TECHNICAL REPORT DATA
fffttte retd Instructions on the rrvtnt btfort completing)
i. REPORT NO.
EPA/600/8-38/051
a.
3. RECIPIENTS ACCESSION NO
PB88-178959
4. TITLE AND SUBTITLE
Health Effects Assessment for N-Nitrosodiphenylamine
6. REPORT DATE
6. PERFORMING ORGANIZATION CODE
7. AUTHOR(S)
I. PERFORMING ORGANIZATION REPORT NO.
9. PERFORMING ORGANIZATION NAME ANO ADDRESS
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO.
12. SPONSORING AGENCY NAME ANO ADDRESS
Environmental Criteria and Assessment Office
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati. OH 45268
13. TYPE OF REPORT ANO PERIOD COVE BED
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 12991 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 AND DOCUMENT ANALYSIS
DESCRIPTORS
b,IDENTIFIERS/OPEN ENDED TERMS C. COSATI Field/Group
18. DISTRIBUTION STATEMENT
19. SECURITY CLASS (Thu Report/
21. NO. OF PAGES
Public
20. SECURITY CLASS (This page I
Unclassified
22- PRICE
EPA form 2220-1 (R«*. 4-77) PREVIOUS COITION is OMOLCTC
-------
EPA/600/8-88/051
May, 1987'
HEALTH EFFECTS ASSESSMENT
FOR N-NITROSODIPHENYLAMINE
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
CINCINNATI. OH 45268
-------
DISCLAIMER
This document has been reviewed 1n 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 N-n1troso-
dlphenylamlne. 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 toxicologic and
environmental data were located through on-line literature searches of the
TOXLINE, CANCERLINE and the CHEMFATE/DATALOG data bases. The basic litera-
ture searched supporting this document 1s current up to October, 1985.
Secondary sources of Information have also been relied upon In the prepara-
tion of this report and represent large-scale health assessment efforts that
entail extensive peer and Agency review. The following Office of Health ad
Environmental Assessment (OHEA) sources have been extensively utilized:
U.S. EPA. 1980a. Ambient Water Quality Criteria Document for
NHrosamlnes. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincin-
nati, OH for the Office of Water Regulations and Standards, Wash-
ington, DC. EPA 440/5-80-064. NTIS PB81-117756.
U.S. EPA. 1986a. Health and Environmental Effects Profile for
NHrosamlnes. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincin-
nati, 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 In
scope, which tended to generate conservative (I.e., protective) estimates.
Nevertheless, the Interim values presented reflect the relative degree of
hazard associated with exposure or risk to the chemlcal(s) addressed.
Whenever possible, two categories of values have been estimated for
systemic toxicants (toxicants for which cancer Is not the endpolnt of
concern). The first, RfD$ (formerly AIS) or subchronlc 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 (I.e., for an
Interval that does not constitute a significant portion of the Hfespan).
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 1n 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$i) and oral (RfD$o)
exposures.
111
-------
The RfO (formerly AIC) 1s similar In concept and addresses chronic
exposure. It 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 llfespan [see U.S. EPA (1980b) for a discussion of Jhls concept]. The
RfD 1s route-specific and estimates acceptable exposure for either oral
(RfDg) or Inhalation (RfDj) with the Implicit assumption that exposure
by other routes Is 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 1s explained 1n U.S.
EPA (1983).
For compounds for which there 1s sufficient evidence of cardnogenldty
RfD$ and RfD values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980b). Since cancer Is a
process that 1s not characterized by a threshold, any exposure contributes
an Increment of risk. For carcinogens, q-|*s have been computed, 1f appro-
priate, based on oral and Inhalation data If available.
1v
-------
ABSTRACT
In order to place the risk assessment evaluation 1'n 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.
N-N1trosod1phenylam1ne administered to F344 rats In their diets for 100
weeks caused a significant Increase 1n the Incidence of bladder transitional
cell carcinoma In both male and female rats (NCI, 1979). Using data from
female rats, a human q-|* of 4.92xlO~3 (mg/kg/day)'1 was calculated
(U.S. EPA, 1980a).
No data concerning the potential cardnogenldty of N-n1trosod1phenyl-
amlne by Inhalation exposure were located 1n the available literature;
therefore, an Inhalation q-|* was not calculated.
-------
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. Or. Christopher DeRosa and Karen
Blackburn were the Technical Project Monitors and John Helms (Office of
Toxic Substances) was the Project Officer. The final documents In 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 A1r 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.
