TOXICOLOGICAL PROFILE FOR
 

1,2-DIPHENYLHYDRAZINE
 

Agency for Toxic Substances and Disease Registry
 

U.S. Public Health Service
 

December 1990
 
ii
 

DISCLAIMER
 

The use of company or product name(s) is for identification only and
 

does not imply endorsement by the Agency for Toxic Substances and Disease
 

Registry.
 










1
 

1. PUBLIC HEALTH STATEMENT
 

This Statement was prepared to give you information about
 

1,2-diphenylhydrazine and to emphasize the human health effects that may
 

result from exposure to it. The Environmental Protection Agency (EPA) has
 

identified 1177 sites on its National Priorities List (NPL). 1,2­

Diphenylhydrazine has been found at 7 of these sites. However, we do not know
 

how many of 1177 NPL sites have been evaluated for 1,2-diphenylhydrazine. As
 

EPA evaluates more sites, the number of sites at which 1,2-diphenylhydrazine
 

is found may change. The information is important for you because 1,2­

diphenylhydrazine may cause harmful health effects and because these sites are
 

potential are actual sources of human exposure to 1,2-diphenylhydrazine.
 

When a chemical is released from a large area, such as an industrial
 

plant, or from a container, such as a drum or bottle, it enters the
 

environment as a chemical emission. This emission, which is also called a
 

release, does not always lead to exposure. You can be exposed to a chemical
 

only when you come into contact with the chemical. You may be exposed to it in
 

the environment by breathing, eating, or drinking substances containing the
 

chemical or from skin contact with it.
 

If you are exposed to a hazardous substance such as 1,2­

diphenylhydrazine, several factors will determine whether harmful health
 

effects will occur and what the type and severity of those health effects will
 

be. These factors include the dose (how much), the duration (how long), the
 

route or pathway by which you are exposed (breathing, eating, drinking, or
 

skin contact), the other chemicals to which you are exposed, and your
 

individual characteristics such as age, sex, nutritional status, family
 

traits, life style, and state of health.
 

1.1 WHAT IS 1,2-DIPHENYLHYDRAZINE?
 

1,2-Diphenylhydrazine is a white solid. It dissolves only slightly in
 

water and does not change into a gas unless it is heated to very high
 

temperatures. It sticks to soil and can be carried into the air along with
 

windblown dust. Once in water or exposed to air it is changed into other
 

chemicals within minutes. These chemicals include the toxic chemicals
 

azobenzene and benzidine. More information about these two chemicals can be
 

found in the ATSDR Toxicological Profile on Benzidine or by contacting the
 

Agency for Toxic Substances and Disease Registry (see Section 1.8).
 

1,2-diphenylhydrazine is used to make fabric dyes in other countries,
 

and to make certain medicines. There are no other major manmade or natural
 

sources of 1,2-diphenylhydrazine. More information on these subjects can be
 

found in Chapters 3, 4, and 5.
 

1.2 HOW MIGHT I BE EXPOSED TO 1,2-DIPHEXYLHYDRAZINE?
 

1,2-Diphenylhydrazine does not dissolve in water easily and reacts
 

quickly when present in water. Therefore, it is extremely unlikely that you
 
2
 

1. PUBLIC HEALTH STATEMENT
 

would be exposed to it by drinking water. Also, 1,2-diphenylhydrazine does not
 

change to a gas at normal outside temperatures. Therefore, it is extremely
 

unlikely that you would be exposed to it by breathing air even if you live
 

near a hazardous waste site. Because 1,2-diphenylhydrazine may stick to soil,
 

it is possible that you could breathe in dust coated with 1,2­

diphenylhydrazine if you entered a hazardous waste site in which it had been
 

recently spilled on the ground. It is also possible that children playing at
 

this hazardous waste site could be exposed by eating dirt or smearing dirt on
 

their skin. It would have to be a site in which the 1,2-diphenylhydrazine was
 

recently spilled on the ground, since once exposed to air, 1,2­

diphenylhydrazine changes into other substances within minutes.
 

You also could be exposed to 1,2-diphenylhydrazine if you work in an
 

industry in which it is used. For example, while working, you could be
 

exposed to dust containing 1,2-diphenylhydrazine when it is moved from one
 

place to another. It has not been found in food or in air or natural soils.
 

If 1,2-diphenylhydrazine exists at all in lakes or streams, it is probably at
 

levels that are less than 1 part 1,2-diphenylhydrazine in l,OOO,OOO parts
 

water (ppm). More information on how you could be exposed to 1,2­

diphenylhydrazine can be found in Chapter 5.
 

1.3 HOW CAN 1,2-DIPHENYLHYDRAZINE ENTER AND LEAVE MY BODY?
 

If you were to breathe in dust coated with 1,2-diphenylhydrazine you
 

would probably breathe out most of it within a few minutes; however, some of
 

it might enter your body. Also, if you were to eat dust or dirt coated with
 

1,2-diphenylhydrazine, some of it might enter your body. However, we do not
 

know how much or how long it would take for the 1,2-diphenylhydrazine that you
 

breathe in or eat to enter your body. It is not known if 1,2-diphenylhydrazine
 

would enter your body if you were to spill it on your skin or if your were to
 

get dirt coated with it on your skin. Some, maybe most of 1,2­

diphenylhydrazine that enters your body leaves your body in the urine. It is
 

not known how long it takes for 1,2-diphenylhydrazine to leave the body in the
 

urine. Additional information on how 1,2-diphenylhydrazine can enter and leave
 

your body is presented in Chapter 2.
 

1.4 HOW CAN 1,2-DIPHENYLHYDRAZINE AFFECT MY HEALTH?
 

It is not known if 1,2-diphenylhydrazine would affect your health if you
 

were to breathe it in or eat it. The health effects of 1,2-diphenylhydrazine
 

in humans have not been studied. Animals die if they swallow large amounts of
 

1,2-diphenylhydrazine, and develop liver disease if they eat small amounts of
 

1,2-diphenylhydrazine for more than a year. Therefore, it is possible that if
 

you were to eat large amounts of 1,2-diphenylhydrazine for a long time you
 

might experience liver damage or die. It is not known whether 1,2­

diphenylhydrazine would harm you if you were to spill it on your skin. It is
 

not known if 1,2-diphenylhydrazine causes birth defects or affects fertility.
 

It is not known if 1,2-diphenylhydrazine causes cancer in humans; however, it
 

has been shown to cause cancer in rats and mice that have eaten it in food for
 

most of their
 
3
 

1. PUBLIC HEALTH STATEMENT
 

lifetime. Additional information on the health effects of 1,2­

diphenylhydrazine is presented in Chapter 2.
 

1.5 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL HEALTH EFFECTS?
 

Tables l-l, l-2, l-3, and l-4 show how little we know about the levels
 

of 1,2-diphenylhydrazine that might affect your health. As is shown in Table
 

l-4, animals that ate food containing 1,2-diphenylhydrazine for a long time
 

developed lung inflammation, stomach damage, and liver damage, and some died.
 

Although the levels of exposure that cause harmful effects in humans are not
 

known, as discussed in Section 1.2, 1,2-diphenylhydrazine is not likely to be
 

found in food, and you are not even likely to be exposed to levels of concern
 

if you live near a hazardous waste site. Additional information on levels of
 

exposure associated with effects can be found in Chapter 2.
 

1.6 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO 1,2­

DIPHENYIHYDRAZINE?
 

There is no test to determine if you have been exposed to
 

1,2-diphenylhydrazine. More information about tests for exposure and
 

effects can be found in Chapters 2 and 6.
 

1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN


 HEALTH?
 

A guideline to protect human health, by limiting exposure to
 

1,2-diphenylhydrazine in water, has been issued by the federal government.
 

The U.S. Environmental Protection Agency (EPA) has made recommendations to
 

limit the concentration of 1,2-diphenylhydrazine in natural waters, such as
 

lakes and streams. The EPA has developed regulations to limit the release
 

of 1,2-diphenylhydrazine by industries. Any release of 1 pound or more of
 

1,2-diphenylhydrazine must be reported to EPA.
 

1.8 WHERE CAN I GET MORE INFORMATION?
 

If you have any more questions or concerns not covered here, please
 

contact your State Health or Environmental Department or:
 

Agency for Toxic Substances and Disease Registry
 

Division of Toxicology
 

1600 Clifton Road, E-29
 

Atlanta, Georgia 30333
 

This agency can also give you information on the location of the
 

nearest occupational and environmental health clinics. Such clinics
 

specialize in the recognizing, evaluating, and treating illnesses that
 

result from exposure to hazardous substances.
 





9
 

2. HEALTH EFFECTS
 

2.1 INTRODUCTION
 

This chapter contains descriptions and evaluations of studies and
 

interpretation of data on the health effects associated with exposure to
 

1,2-diphenylhydrazine. Its purpose is to present levels of significant
 

exposure for 1,2-diphenylhydrazine based on toxicological studies,
 

epidemiological investigations, and environmental exposure data. This
 

information is presented to provide public health officials, physicians,
 

toxicologists, and other interested individuals and groups with (1) an
 

overall perspective of the toxicology of 1,2-diphenylhydrazine and (2) a
 

depiction of significant exposure levels associated with various adverse
 

health effects.
 

2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE
 

To help public health professionals address the needs of persons
 

living or working near hazardous waste sites, the data in this section are
 

organized first by route of exposure -- inhalation, oral, and dermal -- ant
 

then by health effect -- death, systemic, immunological, neurological,
 

developmental, reproductive, genotoxic, and carcinogenic effects. These
 

data are discussed in terms of three exposure periods -- acute,
 

intermediate, and chronic.
 

Levels of significant exposure for each exposure route and duration
 

(for which data exist) are presented in tables and illustrated in figures.
 

The points in the figures showing no-observed-adverse-effect levels (NOAELs)
 

or lowest-observed-adverse-effect levels (LOAELs) reflect the actual doses
 

(levels of exposure) used in the studies. LOAELs have been classified into
 

"less serious" or "serious" effects. These distinctions are intended to
 

help the users of the document identify the levels of exposure at which
 

adverse health effects start to appear, determine whether or not the
 

intensity of the effects varies with dose and/or duration, and place into
 

perspective the possible significance of these effects to human health.
 

The significance of the exposure levels shown on the tables and graphs
 

may differ depending on the user's perspective. For example, physicians
 

concerned with the interpretation of clinical findings in exposed persons or
 

with the identification of persons with the potential to develop such
 

disease may be interested in levels of exposure associated with "serious"
 

effects. Public health officials and project managers concerned with
 

response actions at Superfund sites may want information on levels of
 

exposure associated with more subtle effects in humans or animals (LOAEL) or
 

exposure levels below which no adverse effects (NOAEL) have been observed.
 

Estimates of levels posing minimal risk to humans (minimal risk levels,
 

MRLs) are of interest to health professionals and citizens alike.
 

For certain chemicals, levels of exposure associated with carcinogenic
 

effects may be indicated in the figures. These levels reflect the actual
 

doses associated with the tumor incidences reported in the studies cited.
 
10
 

2. HEALTH EFFECTS
 

Because cancer effects could occur at lower exposure levels, the figures
 

also show estimated excess risks, ranging from a risk of one in 10,000 to one
 

in 10,000,000 (10-4 to 10-7), as developed by EPA.
 

Estimates of exposure levels posing minimal risk to humans (MRLs) have
 

been made, where data were believed reliable, for the most sensitive
 

noncancer end point for each exposure duration. MRLs include adjustments to
 

reflect human variability and, where appropriate, the uncertainty of
 

extrapolating from laboratory animal data to humans. Although methods have
 

been established to derive these levels (Barnes et al. 1987; EPA 1989),
 

uncertainties are associated with the techniques. Furthermore, ATSDR
 

acknowledges additional uncertainties inherent in the application of these
 

procedures to derive less than lifetime MRLs. As an example, acute
 

inhalation MRLs may not be protective for health effects that are delayed in
 

development or are acquired following repeated acute insults, such as
 

hypersensitivity reactions, asthma, or chronic bronchitis. As these kinds
 

of health effects data become available and methods to assess levels of
 

significant human exposure improve, these MRLs will be revised.
 

2.2.1 Inhalation Exposure
 

No studies were located regarding the following health effects in
 

humans or animals after inhalation exposure to 1,2-diphenylhydrazine:
 

2.2.1.1 Death
 

2.2.1.2 Systemic Effects
 

2.2.1.3 Immunological Effects
 

2.2.1.4 Neurological Effects
 

2.2.1.5 Developmental Effects
 

2.2.1.6 Reproductive Effects
 

2.2.1.7 Genotoxic Effects
 

2.2.1.8 Cancer
 

2.2.2 Oral Exposure
 

2.2.2.1 Death
 

No studies were located regarding lethality in humans following oral
 

exposure to 1,2-diphenylhydrazine. Limited information is available
 

regarding the lethality of orally-administered 1,2-diphenylhydrazine in
 

animals. This consists of an incompletely documented acute LD50 of
 

959 mg/kg in rats (Marhold et al. 1968), an unreliable acute lethal dose of
 
11
 

2. HEALTH EFFECTS
 

1213 mg/kg/day in mice (Schafer and Bowles 1985), lethal doses for
 

intermediate duration exposure (4 weeks) of 54 mg/kg/day in rats and 390
 

mg/kg/day in mice (NTP 1983), and nonlethal and lethal doses for chronic
 

exposure in rats (2 and 5 mg/kg/day, respectively) and mice (10 and 52
 

mg/kg/day, respectively) (NTP 1983). The animal lethality data are
 

discussed below and summarized in Table 2-l.
 

A single-dose LD50 of 959 mg/kg was determined for rats treated by 

gavage with 1,2-diphenylhydrazine in water suspension (Marhold et al. 1968). 

