TECHNICAL REPORT DATA „
/near ntd Insavcnont on the revertt be fan eompietuigj •-'
mA/finn/8-88/019
3. RECIPIENT'S ACCESSION NO.
PB-179452/AS
4. TITLE AND SUBTITLE
Health Effects Assessment for Benzidine
S. REPORT DATE
6. PERFORMING ORGANIZATION CODE
. AUTHOR(S)
8. PERFORMING ORGANIZATION REPORT NO.
9. PERFORMING ORGANIZATION NAME AND AOORESS
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO.
12. SPONSORING AGENCY NAME ANO AOORESS
13. TYPE OF REPORT ANO PERIOD COVERED
Environmental Criteria and Assessment Office
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati. OH 45268 __
14. SPONSORING AGENCY CODE
EPA/600/22
15. SUPPLEMENTARY NOTES
16. ABSTRACT
This report summarizes and evaluates information relevant to a preliminary interim
assessment of adverse health effects associated with specific chemicals or compounds.
The Office of Emergency and Remedial Response (Superfund) uses these documents in
preparing cost-benefit analyses under Executive Order 32991 for decision-making under
CERCLA. All estimates of acceptable intakes and carcinogenic potency presented in
this document should be considered as preliminary and reflect limited resources
allocated to .this project. The intent in these assessments is to suggest acceptable
exposure levels whenever sufficient data are available. The interim values presented
reflect the relative degree of hazard associated with exposure or risk to the
chemical(s) addressed. Whenever possible, two categories of values have been
estimated for systemic toxicants (toxicants for which cancer is not the endpoint of
concern). The first, RfDs or subchronic reference dose, is an estimate of an exposure
level that would not be expected to cause adverse effects when exposure occurs during
a limited time interval. The RfD is an estimate of an exposure level that would not
be expected to cause adverse effects when exposure occurs for a significant portion
of the lifespan. For compounds for which there is sufficient evidence of
carcinogenicity, qi*s have been computed, if appropriate, based on oral and
inhalation data if available.
17.
KEY WORDS ANO DOCUMENT ANALYSIS
DESCRIPTORS
b.lOENTIFIERS/OPEN ENDED TERMS C. COSATI Field/Croup
It. DISTRIBUTION STATEMENT
Public
19. SECURITY CLASS (Thit Rtport)
Unrlassified
21. NO. OF PAGES
20. SECURITY CLASS (Thispage!
Unclassified
22. PRICE
EPA
2220-1 (••». 4-77) »MKVIOU» COITION i« OMOUBTK
-------
EPA/600/8-88/019
Hay, 1987
HEALTH EFFECTS ASSESSMENT
FOR BENZIOINE
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
CINCINNATI, OH 45268
.a1 protection Agency
U.S. Environmental Prot ^
-';-f'U ?.! Li!;:'.'rIt!-V:--t/Eoc3i 1670
r" 60604"
-------
DISCLAIMER
This document has been reviewed In accordance with the U.S.
Environmental Protection Agency's peer and administrative review policies
and approved for publication. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
-------
PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with benzldlne.
All estimates of acceptable Intakes and carcinogenic potency presented In
this document should be considered as preliminary and reflect limited
resources allocated to this project. Pertinent toxlcologlc and environ-
mental data were located through on-Hne literature searches of the TOXLINE,
CANCERLINE and the CHEMFATE/DATALOG data bases. The basic literature
searched supporting this document 1s current up to Nay, 1986. Secondary
sources of Information have also been relied upon In the preparation of this
report and represent large-scale health assessment efforts that entail
extensive peer and Agency review. The following Office of Health and
Environmental Assessment (OHEA) sources have been extensively utilized:
U.S. EPA. 1978. Review of the Environmental Effects of Pollu-
tants. II. Benzldlne. Health Effects Research Laboratory, U.S.
EPA, Cincinnati, OH. EPA 600/1-78-024. MTIS PB281076.
U.S. EPA. 1980a. Ambient Water Quality Criteria for Benzldlne.
Prepared by the Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH for
the Office of Water Regulations and Standards, Washington, DC. EPA
440/5-80-023. NTIS PB81-117342.
U.S. EPA. 1983a. Reportable Quantity Document for Benzldlne.
Prepared by the Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH for
. the Office of Emergency and Remedial Response, Washington, DC.
U.S. EPA. 1986. Health and Environmental Effects Profile for
Benzldlne. 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.
The Intent 1n these assessments 1s to suggest acceptable exposure levels
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data were limited 1n
scope tending to generate conservative (I.e., protective) estimates.
Nevertheless, the Interim values presented reflect th? relative degree of
hazard associated with exposure or risk to the chemical(s) addressed.
Whenever possible, two categories of values have been estimated for
systemic toxicants (toxicants for which cancer 1s not the endpolnt of
concern). The first, RfD$ (formerly AIS) or subchronlc reference dose, 1s
an estimate of an exposure level that would not be expected to cause adverse
effects when exposure occurs during a limited time Interval (I.e., for an
Interval that does not constitute a significant portion of the llfespan).
111
-------
This type of exposure estimate has not been extensively used, or rigorously
defined, as previous risk assessment efforts have been primarily directed
towards exposures from toxicants In ambient air or water where lifetime
exposure 1s assumed. Animal data used for RFD$ estimates generally
Include exposures with durations of 30-90 days. Subchronlc human data are
rarely available. Reported exposures are usually from chronic occupational
exposure situations or from reports of acute accidental exposure. These
values are developed for both Inhalation (RfD$j) and oral (RfD$0)
exposures.
The RfD (formerly AIC) 1s similar 1n concept and addresses chronic
exposure. It 1s an estimate of an exposure level that would not be expected
to cause adverse effects when exposure occurs for a significant portion of
the Hfespan [see U.S. EPA (1980a,b) for a discussion of this concept]. The
RfD Is route-specific and estimates acceptable exposure for either oral
(RfDg) or Inhalation (RfO]) with the Implicit assumption that exposure
by other routes 1s Insignificant.