7.
iPPE
ENVIRONMENTAL CHEMISTRY AND FATE '. . .
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . .
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
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
4.2. 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) AND REFERENCE
DOSE (RfO)
6.2. CARCINOGENIC POTENCY (q-)*)
6.2.1. Oral
6.2.2. Inhalation
REFERENCES
NDIX
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6
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7
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12
13
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V11
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LIST OF ABBREVIATIONS
CAS Chemical Abstract Service
OMSO Dimethyl sulfoxlde
ONA Deoxyrlbonuclelc acid
Koc Soil sorptlon coefficient
MTD Maximum tolerated dose
NOEL No-observed-effect level
ppm Parts per million
RfD Reference dose
RfOg Subchronlc reference dose
TWA Time-weighted-average
-------
1. ENVIRONMENTAL CHEMISTRY AND FATE
Selected chemical and physical properties and environmental fate of
4
N-n1trosod1phenylam1ne are presented 1n Table 1-1.
In the atmosphere, N-n1trosod1phenylam1ne 1s expected to undergo rapid
photolytlc transformation. The atmospheric half-life of this compound 1s
estimated to be <1 day based on estimated photolysis half-lives ranging from
-5-30 minutes for n1trosod1methylam1ne to several hours for N-nltrosodl-
methyl-, N-n1trosod1ethyl and N-n1trosod1-n-propylam1ne (CupHt, 1980; Hanst
et al., 1977; Tuazon et al., 1984; Grosjean et al., 1978; Crosby et al.,
1980).
In water, N-n1trosod1phenylam1ne Is probably removed by photochemical
transformation and volatilization. The half-life 1n water listed 1n Table
1-1 1s the volatilization half-life from water 1 m deep. This value was
calculated based on an estimated Henry's Law constant of 6.4xlO~*
atm-mVmol at 25°C using the method of Lyman et al. (1982). Relatively
rapid photolysis of other nltrosamlnes 1n aquatic solutions (Polo and Chow,
1976; Burns and AlHston, 1971) suggests that photolysis of N-n1trosod1-
phenylamlne would be a competitive removal process. An estimated K
value of 1202 suggests that N-nltrosodlphenylamlne would adsorb signifi-
cantly to suspended solids and sediments. B1oaccumulat1on 1n aquatic
organisms should not be significant. The soil half-life listed 1n Table 1-1
Is based on a study by Malllk and Tesfal (1981) 1n which 68% removal of 354
tig N-n1trosod1phenylam1ne/g unamended soil occurred in 30 days and
complete removal In amended soil (17.5% organic matter content) occurred 1n
10 days. Since the experiments were performed In the absence of sunlight,
the effect of photolysis was not determined. The estimated K value
oc
suggests that N-nUrosod1phenylam1ne has low mobility In soil (Swann et al.,
1983)..
0076h -1- 10/30/86
-------
TABLE 1-1
Selected Chemical and Physical Properties and
Environmental Fate of N-NHrosod1phenylam1ne
Property
Value
Reference
CAS number:
Chemical class:
Molecular weight:
Vapor pressure:
at 25°C
Water solubility:
at 25°C
Log octanol/water
partition coefficient:
Bloaccumulatlon factor:
Soil adsorption
coefficient:
Half-lives 1n
A1r:
Water:
Soil:
86-30-6
aromatic nltrosamlne
198.22
0.1 mm Hg
40 mg/l
3.13
217, blueglll
sunflsh (Lepomls
macrochlrus)
1202 (estimated)
<1 day (estimated)
11 hours (estimated)
<22 days
Mabey et al., 1981
Mabey et al., 1981
Hansch and Leo, 1985
Barrows et al., 1980
Lyman et al., 1982
Lyman et al., 1982
MalUk and Tesfal, 1981
0076h
-2-
10/30/86
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
Pertinent quantitative data regarding the absorption of N-n1trosod1-
phenylamlne by either the oral or Inhalation routes of exposure could not be
located 1n the available literature. It can be Inferred from systemic toxic
effects observed after oral exposure that N-n1trosod1phenylam1ne Is absorbed
by the gastrointestinal tract. No Inhalation studies were located.
0076h -3- 08/15/86
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. NCI (1979) performed subchronlc dietary studies with groups
of five male and five female F344 rats and equal numbers of B6C3F1 mice 1n
order to determine the MTD for the chronic carclnogenldty experiment.