Apparently, this value was determined using conventional methodology but the 

duration of observation was not reported and it was not indicated if 

treatment with undegraded compound was assured. Degradation could be an 

issue because 1,2-diphenylhydrazine degrades rapidly in water (Chapter 5). 

The cause(s) of mortality in the rats was not reported. The 959 mg/kg LD50

is recorded in Table 2-l and plotted in Figure 2-l.

 In another study, the average amount of 1,2-diphenylhydrazine consumed
 

by wild deer mice over a 3-day period without killing more than 50% of the
 

mice was determined to be 1213 mg/kg/day (Schafer and Bowles 1985). The
 

validity of this finding is uncertain; however, as the dose was estimated from
 

consumption of seeds treated with only one concentration of chemical, only
 

five mice were treated, and the actual number of deaths was not reported.
 

Because of these limitations, the 1213 "g/kg/day dose is not a
 

reliable effect level for lethality due to acute duration exposure.
 

Small groups (five) of rats or mice of each sex were administered
 

various concentrations of 1,2-diphenylhydrazine in the diet for 4 weeks,
 

followed by 2 weeks without treatment (NCI 1978). Estimated doses ranged
 

from 3.5-210 mg/kg/day (eight dose levels) in male rats and 0.04-2600
 

mg/kg/day (nine dose levels) in female rats. Deaths occurred in 2 of 5 male
 

rats at 54 mg/kg/day and in all rats of both sexes at higher doses,
 

Although small numbers of rats were tested at each dose, it can be assumed
 

that the mortality at 54 mg/kg/day was related to treatment because of death
 

at higher doses. The 54 mg/kg/day dose, therefore, is a LOAEL value for
 

lethality in rats due to intermediate duration exposure (Table 2-1, Figure
 

2-l). In mice, estimated doses ranged from 9.1-550 mg/kg/day (eight dose
 

levels) in males and 0.39-6700 mg/kg/day (nine dose levels) in females.
 

Deaths occurred in 1 of 5 male mice at 390 mg/kg/day, 2 of 5 male mice at
 

550 mg/kg/day, 4 of 5 male mice at 950 mg/kg/day, and in all female mice at
 

6700 mg/kg/day. Using the reasoning used for the rat LOAEL, the 390
 

mg/kg/day dose can be considered a LOAEL for lethality in mice for
 

intermediate duration of exposure (Table 2-1, Figure 2-l). Because of
 

uncertainty related to the small size of the groups, the doses below the rat
 

and mouse LOAELs are not reliable NOAELs for lethality. The cause(s) of the
 

mortality in these studies was not indicated.
 

Rats and mice were fed diets that contained 1,2-diphenylhydrazine for
 

78 weeks, followed by 28-30 weeks (rats) or 17-18 weeks (mice) without
 

treatment (NCI 1978). Estimated doses for the rats were 4 and 15 mg/kg/day
 



15
 

2. HEALTH EFFECTS
 

in males, and 2 and 5 mg/kg/day in females. Mortality was increased
 

significantly only in the high-dose female rats, indicating that 5 mg/kg/day
 

is a LOAEL for decreased survival due to chronic exposure (Table 2-1, Figure
 

2-l). These data suggest that female rats are more sensitive than male
 

rats. Because females appear to be the more sensitive sex and it is not
 

known if 4 mg/kg/day (the NOAEL in males that is below the 5 mg/kg/day LOAEL
 

in females) is lethal in females, the 2 mg/kg/day dose in females is the
 

most reliable NOAEL for lethality in this species. Estimated doses for the
 

mice were 10 and 52 mg/kg/day in males and 5.2 and 52 mg/kg/day in females.
 

Mortality was increased significantly in both the high-dose male and female
 

mice, indicating that the 52 mg/kg/day dose is the LOAEL and 10 mg/kg/day is
 

the highest NOAEL for lethality in mice due to chronic exposure (Table 2-1,
 

Figure 2-l). The cause(s) of the mortality in the rats or mice was not
 

indicated.
 

2.2.2.2 Systemic Effects
 

No studies were located regarding cardiovascular, hematological
 

musculoskeletal, renal, or dermal/ocular systemic effects in humans or
 

animals following oral exposure to 1,2-diphenylhydrazine.
 

Respiratory Effects. No studies were located regarding respiratory
 

effects of 1,2-diphenylhydrazine in humans. One animal study, discussed
 

below, indicates that chronic oral administration of 1,2-diphenylhydrazine
 

produced interstitial inflammation of the lungs in rats (NCI 1978).
 

Evaluation of the incidence data for nonneoplastic lesions in the NCI
 

(1978) chronic oral study shows that there were statistically increased
 

incidences of interstitial inflammation in the lungs of male rats. These
 

rats were treated with 1,2-diphenylhydrazine in the diet at doses of 4 or
 

mg/kg/day for 78 weeks. Increased incidences of this lesion were also
 

observed in female rats treated similarly with a dose of 2 mg/kg/day, but
 

not in mice treated similarly with doses of 5.2 mg/kg/day (females), 10
 

w/k/day (males), or 52 mg/kg/day (males and females). The highest NOAEL
 

value in mice and the LOAEL in rats for respiratory effects due to chronic
 

exposure are recorded in Table 2-1 and plotted in Figure 2-1.
 

Gastrointestinal Effects. No studies were located regarding
 

gastrointestinal effects of 1,2-diphenylhydrazine in humans. As discussed
 

below, gastrointestinal effects were observed in an intermediate duration
 

study with mice (intestinal hemorrhage) (NCI 1978) and a chronic study with
 

rats (stomach hyperkeratosis and acanthosis) (NCI 1978).
 

NCI (1978) concluded from pathological examinations of mice that died
 

in a 4-week diet study of 1,2-diphenylhydrazine that, "Intestinal hemorrhage
 

was the single gross abnormality consistently observed in these mice." The
 

severity of the hemorrhage was not described. As indicated in Section
 

2.2.2.1, deaths occurred in mice at doses 390 mg/kg/day or more but not 280
 

mg/kg/day or less. Intestinal hemorrhage was not observed in rats that
 
16
 

2. HEALTH EFFECTS
 

died from similar treatment with doses as high as 2600 mg/kg/day. Based on
 

these data, the 390 mg/kg/day dose can be considered a LOAEL for
 

gastrointestinal effects in mice due to intermediate duration exposure
 

(Table 2-1, Figure 2-l). As histological examinations were not conducted on
 

any of the animals, reliable NOAELs for gastrointestinal effects due to
 

intermediate exposure in either species cannot be identified.
 

Evaluation of the incidence data for nonneoplastic lesions in the NCI
 

(1978) chronic oral study shows that there were statistically increased
 

incidences of stomach hyperkeratosis and acanthosis in the high dose male
 

rats. These rats were treated with 1,2-diphenylhydrazine in the diet at a
 

dose of 15 mg/kg/day for 78 weeks. Increased incidences of these lesions
 

were not observed in male rats treated with 4 mg/kg/day, female rats
 

treated similarly with doses of 2 or 5 mg/kg/day, or mice treated similarly
 

with doses of 5.2 mg/kg/day (females), 10 mg/kg/day (males), or 52
 

mg/kg/day (males or females). Due to the prevalence of the hyperkeratosis
 

(21% versus 4% in controls) and acanthosis (36% versus 4% in controls),
 

appearance of these lesions due to dietary treatment (they are more commonly
 

associated with gavage treatment), and occurrence of gross intestinal
 

hemorrhage in mice treated with higher doses of 1,2-diphenylhydrazine in the
 

4-week NCI (1978) study, the effects are considered to be adverse. The 15
 

mg/kg/day dose therefore is a LOAEL for gastrointestinal effects in rats
 

due to chronic duration exposure (Table 2-1, Figure 2-l). The highest doses
 

not producing gastrointestinal histologic alterations in the rats (5
 

mg/kg/day) and mice (52 mg/kg/day) are NOAELs for gastrointestinal effects
 

due to chronic exposure (Table 2-1, Figure 2-l).
 

Hepatic Effects. No studies were located regarding hepatic effects of
 

1,2-diphenylhydrazine in humans. Chronic oral administration of
 

1,2-diphenylhydrazine produced degenerative alterations in the liver of rats
 

(fatty metamorphosis) and mice (coagulative necrosis) (NCI 1978).
 

Evaluation of the incidence data for nonneoplastic lesions in the NCI
 

(1978) chronic oral study shows that there was a statistically increased
 

incidence of fatty metamorphosis of the liver in the high-dose male rats
 

(20% versus 0% in controls). These rats were treated with
 

1,2-diphenylhydrazine in the diet at a dose of 15 mg/kg/day for 78 weeks.
 

Fatty metamorphosis was also observed in 20% of the high dose (5 mg/kg/day)
 

female rats. Although the increased incidence in the high dose female rats
 

was not statistically significant when compared with the incidence (12%) in
 

the matched control group, the incidence was statistically significant when
 

compared with the incidence (4%) in the control group for the low dose group
 

of females. Female mice treated similarly with 52 mg/kg/day had a
 

statistically increased incidence of coagulative necrosis of the liver (13%
 

versus 0% in controls). High incidences of focal necrosis were seen in low
 

dose female rats, the high dose control male and female mice, the low dose
 

treated male and female mice, and the high dose treated male mice. The
 

incidence in the low dose female rats was significantly increased above the
 

matching control group, but not above the control group for the high dose
 
17
 

2. HEALTH EFFECTS
 

treated group. A similar effect was not seen in the high dose female rats.
 

The high incidence of focal necrosis in the high dose control groups makes
 

meaningful interpretation of the toxicological significance of this
 

particular lesion difficult. Nevertheless, because of the severity and
 

prevalence of the liver lesions taken together and the fact that hepatic
 

neoplasms were observed in this study, the liver is a major target organ of
 

1,2-diphenylhydrazine in both species. The highest NOAEL value and all
 

reliable LOAEL values for hepatic effects in both species for chronic
 

exposure are recorded in Table 2-l and plotted in Figure 2-l.
 

Other Systemic Effects. No studies were located regarding other
 

systemic effects of 1,2-diphenylhydrazine in humans. Decreased body weight
 

gain and/or weight loss was observed in chronic oral studies with rats and
 

mice (NCI 1978). As discussed below, these effects may be a consequence of
 

other toxic effects or cancer.
 

Initial and final body weights were not significantly different in rats
 

treated with 19 mg/kg/day in the diet for 288 days (Marhold et al. 1968).
 

Other endpoints of systemic toxicity were not reported in this study. Body
 

weights were not depressed consistently in rats and mice treated with
 

1,2-diphenylhydrazine in the diet at doses as high as 2600 mg/kg/day (rats)
 

or 6700 mg/kg/day (mice) for 4 weeks, followed by 2 weeks without treatment
 

(NCI 1978). These NOAELs for rats and mice are presented in Table 2-l and
 

Figure 2-l as other systemic effects for intermediate duration exposure.
 

Male rats treated with 1,2-diphenylhydrazine in the diet at a dose of
 

15 mg/kg/day for 78 weeks had approximately l0-15% decreased body weight
 

gain (NCI 1978). NCI/NTP usually considers effects on body weight of this
 

magnitude to be significant. Treatment-related effects on body weight were
 

not apparent in male or female rats treated similarly with doses of 2-5
 

mg/kg/day . With the exception of respiratory, gastrointestinal, and hepatic
 

alterations at 15 mg/kg/day (discussed previously), comprehensive
 

histological examinations of the rats did not show treatment-related
 

nonneoplastic lesions. Although food consumption data were not reported,
 

the decreased weight gain is probably secondary to toxic or neoplastic
 

effects and should be considered an adverse effect. The doses of 15
 

mg/kg/day and 5 mg/kg/day therefore are the LOAEL and highest NOAEL,
 

respectively, for other systemic effects in rats due to chronic duration
 

exposure (Table 2-1, Figure 2-l).
 

Male and female mice treated with 1,2-diphenylhydrazine in the diet at
 

a dose of 52 mg/kg/day for-78 weeks had decreased weight gain and subsequent
 

weight loss (approximately 30% at termination of the study) (NCI 1978).
 

Treatment-related effects on body weight were not apparent in mice treated
 

similarly with 5.2 mg/kg/day (females) or 10 mg/kg/day (males). Except for
 

hepatic alterations at 52 mg/kg/day (discussed previously), comprehensive
 

histological examinations of the mice showed no treatment-related
 

nonneoplastic lesions. As body weight loss is an adverse effect, the
 

52 mg/kg/day dose is a LOAEL for other systemic effects in mice due to
 
18
 

2. HEALTH EFFECTS
 

chronic duration exposure (Table 2-1, Figure 2-l). The highest NOAEL for
 

other systemic effects in mice is 10 mg/kg/day (Table 2-1, Figure 2-l).
 

2.2.2.3 Immunological Effects
 

No studies were located regarding immunological effects in humans or
 

animals after oral exposure to 1,2-diphenylhydrazine.
 

2.2.2.4 Neurological Effects
 

No studies were located regarding neurological effects in humans after
 

oral exposure to 1,2-diphenylhydrazine.
 

Clinical signs and histological examinations of the brain were
 

unremarkable in rats and mice treated with 1,2-diphenylhydrazine in the diet
 

at doses of 15 and 52 mg/kg/day, respectively, for 78 weeks (NCI 1978).
 

These data provide an inadequate basis for evaluating possible
 

neurotoxicity, as behavioral or neurological evaluations were not conducted.
 

2.2.2.5 Developmental Effects
 

No studies were located regarding developmental effects in humans or
 

animals after oral exposure to 1,2-diphenylhydrazine.
 

