THE RELATIVE CARCINOGENIC POTENTIAL
OF 50 CHEMICALS THAT MAY BE AIR POLLUTANTS
Final Report
Prepared for:
Office of Air Quality Planning and Standards
U.S. Environmental Protection Agency
Prepared by
Clement Associates, Inc.
1515 Wilson Boulevard
Arlington, Virginia 22209
Carl O. Schulz, Ph.D.
David M. Siegel, Ph.D.
March 30, 1984
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Introduction
Methods
Results
Discussion
Appendi x
References
TABLE OF CONTENTS
Page
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8
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Introduction
As part of the Special Study of Toxics, the Office of
Air Quality Planning and Standards of the U.S. Environmental
Protection Agency is assessing the potential risk of human
cancer associated with emissions of 80-90 pollutants from NESHAPS-
type sources. The purpose of this report is to survey the
available information on the adverse health effects of 50 pol-
lutants in order to determine the carcinogenic potential of
these pollutants. For those pollutants that may have the poten-
tial to induce cancer in humans, this report presents unit
risk 8cores that are estimates of the relative carcinogenic
potency of those pollutants. The pollutants reviewed are listed
in Table 1. This list of chemicals was developed by the Strat-
egies and Air Standards Division of OAQPS from the top 100
compounds in the Argonne prioritization ranking. The list
was modified and trimmed to 50 by deleting regulated hazardous
air pollutants, compounds included on the list of 37 candidate
hazardous air pollutants, and compounds with a known or estimated
production volume lower than 50 million pounds per year; and
by adding compounds that are among the top 50 high-volume produc-
tion chemicals in the United States or that were monitored
in the ambient air by numerous investigators in a number of
locations.
Methods
Clement Associates, Inc., searched a number of on-line
data bases and secondary literature resources for information
1
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relevant to the carcinogenic potential of the com pounds in
Table 1. Resources screened in this manner are shown in Table 2,
Which also shows which resources contained information about
specific chemicals on the list. Because there was little pub-
lished information available on the carcinogenic potential
of many of the compounds on the list, it was necessary to attempt
to identify unpublished and ongoing studies that might provide
useful information. Several sources were used in this attempt,
including the National Toxicology Program (OTP) Management
Status Report of December 6, 1983, the Chemical Information
System on-line data file Chemical Carcinogenesis Research Infor-
mation Service (CCRIS), the TSCA Section 8(e) submission file
of EPA, and the Chemical Hazard Information Profiles (CHIPS)
prepared by EPA. For five compounds, carcinogenesis bioassays
have been completed but not published by the OTP. Clement
obtained copies of the draft reports and was able to use them
as a basis for assessing the carcinogenic potential of the
compounds, in addition, five unpublished carcinogenicity bio-
assays were obtained from the TSCA Section 8(e) submission
file. These were also used to evaluate the carcinogenic poten-
tial of the compounds studied. It should be understood that
many of these reports are preliminary and Clement did not critic-
ally evaluate them to independently assess the accuracy of
stated conclusions.
In those cases Where quantitative dose-response data were
available, Clement calculated an estimated unit risk value
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TABLE 1
CHEMICALS REVIEWED FOR CARCINOGENIC POTENTIAL
Chemical Name CAS Number
Acetic acid
64-19-7
Acetonitrile
75-05-8
Acrylamide
79-06-1
Ammonia
7664-41-7
Barium carbonate
513-77-9
1,3-Butadiene
106-99-0
tert-Butyl alcohol
75-65-0
Carbon disulfide
75-15-0
Carbonyl sulfide
463-58-1
Chlorine
7782-50-5
Chloroacetic acid
79-11-8
Chloroethane (Ethyl chloride)
75-00-3
Chromium
7440-47-3
Copper
7440-50-8
Cumene
98-82-8
Cyclohexane
110-82-8
Dibenzofuran
132-64-9
1,2-Dibromoethane (Ethylene dibromide)
106-93-4
1,2-Dichloroe thylene
540-59-0
Diethanolamine
111-42-2
Di (2-ethylhexyl )phthalate (Dioctylphthalate)
117-81-7
Ethylbenzene
100-41-4
Ethyl ester acrylic acid (Ethyl acrylate)
140-88-5
Ethylene
74-85-1
Ethylene glycol
107-21-1
Ethylene glycol monoethyl ether (2-Ethoxyethanol)
i 110-80-5
Hexahydro-2H-azepin-1-one (Caprolactam)
105-60-2
Isobutyraldehyde
78-84-2
Isopropyl alcohol
4,4'-Isopropylidenediphenol (Bisphenol A)
67-63-0
80-05-7
Melamine
108-78-1
Methanol (Methyl alcohol)
67-56-1
Methyl chloride
74-87-3
Methyl ethyl ketone
78-93-3
Methyl methacrylate
4,4'-Methylenedianiline
80-62-6
101-77-9
Molybdenum trioxide
1313-27-5
Napthalene
91-20-3
Pentachlorophenol
87-86-5
Phthalic anhydride
85-44-9
Propene (Propylene)
115-07-1
Propionaldehyde
123-38-6
3
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TABLE 1 (continued)
Chemical Name
CAS Number
Propylene dichloride
78-87-5
Styrene
100-42-5
Terephthalic acid
100-21-0
Titanium dioxide
13463-67-7
2,4-Toluene diisocyanate
584-84-9
Vinyl acetate
108-05-4
Zinc
7440-66-6
Zinc oxide
1314-13-2
4
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Cobpound
RTECS® ACGIHb Patty®
Acetic acid XXX
Acetonitrile X X
Acrylamide XXX
Amonla XXX
Bariua carbonate X X
1,3-Butadiene XXX
tert-Butyl alcohol X X X
Carbon disulfide XXX
Carbonyl sulfide X
Chlorine XXX
Chloroacetic acid X X
Chloroethane XXX
(Ethyl chloride)
Chroalua XXX
Copper XXX
Cuaene X X
Cyclohexane XXX
Dibensofuran
1 • 2-Dibroaoethane XXX
(Ethylene dibroaide)
1,2-Dichloroethylene X X
Diethanolaalne X X
Di(2-ethylhesyl)p)ithalate X X
(Dloctylphthalate)
Ethylbenzene X X
TABLE 2
SOURCES REVIEWED
NTP Bioassay
, m Drinking' _ ^ In , .
NIOSIT AWQC Water IARC9 Complete" Progress1 CHIP* CCRIS*
X
X
X
X X
X XX
X X
X X
X X
X X
X
X
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Compound
RTECS® ACSIHb Patty®
Ethyl ester acrylic acid
(Ethyl acrylate)
Ethylene
Ethylene glycol
Ethylene glycol aonoethyl
ether (2-Ethoxyethanol)
Hexahydro-2H-aiepln-1-one
(Caprolactan)
Ieobutyra1dehyde
Iso propyl alcohol
4,4'-Iaopropylldenedlphenol
(Biaphenol A)
Ot Melealne
Methanol (Methyl alcohol)
Methyl chloride
Methyl ethyl ketone
Methyl aethacrylate
4,4' -Methylened i an i1i ne
Molybdenum trioxide
Napthalene
Pentachlorophenol
Phthalic anhydride
Propene (Propylene)
Propionaldehyde
Propylene dichloride
XXX
X
XXX
X X
X X
XXX
X X
X
XXX
XXX
XXX
XXX
X X
XXX
XXX
XXX
XXX
X
XXX
TABLE 2 (continued)
OTP Bloaasay
- . Drinking v In , . .
