xvEPA
United States
Environmental Protection
Agency
Office of Water
Regulations and Standards
Criteria and Standards Division
Washington DC 20460
EPA 440 5-80-062
October 1980
Ambient
Water Quality
Criteria for
Diphenylhydrazine
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AMBIENT WATER QUALITY CRITERIA FOR
DIPHENYLHYDRAZINE
Prepared By
U.S. ENVIRONMENTAL PROTECTION AGENCY
Office of Water Regulations and Standards
Criteria and Standards Division
Washington, D.C.
Office of Research and Development
Environmental Criteria and Assessment Office
Cincinnati, Ohio
Carcinogen Assessment Group
Washington, D.C.
Environmental Research Laboratories
Corvalis, Oregon
Duluth, Minnesota
Gulf Breeze, Florida
Narragansett, Rhode Island
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DISCLAIMER
This report has been reviewed by the Environmental Criteria and
Assessment Office, U.S. Environmental Protection Agency, and approved
for publication. Mention of trade names or commercial products does not
constitute endorsement or recommendation for use.
AVAILABILITY NOTICE
This document is available to the public through the National
Technical Information Service, (NTIS), Springfield, Virginia 22161.
11
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FOREWORD
Section 304 (a)(l) of the Clean Water Act of 1977 (P.L. 95-217),
requires the Administrator of the Environmental Protection Agency to
publish criteria for water quality accurately reflecting the latest
scientific knowledge on the kind and extent of all identifiable effects
on health and welfare which may be expected from the presence of
pollutants in any body of water, including ground water. Proposed water
quality criteria for the 65 toxic pollutants listed under section 307
(a)(l) of the Clean Water Act were developed and a notice of their
availability was published for public comment on March 15, 1979 (44 FR
15926), July 25, 1979 (44 FR 43660), and October 1, 1979 (44 FR 56628).
This document is a revision of those proposed criteria based upon a
consideration of comments received from other Federal Agencies, State
agencies, special interest groups, and individual scientists. The
criteria contained in this document replace any previously published EPA
criteria for the 65 pollutants. This criterion document is also
published in satisifaction of paragraph 11 of the Settlement Agreement
in Natural Resources Defense Council, et al. vs. Train, 8 ERC 2120
(D.D.C. 1976), modified, 12 ERC 1833 (D.D.C. 1979).
The term "water quality criteria" is used in two sections of the
Clean Water Act, section 304 (a)(l) and section 303 (c)(2). The term has
a different program impact in each section. In section 304, the term
represents a non-regulatory, scientific assessment of ecological ef-
fects. The criteria presented in this publication are such scientific
assessments. Such water quality criteria associated with specific
stream uses when adopted as State water quality standards under section
303 become enforceable maximum acceptable levels of a pollutant in
ambient waters. The water quality criteria adopted in the State water
quality standards could have the same numerical limits as the criteria
developed under section 304. However, in many situations States may want
to adjust water quality criteria developed under section 304 to reflect
local environmental conditions and human exposure patterns before
incorporation into water quality standards. It is not until their
adoption as part of the State water quality standards that the criteria
become regulatory.
Guidelines to assist the States in the modification of criteria
presented in this document, in the development of water quality
standards, and in other water-related programs of this Agency, are being
developed by EPA.
STEVEN SCHATZOW
Deputy Assistant Administrator
Office of Water Regulations and Standards
111
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ACKNOWLEDGEMENTS
Aquatic Life Toxicology:
William A. Brungs, ERL-Narragansett
U.S. Environmental Protection Agency
John H. Gentile, ERL-Narragansett
U.S. Environmental Protection Agency
Mammalian Toxicology and Human Health Effects:
Joseph Borzelleca (author)
Medical College of Virginia
Richard Carchman (author)
Medical College of Virginia
Terence M. Grady (doc. mgr.) ECAO-Cin
U.S. Environmental Protection Agency
Bonnie Smith (doc. mgr.) ECAO-Cin
U.S. Environmental Protection Agency
Edward Calabrese
University of Massachusetts
Thomas Clarkson
University of Rochester
Joan Cranmer
University of Arkansas
Patrick Durkin
Syracuse Research Corporation
George C. Fuller
University of Rhode Island
Roy E. Albert, CAG*
U.S. Environmental Protection Agency
Si Duk Lee, ECAO-Cin
U.S. Environmental Protection Agency
Krystyne Locke, HED
U.S. Environmental Protection Agency
Steven D. Lutkenhoff, ECAO-Cin
U.S. Environmental Protection Agency
Herbert Schumacher
National Center for Toxicological Research
Samuel Shibko
U.S. Food and Drug Administration
Carl C. Smith
University of Cincinnati
Jerry F. Stara, ECAO-Cin
U.S. Environmental Protection Agency
S.L. Schwartz
Georgetown University
Norman Trieff
University of Texas Medical Branch
Technical Support Services Staff: D.J. Reisman, M.A. Garlough, B.L. Zwayer,
P.A. Daunt, K.S. Edwards, T.A. Scandura, A.T. Pressley, C.A. Cooper,
M.M. Denessen.