2.2.2.6 Reproductive Effects
 

No studies were located regarding reproductive effects in humans after
 

oral exposure to 1,2-diphenylhydrazine.
 

Histological examinations of the seminal vesicle, testes, prostate,
 

uterus, ovaries, and mammary gland were unremarkable in rats and mice
 

treated with 1,2-diphenylhydrazine in the diet at doses as high as 15 and 52
 

mg/kg/day, respectively, for 78 weeks (NCI 1978). These data provide an
 

insufficient basis for evaluating reproductive toxicity, as reproductive
 

function was not evaluated.
 

2.2.2.7 Genotoxic Effects
 

No studies were located regarding genotoxic effects in humans after
 

oral exposure to 1,2-diphenylhydrazine.
 

Sex-linked recessive lethal mutations were not produced in Drosophila
 

fed ethanol solution containing 50 ppm 1,2-diphenylhydrazine for 3 days
 

(Yoon et al. 1985). No oral genotoxicity studies of 1,2-diphenylhydrazine
 

in mammals were located.
 
19
 

2. HEALTH EFFECTS
 

2.2.2.8 Cancer
 

No studies were located regarding carcinogenic effects in humans after
 

oral exposure to 1,2-diphenylhydrazine. As discussed below, chronic oral
 

administration of 1,2-diphenylhydrazine was carcinogenic in rats and female
 

mice (NCI 1978).
 

Treatment-related neoplasms occurred in rats and mice that were
 

treated with low or high doses of 1,2-diphenylhydrazine in the diet for 78
 

weeks, followed by untreated observation periods of 28 or 30 weeks (rats)
 

and 17 or 18 weeks (mice) (NC1 1978). Male rats had statistically
 

significant increased incidences of hepatocellular carcinomas or neoplastic
 

nodules in the liver due to treatment with 4 mg/kg/day and 15 mg/kg/day, and
 

squamous-cell carcinomas of the Zymbal's gland and adrenal pheochromocytomas
 

resulted from treatment with 15 mg/kg/day. Incidences of liver neoplastic
 

nodules and mammary gland adenocarcinomas were increased significantly in
 

female rats treated with 5 mg/kg/day, but not 2 mg/kg/day. A significantly
 

increased incidence of hepatocellular carcinoma occurred in female mice
 

treated with 52 mg/kg/day, but not 5.2 mg/kg/day. Doses of 10.4 or 52
 

mg/kg/day were not neoplastic for male mice.
 

Tumors were not observed in male rats treated with 19 mg/kg/day doses
 

of 1,2-diphenylhydrazine in the diet for life (mean survival time =
 

288 days) (Marhold et al. 1968). The significance of this finding is
 

uncertain because the type and scope of pathological examination were not
 

reported. Pliss (1974) reported increased numbers of tumors of the liver,
 

Zymbal's gland, mammary gland and other sites in rats that were treated wit
 

1,2-diphenylhydrazine in the diet at an estimated dose of 85 mg/kg/day, 5
 

days/week for 588 days (Pliss 1974). These findings are inconclusive,
 

however, because of lack of control data and other report inadequacies.
 

The lowest Cancer-Effect-Levels (CELs) in the NCI (1978) bioassay are 

the doses that caused hepatocellular carcinoma in rats (4 mg/kg/day) and 

mice (52 mg/kg/day) (Table 2-1, Figure 2-l). Using the dose-response data 

for the hepatocellular carcinoma in rats, EPA (1980, 198Sa) derived and 

verified an oral slope factor (ql *

) of 8.0 x 10-l (mg/kg/day)-1 for 

1,2-diphenylhydrazine. Using this slope factor, the doses associated with 

upper-bound lifetime cancer risk levels of 10-4 to 10-7 are calculated to 

be 1.3 x l0-4 to 1.3 x 10-7 mg/kg/day, respectively (Figure 2-l). 

2.2.3 Dermal Exposure
 

No studies were located regarding the following health effects in
 

human or animals after dermal exposure to 1,2-diphenylhydrazine.
 

2.2.3.1 Death
 

2.2.3.2 Systemic Effects
 
20
 

2. HEALTH EFFECTS
 

2.2.3.3 Immunological Effects
 

2.2.3.4 Neurological Effects
 

2.2.3.5 Developmental Effects
 

2.2.3.6 Reproductive Effects
 

2.2.3.7 Genotoxic Effects
 

2.2.3.8 Cancer
 

No studies were located regarding carcinogenic effects of
 

1,2-diphenylhydrazine in humans. As discussed below, inconclusive data for
 

carcinogenicity of dermally-applied 1,2-diphenylhydrazine in mice are
 

available.
 

Dermal application of an estimated 1,2-diphenylhydrazine dose of 63
 

mg/kg/day I three times a week for 442 days, caused a 22.2% incidence of
 

tumors in mice (Pliss 1974). Tumors occurred in the lung, liver, and other
 

tissues, and the tumor incidence in control mice was 17%. The significance
 

of these findings cannot be determined, as incidences of specific tumors in
 

the control group were not reported.
 

2.3 TOXICOKINETICS
 

2.3.1 Absorption
 

2.3.1.1 Inhalation Exposure
 

No studies were located regarding absorption in humans or animals
 

after inhalation exposure to 1,2-diphenylhydrazine. Pulmonary absorption of
 

1,2-diphenylhydrazine by rats is suggested by detection of an unidentified
 

metabolite in the urine following intratracheal administration of
 

1,2-diphenylhydrazine in water suspension and dimethyl sulfoxide (DMSO)
 

(Dutkiewicz and Szymanska 1973). It is not known, however, if any of the
 

dose was ingested.
 

2.3.1.2 Oral Exposure
 

No studies were located regarding absorption in humans after oral
 

exposure to 1,2-diphenylhydrazine. Specific information regarding absorption
 

in animals following oral exposure to 1,2-diphenylhydrazine was not located.
 

Gastrointestinal absorption of 1,2-diphenylhydrazine by rodents is indicated
 

by the occurrence of parent compound and metabolites in the urine following
 

oral treatment (Section 2.3.3) and systemic effects in oral carcinogenicity
 

and toxicity studies (Section 2.2).
 
21
 

2. HEALTH EFFECTS
 

2.3.1.3 Dermal Exposure
 

No studies were located regarding absorption in humans or animals
 

after exposure to 1,2-diphenylhydrazine. The inadequately reported dermal
 

carcinogenicity study of 1,2-diphenylhydrazine summarized in Section 2.2.3.8
 

cannot be used to infer dermal absorption of 1,2-diphenylhydrazine because
 

the effects are inconclusive.
 

2.3.2 Distribution
 

2.3.2.1 Inhalation Exposure
 

No studies were located regarding distribution in humans or animals
 

after inhalation exposure to 1,2-diphenylhydrazine.
 

2.3.2.2 Oral Exposure
 

No studies were located regarding distribution in humans or animals
 

after oral exposure to 1,2-diphenylhydrazine.
 

2.3.2.3 Dermal Exposure
 

No studies were located regarding distribution in humans or animals
 

after dermal exposure to 1,2-diphenylhydrazine.
 

2.3.3 Metabolism
 

Limited information is available on the metabolism of
 

1,2-diphenylhydrazine. In the only study involving 1,2-diphenylhydrazine as
 

the parent compound, urine of rats was analyzed for metabolites following
 

single oral, intraperitoneal, intravenous, and intratracheal doses of
 

1,2-diphenylhydrazine (Dutkiewicz and Szymanska 1973). Unchanged
 

1,2-diphenylhydrazine was detected following treatment by all routes, and
 

aniline and benzidine were identified following the oral and intraperitoneal
 

treatments. Other metabolites included two unspecified hydroxy derivatives
 

of benzidine (oral route), 2- and 4- aminophenol (intraperitoneal route),
 

and unidentified compounds (oral, intravenous, and intratracheal routes).
 

Amounts of compounds excreted were not quantitated. Two of the known
 

metabolites, aniline and benzidine, may contribute to the toxicity and/or
 

carcinogenicity of 1,2-diphenylhydrazine. The validity of the findings of
 

this study is uncertain, however, as the analytical methodology (thin-layer
 

chromatography) may have produced degradation products that were identified
 

as unchanged 1,2-diphenylhydrazine or metabolites (see Section 6.1).
 

The metabolites identified by Dutkiewicz and Szymanska (1973) are
 

consistent with a metabolic scheme proposed by Williams (1959) (Figure 2-2),
 

which is based on data for azobenzene and aniline. As summarized by NRC
 

(1981), aniline is oxidized by hydroxylation of a ring carbon to form 2-or
 

23
 

2. HEALTH EFFECTS
 

4-aminophenol or of the nitrogen to form phenylhydroxylamine, and then is
 

conjugated to glucuronic or sulfuric acid. An oral study of azobenzene
 

with conventional and germ-free rats (Macholz et al. 1985) showed that
 

metabolism of 1,2-diphenylhydrazine to aniline resulted from the reductional
 

and hydrolytic capability of gut flora. In vitro metabolism of
 

1,2-diphenylhydrazine to aniline by rat intestinal microorganisms has been
 

demonstrated (Bolton and Griffiths 1978).
 

Benzidine is formed readily from 1,2-diphenylhydrazine by acid
 

rearrangement. It has been suggested that benzidine may be produced from
 

1,2-diphenylhydrazine by acidity in the stomach (IARC 1972).
 

2.3.4 Excretion
 

2.3.4-l Inhalation Exposure
 

No studies were located regarding excretion in humans or animals after
 

inhalation exposure to 1,2-diphenylhydrazine. The presence of an
 

unidentified metabolite in the urine of rats following intratracheal
 

administration of 1,2-diphenylhydrazine in water and DMSO suspensions
 

(Dutkiewicz and Szymanska 1973) suggests that urinary excretion could occur
 

following inhalation exposure.
 

2.3.4.2 Oral Exposure
 

No studies were located regarding excretion in humans after oral
 

exposure to 1,2-diphenylhydrazine. The identification of unchanged
 

1,2-diphenylhydrazine and metabolites in the urine following oral dosing of
 

rats with 1,2-diphenylhydrazine (Dutkiewicz and Szymanska 1973) indicates
 

that some urinary excretion occurs.
 

2.3.4.3 Dermal Exposure
 

No studies were located regarding excretion in humans or animals after
 

dermal exposure to 1,2-diphenylhydrazine.
 

2.4 RELEVANCE TO PUBLIC HEALTH
 

Death. Information regarding death in humans following exposure to
 

1,2-diphenylhydrazine by any route was not found. Some information is
 

available on lethality of orally-administered 1,2-diphenylhydrazine in
 

animals. This information, consisting of a gavage LD50 value in rats 

(Marhold et al. 1968) and an unreliable 3-day dietary lethal dose in mice 

(Schafer and Bowles 1985), indicates that single or several oral doses of 

about 1000 mg/kg/day may be lethal for rodents. Based on these data, 

1,2-diphenylhydrazine does not appear to be highly acutely toxic to humans 

by the oral route. 
24
 

2. HEALTH EFFECTS
 

Intermediate (4-week) and chronic (78-week) duration diet studies with
 

rats found that 1,2-diphenylhydrazine produced death at doses as low as 54
 

and 15 mg/kg/day, respectively (NCI 1978). These doses are substantially
 

lower than those associated with acute lethality. These data suggest that
 

prolonged ingestion of these doses of 1,2-diphenylhydrazine may be lethal
 

for humans. However, as discussed in the introduction to Section 2.8.2,
 

prolonged environmental exposure to 1,2-diphenylhydrazine is unlikely.
 

Systemic Effects. No information regarding systemic effects in humans
 

following exposure to 1,2-diphenylhydrazine by any route was found. Very
 

limited information is available for systemic effects of
 

1,2-diphenylhydrazine in animals.
 

NCI (1978) observed a variety of nonneoplastic lesions in rats and
 

mice exposed to 1,2-diphenylhydrazine in the diet for 78 weeks, concluding
 

that ".. .none appeared to be compound-related." Evaluation of the incidence
 

data for nonneoplastic lesions, however, shows that there were
 

statistically significant increased incidences of lung interstitial
 

inflammation and liver fatty metamorphosis in treated male and female rats,
 

stomach hyperkeratosis and acanthosis in treated male rats, and liver
 

coagulative necrosis in treated female mice. Nonneoplastic liver lesions,
 

hepatocellular carcinomas and/or neoplastic liver nodules in orally-treated
 

rats and mice indicate that the liver is a target of 1,2-diphenylhydrazine
 

toxicity. Gross pathological examinations conducted in the 4-week NCI
 

(1978) diet study showed intestinal hemorrhages in mice that died. A local
 

irritative effect of 1,2-diphenylhydrazine is suggested by the occurrence of
 

the stomach hyperkeratosis/acanthosis in rats and intestinal hemorrhage in
 

mice. Since hydrazine and some hydrazine derivatives are hepatotoxic and
 

local irritants (Reinhardt and Brittelli 1981), it is possible that
 

1,2-diphenylhydrazine could cause similar effects in humans.
 

Intravenous injection of an 18.4 mg/kg dose of 1,2-diphenylhydrazine
 

did not cause methemoglobinemia in rats, although methemoglobin was formed
 

by an equimolar dose of aniline (Pfordte 1973). Information on
 

methemoglobinemia in animals following treatment with 1,2-diphenylhydrazine
 

by other routes was not located. As aniline and other aromatic amino
 

metabolites of 1,2-diphenylhydrazine (e.g., aminophenols) are
 

methemoglobinforming compounds by either oral or inhalation routes of exposure
 

(Beard and Noe 1981), it is possible that 1,2-diphenylhydrazine may cause
 

methemoglobinemia in humans. However, this would occur only if sufficient
 

aniline were formed rapidly enough to exceed the capacity of methemoglobin
 

reductase to reduce methemoglobin.
 

