The Risk Assessment Information System

Toxicity Profiles

Formal Toxicity Summary for INDENO[1,2,3-cd]PYRENE

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: 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

Indeno[1,2,3-cd]pyrene, a crystalline solid with a chemical formula of C₂₂H₁₂ and a molecular weight of 276.3, is a polycyclic aromatic hydrocarbon (PAH). There is no commercial production or known use of this compound (IARC, 1983). Indeno[1,2,3-cd]pyrene is found in fossil fuels and occurs ubiquitously in products of incomplete combustion (IARC, 1983) and has been identified in soils, groundwater, and surface waters at hazardous waste sites (ATSDR, 1990).

No absorption data were available for indeno[1,2,3-cd]pyrene; 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). In vivo metabolites identified in mouse skin include the trans-1,2-dihydrodiol and 8- and 9-hydroxy forms of indeno[1,2,3-cd]pyrene (Rice et al., 1986). Similar metabolites were formed in vitro in rat liver microsomes (Rice et al., 1985).

No data were found concerning the acute, subchronic, chronic, developmental, or reproductive toxicity of indeno[1,2,3-cd]pyrene. Because of a lack of toxicity data, an oral reference dose (RfD) or inhalation reference concentration (RfC) has not been derived (EPA, 1994).

No long-term oral or inhalation bioassays were available to assess the carcinogenicity of indeno[1,2,3-cd]pyrene. The compound was tested for carcinogenicity in dermal application, lung implant, subcutaneous (s.c.) injection, and intraperitoneal (i.p.) injection studies. Dermal application of 0.1-0.5% solutions of indeno[1,2,3-cd]pyrene in acetone produced skin papillomas and carcinomas in mice (Hoffmann and Wynder, 1966). In initiation-promotion assays, indeno[1,2,3-cd]pyrene was active as an initiator of skin carcinogenesis (Hoffmann and Wynder, 1966; Rice et al., 1986). Dose-related increases of epidermoid carcinomas of the lungs were reported in rats receiving single lung implants of 0.16-4.15 mg indeno[1,2,3-cd]pyrene (Deutsch-Wenzel et al., 1983). Injection site sarcomas developed in mice given three s.c. injections of 0.6 mg indeno[1,2,3-cd]pyrene (Lacassagne et al., 1963). The compound was not tumorigenic when newborn mice received 2.1 mol indeno[1,2,3-cd]pyrene via i.p. injection (LaVoie et al., 1987).

Based on no human data and sufficient evidence for carcinogenicity in animals, the United Stated Environmental Protection Agency (EPA) has assigned a weight-of-evidence classification of B2, probable human carcinogen, to indeno[1,2,3-cd]pyrene (EPA, 1994).

1. INTRODUCTION

Indeno[1,2,3-cd]pyrene (CAS Reg. No. 193-39-5), also known as IP, ortho-phenylenepyrene, 1,10-(ortho-phenylene)pyrene, 1,10-(1,2-phenylene)pyrene, and 2,3-ortho-phenylenepyrene (IARC, 1983), is a polycyclic aromatic hydrocarbon (PAH) with one five-membered ring and five six-membered rings. It is a crystalline solid with a chemical formula of C₂₂H₁₂, a molecular weight of 276.3, a melting point of 163.6C (IARC, 1983), and a boiling point of 530C (ATSDR, 1990). Indeno[1,2,3-cd]pyrene is insoluble in water but is soluble in organic solvents. It has a vapor pressure of 1x10^-10 torr at 20C, an estimated octanol/water partition coefficient of 6.584, and a Henry's Law constant of 6.95x10^-8 (ATSDR, 1990).

There is no commercial production or known use of indeno[1,2,3-cd]pyrene (IARC, 1983). The compound 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; lubricating oils; used motor oils (IARC, 1983); and soils, surface waters, and groundwater at hazardous waste sites (ATSDR, 1990). Indeno[1,2,3-cd]pyrene 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 indeno[1,2,3-cd]pyrene in humans or animals were not available. However, data from structurally-related PAHs, primarily benzo[a]pyrene, suggest that indeno[1,2,3-cd]pyrene 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

indeno[1,2,3-cd]pyrene.

