„ . ... FINAL DRAFT
United States er«n nu
Environmental Protection tlAU-CIN-
Agency Hay, 1988
Research and
Development
HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT
FOR 1.2-DIPHENYLHYDRAZINE
Prepared for
OFFICE OF SOLID WASTE AND
EMERGENCY RESPONSE
Prepared by
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Cincinnati, OH 45268
DRAFT: DO NOT CITE OR QUOTE
NOTICE
This document Is a preliminary draft. It has not been formally released
by the U.S. Environmental Protection Agency and should not at this stage be
construed to represent Agency policy. It Is being circulated for comments
on Us technical accuracy and policy Implications.
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DISCLAIMER
This report Is an external draft for review purposes only and does not
constitute Agency policy. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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PREFACE
Health and Environmental Effects Documents (HEEDs) are prepared for the
Office of Solid Waste and Emergency Response (OSWER). This document series
Is Intended to support listings under the Resource Conservation and Recovery
Act (RCRA) as well as to provide health-related limits and goals for emer-
gency and remedial actions under the Comprehensive Environmental Response,
Compensation and Liability Act (CERCLA). Both published literature and
Information obtained for Agency Program Office files are evaluated as they
pertain to potential human health, aquatic life and environmental effects of
hazardous waste constituents. The literature searched for 1n this document
and the dates searched are Included 1n "Appendix: Literature Searched."
Literature search material Is current up to 8 months previous to the final
draft date listed on the front cover. Final draft document dates (front
cover) reflect the date the document Is sent to the Program Officer (OSWER).
Several quantitative estimates are presented provided sufficient data
are available. For systemic toxicants, these Include Reference doses (RfOs)
for chronic and subchronlc exposures for both the Inhalation and oral
exposures. The subchronlc or partial lifetime RfD, 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 Hfespan. This type of
exposure estimate has not been extensively used, or rigorously defined as
previous risk assessment efforts have focused primarily on lifetime exposure
scenarios. Animal data used for subchronlc estimates generally reflect
exposure durations of 30-90 days. The general methodology for estimating
subchronlc RfDs 1s the same as traditionally employed for chronic -estimates,
except that subchronlc data are utilized when available.
In the case of suspected carcinogens, RfOs are not estimated. Instead,
a carcinogenic potency factor, or q-|* (U.S. EPA, 1980b) Is provided.
These potency estimates are derived for both oral and Inhalation exposures
where possible. In addition, unit risk estimates for air and drinking water
are presented based on Inhalation and oral data, respectively.
Reportable quantities (RQs) based on both chronic toxlclty and cardno-
genldty are derived. The RQ 1s used to determine the quantity of a
hazardous substance for which notification 1s required In the event of a
release as specified under the Comprehensive Environmental Response, Compen-
sation and Liability Act (CERCLA). These two RQs (chronic toxlclty and
cardnogenlcHy) represent two of six scores developed (the remaining four
reflect 1gn1tab1lHy, reactivity, aquatic toxlclty, and acute mammalian
toxlclty). Chemical-specific RQs reflect the lowest of these six primary
criteria. The methodology for chronic toxldty and cancer based RQs are
defined In U.S. EPA. 1984 and 1986a, respectively.
111
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EXECUTIVE SUMMARY
1,2-D1phenylhydraz1ne 1s a solid at ambient temperatures; It Is
Insoluble In water but highly soluble 1n ethanol (Heast, 1985). It 1s
unstable In both air and water under normal conditions (U.S. EPA, 1981;
R1gg1n and Howard. 1979). 1,2-D1phenylhydraz1ne 1s commonly produced by the
reduction of nitrobenzene with zinc dust 1n alkaline solution (U.S. EPA.
1981). In 1977. one company In the United States produced between 0.1 and
1.0 million pounds of this chemical. Because of Us adverse health effects,
the production of 1,2-d1phenylhydraz1ne 1n the United States has been
greatly reduced In recent years (U.S. EPA, 1981). Data regarding current
producers or production volumes of 1,2-dlphenylhydrazlne 1n the United
States were not available (USITC, 1986; SRI, 1987). 1,2-D1phenylhydraz1ne
Is used primarily In the production of benz1d1ne-based dyes and 1n the
manufacture of such Pharmaceuticals as sulfInpyrazone and phenylbutazone
(U.S. EPA, 1981).
Limited data were available 1n the literature regarding the fate and
transport of 1,2-dlphenylhydrazlne In any environmental media. In air,
direct photolysis, oxidation by molecular oxygen and reaction with HO* are
expected to convert !,2-d1phenylhydraz1ne Into azobenzene. The half-life
for the conversion of 1,2-d1phenylhydraz1ne to azobenzene by photochemically
produced H0> 1s estimated to be -7 hours (U.S. EPA, 19B6b). The fate and
transport of 1,2-dlphenylhydrazlne In the atmosphere will be controlled
Indirectly by Us oxidation product azobenzene. Photolysis, reaction with
molecular oxygen and blodegradatlon may be responsible for the loss of
!,2-d1phenylhydraz1ne from water (Callahan et al., 1979). The half-life of
1v
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!,2-d1phenylhydraz1ne In clean water may be 7 hours and In wastewater 15
minutes (Rlggln and Howard, 1979); however, 1,2-dlphenylhydrazlne may not be
degraded In water but may be converted Into azobenzene (Callahan et al.,
1979). As In the case of air, the fate of 1,2-d1phenylhydraz1ne in water
will be controlled by azobenzene, which may undergo further degradation Into
aniline and other products (Callahan et al., 1979). Similarly, the trans-
port of !,2-d1phenylhydraz1ne In water will be controlled by azobenzene
formed as a result of oxidation of 1,2-d1phenylhydraz1ne. In soils,
1,2-d1phenylhydraz1ne will undergo rapid oxidation In the presence of 0_
and certain metal cations; It may undergo both aerobic (primarily 1n top
layers) and anaerobic (In deeper soil layers) blodegradatlon. 1,2-D1phenyl-
hydrazlne and particularly Its oxidation product (azobenzene) will be
moderately to strongly adsorbed In soils and are not likely to leach to
groundwater from most soils.
Aquatic, toxlclty Information for 1,2-d1phenylhydraz1ne 1s limited to
acute lethality data for two freshwater animal species. These data Indicate
that the no-d1scern1ble-effect concentration for Daphnla magna Is 0.41
mg/i. that 24-hour LC5Qs for Lepomls macrochlrus and Daphnla magna are
1.2 and 8.1 mg/a, respectively, and that 96-hour LC s for Lepomls
macrochlrus and Daphnla magna are 0.27 and 4.1 mg/a, respectively.
Limited pharmacoklnetlc data for rats Indicate that 1,2-dlphenylhydra-
zlne Is absorbed by the gastrointestinal and respiratory tracts and excreted
as unchanged compound and metabolites In the urine. Specific Information
regarding the rate and extent of absorption or excretion, other excretory
pathways or distribution of 1,2-d1phenylhydraz1ne 1s not available. Identi-
fied urinary metabolites 1n rats Include aniline, benzldlne and amlnophenols.
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Limited toxlclty data are available for 1,2-dlphenylhydrazlne. Four-
week feeding studies conducted by the NCI (1978) showed that diets contain-
ing >0.108 and 0.301% of compound produced deaths 1n rats and mice, respec-
tively. Intestinal hemorrhage In mice at unspecified concentrations was the
only gross pathologic effect attributed to treatment. In chronic oral
studies, rats and mice were given 1,2-dlphenylhydrazlne In the diet for 78
weeks at concentrations of 0.008 or 0.03% (male rats), 0.004 or 0.01%
(female rats). 0.008 or 0.04% (male mice) and 0.004 or 0.04% (female mice)
(NCI, 1978). Effects Included decreased body weight gain In the high-dose
male and low- and high-dose female rats, decreased survival In the high-dose
female rats, and decreased body weight and decreased survival In the high-
dose male and female mice. NCI (1978) concluded that there were no treat-
ment-related nonneoplastlc gross or hlstologlcal alterations In either
species.
Treatment-related neoplastlc effects occurred In the NCI (1978) study,
Including hepatocellular carcinomas In the low- and high-dose male rats,
squamous-cell carcinomas and paplllomas of the Zymbal's gland In high-dose
male rats, adrenal pheochromocytomas In high-dose male rats, neoplastlc
nodules In the liver and mammary gland adenocarclnomas In high-dose female
rats, and hepatocellular carcinomas In high-dose female mice. Also, 1,2-dl-
phenylhydrazlne was tumorlgenlc In rats and mice In Inadequately reported
chronic oral, subcutaneous and dermal cardnogenlcHy studies (PUss, 1974),
and produced positive responses In a Strain A mouse pulmonary tumor assay
(Maronpot et al., 1986). 1,2-D1phenylhydraz1ne was not tumorlgenlc when
administered to rats by subcutaneous Injection once weekly for life (Spitz
et al., 1950).
v1
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1,2-D1phenylhydraz1ne Induced reverse mutations In §_._ typhlmurlum strain
TA100 but not In other strains of S... typhlmurlum or 1n E_^ coll WP2 uvrA
(Haworth et al., 1983; Dunkel et al., 1985). 1,2-D1phenylhydraz1ne Inhib-
ited thymldlne Incorporation Into mouse testlcular ONA when administered by
a single IntraperHoneal Injection (Seller, 1977), but did not Induce
sex-linked recessive lethal mutations 1n Drosophlla melanoqaster (Yoon et
al.. 1985).
Information Is not available regarding the toxlclty or carclnogenldty
of Inhaled 1,2-d1phenylhydraz1ne, or teratogenlclty or other reproductive
effects of !,2-d1phenylhydraz1ne by the oral or Inhalation routes.