Immunological Effects. No studies were located regarding
 

immunological effects of 1,2-diphenylhydrazine in humans or animals by any
 

route of exposure. This lack of data precludes speculation on possible
 

immunotoxicity of 1,2-diphenylhydrazine in humans.
 
25
 

2. HEALTH EFFECTS
 

Neurological Effects. No studies were located regarding neurological
 

effects of 1,2-diphenylhydrazine in humans by any route of exposure. Rats
 

and mice that were treated with lethal doses of 1,2-diphenylhydrazine in a
 

chronic (78-week) diet study did not show symptoms of toxicity or
 

histological alterations in the brain (NCI 1978), but no behavioral or
 

neurological evaluations were conducted. The insufficiency of these data
 

precludes making any conclusions regarding neurotoxicity of
 

1,2-diphenylhydrazine in humans.
 

Developmental Effects. No studies were located regarding
 

developmental effects of 1,2-diphenylhydrazine in humans or animals by any
 

route of exposure. This lack of data precludes speculation on possible
 

developmental toxicity of 1,2-diphenylhydrazine in humans.
 

Reproductive Effects. No studies were located regarding reproductive
 

effects of 1,2-diphenylhydrazine in humans by any route of exposure. Rats and
 

mice that were treated with lethal doses of 1,2-diphenylhydrazine in a chronic
 

(78-week) diet study did not show histological alterations in reproductive
 

organs (NCI 1978), but reproductive function was not evaluated. The
 

insufficiency of these data precludes making any conclusions regarding
 

reproductive toxicity of 1,2-diphenylhydrazine in humans.
 

Genotoxic Effects. No studies were located regarding the genotoxicity of
 

1,2-diphenylhydrazine in humans by any route of exposure. A limited number of
 

assays have been conducted using bacteria, mammalian cell and whole animal
 

systems. As indicated in Table 2-2, 1,2-diphenylhydrazine was mutagenic in
 

Salmonella tynhimurium, but not in Escherichia coli, and produced chromosome
 

aberrations and sister chromatid exchanges in Chinese hamster cells. An
 

exogenous metabolic activation system was necessary for expression of the
 

aforementioned effects. In in vivo studies (Table 2-3), 1,2-diphenylhydrazine
 

inhibited testicular DNA synthesis in mice when administered as a single 100
 

mg/kg intraperitoneal injection, but did not cause sex-linked recessive lethal
 

mutations in Drosophila when administered in the feed or by injection.
 

Although only limited data are available, the weight of evidence
 

indicates that 1,2-diphenylhydrazine is genotoxic in animals. In
 

particular, positive results were obtained in all assays with mammalian
 

systems. Overall, the available evidence suggests that 1,2- diphenylhydrazine
 

may cause chromosomal damage or other genotoxic effects in humans.
 

Cancer. Information regarding the carcinogenicity of
 

1,2-diphenylhydrazine in humans by any route of exposure was not located.
 

In animals, significantly increased incidences of hepatocellular carcinomas,
 

neoplastic liver nodules, mammary adenocarcinomas, Zymbal's gland carcinomas
 

and adrenal pheochromocytomas occurred in rats and/or mice treated with
 

1,2-diphenylhydrazine in the diet for 78 weeks (NCI 1978). Other
 

carcinogenicity studies of 1,2-diphenylhydrazine, involving diet treatment
 


28
 

2. HEALTH EFFECTS
 

in rats (Pliss 1974; Marhold et al. 1978), dermal treatment in mice (Pliss
 

1974), and subcutaneous or intraperitoneal injection in rats and mice
 

(Spitz et al. 1950; Genin et al. 1975; Pliss 1974; Shabad and Genin 1975;
 

Kurlyandskiy et al. 1976; Maronpot et al. 1986), are inconclusive due to
 

inadequate reporting and other limitations. Although inconclusive, most of
 

these studies reported tumors at sites that are generally consistent with
 

sites of tumors in the NCI (1978) bioassay (e.g., liver, mammary gland,
 

adrenal gland, and Zymbal's gland).
 

The NCI (1978) bioassay, which demonstrated carcinogenicity in two
 

species, provides sufficient evidence of carcinogenicity of
 

1,2-diphenylhydrazine in animals. Biotransformation products of
 

1,2-diphenylhydrazine include aniline and benzidine, which are known
 

carcinogens in animals (both chemicals) and humans (benzidine) (EPA
 

1988b,c). Based on the animal evidence for carcinogenicity from the NCI
 

(1978) bioassay and the carcinogenicity of its metabolites,
 

1,2-diphenylhydrazine is likely to be carcinogenic in humans.
 

2.5 BIOMARKERS OF EXPOSURE AND EFFECT
 

Biomarkers are broadly defined as indicators signaling events in
 

biologic systems or samples. They have been classified as markers of
 

exposure, markers of effect, and markers of susceptibility (NAS/NRC, 1989).
 

A biomarker of exposure is a xenobiotic substance or its metabolite(s)
 

or the product of an interaction between a xenobiotic agent and some target
 

molecule or cell that is measured within a compartment of an organism
 

(NAS/NRC 1989). The preferred biomarkers of exposure are generally the
 

substance itself or substance-specific metabolites in readily obtainable
 

body fluid or excreta. However, several factors can confound the use and
 

interpretation of biomarkers of exposure. The body burden of a substance
 

may be the result of exposures from more than one source. The substance
 

being measured may be a metabolite of another xenobiotic (e.g., high urinary
 

levels of phenol can result from exposure to several different aromatic
 

compounds). Depending on the properties of the substance (e.g., biologic
 

half-life) and environmental conditions (e.g., duration and route of
 

exposure), the substance and all of its metabolites may have left the body
 

by the time biologic samples can be taken. It may be difficult to identify
 

individuals exposed to hazardous substances that are commonly found in body
 

tissues and fluids (e.g., essential mineral nutrients such as copper, zinc
 

and selenium). Biomarkers of exposure to 1,2-diphenylhydrazine are
 

discussed in Section 2.5.1.
 

Biomarkers of effect are defined as any measurable biochemical,
 

physiologic, or other alteration within an organism that, depending on
 

magnitude, can be recognized as an established or potential health
 

impairment or disease (NAS/NRC 1989). This definition encompasses
 

biochemical or cellular signals of tissue dysfunction (e.g., increased liver
 

enzyme activity or pathologic changes in female genital epithelial cells),
 
29
 

2. HEALTH EFFECTS
 

as well as physiologic signs of dysfunction such as increased blood pressure
 

or decreased lung capacity. Note that these markers are often not substance
 

specific. They also may not be directly adverse, but can indicate potential
 

health impairment (e.g., DNA adducts). Biomarkers of effects caused by
 

1,2-diphenylhydrazine are discussed in Section 2.5.2.
 

A biomarker of susceptibility is an indicator of an inherent or
 

acquired limitation of an organism's ability to respond to the challenge of
 

exposure to a specific xenobiotic. It can be an intrinsic genetic or other
 

characteristic or a preexisting disease that results in an increase in
 

absorbed dose, biologically effective dose, or target tissue response. If
 

biomarkers of susceptibility exist, they are discussed in Section 2.7,
 

"POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE."
 

2.5.1 Biomarkers Used to Identify or Quantify Exposure to 1,2­

Diphenylhydrazine
 

No studies were located regarding biomarkers of exposure to 1,2­

diphenylhydrazine. The metabolites of 1,2-diphenylhydrazine were identify
 

in one study (Dutkiewicz and Szymanska); however, the validity of the
 

findings is uncertain because of the analytical methodology used (see
 

Section 2.3.3 Metabolism). No enzymatic changes that could be used as
 

biomarkers of 1,2-diphenylhydrazine exposure are known.
 

2.5.2 Biomarkers Used to Characterize Effects Caused by 1,2-Diphenylhydrazine
 

No biomarkers of effects were identified for 1,2-diphenylhydrazine
 

exposure. No specific alterations in the organism that could be recognized
 

as biomarkers were found, and the most susceptible organs or tissues were
 

not identified.
 

2.6 INTERACTIONS WITH OTHER CHEMICALS
 

A carcinogenicity study was reported in which groups of rats were
 

given weekly subcutaneous injections of 1,2-diphenylhydrazine (20 mg), or
 

1,2-diphenylhydrazine (20 mg) concurrently with benzidine sulfate (15 mg)
 

for life (Genin et al. 1975). Combined incidences of tumors (injection
 

site, liver, and other sites) were increased and the mean tumor latent
 

period was decreased in the group with combined 1,2-diphenylhydrazine and
 

benzidine sulfate exposure.. It is unclear whether these findings provide
 

evidence for an interaction between 1,2-diphenylhydrazine and benzidine or
 

additive effects of two carcinogens. The results of this study were also
 

reported by Shabad and Genin (1975) and Kurlyandskiy et al. (1976).
 

Concurrent exposure to 1,2-diphenylhydrazine and benzidine could occur
 

during benzidine production, since 1,2-diphenylhydrazine is used as a
 

starting material in the production of benzidine, which is a degradation or
 

metabolic product of 1,2-diphenylhydrazine.
 
30
 

2. HEALTH EFFECTS
 

2.7 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE
 

No populations with unusual susceptibility to health effects of
 

1,2-diphenylhydrazine have been identified. It is possible that people with
 

chronic liver disease or possibly compromised hepatic function (e.g., very
 

young or very old people, alcoholics) might be unusually susceptible to
 

1,2-diphenylhydrazine, because the liver is a target organ of
 

1,2-diphenylhydrazine in animals.
 

2.8 ADEQUACY OF THE DATABASE
 

Section 104(i)(5) of CERCLA directs the Administrator of ATSDR (in
 

consultation with the Administrator of EPA and agencies and programs of the
 

Public Health Service) to assess whether adequate information on the health
 

effects of 1,2-diphenylhydrazine is available. Where adequate information
 

is not available, ATSDR, in conjunction with the National Toxicology Program
 

(NTP) , is required to assure the initiation of a program of research
 

designed to determine the health effects (and techniques for developing
 

methods to determine such health effects) of 1,2-diphenylhydrazine.
 

The following categories of data needs have been identified by a joint
 

team of scientists from ATSDR, NTP, and EPA. They are defined as
 

substancespecific informational needs that, if met would reduce or eliminate
 

the uncertainties of human health assessment. In the future, the identified
 

data needs will be evaluated and prioritized, and a substance-specific
 

research agenda will be proposed.
 

2.8.1 Existing Information on Health Effects of 1,2-Diphenylhydrazine
 

The existing data on health effects of inhalation, oral, and dermal
 

exposure of humans and animals to 1,2-diphenylhydrazine are summarized in
 

Figure 2-3. The purpose of this figure is to illustrate the existing
 

information concerning the health effects of 1,2-diphenylhydrazine. Each
 

dot in the figure indicates that one or more studies provide information
 

associated with that particular effect. The dot does not imply anything
 

about the quality of the study or studies. Gaps in this figure should not
 

be interpreted as "data needs" information.
 

Information regarding health effects of 1,2-diphenylhydrazine in
 

humans is not available. Except for one dermal study, health effects of
 

1,2-diphenylhydrazine in animals have been investigated only in oral
 

exposure studies. As indicated in Figure 2-3, animal oral data are
 

available for lethality, systemic effects due to intermediate and chronic
 

duration exposure, and genotoxicity and cancer. These data indicate that
 

oral exposure to 1,2-diphenylhydrazine was life-shortening, hepatotoxic,
 

irritating to the stomach, and carcinogenic to rats and/or mice. Limited
 

animal data are available for neurologic and reproductive effects due to
 

oral exposure, and for cancer due to dermal exposure.
 

32
 

2. HEALTH EFFECTS
 

2.8.2 Identification of Data Needs
 

Acute-Duration Exposure. Information is not available on the health
 

effects of 1,2-diphenylhydrazine resulting from inhalation exposure in
 

humans or animals. Because 1,2-diphenylhydrazine is a solid with a low
 

vapor pressure at ambient temperatures, it is highly unlikely that
 

inhalation exposure to this chemical in the vapor state would occur (Chapter
 

5). However, the possibility of inhalation exposure to dusts of 1,2­

diphenylhydrazine either free or adsorbed to soil is conceivable.
 

Therefore, acute studies of inhalation exposure to dusts of 1,2­

diphenylhydrazine could be designed to provide information on possible toxic
 

effects and exposure levels that cause effects. No studies were located
 

regarding acute oral exposure in humans. The only pertinent acute exposure
 

toxicity studies of 1,2-diphenylhydrazine were conducted in rats; these
 

consist of an oral LD50 assay and methemoglobin determination following 

intravenous treatment. Additional acute oral exposure studies could 

corroborate the LD50, identify systemic effects, and provide information on 

thresholds of effects as well as interspecies differences. However, 

although ingestion of 1,2-diphenylhydrazine-contaminated soil from waste 

sites is conceivable, extensive oral studies appear to be unwarranted as the 

possibility of exposure from ingestion of contaminated soil seems unlikely, 

and exposure via drinking water is essentially nonexistent because of the 

rapid oxidation of 1,2-diphenylhydrazine in water (Chapter 5). Because of 

the lack of dose-effect information, no MRL was derived. Pharmacokinetic 

data are insufficient for identification of target organs across routes of 

exposure. No studies were located regarding acute dermal exposure in humans 

or animals. Acute dermal studies of 1,2-diphenylhydrazine with animals 

could provide information on skin and eye irritation, lethality, and other 

toxic effects. Dermal studies of 1,2-diphenylhydrazine appear to be most 

relevant, as dermal exposure is a likely route of environmental exposure. 

