National Academies Press: OpenBook
« Previous: 5 Fluorine
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

6
Hydrazine1
Acute Exposure Guideline Levels

PREFACE

Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances (NAC/AEGL Committee) has been established to identify, review and interpret relevant toxicologic and other scientific data and develop AEGLs for high priority, acutely toxic chemicals.

AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). Three levels—AEGL-1 and AEGL-2 levels, and AEGL-3—will be developed for each of five exposure periods (10 and 30 min, 1 h, 4 h, and 8 h) and will be distinguished by varying degrees of severity of toxic effects. It is believed that the recommended exposure levels are applicable to the general population including infants and children, and other individuals who may be sensitive and susceptible. The three AEGLs have been defined as follows:


AEGL-1 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain

1

This document was prepared by the AEGL Development Team composed of Robert A. Young (Oak Ridge National Laboratory) and Chemical Manager Richard Thomas (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC committee has concluded that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guideline reports (NRC 1993, 2001).

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

asymptomatic, non-sensory effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure.

AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including susceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects, or an impaired ability to escape.

AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including susceptible individuals, could experience life-threatening health effects or death.


Airborne concentrations below the AEGL-1 represent exposure levels that can produce mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic, nonsensory effects. With increasing airborne concentrations above each AEGL, there is a progressive increase in the likelihood of occurrence and the severity of effects described for each corresponding AEGL. Although the AEGL values represent threshold levels for the general public, including sensitive subpopulations, such as infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that certain individuals, subject to idiosyncratic responses, could experience the effects described at concentrations below the corresponding AEGL.

SUMMARY

Hydrazine (m.w. 32.05) is a liquid at room temperature with a vapor pressure of 14.4 mm Hg at 25°C. This simple diamine (H2NNH2) is a powerful reducing agent. The chemical acts as an oxygen scavenger and is highly reactive with many other chemicals. Hydrazine is used in various chemical manufacturing processes (production of flexible and rigid foams, pesticides) and by the military as a missile and rocket propellant, and in power sources. U.S. production is estimated at 20 million pounds and world-wide production at 80 million pounds. Hydrazine has an ammonia-like odor with an odor threshold of 3.0 to 4.0 ppm.

Human data on the toxicity of hydrazine following acute inhalation exposure are limited to anecdotal accounts that lack definitive exposure data. The utility of this information is compromised by non-quantitative exposures, concurrent exposure with other chemicals, and involvement of simultaneous multiple exposure routes.

Data from animal studies indicate that hydrazine may be metabolized to acetylhydrazine, diacetylhydrazine, ammonia, and urea, and may form hydrazones with pyruvate and 2-oxoglutarate. The biotransformation of hydrazine is mediated, at least in part, by hepatic monooxygenases. The role of metabolism and absorption/excretion kinetics is uncertain regarding immediate portal-of-

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

entry toxic effects from acute inhalation exposures. The highly reactive nature of hydrazine per se is a plausible determinant of acute port-of-entry toxic effects.

AEGLs were based upon data sets defining toxicity end points that were specific for the AEGL level. No data were available with which to empirically determine a concentration-exposure duration relationship for hydrazine. This relationship for many irritant and systemically acting vapors and gases may be described by Cn × t = k, where the exponent, n, ranges from 0.8 to 3.5 (ten Berge et al. 1986). Because there were no data to empirically derive the chemical-specific exponent, the default values of n = 3 when extrapolating to shorter time points and n = 1 when extrapolating to longer time points were used in the Cn × t = k equation in accordance with the SOP manual.

AEGL-1 values were based upon a study by House (1964) in which male monkeys exhibited skin flushing and eye irritation after an initial 24-h continuous exposure to 0.4 ppm hydrazine. Although the monkeys in this study were subjected to the 24-h continuous exposure for an additional 89 days, only effects occurring during the first 24 h were considered in the development of the AEGL-1 values. In the absence of chemical specific data, an n of 3 was applied to extrapolate the 24-h (0.4 ppm) exposure from the House (1964) study to the AEGL -1 time frames (k = 0.4 ppm3 × 24 h = 1.54 ppm3 h). An uncertainty factor of 3 was applied for interspecies variability because the surface contact irritation by the highly reactive hydrazine is not likely to vary greatly among species, and because a nonhuman primate was the test species. An uncertainty factor of 3 was applied for intraspecies variability because the contact irritation from the highly reactive hydrazine is not expected to vary greatly among individuals, including susceptible individuals. Because hydrazine is extremely reactive and the sensory-irritation effects are considered to be concentration dependent rather than time dependent, 0.1 ppm (the 30-min, 1-h, 4-h, and 8-h values were all approximately 0.1 ppm) was considered appropriate for all AEGL-1 durations.