Composite scores (CSs) for noncardnogens have also been calculated
where data permitted. These values are used for Identifying reportable
quantities and the methodology for their development Is explained 1n U.S.
EPA (1983).
For compounds for which there 1s sufficient evidence of cardnogen1c1ty
RfD$ and RfD values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980b). Since cancer 1s a
process that 1s not characterized by a threshold, any exposure contributes
an Increment of risk. For carcinogens, q-|*s have been computed. If appro-
priate, based on oral and Inhalation data If available.
-------
ABSTRACT
In order to place the risk assessment evaluation In proper context,
refer to the preface of this document. The preface outlines limitations
applicable to all documents of this series as well as the appropriate
Interpretation and use of the quantitative estimates presented.
Benzldlne has been Implicated as a human carcinogen U.S. EPA Group A, In
workers exposed 1n the manufacturing process (Zavon et al.t 1973). In this
study, 13/25 workers exposed for an average of 11.46 years developed cancer
of the urinary bladder. The U.S. EPA (1980a) derived an estimate of oral
carcinogenic potency from this study of 234.13 (mg/kg/day}"1. An estimate
of carcinogenic potency of 111 (mg/kg/day)"1 was derived from the same
study for Inhalation exposure.
-------
ACKNOWLEDGEMENTS
The Initial draft of this report was prepared by Syracuse Research
Corporation under Contract No. 68-03-3112 for EPA's Environmental Criteria
and Assessment Office, Cincinnati, OH. Dr. Christopher DeRosa and Karen
Blackburn were the Technical Project Monitors and John Helms (Office of
Toxic Substances) was the Project Officer. The final documents 1n this
series were prepared for the Office of Emergency and Remedial Response,
Washington, DC.
Scientists from the following U.S. EPA offices provided review comments
for this document series:
Environmental Criteria and Assessment Office, Cincinnati, OH
Carcinogen Assessment Group
Office of Air Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
Editorial review for the document series was provided by the following:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
Technical support services for the document series was provided by the
following:
Bette Zwayer, Jacky Bohanon and K1m Davidson
Environmental Criteria and Assessment Office
Cincinnati, OH
v1
-------
TABLE OF CONTENTS
1.
2.
3.
4.
5.
6.
ENVIRONMENTAL CHEMISTRY AND FATE
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . .
2.1. ORAL
2.2. INHALATION
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SU8CHRONIC
3.1.1. Oral
3.1.2. Inhalation
3.2. CHRONIC
3.2.1. Oral
3.2.2. Inhalation
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS. . . .
3.4. TOXICANT INTERACTIONS
CARCINOGENICITY
4.1. HUMAN DATA •
4.1.1. Oral
4.1.2. Inhalation
4.2. BIOASSAYS
4.2.1. Oral
4.2,2. Inhalation
4.3. OTHER RELEVANT DATA
4.4. WEIGHT OF EVIDENCE
REGULATORY STANDARDS AND CRITERIA
RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfDs)
6.1.1. Oral (RfDso)
6.1.2. Inhalation (RfDsi)
Paqe
, , . 1
... 4
. . . 4
. . . 4
. . . 5
. . . 5
. . . 5
. . . 6
. , 6
. . . 6
. . . 6
. . . 6
. . . 7
. . . 8
. . . 8
. . . 8
. . . 8
. . . 10
. . . 10
, . . 19
. . . 19
. . . 22
. . . 23
. . . 24
. . . 24
. . . 24
. . . 24
-------
TABLE OF CONTENTS (cont.)
Page
6.2. REFERENCE DOSE (RfP) 24
6.2.1. Oral (RfDo) 24
6.2.2. Inhalation (RfOj) 24
6.3. CARCINOGENIC POTENCY (q-j*) 24
6.3.1. Oral 24
6.3.2. Inhalation 25
7. REFERENCES 27
APPENDIX: Summary Table for Benz1d1ne 35
-------
LIST OF ABBREVIATIONS
B Potency factor
BCF Bloconcentratlon factor
-Bd* Increased cancer Incidence with age
BUN Blood urea nitrogen
CAS Chemical Abstract Service
CS Composite score
DMBA Dimethyl benzanthracene
Koc Soil sorptlon coefficient standardized
with respect to organic matter
MED Minimum effective dose
NOAEL No-observed-adverse-effect level
NOEL No-observed-effect level
ppm Parts per million
ftfD Reference dose
RfDj Inhalation reference dose
RfDg Oral reference dose
RfD$j Subchronlc Inhalation reference dose
RfD$Q Subchronlc oral reference dose
RQ Reportable quantity
RV0 Dose-rating value
RVe Effect-rating value
SGOT Serum glutamlc oxaloactlc transamlnase
SGPT Serum glutamlc pyruvlc transamlnase
TLV Threshold limit value
TWA Time-weighted average
1x
-------
1. ENVIRONMENTAL CHEMISTRY AND FATE
Selected chemical and physical properties and environmental fate of
benzldlne are listed In Table 1-1.
In the atmosphere, benzldlne Is probably removed rapidly by reaction
with OH radical. Based on reaction kinetics (Atkinson, 1985) of struc-
turally similar compounds (aniline and blphenyl), the half-life for the
benzldlne reaction with OH radical 1s expected to be "1 day. Photolysis and
direct oxidation with oxygen atoms may also contribute to the removal of
benzldlne from the atmosphere.
A persistence study conducted with a single lake water found that
benzldlne had a half-life of 4 hours (Howard and Saxena, 1976). In aquatic
systems, oxidation reactions with metal cations, peroxy radicals and oxygen
are probably the most Important fate processes for benzldlne. The estimated
peroxy radical reaction half-life 1s 6.3 hours (Mabey et al., 1981). Photo-
sensitized photolysis of benzldlne or photolysis of benzldlne-oxldatlon
complexes In water may also have some Importance (U.S. EPA, 1981; Callahan
et al., 1979). Benzldlne 1s rapidly and strongly adsorbed to clay particles
(Callahan et al., 1979; Furukawa and Bindley, 1973; Lahav and Razlel, 1971;
U.S. EPA. 1981) and by sediment (Zlerath et al., 1980) Indicating adsorption
In aquatic systems may be significant.