Using the dose-response data for hepatocellular carcinoma and liver
neoplastlc nodules In male rats from the NCI (1978) carclnogenldty
bloassay, a q * of 0.8 (mg/kg/day)'1 was calculated for oral exposure to
1,2-dlphenylhydrazlne (U.S. EPA, 1980a). This q^ was verified and
adopted as the Inhalation q-j* (U.S. EPA, 1987b). An RQ of 100 for
systemic toxlclty was calculated on the basis of decreased survival of rats
In the NCI (1978) bloassay. An RQ of 10 for carclnogenldty was calculated
from the NCI (1978) male rat liver tumor/nodule Incidence data.
vll
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TABLE OF CONTENTS
1. INTRODUCTION 1
1.1. STRUCTURE AND CAS NUMBER 1
1.2. PHYSICAL AND CHEMICAL PROPERTIES 1
1.3. PRODUCTION DATA 2
1.4. USE DATA 2
1.5. SUMMARY 3
2. ENVIRONMENTAL FATE AND TRANSPORT 4
2.1. AIR 4
2.2. WATER 4
2.3. SOIL 7
2.4. SUMMARY 7
3. EXPOSURE 9
4. AQUATIC TOXICITY 10
4.1. ACUTE TOXICITY . . • 10
4.2. CHRONIC EFFECTS 10
4.3. PLANT EFFECTS 10
4.4. SUMMARY 10
5. PHARMACOKINETCS : 11
5.1. ABSORPTION 11
5.2. DISTRIBUTION 11
5.3. METABOLISM 11
5.4. EXCRETION 12
5.5. SUMMARY 12
6. EFFECTS 13
6.1. SYSTEMIC TOXICITY 13
6.1.1. Inhalation Exposures 13
6.1.2. Oral Exposures 13
6.1.3. Other Relevant Information 14
6.2. CARCINOGENICITY 14
6.2.1. Inhalation 14
6.2.2. Oral 14
6.2.3. Other Relevant Information 18
6.3. MUTAGENICITY 19
6.4. TERATOGENICITY 20
6.5. OTHER REPRODUCTIVE EFFECTS 20
6.6. SUMMARY 20
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TABLE OF CONTENTS (cont.)
Page
7. EXISTING GUIDELINES AND STANDARDS 23
7.1. HUMAN 23
7.2. AQUATIC 23
8. RISK ASSESSMENT 24
8.1. CARCINOGENICITY 24
8.1.1. Inhalation 24
8.1.2. Oral 24
8.1.3. Other Routes 25
8.1.4. Weight of Evidence 25
8.1.5. Quantitative Risk Estimates 25
8.2. SYSTEMIC TOXICITY 27
8.2.1. Inhalation Exposure 27
8.2.2. Oral Exposure 27
9. REPORTABLE QUANTITIES 28
9.1. BASED ON SYSTEMIC TOXICITY 28
9.2. BASED ON CARCINOGENICITY 28
10. REFERENCES 35
APPENDIX A: LITERATURE SEARCHED 42
APPENDIX B: CANCER DATA SHEET FOR DERIVATION OF q-(* FOR ORAL
EXPOSURE 45
APPENDIX C: SUMMARY TABLE FOR 1,2-DIPHENYLHYDRAZINE 46
1x
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LIST OF TABLES
No. Title Paqe
6-1 Incidence of Tumors In F344 Rats and B6C3F1 Mice Treated
with Technical Grade 1,2-D1phenylhydraz1ne In the Diet
for 78 Weeks 16
9-1 Oral Toxlclty Summary for 1,2-D1phenylhydraz1ne 29
9-2 Oral Composite Scores for 1,2-D1phenylhydraz1ne 30
9-3 l,2-D1phenylhydraz1ne: Hlmlmum Effective Dose (MED) and
Reportable Quantity (RQ) 31
9-4 Derivation of Potency Factor (F) for 1,2-D1phenylhydraz1ne. . 34
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LIST OF ABBREVIATIONS
ADI Acceptable dally Intake
BCF Bloconcentratlon factor
CAS Chemical Abstract Service
CS Composite score
DNA DeoxyMbonuclelc add
EC5Q Concentration producing 50* Immobilization
Koc Soil sorptlon coefficient
Kow Octanol/water partition coefficient
LC5Q Concentration lethal to 50% of recipients
1050 Dose lethal to 50% of recipients
MED Minimum effective dose
ppm Parts per million
RQ Reportable quantity
RV
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1. INTRODUCTION
1.1. STRUCTURE AND CAS NUMBER
The chemical commonly known as 1,2-d1phenylhydraz1ne 1s also known as
hydrazobenzene; sym-dlphenylhydrazlne; N,N-b1an1l1ne; and benzene,
I,l-hydrazob1s- (HSDB, 1987). The structure, empirical formula, molecular
weight and CAS Registry number for 1,2-dlphenylhydrazlne are as follows:
NH-NH
>^ /J
Empirical formula: £-12^12^2
Molecular weight: 184.24
CAS Registry number: 122-66-7
1.2. PHYSICAL AND CHEMICAL PROPERTIES
1,2-Dlphenylhydrazlne Is a solid at ambient temperatures (Weast, 1985).
It 1s Insoluble 1n water and acetic add, slightly soluble 1n benzene but
very soluble In ethanol (HSDB, 1987). Selected physical properties of
1.2-d1phenylhydraz1ne are listed below (Weast, 1985, unless otherwise
stated):
131°C
not determined
1.158 g/cm8 at 16/4°C
Melting point:
Boiling point:
Density:
water solubility:
Vapor pressure:
Log Kow:
314.5 mg/l (estimated from the Kow value
and the regression equation, log S (ymol/l) =
-1.37 log Kow + 7.26 as given 1n Lyman et al.,
1982)
not determined
2.94 (Hansch and Leo, 1985)
0075d
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12/10/87
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l,2-D1phenylhydrazloe 1s a reactive chemical; H Is not stable In air or
In water. It autooxldlzes 1n air, rearranges to benzldlne In strong mineral
adds and decomposes when heated (U.S. EPA, 1981). l,2-D1phenylhydraz1ne 1s
unstable even 1n aqueous solutions of moderate pH. At a pH of 10, U
apparently decomposes primarily to azobenzene; at a pH of 2, 1t degrades to
benzldlne; and at a pH of 7, 1t degrades to an unidentified oxldlzable
product(s) (Rlggln and Howard, 1979).
1.3. PRODUCTION DATA
Bofors Lakeway Inc., Huskegon, HI, reported that production of 1,2-dl-
phenylhydrazlne In 1977 ranged from 0.1-1.0 million pounds (U.S. EPA, 1981).
No production data for this compound were available from 1979 to date (U.S.
EPA, 1981; SRI, 1987; USITC, 1986). It Is likely that the production of
this compound 1n the United States has been greatly reduced because of the
known adverse health effects; however, FabMcolor Inc., Patterson, NJ, which
manufactures benz1d1ne-based dyes and both C1ba-Ge1gy Corp., Suffern, NY,
and R.S.A Corp., Ardsley, NY. which manufacture 1,2-d1phenylhydraz1ne-based
drugs may still use this chemical (U.S. EPA. 1981; SRI, 1987). It 1s not
known whether these companies produce this chemical on site or use Imported
!,2-d1phenylhydraz1ne. In 1983, only 22,161 pounds of 1,2-d1phenylhydraz1ne
was Imported In the United States through principal custom districts (USITC,
1984). l,2-D1phenylhydraz1ne Is produced by the reduction of nitrobenzene
with zinc dust or Iron powder In an alkaline solution or by the electrolytic
reduction of nitrobenzene (U.S. EPA, 1981).
1.4. USE DATA
1,2-D1phenylhydraz1ne 1s used mainly as the starting material for the
production of benz1d1ne-based dyes and as an Intermediate In the manufacture
of Pharmaceuticals such as sulflnpyrazone and phenylbutazone (U.S. EPA,
1981).
0075d -2- 03/08/88
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1.5. SUMMARY
1,2-D1phenylhydraz1ne 1s a solid at ambient temperatures; It 1s
Insoluble In water but highly soluble 1n ethanol (Heast, 1985). It Is
unstable In both air and water under normal conditions (U.S. EPA, 1981;
Rlggln and Howard, 1979). 1,2-01phenylhydraz1ne Is commonly produced by the
reduction of nitrobenzene with zinc dust In alkaline solution (U.S. EPA.
1981). In 1977, one company In the United States produced between 0.1 and
1.0 million pounds of this chemical. Because of Us adverse health effects,
the production of 1,2-d1phenylhydraz1ne In the United States has been
greatly reduced In recent years (U.S. EPA, 1981). Data regarding current
producers or production volumes of 1,2-dlphenylhydrazlne In the United
States were not available (USITC, 1986; SRI, 1987). 1,2-D1phenylhydraz1ne
Is used primarily In the production of benz1d1ne-based dyes and 1n the
manufacture of such Pharmaceuticals as sulflnpyrazone and phenylbutazone
(U.S. EPA, 1981).
0075d -3- 03/08/88
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2. ENVIRONMENTAL FATE AND TRANSPORT
2.1. AIR
Limited Information regarding the fate of 1,2-d1phenylhydraz1ne In the
atmosphere was located 1n the available literature. In air, 1,2-dlphenyl-
hydrazlne will be rapidly converted to azobenzene (Callahan et al., 1979);
however, the species responsible for this oxidation Is not known with
certainty. Although molecular oxygen may convert 1,2-d1phenylhydraz1ne to
azobenzene In aerated aqueous solution (Callahan et al., 1979), the most
likely species to oxidize 1,2-d1phenylhydraz1ne In the atmosphere Is H0«.
No experimental value for the rate constant of H0» reaction with l,2-d1-
phenylhydrazlne Is available. Based on the Graphical Exposure Modeling
System (GEMS) of the U.S. EPA (1986b), the rate constant for this reaction
was estimated as S.AxlO"11 cmVmolecule-sec. If the concentration of
these radicals In the atmosphere Is assumed to be 8xlOs molecules/cm3
(U.S. EPA. 1986b), the half-life of this reaction Is ~7 hours. Because
!,2-d1phenylhydraz1ne absorbs substantial amounts of light of wavelength
>290 nm (HSOB, 1987), direct photolysis of 1,2-dlphenylhydrazlne In the
atmosphere 1s also likely to occur, although the half-life of this reaction
cannot be estimated.
The fate of 1,2-d1phenylhydraz1ne with respect to transport In and out
of the atmosphere 1s uncertain. Based on the expected short half-life for
the oxidation of 1,2-d1phenylhydraz1ne to azobenzene, It 1s the transport of
azobenzene (azobenzene may be stable In air) that may determine the ultimate
fate of 1,2-dlphenylhydrazlne In air.