Clerical Staff: C.A. Haynes, S.J. Faehr, L.A. Wade, D. Jones, B.J. Bordicks,
B.J. Quesnell, T. Highland, B. Gardiner
*CAG Participating Members: Elizabeth L. Anderson, Larry Anderson, Ralph Arnicar,
Steven Bayard, David L. Bayliss, Chao W. Chen, John R. Fowle III, Bernard Haberman,
Charalingayya Hiremath, Chang S. Lao, Robert McGaughy, Jeffrey Rosenblatt,
Dharm V. Singh, and Todd W. Thorslund.
IV
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TABLE OF CONTENTS
Page
Criteria Summary
Introduction A~l
Aquatic Life Toxicology B-l
Introduction B-l
Effects B-l
Acute Toxicity B~|
Summary B'J
Criteria B'l
References B~3
Mammalian Toxicology and Human Health Effects C-l
Exposure C-l
Ingestion from Water C-l
Ingestion from Food C-l
Inhalation, Dermal, and Other Sources C-2
Pharmacokinetics C-3
Absorption, Excretion, and Distribution C-3
Metabolism C-3
Effects C-3
Acute, Subacute, and Chronic Toxicity C-3
Synergism and/or Antagonism C-5
Teratogenicity C-5
Mutagenicity C-5
Carcinogenicity C-6
Criterion Formulation C-12
Existing Guidelines C-12
Current Levels of Exposure C-12
Special Groups at Risk C-12
Basis and Derivation of Criterion C-12
References C-16
Appendix C-19
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CRITERIA DOCUMENT
DIPHENYLHYORAZINE
CRITERIA
Aquatic Life
The available data for 1,2-diphenylhydrazine indicate that acute toxic-
ity to freshwater aquatic life occurs at concentrations as low as 270 pg/1
and would occur at lower concentrations among species that are more sensi-
tive than those tested. No data are available concerning the chronic toxic-
ity of 1,2-diphenylhadrazine to sensitive freshwater aauatic life.
No saltwater organisms have been tested with 1,2-diphenylhydrazine and
no statement can be made concerning acute or chronic toxicity.
Human Health
For the maximum protection of human health from the potential carcino-
genic effects due to exposure of diphenylhydrazine through ingestion of con-
taminated water and contaminated aauatic organisms, the ambient water con-
centrations should be zero based on the non-threshold assumption for this
chemical. However, zero level may not be attainable at the present time.
Therefore, the levels which may result in incremental increase of cancer
risk over the lifetime are estimated at 10"5, 10 , and 10~ . The
corresponding recommended criteria are 422 ng/1, 42 ng/1, and 4 ng/1, re-
spectively. If the above estimates are made for consumption of aquatic or-
ganisms only, excluding consumption of water, the levels are 5.6 ug/1, 0.56
ug/1, and 0.056 ug/1, respectively.
VI
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INTRODUCTION
Diphenylhydrazine exists as an asymmetrical isomer, 1,1-diphenylhydra-
zine, and a symmetrical isomer, 1,2-diphenylhydrazine (hydrazobenzene). The
hydrochloride of 1,1-diphenylhydrazine is used as a reagent for the sugars,
arabinose and lactose (Windholz, 1976). 1,2-Diphenylhydrazine is used in
the synthesis of phenylbutazone (Wenner, 1967) and as the starting material
in the manufacture of benzidine, an intermediate in the production of dyes
(Lurie, 1964).
The primary method of commercial production of this compound is the re-
+3 +2
duction of nitrobenzene by catalysts such as Fe or Zn in alkaline
solution. 8y this procedure, nearly quantitative yields are obtained (Kirk-
Othmer, 1963). Figure 1 depicts this process as well as the by-products of
diphenylhydrazine, azobenzene and azoxybenzene.
