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Fluorene
CASRN 86-73-7
Contents
0435
Fluorene; CASRN 86-73-7
Health assessment information on a chemical substance is included in IRIS only
after a comprehensive review of chronic toxicity data by U.S. EPA health
scientists from several Program Offices and the Office of Research and
Development. The summaries presented in Sections I and II represent a
consensus reached in the review process. Background information and
explanations of the methods used to derive the values given in IRIS are
provided in the Background Documents.
STATUS OF DATA FOR Fluorene
File On-Line 11/01/1990
Category (section) Status Last Revised
----------------------------------------- -------- ------------
Oral RfD Assessment (I.A.) on-line 11/01/1990
Inhalation RfC Assessment (I.B.) no data
Carcinogenicity Assessment (II.) on-line 12/01/1990
_I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS
__I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD)
Substance Name -- Fluorene
CASRN -- 86-73-7
Last Revised -- 11/01/1990
The oral Reference Dose (RfD) is based on the assumption that thresholds exist
for certain toxic effects such as cellular necrosis. It is expressed in units
of mg/kg-day. In general, the RfD is an estimate (with uncertainty spanning
perhaps an order of magnitude) of a daily exposure to the human population
(including sensitive subgroups) that is likely to be without an appreciable
risk of deleterious effects during a lifetime. Please refer to the Background
Document for an elaboration of these concepts. RfDs can also be derived for
the noncarcinogenic health effects of substances that are also carcinogens.
Therefore, it is essential to refer to other sources of information concerning
the carcinogenicity of this substance. If the U.S. EPA has evaluated this
substance for potential human carcinogenicity, a summary of that evaluation
will be contained in Section II of this file.
___I.A.1. ORAL RfD SUMMARY
Critical Effect Experimental Doses* UF MF RfD
-------------------- ----------------------- ----- --- ----------
Decreased RBC, NOAEL: 125 mg/kg/day 3000 1 4E-2
packed cell volume mg/kg/day
and hemoglobin LOAEL: 250 mg/kg/day
Mouse Subchronic Study
U.S. EPA, 1989
*Conversion Factors: None
___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD)
U.S. EPA. 1989. Mouse oral subchronic toxicity study. Prepared by Toxicity
Research Laboratories, LTD., Muskegon, MI for the Office of Solid Waste,
Washington, DC.
CD-1 mice (25/sex/group) were exposed to 0, 125, 250, or 500 mg/kg/day
fluorene suspended in corn oil by gavage for 13 weeks. Parameters used to
assess toxicity included food intake, body weight, clinical observations,
hematology and serum chemistry and gross and histopathological examinations.
Increased salivation, hypoactivity, and urine-wet abdomens in males were
observed in all treated animals. The percentage of mice exhibiting
hypoactivity was dose-related. In mice exposed at 500 mg/kg/day, labored
respiration, ptosis (drooping eyelids), and unkempt appearance were also
observed. A significant decrease in red blood cell count and packed cell
volume were observed in females treated with 250 mg/kg/day fluorene and in
males and females treated with 500 mg/kg/day. Decreased hemoglobin
concentration and increased total serum bilirubin levels were also observed in
the 500 mg/kg/day group. Decreases in erythrocyte count, packed cell volume,
and hemoglobin concentration were all observed at 125 mg/kg; however, these
effects, although apparently dose-dependent, were not statistically
significant. A significant decreasing trend in BUN and a significant
increasing trend in total serum bilirubin were observed in both high-dose
males and females. A dose-related increase in relative liver weight was
observed in treated mice; a significant increase in absolute liver weight was
also observed in the mice treated with 250 and 500 mg/kg/day fluorene. A
significant increase in absolute and relative spleen and kidney weight was
observed in males and females exposed to 500 mg/kg/day and males at 250
mg/kg/day. Increases in the absolute and relative liver and spleen weights in
the high-dose males and females were accompanied by histopathological
increases in the amounts of hemosiderin in the spleen and in the Kupffer cells
of the liver. No other histopathological lesions were observed. The LOAEL is
250 mg/kg/day based on hematological effects; the NOAEL is 125 mg/kg/day.
___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD)
UF -- An uncertainty factor of 3000 was used: 10 for use of a subchronic study
for chronic RfD derivation, 10 each for inter- and intraspecies variability,
and 3 for lack of adequate toxicity data in a second species and
reproductive/developmental data.