In clay sllty loam, -70% disappearance of benzldlne was observed after 1
week (Lu et al., 1975). Benzldlne will adsorb to soil to form complexes
with clay particles and oxidize by reaction with metal cations (NLM, 1986).
0091h -1- 12/29/86
-------
TABLE 1-1
Selected Chemical and Physical Properties and
Half-Lives for Benz1d1ne
Property
Value
Reference
CAS number:
Chemical class:
Molecular weight:
Vapor pressure:
Water solubility:
Log octanol/water
partition coefficient:
lonlzatlon constant:
Bloconcentratlon factor:
Soil adsorption
coefficient (Koc):
Half-lives:
Air
Mater
Soil
92-87-5
aromatic dlamlne
184.24
5x10-* (estimated at
unspecified temperature)
276 mg/l at 20°C
520 mg/l at 25°C
1.34
pK-| . 4.66 at 30°C
pK2 - 3.57 at 30°C
110 fish (Gambusla
afflnls)
83 Golden orfe
(Leuclscus 1dus)
44 blueglll sunflsh
(Lepomls macrochlrus)
264-82,110
(depending upon pH
and soil surface area)
-1 day
4 hours
- days
Mabey et a!., 1981
Schmlt-Bleek et al.,
1982
Shrlner et al.. 1978
Hansch and Leo, 1985
Ueast, 1985
Weast. 1985
Lu et al., 1975
Shrlner et al., 1978
Zlerathe et al., 1980
Atkinson, 1985
Howard and Saxena, 197i
Lu et al., 1975
0091 h
-2-
12/29/86
-------
The Ionic sorptlon and subsequent oxidation will Increase with the lowering
of pH and Increase of clay containing metal cations capable of catalyzing
the oxidation reaction (Callahan et al., 1979; Zlerath et al., 1980).
Photolysis on sunlit soil surfaces may also occur (Lahav and Razlel, 1971;
Kotzlas et al., 1981).' Based on sorptlon coefficients In 14 different soils
and sediments (Zlerath et al., 1980), benzldlne Is not expected to leach
significantly In most types of soil.
0091h -3- 12/29/86
-------
2. ABSORPTION IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
Lynn et al. (1984) administered l4C-benz1d1ne orally or Intravenously
to male F344 rats and measured the radioactivity excreted In urine and
feces. At doses of 0.5-5.0 mg/kg. fecal excretion at 24 hours was nearly
Identical at 50.4-54.5X following either route of administration. These
data suggest that gastrointestinal absorption of benzldlne Is very rapid and
virtually complete, at least 1n rats. The recovery of -50% of the adminis-
tered radioactivity from the feces was attributed to biliary excretion
rather than to lack of absorption. This was confirmed by the recovery from
the bile of bile duct cannulated rats of 71.2* of the radioactivity
associated with an Intravenous dose of l4C-benz1d1ne within 3 days of
treatment.
2.2. INHALATION
Little Information concerning the Inhalation absorption of benzldlne
could be located In the available literature. Absorption by Inhalation can
be Inferred from systemic toxldty and carclnogenlclty observed 1n humans
and animals following Inhalation exposure (see Chapters 3 and 4). Ghettl
(1960) observed unspecified amounts of benzldlne or Its metabolites 1n the
urine of dogs following Inhalation exposure. As reported In an abstract of
a Polish study by Krajewska et al. (1980), the mean annual dose of benzldlne
absorbed by workers was 0.065 mg. Only 10% of the dose was attributable to
Inhalation exposure.
0091h -4- 12/29/86
-------
3. TOXICITY III HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. Frith and Dooley (1976) gave groups of 24 male and 24
fenale 3-week-old Balb/c mice benzldlne dlhydrochlorlde In their drinking
water at levels of 0, 50, ISO, 300 and 500 ppm for 8, 19 and 39 weeks. A
dose-related Increase In the Incidence and severity of mild perlportal
Mbrosls, Infiltration of lymphocytes and deposits of brown pigment
{suggestive of cerold 1n the Hver) was observed presumably at >50 ppm after
8, 19 or 39 weeks.
Boyland et al. (1954) fed groups of 10 female W1star rats diets contain-
ing 0 or 0.017X benzldlne by weight (170 ppm) until a tumor appeared or
death occurred. All treated rats died within 93-224 days: Most of the
treated rats developed fatty degeneration and regeneration of the bile ducts
and fatty degeneration of the liver.
In a study to determine the MTO for long-term cancer studies, a 6-week
dose tolerance test was conducted In which unspecified numbers of male and
female B6C3F1 mice were fed diets containing benzldlne dlhydrochlorlde In
concentrations of 100, 200, 400, 600 and 800 ppm (VesselInovltch et al.,
1975; Rao et al., 1971). A significant dose-related weight loss of 5, 10
and 18% of Initial body weight was observed In males fed 400, 600 and 800
ppm benzldlne dlhydrochlorlde, respectively, by the end of the experiment.
A less pronounced weight loss of 7.5X was observed In females at the highest
dose. A dose-related Increased severity .of hlstopathologlcal lesions which
Included cloudy swelling of the liver, vacuolar degeneration of the renal
tubules and hyperplasla of myelold elements 1n the bone marrow and lymphold
cells 1n the spleen and thymlc cortex were observed but 1t was not clear If
these lesions occurred at all doses.
009Ih -5- 01/05/87
-------
3.1.2. Inhalation. Subchronlc Inhalation toxlclty data could not be
located In the available literature.
3.2. CHRONIC
3.2.1. Oral. Llttlefleld et al. (1983, 1984) gave groups of 72-120 male
mice of two strains and 72-120 female mice of two strains benzldlne dlhydro-
chlorlde 1n drinking water for -33 months (see Table 4-1 for detailed strain
and dose data). Mice of both strains and sexes exhibited a significantly
Increased Incidence of hemoslderosls of the spleen at 120 ppm as compared
with controls. Females of both strains exhibited liver cytologlcal altera-
tions (acldophlUc, basophlUc, vacuolated and mixed cell types) at concen-
trations >20 ppm. Hyperplasla of the bile duct was observed In females of
both strains at concentrations >40 ppm and 1n both strains of males at 160
ppm. Negakaryocytosls of the bone marrow was observed at concentrations >60
ppm In female mice and >120 ppm In male mice. Brain vacuollzatlon was
observed In all treatment groups. Atrophy of the ovary was observed In F,
mice at 30 ppm and In MC mice at >40 ppm. The carcinogenic effects observed
In this study are discussed In Section 4.2.1.