As discussed in Chapter 5, dermal exposure via direct chemical contact or 

contact with contaminated soil is possible at hazardous waste sites, where 

high concentrations of crystalline 1,2-diphenylhydrazine could occur. 

Intermediate-Duration Exposure. No information was located regarding
 

intermediate-duration inhalation exposure to 1,2-diphenylhydrazine in humans
 

or animals. As discussed for acute-duration exposure, 1,2-diphenylhydrazine is
 

a solid with a low vapor pressure at ambient temperature, which makes
 

inhalation exposure to this chemical in the vapor state unlikely. However, the
 

possibility of inhalation exposure to dusts of 1,2-diphenylhydrazine either
 

free or adsorbed to soil is conceivable. Therefore, intermediateduration
 

studies of inhalation exposure to dusts of 1,2-diphenylhydrazine could be
 

designed to provide information on possible toxic effects and exposure levels
 

that cause effects. A limited number of intermediateduration oral studies
 

provide information on lethality and/or gross pathology in rats and mice.
 

Because of the lack of reliable information about dose-relationship, no MRL
 

was derived. Pharmacokinetic data were insufficient for identification of
 

target organs across routes of exposure.
 
33
 

2. HEALTH EFFECTS
 

Additional studies examining histology or other sensitive endpoints could
 

elucidate systemic effects and thresholds of toxicity. Intermediateduration
 

dermal studies examining systemic toxicity in animals could provide
 

information on whether repeated dermal exposure of humans poses a threat of
 

toxic effects. This information would be useful for an evaluation of health
 

risk in populations living near hazardous waste sites that might be
 

repeatedly exposed to 1,2-diphenylhydrazine-contaminated soil.
 

Chronic-Duration Exposure and Cancer. No studies were located
 

regarding chronic inhalation exposure to 1,2-diphenylhydrazine in humans or
 

animals. As discussed for acute- and intermediate-duration exposure,
 

1,2-diphenylhydrazine is a solid with a low vapor pressure at ambient
 

temperature, which makes inhalation exposure this chemical in the vapor
 

state unlikely. However, the possibility of inhalation exposure to dusts of
 

1,2-diphenylhydrazine either free or adsorbed to soil is conceivable.
 

Therefore, chronic-duration studies of inhalation exposure to dusts of
 

1,2-diphenylhydrazine could be designed to provide information on possible
 

toxic effects and exposure levels that cause effects. The NCI (1978)
 

bioassay of 1,2-diphenylhydrazine provides the only sufficient chronic oral
 

toxicity data for this chemical. This study was not, however, subjected to
 

the peer review process used for current NTP bioassays, and it inadequately
 

evaluated nonneoplastic effects. Additional studies would be particularly
 

useful for corroborating and more fully characterizing 1,2-diphenylhydrazineinduced systemic toxicity. In particular, more studies could provide
 

information on cause(s) of death due to chronic exposure, and delineate
 

carcinogenic and noncarcinogenic doses. No studies were located regarding
 

toxic effects after chronic dermal exposure to 1,2-diphenylhydrazine in humans
 

or animals. Because of the lack of reliable data, no MRL for chronic exposure
 

was derived. Pharmacokinetic data were insufficient for identification of
 

target organs across routes of exposure. More information regarding chronic
 

dermal exposure would be useful for possible extrapolation of results to
 

humans that may be exposed to 1,2-diphenylhydrazine near hazardous waste sites
 

for a long period of time.
 

The paucity of systemic toxicity data for this chemical appears to be
 

related to primary interest in testing for carcinogenicity. Treatment related
 

neoplasms developed in rats and mice that were treated with 1,2­

diphenylhydrazine in a diet. An inconclusive chronic dermal carcinogenicity
 

study of 1,2-diphenylhydrazine with mice was available. The development of
 

neoplasia was reported in the exposed group. The results from the controls
 

were not, however, provided. The available data, although scarce, indicate a
 

possible carcinogenic potential for 1,2-diphenylhydrazine. This finding is
 

supported by some genotoxicity studies. Additional chronic dermal studies
 

would be useful to further investigate
 

1,2-diphenylhydrazine carcinogenicity.
 

Genotoxicity. A limited number of in vitro assays with bacteria and
 

mammalian cells and an in vivo assay with mice indicate that 1,2­

diphenylhydrazine is genotoxic. Replicate essays have not been
 
34
 

2. HEALTH EFFECTS
 

conducted with the exception of assays with Salmonella, and mutation in
 

mammalian systems and genotoxicity in human cells have not been evaluated.
 

Additional studies, particularly involving mammalian systems and providing
 

information on the potential for heritable mutations, would add to the
 

database on genotoxicity and validate available information.
 

Reproductive Toxicity. The unremarkable histology of the reproductive
 

organs of the rats and mice in the NCI (1978) bioassay provides limited
 

information on the lack of reproductive toxicity of 1,2-diphenylhydrazine.
 

Multigeneration or continuous breeding studies in animals would provide a
 

basis for evaluation of potential reproductive effects of
 

1,2-diphenylhydrazine in humans.
 

Developmental Toxicity. It is not known whether 1,2-diphenylhydrazine
 

crosses the placenta, but there is no reason to assume that it (or its
 

metabolites) would not do so. Developmental studies in mammals would provide
 

information on possible fetotoxic and teratogenic effects of 1,2­

diphenylhydrazine that might be relevant to humans.
 

Immunotoxicity. No histopathological effects on immunological organs
 

and tissues of rats and mice were found in the NCI (1978) chronic oral
 

bioassay of 1,2-diphenylhydrazine. Adequate evaluation of immunotoxic
 

potential is precluded by a lack of specific immunotoxicity tests of
 

1,2-diphenylhydrazine. Dermal sensitization tests in animals might provide
 

information on whether an allergic response to 1,2-diphenylhydrazine is
 

likely.
 

Neurotoxicity. No clinical signs of central nervous system toxicity or
 

histological alterations of nervous system organs and tissues were observed in
 

rats or mice in the NCI (1978) chronic oral bioassay. Tests for
 

neurotoxicity in animals may be appropriate if there is clinical evidence of
 

neurological dysfunction in general oral or dermal toxicity studies of
 

1,2-diphenylhydrazine.
 

Epidemiological and Human Dosimetry Studies. Health effects of
 

1,2-diphenylhydrazine have not been described in humans. As discussed in
 

Chapter 5, the potential for environmental exposure to 1,2-diphenylhydrazine
 

is extremely low. Although dermal exposure to 1,2-diphenylhydrazine could
 

occur at a contaminated waste site, it is highly unlikely that segments of
 

the general population will be exposed to 1,2-diphenylhydrazine.
 

If 1,2-diphenylhydrazine or its metabolites in urine can be correlated
 

with dermal exposure in humans, it may be possible to monitor humans for
 

exposure. If toxic effects resulting from dermal exposure to
 

1,2-diphenylhydrazine are identified in humans, it may then be possible to
 

correlate urinary levels of 1,2-diphenylhydrazine or a metabolite with
 

systemic effects.
 
35
 

2. HEALTH EFFECTS
 

Biomarkers of Exposure and Effect. No biomarkers are known that are
 

specific for 1,2-diphenylhydrazine exposure. Continued efforts to devise
 

more sensitive and more specific early biomarkers of disease (especially
 

cancer) would be valuable.
 

Absorption, Distribution, Metabolism, Excretion. The general
 

metabolic pathways of 1,2-diphenylhydrazine are identifiable based on
 

limited evidence for 1,2-diphenylhydrazine in oral, intratracheal, and
 

injection experiments with rats (Dutkiewicz and Szymanska 1973), metabolism
 

data for azobenzene (which is metabolized to 1,2-diphenylhydrazine), and
 

metabolism data for aniline (an initial metabolite). The relative
 

contribution of the different pathways is not established. Although oral
 

absorption of 1,2-diphenylhydrazine and urinary excretion of
 

1,2-diphenylhydrazine and its metabolites are apparent, there is no
 

information on the rate and extent of absorption, or excretion, or tissue
 

distribution following oral exposure. Investigations of the toxicokinetics
 

of 1,2-diphenylhydrazine following dermal exposure have not been conducted.
 

Additional studies of absorption, distribution, metabolism, and excretion in
 

animals by the oral and dermal routes of exposure would provide information
 

needed for sufficient characterization of the toxicokinetics of
 

1,2-diphenylhydrazine. Studies addressing differences in metabolism between
 

oral and dermal routes would be particularly informative, as benzidine may
 

be formed by acidity in the stomach.
 

Comparative Toxicokinetics. No data are available to determine if
 

there are differences in the toxicokinetics of 1,2-diphenylhydrazine among
 

species. Toxicokinetic studies with different species could help explain
 

observed differences in toxicity and carcinogenicity between rats and mice,
 

and help identify the animal species that serves as the best model for
 

extrapolating results to humans.
 

2.8.3 On-going Studies
 

No ongoing studies of 1,2-diphenylhydrazine were identified.
 

37
 

3. CHEMICAL AND PHYSICAL INFORMATION
 

3.1 CHEMICAL IDENTITY
 

Data pertaining to the chemical identity of 1,2-diphenylhydrazine
 

listed in Table 3-1.
 

3.2 PHYSICAL AND CHEMICAL PROPERTIES
 

The physical and chemical properties of 1,2-diphenylhydrazine are
 

presented in Table 3-2.
 



41
 

4. PRODUCTION, IMPORT, USE, AND DISPOSAL
 

4.1 PRODUCTION
 

1,2-Diphenylhydrazine is produced in the stepwise reduction of
 

nitrobenzene by the action of iron or zinc powder in caustic solution (e.g.,
 

caustic soda, alcoholic alkaline) first to azoxybenzene, then azobenzene,
 

and finally 1,2-diphenylhydrazine (Sandridge and Staley 1978). A batch
 

process is used in which a caustic soda solution is added to a heated vessel
 

charged with nitrobenzene and iron borings. Additions of iron in caustic
 

soda solution are made to continue the reaction. When the reaction is
 

complete, separation of the 1,2-diphenylhydrazine from the iron sludge is
 

accomplished by solvent extraction or by alternative methods, such as
 

stopping the reaction at the azobenzene step and performing the final
 

reduction in a zinc-alcoholic alkali solution followed by filtration and
 

washing of the sodium zincate mass.
 

No recent information was located regarding production volumes of
 

1,2-diphenylhydrazine. The U.S. International Trade Commission last
 

reported production of 1,2-diphenylhydrazine for the 1978 production year
 

(USITC 1979). In that year, Bofors Lakeway, Muskegon, MI, reportedly
 

produced and isolated 1,2-diphenylhydrazine, but no volumes were published.
 

The USITC will not publish production volumes of chemicals for which there
 

are less than three manufacturers. No producers have been reported by the
 

USITC since 1978, indicating either that less than 5000 pounds were produced
 

or that the product was never isolated, but was used directly in the next
 

reaction step.
 

4.2 IMPORT
 

No information concerning the importation or exportation of
 

1,2-diphenylhydrazine in the United States was located in the literature.
 

4.3 USE
 

One of the major uses of 1,2-diphenylhydrazine is as a starting
 

material in the production of benzidine; however, it is no longer produced
 

in the United States. 1,2-Diphenylhydrazine rearranges to benzidine upon
 

treatment with strong acid; benzidine is used by the dye industry for the
 

production of benzidine-based dyes including many of the Direct dyes (e.g.,
 

Direct Red 28, Direct Black 4, Direct Blue 2) (Ferber 1978; Lurie 1964).
 

Fabricolor, the last producer of benzidine based dyes, discontinued
 

production in 1988 (Personal communication, Alvarez 1989).
 

1,2-Diphenylhydrazine is used for the production of the drugs
 

phenylbutazone (trade name Butazolidin, an anti-inflammatory agent) and
 

sulfinpyrazone (trade name Anturane, a uricosuric agent for the treatment of
 

gouty arthritis) (Barnhart 1988; Hughes 1981; Kornis 1982). These drugs are
 

made by the condensation of 1,2-diphenylhydrazine with malonic acid
 

derivatives to form pyrazolidinedione structures. It is not clear from the
 

literature if the 1,2-diphenylhydrazine used in the condensation reaction is
 
42
 

4. PRODUCTION, IMPORT, USE, AND DISPOSAL
 

produced by the manufacturers that use it or if it is purchased by them as
 

an isolated product.
 

4.4 DISPOSAL
 

Very little information was located in the literature concerning the
 

disposal of 1,2-diphenylhydrazine. Dietrich et al. (1985) reported that wet
 

air oxidation (heating wastewater under pressure with the addition of an
 

oxygen-containing gas such as air) would remove 99.88% of the
 

1,2-diphenylhydrazine in the water (initial concentration, 5000 mg/L). Wet
 

air oxidation can effectively treat aqueous waste streams that are too
 

dilute to incinerate, yet too toxic to treat using biological processes.
 

Results of treatment by wet air oxidation are in keeping with the
 

observation that 1,2-diphenylhydrazine oxidizes on standing to azobenzene
 

(Riggin and Howard 1979). Information regarding the amount of
 

1,2-diphenylhydrazine disposed of in the United States was not located in
 

the literature.
 
43
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

5.1 OVERVIEW
 

1,2-Diphenylhydrazine oxidizes rapidly in the environment under aerobic
 

conditions, with a half-life in water as short as 15 minutes. This rapid
 

oxidation coupled with the lack of straightforward sampling methods makes the
 

assessment of the literature difficult. For example, while a few
 

monitoring papers report the detection of 1,2-diphenylhydrazine in the
 

environment, their analytical methodology suggests that it is unlikely that
 

1,2-diphenylhydrazine would have been detected even if present. In
 

addition, little information is available to assess the potential for
 

environmental contamination, making the estimation of environmental releases
 

difficult. Therefore, not only is the significance of reported
 

environmental concentrations difficult to interpret, environmental
 

concentrations are difficult to predict. The fate, transport, and
 

distribution of 1,2-diphenylhydrazine in the environment are uncertain.
 