2.2. WATER
Limited experimental data are available regarding the fate of 1,2-dl-
phenylhydrazlne 1n water. The photolysis of l,2-d1phenylhydraz1ne with UV
0075d -4- 03/08/88
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light consisting of wavelengths <290 nm (solar cutoff wavelength) was
reported by Callahan et al. (1979) and Shlzuka et al. (1970). In aerated
solutions, 1,2-dlphenylhydrazlne was oxidized to azobenzene, and In the
presence of hydrogen-donating solvents both azobenzene and aniline were
formed. Since the photooxldatlon reaction 1s easily reversible and
azobenzene may not undergo further photolysis, this reaction may not serve
as a significant process for the degradation of 1,2-dlphenylhydrazlne. If
1,2-d1phenylhydraz1ne or Us oxidized product (azobenzene), however, remain
sorbed to organic partlculate matters that are capable of producing hydrogen
donors (e.g., chlorophyll or Us derivatives) In water, 1,2-dlphenylhydra-
zlne may be degraded to aniline during photolysis (Callahan et al., 1979).
Therefore, 1,2-dlphenylhydrazlne which can absorb significant solar radia-
tion may undergo significant photodegradatlon by the above pathway (Callahan
et al., 1979). 1,2-D1phenylhydraz1ne 1s rapidly and reverslbly oxidized to
azobenzene by molecular oxygen 1n aerated solution, even In the absence of
light. This reaction Is pH-dependent and Is catalyzed by common cations,
e.g., Cu(*2) found In natural water. At a pH of 10, the half-life for the
formation of azobenzene 1n this reaction Is -6 minutes In the absence of
Cu(+2) catalyst and 1 minute In the presence of Cu(+2) catalyst (Callahan et
al., 1979). The stability of 1,2-dlphenylhydrazlne In aqueous solution In
the pH range of 2-10 at room temperature and 4°C was studied by Rlggln and
Howard (1979). More than 9OX of 1,2-dlphenylhydrazlne disappeared In <1 day
under all conditions, and the rate of disappearance was even faster In the
presence of chlorine. Rlggln and Howard (1979) concluded that azobenzene 1s
formed at a pH of 10 and benzldlne Is formed at a pH of 2. The product
formed at pH 7 could not be Identified.
0075d -5- 03/08/88
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The hydrolysis of 1,2-d1phenylhydraz1ne In aqueous solutions 1s not
expected to be significant (Callahan et al., 1979). 1,2-D1phenylhydraz1ne
was not readily biodegradable with aniline-acclimated mixed microorganisms
(Malaney, 1960). Tabak et al. (1981) used the static-culture flask-
screening procedure with settled domestic wastewater as mlcroblal Inoculum
to assess the blodegradablllty of 1,2-dlphenylhydrazlne, and concluded that
1,2-dlphenylhydrazlne may undergo significant degradation with gradual
adaptation, followed by a decrease In degradation rate because of the toxlc-
Ity of the compound toward the microorganisms. The study by Rlggln and
Howard (1979), although not designed to test blodegradablllty, provided some
evidence for the blodegradablllty of 1,2-dlphenylhydrazlne. The disappear-
ance time of 1,2-d1phenylhydraz1ne In wastewater (half-life of 15 minutes)
was much faster than Us disappearance from distilled water solution (half-
life of 7 hours) under similar conditions. In wastewater, the half-life of
disappearance of 1,2-dlphenylhydrazlne under anaerobic conditions was 1 hour.
No experimental data regarding the transport of 1,2-d1phenylhydraz1ne 1n
water were located In the available literature. According to Callahan et
al. (1979), volatilization of 1,2-dlphenylhydrazlne from water Is likely to
be Insignificant. The estimated KQ(. value of 561 (HSOB, 1987) for 1,2-dl-
phenylhydrazlne Indicates moderate adsorption to suspended particles and
sediments 1n water; however, this compound 1s expected to exist In equilib-
rium with azobenzene In aerated water. Since the K value for azobenzene
Is much higher (670-6410) (HSDB, 1987) than 1,2-dlphenylhydrazlne, adsorp-
tion and subsequent possible donation of hydrogen by the adsorbent during
photolysis may become an Important process (HSOB, 1987; Callahan et al.,
1979).
0075d -6- 03/08/88
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The estimated log BCF value of 2.00 Indicates that 1,2-dlphenylhydrazlne
will have a relatively low bloconcentratlon potential In fish. The esti-
mated log BCF of azobenzene, the equilibrium product of 1,2-dlphenyl-
hydrazlne, Is much higher (3.82), however, and azobenzene would therefore
have a higher potential for bloconcentratlon In fish (HSOB, 1987).
2.3. SOIL
No experimental data regarding the fate of 1,2-dlphenylhydrazlne 1n soil
were located 1n the available literature. Based on the predicted fate of
this chemical In water, 1,2-dlphenylhydrazlne will probably (because of
oxidation by 0-) be unstable on soil surfaces. The oxidation may be
further enhanced by the catalytic actions of common cations In soil. Beyond
the surfldal layer where anaerobic conditions exist, some loss of
l.2-d1phenylhydraz1ne due to blodegradatlon 1s expected to occur. Since the
compound and Us equilibrium product have moderate to high soil sorptlon
coefficients and may not have a long lifetime 1n soils, they may not leach
Into groundwater under most circumstances.
2.4. SUMMARY
Limited data were available In the literature regarding the fate and
transport of 1,2-d1phenylhydraz1ne In any environmental media. In air,
direct photolysis, oxidation by molecular oxygen and reaction with H0> are
expected to convert 1,2-d1phenylhydraz1ne Into azobenzene. The half-life
for the conversion of 1,2-dlphenylhydrazlne to azobenzene by photochemlcally
produced HO- Is estimated to be -7 hours (U.S. EPA, 1986b). The fate and
transport of l.2-d1phenylhydraz1ne 1n the atmosphere will be controlled
Indirectly by Us oxidation product azobenzene. Photolysis, reaction with
molecular oxygen and blodegradatlon may be responsible for the loss of
1,2-d1phenylhydraz1ne from water (Callahan et al., 1979). The half-life of
0075d -7- 03/08/88
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1,2-dlphenylhydrazlne In clean water may be 7 hours and In wastewater 15
minutes (Rlggln and Howard, 1979); however, 1,2-dlphenylhydrazlne may not be
degraded In water but may be converted Into azobenzene (Callahan et al.,
1979). As In the case of air, the fate of 1,2-d1phenylhydraz1ne In water
will be controlled by azobenzene, which may undergo further degradation Into
aniline and other products (Callahan et al., 1979). Similarly, the transport
of 1,2-d1phenylhydraz1ne In water will be controlled by azobenzene formed as
a result of oxidation of 1,2-d1phenylhydraz1ne. In soils, l,2-d1phenyl-
hydrazlne will undergo rapid oxidation In the presence of 0. and certain
metal cations and may undergo both aerobic (primarily In top layers) and
anaerobic (In deeper soil layers) blodegradatlon. 1,2-Dlphenylhydrazlne and
particularly Its oxidation product (azobenzene) will be moderately to
strongly adsorbed In soils and are not likely to leach to groundwater from
most soils.
0075d -8- 03/08/88
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3. EXPOSURE
Workers Involved In the manufacture of certain dyes and Pharmaceuticals
are likely to be occupatlonally exposed to 1,2-d1phenylhydraz1ne both
through Inhalation and dermal routes of exposure; however, no experimental
data other than a reported level of 0.006-3000 pg/4. In the air of a
Czeckoslovaklan benzldlne manufacturing plant were located In the available
literature to confirm this prediction. Although a survey of drinking water
from 10 U.S. cities for the presence of carcinogenic substances found no
1,2-dlphenylhydrazlne 1n the finished water at the treatment plant, one tap
water sample was found to contain 1 pg/l of 1,2-d1phenylhydraz1ne (U.S.
EPA, 1980a). 1,2-D1phenylhydraz1ne was not found In water from Lake Erie
and Lake Michigan (Great Lakes Water Quality Board, 1983), but was quantita-
tively detected In sedlment/soll/water samples from Love Canal, Niagara
Falls, NY (Hauser and Bromberg, 1982). 1,2-01phenylhydraz1ne has not been
detected In any foods In the United States or elsewhere.
0075d -9- 03/08/88
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4. AQUATIC TOXICITY
4.1. ACUTE TOXICITY
In statU tests with 1,2-dlphenylhydrazlne, 24-hour and 96-hour LC5Qs
of 1.2 and 0.27 mg/l, respectively, were determined for the blueglll,
Lepomls macrochlrus (Buccafusco et al., 1981; U.S. EPA, 1978).
LeBlanc (1980) and U.S. EPA (1978) determined 24- and 96-hour LC5Qs of
8.1 and 4.1 mg/l, respectively, for Daphnla magna In static tests; a no-
dlscernlble-effect concentration was determined to be 0.41 mg/l. A
48-hour EC,, was determined for Daphnla magna (Randall and Knopp, 1980).
3U
4.2. CHRONIC EFFECTS
Pertinent data regarding the chronic effects of 1,2-dlphenylhydrazlne 1n
aquatic animals were not located In the available literature cited 1n
Appendix A.
4.3. PLANT EFFECTS
Pertinent data regarding effects of 1,2-d1phenylhydraz1.ne on aquatic
plants were not located 1n the available literature cited In Appendix A.
4.4. SUMMARY
Aquatic toxlclty Information for 1,2-dlphenylhydrazlne Is limited to
acute lethality data for two freshwater animal species. These data Indicate
that the no-d1scern1ble-effect concentration for Daphnla magna Is 0.41
mg/l, that 24-hour LCcns for Lepomls macrochlrus and Daphnla magna are
t>u — — —
1.2 and 8.1 mg/l, respectively, and that 96-hour LC s for Lepomls
macrochlrus and Daphnla magna are 0.27 and 4.1 mg/l, respectively.
0075d -10- 03/08/88
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5. PHARMACOKINETICS
5.1. ABSORPTION
Pertinent data regarding the rate and extent of absorption of 1,2-dl-
phenylhydrazlne were not located In the available literature cited In
Appendix A. The Identification of unchanged 1,2-dlphenylhydrazlne and
metabolites 1n the urine of rats following oral and Intratracheal dosing
with l,2-d1phenylhydraz1ne (Dutklewkz and Szymanska, 1973) (Section 5.3.)
Indicates that absorption by the gastrointestinal and respiratory tracts
occurs.
5.2. DISTRIBUTION
Pertinent data regarding the distribution of 1,2-d1phenylhydraz1ne were
not located 1n the available literature cited 1n Appendix A.
5.3. METABOLISM
The results of thin-layer chromatographlc analyses of urine from rats
that were treated wHh 1,2-dlphenylhydrazlne by different routes were
reported 1n an abstract of a Polish study (Dutk1ew1cz and Szymanska, 1973).