3.2.2. Inhalation. Zabezh1n;k11 (1970) exposed a group of 48 nonlnbred
albino rats of both sexes, weighing 100-120 g, to benzldlne by Inhalation at
a concentration of 10-20 mg/m3 (0.755-1.5 mg/kg/day), 4 hours/day, 5
times/week for up to 28 months. Controls were exposed to "pure air." After
11 months of exposure, liver cirrhosis was observed.
3.3. TERATOGENIC AND OTHER REPRODUCTIVE EFFECTS
Very little Information concerning the teratogenldty of benzldlne was
located. VesselInovltch et al. (1979) observed an Increased Incidence of
hepatocellular carcinomas In the male offspring of female mice maintained on
a diet containing 150 ppm benzldlne dlhydrochlorlde during gestation.
Female offspring were not affected.
0091h -6- 12/29/86
-------
3.4. TOXICANT INTERACTIONS
Data concerning toxicant Interactions could not be located In the
available literature.
0091h -7- 12/29/86
-------
4. CARCINOGENICITY
4.1. HUMAN DATA
4.1.1. Oral. Human oral carclnogenlclty data could not be located In the
available literature.
4.1.2. Inhalation. Zavon et al. (1973) observed 13/25 workers (average
age = 56.5 years) exposed to benzldlne primarily by Inhalation at levels of
<0.005-17.6 mg/m3 for -11.46 years had bladder cancer. Metastases to the
neck and abdomen were noted In two workers; three workers also had four
renal tumors. Eleven of the thirteen cases were attributed to benzldlne
exposure alone. From a mean concentration of -0.035 mg/i benzldlne 1n the
urine of the exposed workers, U.S. EPA (1980a) estimated a mean total
accumulated dose of 130 mg/kg. Several limitations of the study were noted,
Including the absence of controls. The number of tumors expected was not
reported, preventing relative risk from being calculated. (Using "Third
National Cancer Survey: Incidence Data," however, a relative risk of -100
can be estimated.) Smoking and exposure to other chemicals wasv>°t
controlled, but because of the unusually high apparent oncogenlc potency of
benzldlne these may not be major contributing factors (NCI, 1975).
Tsuchlya et al. (1975) observed 72 bladder cancer cases (21 were fatal)
In 1015 benzldlne production and use workers. The Incidence of bladder
cancer 1n production workers was 61/346 (17.6%) and In use workers was
11/669 (1.6X). No control population was Included 1n the study design and
relative risk could not be calculated because the number of tumors expected
was not reported.
Nelgs et al. (1986) conducted a 30-year follow-up study on the Incidence
of bladder tumors among workers In Connecticut exposed to benzldlne. There
was a statistically significant excess of bladder tumors among male cohort
0091h -8- 12/29/86
-------
members which was confined to those males with the highest estimated level
of benzldlne exposure. Exposure was estimated as high, medium or low
according to the length of Individual exposure to benzldlne (>2 years *
high; 6 months to 2 years - medium; <6 months = low). Among the 830 males,
a total of 48 first primary cancers were reported; of these 48, eight cases
of bladder cancer were found. Benzldlne exposure was present In 7 (6 high;
1 medium) of the 8 cases of bladder cancer. No significantly elevated risks
were found for cancers at other anatomic sites 1n men or at any anatomic
site for women; nor was there any pattern of Increasing risk with Increasing
benzldlne exposure for site other than bladder. In addition, the elevated
bladder cancer was greater for men first employed during the earliest years
of the plant, namely, 1945-1949. Smoking histories were available for 21 of
the 48 primary cancers; of the 8 cases of bladder cancer, 3 were long-term
cigarette smokers.
Numerous case reports were cited 1n 'the available literature concerning
the occurrence of bladder cancer 1n dyestuff Industry workers. These
reports provide qualitative evidence of the carcinogenic effect of benzl-
dlne. Several sources that contain reviews of these studies are IARC (1972,
1982), U.S. EPA (1980a,b), ACGIH (1980) and NIOSH (1978). Haley (1975),
Hamilton and Hardy (1974) and Parkes (1976) reviewed the history of
benzldlne-lnduced cancer In humans. Haley (1975) also discussed the Inter-
national dimensions of benzldlne-lnduced cancer. Several early reports came
from Industrial settings 1n which workers were exposed to benzldlne alone.
Aboulker and Smagghe (1953) reported 21 cases of bladder tumors In workers
at a dyestuff plant. In two of these cases, the workers were exposed to
benzldlne alone. Uebelln and Pletscher (1954) observed 100 cases of urinary
tract tumors In Swiss dyestuff workers. Twenty of these workers were
0091h -9- 12/29/86
-------
exposed to benzldlne alone. Duration of exposure was -11.6 years (range.
1-29 years). The mean Induction period was 14.8 years (range 5-29 years).
BllHard-Ouschesne (I960) described 12 bladder cancer cases using workers at
a plant where the only aromatic amlne manufactured was benzldlne. Goldwater
et al. (1965) reported 17 cases of bladder cancer In a population of 76 men
occupational1y exposed to benzldlne only for up to 33 years, and commented
that this Incidence may be deceptively low since many workers quit their
jobs after the first examination. Ferber et al. (1976) reported that 36
cases of bladder tumors occurred 1n workers exposed to benzldlne alone
during the period of 1930-1975.