1,2-Diphenylhydrazine has been reported at 7 of 1177 sites in the National
 

Priority List database (ATSDR 1990); the frequency of these sites within the
 

United States can be seen in Figure 5-l.
 

5.2 RELEASES TO THE ENVIRONMENT
 

5.2.1 Air
 

No information concerning the release of 1,2-diphenylhydrazine to air 

was located in the literature. The vapor pressure of 1,2-diphenylhydrazine 

is low (2.6 x 10-5 mmHg at 25 C), indicating that little 1,2-diphenylhydrazine 

will volatilize from manufacturing and use operations. Dust generated from the 

loading and off-loading of 1,2-diphenylhydrazine during use may cause local 

atmospheric concentrations. If present in water, 

1,2-diphenylhydrazine will probably oxidize to azobenzene before it 

volatilizes. Volatilization of 1,2-diphenylhydrazine is not expected to be 

an environmentally relevant fate process given the low Henry's Law constant 

(9.42 x 10-8 atm-m3 mol-1). 

5.2.2 Water
 

No information concerning the release of 1,2-diphenylhydrazine to water
 

was located in the literature. If discharged to water, detectable
 

concentrations will probably persist for only a short time, since the halflife
 

of (100 μg/L) 1,2-diphenylhydrazine in wastewater is about 15 minutes (Riggin 

and Howard 1979, 1982) 

5.2.3 Soil
 

No information concerning the release of 1,2-diphenylhydrazine to soil
 

was located in the literature. The manufacturing process for
 

1,2-diphenylhydrazine generates a sludge containing iron and/or zinc
 

45
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

compounds, probably along with small amounts of unextracted
 

1,2-diphenylhydrazine. Some of this material may be disposed of in
 

landfills, but no information is available concerning the
 

1,2-diphenylhydrazine disposal practices of the manufacturing industry.
 

5.3 ENVIRONMENTAL FATE
 

5.3.1 Transport and Partitioning
 

No information concerning the transport and partitioning of 

1,2-diphenylhydrazine in the environment was located in the literature. In 

water, 1,2-diphenylhydrazine is not expected to volatilize because of its 

rapid oxidation in aerated water (near-surface water) to azobenzene and its 

low calculated Henry's Law constant (9.42 x 10-8 atm-m3

 mol-l) (Lyman et al. 

1982). The calculated log Koc (2.76) suggests that 1,2-diphenylhydrazine 

may sorb to sediments or suspended particles. This is based on the analysis 

of Kenaga (1980), who stated that chemicals with a Koc <lOO tend to be 

mobile in soil, while those with a Koc >lOOO tend to sorb. In soil, 

1,2-diphenylhydrazine is not expected to leach to groundwater, based on its 

physical and chemical properties (i.e., 1,2-diphenylhydrazine reacts rapidly 

under environmental conditions and, based on its Koc, will not rapidly leach 

downward in the soil column). 

5.3.2 Transformation and Degradation
 

5.3.2.1 Air
 

No studies were located regarding the rates or products of reaction of
 

1,2-diphenylhydrazine in the atmosphere. Based on its behavior in aerated
 

water, 1,2-diphenylhydrazine may react rapidly in air to form azobenzene as
 

well as other products resulting from the abstraction of a hydrogen from a
 

nitrogen by hydroxyl radical. Atkinson (1987) developed a method to
 

estimate the hydroxyl radical (HO•) reaction rate based on structure. 

this method, an overall reaction rate of 211 x l0-l2 cm 3

 molecule-1 sec -1 

was calculated, which yields a half-life of less than 2 hours for an 

atmospheric HO•. concentration of 0.5 x l06

 molecules cm-3. This is an 

estimated annually averaged concentration for a 24-hour period (Atkinson 

1985). 1,2-Diphenylhydrazine also absorbs light above 290 nm (Sadtler
 

Index, no date) and may be susceptible to photolysis. No information was
 

found concerning the characteristics of this potential reaction.
 

5.3.2.2 Water
 

Very little information was located concerning the fate of
 

1,2-diphenylhydrazine in water. Riggin and Howard (1979, 1982) reported the
 

results of a study on the stability of 1,2-diphenylhydrazine in a number of
 

solvents including distilled water and wastewater. In distilled water at pH
 

values of 2, 4.7, 7, and 10 and at 4°C or at room temperature, less than 10%
 

of the initial 10 μg/L of 1,2-diphenylhydrazine remained in the water after 
46
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

1 day. At pH 2, 1,2-diphenylhydrazine degraded to benzidine, while at pH 7
 

it degraded to an unidentifiable oxidizable product. At pH 10,
 

1,2-diphenylhydrazine degraded to azobenzene, and at pH 4.7, it degraded
 

into two unidentifiable products, which were not azobenzene or benzidine.
 

In secondary municipal sewage effluent, Riggin and Howard (1979, 1982)
 

reported that 100 μg/L of 1,2-diphenylhydrazine had a half-life of about 15 

minutes in the presence of oxygen, and about 60 minutes when no oxygen was 

present. These results suggest that 1,2-diphenylhydrazine is unlikely to 

persist in the environment, particularly under aerobic conditions. 

Weber and Wolfe (1986, 1987) reported that azobenzene, when incubated
 

in air with four anaerobic lake sediments containing about 2-4% organic
 

matter, was reduced to aniline with a reaction half-life of about 2700-5700
 

minutes, depending on the source and date of specimen collection.
 

1,2-Diphenylhydrazine was not detected as an intermediate. The authors
 

postulate a four-electron mechanism involving the intermediate formation of
 

1,2-diphenylhydrazine.
 

In reporting the same data, Tabak et al. (1981a,b) and Patterson and
 

Kodukala (1981) stated that 5 or 10 mg/L of 1,2-diphenylhydrazine was
 

degraded up to 80% when initially cultured with settled domestic wastewater.
 

This degradation rate, however, was reduced to 40% in the case of the 10
 

mg/L concentration, after the third subculture. The authors suggested that
 

a de-adaptive and toxification process was occurring with
 

1,2-diphenylhydrazine. It is unclear if the analytical methods used by
 

these authors would have been able to detect 1,2-diphenylhydrazine if
 

present. Both dissolved organic carbon and gas chromatography (GC) analyses
 

were performed on the samples. Considering the sample preparation
 

procedures, however, the compound detected might not have been
 

1,2-diphenylhydrazine, but a decomposition product such as azobenzene.
 

5.3.2.3 Soil
 

No information concerning the fate of 1,2-diphenylhydrazine in soil was
 

located in the literature. Based on the fate of 1,2-diphenylhydrazine in
 

water and sediment, detectable concentrations probably will not persist for
 

long periods, but this may depend on the initial concentration.
 

5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT
 

The rapid oxidation of 1,2-diphenylhydrazine in water to form
 

azobenzene and other compounds makes its sampling and analysis difficult.
 

Storing a sample containing 1,2-diphenylhydrazine for even short periods can
 

result in complete oxidation; in gas chromatography, 1,2-diphenylhydrazine
 

is oxidized to azobenzene upon injection onto the chromatographic column
 

(Riggin and Howard 1982). Therefore, unless sampling and analysis are
 

performed under conditions that will prevent oxidation or unless
 

concentrations of 1,2-diphenylhydrazine in the sample are very high,
 

analyses of environmental samples for 1,2-diphenylhydrazine are inaccurate
 
47
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

(Ahuja et al. 1988; Riggin and Howard 1979). It is doubtful that the
 

concentrations measured reflect on the concentrations present in the sample
 

at the time of collection (i.e., measured concentrations would
 

]underestimate actual concentrations (Riggin and Howard 1982).
 

5.4.1 Air
 

No ambient air monitoring for 1,2-diphenylhydrazine was located in the
 

literature. This may be due to both the rapid oxidation of
 

1,2-diphenylhydrazine and its low vapor pressure, which limit the amount of
 

1,2-diphenylhydrazine entering the atmosphere. In addition, no information
 

was located suggesting that any studies have sought but not found
 

1,2-diphenylhydrazine.
 

5.4.2 Water
 

Two reported identifications of 1,2-diphenylhydrazine in water samples
 

were located in the literature. Melton et al. (1981) reported that
 

1,2-diphenylhydrazine was present in Cincinnati, OH, drinking water (river
 

water treated by coagulation, sand filtration, and chlorination).
 

1,2-Diphenylhydrazine was reported at a concentration of 1 ng/L. Since the
 

sample preparation involved aeration and the original sample was
 

chlorinated, it is unclear if the detected material was 1,2-diphenylhydrazine.
 

Riggin and Howard (1982) found that, in addition to injection onto a GC
 

column, either chlorination or aeration of a sample resulted In total
 

disappearance of 1,2-diphenylhydrazine. Tang et al. (1983) reported 1,2­

diphenylhydrazine in coal gasification wastewater at concentrations of 0.149
 

and 1.786 μg/L. Sample preparation in this case involved separation into 

classes by pH, liquid-liquid extraction, concentration, and gas 

chromatography/mass spectroscopy (GC/MS) analysis. No precautions were taken 

to reduce the aeration of the sample. Also, the analytical procedure indicates 

that no 1,2-diphenylhydrazine would have been able to survive the conditions 

of the sample preparation and the detection may be of another chemical or of 

1,2-diphenylhydrazine from another source (e.g., decomposition of another 

compound to 1,2-diphenylhydrazine). 

Hall et al. (1985) reported that no 1,2-diphenylhydrazine (less than 

1 μg/L) was detected in the Nanticoke River near the Chesapeake Bay. The 

analytical method involved liquid-liquid extraction, concentration, and 

analysis by GC/MS. The Contract Laboratory Program statistical database 

(queried April 13, 1987) reported that 1,2-diphenylhydrazine has been 

detected in water at 1 of 357 hazardous waste sites at a concentration of 

96 ppb (CLPSDB 1987), and has been reported at 7 of 1177 sites in the 

National Priority List database (ATSDR 1990). The U.S. EPA Contract 

Laboratory Program uses GC methods to analyze the contaminants of interest. 

Since 1,2-diphenylhydrazine oxidizes to azobenzene in the GC injector port 

and both 1,2-diphenylhydrazine and azobenzene have the same GC retention 

time and mass spectra, reports of 1,2-diphenylhydrazine from the Contract 
48
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

Laboratory Program may actually represent detections of 1,2-diphenylhydrazine,
 

azobenzene, or both (see Chapter 6 for more details).
 

5.4.3 Soil
 

1,2-Diphenylhydrazine has been identified in soil only at hazardous
 

waste sites. The Contract Laboratory Program statistical database (queried
 

April 13, 1987) reported that 1,2-diphenylhydrazine has been detected in the
 

soil at 2 of 357 hazardous waste sites in both cases at 18,200 ppm (CLPSDB
 

1987). The Contract Laboratory Program uses GC methods to analyze the
 

contaminants of interest. As discussed in Section 5.4.2, this may actually
 

represent detections of either 1,2-diphenylhydrazine or azobenzene (see
 

Chapter 6 for more details). Furthermore, the fact that identical
 

concentrations were reported increases uncertainty about the validity of the
 

data.
 

5.4.4 Other Media
 

1,2-Diphenylhydrazine has been assayed but not detected in fish samples
 

from the Great Lakes area. Camanzo et al. (1987) reported that no
 

1,2-diphenylhydrazine was detected in fish samples from 13 Lake Michigan
 

tributaries and Grand Traverse Bay fish. Analyses were made by GC/MS and no
 

detection limits were given. Similarly, DeVault (1985) reported that a
 

GC/MS did not identify any of the peaks present in fish samples from Great
 

Lakes Harbors and Tributaries as 1,2-diphenylhydrazine.
 

Phenylbutazone and sulfinpyrazone can hydrolyze to yield
 

1,2-diphenylhydrazine and these drugs may contain some 1,2-diphenylhydrazine
 

(Ahuja et al. 1988; Fabre et al. 1984; Matsui et al. 1983). Phenylbutazone
 

is a drug used for the treatment of inflammatory conditions (e.g.,
 

arthritis) and sulfinpyrazone is used to treat gouty arthritis. Although
 

potential exists for exposure to 1,2-diphenylhydrazine via from treatment
 

with these drugs, no information regarding body burden was located in the
 

literature.
 

5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE
 

Virtually no information concerning general population or occupational
 

exposure was located in the literature. General population exposure may
 

come from those on phenylbutazone or sulfinpyrazone therapy, since these
 

drugs may contain some 1,2-diphenylhydrazine (Fabre et al. 1984; Matsui
 

et al. 1983). The National Institute for Occupational Safety and Health
 

(NIOSH), National Occupational Exposure Survey (NOES) reported as of May
 

1988 that 977 total employees and 154 female employees are potentially
 

exposed to 1,2-diphenylhydrazine (100% from actual observations) (NIOSH
 

1988).
 

The available database limits analysis of exposures in two ways.
 

First, very little information is available concerning the manufacturing
 
49
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

processes used in the production of phenylbutazone and sulfinpyrazone, the
 

two drugs that use 1,2-diphenylhydrazine as a starting material. A better
 

understanding of these processes would allow the estimation of worker
 

exposure potentials. Second, dye manufacturers in the United States no
 

longer produce benzidine based dyes (the last manufacturer stopped
 

production in 1988) and the number of workers potentially exposed to
 

1,2-diphenylhydrazine is now less than at the time of the NOES survey cited
 

above. Thus, the survey may no longer accurately reflect the number of
 

workers potentially exposed to 1,2-diphenylhydrazine.
 