Urine contained 1,2-dlphenylhydrazlne, benzldlne, aniline, two unspecified
hydroxy derivatives of benzldlne and two unknown compounds following oral
doses of 200 or 400 mg/kg, and 1,2-dlphenylhydrazlne, aniline, benzldlne,
p-amlnophenol and o-amlnophenol following Intraperltoneal doses of 100 or
200 mg/kg. One urinary metabolite, which appeared to be phenolic but was
otherwise uncharacterlzed, was found after Intratracheal or Intravenous
Injection of unspecified doses. Additional Information regarding the design
or results of these experiments was not reported.
It has been suggested that benzldlne may be produced from 1,2-dlphenyl-
hydrazlne by acidity 1n the stomach (IARC, 1972).
0075d -11- 12/10/87
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5.4. EXCRETION
Pertinent data regarding the rate and extent of excretion of l,2-d1-
phenylhydrazlne were not located 1n the available literature dted In
Appendix A. The Identification of unchanged 1,2-dlphenylhydrazlne and
metabolites In the urine following oral dosing of rats with 1,2-dlphenyl-
hydrazlne (Dutklewlcz and Szymanska, 1973) (see Section 5.3.) Indicates that
some excretion occurs 1n the urine.
5.5. SUMMARY
Limited pharmacoklnetlc data for rats Indicate that 1,2-dlphenylhydra-
zlne 1s absorbed by the gastrointestinal and respiratory tracts and excreted
as unchanged compound and metabolites 1n the urine. Specific Information
regarding the rate and extent of absorption or excretion, other excretory
pathways or distribution of 1,2-dlphenylhydrazlne 1s not available. Identi-
fied urinary metabolites In rats Include aniline, benzldlne and amlnophenols.
0075d -12- 12/10/87
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6. EFFECTS
6.1. SYSTEMIC TOXICITY
6.1.1. Inhalation Exposures. Pertinent data regarding the subchronlc or
chronic toxic effects of Inhaled 1,2-dlphenylhydrazlne were not located 1n
the available literature cited 1n Appendix A.
6.1.2. Oral Exposures.
6.1.2.1. SUBCHRONIC — In dose-selection studies for the NCI (1978)
carclnogenesls bloassay, groups of five F344 rats and five B6C3F1 mice of
each sex were maintained for 4 weeks on diets that contained technical grade
1,2-d1phenylhydraz1ne, followed by a 2-week observation period. Hale rat
and male mouse groups received diets containing 0, 0.007, 0.014, 0.028,
0.055. 0.108, 0.214. 0.301 or 0.423% of the compound. Female rat groups
received diets containing 0, 0.00008, 0.0003, 0.0011, 0.002, 0.004, 0.015,
0.104, 0.731 or 5.138% of the compound. Female mouse groups received diets
containing 0, 0.0003, 0.0008, 0.0011, 0.002, 0.004, 0.015, 0.104. 0.731 or
5.138% of the compound. Deaths occurred In 2/5 male rats at 0.108% and In
all rats of both sexes at higher concentrations. Deaths occurred In 1/5
male mice at 0.301%, In 2/5 male mice at 0.423%. 1n 4/5 female mice at
0.731% and 1n all female mice at 5.138%. Body weight and gross pathologic
evaluations were conducted 1n both species, but Information regarding these
endpolnts was limited and ambiguous; NCI (1978) Indicated that the only
consistent effect was Intestinal hemorrhage In mice at unspecified
concentrations.
6.1.2.2. CHRONIC -- Groups of 50 F344 rats or 47 or 50 B6C3F1 mice of
each sex were maintained for 78 weeks on diets that contained technical
grade 1,2-d1phenylhydraz1ne 1n a carclnogenldty bloassay (NCI, 1978). As
detailed In Section 6.2.2., the diet concentrations were 0.008% (TWA concen-
tration) and 0.03% for male rats. 0.004% and 0.01% for female rats, 0.008%
0075d -13- 12/10/87
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(TWA concentration) and 0.04% for male mice and 0.004% and 0.04X for female
mice. The rats and mice were observed for 28-30 weeks and 17-18 weeks,
respectively, following treatment, and separate control groups of 49-50 rats
or 50 mice of each sex were used for each treatment group. Treatment-
related effects In the rats Included slight mean group body weight depres-
sion In the high-dose males and low- and high-dose females, and reduced
survival 1n the high-dose females. In mice, mean group body weights were
depressed and survival was reduced In the high-dose male and female groups.
NCI (1978) concluded that there were no treatment-related nonneoplastlc
lesions In the rats or mice.
6.1.3. Other Relevant Information. The average amount of 1,2-d1phenyl-
hydrazlne Ingested by deer mice over a 3-day period without killing >50X of
the animals was determined to be 1213 mg/kg/day (Schafer and Bowles, 1985).
NIOSH (1987) reported an oral L05Q of 301 mg/kg for rats.
6.2. CARCINOGENICITY
6.2.1. Inhalation. Pertinent data regarding the carclnogenlclty of
Inhaled 1,2-d1phenylhydraz1ne were not located In the available literature
cited In Appendix A.
6.2.2. Oral. NCI (1978) conducted a carclnogenlclty bloassay 1n which
groups of 50 F344 rats or 47 or 50 B6C3F1 mice of each sex were maintained
on diets containing technical grade 1,2-d1phenylhydraz1ne for 78 weeks,
followed by untreated observation periods of 28 or 30 weeks (rats) and 17 or
18 weeks (mice). Separate groups of 49-50 rats or 50 mice of each sex
served as controls for each treatment group. Comprehensive gross and hUto-
loglcal examinations were conducted on all animals that died during the
study (unless precluded by unspecified factors), were sacrificed when
moribund, or were sacrificed at termination of the study.
0075d -14- 03/08/88
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The diet concentrations of 1,2-d1phenylhydraz1ne used In the rat study
were 0.007% for 9 weeks and 0.008% for the subsequent 69 weeks (0.008% TWA
concentration) In low-dose males, 0.03% In high-dose males, 0.004% In low-
dose females and 0.01% In high-dose females (NCI, 1978). As detailed In
Table 6-1, there were statistically significant Increased Incidences of
hepatocellular carcinomas or neoplastlc nodules In the liver 1n low- and
high-dose males and squamous-cell carcinomas and paplllomas of the Zymbal's
gland, ear canal or skin of the ear and adrenal pheochromocytomas 1n the
high-dose males. Statistically Increased Incidences of neoplastlc nodules
1n the liver and mammary gland adenocarclnomas occurred In high-dose female
rats.
The diet concentrations of 1,2-dlphenylhydrazlne In the mouse study were
0.007% for 9 weeks and 0.008% for the subsequent 69 weeks (0.008% TWA) In
low-dose males, 0.04% In high-dose males. 0.004% In low-dose females and
0.04% In high-dose females (NCI, 1978). An Increased Incidence of hepato-
cellular carcinomas or adenomas 1n the high-dose females was the only
treatment-related neoplastlc effect In the mice.
Survival and body weight data for the rats and the mice 1n the NCI
(1978) study are summarized In Section 6.1.2.2. Treatment-related decreased
survival occurred In the high-dose groups of both species, but adequate
numbers of animals survived to be at risk for late-developing tumors.
l,2-D1phenylhydraz1ne In sunflower oil was administered to mice and rats
1n the diet at doses of 30 mg/an1mal, 5 times/week over a period of 588
days. In a Russian study (PUss, 1974). Neoplasms Including pulmonary
adenomas, liver tumors or leukemia developed In 50% of the treated mice and
rats. Tumor Incidence data were not reported for control groups. The only
additional Information regarding this study reported by U.S. EPA (1980a,
0075d -15- 03/08/88
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TABLE 6-1
Incidence of Tuoors In F344 Rats and B6C3F1 Nice Treated with Technical Grade 1,2-Dlphenylhydrazlne In the Diet for 78 Weeks3
4
1
L
_J
T>
ISJ
o
00
Diet
Species Sex Concentration
(*)b
Rat N Oc
of
0.0089
0.03
N Oe
of
0.0089
0.03
M 0*
of
0.008e
0.03
F 0*
of
Duration
of Study
(weeks)
108
109
107
106
108
109
107
106
108
109
107
107
109
109
Tuaor Site
liver
liver
liver
liver
Zymbal's gland ear
canal. Zymbal's gland
and skin of ear
Zyobal's gland ear
canal. Zyabal's gland
and skin of ear
Zymbal's gland ear
canal. Zymbal's gland
and skin of ear
Zymbal's gland ear
canal. Zymbal's gland
and skin of ear
adrenal
adrenal
adrenal
adrenal
liver
liver
Tumor Type
hepatocellular carcinoma
hepatocellular carcinoma or neoplastlc nodule
hepatocellular carcinoma
hepatocellular carcinoma or neoplastlc nodule
hepatocellular carcinoma
hepatocellular carcinoma or neoplastlc nodule
hepatocellular carcinoma
hepatocellular carcinoma or neoplastlc nodule
squamous-cell carcinoma
squamous-cell carcinoma or papllloma
squamous-cell carcinoma
squamous-cell carcinoma or papllloma
squamous-cell carcinoma
squamous-cell carcinoma or papllloma
squannus-cell carcinoma
squamous-cell carcinoma or papllloma
pheochromocytoma or malignant pheochromocytoma
pheochromocytoma or malignant pheochronncytoma
pheochromocytoma or malignant pheochroroocytoma
pheochromocytoma or malignant pheochromocytoma
neoplastlc nodule
neoplastlc nodule
Tumor Incidence0
(p value)*)
0/47
5/«7
1/48
1/48
5/49 (p=0.031)
13/49 (p=0.040)
31/49 (p<0.001)
37/49 (p<0.001)
0/47
1/47
0/48
0/48
I/SO (NS)
?/SO (NS)
5/49 (p.O. 030)
7/49 |p=0.007)
7/47
8/47
7/48 (NS)
16/46 (p=0.04?)
0/47
0/50
-------
TABU 6-1 (cont.)