In 1977 the commercial production of 1,2-diphenylhydrazine was in excess
of 1,000 Ibs. [Stanford Research Institute (SRI), 1977]. However, this
figure is probably an underestimate of the amount of diphenylhydrazine that
was actually available. Diphenylhydrazine is produced in several synthetic
processes as an intermediate or as a contaminant, but it is not possible to
estimate these quantities, which are probably substantial.
The reaction of 1,2-diphenylhydrazine with acid results in the benzidine
rearrangement (Kenner, 1968). This reaction is presented in Figure 2. In
addition to benzidine, other products formed include diphenyline, o-benzi-
dine, and o-semidine. In the stomach, 1,2-diphenylhydrazine can be convert-
ed into benzidine, a known human carcinogen [Haley, 1975; International
Agency for Research on Cancer (IARC), 19721.
A-l
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N-N
*Azobenzene
Nitrobenzene
Alka^ne
Zn
*Azoxybanzene
1,2-diphenylhydrazine
FIGURE 1
Synthesis of 1, 2-diphenylhydrazine
Source: Williams, 1959
*Carcinogenic
A-2
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H
2-diphenylhydrazine
* Carcinogenic
*Benzidine
Diphenyline
o-Benzidine
o-Semidine
FIGURE 2
Benzidine Rearrangement of 1, 2-diphenylhydrazine
Source: Williams, 1959
A-3
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The structure and physical data for 1,2-diphenylhydrazine are presented
in Figure 3.
No data were found on the environmental presence or persistence of di-
phenylhydrazines, except for one report of detection in drinking water at a
concentration of 1 ug/1 (U.S. EPA, 1975). 1,1-Diphenylhydrazine and 1,2-di-
phenylhydrazine have been characterized as slightly soluble and insoluble in
water, respectively (Windholz, 1976; Bennett, 1974). No quantitative data
were found for the water solubilities and vapor pressures of these com-
pounds; consequently, no predictions can be made about their persistence in
water.
A-4
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FIGURE 3
1,2-diphenylhydrazine: Chemical and Physical Properties
Source: Weast, 1978.
Synonyms
- Hydrazobenzene
Symmetrical diphenylhydrazine
N, N'-Diphenylhydrazine
N, N'-Bianiline
1,1' -Hydrazodibenzene
Cas No.
530-50-7
Molecular weight = 184.24
Melting Point = 131°C
Boiling Point = 220°C
Solubility = Slightly soluble in water
Very soluble in benzene, ether, alcohol
A-5
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REFERENCES
Bennett, H. (ed.) 1974. Concise Chemical and Technical Dictionary. Chemi-
cal Publishing Co. Inc., New York.
Haley, T.J. 1975. Benzidine revisited: A review of the literature and
problems associated with the use of benzidine.
International Agency for Research on Cancer. 1972. Aromatic amines. Mono-
graph on the evaluation of carcinogenic risk of chemicals to man. 1: 69.
Kenner, J. 1968. Benzidine rearrangement. Nature. 219: 153.
Kirk, R.E. and D.F. Othmer. 1963. Encyclopedia of Chemical Technology.
2nd ed. John Wiley and Sons, Inc., New York.
Lurie, A.P. 1964. Benzidine. In: Kirk-Othmer Encyclopedia of Chemical
Technology. 2nd ed. Interscience Publishers, New York. 3: 408.
Stanford Research Institute. 1977. Directory of Chemical Producers. Menlo
Park, California.
U.S. EPA. 1975. Preliminary assessment of suspected carcinogens in drink-
ing water. Off. Tox. Subst., Washington, D.C.
Weast, R.C. (ed.) 1978. Handbook of Chemistry and Physics. 59th ed.
Chemical Rubber Company Press, West Palm Beach, Florida.
A-6
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Wenner, W. 1967. Malonlc Acid and Derivatives. In; Kirk-Othmer Encyclo-
pedia of Chemical Technology. 2nd ed. Interscience Publishers, New York.
12: 857.
Williams, R. 1959. Detoxication Mechanisms. John Wiley and Sons, Inc.,
New York. p. 480.
Windholz, M. (ed.) 1976. The Merck Index. Merck and Co. Inc., Rahway, New
Jersey.
A-7
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Aquatic Life Toxicology*
INTRODUCTION
Toxicity tests with 1,2-diphenylhydrazine and the bluegill and Daphnia
magna have been conducted using static procedures, and the results demon-
strated adverse effects as low as 270 ug/1. No data are available for any
saltwater species.