NlOSir AMOC Water IARC9 Complete" Progrees* CHIP3 CCRIS*
X
X
X
X
X X
X
X X
X X
X X
X
XX X
X
X X
X
X X
XXX
X X
X X
X X
X
X
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by fitting the data to the one-hit model and obtaining the
upper 95% confidence limit for the unit risk. This value has
the units (yg/m^)*"1 and is an estimate of risk at an air con-
centration of 1 jig/m3. Unit risks calculated from studies
in Which doses were expressed as mg/kg/day were converted to
air concentrations by assuming that a 70-kg person inhales
20 m of air per day. Thus, estimated unit risks in (mg/kg/day)
were multiplied by 2.9xl0~4 for this conversion. No scaling
factors were used to convert unit risks calculated from animal
data to values more appropriate to humans.
Results
Table 3 presents unit risk estimates with associated uncer-
tainty scores for 49 chemicals. For many of the chemicals
on the list, extensive searching of the sources described in
Table 2 failed to indicate any evidence of carcinogenic activity.
Therefore, risk values could not be estimated for them in the
subsequent analysis. It should be noted that, of the compounds
in Table 3 without unit risk estimates, only three, i.e., capro-
lactam, phthalic anhydride, and propene, have been tested for
their carcinogenic potential and even this testing has not
been extensive. The 29 compounds from ammonia through zinc
oxide have not been tested. Furthermore, three compounds for
Which unit risks were estimated, i.e., ethylene, diethanolamine,
and pentachlorophenol, have not been tested for their carcino-
genic potential. For this reason, Clement reviewed the liter-
ature for information on the genetic toxicity of these compounds
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TABLE 3
ESTIMATED UNIT RISKS FOR
49 POLLUTANTS EMITTED BY NESHAPS-TYPE SOURCES
Compound
Estimated Unit
Risk (yg/m3)-l
Uncertainty
Score
Chromium
1.2-Dibromoe thane
Acrylamide
4,4'-Methylenedianiline
Di {2-ethylhexyl)-
phthalate
Methyl chloride
Propylene dichloride
4,4'-Isopropylidenedi-
phenol
1.3-Butadiene
Ethyl ester acrylic acid
Melamine
Titanium dioxide
Ethylene
Diethanolamine
Styrene
Pentachl orophenol
Terephthalic acid
Ammonia
tert-Butyl alcohol
Chlorine
Chloroacetic acid
Chi or oe thane
1.2xl0~2
2.5xl0~3
1.7x10
2.1x10
1.3x10
-5
-5
-7
1.4x10
7.2x10
-7
-7
1.4x10
-6
4.6x10
5.0x10
4.1x10
5.6x10
-7
-7
-7
-7
2.7x10
1.1x10
2.9x10
3.9x10
1.8x10
NS
NS
NS
NS
NS
-6
-7
-7
-7
-8
1
1
2
2
2
2
2
3
3
3
3
9
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TABLE 3 (continued)
Compound
Estimated Unit
Risk (yg/m3)-l
Uncertainty
Score
1,2-Dichloroethylene
NS
4
Ethylene glycol
monoethyl ether
NS
4
Isobutyraldehyde
NS
4
Methanol
NS
4
Methyl methacrylate
NS
4
Molybdenum trioxide
NS
4
Propionaldehyde
NS
4
Vinyl acetate
NS
4
Acetic acid
NS
3
Acetonitrile
NS
3
Barium carbonate
NS
3
Carbon disulfide
NS
3
Carbonyl sulfide
NS
3
Copper
NS
3
Cumene
NS
3
Cyclohexane
NS
3
Dibenzofuran
NS
3
Ethylbenzene
NS
3
Ethylene glycol
NS
3
Isopropyl alcohol
NS
3
Methyl ethyl ketone
NS
3
Naphthalene
NS
3
Zinc
NS
3
Zinc oxide
NS
3
Hexahydro-2H-azepin-1-
¦one NS
2
Phthalic anhydride
NS
2
Propene (Propylene)
NS
2
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and £or information on the carcinogenic potential of structurally
or pharmacologically similar compounds. This type of information
is included in the discussion of the individual compounds in
the appendix to this report.
For each compound, an uncertainty score from 1 to 4 was
assigned to the unit risk. The criteria for assigning these
uncertainty scores are described in Table 4.
The compounds in Table 3 are grouped according to the
uncertainty score associated either with the unit risk estimate
or with the evidence that the compound is not carcinogenic.
Within each uncertainty group, the compounds with unit risk
estimates are listed in decreasing order of carcinogenic potency.
Those compounds without unit risk estiamtes are listed in alpha-
betical order within each uncertainty group.
Discussion
Because most of the compounds listed in Table 3 have not
been adequately tested for their carcinogenic potential, it
is not possible to provide a quantitative basis for ranking
these chemicals according to their potential carcinogenic hazard.
In Table 5, subjective qualitative judgments have been applied
to reorder the chemicals according to their potential carcinogenic
risk to humans. In arriving at this ranking three factors
were considered: the quantitative unit risk estimate, where
available; the weight of the evidence, if any, that a chemical
was carcinogenic; and chemical structure and mechanism of toxic
action. Chemicals that are grouped together cannot be differen-
tiated on the basis of estimated carcinogenic potency.
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TABLE 4
CRITERIA FOR ASSIGNING UNCERTAINTY SCORES
Compounds with Cancer Potency Scores
1—More than one positive study and the potency score is based
on a complete risk assessment performed by EPA-CAG using
a multistage model
2—One or more positive studies by an appropriate route of
administration and the potency score is based on an extrapo-
lation from actual tumor incidence using a one-hit model
3—One positive or suggestive study and the potency score is
based on an extrapolation from tumor incidence (may not be
statistically significant) using a one-hit model.
4—Suggestive evidence of carcinogenicity and the potency score
is estimated by analogy to structurally similar compounds
Compounds with No Cancer Potency Scores
1—Compound has been extensively tested for carcinogenic poten-
tial and found not to be carcinogenic
2—Compound has been tested in a single bioassay and found
not to be carcinogenic
3—Compound has not been tested but, by comparison to structur-
ally similar compounds or from in vitro data, it is not
expected to be carcinogenic
4—Compound has not been tested, but, on the basis of either
structure or some other toxic effect (mutagenesis, terato-
?enesis), there is some concern that it may be carcinogenic
f adequately tested.