MF -- None
___I.A.4. ADDITIONAL COMMENTS (ORAL RfD)
Morris et al. (1960) fed 18 female Buffalo strain rats 12.3 mg fluorene/kg/day
for 6 months or 13.1 mg fluorene/kg/day for 18 months. The diet in the 6-
month study was composed of purified materials, low in protein and fat, and
prepared in 3% propylene glycol. The diet in the longer study was composed of
a mixture of natural foodstuffs in 3% corn oil. In the 6-month study, of 11
animals examined, the incidences of non-neoplastic reactions were reported by
organ as follows: forestomach (acanthosis, hyperkeratosis), 5 animals; kidney
(squamous metaplasia of pelvis), 7 animals; uterus (squamous metaplasia), 1
animal; small intestine (epithelial ulcer, acute), 1 animal; and liver
(cirrhosis), 3 animals.
In the longer study using 18 rats, none of the effects seen in the 6-month
study were observed. The only effect reported in this experiment was
hyperplasia of the pituitary (predominantly chromophobe cells) in two animals.
It appears that the effects observed in the 6-month study were related to
either dietary composition or propylene glycol, since none of these effects
were observed after 18 months at a similar dosage using a different diet and
vehicle. Consequently, this study is not considered acceptable as a basis for
chronic RfD derivation.
No other studies on the toxicity of orally administered fluorene were located.
___I.A.5. CONFIDENCE IN THE ORAL RfD
Study -- Medium
Data Base -- Low
RfD -- Low
Confidence in the principal study is medium: it is a well-designed study that
examined and identified both a LOAEL and NOAEL for several sensitive endpoints
using an adequate number of animals. Confidence in the data base is low;
developmental, reproductive, and chronic toxicity following oral exposure to
fluorene have not been tested, and a NOAEL was not identified. Confidence in
the RfD is accordingly low.
___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD
Source Document -- This assessment is not presented in any existing U.S. EPA
document.
Other EPA Documentation -- U.S. EPA, 1987
Agency Work Group Review -- 10/19/1989, 11/15/1989
Verification Date -- 11/15/1989
___I.A.7. EPA CONTACTS (ORAL RfD)
Please contact the Risk Information Hotline for all questions concerning this
assessment or IRIS, in general, at (513)569-7254 (phone), (513)569-7159 (FAX)
or RIH.IRIS@EPAMAIL.EPA.GOV (internet address).
__I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC)
Substance Name -- Fluorene
CASRN -- 86-73-7
Not available at this time.
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
Substance Name -- Fluorene
CASRN -- 86-73-7
Last Revised -- 12/01/1990
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 CLASSIFICATION AS TO HUMAN CARCINOGENICITY
___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION
Classification -- D; not classifiable as to human carcinogenicity
Basis -- Based on no human data and inadequate data from animal bioassays.
___II.A.2. HUMAN CARCINOGENICITY DATA
None.
___II.A.3. ANIMAL CARCINOGENICITY DATA
Inadequate. Morris et al. (1960) fed female buffalo rats a diet
containing 0.05% fluorene in 3% corn oil for approximately 18 months or in
propylene glycol for about 6 months (approximately 11 mg/kg/day). Various
types of tumors occurred in controls and exposed animals at approximately the
same incidences, ranging from 6 to 34%. No statistical analysis was reported.
Studies of fluorene for complete carcinogenic activity, inititating
activity or co-carcinogenicity with 3-methylcholanthrene in mouse skin
painting assays were not positive or were inconclusive (Kennaway, 1924; Riegel
et al., 1951; LaVoie et al., 1979, 1981).
No injection site tumors occurred within 18 months in 10 strain A mice
after seven subcutaneous injections of 10 mg fluorene in glycol (Shear, 1938).
No control groups appear to have been utilized in this study.
Wilson et al. (1947) fed two groups of albino rats various concentrations
of fluorene in the diet. One set of rats was exposed to several
concentrations (number not specified) ranging from 0.062-1.0% fluorene in the
diet for 104 days. These rats were maintained on diets with fluorene
concentrations of 0.5 and 1.0%; they experienced significant decreases in
their rate of growth, but in other aspects they appeared normal. The second
set received either 0.125, 0.25 or 0.5% fluorene in the diet for 453 days.
One rat exposed to 0.125% fluorene in the diet developed a small benign kidney
tubular adenoma. The total number of animals treated was not indicated, nor
was a control group described.