EFFECTS
Acute Toxicity
The 48-hour EC™ for Daphnia magna and the 96-hour LCj.g for the
bluegill are 4,100 ug/1 and 270 ug/1, respectively, for 1,2-diphenylhydra-
zine (Table 1).
Summary
Only two freshwater species have been tested with 1,2-diphenylhydra-
zine. The range of 50 percent effect levels for the bluegill and Daphnia
magna was 270 to 4,100 ug/1. No data are available for 1,2-diphenylhydrazine
and saltwater organisms.
CRITERIA
The available data for 1,2-diphenylhydrazine indicate that acute toxici-
ty to freshwater aquatic life occurs at concentrations as low as 270 ug/1
and would occur at lower concentrations among species that are more sensi-
tive than those tested. No data are available concerning the chronic toxic-
ity of 1,2-diphenylhydrazine to sensitive freshwater aguatic life.
No saltwater organisms have been tested with 1,2-diphenylhydrazine and
no statement can be made concerning acute or chronic toxicity.
*The reader is referred to the Guidelines for Deriving Water Quality Criter-
ia for the Protection of Aquatic Life and Its Uses in order to better under-
stand the following discussion and recommendation. The following tables
contain the appropriate data that were found in the literature, and at the
bottom of each table are calculations for deriving various measures of tox-
icity as described in the guidelines.
B-l
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Table I. Acut* valiM* for 1,2-dlpb*oylhy
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REFERENCES
U.S. EPA. 1978. In-depth studies on health and environmental impacts of
selected water pollutants. U.S. Environ. Prot. Agency, Contract No.
68-01-4646.
B-3
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Mammalian Toxicology and Human Health Effects
EXPOSURE
Inqestion from Water
1,2-Diphenylhydrazine (DPH) was not detected in the finished
water of any of 10 cities selected for a detailed study by U.S. EPA
(1975). However, the same study demonstrated the presence of DPH
in drinking water in concentrations up to 1 yg/1 (1 ppb).
Ingestion from Food
There are no available data identifying DPH as a direct or
indirect food additive, or as a naturally occurring constituent of
any food.
A bioconcentration factor (BCF) relates the concentration of a
chemical in aquatic animals to the concentration in the water in
which they live. The steady-state BCFs for a lipid-soluble com-
pound in the tissues of various aquatic animals seem to be propor-
tional to the percent lipid in the tissue. Thus, the per capita
ingestion of a lipid-soluble chemical can be estimated from the per
capita consumption of fish and shellfish, the weighted average per-
cent lipids of consumed fish and shellfish, and a steady-state BCF
for the chemical.
Data from a recent survey on fish and shellfish consumption in
the United States were analyzed by SRI International (U.S. EPA,
1980). These data were used to estimate that the per capita con-
sumption of freshwater and estuarine fish and shellfish in the
United States is 6.5 g/day (Stephan, 1980). In addition, these
data were used with data on the fat content of the edible portion of
C-l
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the same species to estimate that the weighted average percent
lipids for consumed freshwater and estuarine fish and shellfish is
3.0 percent.
No measured steady-state bioconcentration factor (BCF) is
available for lf2-diphenylhydrazine, but the equation "Log BCF =
(0.85 Log P) - 0.70" can be used (Veith, et al. 1979) to estimate
the BCF for aquatic organisms that contain about 7.6 percent lipids
(Veith, 1980) from the octanol/water partition coefficient (P) .
Based on a measured log P value of 2.94 (Hansch and Leo, 1979), the
steady-state bioconcentration factor for 1,2-diphenylhydrazine is
estimated to be 63. An adjustment factor of 3.0/7.6 » 0.395 can be
used to adjust the estimated BCF from the 7.6 percent lipids on
which the equation is based to the 3.0 percent lipids that is the
weighted average for consumed fish and shellfish. Thus, the
weighted average bioconcentration factor for 1,2-diphenylhydrazine
and the edible portion of all aquatic organisms consumed by Ameri-
cans is calculated to be 63 x 0.395 = 24.9.
Inhalation, Dermal, and Other Sources
Laboratory workers, workers in forensic medicine, and workers
involved in the manufacture of dyes, certain Pharmaceuticals, and
chemicals, are subject to occupational exposure to 1,2-diphenyl-
hydrazine. Both inhalation and dermal contact are possible routes
of exposure in these settings. However, no experimental data are
available to quantitate either the dermal or inhalation exposure
risks to this population.