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TABLE 5
LISTING OP POLLUTANTS IN DECREASING ORDER
OF POTENTIAL CARCINOGENIC RISK TO HUMANS
1.2-Dibromoethane
Acrylamide
Chromium
4,4'-Methylenediani1ine
Di(2-ethylhexyl)phthalate
Methyl chloride
Propylene dichloride
4,4'-Isopropylidenediphenol
1.3-Butadlene
Ethyl ester acrylic acid
Melamine
Titanium dioxide
Styrene
Terephthalic acid
Ammonia
Chorine
Chloroacetic acid
Diethanolamine
Ethylene
Isobutyraldehyde
Methyl methacrylate
Pentachlorophenol
Propr ionaldehyde
Chloroethane
1,2-Dichloroethylene
Acetic acid
Acetonitrile
Carbon disulfide
Ethylene glycol
Ethylene glycol monoethyl ether
Isopropyl alcohol
Methanol
Methyl ethyl ketone
Molybdenum trioxide
Naphthalene
tert-Butyl alcohol
Vinyl acetate
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TABLE 5 (cont'd.)
Barium carbonate
Carbonyl sulfide
Copper
Cumene
Cyclohexane
Dibenzofuran
Ethylbenzene
Zinc
Zinc Oxide
Phthalic anhydride
Hexahydro-2H-azepin-l-one
Propene
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Among the chemicals in Table 5 that have been shown to
be carcinogenic, chromium is grouped with acrylamide and 4,4'-
methylenediamiline because it is unlikely that all the chromium
present in air is present as carcinogenic compounds of chromium VI.
Insofar as some chromium is present as chromium III or metallic
chromium, the risk will be proportionally lower. Some chemicals
that were assigned unit risks in Table 3, i.e., diethanolamine,
ethylene, and pentachlorophenol, are grouped with chemicals
for which no unit risks were estimated, e.g., ammonia and chlorine.
This id done because the evidence that diethanolamine, ethylene,
and pentachlorophenol are carcinogenic is extremely weak while
ammonia, chlorine, chloroacetic acid, isobutyraldehyde, methyl
methacylate, and propionaldehyde are irritant gases or volatile
liquids that may contribute to an increased incidence of cancer
in the upper respiratory tract as a result of long-term low
level exposure.
Chloroethane and 1,2-dichloroethylene are placed just
below the irritant gases and vapors because their structural
relationship to the carcinogenic halogenated hydrocarbons such
as vinyl chloride and 1,2-dichloroethylene make them somewhat
suspect.
All of the chemicals in the group headed by acetic acid
and acetonitrile are unlikely to be carcinogenic but deserve
further study because they either are structurally related
to known carcinogens (vinyl acetate, naphthalene), are metab-
olized to carcinogenic intermediates (methanol), are somewhat
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irritating vapors (acetic acid, acetonitrile, isopropyl alcohol,
methanol, tert-butyl alcohol, vinyl acetate) or they are known
to cause other chronic or acute toxic effects that could possibly
be interrelated with a carcinogenic response (carbon disulfide,
ethylene glycol, ethylene glycol monoethyl ether, methyl ethyl
ketone, molybdenum trioxide). The compounds grouped with barium
carbonate, on the other hand, are relatively benign and have
no known physiological effect.
Phthalic anhydride, though tested and found not to be
carcinogenic, can be an upper respiratory irritant and for
this reason is placed above hexahydro-2H-azepin-l-one and propene
in the ranking.
More detailed discussions of the health effects information
on each chemical are included in the appendix to this report.
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APPENDIX
Acetic Acid
There is no evidence, in the sources reviewed, that acetic
acid is carcinogenic. Occupational exposure to an airborne
concentration of 60 ppm for 7-12 years was reported to cause
conjunctivitis, bronchitis, pharyngitis, and erosion of exposed
teeth but no other more serious effects (ACGIH 1980). No chronic
animal studies were found. Acetic acid has been reported to
cause mutagenic effects in Drosophila melanoqaster and E. coli
(RTECS 1983). The molecular structure of acetic acid does
not suggest that it is carcinogenic.
Acetonitrile
There is no evidence, in the sources reviewed, that aceto-
nitrile is carcinogenic. No studies on long-term occupational
exposure were reported by NIOSH (1978b), and no chronic animal
studies have been reported in the sources reviewed. Acetonitrile
is currently on study in the National Toxicology Program Research
and Testing Program (NTP 1983g).
Acrylamide
There is some evidence to suggest acrylamide is carcinogenic.
In a recent study reported by the Dow Chemical Company (1983),
statistically significant Increased incidences of specific
tumors were found in several organs of female rats treated
for 2 years with acrylamide. Male and female Fischer 344 rats
were divided into two groups of 90 rats/sex/group. Acrylamide
was administered to both sexes at doses of 0, 0.01, 0.1, 0.5,
A-l
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and 2.0 mg/kg of body weight in the drinking water. The tissues
affected were the brain, spinal cord, mammary gland, clitoral
gland, uterus, oral cavity, pituitary gland, and thyroid gland.
There are few reports on long term occupational exposure to
acrylamide, and none suggests an increased incidence of cancer
related to exposure.
A unit risk was estimated from the reported incidence
of uterine adenocarcinomas in the Dow Chemical Company study.
The tumor incidences in the groups from the control group to
the highest dose group were 1/60, 2/60, 1/60, 0/59, 5/60 (numDer
with tumor/number examined), respectively. The unit risk is
1.7xl0~5 (ug/m3)-1. This represents an isolated report study
and has not been fully evaluated. The route of exposure is not
completely appropriate for assessing cancer risk via inhalation.
Ammonia
One epidemiological study (reviewed by NIOSH 1974) on
chemical workers has suggested an association between occupa-
tional exposure to ammonia and cancer morbidity. In two ammonia
plants with airborne concentrations of 75-150 ppm, the 10-year
cancer morbidity was 1,000-1,250/10,000 for male workers and
370/10,000 for female workers compared to 160/10,000 for the
entire factory of 30,000 workers where the ammonia plants were
located. Excess neoplasms were noted for the lung, urinary
tract, intestinal tract, and lymphatic system. NIOSH (1974)
found this study poorly reported and documented and inadequate
to support a conclusion that ammonia was the causal factor.
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Other epidemiological studies have reported only irritation
of the eyes or respiratory tract and have not examined a poten-
tial carcinogenic effect. No animal study was found in the
sources reviewed that adequately examined the effects of long
term exposure to ammonia. Two mutagenicity studies reported
by RTECS (19S3) indicated positive effects. One study was
in rats and another in E. coli.
Barium
There is no evidence, in the sources reviewed, that barium
carbonate is carcinogenic. Barium carbonate is a soluble salt
and tends to be more acutely injurious than the insoluble salts
of barium. There were no animal chronic studies or epidemio-
logical studies found in the sources reviewed. Barium chloride
another soluble barium salt, is currently under study by the
National Toxicology Program in a carcinogenicity bioassay (NTP
1983g).
1,3-Butadiene
There is evidence that 1,3-butadiene is carcinogenic.
Two separate chronic inhalation studies have recently been
completed. One study conducted in rats, sponsored by the Inter
national Institute of Synthetic Rubber Producers, Inc., (1982),
found significant increased incidences of tumors occurring
in a number of tissues. The other study conducted on nice
as part of the National Toxicology Program, (NTP 1983a) also
found significantly increased incidences of nunerous tumors.
