Indeno[1,2,3-cd]pyrene (CASRN 193-39-5) 

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Reference Dose for Chronic Oral Exposure (RfD)

0457

Indeno[1,2,3-cd]pyrene; CASRN 193-39-5

Human health assessment information on a chemical substance is included in the IRIS database only 

after a comprehensive review of toxicity data, as outlined in the IRIS assessment development 

process. Sections I (Health Hazard Assessments for Noncarcinogenic Effects) and II (Carcinogenicity 

Assessment for Lifetime Exposure) present the conclusions that were reached during the assessment 

development process. Supporting information and explanations of the methods used to derive the 

values given in IRIS are provided in the guidance documents located on the IRIS website. 

STATUS OF DATA FOR Indeno[1,2,3-cd]pyrene

File First On-Line 12/01/1990

Category (section) Status Last Revised

Oral RfD Assessment (I.A.) no data

Inhalation RfC Assessment (I.B.) no data

Carcinogenicity Assessment (II.) on-line 03/01/1994 

_I. Chronic Health Hazard Assessments for Noncarcinogenic Effects
_I.A. Reference Dose for Chronic Oral Exposure (RfD)

Substance Name — Indeno[1,2,3-cd]pyrene

CASRN — 193-39-5 

Not available at this time.

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_I.B. Reference Concentration for Chronic Inhalation Exposure (RfC)

Substance Name — Indeno[1,2,3-cd]pyrene

CASRN — 193-39-5 

Not available at this time.

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_II. Carcinogenicity Assessment for Lifetime Exposure

Substance Name — Indeno[1,2,3-cd]pyrene

CASRN — 193-39-5

Last Revised — 03/01/1994

Section II provides information on three aspects of the carcinogenic assessment for the substance in 

question; the weight-of-evidence judgment of the likelihood that the substance is a human 

carcinogen, and quantitative estimates of risk from oral exposure and from inhalation exposure. The 

quantitative risk estimates are presented in three ways. The slope factor is the result of application of 

a low-dose extrapolation procedure and is presented as the risk per (mg/kg)/day. The unit risk is the 

quantitative estimate in terms of either risk per ug/L drinking water or risk per ug/cu.m air breathed. 

The third form in which risk is presented is a drinking water or air concentration providing cancer risks 

of 1 in 10,000, 1 in 100,000 or 1 in 1,000,000. The rationale and methods used to develop the 

carcinogenicity information in IRIS are described in The Risk Assessment Guidelines of 1986 

(EPA/600/8-87/045) and in the IRIS Background Document. IRIS summaries developed since the 

publication of EPA's more recent Proposed Guidelines for Carcinogen Risk Assessment also utilize 

those Guidelines where indicated (Federal Register 61(79):17960-18011, April 23, 1996). Users are 

referred to Section I of this IRIS file for information on long-term toxic effects other than 

carcinogenicity. 
_II.A. Evidence for Human Carcinogenicity

__II.A.1. Weight-of-Evidence Characterization

Classification — B2, probable human carcinogen

Basis — Based on no human data and sufficient data from animal bioassays. Indeno[1,2,3-cd]pyrene 

produced tumors in mice following lung implants, subcutaneous injection and dermal exposure. 

Indeno[1,2,3-cd]pyrene tested positive in bacterial gene mutation assays. 

__II.A.2. Human Carcinogenicity Data

None. 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 include coal tar, soots, coke oven emissions and cigarette smoke (U.S. EPA, 

1984, 1990; IARC, 1984). 

__II.A.3. Animal Carcinogenicity Data

Sufficient. In carcinogen bioassays indeno[1,2,3-cd]pyrene exposure resulted in increased incidences 

of epidermoid carcinomas in a lung implantation study (Deutsch-Wenzel et al., 1983), injection site 

sarcomas in a subcutaneous injection assay (Lacassagne et al., 1963) and skin tumors in dermal 

application studies (Hoffman and Wynder, 1966; Rice et al., 1985a, 1986). 

In a lifetime implant study, 3-month-old female Osborne-Mendel rats (35/group) received lung 

implants of indeno[1,2,3-cd]pyrene in 0.05 mL of a 1:1 (v:v) mixture of beeswax and trioctanoin 

(Deutsch-Wenzel et al., 1983). Rats received either 0.16 mg (0.65 mg/kg), 0.83 mg (3.4 mg/kg) or 

4.15 mg (17 mg/kg) indeno[1,2,3-cd]pyrene. Controls consisted of an untreated group and a group 

receiving an implant of the vehicle. Median survival times in weeks were as follows: untreated 

controls, 118; vehicle controls, 104; low-dose, 116; mid-dose, 109; and high-dose, 92. Incidence of 

epidermoid carcinomas in the lung and thorax (combined) showed a statistically significant doserelated increase. The incidences were: untreated controls, 0/35; vehicle controls, 0/35; low-dose, 

4/35 (11%); mid-dose, 8/35 (23%); and high-dose, 21/35 (60%). 

