Toxicity Profiles
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.
 Download a WordPerfect version of this toxicity profile. Please note that this document has been saved in WordPerfect 5.1/5.2 for greater accessibility but may have been originally formatted in later versions of WordPerfect (i.e., WordPerfect 6.1, Suite 7, etc.); therefore, formatting changes (i.e., Contents and Page Numbering) may occur when downloading this document.
- 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.
Retrieve Toxicity Profiles
Condensed Version
Last Updated 2/13/98
|