These subchronlc studies lasted 11 weeks for male rats and 8 weeks for
female rats, male mice and female mice. Parameters of tox1c1ty evaluated
were survival, body weight, gross appearance at necropsy and a limited
hlstopathologlcal examination of unspecified organs and tissues. Male rats
were fed diets containing 1000-10,000 ppm n-n1trosod1phenylam1ne and female
rats were fed diets containing 4000-46,000 ppm. All male rats survived and
body weights at termination were depressed >10X, relative to controls at
>4000 ppm. In female rats, diets >16,000 ppm resulted 1n mortality, and
terminal body weight depression >10X was observed at 4000 ppm, the lowest
dietary concentration tested.
In the first of two 8-week studies using mice, both sexes were fed diets
containing 3160-14,700 ppm N-n1trosod1phenylam1ne (NCI, 1979). All mice
survived and body weights appeared to be unaffected. In the second experi-
ment, male mice received diets containing 4250-22,000 ppm and female mice
received diets containing 22,000-46,000 ppm; all mice survived. The
threshold for a 10% depression In terminal body weight relative to controls
appeared to be at 9500-15,000 ppm for male mice and 46,000 ppm, the highest
dietary concentration tested, for female mice. Gross examination at
necropsy revealed no abnormalities In either species. The only hlstopatho-
loglcal lesion observed was a trace of pigmentation In the Kupffer cells In
the livers of female mice at 46,000 ppm.
0076h -4- 10/30/86
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3.1.2. Inhalation. No pertinent data regarding the subchronlc Inhalation
toxldty of N-n1trosod1phenylam1ne were located 1n the available literature.
3.2. CHRONIC
3.2.1. Oral. NCI (1979) reported the chronic effects of N-n1trosod1-
phenylamlne (98X pure) 1n rats and mice 1n a cardnogenlclty experiment.
Groups of 50 male and 50 female 6-week-old F344 rats and 50 male and 50
female 6-week-old B6C3F1 mice were fed N-n1trosod1phenylamine In their
diets. Rats were fed 1000 or 4000 ppm of the compound 1n their diet for 100
weeks and male mice were fed diets containing 10,000 or 20,000 ppm for 101
weeks. Female mice were started on diets containing 5000 or 10,000 ppm, but
at 38 weeks, because of excessive depression of mean weight gain, treatment
was discontinued for 3 weeks and dietary concentrations were changed to 1000
or 4000 ppm for 60 weeks. The TWA dietary concentrations for the low- and
high-dose female mice were 2475 and 6139 ppm, respectively. Controls
consisted of 20 rats/sex and 20 mice/sex that were given untreated diets.
The chronic effects observed 1n rats were higher Incidences of cornea!
opacity In high-dose males (15/50) and low-dose females (15/50) than 1n
corresponding control groups (males 0/20; females 1/20). Epithelial hyper-
plasla of the bladder was also observed In treated rats but not 1n controls
[male, 0/19 (control), 2/46, 6/45; female, 0/18 (control), 4/48, 7/49]. In
mice, submucosal Inflammation of the urinary bladder was observed In treated
groups of both sexes. Incidences In the control, low-dose and high-dose
groups were 0/18, 12/49 and 31/48, respectively, 1n males and 0/20, 31/49
and 30/38, respectively, 1n females. Epithelial hyperplasla of the bladder
also occurred at low Incidences In treated mice [male, 0/20 (control), 2/49,
7/46; female, 0/18 (control). 3/47, 5/38].
0076h -5- 08/15/86
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3.2.2. Inhalation. No pertinent data regarding chronic effects of
N-n1trosod1phenylam1ne following Inhalation exposure were located--In the
available literature.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
Pertinent data regarding teratogenldty and other reproductive effects
of N-n1trosod1phenylam1ne following oral or Inhalation exposure could not be
located 1n the available literature.
3.4. TOXICANT INTERACTIONS
Pertinent data regarding the Interaction of N-n1trosod1phenylam1ne with
other toxicants could not be located 1n the available literature.
0076h -6- 08/15/86
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4. CARCINOGENICITY
4.1. HUNAN DATA
«
Pertinent data regarding the carcinogenic potential of N-n1trosod1-
phenylamlne by either the oral or Inhalation routes of exposure could not be
located 1n the available literature.
