils; used motor oils; crude oils (IARC, 1983); and in soils, surface waters, and groundwater at hazardous waste sites (ATSDR, 1990). Benzo[k]fluoranthene is one of a number of PAHs on 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[k]fluoranthene in humans or animals were not available. However, data from structurally-related PAHs, primarily benzo[a]pyrene, suggest that benzo[k]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[k]fluoranthene.
2.3 METABOLISM
No data were available concerning the in vivo metabolism of benzo[k]fluoranthene. In in vitro metabolism studies using rat liver microsomes, LaVoie et al. (1980) identified 8,9-dihydro-8,9-dihydroxy benzo[k]fluoranthene as the major metabolite of benzo[k]fluoranthene.
2.4 EXCRETION
No human or animal data were available concerning the excretion of benzo[k]fluoranthene.
3. NONCARCINOGENIC HEALTH EFFECTS
3.1 ORAL EXPOSURES
Information on the acute, subchronic, chronic, developmental, or reproductive oral toxicity of benzo[k]fluoranthene in humans or animals was not available. Because of a lack of toxicity data, an oral reference dose (RfD) for benzo[k]fluoranthene has not been derived (EPA, 1994).
3.2 INHALATION EXPOSURES
Information on the acute, subchronic, chronic, developmental, or reproductive oral toxicity of benzo[k]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[k]fluoranthene has not been derived (EPA, 1994).
3.3 OTHER ROUTES OF EXPOSURE
Information on the acute, subchronic, chronic, developmental, or reproductive oral toxicity of benzo[k]fluoranthene in humans or animals by other routes of exposure was not available.
3.4 TARGET ORGANS/CRITICAL EFFECTS
No data were available to identify target organs/critical effects for oral, inhalation, or other routes of exposure to benzo[k]fluoranthene.
4. CARCINOGENICITY
4.1 ORAL EXPOSURES
Information on the carcinogenicity of benzo[k]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[k]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[k]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[k]fluoranthene in humans by other routes of exposure was not available.
4.3.2 Animal
Benzo[k]fluoranthene was tested for carcinogenicity in skin application, initiation-promotion, lung implant, subcutaneous (s.c.) injection, and intraperitoneal (i.p.) injection bioassays.
Wynder and Hoffmann (1959) applied 0.1 or 0.5% solutions of benzo[k]fluoranthene in acetone three times weekly to the skin of three groups of 20 female Swiss mice; no untreated or vehicle controls were used. At the end of the 13th month, all surviving mice (8/20 and 3/20 treated with the low and high dose, respectively) were killed. Skin papillomas developed in two mice receiving the high dose; no skin tumors were seen in the low dose group. Habs et al. (1980) found no significant increase in tumor incidence when groups of 40 female NMRI mice were given dermal applications of 3.4, 5.6, or 9.2 ug benzo[k]fluoranthene two times weekly for life. Only one tumor was found in a mouse receiving the highest dose.
LaVoie et al. (1982) evaluated the tumor-initiating activity of benzo[k]fluoranthene by applying initiation doses of 0, 3, 10, or 100 ug benzo[k]fluoranthene in acetone (10 doses, every other day) to the skin of groups of 20 Crl:CD-1 mice. 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, 5, 25, and 75% of mice treated with 0, 10, 30, or 100 ug benzo[k]fluoranthene, respectively. Using a similar initiation/promotion protocol, Amin et al. (1985) applied 101 ug benzo[k]fluoranthene in acetone every 2 days for 20 days to the skin of 20 female Crl:CD-1 mice, followed 10 days later by TPA treatment 3 times weekly for 20 weeks. Skin tumors were reported in 0 and 37% of vehicle control and treated mice, respectively.
Female Osborne-Mendel rats (27-35/group) received single lung implants of 0.16, 0.83, or 4.15 mg benzo[k]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 increase of epidermoid carcinomas of the lung. The observed incidences were untreated controls, 1/35; vehicle controls, 0/35; low dose group, 0/35; mid-dose group, 3/31; and high dose group, 12/27.
Sixteen male and 14 female XVII nc/Z mice were given s.c. injections of 0.6 mg benzo[k]fluoranthene in olive oil once a month for 3 months (Lacassagne et al., 1963). Injection site sarcomas developed in both male and female mice, respectively. The average latency period for sarcomas was 203 days (males) and 210 days (females).
LaVoie et al. (1987) administered i.p. injections of benzo[k]fluoranthene in dimethyl sulfoxide to 16 male and 18 female CD-1 mice on days 1, 8, and 15 of life at a total dose of 2.1 umol/mouse. The animals were sacrificed at 52 weeks of age. Hepatic tumors (adenomas and hepatomas combined) were seen in 3/16 of treated male mice; one hepatoma was seen in 1/17 of male controls. No hepatic tumors developed in female treated mice or in female controls. Lung adenomas were found in 1/16 and 3/18 treated male and female mice, respectively; 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[k]fluoranthene produced tumors in mice after lung implantation and when administered by dermal application with a promoting agent. Equivocal results were obtained in a lung adenoma assay with mice. Benzo[k]fluoranthene was mutagenic in bacteria.
4.5 CARCINOGENICITY SLOPE FACTORS
No carcinogenicity slope factors were calculated.
5. REFERENCES
Amin, S., N. Hussain, G. Balanikas, et al. 1985. "Mutagenicity and tumor initiating activity of methylated benzo[k]fluoranthenes." Cancer Lett. 26: 343-347.
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.
Habs, M., D. Schmahl and J. Misfield. 1980. "Local carcinogenicity of some environmentally relevant polycyclic aromatic hydrocarbons after lifelong topical application to mouse skin." Arch. Geschwulstforsch. 50: 266-274.
IARC (International Agency for Research on Cancer). 1983. "Benzo[k]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. IARC, Lyon, France, pp. 163-170.
Lacassagne, A., N.P. Buu-Hoi, F. Zajdela, et al. 1963. "Activite cancerogene d'hydrocarbures aromatiques polycycliques a noyau fluoranthene." Un. Int. Cancer Acta 19: 490-496. (French; cited in IARC, 1973)
LaVoie, E.J., S.S. Hecht, S.S. Amin, et al. 1980. "Identification of mutagenic dihydrodiols as metabolites of benzo[j]fluoranthene and benzo[k]fluoranthene." Cancer Res. 40: 4528-4532.
LaVoie, E.J., S. Amin, S.S. Hecht, et al. 1982. "Tumor-initiating activity for dihydrodiols of benzo[b]fluoranthene, benzo[j]fluoranthene and benzo[k]fluoranthene." Carcinogenesis 3: 49-52.
LaVoie, E.J., J. Braley, J.E. Rice and A. Rivenson. 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.
United States Environmental Protection Agency (EPA). 1987. Health and Environmental Effects Profile for Benzo[k]fluoranthene Prepared by the Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Cincinnati, OH, for the Office of Solid Waste and Emergency Response. ECAO-CIN-P229.
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.
Wynder, E.L. and D. Hoffmann. 1959. "The carcinogenicity of benzofluoranthenes." Cancer 12: 1194-1199.
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