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N-Nitrosodiphenylamine
CASRN 86-30-6
Contents
0178
N-Nitrosodiphenylamine; CASRN 86-30-6
Health assessment information on a chemical substance is included in IRIS only
after a comprehensive review of chronic toxicity data by U.S. EPA health
scientists from several Program Offices and the Office of Research and
Development. The summaries presented in Sections I and II represent a
consensus reached in the review process. Background information and
explanations of the methods used to derive the values given in IRIS are
provided in the Background Documents.
STATUS OF DATA FOR N-Nitrosodiphenylamine
File On-Line 03/31/1987
Category (section) Status Last Revised
----------------------------------------- -------- ------------
Oral RfD Assessment (I.A.) no data
Inhalation RfC Assessment (I.B.) no data
Carcinogenicity Assessment (II.) on-line 07/01/1993
_I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS
__I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD)
Substance Name -- N-Nitrosodiphenylamine
CASRN -- 86-30-6
Not available at this time.
__I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC)
Substance Name -- N-Nitrosodiphenylamine
CASRN -- 86-30-6
Not available at this time.
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
Substance Name -- N-Nitrosodiphenylamine
CASRN -- 86-30-6
Last Revised -- 07/01/1993
Section II provides information on three aspects of the carcinogenic
assessment for the substance in question; the weight-of-evidence judgment of
the likelihood that the substance is a human carcinogen, and quantitative
estimates of risk from oral exposure and from inhalation exposure. The
quantitative risk estimates are presented in three ways. The slope factor is
the result of application of a low-dose extrapolation procedure and is
presented as the risk per (mg/kg)/day. The unit risk is the quantitative
estimate in terms of either risk per ug/L drinking water or risk per ug/cu.m
air breathed. The third form in which risk is presented is a drinking water
or air concentration providing cancer risks of 1 in 10,000, 1 in 100,000 or 1
in 1,000,000. The rationale and methods used to develop the carcinogenicity
information in IRIS are described in The Risk Assessment Guidelines of 1986
(EPA/600/8-87/045) and in the IRIS Background Document. IRIS summaries
developed since the publication of EPA's more recent Proposed Guidelines for
Carcinogen Risk Assessment also utilize those Guidelines where indicated
(Federal Register 61(79):17960-18011, April 23, 1996). Users are referred to
Section I of this IRIS file for information on long-term toxic effects other
than carcinogenicity.
__II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY
___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION
Classification -- B2; probable human carcinogen
Basis -- Increased incidence of bladder tumors in male and female
rats and reticulum cell sarcomas in mice, and structural relationship to
carcinogenic nitrosamines
___II.A.2. HUMAN CARCINOGENICITY DATA
Inadequate. Human exposure to nitrosamines results from contact with
mixtures containing these compounds (e.g., cutting oils, tobacco products).
Because of potential confounding by the other substances in these mixtures,
data are of limited use in the evaluation of carcinogenicity of individual
nitrosamines.
___II.A.3. ANIMAL CARCINOGENICITY DATA
N-nitrosodiphenylamine (98% pure containing two unspecified impurities)
was administered at 0, 1000 or 4000 ppm in diet to groups of 50 F344 rats/
sex. Matched controls consisted of 20 rats/sex. Dose-related mortality was
noted in females. Statistically increased incidence of urinary bladder
transitional cell carcinomas was observed in both sexes. Epithelial
hyperplasia and squamous metaplasia also occurred, as did integumentary
fibromas in males (NCI, 1979).
In the same study no increased tumor incidence was observed in B6C3F1
mice receiving dietary doses of 10,000 and 20,000 ppm (males) or 2475 and
6139 ppm (TWA, females). Likewise, no evidence of carcinogenicity was
observed in BD rats administered 120 mg nitrosodiphenylamine/kg in water for
541 days or in male Wistar rats gavaged with 1.07 mg/day in 1.1% aqueous
methylcellulose 5 days/week for 45 weeks (Druckrey et al., 1967; Argus and
Hoch-Ligeti, 1961). Neither B6C3F1 nor B6AKF1 mice showed statistically
significant increases in tumor incidence following gavage with 1000
mg/kg/day from day 7-28 of age followed by dietary exposure to 3769 ppm
until weeks 77-79 of life (BRL, 1968; Innes et al., 1969). Weekly topical
application of diphenylnitrosoamine for 20 weeks did not induce tumors in
hr/hr Oslo mice, nor did weekly i.p. injection of 2.5 mg in PEG 400
(Iverson, 1980; Boyland et al., 1968). A single s.c. injection of 1000
mg/kg/day resulted in significantly increased incidence of reticulum cell
sarcomas in male B6C3F1 mice, but not in females or B6AKF1 mice of either
gender (BRL, 1968).