4.2. BIOASSAYS
4.2.1. Oral. In the NCI (1979) study, groups of fifty 6-week-old F344
rats/sex were fed diets containing 1000 or 4000 ppm N-n1trosod1phenylam1ne
for 100 weeks. Groups of fifty 6-week-old 86C3F1 male mice were fed diets
containing 10,000 or 20,000 ppm of the compound, while groups of 50 female
mice were fed diets containing a THA concentrations of 2475 or 6139 ppm (see
Section 3.2.1.) for 101 weeks. Matched controls consisted of 20 rats/sex
and 20 mice/sex given untreated diets. Comprehensive pathological examina-
tions were conducted on all moribund animals, survivors and animals that
died during the study, unless precluded by autolysls or cann1ba!1zat1on.
All treated mice had decreased body weight gain, but mortality was not
significantly affected by treatment. Tumor Incidences and types of tumors
1n treated mice were similar to those of controls. Submucosal Inflammation
and epithelial hyperplasla of the bladder occurred In treated mice of both
sexes (see Section 3.2.).
Compared with the corresponding controls, all treated groups of male and
female rats showed lower mean body weights, which were dose-related 1n males
throughout the experiment and became dose-related for females between weeks
40 and 68 (body weights were not recorded during this period). Mortality
was dose-related 1n female rats (p=0.024) but not 1n males. At termination,
survival substantially below "hat of controls occurred only In high-dose
females. In both sexes of rats, a statistically Increased Incidence
0076h -7- 10/30/86
-------
(p<0.001) of transitional cell carcinoma of the urinary bladder was observed
1n the high-dose group. Incidences are presented 1n Table 4-1. Flbromas of
the Integumentary system also occurred 1n male rats at Incidences (1/19,
1/46 and 10/45 In control, low- and high-dose males, respectively) that were
dose-related (p<0.003), but not significantly higher than those 1n the
control group. When compared with historical controls from the same
laboratory that have an Incidence of Integumentary system flbromas of 6/285,
these results suggest an association of the flbromas with treatment.
Other carclnogenldty bloassays of N-n1trosod1phenylam1ne have not shown
statistically significant Increases 1n tumor Incidences. Druckrey et al.
(1967) gave N-n1trosod1phenylam1ne to 20 BD rats of unspecified sex In
drinking water at a dally dose of 120 mg/kg (total dose 65 g/kg). No tumors
were observed within 700 days. Additional details were not available.
Argus and Hoch-L1get1 (1961) treated 25 male Wlstar rats by gavage with
1.07 mg N-n1trosod1phenylam1ne In 1 ml of 1% aqueous methylcellulose, 5
days/week for 45 weeks (244 mg/rat = total dose). The rats were killed at
53 weeks. No tumors were observed In any rats by gross or hlstologlcal
examination. The dose given may have been too low to Induce tumors within
the observation period.
BRL (1968) and Innes et al. (1969) studied the potential carclnogenldty
of N-n1trosod1phenylam1ne 1n B6C3F1 and B6AKF1 mice. Commercial grade
N-n1trosod1phenylam1ne was given to groups of 18 mice/sex/strain dally by
gavage at 1000 mg/kg from 7-28 days of age, followed by 3769 ppm In the diet
until 81 weeks (B63CF1 mice) and 83 weeks (B6AKF1 mice) of age. At the end
of the treatment period, 12 male and 15 female B6C3F1 mice and 18 male and
17 female B6AKF1 mice had survived. Pathological and hlstologlcal examina-
tions were conducted on selected tissues (chest contents, Hver, spleen,
0076h . -8- 08/15/86
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TABLE 4-1
Carcinogenic Potency of N-N1trosod1phenylam1ne (98% pure)
Administered In the Diet to F344 Rats3
Sex
M
M
H
F
F
F
Dose
(ppm)
0
1000
4000
0
1000
4000
Duration of
Treatment
(weeks)
100
100
100
100
100
100
Duration
of Study
(weeks )
100
100
100
100
100
100
Target
bladder
bladder
bladder
bladder
bladder
bladder
Tumor Type
transitional
cell carcinoma
transitional
cell carcinoma
transitional
cell carcinoma
transitional
cell carcinoma
transitional
cell carcinoma
transitional
cell carcinoma
Tumor
Incidence
(p value)
0/19
(p<0.001)b
0/46
(NS)
16/45
(p<=0.001)c
0/18
(p<0.001)b
0/48
(NS)
40/49
(p<0.001)c
aSource: NCI, 1979
bCochran-Armltage Test for linear trend
C0ne-ta1led Fisher Exact Test
NS = Mot statistically significant
0076h
-9-
10/30/86
-------
kidneys, adrenals, stomach, Intestines and genitals) of survivors. No
statistically significant (p<0.05) Increases 1n tumor. Incidences were
observed In the treated groups.