0
0
-J
in
a.
i
-j
Diet
Spectes Sex Concentration
<*)b
Rat F 0.004
0.01
f 0*
0'
0.004
0.01
House F Oe
Qf
0.004
0.04
Duration
of Study
(weeks)
108
107
109
109
108
107
96
96
95
96
Tumor Site
liver
liver
nanndry gland
•anoary gland
oamary gland
naonary gland
liver
liver
liver
liver
Tumor Type
neoplastlc nodule
neoplastlc nodule
adenocarclnona NOS
adenocarclnona NOS
adenocarclnoma NOS
adenocarclnona NOS
hepatocellular carcinoma
hepatocellular adenoma or carcinoma
hepatocellular carcinoma
hepatocellular adenoma or carcinoma
hepatocellular carcinoma
hepatocellular adenoma or carcinoma
hepatocellular carcinoma
hepatocellular adenoma or carcinoma
Tumor Incidence
(p value)0*
0/50 (NS)
6/50 (p.O. 013)
1/48
0/50
3/50 (HS)
6/50 (p=0.013)
2/47
2/47
1/50
1/50
4/39 (NS)
4/39 (NS)
20/43 (p<0.001)
22/43 (p<0.001)
Strength of Study:
Overall Adequacy:
QUALITY OF EVIDENCE
The compound was adntnlstered to both sexes of two species at two dose levels by a natural route. Adequate numbers of
animals survived to be at risk for late-developing tumors.
Adequate
rxj
>^
o
00
aSource: NCI. 1978
Control groups were used for each treatment group.
cTumor Incidence Is expressed as number of animals with tumors/number of animals examined hlstologlcally.
The p value for the Fisher Exact test Is shown next to the Incidence In the treated group when p<0.05; otherwise. NS Is Indicated.
eLow dose control group
High dose control group
9THA concentration (see text)
HS = Not significant; NOS = not otherwise specified
-------
1981) Is that the rats received a total dose of 12.57 g, that the minimal
tumor latency period was 372 days and that some animals (number unspecified)
had to be replaced during the experiment because of a parasitic Infection.
6.2.3. Other Relevant Information. Additional cardnogenldty studies of
1,2-d1phenylhydraz1ne, Inadequately reported, were conducted by Pllss (1974)
and summarized by U.S. EPA (1980a. 1981). It appears that these studies
also were conducted over a period of 588 days. Eplcutaneous application of
2 mg 3 times/week (360 mg total) to mice produced a 22.2% Incidence of skin,
lung or liver tumors; the Incidence of tumors In a control group was 17%.
Eplcutaneous application of 30 mg 5 times/week to rats was not tumorlgenlc.
Subcutaneous Injection of 5 mg/week (370 mg total) to mice produced a 36.6%
Incidence of rhabdomyosarcomas, and subcutaneous Injection of 40 mg/week
(3.8 g total) to rats produced a 22.6% Incidence of total tumors, consisting
of tumors of the uterus, mammary gland, Zymbal's gland, liver and spleen and
lymphold leukemia. The minimal latent period for tumor formation following
subcutaneous Injection was 188 days, but control data for the subcutaneous
studies and additional data for all of the studies were not reported.
l,2-D1phenylhydraz1ne In olive oil vehicle was administered to 52
Sherman rats of both sexes by subcutaneous Injection once a week at an
average dose of 60 mg (Spitz et al., 1950). Treatment was continued for
life or until grossly obvious tumors appeared, unless contralndlcated by
weight loss or Illness (total amount administered, 6.4 g). A control group
consisted of 50 vehicle-treated rats. H1stopatholog1c examination of the
liver, external auditory canal, colon and bladder showed a squamous cell
carcinoma of the auditory canal sebaceous glands In one of the treated rats.
0075d -18- 03/08/88
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It appears that comprehensive hlstopathologlcal examinations were conducted
1n this study, but data for other sites were not reported and the extent of
the examinations was not specified.
The tumor 1 gen 1cHy of 1,2-d1phenylhydraz1ne was evaluated In a Strain A
mouse pulmonary tumor assay (Haronpot et al., 1986). Groups of 10 male and
10 female mice were given Intraperltoneal Injections of 50, 100 or 200 mg/kg
In trlcaprylln vehicle 3 times/week for 8 weeks. Examinations for adenomas
16 weeks after cessation of treatment showed a positive response 1n the
high-dose males (statistically significant Increases In the Incidence of
tumor-bearing mice and tumors per mouse). There was an equivocal response
In the high-dose females (significant Increase In tumors per mouse but not
Incidence of tumor-bearing mice).
Abstracts of several Russian studies report that combined subcutaneous
administration of 1,2-d1phenylhydraz1ne (20 mg/week) and benzldlne sulfate
.(15 mg/week) to rats Increased the Incidence of tumors and decreased tumor
latency periods when compared with the activities of the Individual com-
pounds (Genln et al., 1975; Shabad and Genln, 1975; Kurlyandsk11 et al.,
1976). The Kurlyandskll et al. (1976) abstract Indicates that these
observations refer to bladder cancer. Duration of treatment and additional
relevant Information were not reported In any of the abstracts.
6.3. MUTAGENICITY
1,2-D1phenylhydraz1ne (practical grade) Induced reverse mutations In
Salmonella typhlmurlum strain TA100, but not strains TA1535, TA1537 or TA98,
when tested In a liquid suspension assay with rat liver S-9 metabolic acti-
vation preparation (Haworth et al., 1983). The compound was not mutagenlc
1n any of the strains when tested with hamster liver S-9 or without S-9
preparations.
0075d -19- 03/08/88
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Reverse mutation plate Incorporation assays were conducted In which
Salmonella typhlmurlum strains TA98, TOO, 1535, 1537 or 1538 or Escher1ch1a
coll strain WP2 uvrA were exposed to 1,2-d1phenylhydraz1ne (technical grade,
purity >65%) with or without rat, mouse or hamster liver S-9 metabolic
activation preparations (Dunkel et al., 1985). Consistent and unequivocal
positive responses were obtained only with SL. typhlmurlum strain TA100 when
assayed with rat or mouse liver S-9 preparations.
Thymldlne Incorporation Into testlcular DMA was significantly Inhibited
In mice that received a single Intraperltoneal dose of 100 mg/kg l,2-d1-
phenylhydrazlne (purity not stated) (Seller, 1977).
Practical grade 1,2-d1phenylhydraz1ne In ethanol did not Induce
sex-linked recessive lethal mutations In male DrosophUa melanoqaster when
administered by feeding for 3 days at a concentration of 50 ppm or by Intra-
perltoneal Injection at a concentration of 80 ppm (additional dose Informa-
tion not reported) (Yoon et al., 1985).
6.4. TERATOGENICITY
Pertinent data regarding the teratogenldty of 1,2-d1phenylhydraz1ne
were not located 1n the available literature cited 1n Appendix A.
6.5. OTHER REPRODUCTIVE EFFECTS
Pertinent data regarding other reproductive effects of 1,2-d1phenyl-
hydrazlne were not located In the available literature dted In Appendix A.
6.6. SUMMARY
Limited toxlclty data are available for 1,2-d1phenylhydraz1ne. Four-
week feeding studies conducted by the NCI (1978) showed that diets contain-
ing >0.108 and 0.301% of compound produced deaths 1n rats and mice, respec-
tively. Intestinal hemorrhage 1n mice at unspecified concentrations was the
only gross pathologic effect attributed to treatment. In chronic oral
0075d -20- 12/10/87
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studies, rats and mice were treated 1n the diet for 78 weeks at concentra-
tions of 0.008 or 0.03X (male rats), 0.004 or 0.01% (female rats), 0.008 or
0.04% (male mice) and 0.004 or 0.04% (female mice) (NCI, 1978). Effects
Included decreased body weight gain In the high-dose male and low- and high-
dose female rats, decreased survival 1n the high-dose female rats, and
decreased body weight and decreased survival In the high-dose male and
female mice. NCI (1978) concluded that there were no treatment-related
nonneoplastlc gross or Mstologlcal alterations In either species.
Treatment-related neoplastlc effects occurred 1n the NCI (1978) study.
Including hepatocellular carcinomas 1n the low- and high-dose male rats,
squamous-cell carcinomas and pap 1 Hernias of the Zymbal's gland In high-dose
male rats, adrenal pheochromocytomas 1n high-dose male rats, neoplastlc
nodules In the liver and mammary gland adenocarclnomas In high-dose female
rats, and hepatocellular carcinomas 1n high-dose female mice. Also, l,2-d1-
phenylhydrazlne was tumoMgenlc In rats and mice In Inadequately reported
chronic oral, subcutaneous and dermal cardnogenlclty studies (Pllss, 1974),
and produced positive responses 1n a Strain A mouse pulmonary tumor assay
(Maronpot et al., 1986). 1,2-D1phenylhydraz1ne was not tumorlgenlc when
administered to rats by subcutaneous Injection once weekly for life (Spitz
et al., 1950).
1,2-D1phenylhydraz1ne Induced reverse mutations In S. typhlmuMum strain
TA100 but not 1n other strains of $_._ typhlmurlum or In E_._ coll WP2 uvrA
(Haworth et al., 1983; Dunkel et al., 1985). 1,2-D1phenylhydraz1ne Inhib-
ited thymldlne Incorporation Into mouse testlcular DNA when administered by
a single Intraperltoneal Injection (Seller, 1977), but did not Induce
sex-linked recessive lethal mutations 1n DrosophUa melanogaster (Yoon et
al., 1985).
0075d -21- 03/08/88
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Information Is not available regarding the toxIcHy or carclnogenldty
of Inhaled 1,2-d1phenylhydraz1ne, or teratogenlclty or other reproductive
effects of 1,2-d1phenylhydraz1ne by the oral or Inhalation routes.
0075d -22- 12/10/87
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7. EXISTING GUIDELINES AND STANDARDS
7.1. HUMAN
U.S. EPA (1980a) recommended ambient water quality criteria of 422, 42
and 4 ng/8. for dlphenylhydrazlne, which correspond to excess cancer risk
levels of 10~5, 10~6 and 10~7, respectively. The criteria are derived
from a q,* that 1s based on the Induction of hepatocellular carcinomas and
liver neoplastlc nodules 1n male rats (Section 8.1.5.2.). The q * of 0.8
(mg/kg/day)'1 has been verified by U.S. EPA (1987a) and corresponds to
drinking water levels of 4.5, 4.5XKT1 and 4.5xlO~a jig/9, and air
levels of 4.5xlO~1, 4.5xlO~2 and 4.5xlO"3 yg/m3 for risk levels of
10~4, 10~5 and 10~6, respectively.
U.S. EPA (1987b) has proposed an RQ of 10 for 1,2-d1phenylhydraz1ne.
Other pertinent guidelines or standards, Including drinking water
standards, FAO/HHO ADIs. and ACGIH, OSHA and NIOSH occupational exposure
limits, were not located 1n the available literature cited 1n Appendix A.