5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURE
 

The only populations with potentially high exposure appear to be
 

persons receiving phenylbutazone or sulfinpyrazone therapy, those living
 

near hazardous waste sites, and those in occupations that manufacture or use
 

1,2-diphenylhydrazine. Very little information concerning these
 

populations, however, is available to clearly understand the extent of these
 

potential exposures.
 

5.7 ADEQUACY OF THE DATABASE
 

Section 104(i)(5) of CERCLA, directs the Administrator of ATSDR (in
 

consultation with the Administrator of EPA and agencies and programs of the
 

Public Health Service) to assess whether adequate information on the health
 

effects of 1,2-diphenylhydrazine is available. Where adequate information
 

is not available, ATSDR, in conjunction with the NTP, is required to assure
 

the initiation of a program of research designed to determine the health
 

effects (and techniques for developing methods to determine such health
 

effects) of 1,2-diphenylhydrazine.
 

The following categories of possible data needs have been identified by
 

a joint team of scientists from ATSDR, NTP, and EPA. They are defined as
 

substance-specific informational needs that, if met would reduce or
 

eliminate the uncertainties of human health assessment. In the future, the
 

identified data needs will be evaluated and prioritized, and a
 

substance-specific research agenda will be proposed.
 

5.7.1 Identification of Data Needs
 

Physical and Chemical Properties. Physical and chemical properties are
 

essential for estimating the partitioning of a chemical in the environment.
 

Data are available for only a few physical and chemical properties of
 

1,2-diphenylhydrazine, and most of these have limited experimental
 

descriptions. Therefore, an evaluation of the accuracy of the data is
 

difficult. Specifically, measured solubility, vapor pressure, Koc, pKa, and
 

Henry's Law constant at environmentally significant temperatures would help
 

to remove any doubt concerning the accuracy of the partitioning estimates,
 

especially in circumstances where 1,2-diphenylhydrazine does not oxidize
 

rapidly (such as when high concentrations are present). These data form the
 
50
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

basis of much of the input requirements for environmental models that
 

predict the behavior of a chemical under specific conditions including
 

hazardous waste landfills. In addition, the uncertainty in these
 

measurements can be used to estimate the sensitivity of these properties in
 

determining the overall fate of 1,2-diphenylhydrazine in the environment.
 

Production, Use, Release, and Disposal. Production methods for
 

1,2-diphenylhydrazine are well described in the literature (including the
 

patent literature); there does not appear to be a need for further
 

information in this area. Uses of 1,2-diphenylhydrazine are documented but
 

no recent production figures or detailed descriptions of uses are available.
 

This information is useful for estimating the potential for environmental
 

releases from manufacturing and use industries as well as the potential
 

environmental burden, but it is difficult to obtain in the detail desired
 

since it is considered confidential business information for those
 

industries that manufacture 1,2-diphenylhydrazine. Release information is
 

similar to use information in that it is not obtained easily and can be used
 

to estimate environmental burdens and potentially exposed populations. A
 

Toxic Release Inventory will provide some of this information in the
 

future. Disposal information is useful for determining environmental burden
 

and potential concentrations where environmental exposures may be high.
 

Data on different disposal methods for 1,2-diphenylhydrazine are lacking.
 

According to the Emergency Planning and Community Right to Know Act of 1986
 

(EPCRTKA), (§313), (Pub. L. 99-499, Title III, §313), industries are
 

required to submit release information to the EPA. The Toxic Release
 

Inventory (TRI), which contains release information for 1987, became
 

available in May of 1989. This database will be updated yearly and should
 

provide a more reliable estimate of industrial production and emission.
 

Environmental Fate. Photolysis, photooxidation, and chemical oxidation
 

studies in air and water are lacking, as are persistence studies in soil and
 

groundwater. These kinds of studies are important since they address the
 

fundamental removal mechanisms available to 1,2-diphenylhydrazine in the
 

environment. In addition, removal mechanisms such as atmospheric
 

photooxidation may be several orders of magnitude faster than any other
 

removal mechanism; understanding these reactions is crucial to an
 

understanding of the fate of 1,2-diphenylhydrazine in the environment.
 

Biodegradation studies in water may not be important, even though they are
 

lacking, since 1,2-diphenylhydrazine oxidizes rapidly.
 

Bioavailability from Environmental Media. No studies were located
 

regarding the bioavailability of 1,2-diphenylhydrazine from environmental
 

media, but lack of these data does not necessarily indicate a lack of
 

bioavailability. As exposure to 1,2-diphenylhydrazine could occur at waste
 

sites by dermal contact with contaminated soil or by ingestion of
 

contaminated soil, it would be useful to know if dermal or oral absorption
 

of 1,2-diphenylhydrazine from environmental media could occur. Information
 

on dermal absorption of 1,2-diphenylhydrazine from other media is not
 
51
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

available, but qualitative evidence indicates that 1,2-diphenylhydrazine in
 

diet or oil media is absorbed from the gastrointestinal tract (Section 2.3).
 

Food Chain Bioaccumulation. 1,2-Diphenylhydrazine reacts rapidly in
 

water to form azobenzene and other oxidation products (half-life in
 

wastewater is 60 minutes). Because of this and based upon the log
 

octanol/water partition coefficient, no bioaccumulation is expected in any
 

aquatic organism.
 

Exposure Levels in Environmental Media. Environmental monitoring data
 

are not available or are of questionable accuracy for water, soil, and air.
 

These data would be helpful in determining the ambient concentrations of 1,2­

diphenylhydrazine so that exposure estimates for the general population could
 

be made as well as 1,2-diphenylhydrazine exposure estimates for terrestrial
 

and aquatic organisms.
 

Exposure Levels in Humans. The database for exposure levels in humans is
 

very limited, and it is unclear if an exposed population exists given the
 

rapid disappearance of 1,2-diphenylhydrazine from the environment. While a
 

more complete database would be helpful in determining the current exposure
 

levels and thereby estimating the average daily dose associated with various
 

scenarios (e.g., living near a hazardous waste site, taking phenylbutazone), a
 

number of factors limit establishing such a program, including the lack of
 

appropriate analytical methods.
 

Exposure Registries. An exposure registry is not available. The
 

development of such a registry would be a useful reference tool in
 

assessing exposure levels and frequency. In addition, a registry would
 

allow an assessment of the variations in exposure concentrations from, for
 

example, geography, season, regulatory actions, presence of hazardous waste
 

landfills, or manufacturing and use facilities. These assessments, in
 

turn, would provide a better understanding of the need for research or data
 

acquisition based on the current exposure concentrations.
 

5.7.2 On-Going Studies
 

No on-going studies were located in the literature.
 

53
 

6. ANALYTICAL METHODS
 

The purpose of this chapter is to describe the analytical methods that
 

are available for detecting and/or measuring and monitoring
 

1,2-diphenylhydrazine in environmental media and in biological samples. The
 

intent is not to provide an exhaustive list of analytical methods that could
 

be used to detect and quantify 1,2-diphenylhydrazine. Rather, the intention
 

is to identify well-established methods that are used as the standard
 

methods of analysis. Many of the analytical methods used to detect
 

1,2-diphenylhydrazine in environmental samples are the methods approved by
 

federal agencies such as EPA and the National Institute for Occupational
 

Safety and Health (NIOSH). Other methods presented in this chapter are
 

those that are approved by a trade association such as the Association of
 

Official Analytical Chemists (AOAC) and the American Public Health
 

Association (APHA). Additionally, analytical methods are included that
 

refine previously used methods to obtain lower detection limits, and/or to
 

improve accuracy and precision.
 

6.1 BIOLOGICAL MATERIALS
 

No adequate methods were located for the analysis of
 

1,2-diphenylhydrazine in biological materials. While thin-layer
 

chromatography methods have been published, it is not clear if these methods
 

would be capable of resolving 1,2-diphenylhydrazine from degradation
 

products that appear rapidly in a sample upon standing (Bolton and Griffiths
 

1978; Dutkiewicz and Szymanska 1973). These products (some unidentified)
 

are produced rapidly, and vary depending on the exact conditions (see
 

below). In addition, none of the metabolites identified (e.g., benzidine,
 

aniline) are suitable surrogates since they cannot be linked exclusively to
 

1,2-diphenylhydrazine exposure, but may result from exposure to other
 

chemicals (and possibly drugs; see above).
 

6.2 ENVIRONMENTAL SAMPLES
 

Adequate analytical methods exist for the analysis of
 

1,2-diphenylhydrazine in environmental samples and are presented below.
 

However, adequate methods are not available for the sampling, sample
 

preservation, and sample preparation (extraction) of environmental media.
 

Neither EPA nor NIOSH have standard methods for analyzing
 

1,2-diphenylhydrazine in any medium; 1,2-diphenylhydrazine is no longer on
 

the Target Compound List (TCL) for the Contract Laboratory Program, but is
 

identified as a semi-volatile compound (EPA 1987a). Riggin and Howard
 

(1982) reported that 1,2-diphenylhydrazine at 100 μg/L in a municipal sewage 

effluent (after secondary treatment) had a time to 50% disappearance of 15 

minutes (it degraded completely within 1 hour), but the half-life was 

extended to 60 minutes when the wastewater was deaerated. Also, the authors 

stated that 1,2-diphenylhydrazine "... analysis in wastewater is virtually 

meaningless, since the DPH level determined cannot be directly related to 

the DPH in the sample at the time of collection." This limitation may apply 

to all environmental media, depending on the exact conditions used to 

acquire and store the sample, as well as the sample itself. Even excellent 
54
 

6. ANALYTICAL METHODS
 

methods for the analysis of 1,2-diphenylhydrazine will not necessarily yield
 

concentrations that are representative of the concentrations present in the
 

medium sampled.
 

Extracting and concentrating the 1,2-diphenylhydrazine in an
 

environmental sample may give poor results. Riggin and Howard (1979)
 

reported that 1,2-diphenylhydrazine extraction from water was
 

"irreproducible" because of instability when the extract was concentrated.
 

An extraction efficiency of more than 50% was reported for chloroform
 

extraction at pH 7. If stored for longer than 1 day, however, the extract
 

contained less than 10% of the initial 1,2-diphenylhydrazine concentration.
 

At different pH values, 1,2-diphenylhydrazine degraded into different
 

products, not all of which were identifiable. This lack of clearly
 

identifiable degradation products makes identification of a degradation
 

product as a surrogate for 1,2-diphenylhydrazine difficult. Ahuja et al.
 

(1988) found that extraction of 1,2-diphenylhydrazine in water containing
 

THAM buffer (pH 9.2) showed only 0.9% loss over 30 minutes, although
 

chromatography was performed within 30 minutes of extraction. Although this
 

procedure was applied to pharmaceutical analysis, there is no apparent
 

reason to believe it will not work for environmental analysis.
 

In addition, Riggin and Howard (1982) reported that analytical
 

standards of 1,2-diphenylhydrazine prepared in benzene, methylene chloride,
 

methanol, triethyl amine, acetonitrile, or acetic acid decomposed
 

completely in 3 days or less. Matsui et al. (1983) reported that
 

1,2-diphenylhydrazine was oxidized to azobenzene in n-hexane solution at a
 

rate of about 5%/hr; flushing the n-hexane with nitrogen reduced the
 

conversion rate to about 4% in 2 hours. These authors also found that
 

nitrogen flushed standards were stable over a l-hour period, based on the
 

detector response factors during liquid chromatography. These limitations
 

should be considered when interpreting analytical results.
 

Riggin and Howard (1982) reported that 1,2-diphenylhydrazine
 

“. . . instantaneously decomposes to azobenzene in the GC injection port." The
 

authors further stated that:
 

"It is interesting to note that only one peak resulted from DPH
 

injection. Occasionally, it was found that a second, later
 

eluting peak was present . . . . but this was not always the case.
 

This additional component may have been a solution decomposition
 

product."
 

Because of this, GC, including GC/MS, does not appear to be an acceptable
 

analytical tool for the analysis of 1,2-diphenylhydrazine in any sample.
 

Riggin and Howard (1979, 1982), Matsui et al. (1983), Fabre et al.
 

(19841, and Ahuja et al. (1988) reported that High Performance Liquid
 

Chromatography (HPLC) with UV or electrochemical detection is capable of
 

analyzing 1,2-diphenylhydrazine. Reversed phase chromatographic columns
 
55
 

6. ANALYTICAL METHODS
 

have been used most often (Ahuja et al. 1988; Fabre et al. 1984; Riggin and
 

Howard 1979, 1982). Cyano-amino polar bonded phase columns also have been
 

used (Matsui et al. 1983). Using a reversed phase and UV detection, the
 

minimum amount detected (on column amounts) is approximately 6-7 ng and the
 

minimum amount quantifiable is less than 1 μg (Ahuja et al. 1988; Fabre
 

et al. 1984; Matsui et al. 1983).
 

In conclusion, HPLC is preferred over GC for analysis of
 

1,2-diphenylhydrazine. Sample preservation and extraction methods need
 

improvement.
 

6.3 ADEQUACY OF THE DATABASE
 

Section 104(i)(5) of CERCIA, directs the Administrator of ATSDR (in
 

consultation with the Administrator of EPA and agencies and programs of the
 

Public Health Service) to assess whether adequate information on the health
 

effects of 1,2-diphenylhydrazine is available. Where adequate information
 

is not available, ATSDR, in conjunction with the NTP, is required to assure
 

the initiation of a program of research designed to determine the health
 

effects (and techniques for developing methods to determine such health
 

effects) of 1,2-diphenylhydrazine.
 