The lack of evidence of carclnogenldty In gavage and drinking water
studies may be the result of differences 1n the method of oral exposure,
dose, duration of treatment or length of observation period. NCI (1979)
noted that the actual mechanism of bladder tumor Induction 1s not known, but
that one possible mechanism Is by the nltrosatlon of amines 1n food.
4.2.2. Inhalation. Pertinent data regarding the carcinogenic potential
of N-n1trosod1phenylam1ne following Inhalation exposure could not be located
In the available literature.
4.3. OTHER RELEVANT DATA
In a sk1n-pa1nt1ng study by Iversen (1980), groups of 16 male and 24
female hairless hr/hr Oslo strain mice were treated 1n the Intrascapular
region with single weekly applications of 0.1 ml of a 1% solution of
N-n1trosod1phenylam1ne for 20 weeks. Mice surviving 80 weeks (14 males, 21
females) were necropsled, but the necropsy Included only palpable lesions
and hlstologlcal examinations of the lungs. The only tumors observed were
lung adenomas In three males. Control groups were not used 1n this study,
although the author Indicated that lung adenomas 1n the past were observed
In dermal studies only after treatment with known carcinogens.
BRL (1968) Injected groups of 18 B6C3F1 and B6AKF1 mice of each sex
subcutaneously with N-n1trod1phenylam1ne In DMSO. Mice were Injected In the
nape of the neck with a single dose (1000 mg/kg) at -28 days of age and were
observed for -18 months. Pathological and hlstologlcal examinations were
conducted on selected tissues (chest contents, liver, spleen, kidneys,
adrenals, stomach, Intestines and genitals) of survivors. The Incidence of
0076h -10- 08/15/86
-------
retlculum cell sarcoma In male B6C3F1 treated mice was significantly
Increased (4/16 vs. 0/24 1n the vehicle-treated control group). Increased
Incidences of retlculum cell sarcoma were not observed 1n female mice of
either strain.
Boyland et al. (1968) gave groups of 24 male CB rats (6-7 weeks of age)
weekly Intraperltoneal Injections of 2.5 mg N-n1trosod1phenylam1ne In
polyethylene glycol 400, or vehicle only, for 6 months. Treatment-related
tumors were not observed 1n the 5 treated and 10 control rats that survived
18-24 months.
N-N1trosod1phenylam1ne has been found to be negative 1n numerous muta-
genldty screening assays. IARC (1982) reviewed these studies and reported
that N-n1trosod1phenylam1ne was negative 1n reverse/forward mutation repair
assays In bacteria (E.. coll. S. typhlmuMum) strains TA98, TA100, TA1535,
TA1536, TA1537, TA1538, G46, C3076 and D3052), gene mutation and recomblno-
genlclty assays In yeast and mutation assays with mouse lymphoma
L5178Y/TK+/- cells and Chinese hamster V79 and ovary cells. N-N1trosod1-
phenylamlne was also negative for sex-linked recessive lethal mutations 1n
D. melanoqanter (Vogel et al., 1981), chromosomal aberrations In rat liver
cells in vitro (Dean, 1981), sister chromatld exchange In Chinese hamster
cells (Neal and Probst, 1983) and 1n mlcronucleus assays (Salamone et al.,
1981).
N-NHrosod1phenylam1ne tested positive In several ^n vitro assays with
the yeast S. cerevlslae. Including a reversion assay 1n strain XV185-14C,
DNA repair assay In red mutant strain and 1n a test for mltotlc aneuploldy
1n strain D6 (deSerres and Hoffman, 1981). The compound was also positive
1n unscheduled ONA synthesis In rat hepatocytes (Althaus et al., 1982) and
alkaline elutlon tests also using rat hepatocytes (S1na et al., 1983).
0076h -11- 10/30/86
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Results In various cell transformation tests In mammalian systems were.some-
what contradictory. Transformations In Syrian hamster embryo cells (-Plenta
4
and Kawalek, 1981), In BHK cells (Daniel and Dehnell, 1981) and F344 rat
embryo cells Infected with Rauscher muMne leukemia virus (Dunkel et al.,
1981) were Induced by N-n1trosod1phenylam1ne. Styles (1981) and Dunkel et
al. (1981), however, did not observe N-n1trosod1phenylam1ne-1nduced trans-
formations 1n BHK cells, Srylan hamster embryo cells or Balb/373 cells.