2.3. METABOLISM

In mouse skin, Rice et al. (1986) identified 8-hydroxyindo[1,2,3-cd]pyrene as the most abundant metabolite; other major metabolites included 9-hydroxyindo[1,2,3-cd]pyrene and trans-1,2-dihydro-1,2-dihydroxyindenol[1,2,3-cd]pyrene. In vitro metabolism studies using rat liver microsomes show that some metabolites identified included the trans-1,2-dihydrodiol of indeno[1,2,3-cd]pyrene, the trans-1,2-dihydrodiols of 8- and 9-hydroxy-indeno[1,2,3-cd]pyrene, and the 1,2-quinone form of indeno[1,2,3-cd]pyrene (Rice et al., 1985).

2.4. EXCRETION

No human or animal data were available concerning the excretion of indeno[1,2,3-cd]pyrene.

3. NONCARCINOGENIC HEALTH EFFECTS

3.1. ORAL EXPOSURES

Information on the acute, subchronic, chronic, developmental, or reproductive oral toxicity of indeno[1,2,3-cd]pyrene in humans or animals was not available. Because of the lack of toxicity data, an oral reference dose (RfD) for indeno[1,2,3-cd]pyrene has not been derived (EPA, 1994).

3.2. INHALATION EXPOSURES

Information on the acute, subchronic, chronic, developmental, or reproductive toxicity of indeno[1,2,3-cd]pyrene in humans or animals following inhalation exposure was not available. Because of a lack of toxicity data, an inhalation reference concentration (RfC) for indeno[1,2,3-cd]pyrene has not been derived (EPA, 1994).

3.3. OTHER ROUTES OF EXPOSURE

Information on the acute, subchronic, chronic, developmental, or reproductive toxicity of indeno[1,2,3-cd]pyrene 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 or critical effects for oral, inhalation, or other routes of exposure to indeno[1,2,3-cd]pyrene.

4. CARCINOGENICITY

4.1. ORAL EXPOSURES

Information on the carcinogenicity of indeno[1,2,3-cd]pyrene 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 indeno[1,2,3-cd]pyrene to human cancers, indeno[1,2,3-cd]pyrene 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 indeno[1,2,3-cd]pyrene in animals following inhalation exposure was not available.

4.3. OTHER ROUTES OF EXPOSURE

4.3.1 Human

Information on the carcinogenicity of indeno[1,2,3-cd]pyrene in humans by other routes of exposure was not available.

4.3.2 Animal

Indeno[1,2,3-cd]pyrene was tested for carcinogenicity in skin application, initiation-promotion, lung implant, subcutaneous (s.c.) injection, and intraperitoneal (i.p.) injection bioassays.

Hoffmann and Wynder (1966) applied solutions of indeno[1,2,3-cd]pyrene in dioxane or acetone to the skin of groups of 20 female Swiss albino mice. Solutions of 0.05 or 0.1% indeno[1,2,3-cd]pyrene in dioxane did not induce skin tumors, whereas acetone solutions induced a dose-related increased incidence of skin tumors. No tumors were observed following treatment with 0.01 or 0.05% solutions in acetone; a concentration 0.1% induced six papillomas and three carcinomas beginning at 9 months, and a concentration of 0.5% induced seven papillomas and five carcinomas, with the first tumor appearing after 3 months. By contrast, repeated topical application of up to 9.2 g of indeno[1,2,3-cd]pyrene in acetone for a lifetime did not produce skin tumors in mice (Habs et al., 1980).