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No epidemiological studies on cancer morbidity or mortality
were found in the sources reviewed.
The mouse study had higher tumor incidences at lower exposure
doses than did the rat study, and therefore the unit risk was
estimated from data from the mouse study. The mice in the
study were exposed to 0, 625, or 1,250 ppm 1,3-butadiene.
The incidences of maglignant lymphoma in male mice were 0/50,
23/50, and 29/50 (number with lymphoma/number examined), res-
pectively. The unit risk is 4.6x10**^ (ng/m3)-1.
Carbon Disulfide
There is no evidence, in the sources reviewed, that carbon
disulfide is carcinogenic. Although there have been a number
of epidemiological studies conducted on occupationally exposed
workers, none have examined or reported any association between
exposure and excess cancer incidences. No adequate animal
carcinogenicity bioassay were reported in the sources reviewed,
but one is now being conducted as part of the National Toxicology
Program (NTP 1983g). RTECS (1983) reported one study that
found a positive mutagenic effect in the Ames assay and one
study that found increased sister chromatid exchanges in human
lymphocytes.
Carbonyl Sulfide
There is no evidence, in the sources reviewed, that carbonyl
sulfide is carcinogenic. No chronic animal studies or epidemi-
ological studies were found in these sources. The structural
A-4
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similarities among carbonyl sulfide, carbon dioxide, and carbon
disulfide suggest that the carcinogenic potential for carbonyl
sulfide is negligible.
Chlorine
There is no evidence, in the sources reviewed, that chlorine
is carcinogenic. Epidemiological studies on acutely or chron-
ically exposed people have focused mainly on pulmonary effects
and have not examined potential carcinogenic effects. No adequate
chronic animal study has been found that could be used to assess
chlorine's carcinogenic potential. RTECS (1983) does report
one positive mutagenicity study that reported a cytogenetic
effect in human lymphocytes.
Chloracetic Acid
There is little evidence, in the sources reviewed, that
chloroacetic acid is carcinogenic. In a study with a duration
of 200 days reviewed by Patty (1963), rats fed 0.1% chloroacetic
acid exhibited no specific lesions. RTECS (1983), however,
reported two subcutaneous injection studies in which chloroacetic
acid was considered an equivocal tumorigenic agent. RTECS
(1983) also reported two studies where chloroacetic acid was
considered mutagenic. Chloroacetic acid reacts with sulfhydral
groups of essential enzymes (Patty 1963), suggesting that it
may be an alkylating agent. If so, it may have a significant
carcinogenic potential, but this cannot be determined with
the available information.
A-5
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Chloroethane
There is no current evidence, in the sources reviewed,
that chloroethane is carcinogenic. No animal chronic toxicity
studies or epidemiological studies were found in these sources.
On the basis of structural considerations there is some concern
about potential carcinogenic activity. Many congeners of chloro-
ethane, e.g., 1,2-dichloroethane, 1,1,2-trichloroethane, 1,1,2,2-
tetrachloroethane, and hexachloroethane, have been found to
be carcinogenic in test animals (USEPA 1980a). All these com-
pounds, however, are chlorinated on both carbons, unlike chloro-
ethane. 1,1,1-Trichloroethane did not induce cancer in test
animals during a National Cancer Institute bioassay, but the
study was considered limited because of mortality, and the
compound is being retested. Chloroethane is the only chlorinated
ethane not being tested for its carcinogenic potential in the
National Toxicology Program (NTP 1983g), presumably because
it is felt to have little or no carcinogenic potential.
Chromium
IARC (1980) considers that there is sufficient evidence
that certain forms of chromium VI are carcinogenic to rats.
These forms include calcium chronate, sintered calcium chromate,
lead chromate, strontium chronate, sintered chromium trioxide,
and sine chromate. All except calcium chrcnate are relatively
soluble, and all except lead chromate produced tumors only
at the site of injection. Lead chronate-treated animals also
had a small ntimber of renal carcinomas that were not observed
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in control animals. There were no adequate inhalation or intra-
tracheal injection studies reported by IARC (1980) that showed
a positive carcinogenic effect, although many such studies
were evaluated.
IARC (1980) also considers that there is sufficient evidence
of respiratory carcinogenicity in men occupationally exposed
during chromate production. There is also epidemiological
evidence to suggest that workers in occupations involving exposure
to chromium products are at higher risk of respiratory cancer.
Chromium VI compounds probably carry the greatest carcinogenic
risk, although the epidemiological evidence is not sufficient
to make a distinction between chromium III or VI.
The Cancer Assessment Group of EPA has calculated the
unit risk for cancer from chromium exposure as 1.2xl0~2 (yg/m3)"1.
Copper
There is no evidence that copper is carcinogenic. However,
no chronic animal studies examining the carcinogenic potential
of copper were found. Available evidence on long term oral
intake of low (
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including arsenic, nickel, and chromium, which are known car-
cinogens (Mackey et al. 1980).
Cumene
There is no evidence, in the sources reviewed, that cumene
is carcinogenic. Although some chronic animal toxicity studies
have been performed and reported by ACGIH (1980), these studies
are not likely to be adequate to assess the carcinogenicity
of cumene. Neither ACGIH (1980) nor a review by the National
Academy of Sciences (1980) cited epidemiological studies on
cumene. There is a lack of useful information on which to
assess the carcinogenic potential of cumene, but the similarity
in structures of cumene and ethylbensene would suggest cumene
like ethylbensene is not carcinogenic (see Ethylbensene).
Cvclohexane
There is no evidence, in the sources reviewed that, cyclo-
hexane is carcinogenic. No animal chronic toxicity studies
or epidemiological studies were found. The saturated cyclic
structure of cyclohexane suggests that its potential to induce
neoplasms is small.
Dibengofuran
No information was found on dibenzofuran. The polycyclic
structure of the compound is similar to that of naphthalene,
i.e., they are both planer molecules. As such, the structural
considerations used for naphthalene argue against the presumption
of carcinogenic activity for dibensofuran (see Naphthalene).
A-8
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Further support is contributed by the fact that a lifetime
carcinogenesis bioassay of dibenzo-p-dioxin (a structural ana-
logue) in rats and nice was negative (NCI 1979a).
1,2-Dibromoethane
There is substantial evidence that 1,2-dibromoethane is
carcinogenic to animals. Both inhalation and gavage oncogenicity
studies were positive in mice and rats (NCI 1978, NTP 1982c).
NIOSH (1977b) reviewed only one epidemiological study on exposed
workers. This study had equivocal findings. The EPA Cancer
Assessment Group has calculated the unit risk for carcinogenic
potency of 1,2-dibromoethane to be S.SKmg/kg/day)""1, which
is equivalent to 2.5x10"* (yg/m^)"*.