7.2. AQUATIC
The U.S. EPA (1980a) did not recommend criteria for the protection of
aquatic life from the effects of 1,2-d1phenylhydraz1ne. It was stated that
acute toxlclty to freshwater aquatic life occurs at concentrations as low as
270 ug/8., and would occur at lower concentrations among species that are
more sensitive than those tested.
0075d -23- 03/08/88
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8. RISK ASSESSMENT
8.1. CARCINOGENICITY
8.1.1. Inhalation. Pertinent data regarding the carclnogenlclty of
Inhaled 1,2-d1phenylhydraz1ne were not located In the available literature
cited In Appendix A.
8.1.2. Oral. NCI (1978) conducted a cardnogenldty bloassay In which
groups of 50 F344 rats or 47 or 50 B6C3F1 mice of each sex were maintained
on diets containing technical grade 1,2-d1phenylhydraz1ne for 78 weeks,
followed by untreated observation periods of 28 or 30 weeks (rats) and 17 or
18 weeks (mice). The dietary concentrations of 1,2-d1phenylhydraz1ne used
In the rat study were 0.008% (TWA concentration) or 0.03% In males, and
0.004 or 0.01% In females. The dietary concentrations used 1n the mouse
study were 0.008% (TWA concentration) or 0.04% In males, and 0.004 or 0.04%
1n females. Separate groups of 49-50 rats or 50 mice of each sex served as
controls for for each treatment group. As detailed In Table 6-1, there were
statistically Increased Incidences of hepatocellular carcinomas or neo-
plastlc nodules 1n the liver In low- and high-dose male rats, squamous-cell
carcinomas and paplllomas of the Zymbal's gland 1n high-dose male rats,
adrenal pheochromocytomas In high-dose male rats, and neoplasUc nodules In
the liver and mammary gland adenocardnomas In high-dose female rats. In
mice, there was a statistically Increased Incidence of hepatocellular
carcinomas or adenomas 1n the high-dose females.
1,2-01phenylhydraz1ne 1n sunflower oil was administered to mice and rats
In the diet at concentrations of 30 mg/anlmal, 5 times/week for 588 days, 1n
an Inadequately reported Russian study (PUss, 1974). Pulmonary adenomas,
liver tumors or leukemia occurred 1n 50% of the treated mice and rats, but
Incidences of tumors by type and In control groups were not reported.
0075d -24- 03/08/88
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8.1.3. Other Routes. Inadequately reported subcutaneous studies with
mice (5 mg/week) and rats (40 mg/week) and eplcutaneous studies with mice (2
mg, 3 times/week) were conducted by PUss (1974). Various tumors were
attributed to treatment (see Section 6.2.3.), but Incidences were not
reported for specific tumor types and control data were not reported for the
subcutaneous Injection studies.
1,2-D1phenylhydraz1ne was not tumorlgenlc when administered to rats by
subcutaneous Injection at an average dose of 60 mg once a week for life
(total dose 6.4 g) (Spitz et al., 1950).
The tumorlgenldty of 1,2-dlphenylhydrazlne was evaluated In a Strain A
mouse pulmonary assay (Maronpot et al., 1986). There was a positive
response 1n males and an equivocal response 1n females at the highest dose
tested (200 mg/kg IntraperUoneally).
8.1.4. Height of Evidence. The carclnogenlclty of 1,2-d1phenylhydraz1ne
has been demonstrated In both rats and mice In .adequate oral bloassays (NCI,
1978). 1,2-Dlphenylhydrazlne was also tumorlgenlc In rats and mice 1n
Inadequately reported oral, subcutaneous and dermal carclnogenlclty studies,
and produced positive responses In a Strain A mouse pulmonary tumor assay
and In mutagenldty assays. Additionally, the carclnogenlclty of other
substituted hydrazlnes has been documented (IARC. 1974). Based on the
carcinogenic responses In rats and mice In the NCI (1978) bloassay, 1,2-dl-
phenylhydrazlne Is classified as an EPA Group Bl carcinogen (U.S. EPA,
1987a).
8.1.5. Quantitative Risk Estimates.
8.1.5.1. INHALATION — Inhalation carclnogenlclty data for l,2-d1-
phenylhydrazlne are not available. The human q * of 0.8 (mg/kg/day)"1
for oral exposure was adopted by the U.S. EPA (1987a) as the q * for
0075d -25- 05/11/88
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Inhalation exposure by assuming equal potency by either route. The concen-
trations of 1,2-d1phenylhydraz1ne 1n air associated with Increased lifetime
risk of cancer at risk levels of 10~s, 10"* and 10"7 are 4.5xlO~a,
4.5xlO"3 and 4.5xl(T« pg/m3, respectively (U.S. EPA, 1986b). If It 1s
assumed that absorption by the Inhalation route Is 50%, the concentrations
associated with the 10~5, 10~* and 10~7 risk levels are twice as high
as those reported above. U.S. EPA (1987a) noted that the q * may differ
from that stated above 1f air concentrations of 1,2-dlphenylhydrazlne exceed
45 vg/m3, and that there Is low confidence In the Inhalation risk
estimate derived from oral data.
8.1.5.2. ORAL -- The U.S. EPA (1980a) used the dose-response data for
hepatocellular carcinoma and liver neoplastlc nodules In male rats from the
NCI (1978) bloassay to calculate a human q^ of 0.768 (mg/kg/day)"1 for
1,2-d1phenylhydraz1ne. The data reported 1n Appendix B were used with the
linearized multistage model (U.S. EPA, 1980b) . for the computation. The
q * [0.8 (mg/kg/day)"1] has been verified by the Agency CRAVE Work Group
Review (U.S EPA, 1987a) and 1s adopted for this document. Concentrations of
1,2-dlphenylhydrazlne 1n drinking water associated with Increased lifetime
risk of cancer at risk levels of 10~5, 10"* and 10"7 are 4.5X10"1,
4.5xlO"2 and 4.5xlO"3 wg/l, respectively (U.S. EPA, 1987a). It was
noted that the q * may differ from that stated above 1f the water concen-
tration of 1,2-dlphenylhydrazlne exceeds 450 yg/l, and that confidence
In the q,* 1s low to medium since not all neoplastlc nodules may progress
to tumors (U.S. EPA. 1987a).
0075d -26- 03/08/88
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8.2. SYSTEHIC TOXICITY
8.2.1. Inhalation Exposure. Derivation of an RfD for less than lifetime
(subchronlc) or chronic Inhalation exposure to 1,2-d1phenylhydraz1ne 1s
precluded by the lack of Inhalation toxlclty data and Is Inappropriate
because of carclnogenlclty by the oral route.
8.2.2. Oral Exposure. In a 4-week feeding study, diets that contained
>0.108 and 0.301X 1,2-d1phenylhydraz1ne produced deaths 1n rats and mice,
respectively (NCI, 1978). Chronic exposure of rats resulted In decreased
body weight gain at dietary concentrations >0.004X and decreased survival at
0.01X (NCI, 1978). Chronic exposure of mice resulted 1n decreased body
weight and survival at 0.04X. Derivation of an RfD for less than lifetime
(subchronlc) or chronic oral exposure to 1,2-d1phenylhydraz1ne Is Inappro-
priate because of carclnogenlclty by the oral route.
0075d -27- 03/08/88
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9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
Pertinent toxlclty data for 1,2-d1phenylhydraz1ne are available only
from the NCI (1978) cardnogenesls bloassay. As discussed 1n Section
6.1.2.2. and summarized In Table 9-1, 1,2-d1phenylhydraz1ne was administered
to rats and mice In the diet for 78 weeks at concentrations of 0.008% (TWA
concentration) or 0.03% for male rats, 0.004% or 0.01% for female rats,
0.008% (TWA concentration) or 0.04% for male mice and 0.004 or 0.04% for
female mice. Treatment-related nonneoplastlc effects Included slightly
decreased mean group body weight gain 1n the high-dose male and low- and
high-dose female rats, decreased survival 1n the high-dose female rats, and
decreased mean group body weight and decreased survival In the high-dose
male and female mice.
The lowest equivalent human doses at which decreased body weight and
decreased survival occurred are 0.31 and 0.76 mg/kg/day, respectively (see
Table 9-1). Multiplication of these doses by 70 kg yields MEDs of 21.7 and
53.2 mg/day, respectively (Table 9-2). The RV s corresponding to the MEDs
are 3.5 and 2.9, respectively. The most appropriate RV for decreased
weight gain 1s 4 and the RVg for life shortening Is 10. Multiplication of
the RV.s by the RV s yields CSs of 14 for decreased weight gain and 29
for life shortening. Since the CS of 29 for life shortening Is the highest
CS, U 1s the appropriate basis for the RQ. A CS of 29 corresponds to an RQ
of 100 (Table 9-3).
9.2. BASED ON CARCINOGENICITY
NCI (1978) conducted a carclnogenlcHy bloassay 1n which groups of 47-50
F344 rats or B6C3F1 mice of each sex were maintained on diets containing
technical grade 1,2-d1phenylhydraz1ne for 78 weeks, followed by untreated
observation periods of 28 or 30 weeks (rats) and 17 or 18 weeks (mice).