C-2
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PHABMACOKINETICS
Absorption, Excretion, and Distribution
There is little available data on the absorption or excretion
of 1,2-diphenylhydrazine by mammals. The administration of DPH by
various routes results in systemic effects and the presence of DPH
metabolites in the urine, indicating some degree of absorption.
Metabolism
The metabolism of 1,2-diphenylhydrazine in the rat is present-
ed in Figure 1 (Williams, 1959). The compound was administered to
rats orally (p.o.) (200, 400 mg/kg), intraperitoneally (i.p.) (200
mg/kg), intratracheally (5, 10 mg/kg}, and intravenously (i.v.) (4,
8 mg/kg). Urine was analyzed chromatographically (TLC) and the
metabolic scheme shown in Figure 1 was proposed. Benzidine was
identified as a metabolite. The metabolites detected were not
dependent upon the dose or the route of administration.
EFFECTS
Acute, Subacute, and Chronic Toxicity
Two studies reporting oral LD5Q values for DPH were identi-
fied. Marhold, et al. (1968) used 10 male Wistar rats and admin-
istered DPH as a 5 percent aqueous suspension. The LD^Q value was
reported to be 959 mg/kg. Liver damage is an important feature of
diphenylhydrazine toxicity, particularly after chronic exposure.
Sutton (1967) noted that phenylhydrazines cause prominent kidney
damage and more diffuse liver damage in animals.
No epidemiological studies of DPH exposure have been con-
ducted.
C-3
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OH
NHAC
FIGURE 1
1,2-Diphenylhydrazine Metabolites in Rat Urine
Source: Williams, 1959
C-4
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Synergism and/or Antagonism
Marhold, et al. (1968) demonstrated that diphenyline, a pro-
duct of benzidine rearrangement, acts synergistically with benzi-
dine to produce tumors. Genin (1975) showed synergism of hydrazo-
benzene with benzidine sulfate. Kurlyandskii, et al. (1976) ob-
served that benzidine sulfate-hydrazobenzene or benzidine sulfate-
dianisidine sulfate mixtures when administered subcutaneously to
rats increased the incidence of bladder cancer and decreased the
latent period for tumor development when compared with the carcino-
genic activity of the individual compounds. The authors emphasized
the importance of preventing the possible exposure of industrial
workers to combinations of 1,2-diphenylhydrazine and benzidine dur-
ing the manufacture of benzidine sulfate.
Teratogenicity
Pertinent data could not be located in the available litera-
ture on the teratogenicity of DPH.
Mutagenicity
Sieler (1977) studied the incorporation of H-thymidine into
testicular DNA using the technique developed by Friedman and Staub
(1976). When DPH was administered i.p. in a dose of 100 mg/kg, an
inhibitory effect on testicular DNA synthesis was observed. In
this study, a limited number of structurally related compounds were
assayed. The relationship between the known mutagenicity of some
of these agents agreed favorably with effects on depressed testicu-
lar DNA synthesis. These authors then concluded that agents which
can depress testicular DNA synthesis may have a mutagenic poten-
tial.
C-5
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Carcinogenicity
Concern over 1,2-diphenylhydrazine is based on several fac-
tors: (1) its presence in drinking water (at concentrations up to
1 yg/1 (U.S. EPA, 1975); (2) the likely production of benzidine
from DPH in the stomach due to gastric acidity [International
Agency for Research on Cancer (IAJRC) , 1972]; (3) the documented
carcinogenicity of diphenylhydrazine and selected substituted
hydrazines (IARC, 1974); (4) the increased incidence of bladder
cancer among workers involved in the manufacture of dyes (Wynder,
et al. 1963; Anthony, et al. 1970); (5) the carcinogenicity of
azobenzene, a metabolite of DPH, as well as the established car-
cinogenicity of benzidine to which DPH is converted.
There are several reports on the possible carcinogenicity of
DPH. In a study by the National Cancer Institute (NCI, 1978),
technical grade DPH* was fed as a dietary admixture to Fischer 344
rats and mice (B6C3F1) of both sexes. Dietary concentrations of
DPH fed to rats and mice are indicated in Tables 1 and 2. In this
study, DPH was fed to mice and rats for 78 weeks followed by obser-
vation periods of 17 to 96 weeks and 28 to 109 weeks, respectively.