4.4. WEIGHT OF EVIDENCE
Although drinking water and gavage studies of N-n1trosod1phenylam1ne
(see Section 4.3.) have not demonstrated a carcinogenic effect, a signifi-
cant Increase In bladder transitional cell carcinoma was observed In F344
rats fed N-n1trosod1phenylam1ne In their diets (NCI, 1979). In the NCI
(1979) study, groups of 50 F344 rats of each sex were fed 0, 1000 or 4000
ppm N-n1trosod1phenylam1ne In their diets for 100 weeks. The significant
Increase 1n bladder transitional cell carcinoma was observed 1n both sexes.
The evidence that N-n1trosod1phenylam1ne 1s carcinogenic In rats
combined with a structure-activity relationship with other carcinogenic
nltroso compounds Is sufficient to classify the compound In IARC Group 2B,
sufficient evidence for carclnogenUKy In experimental animals, and place
It 1n EPA Group B2 (U.S. EPA, 1986b).
0076h -12- 12/04/86
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5. REGULATORY STANDARDS AND CRITERIA
No occupational guidelines or standards for N-n1trosod1phenylam1ne are
available from ACGIH, NIOSH or OSHA.
U.S. EPA (1980a) derived an ambient water quality criterion of 49
vg/l for N-n1trosod1phenylam1ne, based on a q * of 4.92xlO~3
{mg/kg/day)'1. This estimate of carcinogenic potency was based on the
Incidence of transitional cell carcinomas In the bladders of female rats In
the NCI (1979) cancer study. The criterion 1s based on the level In water
with consumption of 2 I of water and 6.5 g of fish and shellfish asso-
ciated with an excess cancer risk of 10~5.
0076h -13- 08/15/86
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6. RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfOc) AND REFERENCE DOSE (RfO)
^ • •
N-NHrosod1phenylam1ne has been shown to be a carcinogen In rats (NCI,
1979); therefore, no RfD or RfO$ will be calculated.
6.2. CARCINOGENIC POTENCY (q^)
6.2.1. Oral. In the NCI (1979) bloassay, male and female F344 rats fed
N-n1trosod1phenylam1ne In the diet showed significantly Increased Incidences
of bladder transitional cell carcinoma. The U.S. EPA (1980a) used the
Incidence of bladder carcinoma In females to calculate a human q * of
4.92xlO~3 (mg/kg/day)"1 for N-n1trosod1phenylam1ne. The data used In
the derivation of this q * are presented 1n Table 6-1.
6.2.2. Inhalation. Pertinent data regarding the carcinogenic potential
of N-n1trosod1phenylam1ne following Inhalation exposure could not be
located; therefore, an Inhalation q * will not be derived.
0076h -14- 05/14/87
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TABLE 6-1
Cancer Data Sheet for Derivation of q-|*
for N-NHrosod1phenylam1ne
Compound: N-N1trosod1phenylam1ne
Reference: NCI, 1979
Specles/Straln/Sex: rat/F344/female
Route/vehicle: oral, diet
Length of exposure (le): 700 days
Length of experiment (Le): 700 days
Llf.espan of animal (L): 700 days
Body weight = 0.250 kg
Tumor type and site: bladder, transitional cell carcinoma
Dose
(mg/kg/day)
0
50
200
Incidence
No. Responding/No.
0/18
0/48
40/49
Tested
Human q-|* = 4.92xlO~3 (mg/kg/day)'1 derived by U.S. EPA (1980a) using
linearized multistage model adopted by U.S. EPA (1980b).
0076h -15- 08/15/86
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7. REFERENCES
*
Althaus, F.R., S.D. Lawrence, G.L. Sattler, D.G. Longfellow and H.C. PHot.
1982. Chemical quantification of unscheduled ONA synthesis In cultured
hepatocytes as an assay for the rapid screening of potential chemical
carcinogens. Cancer Res. 42(8): 3010-3015.
Argus, M.F. and C. Hoch-L1get1. 1961. Comparative study of the carcino-
genic activity of nltrosamlnes. J. Natl. Cancer Inst. 27: 695-709.