0075d -28- 03/08/88
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o
o
ex
TABLE 9-1
Oral Toxlclty Suraury for Technical Grade '
Species/
Strain
Rat/F344
Rat/F344
Rat/F344
i
** House/
B6C3F1
Average
Sex No. at Me1ghtb
Start (kg)
N SO 0.35
F SO 0.25
F SO 0.25
H.F SO 0.03 (N)
0.025 (F)
Vehicle/
Physical Exposure
State
diet 0.03X for
78 weeks
diet 0.004X for
78 weeks
diet 0.01X for
78 weeks
diet 0.04X for
78 weeks
l.2-D1phenylhydrai1ned
Transformed Equivalent
Animal Dosec Human Dosed
(mg/kg/day) (mg/kg/day)
15 2.56
2 0.31
5 0.76
52 3.69e
Response
decreased body
weight gain
decreased body
weight gain
decreased body
weight gain and
Increased mortality
decreased body
weight gain and
Increased mortality
^Source: NCI. 1978
'•Estimated from growth curves In the study
Calculated by multiplying dietary concentration In ppn by reference food consumption estimates (5X bw/day for rats. 13% bw/day for mice)
(U.S. EPA. 1985)
^Calculated by multiplying the transformed animal dose by the cube root of the ratio of the animal body weight to reference human body
weight (70 kg)
Calculated using female mouse body weight
ro
o
00
-------
TABLE 9-2
Oral Composite Scores for l,2-D1phenylhydraz1ne Using the Rat*
Animal Dose
(mg/kg/day)
2
5
Chronic
Human MED
(mg/day)
21.7
53.2
RVd Effect
3.5 decreased weight
gain
2.9 decreased sur-
vival and de-
creased weight
RVe CS RQ
4 14 1000
10 29 100
*Source: NCI, 1978
0075d
-30-
12/10/87
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TABLE 9-3
1,2-Dlphenylhydrazlne
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route: oral
Dose*: 0.76 mg/kg/day
Effect: decreased survival and decreased weight
Reference: NCI, 1978
RVd: 2.9
RVe: 10
Composite Score: 29
RQ: 100
'Equivalent human dose
0075d -31- 12/10/87
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The dietary concentrations were 0.008 or 0.03% 1n the male rats, 0.004 or
0.01% 1n the female rats, 0.008 or 0.04% 1n the male mice, and 0.004 or
0.04% In the female mice. Separate groups of 49-50 rats or 50 mice of each
sex served as controls for each treatment group. As detailed In Table 6-1,
there were statistically Increased Incidences of hepatocellular carcinomas
or neoplastlc nodules In the liver 1n low- and high-dose male rats,
squamous-cell carcinomas and papHlomas of the Zymbal's gland 1n high-dose
male rats, adrenal pheochromocytomas 1n high-dose male rats, and neoplastlc
nodules In the liver and mammary gland adenocarclnomas 1n high-dose female
rats. In mice, there was a statistically Increased Incidence of
hepatocellular carcinomas or adenomas 1n the high-dose females.
1,2-Olphenylhydrazlne also was tumorlgenlc In rats and mice In Inade-
quately reported chronic oral, subcutaneous and dermal cardnogenlcHy
studies (PUss, 1974), and produced positive responses 1n a Strain A mouse
pulmonary tumor assay (Haronpot et al., 1986) (see Section 6.2.). 1,2-01-
phenylhydrazlne was not tumorlgenlc when administered to rats by subcuta-
neous Injection at an average dose of 60 mg once a week for life (total dose
6.4 g) (Spitz et al., 1950).
Based primarily on the carcinogenic responses In the rats and mice In
the NCI (1978) bloassay, 1,2-dlphenylhydrazlne 1s classified as an EPA Group
Bl carcinogen (U.S. EPA, 1987a).
The NCI (1978) bloassay provides a basis for derivation of an F factor
for 1,2-dlphenylhydrazlne because U 1s the only adequate cardnogenlcHy
study and was used for derivation of a verified q^ (U.S. EPA, 1980b,
1987a). Using the Incidence data for hepatocellular carcinoma and neo-
plastlc nodules In the liver In male rats and the computerized multistage
linear model adopted by the U.S. EPA (Howe and Crump, 1982), the unadjusted
0075d -32- 05/11/88
-------
1/ED10 Is calculated to be 0.72 (mg/kg/day)"i (Table 9-4). Multiplying
by the cube root of the ratio of reference human body weight (70 kg) to
measured rat body weight (0.38 kg) results In an F factor of 4.1. This F
factor Indicates that !,2-d1phenylhydraz1ne should be placed In Potency
Group 2. A Potency Group 2 and an EPA Group Bl chemical has a Medium hazard
ranking under CERCLA. A Medium hazard ranking Is assigned an RQ of 10.
0075d -33- 05/11/88
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TABLE 9-4
Derivation of Potency Factor (F) for 1,2-D1phenylhydraz1ne
Reference:
Exposure route:
Species:
Strain:
Sex:
Vehicle or physical state:
Body weight:
Duration of treatment:
Duration of study:
Llfespan of animal:
Target organ:
Tumor type:
Experimental doses/exposures:
Transformed doses (mg/kg/day)
Tumor Incidence:
Unadjusted 1/ED10:
Adjusted 1/ED10 (F Factor):
NCI, 1978
oral
rat
F344
male
diet
0.38 kg (measured)
78 weeks
108-109 weeks (control), 107 weeks (low
dose), 106 weeks (high dose)
108-109 weeks (control), 107 weeks (low
dose), 106 weeks (high dose)
liver
hepatocellular carcinoma and neoplastlc
nodules
OX, 0.008%, 0.03X
0, 2.92, 11.04
6/95*. 13/49, 37/49
0.721407 (mg/kg/day)'1
4.1047356 (mg/kg/day)"1
*Pooled Incidences from low dose control and high dose control groups
00750
-34-
12/10/87
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10. REFERENCES
Buccafusco R.J., S.J. Ells and G.A. LeBlanc. 1981. Acute toxlclty of
priority pollutants to blueglll (Lepomls macrochlrus). Environ. Contam.
Toxlcol. 26(4): 446-452.
Callahan, H.A., M.W. Sllmak, N.W. Gabel, et al. 1979. Water-Related
Environmental Fate of 129 Priority Pollutants. Vol. 2. Office of Water
Planning and Standards, Office of Water and Waste Management, U.S. EPA,
Washington, DC. EPA 440/4-79-029b. p. 104-1 to 104-9.
Dunkel V.C., E. Zelger, D. Bruslck, et al. 1985. Reproduc1b1lHy of
mlcroblal mutagenlcHy assays. II. Testing of carcinogens and noncardno-
gens In Salmonella typh1mur1um and EscheMchla coll. Environ. Mutagen.
7(Suppl. 5): 1-12, 15-19, 37.
Dutklewlcz T. and J. Szymanska. 1973. Chromatographlc determination of
hydrazobenzene metabolites In rats. Bromatol. Chem. Toksykol. 6(3):
323-327. (CA 80:116838k)
Genln V.A., A.G. Medvedovskll and V.M. Voronln. 1975. Increase of the
carcinogenic activity during the joint effect of hydrazobenzene and
benzldlne sulfate. G1g. Tr. prof. Zabol. 6: 28-31. (CA 83:173640a)
Great Lakes Water Quality Board. 1983. An Inventory of Chemical Substances
Identified In the Great Lakes Ecosystem. Report. Great Lakes Water Quality
Board, Windsor Ontario, Canada, p. 17.
0075d -35- 12/10/87
-------
Hansch, C. and A.J. Leo. 1985. Medchem Project, Issue No. 26. Pomona
College, Claremont, CA.
Mauser, T.R. and S.H. Bromberg. 1982. EPA's monitoring program at Love
Canal 1980. Environ. MonH. Assess. 2: 249-271.
Haworth, S., T. Lawlor. K. Mortelmas, W. Speck and E. Zelger. 1983.
Salmonella mutagenlclty test rules for 250 chemicals. Environ. Mutagen.
5(Suppl. 1): 21, 38, 38, 51, 102.
Howe, R.B. and K.S. Crump. 1982. GLOBAL 82. A Computer Program to
Extrapolate Quantal Animal Toxldty Data to Low Doses. Prepared for Office
of Carcinogen Standards. OSHA, U.S. Dept. of Labor. Contract No.
41USC252C3.
HSDB (Hazardous Substances Data Bank). 1987. On-line: 10/19/87. CAS No.
122-66-7.
IARC (International Agency for Research on Cancer). 1972. IARC Monographs
on the Evaluation of Carcinogenic Risk of Chemicals to Han. Benzldlne.
IARC, WHO, Lyons, France. Vol. 1, p. 80-86.
IARC (International Agency for Research on Cancer). 1974. Monograph on the
Evaluation of Carcinogenic Risk of Chemicals to Han. Hydrazlne and Its
Derivatives. IARC, WHO, Lyons, France. Vol. 4, p. 127-136.
0075d -36- 12/10/87
-------
Kurlyandskll, B.A., A.G. Medvedovskll, V.A. Genln, V.M. Voronln and P.O.
MashbHs. 1976. Experimental study on the combined effect of some
dlphenylamlno derivatives with regard to the prevention of occupational
urinary bladder growths. Gig. Tr. Prof. Zabol. 20(5): 34-38. (CA
85:105041x)
LeBlanc, G.A. 1980. Acute toxlclty of priority pollutants to water flea
(Daphnla maqna). Bull. Environ. Contain. Toxlcol. 24(5): 684-691.
Lyman, W.J., W.F. Reehl and D.H. Rosenblatt. 1982. Handbook of Chemical
Property Estimation Methods. Environmental Behavior of Organic Compounds.
McGraw-Hill Book Co.. New York. p. 2-14.
Malaney, G.W. 1960. Oxldatlve abilities of aniline-acclimated activated
sludge. J. Hater Pollut. Control Fed. 32: 1300-1311.
Maronpot R.R., M.B. Shlmkln, H.P. Wltschl, L.H. Smith and J.M. Cllne. 1986.
Strain A mouse pulmonary tumor test results for chemicals previously tested
1n the National Cancer Institute cardnogenldty tests. J. Natl. Cancer
Inst. 76(6): 1101-1112.
NCI (National Cancer Institute). 1978. Bloassay of Hydrazobenzene for
Possible Carc1nogen1c1ty. NCI Carclnogenesls Tech. Rep. Ser. No. 92. [Also
published as NIH 78-1342.]
NIOSH (National Institute for Occupational Safety and Health). 1987. RTECS
(Registry of Toxic Effects of Chemical Substances). Online: Oct. 1987. CAS
No. 122-66-7.
0075d -37- 12/10/87
-------
Pllss, G.B. 1974. Carcinogenic properties of hydrazobenzene. Vop. Onkol.
20: 53. (Cited In U.S. EPA, 1980a, 1981)
Randall, T.L. and P.V. Knopp. 1980. Detoxification of specific organic
substances by wet oxidation. J. Water Pollut. Control Fed. 52(8):
2117-2130.
Rlggln, R.M. and C.C. Howard. 1979. Determination of benzldlne, dlchloro-
benzldlne, and dlphenylhydrazlne In aqueous media by high performance liquid
chromatography. Anal. Chem. 51: 210-214.
Schafer E.H., Jr. and W.A. Bowles, Jr. 1985. Acute oral toxlclty and
repellency of 933 chemicals to house and deer mice. Arch. Environ. Contam.
Toxlcol. 14(1): 111-129.
Seller, J.P. 1977. Inhibition of testlcular DMA synthesis by chemical
mutagens and carcinogens. Preliminary results In the validation of a novel
short term test. Mutat. Res. 46: 305-310.