4.2. BIOASSAYS
4.2.1. Oral. Llttlefleld et al. (1983. 1984) studied the cardnogenlclty
of benzldlne 1n two strains of male and female mice (Table 4-1). Groups of
72-120 male mice of each strain and groups of 72-120 female mice of each
strain were exposed to benzldlne dlhydrochloMde In drinking water for ~33
months. Strain and dosage data and results are presented In Table 4-1. The
Incidence of hepatocellular carcinomas Increased with Increased dose, with
the exception of MC males whose hepatocellular carcinoma Incidence reached a
maximum of 37/71 at 120 ppm and diminished to 32/71 at 160 ppm. Time to
tumor was decreased as demonstrated by F, females (representative of
trends for both strains and sexes) 1n which only a mean of 464 days was
required for tumor formation as compared with 1023 days for controls.
LHtlefleld et al. (1983) also reported treatment-related Increased
Incidences of adenoma of the Harderlan gland and uterine angloma. Since
these Incidences were much lower than those reported for hepatocellular
carcinomas, they will not be considered here.
0091 h -10- 12/29/86
-------
TABLE 4-1
Incidence of Hepatocellular Carcinoma In Two Strains of Nice Given
100% Benzldlne Dlhydrochlorlde In Drinking Water for -33 Months3
Stra1nb
FT
FT
FT
FT
FI
FT
FI
FI
FI
FI
FI
FI
FI
FT
NC
NC
MC
MC
MC
MC
MC
MC
MC
MC
MC
MC
MC
MC
Sex
M
M
M
M
M
M
M
F
F
F
F
F
F
F
M
M
M
M
M
M
M
F
F
F
F
F
F
F
Concentration
(ppra)
0
30
40
60
80
120
T60
0
20
30
40
60
80
120
0
30
40
60
80
T20
T60
0
20
30
40
60
80
120
Corresponding Dose
(mg/kg/day)c
0
3.7
4.7
7.5
9.1
13.7
16.6
0
2.6
4.0
5.2
8.1
11.2
22.3
0
3.5
4.7
7.0
9.4
13.2
16.4
0
2.5
3.8
5.1
7.8
10.0
14.8
Tumor Incidence
(%)
14/T25 (Tl)
24/1T9 (20)
30/96 (31)
23/7T (32)
35/71 (49)
51/71 (72)
49/71 (69)
3/124 (2)
51/120 (43)
52/95 (55)
45/72 (63)
55/71 (77)
60/69 (87)
64/72 (89)
17/123 (14)
20/118 (17)
20/95 (21)
23/72 (32)
24/71 (34)
37/7T (52)
32/7 T (45)
TO/T25 (8)
54/TT9 (45)
43/95 (45)
31/71 (44)
37/72 (51)
51/69 (74)
56/72 (78)
aSource: LHtlefleld et al., 1984
» hybrids from crossing BALB/c males to C57BL females; MC * monohybrld
cross offspring of mating FI females with FT males
C0ose In mg/kg/day calculated from data provided by Investigators
0091 h
-11-
12/29/86
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Frith et al. (1979, 1980) exposed groups of male and female weanling
mice (Table 4-2) to drinking water containing 0, 30, 60, 120, 200 or 400 ppm
benzldlne dlhydrochlorlde for 40, 60 or 80 weeks. Mice that died before 30
weeks (12 females and 22 males) were not Included In the data analysis;
these mice had no liver lesions. The ratio of hepatocellular carcinomas to
adenomas Increased with Increased dose and longer length of administration
1n female mice. The ratio of hepatocellular carcinomas Increased with
Increased length of administration, but not with dose In male mice. Frith
et al. (1980) suggested a sequential morphogenesis from cellular alteration
to adenoma to carcinoma and reported that the Incidence of pulmonary
metastases Increased with Increased length of administration.
Frith and Dooley (1976) gave groups of 24 male and 24 female Balb/c,
3-week-old mice benzldlne dlhydrochlorlde 1n drinking water at levels of 0,
50, 150, 300 and 500 ppm. After 8, 19 and 39 weeks of exposure, groups of
4, 4 and 16 animals of each sex, respectively, were killed for comprehensive
gross and microscopic examination of a wide variety of organs and tissues.
The Incidence of tumors In the 300 and 500 ppm groups at 8 or 19 weeks or 1n
the control, 50 or 100 ppm groups was not reported. Presumably, no tumors
were found 1n these groups at these times. Liver tumors were observed 1n
300 and 500 ppm mice at 39 weeks; the Incidence of tumors was 1/12 and-3/7
In males and 1/9 and 3/12 In females In the 300 and 500 ppm dose groups,
respectively.
In a series of experiments, Vessellnovltch et al. (1975) administered 50
or 100 ppm benzldlne dlhydrochlorlde In ihe diet to groups of 50 male and 50
female B6C3F1 mice for 90 weeks. Presuuably, a control group was maintained
on a diet without benzldlne dlhydrochlorlde, but this was not explicitly
reported. The authors reported that complete autopsies were performed but
0091h -12- 12/29/86
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TABLE 4-2
Incidence of Liver Tumors In a Drinking Water Study
of Pure Benzldlne DlhydrochloMde In H1cea»b
Sex
F
F
F
F
F
F
F
F
F
F
F
F .
F
F
F
F
F
F
N
N
M
N
M
M
M
N
M
M
M
N
Concentration
(ppfli)
0
30
60
120
200
400
0
30
60
120
200
400
0
30
60
120
200
400
0
30
60
120
200
400
0
30
60
120
200
400
Duration of
Treatment
and Study
(weeks)
40
40
40
40
40
40
60
60
60
60
60
60
80
80
80
80
80
80
40
40
40
40
40
40
60
60
60
60
60
60
Tumor Type
adenoma
adenoma
adenoma
adenoma
adenoma
adenoma
adenoma
adenoma
adenoma
adenoma
adenoma
adenoma
adenoma
adenoma
adenoma
adenoma
adenoma
adenoma
adenoma
adenoma
adenoma
adenoma
adenoma
adenoma
adenoma
adenoma
adenoma
adenoma
adenoma
adenoma
Tumor Incidence
(X)
0/96 (0)
2/195 (1)
1/144 (1)
2/100 (2)
7/100 (7)
13/55 (24)
1/96 (1)
7/146 (5)
9/106 (8)
17/114 (15)
15/121 (12)
2/79 (3*
0/95 (0)
9/86 (10)
11/85 (13)
5/69 (7)
1/17 (6)
0/7 (0)
0/99 (3)
0/199 (0)
0/143 (0)
1/100 (1)
2/102 (2)
1/55 (2)
0/96 (0)
2/142 (1)
3/95 (3)
9/98 (9)
6/90 (7)
7/49 (14)
0091 h
-13-
12/29/86
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TABLE 4-2 (cent.)