Barrows, M.E., S.R. Petrocelll, K.J. Macek and J..J. Carroll. 1980. Blocon-
centratlon and elimination of selected water pollutants by blueglll sunflsh
(Lepomls macrochlrus). lr\: Pap. Symp. Dyn. Exposure Hazard Assess. Toxic
Chem., 1978, Ann Arbor, HI. p. 379-392.
Boyland, D., R.L. Carter, J.H. Gorrod and F.J.C. Roe. 1968. Carcinogenic
properties of certain rubber additives. Eur. J. Cancer. 4(2): 223-239.
BRL (B1onet1cs Research Laboratory). 1968. Evaluation of Carcinogenic,
Teratogenlc and Mutagenlc Activities of Selected Pesticides and Industrial
Chemicals. Vol. 1. Carcinogenic study. NTIS PB 223-159.
Burns, D.T. and G.V. AlHston. 1971. Photolytlc decomposition stage In the
estimation of N-n1trosam1nes. J. Food Technol. 6(4): 433-438. (CA
76:71089r)
0076h -16- 08/15/86
-------
Crosby, D.G., 3.R. Humphrey and K.W. Mollanen. 1980. The photodecqmposl-
tlon of dlpropylnUrosamlne vapor. Chemosphere. 9: 51-54.
«
CupHt, L.T. 1980. Fate of Toxic and Hazardous Materials In the A1r
Environment. U.S. EPA, Research Triangle Park, NC. EPA 600/3-90-084.
Daniel, M.R. and J.N. Dehnell. 1981. Cell transformation test with baby
hamster kidney cells. Prog. Mutat. Res. 1: 626-637.
Dean, B.J. 1981. Activity of 27 coded compounds 1n the RL, chromosome
assay. Prog. Mutat. Res. 1: 570-579.
deSerres, F.J. and G.R. Hoffman. 1981. Summary report on the performance
of yeast assays. Prog. Mutat. Res. 1: 68-76.
Druckrey, H., R. Preussmann, S. luankovlc and D. Schmaehl. 1967. Organo-
troplc carcinogenic effects of 65 different N-nHroso compounds on BO-rats.
Z. Krebsforsch. 69(2): 103-201.
Dunkel, V.C., R.J. Plenta, A. S1vak and K.A. Traul. 1981. Comparative
neoplastlc transformation responses of Balb/373 cells, Syrian hamster embryo
cells and Rauscher murlne leukemia virus-Infected Fischer 344 rat embryo
cells to chemical carcinogens. J. Natl. Cancer Inst. 67(6): 1303-1315.
Grosjean, D., K. Van Cauwengerghe, J. Schmld and J.N. P1tt, Jr. 1978.
Formation of nltrosamlnes and nltramlnes by photo-oxidation of amines under
simulated atmospheric conditions. Ln: Proc. 4th Int. Conf. Sens. Environ.
Poll., 1977, Washington, DC. p. 196-199. [CA 89(4):30032S]
0076h -17- 08/15/86
-------
Hansch, C. and A.J. Leo. 1985. Medchem Project. Issue No. 26. .Pomona
College, Claremont, CA.
4
Hanst, P.L., J.W. Spence and M. Miller. 1977. Atmospheric chemistry of
N-n1trosod1methylam1ne. Environ. Sd. Technol. 11(4): 403-405.
IARC (International Agency for Research on Cancer). 1982. IARC Monographs
on the Evaluation of the Carcinogenic Risk of Chemicals to Man. N-Nltroso-
dlphenylamlne. Some aromatic amines, anthroqulnones and nltroso compounds
and Inorganic fluorides used 1n drinking water and dental preparations.
IARC, WHO, Lyon, France. Vol. 27, p. 213-225.
Innes, J.R.M., B.M. Ulland, M.G. Valeria, et al. 1969. Bloassay of pesti-
cides and Industrial chemicals for tumor1gen1c1ty In mice: A preliminary
note. J. Natl. Cancer Inst. 42: 1101-1114.
Iversen, O.H. 1980. Tumor1gen1c1ty of N-n1troso-d1ethyl, -dimethyl and
-dlphenylamlnes In skin-painting experiments. A study utilizing the
tetrazollum test and skin applications on hairless mice. Eur. J. Cancer.
16(5): 695-698.
Lyman, H.3., W.F. Reehl and O.H. Rosenblatt. 1982. Handbook of Chemical
Property Estimation Methods. McGraw-Hill, Inc., New York. p. 4-9, 13-15,
15-21.