Controls consisted of 47 to 50 animals of each sex. The results of
this study are summarized in Tables 1 and 2. There were differ-
ences in the nature and organ distribution of tumors between sexes
and species. DPH was carcinogenic to Fischer 344 rats of both
sexes and caused significant increases in hepatocellular carcinoma
*mp » 120 - 124°C (K & K labs)
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TABLE 1
Carcinogenicity of 1,2-Diphenylhydrazine in B6C3F-^ Mice*
Sex
Male
Female
1
50
50
50
50
50
50
47
50
Dosea
LD control
HD control
0.008
0.040
LD control
HD control
0.004
0.040
Treated
0
0
78
78
0
0
78
78
Weeks
Observed
Post Treatment
95
96
17
17
96
96
17
18
Effects
Hepatocellular
Carcinomas
12/50
6/48
11/47
8/46
2/47
1/50
4/39
20/43 p^O.OOl
Pulmonary
Carcinomas
5/50
5/49
1/47
0/46
2/46
3/50
3/38
2/40
*Source: NCI, 1978.
aDose = % DPH in diet.
LD = Low dose.
HD = High dose.
C-7
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Sex
Male
TAHLE 2
Carcinogenic!ty of 1,2-Diphenylhydrazine in Fischer 344 Rats*
Weeks
1
50
49
50
50
50
50
50
50
Dose3
LO control
HD control
0.008
0.03
LD control
HD control
0.004
0.010
Treated
0
0
78
78
0
0
78
78
Observed
108
109
29
28
109
109
30
29
llepatocellular
Carcinomas or
Neoplastic
Nodules
5/47
1/48
13/49 p = 0.040
37/49 p
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or neoplastic nodules in male rats at both doses; Zymbal's gland
squamous-cells or adrenal tumors in male rats at the high dose; and
neoplastic liver nodules or mammary carcinomas in female rats at
the high dose. Female mice showed an increase in hepatocelluar
carcinomas only at the high dose. DPH was not carcinogenic in
B6C3F1 male mice.
In a study by Pliss (1974) , the carcinogenic properties of DPH
were studied over a period of 588 days in rats (N = 163) and C57
mice (N = 110). DPH was suspended in sunflower seed oil and admin-
istered by subcutaneous (s.c.) injection (40 mg/wk/rat and 5
mg/wk/mouse), and by addition to food (30 mg/5 times/wk) or appli-
cation to the skin (2 mg/3 times/wk/mouse).
The data summarized in Table 3 indicate that DPH produces a
wide variety of tumors in both mice and rats.
In contrast to the studies of NCI (1978) and Pliss (1974),
Marhold, et al. (1968) and Spitz (1950) did not find DPH to be car-
cinogenic. The latter two studies were difficult to interpret due
to the lack of specific information on the purity of DPH, experi-
mental design, or statistical analysis. The Pliss study (1974)
should be used in a cautious manner in indicting DPH as a carcino-
gen. The author indicated that animals had to be added to the study
in order to replace animals afflicted with a parasitic infection.
In addition, although the tumor incidence was given for DPH-treated
animals, the incidence of tumors in control animals was not pre-
sented except in the case of the epicutaneous administration of
DPH. Values of 17 percent vs. 22.2 percent for control and DPH
C-9
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TABLE 3
Carcinogenicity of DPH in Mice and Rats*
Species
Effects
Route
% Tumor
Incidence
Tumors
Mice
Rats
s.c.
P.O.
epicutaneous
s.c.
36.6 Rhabdomyosarcoma
50 Pulmonary adenoma,
leukemia, liver
22.2 Skin, lung, liver
22.6 Uterus, mammary,
Zymbal's gland, liver,
spleen, lymphoid leukemia
*Source: Pliss, 1974.
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groups, respectively, were presented but no statistical analysis of
these incidences was given. In light of the available information,
the NCI data indicates that DPH is carcinogenic.
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CRITERION FORMULATION
Existing Guidelines and Standards
Existing guidelines or standards were not found for 1,2-di-
phenylhydrazine.
Current Levels of Exposure
Pertinent data could not be located in the available litera-
ture on the concentration of 1,2-diphenylhydrazine in the atmos-
phere.
1,2-Diphenylhydrazine has been found to be present in drinking
water at levels of 1 ug/1 » 1 ppb (U.S. EPA, 1975).
1,2-Diphenylhydrazine has not been found to be a natural con-
stituent of food.
Special Groups at Risk
Manufacturers of dyes and Pharmaceuticals are subject to occu-
pational exposure. Groups working in the laboratory and forensic
medicine may also be subject to 1,2-diphenylhydrazine exposure.