Rice et al. (1986) evaluated the tumor-initiating activity of indeno[1,2,3-cd]pyrene by applying indeno[1,2,3-cd]pyrene in acetone every other day for 10 days (total dose 1 mg) to the skin 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. The incidence of skin tumors was close to 100%. Hoffmann and Wynder (1966) reported that 10 skin applications at 2-day intervals at a total dose of 250 g initiated skin carcinogenesis when female Swiss albino mice were subsequently treated with croton oil. A total of 10 papillomas developed in 5 animals treated with croton oil.

Female Osborne-Mendel rats (35/group) received single lung implants of 0.16, 0.83, or 4.15 mg indeno[1,2,3-cd]pyrene 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, the incidence of epidermoid carcinomas in the lung showed a statistically significant (p=0.05) dose-related increase. The observed incidences were 3/35, 8/35, and 21/35, respectively, in the low-, mid-, and high-dose groups. In addition, one pleomorphic lung sarcoma developed in one low-dose rat. No lung tumors occurred in untreated or vehicle control animals.

Male and female XVII nc/Z mice (14/sex) were given s.c. injections of 0.6 mg indeno[1,2,3-cd]pyrene in olive oil once a month for 3 months (Lacassagne et al., 1963). Injection site sarcomas developed in 10 male mice within 265 days and in 1 female mouse within 145 days. Although no concurrent controls were used, the authors reported that no spontaneous skin tumors had been observed in historical controls.

LaVoie et al. (1987) administered i.p. injections of indeno[1,2,3-cd]pyrene in dimethyl sulfoxide to 30 CD-1 mice (males and females combined) on days 1, 8, and 15 of life at a total dose of 2.1 mol/mouse. The animals were sacrificed at 52 weeks of age. A lung adenoma developed in 1/11 surviving male mice; no lung tumors were seen in female treated mice or in vehicle controls.

Although several noncarcinogenic PAHs have been shown to reduce the ability of benzo[a]pyrene to produce injection site sarcomas, s.c. injections of indeno[1,2,3-cd]pyrene in tricaprylin vehicle had no such inhibiting effect (Falk et al., 1964).

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. Indeno[1,2,3-cd]pyrene produced tumors in mice after lung implants, s.c. injection, and dermal exposure. Indeno[1,2,3-cd]pyrene tested positive in bacterial gene mutation assays.

4.5. CARCINOGENICITY SLOPE FACTORS

No carcinogenicity slope factors were calculated.

5. REFERENCES

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.

Falk, H.L., P. Kotin, and S. Thompson. 1964. "Inhibition of carcinogenesis. The effect of polycyclic hydrocarbons and related compounds." Arch. Environ. Health 9: 169-179.

Habs, M., D. Schmahl, and J. Misfeld. 1980. "Local carcinogenicity of some environmentally relevant polycyclic aromatic hydrocarbons after lifelong topical application to mouse skin." Arch. Geschwulstforsch. 50: 266-274.

Hoffmann, D. and E.L. Wynder. 1966. "Beitrag zur carcinogen Wirkung von Dibenzopyrene." Z. Krebsforsch. 68: 137-149.

IARC (International Agency for Research on Cancer). 1973. "Indeno(1,2,3-cd)pyrene." In: IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. Certain Polycyclic Aromatic Hydrocarbons and Heterocyclic Compounds, Vol 3. IARC, Lyon, France, pp. 229-237.

IARC (International Agency for Research on Cancer). 1983. "Indeno[1,2,3-cd]pyrene." 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. 373-378.

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.

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.

Rice, J.E., D.T. Coleman, T.J. Hosted, Jr., et al. 1985. "Identification of mutagenic metabolites of indeno[1,2,3-cd]pyrene formed in vitro with rat liver enzymes." Cancer Res. 45: 5421-5425.

Rice, J.E., T.J. Hosted, Jr., M.C. DeFloria, et al. 1986. "Tumor-initiating activity of major in vivo metabolites of indeno[1,2,3-cd]pyrene on mouse skin." Carcinogenesis 7: 1761-1764.

U.S. 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.

U.S. EPA. 1994. Integrated Risk Information System (IRIS). Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Cincinnati, OH.

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