Groups of male and female CD-1 mice (n=32) received intraperitoneal injections of indeno[1,2,3-

cd]pyrene in dimethyl sulfoxide (DMSO) on days 1, 8 and 15 after birth (total dose = 580 ug/mouse) 

and were evaluated for tumors upon sacrifice at 52 weeks of age (LaVoie et al., 1987). One male 

mouse (1/11) developed a lung adenoma, no tumors occurred in female mice. Tumor incidence was 

not significantly different from vehicle controls. This test is considered to be a short-term lung tumor 

assay. 
In mouse skin painting assays, indeno[1,2,3-cd]pyrene tested positive for cancer-initiating activity in 

several mouse strains (Hoffmann and Wynder, 1966; Rice et al., 1985a, 1986). In the Hoffmann and 

Wynder (1966) study female Swiss albino Ha/ICR/Mil mice (20/group) were given topical applications 

of indeno[1,2,3-cd]pyrene prepared as dioxane (at 0.05 and 0.1%) or in acetone solutions (at 0.01, 

0.05 and 0.1%). Dioxane preparations did not induce skin tumors. By contrast, acetone solutions of 

indeno[1,2,3-cd]pyrene produced skin tumors in a dose-related fashion. No tumors were observed in 

animals painted with 0.01 or 0.05% indeno[1,2,3-cd]pyrene in acetone; 0.1% induced six papillomas 

and three carcinomas beginning at 9 months; and 0.5% resulted in seven papillomas and five 

carcinomas with the first tumor appearing at 3 months. The authors also reported that a total dose of 

250 mg indeno[1,2,3- cd]pyrene delivered in 10 applications in 2 days was a sufficient initiating dose 

when followed by promotion with croton oil. 

To examine the initiating capability of the compound's major metabolites in mouse skin, indeno[1,2,3-

cd]pyrene was applied to the shaved backs of 20 Crl:CD-1(ICR)BR female mice (Rice et al., 1986). 

Acetone solutions were applied every other day for 10 days for a total initiating dose of 1 mg 

indeno[1,2,3-cd]pyrene. This was followed 10 days later by applications of the promotor 

tetradecanoylphorbol (TPA) (0.0025% in 100 mL acetone) 3 times/week for 20 weeks. Tumor 

incidence was essentially 100%. Indeno[1,2,3- cd]pyrene-1,2-diol and -1,2-oxide treatment both 

resulted in 80% tumor incidence in contrast to 8-hydroxy- and acetone-treated controls 

(approximately 25 and 5%, respectively). 

An earlier initiation-promotion bioassay performed by Rice et al. (1985a) showed a pronounced doseresponse relationship for tumors. Following the same protocol described above, an 80% tumor 

incidence was observed in mice receiving a total initiating dose of 1 mg indeno[1,2,3-cd]pyrene with 

an average of about four tumors/mouse after 22 weeks of promotion. However, when the total 

initiating dose was decreased to 100 or 300 mg/mouse, the number of tumor-bearing mice was not 

significantly increased. 

Injection site sarcomas were reported in 10/14 male and 1/14 female XVIIc/Z mice administered 3 

injections at 1-month intervals of 0.6 mg indeno[1,2,3-cd]pyrene. No concurrent controls appear to 

have been run in this experiment; the authors report, however, that in this mouse strain no 

spontaneous subcutaneous tumors have been reported (Lacassagne et al., 1963). 

__II.A.4. Supporting Data for Carcinogenicity 

Indeno[1,2,3-cd]pyrene produced positive results in reverse mutation assays in Salmonella 

typhimurium strains TA100 and TA98 (2-3 ug/plate) (LaVoie et al., 1979; Hermann et al., 1980; Rice 

et al., 1985b). 

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_II.B. Quantitative Estimate of Carcinogenic Risk from Oral Exposure

Not available.

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_II.C. Quantitative Estimate of Carcinogenic Risk from Inhalation Exposure

Not available.

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_II.D. EPA Documentation, Review, and Contacts (Carcinogenicity 

Assessment)

__II.D.1. EPA Documentation

Source Document — U.S. EPA, 1984, 1990

The 1990 Drinking Water Criteria Document for Polycyclic Aromatic Hydrocarbons has received Agency 

and external review. 

__II.D.2. EPA Review (Carcinogenicity Assessment)

Agency Work Group Review — 02/07/1990, 08/05/1993, 09/21/1993, 02/02/1994

Verification Date — 02/07/1990 

__II.D.3. EPA Contacts (Carcinogenicity Assessment)

Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at 

(202)566-1676 (phone), (202)566-1749 (FAX) or hotline.iris@epa.gov (internet address). 

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_III. [reserved]

_IV. [reserved] 

_V. [reserved]

_VI. Bibliography 

Substance Name — Indeno[1,2,3-cd]pyrene

CASRN — 193-39-5

Last Revised — 12/01/1990

_VI.A. Oral RfD References

None

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_VI.B. Inhalation RfC References

None

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_VI.C. Carcinogenicity Assessment References

Deutsch-Wenzel, R., H. Brune, G. Grimmer, G. Dettbarn and J. Misfeld. 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(3): 539-544. 