___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
Fluorene produced no positive results in reverse mutation assays in five
strains of Salmonella typhimurium (1000 ug/plate) or in forward mutation
assays in Salmonella strain TM677 (50 ug/mL) (McCann et al., 1975; LaVoie et
al., 1979, 1981; Sakai et al., 1985; Bos et al., 1988; Kaden et al., 1979;
Mamber et al., 1983). In a DNA damage assay using S. typhimurium TA1535,
Nakamura et al. (1987) reported that fluorene at concentrations of up to 16.7
ug/mL was not positive. DNA damage assays with fluorene were not positive in
Escherichia coli at concentrations of up to 2 mg/mL (Mamber et al., 1983,
1984) or in primary rat hepatocyte cultures at a maximum concentration of 3 mM
(Sina et al., 1983). In a phage induction assay using Escherichia coli as a
host, fluorene was not positive at concentrations of up to 1 mg/mL (Mamber et
al., 1984).
In an unscheduled DNA synthesis assay the exposure of primary rat
hepatocytes to 10 nmol and 100 nmol/mL fluorene did not yield positive results
(Probst et al., 1981; Williams et al., 1989). Fluorene produced positive
results in a DNA dammage assay (strand-break assay) in L5178Y/mouse lymphoma
cells at 0.15 uM in the presence of hepatic homogenates and at 0.5 uM in the
absence of hepatic homogenates (Garberg et al., 1988). In forward mutation
assays in L5178Y/mouse lymphoma cells, fluorene was not positive at
concentrations of up to 30 and 60 ug/mL in the presence and absence of hepatic
homogenates, respectively (Amacher et al., 1981; Oberly et al., 1984).
__II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE
None.
__II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE
None.
__II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT)
___II.D.1. EPA DOCUMENTATION
Source Document -- U.S. EPA, 1990
The 1990 Drinking Water Criteria Document for Polycyclic Aromatic Hydrocarbons
has received Agency and external review.
___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT)
Agency Work Group Review -- 02/07/1990
Verification Date -- 02/07/1990
___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT)
Please contact the Risk Information Hotline for all questions concerning this
assessment or IRIS, in general, at (513)569-7254 (phone), (513)569-7159 (FAX)
or RIH.IRIS@EPAMAIL.EPA.GOV (internet address).
_VI. BIBLIOGRAPHY
Substance Name -- Fluorene
CASRN -- 86-73-7
Last Revised -- 12/01/1990
__VI.A. ORAL RfD REFERENCES
Morris, H.P., C.A. Velat, B.P. Wagner, M. Dahlgard and F.E. Ray. 1960.
Studies of carcinogenicity in the rate of derivatives of aromatic amines
related to N-2-fluorenyl acetamide. J. Natl. Cancer Inst. 24: 149-180.
U.S. EPA. 1987. Health Effects Assessment for Fluorenes. Prepared by the
Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency
Response, Washington, DC.
U.S. EPA. 1989. 13-Week Mouse Oral Subchronic Toxicity Study. Prepared by
Toxicity Research Laboratories, Ltd., Muskegon, MI for the Office of Solid
Waste, Washington, DC.
__VI.B. INHALATION RfC REFERENCES
None
__VI.C. CARCINOGENICITY ASSESSMENT REFERENCES
Amacher, D., S. Paillet and J. Elliott. 1981. The metabalism of N-acetyl-2-
aminofluorene to a mutagen in L5178Y/TK+/- mouse lymphoma cells. Mutat. Res.
89: 311-320.
Bos, R.P., J.L.G. Theuws, F.J. Jongeneelen and P.Th. Henderson. 1988.
Mutagenicity of bi-, tri and tetra-cyclic aromatic hydrocarbons in the "taped-
plate assay" and in the conventional Salmonella mutagenicity assay. Mutat.
Res. 204: 203-206.
Garberg, P., E. Akerblom and G. Bolcsfoldi. 1988. Evaluation of a
genotoxicity test measuring DNA-strand breaks in mouse lymphoma cells by
alkaline unwinding and hydroxyapatite elution. Mutat. Res. 203: 155-176.
Kaden, D.A., R.A. Hites and W.G. Thilly. 1979. Mutagenicity of soot and
associated polycyclic aromatic hydrocarbons to Salmonella typhimurium. Cancer
Res. 39: 4152-4159.
Kennaway, E.L. 1924. On cancer-producing tars and tar-fractions. J. Ind.
Hyg. 5(12): 462-488.