1,2-Dichloroethylene
1,2-Dichloroethylene occurs as two distinct geometric
isomers, cis and trans 1,2-dichloroethylene. Neither has been
tested for its carcinogenic potential. Evidence for mutagenic
activity is equivocal, but neither isomer is a potent mutagen
in bacterial assay systems. On the basis of structure-activity
considerations, there is some suggestion that the dichloroethyl-
enes may have carcinogenic potential} monochloroethylene (vinyl
chloride) is a proven human carcinogen, and 1,1-dichloroethylene
and trichioroethylene may induce liver cancer in experimental
animals, although the evidence is less than convincing. On
the other hand, several investigators have suggested that unsym-
metrically halogenated ethylenes, e.g., vinyl chloride and
A-9
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TCE, are more likely to be metabolically activated to carcino-
genic intermediates than are symmetrically substituted ethylenes,
e.g., 1,2-dichloroethylene. On this basis it is reasonable
to conclude that it is unlikely that cis- and trans-l,2,-di-
chloroethylene are carcinogenic, butr if they are, they would
not be expected to be very potent.
Piethanolamine
There is no evidence, in the sources reviewed, that diethan-
olamine is carcinogenic. No animal chronic toxicity studies
or epidemiological studies were £ound. The compound is currently
under study in the National Toxicology Program in oncogenicity
bioassays (NTP 1983g). The animal study has been completed,
and the technical report is being drafted. The structure of
diethanolamine makes biotransformation to a nitrosoamine possible,
although no evidence was found to indicate that this does occur.
EPA (1980) did review a study that found nitrosodiethaqolamine
to be a liver carcinogen in rats. The nitroso-compound was
fed to rats intermittently at a dose of 600 mg/kg over a 41-week
period. All treated rats developed malignant tumors. Assuming
that no hepatocarcinomaB occurred in control rats, the calculated
unit risk is 1.1x10"^ (yg/m3)~*. The risk associated with
•thanolamine should be much less, so a factor of 100 will be
used, making the unit risk 1.1x10**^ (yg/m3)"1.
A-10
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Di(2-ethylhexyl)Phthalate
Di(2-ethylhexyl)phthalate was found to cause a significant
increase in the incidence of hepatocellular carcinoma in rats
and mice during a chronic feeding study conducted by the National
Toxicology Program (1982d). Other chronic toxicity studies
reviewed by EPA (1980i) in which animals were orally administered
di(2-ethylhexyl)phthalate did not indicate that the compound
was carcinogenic. The highest dose levels in these negative
studies were somewhat lower than the low dose level in the
positive study. No adequate epidemiological studies were avail-
able for the IARC Working Group to review (IARC 1982). Di(2-
ethylhexyl) phthalate was not found to be mutagenic in the
reviewed studies.
A unit risk for di(2-ethylhexyl)phthalate was calculated
based on hepatocellular carcinomas found in male and female
rats in the National Toxicology Program bioassay. The average
daily intakes for the three groups were 0, 358, and 724 mg/kg/day.
The combined tumor incidences for each of these groups were
3/100, 12/98, and 25/98 (number with tumor/number examined),
respectively. The unit risk is 1.3xl0~7 (yg/m3)-1. Since
the unit risk was based on a feeding study, there is additional
uncertainty with this value.
Ethvlbentene
There was no evidence in the sources reviewed, including
a review by the National Academy of Sciences (1980), that ethyl-
bensene was carcinogenic. Only one long-term study was reviewed
A-ll
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in these sources. This was a 6-month subchronic toxicity study,
using guinea pigs, monkeys, and rabbits. There was no evidence
that ethylbenzene is carcinogenic, and the study was inadequate
to evaluate the compound's carcinogenic potential. EPA (1980e),
speculating on the possibility that ethylbenzene was mutagenic
or carcinogenic, concluded:
Gillete, et al. (1974) have reviewed certain considerations
of drug toxicity including those related to possiDle carcino-
gens. EB or its known metabolites in man and in animals
(Bardodej and Bardedjova, 1970; Kiese and Lenk, 1973,
1974} McMahon and Sullivan, 1966) do not fit into any
of the presently known physical/chemical categories of
mutagenic and/or carcinogenic agents.
Ethylbenzene was deferred from testing by the National Toxicology
Program (NTP I983g).
Ethyl Ester Acrylic Acid
There is some evidence that ethyl ester acrylic acid is
carcinogenic. Four animal chronic toxicity studies have been
reported. One study, in which rats ingested the compound in
drinking water, found no treatment-related lesions. This study
report was reviewed by IARC (1979a) and found to contain insuffi-
cient detail to evaluate the finding adequately. Two recent
inhalation studies conducted by Dow Chemical's Toxicology Research
Laboratory and released by Celanese (1983a, 1983b) also report
finding no increased tumor incidences in either mice or rats
exposed to ethyl ester acrylic acid. These studies have not
yet been critically evaluated, but they do appear to be adequate
tests for carcinogenicity. A National Toxicology Program onco-
genicity bioassay on mice and rats has been conpleted and a
A-12
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draft report prepared (NTP 1983c). In this gavage study, treated
male rats and mice had a significantly increased incidence
of forestomach squamous cell carcinana. Mo epidemiological
studies have been found concerning ethyl ester acrylic acid.
Based on the National Toxicology Program oioassay, a unit
risk for ethyl ester acrylic acid was estimated. Male rats
in this study received doses of 0f 100, or 200 mg/kg/day.
The respective tumor incidences for these dose groups were
0/50, 5/50, and 12/50 (number with tumor/number examined).
The estimated unit risk is 5.0x10 (vg/m ) . Because this
value is based on a positive gavage study while inhalation
studies were negative, there is uncertainty about how relevant
the value is to human inhalation exposure.
Ethylene
There is no evidence, in the sources reviewed, that ethylene
is carcinogenic. No chronic toxicity studies in animals or
epidemiological studies were found. Although IARC (1979a)
indicated that an oncogenicity study in rats was in progress,
no report of such a study was found. Ethylene oxide is known
to be a metabolite of ethylene (IARC 1979a) and has been shown
to be an animal carcinogen. Thus, it is possible that ethylene
may also prove to be carcinogenic. The EPA Carcinogen Assessment
Group has calculated a unit risk for ethylene oxide of 1.8xl0~4
(pg/m3)"1. Assuming a difference in potency between ethylene
and ethylene oxide of 100, the unit risk of ethylene would
be 2.7xl0~* (yg/m3)'1. A recent finding that propylene was
A-13
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not carcinogenic may suggest, on a structural basis, that ethylene
is not carcinogenic (see Propylene).
Ethylene Glycol
There is no evidence, in the sources reviewed, that ethylene
glycol is carcinogenic. ACGIH (1980) reviewed some subchronic
toxicity studies in animals that did not show neoplastic effects,
but these studies are not adequate to assess the carcinogenic
potential of ethylene glycol. A report on a 2-year feeding
study using a small number of rats did not indicate that ethylene
glycol induced an increased incidence of tumors, although this
study was not an adequate oncogenicity bioassay. No epidemi-
ological studies were found in the sources reviewed. Ethylene
glycol is currently under study by the National Toxicology
Program (NTP 1983g), which is conducting a lifetime feeding
study in mice.