Basis and Derivation of Criterion
An evaluation of the subacute, acute and chronic toxicity,
with the exception of carcinogenicity is impossible because of
scanty data. Guidelines or standards presently do not exist for
DPH. Diphenylhydrazine has been shown to produce carcinogenic re-
sponses in rats and mice (NCI, 1978; Pliss, 1974). Since the NCI
(1978) study represents the only report in which all the data can
be analyzed, it will be used as a basis for formulating a cri-
terion.
Under the Consent Decree in NRDC v. Train, criteria are to
state "recommended maximum permissible concentrations (including
C-12
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where appropriate, zero) consistent with the protection of aquatic
organisms, human health, and recreational activities." DPH is sus-
pected of being a human carcinogen. Because there is no recognized
safe concentration for human carcinogens, the recommended concen-
tration of DPH in water for maximum protection of human health is
zero.
Because attaining a zero concentration level may be infeasible
in some cases and in order to assist the Agency and states in the
possible future development of water quality regulations, the con-
centrations of DPH corresponding to several incremental lifetime
cancer risk levels have been estimated. A cancer risk level pro-
vides an estimate of the additional incidence of cancer that may be
expected in an exposed population. A risk of 10 for example,
indicates a probability of one additional case of cancer for every
100,000 people exposed, a risk of 10~6 indicates one additional
case of cancer for every million people exposed, and so forth.
In the Federal Register notice of availability of draft ambi-
ent water quality criteria, EPA stated that it is considering set-
ting criteria at an interim target risk level of 10 , 10" , or
10 as shown in the following information.
Exposure Assumptions
2 liters of drinking
water and consumption
of 6.5 g fish and
shellfish (2)
Consumption of fish
and shellfish only
Risk Levels
and Corresponding Criteria (1)
Q
0
io-7
4 ng/1
IP"6
42 ng/1
IP"5
422 ng/1
56 ng/1 560 ng/1 5,600 ng/1
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(1) Calculated by applying a linearized multistage model as dis-
cussed in the Human Health Methodology Appendices to the Octo-
ber 1980 Federal Register notice which announced the avail-
ability of this document. Appropriate bioassay data used in
the calculation of the model are presented in the Appendix.
Since the extrapolation model is linear to low doses, the
additional lifetime risk is directly proportional to the water
concentration. Therefore, water concentrations corresponding
to other risk levels can be derived by multiplying or dividing
one of the risk levels and corresponding water concentrations
shown in the table by factors such as 10, 100, 1,000 and so
forth.
(2) Seven percent of the DPH exposure results from the consumption
of aquatic organisms which exhibit an average bioconcentration
potential of 24.9-fold. The remaining 93 percent of DPH expo-
sure results from drinking water.
Concentration levels were derived assuming a lifetime exposure
to various amounts of DPH, (1) occurring from the consumption of
both drinking water and aquatic life grown in water containing the
corresponding DPH concentrations and, (2) occurring solely from
consumption of aquatic life grown in the waters containing the cor-
responding DPH concentrations.
Although a total exposure evaluation for DPH is desirable
there is no data to support a total exposure analysis. The cri-
teria presented, therefore, assume an incremental risk from assumed
ambient water exposure only.
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For DPH the case for criterion development is based upon the
existence of carcinogenicity responses in animals (rats and mice).
Because of the lack of investigations for other chronic and
acute responses, no information on other effects exists in either
human or animal systems. Thus, the criterion proposed should be
considered as precautionary until further studies can be used in
the overall toxicity evaluations.
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REFERENCES
Anthony, A.M., et al. 1970. Tumors of the urinary bladder: An
analysis of the occupations of 1,030 patients in Leeds, England.
Jour. Natl. Can. Inst. 45: 879.
Friedman, M. and J. Staub. 1976. Inhibition of mouse testicular
DNA synthesis by mutagens and carcinogens as a potential mammalian
assay for mutagenesis. Mutat. Res. 37: 67.
Genin, V.A. 1975. Increase in carcinogenic activity during joint
effect of hydrazobenzene and benzidine sulfate. Gig. Tr. Prof.
Zabol. 6: 28.
Hansch, C. and A.J. Leo. 1979. Substituent Constants for Correla-
tion Analysis in Chemistry and Biology. Wiley-Interscience, New
York.
International Agency for Research on Cancer. 1972. Aromatic
amines. Monograph on the evaluation of carcinogenic risk of chemi-
cals to man. 1: 69.
International Agency for Research on Cancer. 1974. Hydrazine and
its derivatives. Monograph on the evaluation of carcinogenic risk
of chemicals to man. 4: 81.