Sex
M
M
H
N
M
M
F
F
F
F
F
F
F
F
F
F
F
F
F
M
N
N
M
M
M
N
N
M
M
H
M
Concentration
(ppm)
0
30
60
120
200
400
0
30
60
120
200
400
0
30
60
120
200
400
0
30
60
120
200
400
0
30
60
120
200
400
0
30
60
120
200
400
Duration of
Treatment
and Study
(weeks)
80
80
80
80
80
80
40
40
40
40
40
40
60
60
60
60
60
60
80
80
80
80
80
80
40
40
40
40
40
40
60
60
60
60
60
60
Tumor Type
adenoma
adenoma
adenoma
adenoma
adenoma
adenoma
carcinoma
carcinoma
carcinoma
carcinoma
carcinoma
carcinoma
carcinoma
carcinoma
carcinoma
carcinoma
carcinoma
carcinoma
carcinoma
carcinoma
carcinoma
carcinoma
carcinoma
carcinoma
carcinoma
carcinoma
carcinoma
carcinoma
carcinoma
carcinoma
carcinoma
carcinoma
carcinoma
carcinoma
carcinoma
carcinoma
Tumor Incidence
(X)
2/91 (2)
2/85 (2)
6/90 (7)
11/89 (Ti)
5/40 (13)
4/37 (11)
0/96 (0)
0/195 (0)
0/144 (0)
1/100 (1)
4/100 (4)
10/55 (19)
1/96 (1)
3/146 (2)
7/106 (7)
33/114 (29)
86/121 (71)
72/79 (91)
0/95 (0)
12/86 (14)
32/85 (38)
60/69 (87)
15/17 (88)
6/7 (86)
0/99 (0)
1/199 (1)
0/143 {(U
0/100 (0)
1/102 (1)
1/55 (2)
1/96 (1)
1/142 (1)
4/95 (4)
8/98 (9)
11/90 (12)
12/49 (24)
0091 h
-14-
12/29/86
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TABLE 4-2 (cont.)
Sex
M
M
M
M
N
H
Concentration
(ppm)
0
30
60
120
200
400
Duration of
Treatment
and Study
(weeks)
80
80
80
80
80
80
Tumor Type
carcinoma
carcinoma
carcinoma
carcinoma
carcinoma
carcinoma
Tumor Incidence
(X)
0/91 (0)
5/85 (6)
7/90 (8)
16/89 (18)
10/40 (25)
23/37 (62)
aSource: Frith et al., 1979. 1980
bF-| (C57B1 females x Balb/c males) and HC (F] females x F] males)
mice combined. Incidence data for the two strains were combined because
there were no statistical differences between the two strains.
0091 h
-15-
12/29/86
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did not provide sufficient detail for a determination of the adequacy of the
gross and microscopic examination. The HTO was estimated by pretesting the
mice. Vesse11nov1tch et al. (1975) also conducted gavage studies In mice.
Groups of 75 male and 75 female B6C3F1 mice were gavaged twice weekly with
doses of 0.5 or 1.0 mg benzldine/mouse at each Intubation for 90 weeks.
These Intermittent doses were considered to be equivalent to the weekly
Intake of benzldlne dlhydrochloMde by the mice exposed continuously to 50
and 100 ppm 1n the diet (Table 4-3). Higher Incidences of liver tumors and
Harderlan gland tumors were observed In the mice treated continuously In the
diet compared with the mice receiving Intermittent equivalent gavage doses.
The Incidence of lung adenomas, however, was higher In the mice treated by
gavage than In the mice treated by dietary administration.
In addition to the tumors presented In Table 4-3, a marginally Increased
Incidence of lymphoretlcular tumors were observed 1n the treated mice com-
pared with controls. (This was the only mention of controls In the entire
report.) The Incidences In Individual groups were low; therefore, Vessel-
Inovltch et al. (1975) reported the combined Incidences regardless of dose
or sex to be 19/200 (9.5%) for the continuously (diet) exposed mice; 17/300
(5.7%) for the Intermittently (gavage) exposed mice and 4/194 (2.0%) for the
controls.
Gr1swold et al. (1968) exposed groups of twenty 40-day-old female
Sprague-Dawley rats to a total of 12. 25, 35 and 50 mg benzldlne/rat by
garage In sesame oil, given In 10 doses at 3-day Intervals over a SO^day
tieatment period. Controls were dosed with sesame oil alone. The rats were
observed for 9 months before sacrifice. Gross lesions were recorded, and
the pituitary, adrenals, kidneys, spleen and liver were weighed. In addi-
tion to diseased tissues, the mammary. Intestinal tract, pituitary, liver,
0091h -16- 12/29/86
-------
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ovaries and adrenals were prepared for hlstologlcal examination. The 12, 25
and 50 rog dosage group had carcinomas and adenomas of the mammary glands
(Table 4-4). There were no survivors In the 35 mg group at 9 months. The
authors noted spontaneous regression of some of the palpable masses; there-
fore, some tumors were not present at autopsy.
4.2.2. Inhalation. Zabezhlnskll (1970) exposed a group of 48 nonlnbred
albino rats of both sexes, weighing 100-120 g, to benzldlne by Inhalation at
a concentration of 10-20 mg/m3, 4 hours/day, 5 times/week for 28 months.
Control rats were exposed to "pure air." Myelold leukemia developed In five
rat:: after 13, 22, 24, 25 and 28 months of the experiment. Mammary gland
Hbroadenomas occurred 1n 2/28 rats, and mammary gland carcinomas occurred
1n 2/28 rats, one of which was found In a male rat. A hepatoma was observed
In one rat. These tumor types appeared In 8/28 rats; presumably, more than
one tumor type was found In some of the rats. The Incidence of mammary
adenomas In control rats was 2/21.