0076h -18- 10/30/86
-------
Mabey, W.R., J.H. Smith, R.T. Podell, et al. 1981. Aquatic: Fate Process
Data for Organic Priority Pollutants. Monitoring and Data Support Dlv. (WH
553). Office of Water Regulations and Standards, U.S. EPA, Washington, DC.
EPA 440/4-81-014.
Malllk, M.A.B. and K. Tesfal. 1981. Transformation of nltrosamlnes In soil
and in vitro by soil microorganisms. Bull. Environ. Contam. Toxkol.
27(1): 115-121.
NCI (National Cancer Institute). 1979. Bloassay of N-nHrosodlphenylamlne
for possible cardnogenlclty. NCI Carc1nogenes1s. Tech. Rep. Ser. No. 164.
106 p. (Also publ. as NIH 79-1720 and NTIS PB 298-275)
Neal, S.B. and G.S. Probst. 1983. Chemically-Induced sister chromatld
exchange In vivo In bone marrow of Chinese hamsters: An evaluation of 24
compounds. Mutat. Res. 113: 33-43.
Plenta, R.J. and J.C. Kawalek. 1981. Transformation of hamster embryo
cells by aromatic amines. Natl. Cancer Inst. Monogr. 58: 243-251.
Polo, J. and Y.L. Chow. 1976. Efficient photolytlc degradation of nltros-
amlnes. J. Natl. Cancer Inst. 56: 997-1001. (CA 85:191838s)
Salamone, M.F., 3.A. Meddle and M. Katz. 1981. Mutagenlc activity of 41
compounds In the Ui vivo mlcronucleus assay. Prog. Mutat. Res. 1: 686-697.
0076h -19- 08/15/86
-------
S1na, J.F., C.L. Bean, G.R. Dysart, V.I. Taylor and M.O. Bradley. 1983.
Evaluation of the alkaline elut1on/rat hepatocyte assay as a predictor of
cardnogen/mutagenlc potential. Mutat. Res. 113(5): 357-391.
Styles, J.A. 1981. Activity of 42 coded compounds In the BHK-21 cell
transformation test. Prog. Mutat. Res. 1: 638-646.
Swann, R.L., D.A. Laskowskl, P.J. McCall, K. VanderKuy and H.J. Dlshburger.
1983. A rapid method for the estimation of the environmental parameters
octanol/water partition coefficient, soil sorptlon constant, water to air
ratio and water solubility. Res. Rev. 85: 17-28.
Tuazoh, E.G., W.P.L. Carter, R. Atkinson, A.M. Winer and J.N. Pitts. 1984.
Atmospheric reactions of N-n1trosod1methylam1ne and dimethylnltramlne.
Environ. Sd. Techno!. 18{1): 49-54.
U.S. EPA. 1980a. Ambient Water Quality Criteria Document for NHrosamlnes.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Water Regu-
lations and Standards, Washington, DC. EPA 440/5-80-064. NTIS PB81-117756.
U.S. EPA. 1980b. Guidelines and Methodology Used In the Preparation of
Health Effect Assessment Chapters of the Consent Decree Water Criteria
Documents. Federal Register. 45(231): 79347-79357.
0076h -20- 02/10/87
-------
U.S. EPA. 1983. Methodology and Guidelines for Reportable Quantity. Deter-
minations Based on Chronic Toxldty Data. Prepared by the Office af Health
•#
and Environmental Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH for the Office of Solid Waste and Emergency Response,
Washington, DC.
U.S. EPA. 1986a. Health and Environmental Effects Profile for NHrosamlnes.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste
and Emergency Response, Washington, DC.
U.S. EPA. 1986b. Guidelines for Carcinogen Risk Assessment. Federal
Register. 51(185): 33992-34003.
Vogel, E., W.G.H. Blljleuen, M.J.H. Kentsellum and J.A. Zljlstra. 1981.
Mutagenlc activity of 17 coded compounds 1n the sex-linked recessive lethal
test In Drosphlla melanoqaster. Prog. Hutat. Res. 1: 660-665.
0076h -21- 02/10/87
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APPENDIX
Summary Table for N-N1trosod1phenylam1ne*
Route
Oral
Species/
Strain/
Sex
rat/
F344/F
Experimental
Exposure/Dose
(rogAg/day)
0
50
200
Effect
transitional
cell carcinoma
of bladder
Human q-|*
(mg/kg/dayr*
4.92xlO~3
*Source: NCI, 1979; U.S. EPA, 1980a, 1986a
0076h
-22-
10/30/86
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