Shabad, L.H. and V.A. Genln. 1975. Combined action of amlno-substltuted
blphenyls causing bladder tumors. Urol. Nefrol. 1: 38-42. (CA 83:127207s)
Shlzuka, H., H. Kayoljl and T. MorHa. 1970. The photolysis of hydrazo-
benzene In solution. Mol. Photochem. 2: 165-176.
Spitz, S., W.H. Hagulgaw and K. Dobrlner. 1950. The carcinogenic action of
benzldlne. Cancer. 3: 789-804.
0075d -38- 03/08/88
-------
SRI (Stanford Research Institute). 1987. Directory of Chemical Producers.
United States of America. SRI International, Menlo Park, CA. p. 604, 773,
777.
Tabak, H.H., S.A. Quave, C.I. Mashnl and E.F. Barth. 1981. B1odegradab1l-
Ity studies with organic priority pollutant compounds. J. Water Pollut.
Control Fed. 53: 1503-1518.
U.S. EPA. 1978. In-depth Studies on Health and Environmental Impacts of
Selected Water Pollutants. Contract No. 68-01-4646. (Cited In U.S. EPA,
1980a)
U.S. EPA. 1980a. Ambient Water Quality Criteria for D1phenylhydraz1ne.
Prepared by the Environmental Criteria and Assessment Office, Cincinnati, OH
for the Office of Water Regulations and Standards, Washington, .DC. EPA
440/5-80-062.
U.S. EPA. 1980b. Guidelines and Methodology Used In the Preparation of
Health Effects Assessment Chapters of the Consent Decree Water Criteria
Documents. Federal Register. 45(231): 49347-49357.
U.S. EPA. 1981. CHIP (Chemical Hazard Information Profile). Draft Report.
Hydrazobenzene. OTS, OPTS. U.S. EPA, Washington. DC.
0075d -39- 03/08/88
-------
U.S. EPA. 1984. Methodology and Guidelines for Reportable Quantity
Determinations Based on Chronic Toxldty Data. 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. 1985. Reference Values for Risk Assessment. Prepared by the
Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH for the Office of Solid Waste, Washington,
DC.
U.S. EPA. 1986a. Methodology for Evaluating Carc1nogen1c1ty 1n Support of
Reportable Quantity Adjustment Pursuant to CERCLA Section 102. Prepared by
the Office of Health and Environmental Assessment, Carcinogen Assessment
Group, Washington, DC for the Office of Solid Waste and Emergency Response,
Washington, DC.
U.S. EPA. 1986b. Graphical Exposure Modeling System (GEMS) Fate of Atmo-
spheric Pollutants (FAP). Office of Toxic Substances. Washington, DC.
U.S. EPA. 1987a. IRIS (Integrated Risk Information System), CRAVE
(Carcinogen Risk Assessment Validation Endeavor) for 1,2-D1phenylhydraz1ne.
Online: Verification date: 10/29/86. Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH.
U.S. EPA. 1987b. Reportable Quantity Adjustments. Federal Register.
52(50): 5139.
0075d -40- 03/08/88
-------
USITC (U.S. International Trade Commission). 1984. Imports of Benzenold
Chemicals and Products: 1983. USITC Publ. 1548, Washington, DC. p. 19.
USITC (U.S. International Trade Commission). 1986. Imports of Benzenold
Chemicals and Products: 1985. USITC Publ. 1892, Washington, DC.
Weast, R.C., Ed. 1985. CRC Handbook of Chemistry and Physics, 66th ed.
CRC Press, Boca Raton, PL. p. c-313.
Yoon, J.S., J.H. Mason, R. Valencia, R.C. Woodruff and S. Zlmmerlng. 1985.
Chemical mutagenesls testing In DrosophHa. IV. Results of 45 coded com-
pounds tested for the National Toxicology Program. Environ Mutagen. 7(3):
349-367.
0075d -41- 03/08/88
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APPENDIX A
LITERATURE SEARCHED
This HEED 1s based on data Identified by computerized literature
searches of the following:
CHEMLINE
TSCATS
CASR online (U.S. EPA Chemical Activities Status Report)
TOXLINE
TOXLIT
TOXLIT 65
RTECS
OHM TADS
STORET
SRC Environmental Fate Data Bases
SANSS
AQUIRE
TSCAPP
NTIS
Federal Register
CAS ONLINE (Chemistry and Aquatic)
HSDB
These searches were conducted In October 1987, and the following secondary
sources were reviewed:
ACGIH (American Conference of Governmental Industrial Hyg1en1sts).
1986. Documentation of the Threshold Limit Values and Biological
Exposure Indices. 5th ed. Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1987. TLVs: Threshold Limit Values for Chemical Substances 1n the
Work Environment adopted by ACGIH with Intended Changes for
1987-1988. Cincinnati, OH. 114 p.
Clayton, G.O. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2A. John Wiley and
Sons, NY. 2878 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 28. John Wiley and
Sons, NY. p. 2879-3816.
Clayton, G.D. and F.E. Clayton, Ed. 1982. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2C. John Wiley and
Sons, NY. p. 3817-5112.
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Grayson, M. and 0. Eckroth, Ed. 1978-1984. Klrk-Othmer Encyclo-
pedia of Chemical Technology, 3rd ed. John Wiley and Sons, NY. 23
Volumes.
Hamilton, A. and H.L. Hardy. 1974. Industrial Toxicology, 3rd ed.
Publishing Sciences Group, Inc., Littleton, MA. 575 p.
IARC (International Agency for Research on Cancer). IARC Mono-
graphs on the Evaluation of Carcinogenic Risk of Chemicals to
Humans. IARC, MHO, Lyons. France.
Jaber, H.M., W.R. Mabey, A.T. L1eu, T.W. Chou and H.L. Johnson.
1984. Data acquisition for environmental transport and fate
screening for compounds of Interest to the Office of Solid Waste.
EPA 600/6-84-010. NTIS PB84-243906. SRI International, Menlo
Park, CA.
NTP (National Toxicology Program). 1987. Toxicology Research and
Testing Program. Chemicals on Standard Protocol. Management
Status.
Ouellette, R.P. and J.A. King. 1977. Chemical Week Pesticide
Register. McGraw-Hill Book Co., NY.
Sax. I.N. 1984. Dangerous Properties of Industrial Materials, 6th
ed. Van Nostrand Relnhold Co., NY.
SRI (Stanford Research Institute). 1987. Directory of Chemical
Producers. Menlo Park. CA.
U.S. EPA. 1986. Report on Status Report In the Special Review
Program, Registration Standards Program and the Data Call In
Programs. Registration Standards and the Data Call In Programs.
Office of Pesticide Programs, Washington, DC.
USITC (U.S. International Trade Commission). 1986. Synthetic
Organic Chemicals. U.S. Production and Sales, 1985, USITC Publ.
1892, Washington, DC.
Verschueren, K. 1983. Handbook of Environmental Data on Organic
Chemicals, 2nd ed. Van Nostrand Relnhold Co., NY.
Worthing, C.R. and S.B. Walker, Ed. 1983. The Pesticide Manual.
British Crop Protection Council. 695 p.
Wlndholz, M., Ed. 1983. The Merck Index, 10th ed. Merck and Co.,
Inc., Rahway. NJ.
0075d -43- 03/08/88
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In addition, approximately 30 compendia of aquatic toxlclty data were
reviewed, Including the following:
Battelle's Columbus Laboratories. 1971. Water Quality Criteria
Data Book. Volume 3. Effects of Chemicals on Aquatic Life.
Selected Data from the Literature through 1968. Prepared for the
U.S. EPA under Contract No. 68-01-0007. Washington. DC.
Johnson, W.W. and M.T. Flnley. 1980. Handbook of Acute Toxlclty
of Chemicals to Fish and Aquatic Invertebrates. Summaries of
Toxlclty Tests Conducted at Columbia National Fisheries Research
Laboratory. 1965-1978. U.S. Oept. Interior, Fish and Wildlife
Serv. Res. Publ. 137, Washington, DC.
HcKee, J.E. and H.W. Wolf. 1963. Water Quality Criteria, 2nd ed.
Prepared for the Resources Agency of California, State Water
Quality Control Board. Publ. No. 3-A.
Plmental, 0. 1971. Ecological Effects of Pesticides on Non-Target
Species. Prepared for the U.S. EPA, Washington, DC. PB-269605.
Schneider, B.A. 1979. Toxicology Handbook. Mammalian and Aquatic
Data. Book 1: Toxicology Data. Office of Pesticide Programs, U.S.
EPA, Washington, DC. EPA 540/9-79-003. NTIS PB 80-196876.
0075d -44- 03/08/88
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APPENDIX B
Cancer Data Sheet for Derivation of q-|* for Oral Exposure!"
Compound:
Reference:
Species, strain, sex:
Body weight:
Length of exposure (le):
Length of experiment (Le)
Llfespan of animal (L):
Tumor site and type:
Route, vehicle:
1,2-d1phenylhydraz1ne
NCI, 1978
•rat, F344, male
0.38 kg (measured)
78 weeks
104 weeks
104 weeks
liver, hepatocellular carcinoma and neoplastlc
nodules
oral, diet
Dose
(mq/kg/day)
0
4
15
Incidence
No. Responding/No. Tested
6/95
13/49
37/49
Human q-j* = 0.768 (mg/kg/day)'1
^Parameters reported by U.S. EPA (1980a); see text for additional
Information. Le was reported to be 107 weeks (low dose) and 106 weeks
(high dose) by NCI (1978).
0075d
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03/08/88
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o
o
-J
in
a.
APPENDIX C
Sunary Table for 1.2-Dlphenylhydraztne
CO
CO
CO
Inhalation Exposure
Subchronlc
Chronic
Carctnogenlctty
Oral Exposure
Subchronlc
Chronic
Carclnogentclty
RE PORT ABLE QUANTITIES
Based on chronic toxtclty:
Based on carctnogentclty:
Species Exposure Effect RfO or qj* Reference
NA NA NA RfD - NA NA
NA NA NA RfO = NA NA
rat NA NA q!*:0.8 (ag/kg/dayf>t NA
NA NA NA RfO = NA NA
NA NA NA RfO = NA NA
rat 0.008 and 0.03% In hepatocellular carcinoma q^: 0.8 (og/kg/day)"1 NCI. 1978
diet for 78 weeks and 'neoplasttc nodules
In liver
100
10
tlhe oral qi* was adopted as the Inhalation
NA = Not applicable
(U.S. EPA. 1987a)
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