4.3. OTHER RELEVANT INFORMATION
Several other oral exposure studies were conducted with benzldlne
dlhydrochlorlde 1n mice by VesselInovltch et al. (1975, 1979). Although
Insufficiently reported for consideration In the quantitative estimation of
carcinogenic potential, these reports qualitatively Indicate the carclno-
genlclty of benzldlne. In 84-90 week studies In B6C3F1 mice, dietary levels
of 100-150 ppm and gavage doses of 1.0 mg twice weekly resulted 1n Increased
Incidences of liver carcinoma, Harderlan gland tumors and lung adenomas. In
mice fed a diet containing 150 ppm benzldlne hydrochloMde for 39, 54 or 84
weeks and killed at 90 weeks of age. The Incidence of liver carcinomas at
termination was Inversely related to length of exposure. When mice were fed
0091h -19- 12/29/86
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TABLE 4-4
Incidence of Mammary Gland Tumors In Female Sprague-Dawley Rats
Treated by Gavage With Benz1d1ne (Pure) 1n Sesame 011
for 30 Days and Observed for 9 Months3
Doseb
(rag/rat)
50
35
25
12
0
Tumor Type
carcinoma
no survivors at 9 months
carcinoma
carcinoma, adenoma
carcinoma, adenoma, hyperplasla
Tumor Incidence
(X)
4/5
NA
7/9
5/10
5/132
(80)
(78)
(50)
(4)
QUALITY OF EVIDENCE
Strengths of Study: Several doses were administered by a relevant route of
administration (oral); the MTO was estimated through
pretests.
Weakness of Study: Only female rats of one species were used; dos'ng
occurred at 3-day Intervals over a 30-day period, which
Is a period substantially less than the llfespan of a
rat; hlstopathology was not comprehensive and the data
were not subjected to statistical analysis.
Overall Adequacy: Limited
aSource: GrIswoId et al.. 1968
b!0 doses at 3-day Intervals; dose reported » total dose
NA = Not applicable
0091h -20- 12/29/86
-------
the test diet from 6-45 weeks of age followed by control diet until termina-
tions at 45. 60. 75 or 90 weeks of age, the Incidence of. total liver tumors
Increased with Increasing duration of Hfespan. The author concluded that
"once carclnogenesls has been Initiated, the neoplastlcally-commltted cells
express their malignant character once a sufficient observational period has
been allowed." In experiments with dietary benzldlne dlhydrochlorlde In the
prenatal and adult periods. H appeared that younger animals were jnore
susceptible to a carcinogenic response.
Increased Incidence of hepatomas were observed In ICR/SCL mice fed
dietary benzldlne at 500-100 ppm (Osanal, 1976; Ikuyama et al., 1978). By
varying the amount of forced exercise to which the mice were subjected,
Ikuyama et al. (1978) concluded that exercise decreased the carcinogenic
response.
Other species of animals appear to form other types .of tumors following
oral exposure to benzldlne. Mammary tumors Including carcinomas developed
In male and female rats treated with benzldlne by gavage (Gr Is wold et al.,
1968; Zabezhlnskll, 1967). Cholanglomas as well as hepatomas were Increased
In Syrian golden hamsters exposed to benzldlne or benzldlne dlhydrochlorlde
for life {Safflottl et al., 1967; Sellakumar et al., 1969).
Numerous Intraperltoneal, Intramuscular and subcutaneous studies yield-
Ing positive results were summarized 1n U.S. EPA (1980a, 1986a). Benzldlne
has been widely studied for mutagenldty and genotoxlclty In bacterial and
yeast systems. In cultured mammalian cell systems and 1n rodents in vivo.
and results were generally positive. It Is beyond the scope of this
document to review these studies here.
0091IH -21- 12/29/86
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4.4. HEIGHT OF EVIDENCE
The evidence that benzldlne Is carcinogenic to humans and animals 1s
overwhelming. Numerous epldemlologlcal studies and case reports have demon-
strated that benzldlne Is a human carcinogen (Zavon et al., 1973; Tsuchlya
et al., 1975; U.S. EPA, 1986a). These data provided sufficient evidence to
support a causal connection between exposure to benzldlne and bladder
cancer. In addition, the oral exposure of rats and mice to benzldlne
dlhydrochlorlde Induced liver and Harder1an gland tumors and uterine
anglomas (LHtlefleld et al., 1983; Firth et al., 1979, 1980; Vessel1nov1tch
et al., 1975). According to U.S. EPA Guidelines for Carcinogenic Risk
Assessment (U.S. EPA, 1986b) benzldlne Is a Group A human carcinogen.
0091h -22- 04/29/87
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5. REGULATORY STANDARDS AND CRITERIA
Many agencies, administrations and organizations consider benzldlne a
carcinogen (OSHA, 1984; ACGIH, 1986; NIOSH, 1978; U.S. EPA. 1980a, 1986a).
Absorption through the skin contributes to the overall exposure to the
chemical (ACGIH, 1986); therefore. ACGIH (1986) recommended no exposure to
or contact with benzldlne by any route. U.S. EPA (1980a) recommended zero
exposure to benzldlne based on the nonthreshold assumption, and has
suggested criteria of 1.2. 0.12 and 0.01 ng/i corresponding to Incremental
Increased lifetime cancer risks of 10-5, 10-* and 10-7, respectively.
These criteria were based on the excess cancer risk to humans exposed to
benzldlne In the work place as estimated from the data by Zavon et al.
(1973).
0091 h -23- 12/29/86
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6. RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfDs)
6.1.1. Oral (RfDgg). Benzldlne Is a human bladder carcinogen (Zavon et
al., 1973; Tsuchlya et al., 1975; U.S. EPA, 1986a); therefore, H Is
Inappropriate to derive an RfDso-
6.1.2. Inhalation (RfD,.,). Benzldlne Is a human bladder carcinogen
(Zavon et al., 1973; Tsuchlya et al., 1975; U.S. EPA, 1986a); therefore, H
1s Inappropriate to derive an RfDSI-
6.2. REFERENCE DOSE (RfO)
6.2.1. Oral (RfDQ). Benzldlne Is a human bladder carcinogen (Zavon et
al., 1973; Tsuchlya et al., 1975; U.S. EPA, 1986a); therefore, H 1s
Inappropriate to derive an RfDQ.