Hermann, M., J.P. Durand, J.M. Charpentier, et al. 1980. Correlations of mutagenic activity with 

polynuclear aromatic hydrocarbon content of various mineral oils. In: Polynuclear Aromatic 

Hydrocarbons: Chemisty and Biological Effects, 4th Int. Symp., A. Bjorseth and A.J. Dennis, Ed. 

Battelle Press, Columbus, OH. p. 899-916. 

Hoffmann, D. and E.L. Wynder, 1966. Beitrag zur carcinogen Wirkung von Dibenzopyrene. Z. 

Krebsforsch. 68(2): 137-149. (Ger.) Contribution on the carcinogenic effect of dibenzopyrenes.
IARC (International Agency for Research on Cancer). 1984. Monographs on the Evaluation of the 

Carcinogenic Risk of the Chemical to Man. Polynuclear Aromatic Hydrocarbons. Part 3. Industrial 

Exposures in Aluminum Production, Coal Gasification, Coke Production, and Iron and Steel Founding. 

Vol. 34. World Health Organization.

Lacassagne, A., N.P. Buu-Hoi, F. Zajdela, D. Lavit-Lamy and O. Chalvet. 1963. Activite cancerogene 

d'hyrocarbures aromatiques polycycliques a noyau flouranthene. Un. Int. Cancer Acta. 19(3-4): 490-

496. (Fre.) 

LaVoie, E.J., E.V. Bedenko, N. Hirota, S.S. Hecht and D. Hoffmann. 1979. A comparison of the 

mutagenicity, tumor-initiating activity and complete carcinogenicity of polynuclear aromatic 

hydrocarbons. In: Polynuclear Aromatic Hydrocarbons, P.W. Jones and P. Leber, Ed. Ann Arbor 

Science Publishers, Ann Arbor, MI. p. 705-721. 

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, E.J. LaVoie, D.J. McCaustland and J.C. Wiley. 1985a. On the 

metabolism, mutagenicity, and tumor-initiating activity of indeno[1,2,3-cd]pyrene. In: Polynuclear 

Aromatic Hydrocarbons: Mechanism, Methods and Metabolism, M. Cooke and A.J. Dennis, Ed. Batelle 

Press, Columbus, OH. p. 1097-1109. 

Rice, J.E., D.T. Coleman, T.J. Hosted, Jr., E.J. LaVoie, D.J. McClausland and J.C. Wiley, Jr. 1985b. 

Identification of mutagenic metabolites in 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, E.J. LaVoie, D.L. Fischer and J.C. Wiley, Jr. 1986. Tumorinitiating activity of major in vivo metabolites of indeno[1,2,3-cd]pyrene on mouse skin. 

Carcinogenesis. 7(10): 1761-1764. 

U.S. EPA. 1984. Carcinogen Assessment of Coke Oven Emissions. Office of Health and Environmental 

Assessment, Washington, DC. EPA 600/6-82-003F. NTIS PB 84-170181. 

U.S. EPA. 1990. Drinking Water Criteria Document for Polycyclic Aromatic Hydrocarbons (PAHs). 

Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and 

Assessment Office, Cincinnati, OH for the Office of Drinking Water, Washington, DC. Final Draft. 

ECAO-CIN-D010, September, 1990. 

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_VII. Revision History

Substance Name — Indeno[1,2,3-cd]pyrene

CASRN — 193-39-5 

Date Section Description

12/01/1990 II. Carcinogen assessment on-line

12/01/1990 VI. Bibliography on-line

01/01/1992 IV. Regulatory Action section on-line

09/01/1993 II. Carcinogenicity assessment noted as pending change

09/01/1993 II.D.2. Work group review date added

11/01/1993 II.D.2. Work group review date added

03/01/1994 II. Pending change note removed; no change

03/01/1994 II.D.2. Work group review date added

08/01/1995 II., 

II.D.2.

EPA's RfD/RfC and CRAVE workgroups were discontinued in May, 1995. 

Chemical substance reviews that were not completed by September 1995 were 

taken out of IRIS review. The IRIS Pilot Program replaced the workgroup 

functions beginning in September, 1995.

04/01/1997 III., IV., 

V.

Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary 

Data were removed from IRIS on or before April 1997. IRIS users were directed 

to the appropriate EPA Program Offices for this information.

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_VIII. Synonyms

Substance Name — Indeno[1,2,3-cd]pyrene

CASRN — 193-39-5

Last Revised — 12/01/1990

 193-39-5 

 Indeno(1,2,3-cd)pyrene 

 HSDB 5101 

 indeno(1,2,3-cd)pyrene 

 o-PHENYLENEPYRENE 

 RCRA WASTE NUMBER U137 
 1,10-(O-PHENYLENE)PYRENE 

 1,10-(1,2-Phenylene)pyrene 

 2,3-o-PHENYLENEPYRENE 

 2,3-PHENYLENEPYRENE