___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
Nitrosodiphenylamine has produced mixed responses in genetic toxicology
tests. It was negative in bacterial mutation assays, mutation assays in V79
and CHO and mouse lymphoma cells and SCE in CHO cells (IARC, 1982). Positive
responses have been obtained for several endpoints in S. cerevisiae (de Serres
and Hoffmann, 1981) and in DNA damage assays in rat hepatocytes (Althaus et
al., 1982; Sina et al., 1983). N-nitrosodiphenylamine produced transformation
of Syrian hamster embryo cells, BHK cells and F344 rat embryo cells infected
with Rauscher murine leukemia viruses (Pienta and Kawalek, 1981; Daniel and
Dehnel, 1981; Dunkel et al., 1981).
N-nitrosodiphenylamine is structurally related to carcinogenic
nitrosamines.
__II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE
___II.B.1. SUMMARY OF RISK ESTIMATES
Oral Slope Factor -- 4.9E-3/mg/kg/day
Drinking Water Unit Risk -- 1.4E-7/ug/L
Extrapolation Method -- Linearized multistage procedure, extra risk
Drinking Water Concentrations at Specified Risk Levels:
Risk Level Concentration
-------------------- -------------
E-4 (1 in 10,000) 7E+2 ug/L
E-5 (1 in 100,000) 7E+1 ug/L
E-6 (1 in 1,000,000) 7E+0 ug/L
___II.B.2. DOSE-RESPONSE DATA (CARCINOGENICITY, ORAL EXPOSURE)
Tumor Type -- transitional cell carcinoma of the bladder
Test Animals -- Rat/F344, female
Route -- drinking water
Reference -- NCI, 1979
Administered Dose Human Equivalent Tumor
(ppm) (mg/kg)/day Dose (mg/kg)/day Incidence
----- ----------- ---------------- ---------
0 0 0 0/18
1000 50 7.7 0/48
4000 200 30.6 40/49
___II.B.3. ADDITIONAL COMMENTS (CARCINOGENICITY, ORAL EXPOSURE)
The unit risk should not be used if the water concentration exceeds 7E+4
ug/L, since above this concentration the slope factor may differ from that
stated.
___II.B.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, ORAL EXPOSURE)
Adequate numbers of animals were treated and observed for their lifetime.
Significant increases in tumor incidence were observed only in high-dose
animals. NCI noted that the mechanism by which bladder tumors were induced
(e.g., calculus formation or nitrosation of amines in feed) is not known.
__II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE
Not available.
__II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT)
___II.D.1. EPA DOCUMENTATION
Source Document -- U.S. EPA, 1986
The 1986 Health and Environmental Effects Profile for Nitrosoamines has
received Agency review.
___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT)
Agency Work Group Review -- 02/11/1987
Verification Date -- 02/11/1987
___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT)
Please contact the Risk Information Hotline for all questions concerning this
assessment or IRIS, in general, at (513)569-7254 (phone), (513)569-7159 (FAX)
or RIH.IRIS@EPAMAIL.EPA.GOV (internet address).
_VI. BIBLIOGRAPHY
Substance Name -- N-Nitrosodiphenylamine
CASRN -- 86-30-6
Last Revised -- 04/01/1990
__VI.A. ORAL RfD REFERENCES
None
__VI.B. INHALATION RfD REFERENCES
None
__VI.C. CARCINOGENICITY ASSESSMENT REFERENCES
Althaus, F.R., S.D. Lawrence, G.L. Sattler, D.G. Longfellow and H.C. Pitot.
1982. Chemical quantification of unscheduled DNA 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-Ligeti. 1961. Comparative study of the carcinogenic
activity of nitrosamines. J. Natl. Cancer Inst. 27: 695-709.
Boyland, D., R.L. Carter, J.W. Gorrod and F.J.C. Roe. 1968. Carcinogenic
properties of certain rubber additives. Eur. J. Cancer. 4(2): 233-239.
BRL (Bionetics Research Laboratory). 1968. Evaluation of carcinogenic,
teratogenic and mutagenic activities of selected pesticides and industrial
chemicals. Vol. 1, Carcinogenic study. NTIS PB 223-159.