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.L. Tulley-Freiler, V. Bedenko, Z. Girach and D. Hoffmann.
1981. Comparative studies on the tumor inititating activity and metabolism of
methylfluorenes and methylbenzofluorenes. In: Polynuclear Aromatic
Hydrocarbons: Chemical Analysis and Biological Fate, M. Cooke and A.J. Dennis,
Ed. Batelle Press, Columbus, OH. p. 417-427.
Mamber, S., V. Bryson and S. Katz. 1983. The Escherichia coli WP2/WP100 rec
assay for detection of potential chemical carcinogens. Mutat. Res. 119: 135-
144.
Mamber, S., V. Bryson and S. Katz. 1984. Evaluation of the Escherichia coli
K12 inductest for detection of potential chemical carcinogens. Mutat. Res.
130: 141-151.
McCann, J.E., E. Choi, E. Yamasaki and B.N. Ames. 1975. Detection of
carcinogens as mutagens in the Salmonella/microsome test: Assay of 300
chemicals. Proc. Natl. Acad. Sci. USA. 72(12): 5135-5139.
Morris, H.P., C.A. Velat, B.P. Wagner, M. Dahlgard and F.E. Ray. 1960.
Studies of carcinogenicity in the rate of derivatives of aromatic amines
related to N-2-fluorenylacetamide. J. Natl. Cancer Inst. 24(1): 149-180.
Nakamura, S., Y. Oda, T. Shimada, I. Oki and K. Sugimoto. 1987. SOS-inducing
activity of chemical carcinogens and mutagens in Salmonella typhimurium
TA1535/pSK 1002: Examination with 151 chemicals. Mutat. Res. 192: 239-246.
Oberly, T., B. Beusey and G. Probst. 1984. An evaluation of the L5178Y TK+/-
mouse lymphoma forward mutation assay using 42 chemicals. Mutat. Res. 125:
291-306.
Probst, G.S., R.E. McMahon, L.E. Hill, C.Z. Thompson, J.K. Epp and S.B. Neal.
1981. Chemically-induced unscheduled DNA synthesis in primary rat hepatocyte
cultures: A comparison with bacterial mutagenicity using 218 compounds.
Environ. Mutagen. 3: 11-32.
Riegel, B., W.B. Watman, W.T. Hill, et al. 1951. Delay of methylcholanthrene
skin carcinogensis in mice by 1,2,5,6-dibenzofluorene. Cancer Res. 11:
301-303.
Sakai, M., D. Yoshida and S. Mizusdki. 1985. Mutagenicity of polycyclic
aromatic hydrocarbons and quinones on Salmonella typhimurium TA97. Mutat.
Res. 156: 61-67.
Shear, M.J. 1938. Studies in carcinogenesis. V. Methyl derivatives of 1,2-
benzanthracene. Am. J. Cancer. 33(4): 499-537.
Sina, J., C. Bean, G. Dysart, V. Taylor and M. Bradley. 1983. Evaluation of
the alkaline elution/rat hepatocyte assay as a predictor of carcinogenic/
mutagenic potential. Mutat. Res. 113: 357-391.
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.
Williams, G., H. Mori and C. McQueen. 1989. Structure-activity relationships
in the rat hepatocyte DNA-repair test for 300 chemicals. Mutat. Res. 221:
263-286.
Wilson, R.H., F. DeEds and A.J. Cox. 1947. The carcinogenic activity of 2-
acetominofluorene. IV. Action of related compounds. Cancer Res. 7: 453-458.
_VII. REVISION HISTORY
Substance Name -- Fluorene
CASRN -- 86-73-7
-------- -------- --------------------------------------------------------
Date Section Description
-------- -------- --------------------------------------------------------
11/01/1990 I.A. Oral RfD summary on-line
11/01/1990 VI. Bibliography on-line
12/01/1990 II. Carcinogen assessment on-line
12/01/1990 VI.C. Carcinogen assessment references added
01/01/1992 IV. Regulatory Action section on-line
VIII. SYNONYMS
Substance Name -- Fluorene
CASRN -- 86-73-7
Last Revised -- 11/01/1990
86-73-7
9H-Fluorene
Diphenylenemethane
Fluorene
HSDB 2165
Methane, diphenylene-
NSC 6787
o-BIPHENYLENEMETHANE
2,2'-METHYLENEBIPHENYL
9H-fluorene
Last updated: 5 May 1998
URL: http://www.epa.gov/iris/SUBST/0435.HTM
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