Ethylene Glycol Monoethyl Ether
There is no evidence, in the sources reviewed, that ethylene
glycol monoethyl ether is carcinogenic. One chronic toxicity
study in rats was reviewed in several sources. There was no
reported increase of tumor incidence in the treated animals,
although the study may not have been adequate to assess the
carcinogenic potential of the compound. Ethylene glycol mono-
ethyl ether is presently under study in the National Toxicology
Program (NTP 1983g). No epidemiological studies were reported
in the sources reviewed. Ethylene glycol monoethyl ether has
A-14
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been found to be teratogenic in experimental animals and epidemi-
ologic evidence suggests an association between exposure o£
pregnant women to this chemical and birth defects. The relevance
of these findings to assessing the potential carcinogenic risk
from ethylene glycol monoethyl ether is unclear.
Hexahydro-2H-a2epin-l-one
There is no evidence, in the sources reviewed, that hexa-
hydro-2H-azepin-l-one (E-caprolactam) is carcinogenic. The
National Toxicology Program (1982b) found no evidence that
E-caprolactam induced neoplastic effects in mice or rats during
a 2-year feeding study. The epidemiology studies reviewed
by ACGIH (1980) also found no indication that E-caprolactam
caused adverse health effects in occupationally exposed workers.
It was not determined whether these studies were adequate to
detect increased cancer morbidity or mortality. RTECS (1983)
reported one study that found an effect on rat sperm morphology
following in vivo exposure to E-caprolactam.
Isobutyraldehyde and Propionaldehyde
Isobutyraldehyde and proprionaldehyde are saturated aliphatic
aldehydes, and they have not been studied for their potential
to induce cancer or other chronic toxic effects. If these
are considered as members of a homologous series beginning
with formaldehyde (one carbon), acetaldehyde (two carbons),
propionaldehyde (three carbons), and isobutyraldehyde (four
carbons), there is some evidence for carcinogenic potential,
A-15
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because formaldehyde is a confirmed animal carcinogen and acetal-
dehyde was shown to induce nasal and laryngeal cancer in hamsters
exposed by inhalation for 7 hours a day, S days a week, for
52 weeks (Feron et al. 1982). However, it is important to
note that the concentrations of acetaldehyde to which hamsters
were exposed were very high (1,650-2,500 ppm), approximately
100 times greater than the concentrations of formaldehyde that
induced cancer in rats. Furthermore, the mechanism by which
the lower aldehydes induce cancer is unknown and may be secondary
to their irritant properties. Therefore, if propionaldehyde
and isobutyraldehyde follow the trend, they would not be expected
to induce cancer, and if they did, only at extremely high con-
centrations. Isobutyraldehyde is presently under study by
the National Toxicology Program (OTP 1983g).
Isopropyl Alcohol
There is evidence, in the sources reviewed, that occupa-
tional exposure to the strong acid production process of iso-
propyl alcohol is carcinogenic. This carcinogenic effect haB
been attributed to isopropyl oils, which are by-products of
the production process, and not to isopropyl alcohol. The
manufacturing process has been discontinued. Isopropyl oil
mixtures have been shown to be tumorigenic in mice, but IARC
(1977) did not consider these studies adequate to provide suffi-
cient evidence of carcinogenicity. No chronic toxicity studies
on isopropyl alcohol were found in the sources reviewed. One
inhalation exposure study on mice, which had a duration of
A-16
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up to 12 months, did not show an Increased Incidence in lung
tumorss however, this study was not adequate to evaluate the
carcinogenicity of isopropyl alcohol. Based on its structure,
it is not likely that isopropyl alcohol is carcinogenic.
4.4-Isopropylldenedlphenol
There is equivocal evidence, in the sources reviewed,
that 4,4-lsopropylldenedlphenol (blsphenol A) is carcinogenic.
Rats fed blsphenol A in a 2-year oncogenicity study developed
a higher Incidence of leukemlas than did the control rats (NTP
1982a). This Increase in both Dale and female rats was not
statistically significant, although there was a significant
dose-related trend in the male rats. A statistically significant
increased incidence in lnterstltlal-cell tumors of the testes
was also found in male rats, but was not considered a significant
compound-related effect because of the normally high incidence
found in aging rats of the strain used. Hale mice also had
an Increased incidence of leukemias/lymphomas, but it was not
significant. The National Toxicology Program concluded that
there was no convincing evidence that blsphenol A was carcino-
genic to rats and mice in this bloassay. However, since increased
incidences of leukemia were found in the male and female rats
and male mice and a significant dose-related trend wsb found
for this type of neoplasia, a unit risk was calculated using
the male rat incidence data. The dietary levels fed to the
rats were 0, 1,000, and 2,000 ppo, which gave an average dally
dose of 0, 74, and 148 ag/kg/dayi respectively. The tumor
A-17
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incidence data was 13/50, 12/50, and 23/50 (number with leukemia/
number examined), respectively. The calculated unit risk is
2.2xl0~® (yg/m*). Because this value is calculated on nonsig-
nificant incidence data, the uncertainty associated with it
is high.
Melamine
A recent 2-year feeding study in rats and mice under super-
vision of the National Toxicology Program (1983d) found that
melamine caused a significantly increased incidence of transi-
tional-cell carcinoma of the bladder in male rats. There were
no other tumor incidences that were significantly increased
over control values in the male and female rats and mice.
In a separate study, reviewed by NTP (1983d), rats of a different
strain were fed melamine for 2 years. Benign papillomas in
the bladder of some high-dose animals were found, but no malignant
tumors were seen. Bladder stones were associated with these
benign tumors. Bladder stones were also found in a large number
of the high-dose rats of the NTP study. No other information
on the carcinogenicity of melamine was found in the sources
reviewed except that melamine was not mutagenic in Drosophila
melanogaster or several strains of Salmonella typhimurium.
A unit risk for melamine was calculated on the incidence
of transitional-cell tumors in the bladder of male rats. These
animals were fed diets containing 0, 4,500, and 9,000 ppm mela-
mine, which gave average daily doses of 0, 126, and 263 mg/kg/day,
respectively. The tunor incidence was 0/45, 0/50, and 8/49
A-18
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(number with tumor/number examined), respectively. The calcu-
lated unit risk is 4.1x10"*^ (yg/m')""*". Because there are scien-
tists of the opinion that the appearance of bladder tumors
in the presence of bladder stones is evidence that the tumor-
igenic response is secondary to the primary response of bladder
stone formation, the use of a nonthreshold model to estimate
cancer risk in such a case may be overly conservative and inap-
propriate.
Methanol
There is no evidence, in the sources reviewed, that methanol
is carcinogenic. In one chronic study in dogs, reviewed by
ACGIH (1980), no effect was observed, although the study was
not an adequate oncogenicity study. Several studies on occupa-
tional exposure were also reported by ACGIH (1980), but none
appeared to be concerned with cancer morbidity or mortality.
Methanol is metabolized to formic acid and formaldehyde. For-
maldehyde has been shown to cause cancer in rats. This effect
occurs at the site of application, and thus formation within
the body from methanol may not be an important factor in the
determination of methanol*s carcinogenic potential.
Methyl Chloride
Methyl chloride has been tested in a 2-year inhalation
bioassay on mice and rats that was sponsored by CUT (1981).