The following categories of possible data needs have been identified by
 

a joint team of scientists from ATSDR, NTP, and EPA. They are defined as
 

substance-specific informational needs that, if met would reduce or
 

eliminate the uncertainties of human health assessment. In the future, the
 

identified data needs will be evaluated and prioritized, and a
 

substance-specific research agenda will be proposed.
 

6.3.1 Identification of Data Needs
 

Methods for Determining Biomarkers of Exposure and Effect. No
 

biomarker that can be associated quantitatively with exposure to 1,2­

diphenylhydrazine has been identified (see Section 2.5). No adequate
 

methods are available for the analysis of 1,2-diphenylhydrazine in
 

biological materials. If this information were available, it would allow
 

both investigators and reviewers to assess the accuracy and uncertainty of
 

the methods used in toxicological studies. Furthermore, the ready
 

availability of tested analytical methods, including sample preservation,
 

would permit a standardized approach to the analysis of biological materials
 

to assist in measuring human exposure and monitoring effects in humans.
 

Adequate methods appear to be available for the analysis of 1,2­

diphenylhydrazine metabolites in biological materials. Metabolites include
 

azobenzene and aniline, both of which appear to be amenable to analysis by
 

standard methods. 1,2-Diphenylhydrazine and its metabolites, however, have
 

not been established as a quantitative biomarker of exposure to
 

1,2-diphenylhydrazine.
 
56
 

6. ANALYTICAL METHODS
 

No biomarker that can be associated quantitatively with effect has been
 

identified (see Section 2.5). Thus, there are no analytical methods for the
 

determination of biomarkers of effect for 1,2-diphenylhydrazine.
 

Methods for Determining Parent Compound and Degradation Products in
 

Environmental Media. While analytical methods appear to be available for the
 

analysis of 1,2-diphenylhydrazine, no methods were found for the preservation
 

of 1,2-diphenylhydrazine in ambient air, water, or soil
 

samples. Such methods would allow the development and analysis of a
 

monitoring program designed to better assess the concentrations of
 

1,2-diphenylhydrazine in and around hazardous waste sites.
 

Methods for Determining Degradation Products in Environmental Media.
 

Adequate methods are available for the analysis of some
 

1,2-diphenylhydrazine degradation products in environmental media; however,
 

not all of the major degradation products have been identified. In
 

addition, the number and nature of degradation products appear to change
 

depending on conditions (e.g., pH). The development of adequate analytical
 

methods for identifying degradation products would allow a monitoring
 

program designed to assess the ambient concentrations of
 

1,2-diphenylhydrazine degradation products in environmental media to be
 

established; this would provide information concerning both human and
 

environmental exposure, since it would allow an estimation of the
 

concentration of 1,2-diphenylhydrazine in environmental media to be
 

established prior to degradation. The development of analytical methods,
 

however, must be subsequent to generalized environmental fate studies that
 

identify the degradation products. A standardized method could then be
 

developed using spike recoveries from different media to determine the
 

recovery efficiencies and precision and accuracy of the method.
 

6.3.2 On-going Studies
 

No studies were located regarding on-going analytical methods
 

development for 1,2-diphenylhydrazine.
 
57
 

7. REGULATIONS AND ADVISORIES
 

National and state regulations and advisories pertinent to human
 

exposure to 1,2-diphenylhydrazine are summarized in Table 7-l. Guidance
 

from the World Health Organization (WHO) and the International Agency for
 

Research on Cancer (IARC) is not available.
 

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hydrazobenzene by liver fractions. Naunyn-Schmeidebergs Arch Pharmacol
 

293:54.
 

*Williams RT. 1959. The metabolism of dyestuffs and other colouring
 

matters. In: Detoxication mechanisms. The metabolism and detoxication of
 

drugs, toxic substances and other organic compounds, 2nd ed. New York, NY:
 

John Wiley and Sons, Inc., 472-488.
 

*Yoon JS, Mason JM, Valencia R, et al. 1985. Chemical mutagenesis testing
 

in Drosophila. IV. Results of 45 coded compounds tested for the National
 

Toxicology Program. Environ Mutagen 7:349-367.
 

Zeiger E. 1987. Carcinogenicity of mutagens: predictive capability of the
 

Salmonella mutagenesis assay for rodent carcinogenicity. Cancer Res
 

47:1287-1296.
 
67
 

9. GLOSSARY
 

Acute Exposure -- Exposure to a chemical for a duration of 14 days or less,
 

as specified in the Toxicological Profiles.
 

Adsorption Coefficient (Koc) -- The ratio of the amount of a chemical
 

adsorbed per unit weight of organic carbon in the soil or sediment to the
 

concentration of the chemical in solution at equilibrium.
 

Adsorption Ratio (Kd) -- The amount of a chemical adsorbed by a sediment or
 

soil (i.e., the solid phase) divided by the amount of chemical in the
 

solution phase, which is in equilibrium with the solid phase, at a fixed
 

solid/solution ratio. It is generally expressed in micrograms of chemical
 

sorbed per gram of soil or sediment.
 

Bioconcentration Factor (BCF) -- The quotient of the concentration of a
 

chemical in aquatic organisms at a specific time or during a discrete time
 

period of exposure divided by the concentration in the surrounding water at
 

the same time or during the same period.
 

Cancer Effect Level (CEL) -- The lowest dose of chemical in a study, or
 

group of studies, that produces significant increases in the incidence of
 

cancer (or tumors) between the exposed population and its appropriate
 

control.
 

Carcinogen -- A chemical capable of inducing cancer.
 

Ceiling Value -- A concentration of a substance that should not be
 

exceeded, even instantaneously.
 

Chronic Exposure -- Exposure to a chemical for 365 days or more, as
 

specified in the Toxicological Profiles.
 

Developmental Toxicity -- The occurrence of adverse effects on the
 

developing organism that may result from exposure to a chemical prior to
 

conception (either parent), during prenatal development, or postnatally to
 

the time of sexual maturation. Adverse developmental effects may be
 

detected at any point in the life span of the organism.
 

Embryotoxicity and Fetotoxicity -- Any toxic effect on the conceptus as a
 

result of prenatal exposure to a chemical; the distinguishing feature
 

between the two terms is the stage of development during which the insult
 

occurred. The terms, as used here, include malformations and variations,
 

altered growth, and in utero death.
 

EPA Health Advisory -- An estimate of acceptable drinking water levels for a
 

chemical substance based on health effects information. A health advisory is
 

not a legally enforceable federal standard, but serves as technical guidance
 

to assist federal, state, and local officials,
 
68
 

9. GLOSSARY
 

Immediately Dangerous to Life or Health (IDLH) -- The maximum environmental
 

concentration of a contaminant from which one could escape within 30 min
 

without any escape-impairing symptoms or irreversible health effects.
 

Intermediate Exposure -- Exposure to a chemical for a duration of 15-364 days
 

as specified in the Toxicological Profiles.
 

Immunologic Toxicity-- The occurrence of adverse effects on the immune
 

system that may result from exposure to environmental agents such as
 

chemicals.
 

In Vitro -- Isolated from the living organism and artificially maintained,
 

as in a test tube.
 

In Vivo -- Occurring within the living organism.
 

Lethal Concentration(LO) (LC50) -- The lowest concentration of a chemical in 

air which has been reported to have caused death in humans or animals. 

Lethal Concentration(50) (LC50) -- A calculated concentration of a chemical in 

air to which exposure for a specific length of time is expected to cause death 

in 50% of a defined experimental animal population. 

Lethal Dose(LO) (LD LO) -- The lowest dose of a chemical introduced by a 

route other than inhalation that is expected to have caused death in humans 

or animals. 

Lethal Dose(50) (LD50) -- The dose of a chemical which has been calculated 

to cause death in 50% of a defined experimental animal population. 

Lethal Time(50) (LT50) -- A calculated period of time within which a 

specific concentration of a chemical is expected to cause death in 50% of a 

defined experimental animal population. 

Lowest-Observed-Adverse-Effect Level (LOAEL) -- The lowest dose of chemical in
 

a study, or group of studies, that produces statistically or biologically
 

significant increases in frequency or severity of adverse effects between the
 

exposed population and its appropriate control.
 

Malformations -- Permanent structural changes that may adversely affect
 

survival, development, or function.
 

Minimal Risk Level -- An estimate of daily human exposure to a chemical that
 

is likely to be without an appreciable risk of deleterious effects
 

(noncancerous) over a specified duration of exposure.
 
69
 

9. GLOSSARY
 

Mutagen -- A substance that causes mutations. A mutation is a change in the
 

genetic material in a body cell. Mutations can lead to birth defects,
 

miscarriages, or cancer.
 

Neurotoxicity -- The occurrence of adverse effects on the nervous system
 

following exposure to chemical.
 

No-Observed-Adverse-Effect Level (NOAEL) -- The dose of chemical at which
 

there were no statistically or biologically significant increases in
 

frequency or severity of adverse effects seen between the exposed population
 

and its appropriate control. Effects may be produced at this dose, but they
 

are not considered to be adverse.
 

Octanol-Water Partition Coefficient (Kow) -- The equilibrium ratio of the 

concentrations of a chemical in n-octanol and water, in dilute solution. 

Permissible Exposure Limit (PEL) -- An allowable exposure level in
 

workplace air averaged over an g-hour shift.
 

ql* -- The upper-bound estimate of the low-dose slope of the dose-response
 

curve as determined by the multistage procedure. The qL* can be used to
 

calculate an estimate of carcinogenic potency, the incremental excess cancer
 

risk per unit of exposure (usually μg/L for water, mg/kg/day for food, and 

μg/m3

 for air). 

Reference Dose (RfD) -- An estimate (with uncertainty spanning perhaps an
 

order of magnitude) of the daily exposure of the human population to a
 

potential hazard that is likely to be without risk of deleterious effects
 

during a lifetime. The RfD is operationally derived from the NOAEL (from
 

animal and human studies) by a consistent application of uncertainty factors
 

that reflect various types of data used to estimate RfDs and an additional
 

modifying factor, which is based on a professional judgment of the entire
 

database on the chemical. The RfDs are not applicable to nonthreshold
 

effects such as cancer.
 

Reportable Quantity (RQ) -- The quantity of a hazardous substance that is
 

considered reportable under CERCLA. Reportable quantities are (1) 1 lb or
 

greater or (2) for selected substances, an amount established by regulation
 

either under CERCLA or under Sect. 311 of the Clean Water Act. Quantities
 

are measured over a 24-hour period.
 

Reproductive Toxicity -- The occurrence of adverse effects on the
 

reproductive system that may result from exposure to a chemical. The
 

toxicity may be directed to the reproductive organs and/or the related
 

endocrine system. The manifestation of such toxicity may be noted as
 

alterations in sexual behavior, fertility, pregnancy outcomes, or
 

modifications in other functions that are dependent on the integrity of
 

this system.
 
70
 

9. GLOSSARY
 

Short-Term Exposure Limit (STEL) -- The maximum concentration to which
 

workers can be exposed for up to 15 min continually. No more than four
 

excursions are allowed per day, and there must be at least 60 min between
 

exposure periods. The daily TLV-TWA may not be exceeded.
 

Target Organ Toxicity -- This term covers a broad range of adverse effects
 

on target organs or physiological systems (e.g., renal, cardiovascular)
 

extending from those arising through a single limited exposure to those
 

assumed over a lifetime of exposure to a chemical.
 

Teratogen -- A chemical that causes structural defects that affect the
 

development of an organism.
 

Threshold Limit Value (TLV) -- A concentration of a substance to which most
 

workers can be exposed without adverse effect. The TLV may be expressed as
 

a TWA, as a STEL, or as a CL.
 

Time-Weighted Average (TWA) -- An allowable exposure concentration averaged
 

over a normal 8-hour workday or 40-hour workweek.
 

Toxic Dose (TD50) -- A calculated dose of a chemical, introduced by a route 

other than inhalation, which is expected to cause a specific toxic effect in 

50% of a defined experimental animal population. 

Uncertainty Factor (UF) -- A factor used in operationally deriving the RfD
 

from experimental data. UFs are intended to account for (1) the variation
 

in sensitivity among the members of the human population, (2) the
 

uncertainty in extrapolating animal data to the case of human, (3) the
 

uncertainty in extrapolating from data obtained in a study that is of less
 

than lifetime exposure, and (4) the uncertainty in using LOAEL data rather
 

than NOAEL data. Usually each of these factors is set equal to 10.
 
71
 

APPENDIX: PEER REVIEW
 

A peer review panel was assembled for 1,2-diphenylhydrazine. The
 

panel consisted of the following members: Dr. Judith S. Bellin, Private
 

Consultant; Dr. Rolf Hartung, Department of Environmental and Industrial
 

Health, University of Michigan; Dr. Michael Norvell, Private Consultant; and
 

Dr. Richard Carchman, Department of Pharmacology and Toxicology, Medical
 

College of Virginia. These experts collectively have knowledge of 1,2­

diphenylhydrazine's physical and chemical properties, toxicokinetics, key
 

health end points, mechanisms of action, human and animal exposure, and
 

quantification of risk to humans. All reviewers were selected in conformity
 

with the conditions for peer review specified in Section 104(i)(13) of the
 

Comprehensive Environmental Response, Compensation, and Liability Act as
 

amended.
 

A joint panel of scientists from ATSDR and EPA has reviewed the peer
 

reviewers' comments and determined which comments will be included in the
 

profile. A listing of the peer reviewers' comments not incorporated in the
 

profile, with brief explanation of the rationale for their exclusion, exists
 

as part of the administrative record for this compound. A list of databases
 

reviewed and a list of unpublished documents cited are also included in the
 

administrative record.
 

The citation of the peer review panel should not be understood to
 

imply its approval of the profile's final content. The responsibility for
 

the content of this profile lies with the Agency for Toxic Substances and
 

Disease Registry.