6.2.2. Inhalation (RfD,). Benzldlne 1s a human bladder carcinogen
(Zavon et al., 1973; Tsuchlya et al., 1975; U.S. EPA, 1986a); therefore, H
1s Inappropriate to.derive an RfD,.
6.3. CARCINOGENIC POTENCY (q^)
6.3.1. Oral. U.S. EPA (1980a) derived and U.S. EPA (1986a) recommended
as an Interim value a potency factor (B) of 234.13 (mg/kg/day)"1 based on
the study by Zavon et al. (1973) 1n which 13/25 workers exposed to benzldlne
by Inhalation developed bladder cancer. U.S. EPA (1980a) calculated the
potency factor (B) by estimating that Increased cancer Incidence with age
(-Bd ) varied by the third power of age. For bladder cancer, however, the
rate may Increase with the sixth power of age (U.S. EPA, 1986a); thus, the
q,* If recalculated may be approximately double (U.S. EPA. 1986a). U.S.
EPA (1986a) considered this limitation and uncertainties related to exposure
estimates sufficient to warrant revaluation and possibly development of a
new quantitative risk estimate for benzldlne.
0091h -24- 05/07/87
-------
6.3.2. Inhalation. The occupational study by Zavon et al. (1973). which
served as the basis for an estimate of carcinogenic potency by the oral
route (U.S. EPA. 1980a), may also be used to estimate a carcinogenic potency
for Inhalation exposure. In the derivation of carcinogenic potency for oral
exposure, an absorbed dose of 0.0473 mg/kg/workday, was estimated based on
the level of benzldlne recovered from the urine of the exposed workers.
This estimate was based on a value for benzldlne In the urine of 0.04 mg/i
at the end of the workday. It was assumed that humans weigh 70 kg, produce
1.2 l of urine/day and eliminate 1.45% of the absorbed benzldlne as
unchanged compound 1n the urine (Rhlnde and Troll, 1974).
Zavon et al. (1973) measured concentrations of benrldlne 1n workroom air
and found levels from <0.005-17.6 mg/m3, depending on the work station
evaluated. It was Impossible to estimate a mean exposure level, however,
because how long each Individual remained at each work station or how the
.duties at the various work stations were shared or delegated among the
workers were not reported. Assuming an Inhalation absorption factor of 0.5,
an Inhalation "dose" of 0.0946 mg/kg/workday can be estimated by dividing
the estimated equivalent absorbed dose of 0.0473 mg/kg/workday by 0.5. To
estimate an equivalent absorbed dose, U.S. EPA (1980a) assumed that 240
days/year are worked and that exposure averaged 11.46 years, with an average
age of 56.5 years at the end of a 13-year postexposure observation period.
Applying these assumptions to the estimated Inhalation dose of 0.0946 mg/kg/
workday results In a TWA estimated lifetime exposure of 0.0126 mg/kg/day, as
follows:
0.0946 x 240/365 x 11.46/56.5 = 0.0126 mg/kg/day.
0091 h -25- 12/29/86
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A carcinogenic potency for Inhalation exposure to benzldlne can be
estimated by using the model P * l-exp[-8dt3], which rearranged yields the
following: B=[-ln(l-13/25J]/[0.0126 x (56.5/70.O)3], where 13/25 1s the
Incidence of bladder cancer 1n exposed workers, 0.0126 mg/kg/day Is the
estimated average lifetime exposure to benzldlne, 56.5 years 1s the average
age of workers at the end of the 13-year observation period and 70.0 years
1s the reference human "Hfespan. The estimate of carcinogenic potency by
Inhalation exposure (B) Is 111 (mg/kg/day)-1.
0091h -26- 12/29/86
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7. REFERENCES
ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1986.
Documentation of the Threshold Limit Values, 5th ed. Cincinnati, OH. p. 53.
Aboulker, P. and G. Snagghe. 1953. Bladder tumors In dyestuff workers (21
observations). Importance of systemic screening and choice of methods.
Arch,. Hal. Prof. 14: 380-386. (Fre.)
Atkinson. R. 1985. Kinetics and mechanisms of the gas phase reactions of
the hydroxyl radical with organic compounds under atmospheric conditions.
Chera., Rev. 85: 170-171.
Bllltird-Dachesne, J.L. 1960. French cases of occupational tumours of the
bladder. Statistics-remarks. Acta. Unlo. Int. Cancrum. 16: 284-288.
Boylcind, E., J. Harris and E.S. Horning. 1954. The Induction of carcinoma
of the bladder In rats with acetamldofluorene. Br. J. Can. 18: 647-654.
Callcihan, M.A., H.W. Sllmak, N.M. Gabel, et al. 1979. Water-related
Environmental Fate of 129 Priority Pollutants. Vol. II. EPA 440/4-9-029b.
U.S. EPA. Washington. DC. p. 508.
Feber, K.H. 1978. Benzldlne and blphenylamlnes. In.: Klrk-Othmer Encyclo-
pedia of Chemical Technology, Vol. 3. 3rd. ed.. M. Grayson and D. Eckroth,
Ed. John Wiley and Sons, Inc.. New York. p. 772-777.
0091 h -27- 01/05/87
-------
Frith, C.H. and K. Dooley. 1976. Brief Communication: Hepatic cytologlc
and neoplastlc changes In nice given benzldlne dlhydrochlorlde. J. Natl.
Cancer Inst. 56: 679-682.
Frith, C.H,, K.P. Baetcke, C.J. Nelson and G. Schlefersteln. 1979.
Importance of the mouse liver tumor In cardnogenesls bloassay studies using
benzldlne dlhydrochlorlde as a mode. Toxlcol. Lett. 4(6): 507-518.
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*
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°
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