A significantly increased incidence of renal tumors was found
in male mice. No increased incidence of any tumor was found
A-19
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in female nice and male and female cats. There is very little
other information on the carcinogenic potential of methyl chloride,
in the sources reviewed, except that it has been found to be
mutagenic in Salmonella typhimurium (CCRIS 1983).
A unit risk was calculated based on the incidence of renal
tumors (cortical adenomas and cortical adenocarcinomas) in
the male mice. The mice were exposed to airborne concentrations
of 0, 104, 469, and 1,086 mg/m^ and had tumor inci dences of
0/67, 0/61, 2/57, and 18/82 (number with tumor/number examined),
—7 3 —1
respectively. The calculated unit risk is 1.4x10 (yg/m) .
Methyl Ethyl Ketone
There is no evidence, in the sources reviewed, that methyl
ethyl ketone is carcinogenic. No studies werereviewed in these
sources that examined the chronic toxicity of the compound
in animals or humans. The only aliphatic ketone that has under-
gone long-term testing is acetone, which was applied to the
skin of mice for 1 year without producing tumors (NIOSH 1978a).
NIOSH also reported studies showing negative findings in mutagen-
icity assays of acetone. Although these results are not adequate
evidence that acetone is not carcinogenic, they are suggestive.
Since acetone and methyl ethyl ketone are structurally very
similar they are expected to act in a similar manner.
Methyl Methacrvlate
There is no evidence, in the sources reviewed, that methyl
methacrylate is carcinogenic. No animal chronic toxicity studies
A-20
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or epidemiological studies were found in these sources. Methyl
methacrylate is structurally similar to ethyl acrylate. Ethyl
acrylate has been shown to be carcinogenic in one of several
chronic studies. Based on this, methyl methacrylate should
also be considered to be a possible carcinogen. A structure-
activity relationship has been developed for the acute toxicity
of the alkyl acrylates (Autian 1975). Methyl methacrylate
is much less potent than ethylacrylate. Because the qualitative
evidence for the carcinogenicity of methyl methacrylate is
so weak, a unit risk will not be calculated.
4,4-Methylenedianiline
There are several animal studies that examined the carcino-
genic effect of 4,4-methylenedianiline (IARC 1974). In a subcu-
taneous injection study, the con pound produced an increased
incidence of benign and malignant tumors. A recently released
National Toxicology Program bioassay of 4,4-methylenedianiline
dihydrochloride found the compound to be carcinogenic to both
mice and rats (NTP 1983e). ACGIH (1980) reviewed one study
on workers exposed to the compound at levels of 0.03-3.8 ppm
that showed no increased mortality or morbidity, but a struc-
turally similar compound, 4,4-methylene bis(2-methylaniline),
was found to be associated with an increased incidence of mor-
tality from urinary bladder cancer in dye stuff factory workers.
A unit risk for 4,4-methylenedianiline was calculated
on an increased incidence of thyroid follicular-cell adenoma
or carcinoma found in female rats in the NTP study. These
A-21
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rats were given 4,4-methylenedianiline <5ihydrochloride in their
drinking water and received an average lifetime daily dose
of 0, 6.4, or 12.2 mg/kg/day. (These doses have been converted
to actual doses of 4,4-methylene dianiline and not its dihydro-
chloride salt). The tumor incidences in these dose groups
were 0/47, 4/47, and 19/48 (number with tumors/number examined),
respectively. The calculated unit risk is 2.1x10"^ (yg/m^)"1.
Molybdenum Trioxide
There is some evidence, in the sources reviewed, that
molybdenum trioxide may be carcinogenic. RTECS (1983) cites
a study by Stoner et al. (1976) in which molybdenum trioxide
significantly increased the incidence of lung adenomas in strain A
mice after 19 subcutaneous injections over a 30-week period.
The same study cites a personal communication that a molyodenum
compound was found carcinogenic when administered by intramuscular
injection to rats. No other information on the carcinogenc
potential of molybdenum trioxide was found in the sources reviewed.
Although, there is a possibility that molybdenum trioxide
is carcinogenic there is insufficient information on which
to calculate a unit risk. The strain A lung adenoma bioassay
is not an actual oncogenicity bioassay and therefore should
not be used for unit risk calculations.
naphthalene
There is little evidence, in the sources reviewed, that
naphthalene is carcinogenic. EPA (1980g) has reviewed several
A-22
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animal studies that examined the carcinogenicity of naphthalene.
Two studies reported by the same researcher found increased
incidences of lymphosarcomas or leukemia in treated rats.
Because of defects in these studies EPA (1980g) concluded that
they could not be used as a basis for a naphthalene water cri-
terion. The other animal chronic studies gave negative results.
Two mutagenicity studies reviewed by EPA (1980g) found that
naphthalene did not produce a mutagenic effect in E. coli or
several strains of Salmonella typhimurium. A study of workers
(USEPA 1980g) exposed to naphthalene and coal tar for up to
32 years found several cases of malignant tumors, but this
study had no control population and confounding factors do
not allow any finding on association between naphthalene exposure
and cancer. Naphthalene is currently undergoing oncogenicity
testing by the National Toxicology Program (NTP 1983g). On
the basis of structure-activity considerations, naphthalene
would not be expected to be carcinogenic. Among the unsubstituted
polycyclic aromatic hydrocarbons with fewer than four condensed
rings that have been tested, none has shown tumorigenic activity
(Santodonato et al. 1981). Although benzene is a proven leukemo-
gen, this property appears to be extremely structure specific
in that such very close structural analogs as toluene, phenol,
and monochlorobenzene appear not to have the capacity to induce
tumor8.
A-23
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Pentachlorophenol
There is no evidence, in the sources reviewed, that penta-
chlorophenol is carcinogenic. Studies on workers who treated
wood with pentachlorophenol preservatives were reviewed by
EPA (1980h). There was no mention of an increased incidence
in cancer morbidity or mortality in these reviews. The studies
may not have examined that aspect of the workers health since
only clinical chemistry information was given. No other epidemio-
logical study was found in the sources review. Chronic feeding
studies of commercial grade pentachlorophenol in both mice
and rats have been reviewed by EPA (1980h) and IARC (1979b).
In both species there were no increased incidences of tumors.
A subcutaneous injection study, of the same commercial product,
using two strains of mice was also reviewed by IARC (1979b).
The male mice of one strain were found to have a significantly
greater incidence of hepatocellular carcinomas compared to
the control mice. Although there was a positive response in
this study it is an inadequate study on which to evaluate the
carcinogenicity of pentachlorophenol. The animals received
only one injection of compound and the compound was not pure,
containing the known carcinogens trichlorophenol and hexachloro-
dibenzodioxins (NCI 1979e, NTP 1980).
Because pentachlorophenol Ib structurally related to 2,4,6-
trichlorophenol, which was found to be carcinogenic in rats
and mice (NCI 1979e) it may also be carcinogenic. Therefore,
a unit risk for pentachlorophenol will be derived from tumor
A-24
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incidence data of hepatocellular adenomacarcinoma in male mice.
In this study the animals were fed diets containing the compound.