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Kurlyandskii, B.A., et al. 1976. Experimental study on the com-
bined effect of some diphenylamino derivatives with regard to the
prevention of occupational urinary bladder growths. Gig. Tr. Prof.
Zabol. 5: 34.
Marhold, J., Jr., et al. 1968. The possible complicity of di-
phenyline in the origin of tumors in the manufacture of benzidine.
Neoplasma. 15: 3.
National Cancer Institute. 1978. Bioassay of hydrazobenzene for
possible carcinogenicity. Publication NO. (NIH) 78-1342.
Pliss, G.B. 1974. Carcinogenic properties of hydrazobenzene.
Vop. Onkol. 20: 53.
Sieler, J.P. 1977. Inhibition of testicular DNA synthesis by
chemical mutagens and carcinogens. Preliminary results in the
validation of a novel short term test. Mutat. Res. 46: 305.
Spitz, S. 1950. The carcinogenic action of benzidine. Cancer.
3: 789.
Stephan C.E. 1980. Memorandum to J. Stara. U.S. EPA. July 3.
U.S. EPA. 1975. Preliminary assessment of suspected carcinogens
in drinking water. Rep. to Congress. 11.
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U.S. EPA. 1980. Seafood consumption data analysis. Stanford
Research Institute International, Menlo Park, California. Final
rep., Task II. Contract 68-01-3887.
Veith, G.D. 1980. Memorandum to C.E. Stephan. April 14.
Veith, G.D., et al. 1979. Measuring and estimating the bioconcen-
tration factor of chemicals in fish. Jour. Fish. Res. Board Can.
36: 1040.
Williams, R. 1959. Detoxication Mechanisms. John Wiley and Sons,
New York. p. 480.
Wynder, E.L., et al. 1963. An epidemiological investigation of
cancer in the bladder. Cancer. 16: 1388.
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APPENDIX
Summary and Conclusions Regarding the
Carcinogenicity of 1,2,-Diphenylhydrazine*
1,2-Diphenylhydrazine is used primarily in dye manufacturing
industries as a precursor in the synthesis of benzidine. There are
no data showing carcinogenic effects of 1,2-diphenylhydrazine in
humans. However, two studies have shown that 1,2-diphenylhydrazine
is carcinogenic in mice and rats via subcutaneous and oral routes
of administration. Male rats, receiving dietary concentrations of
0.03 percent 1,2-diphenylhydrazine, developed hepatocellular car-
cinomas, squamous cell carcinomas of the Zymbal's gland, and adre-
nal tumors. Female rats, receiving 0.01 percent 1,2-diphenylhydra-
zine in the diet, developed neoplastic nodules of the liver and
mammary adenocarcinomas. Female mice, exposed to 0.04 percent 1,2-
diphenylhydrazine in the diet, developed hepatocellular car-
cinomas.
The carcinogenic responses induced in male and female rats and
female mice constitute substantial evidence that 1,2-diphenylhy-
drazine is likely to be a human carcinogen.
The water quality criterion for 1,2-diphenylhydrazine is based
on the induction of hepatocellular carcinoma and neoplastic nodules
in male Fischer 344 rats, exposed to a time-weighted average con-
centration of 0.008 or 0.03 percent (80 or 300 ppm) 1,2-diphenyl-
hydrazine in the diet for 78 weeks (NCI, 1978). The concentration
of 1,2-diphenylhydrazine in water calculated to keep the lifetime
cancer risk below 10"5 is 0.42 ug/1.
*This summary has been prepared and approved by the Carcinogens
Assessment Group of EPA on June 15, 1979.
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Summary of Pertinent Data
The water quality criterion for 1,2-diphenylhydrazine is based
on the induction of hepatocellular carcinomas and neoplastic nod-
ules in male Fischer 344 rats, exposed to various concentrations of
1,2-diphenylhydrazine in the diet ad libitum for 78 weeks (NCI,
1978) . The criterion was calculated from the following parameters:
Dose Incidence
(mg/kg/day) (no. responding/no, tested)
0 6/95
4 13/49
15 37/49
le = 78 weeks w = 0.380 kg
Le = 104 weeks R = 24.9 I/kg
L = 104 weeks
With these parameters the carcinogenic potency for humans,
q *, is 0.768 (mg/kg/day) . The resulting water concentration of
1,2-diphenylhydrazine, calculated to keep the individual lifetime
— 5
cancer risk below 10 , is 0.42 yg/1.
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U. S. GOVERNMENT PRINTING OFFICE 1MO 720-C16/4377
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