Daniel, M.R. and J.M. Dehnel. 1981. Cell transformation test with baby
hamster kidney cells. Prog. Mutat. Res. 1: 626-637.
de Serres, F.J. and G.R. Hoffmann. 1981. Summary report on the performance
of yeast assays. Prog. Mutat. Res. 1: 68-76.
Druckrey, H., R. Preussmann, S. Ivankovic and D. Schmael. 1967.
Organotropism and carcinogenic activities of 65 different N-Nitrosodi
compounds on BD-rats. Z. Kerbsforsch. 69(2): 103-201.
Dunkel, V.C., R.J. Pienta, A. Sivak and K.A. Traul. 1981. Comparative
neoplastic transformation responses of Balb/3T3 cells, Syrian hamster embryo
cells, and Rauscher murine leukemia virus-infected Fischer 344 rat embryo
cells to chemical carcinogens. J. Natl. Cancer Inst. 67(6): 1303-1315.
IARC (International Agency for Research on Cancer). 1982. IARC Monographs on
the Evaluation of the Carcinogenic Risk of Chemicals to Man
N-Nitrosodiphenylamine. Some Aromatic Amines, Anthroquinones and Nitroso
Compounds, and Inorganic Fluorides Used in Drinking Water and Dental
Preparations. WHO, IARC, Vol. 27, Lyon, France. p. 213-225.
Innes, J.R.M., B.M. Ulland, M.G. Valeria, et al. 1969. Bioassay of
pesticides and industrial chemicals for tumorigenicity in mice : A preliminary
note. J. Natl. Cancer Inst. 42: 1101-1114.
Iverson, O.H. 1980. Tumorigenicity of N-nitroso-diaethyl, -dimethyl and
-diphenyl-amines in skin painting experiments. A study utilizing the
tetrazolium test and skin applications on hairless mice. Eur. J. Cancer.
16(5): 695-698.
NCI (National Cancer Institute). 1979. Bioassay of N-Nitrosodiphenylamine
for Possible Carcinogenicity. NCI Carcinogenesis Technical Report Series No.
164. NIH 79-1720. NTIS PB 298-275.
Pienta, R.J. and J.C. Kawalek. 1981. Transformation of hamster embryo cells
by aromatic amines. Natl. Cancer Inst. Monogr. 58: 243-251.
Sina, J.F., C.L. Bean, G.R. Dysart, V.I. Taylor and M.O. Bradley. 1983.
Evaluation of the alkaline elution/rat hepatocyte assay as a predictor of
carcinogenic/mutagenic potential. Mutat. Res. 113(5): 357-391.
U.S. EPA. 1980. Ambient Water Quality Criteria Document for Nitrosamines.
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. NTIS PB 81-117756.
U.S. EPA. 1986. Health and Environmental Effects Profile for Nitrosamines.
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.
_VII. REVISION HISTORY
Substance Name -- N-Nitrosodiphenylamine
CASRN -- 86-30-6
-------- -------- --------------------------------------------------------
Date Section Description
-------- -------- --------------------------------------------------------
03/01/1988 II.B.4. Confidence statement revised
03/01/1988 II.D.1. Documentation revised
03/01/1988 II.D.3. Contacts switched
03/01/1990 VI. Bibliography on-line
04/01/1990 VI.C. Druckrey et al., 1967 citation corrected
01/01/1992 IV. Regulatory actions updated
07/01/1993 II.D.3. Primary contact's phone number changed
VIII. SYNONYMS
Substance Name -- N-Nitrosodiphenylamine
CASRN -- 86-30-6
Last Revised -- 03/31/1987
86-30-6
BENZENAMINE, N-NITROSO-N-PHENYL-
CURETARD A
DELAC J
DIPHENYLAMINE, N-NITROSO-
DIPHENYLNITROSAMIN
DIPHENYLNITROSAMINE
DIPHENYL N-NITROSOAMINE
NAUGARD TJB
NCI-C02880
NDPA
NDPhA
NITROSODIPHENYLAMINE
Nitrosodiphenylamine, N-
NITROUS DIPHENYLAMIDE
N,N-DIPHENYLNITROSAMINE
N-NITROSODIFENYLAMIN
N-Nitrosodiphenylamine
N-NITROSO-N-PHENYLANILINE
REDAX
RETARDER J
TJB
VULCALENT A
VULCATARD
VULCATARD A
VULKALENT A
VULTROL
Last updated: 5 May 1998
URL: http://www.epa.gov/iris/SUBST/0178.HTM
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