These diets delivered average daily doses of 0, 620, 1,240 mg/kg/day
to the mice. The respective tumor incidences are (number with
tumor/number examined) 4/20, 32/49, and 39/47. The unit risk
—7 3 —1
is 3.9x10 (yg/nr) *. There is a great deal of uncertainty
in this value, because it not based on a pentachlorophenol
study and because the trichlorophenol used may have been contam-
inated with polychlorinated dibenzodioxins, which can induce
hepatocellular carcinomas at very low dose levels.
Phthalic Anhydride
There is no evidence, in the sources reviewed, that phthalic
anhydride is carcinogenic. No epidemiological studies were
found that examined cancer mortality or morbidity in exposed
populations. The National Cancer Institute conducted oncogeni-
city bioassays of phthalic anhydride on mice and rats (NCI 1979b).
The feeding study found that phthalic anhydride was not carcin-
ogenic to either species under the condition of the bioassays.
The compound is highly reactive and probaoly reacts with water
to form phthalic acid. Because the lungs may be more sensitive
to an effect by phthalic anhydride, the negative finding in
the feeding still leaves uncertainty about its possible effect
via inhalation.
A-25
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Styrene
There is some evidence, in the sources reviewed, that
styrene is carcinogenic. IARC (1979a) reviewed a study on
cancer mortality of chemical workers producing styrene monomer.
Three leukemias and two lymphomas were £ound among 104 deaths
studied, which indicated to the study authors that further
studies were needed. IARC (1979a) found that this study failed
to identify clearly the population at risk and that there was
no comparison to a control population. A National Cancer Institute
report (1979c) on an oncogenicity bioassay in rats and mice
concluded that there was no convincing evidence that styrene
was carcinogenic to rats or mice under the conditions of the
bioassay. There was, however, an increased incidence of a
combination of lung adenomas and carcinomas in male mice, which
was considered to be suggestive evidence. IARC (1982) states
that "there is limited evidence in humans and animals that
acrylonitrile, epichlorohydrin and styrene are carcinogenic."
Thus, a unit risk for styrene was calculated on the incidence
of mouse lung tumors in the National Cancer instituted bioassay.
The mice were given daily doses of 0, 150, and 300 mg/kg/day
by gavage. The respective tumor incidences for these dose
groups were 0/20, 6/44, and 9/43 (number with tumor/number
examined). The calculated unit risk is 2.9xl0~7 (yg/m3)"1.
There is uncertainty in this value since the tumor incidences
used were not considered sufficient evidence that styrene induced
a carcinogenic response.
A-2 7
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Terephthalic Acid
There is some evidence that terephthalic acid is carcino-
genic. EPA (1982b) reviewed a study citing another study that
showed that terephthalic acid induced bladder and ureteral
neoplasms in both male and £ en ale rats in a 2-year feeding
study. Rat8 fed a dietary level of 5% terephthalic acid had
tumors and bladder stones, while those fed a dietary level
of 1% did not. The study reviewed by EPA (1982b) showed that
only the treated rats with bladder stones developed hyperplasia
of the transitional epithelium in the urinary bladder. This
suggests that hyperplasia and possibly neoplasms would not
be induced by terephthalic acid without irritation from bladder
calculi. As with melamine a causal association has still not
been shown. Therefore, a unit risk was estimated for terephthalic
acid. Because the chronic toxicity study was not in the published
literature, information from the study was taken from the study
reviewed by EPA (1982b) (Chin et al. 1981) and assumptions
were made. Two dietary levels were mentioned, 1% and 5%.
It is assumed that a control gorup was also included. No tumor
incidence was mentioned so it was assumed that no tumors occurred
in the control or loir-dose groups and a 10% incidence was found
in the high-dose group. Dietary levels of 1% and 5% approximate
a daily intake for rats of 490 and 2,450 mg/kg/day, respectively.
The calculated risk based on these assumptions is 1.8x10'** (yg/m3)"^.
There is a large degree of uncertainty associated with, this
value.
A-28
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Tert-Butyl Alcohol
There is no evidence, in the sources reviewed, that tert-
butyl alchol is carcinogenic. No animal chronic-toxicity studies
were cited in these sources except Cor a skin painting promotion
study in mice in which tert-butyl alcohol failed to increase
carcinogenic activity after an initiating dose of 4-nitroquinoline-
1-oxide (reviewed by NAS 1977). No epidemiological studies
concerning cancer morbidity or mortality were found in the
sources reviewed. Tert-butyl alcohol is currently under study
by the National Toxicology Program (NTP 1983g).
Titanium Dioxide
There is some evidence, in the sources reviewed, that
titanium dioxide is carcinogenic. RTECS (1983) cites two studies,
from the same source, that indicate that titanium dioxide has
a tumorigenie effect when injected intramuscularly. E.I. DuPont
(1983) reported the preliminary results of a 2-year inhalation
study in rats. They report that at the highest airborne concen-
tration used, significantly increased incidences of lung squamous
cell carcinoma and bronchioalveolar adenoma were found. On
the other hand, the National Cancer Institute reported (1979d)
on a 2-year feeding study in nice and cats that found that
titanium dioxide was not carcinogenic under the conditions
of the bioassay. There was, however, a dose-related increase
in the incidence of C-cell adenomas or carcinomas in the thyroid
of female rats, although the increase was not statistically
significant.
A-29
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Because there was a positive finding in the 2-year inhala-
tion study, a unit risk for titanium was calculated. The unit
risk was based on the incidence of squamous cell carcinoma
in the lung. The rats in this study were exposed to airborne
concentrations of 0* 10, 50, and 250 mg/m^. The corresponding
incidence data were 0, 0, 0, and "about 101," respectively.
The unit risk is 5.6x10'^ (yg/m^)"1.
2,4-Toluene Diisocvanate
There is some evidence, in the sources reviewed, that
2,4-toluene diisocyanate is carcinogenic. A National Toxicology
Program 2-year gavage study in mice and rats using a mixture
of toluene diisocyanates, 86% 2,4-isomer and 14% 2,6-isomer,
found dose-related increased incidences of tumors in several
tissues (NTP 1982e). The low- and high-dose rats received
30 and 60 mg/kg/day, respectively, and the low- and high-dose
mice received 120 and 240 mg/kg/day, respectively. No other
animal chronic toxicity studies or epidemiological studies
on cancer morbidity or mortality were reported in the sources
reviewed. A list of tumor incidences found at a statistically
significant higher level in treated rats and mice from the
NTP study is given below:
A-30
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will be calculated for the compound, there is an uncertainty
about its carcinogenic potency.
Zinc
There is no evidence, in the sources reviewed, that zinc
is carcinogenic, although it was reported to induce testicular
tumors in rats after direct injection of zinc salt into the
testes (EPA 1980j). EPA (1980j) states that "zinc is of interest
with regard to cancer since zinc seems to be indirectly involved
by being important for the growth of tumors•" There is also
no indication zinc is mutagenic.
Zinc Oxide
There is no evidence, in the sources reviewed, that zinc
oxide is carcinogenic. No animal chronic toxicity studies or
epidemiological studies on cancer morbidity or mortality were
found in these sources. The National Toxicology Program has
deferred the testing of zinc oxide in its bioassay program
(NTP 1983g).
A-32
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7
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