The level of distinct odor awareness (LOA) for hydrazine is 63 ppm (see Appendix E). The odor LOA represents the concentration above which it is predicted that more than half of the exposed population will experience at least a distinct odor intensity, about 10 % of the population will experience a strong odor intensity. The LOA may assist chemical emergency planners and responders in assessing the public awareness of the exposure due to odor perception.

The AEGL-2 was derived based upon data from a study by Latendresse et al. (1995) in which rats exposed to hydrazine (750 ppm) for 1 h exhibited nasal lesions. The 1-h exposure to 750 ppm values was scaled to AEGL-specific durations using n = 3 when extrapolating to shorter time points and n = 1 when extrapolating to longer time points. An uncertainty factor of 3 for interspecies variability was applied to account for uncertainties regarding species variability in the toxic response to inhaled hydrazine. Because the toxic response to acute low-level exposures results from direct contact of the highly reactive hydrazine, the reduction from a default value of 10 is justified. Similarly, an uncertainty factor of 3 was applied for intraspecies variability because the portal-of-entry effect of the reactive hydrazine is likely attributed to direct interaction with res-

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

piratory tract tissues. This contact irritation is not likely to vary considerably among individuals. A modifying factor of 2 was applied to account for data inadequacies regarding identification of toxic responses consistent with AEGL-2 level effects (i.e., serious or irreversible, but nonlethal, effects of acute inhalation exposure to hydrazine). Although the more recent studies such as those by Latendresse et al. (1995) and HRC (1993) appear to have reliable determinations of hydrazine concentrations, the overall data set for hydrazine is compromised by uncertainties in the accuracy of exposure concentration measurements due to the reactivity of hydrazine with the surfaces of the exposure apparatus. Therefore, an additional modifying factor of 3 has been applied to account for the impact of these deficiencies. This resulted in a total adjustment of 60-fold for derivation of AEGL-2 values. The critical effect (nasal lesions) is consistent with the continuum of hydrazine toxicity (i.e., respiratory tract irritation, pulmonary tissue damage, and potential tumorigenicity) and, therefore, was considered appropriate for AEGL-2 development.

The AEGL-3 values were derived based upon a rat inhalation study (HRC 1993). The lethality threshold was estimated by a three-fold reduction of the 1-h LC50 (3192 ppm/3 = 1064 ppm). This was considered a tenable estimate considering that rats survived multiple 1 h exposures to 750 ppm of hydrazine (Latendresse et al. 1995). This approach was also justified by the steep exposure-response curve for hydrazine. Temporal scaling was again applied using the exponential expression Cn × t = k where n = 3 for extrapolation to shorter times and n = 1 when extrapolating to longer times. A total uncertainty factor of 10 was applied for derivation of the AEGL-3 values as described for AEGL-2. Although the more recent study by HRC (1993) had reliable determinations of hydrazine concentrations, the overall data set for hydrazine is compromised by uncertainties in the accuracy of exposure concentration measurements due to the reactivity of hydrazine with the surfaces of the exposure apparatus. Therefore, an additional modifying factor of 3 was applied to account for the impact of these deficiencies. This resulted in a total adjustment of 30-fold for derivation of AEGL-3 values.

Cancer inhalation slope factors for hydrazine were derived and compared to AEGL values based upon 10−4, 10−5, and 10−6 cancer risk levels. The assessment revealed that AEGL-2 values derived from noncarcinogenic toxicity end points were greater than the exposure concentrations calculated for the 10−4 excess cancer risk level. However, the available animal data suggest that the tumorigenic response to inhaled hydrazine is a function of prolonged tissue irritation resulting from repeated exposures and not the result of a single low exposure. For this reason and because the AEGL values are applicable to rare events or single, once-in-a-lifetime exposures to limited geographic areas and small populations, the AEGL values based on noncarcinogenic end points were considered to be more appropriate.

The AEGL values, their respective toxicity end points, and references are summarized below in Table 6-1.

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

TABLE 6-1 Summary of AEGL Values for Hydrazine

Classification

10-min

30-min

1-h

4-h

8-h

End Point (Reference)

AEGL-1 (Nondisabling)

0.1 ppm (0.1 mg/m3)

0.1 ppm (0.1 mg/m3)

0.1 ppm (0.1 mg/m3)

0.1 ppm (0.1 mg/m3)

0.1 ppm (0.1 mg/m3)

Eye and facial irritation in monkeys (House 1964)a

AEGL-2 (Disabling)

23 ppm 30 mg/m3

16 ppm (21 mg/m3)

13 ppm (17 mg/m3)

3.1 ppm (4.0 mg/m3)

1.6 ppm (2.1 mg/m3)

Nasal lesions in rats (Latendresse et al. 1995)

AEGL-3 (Lethal)

64 ppm (83 mg/m3)

45 ppm (59 mg/m3)

35 ppm (46 mg/m3)

8.9 ppm (12 mg/m3)

4.4 ppm (5.7 mg/m3)

Lethality in rats (HRC 1993)

aBecause the contact irritation response to the extremely reactive hydrazine is concentration dependent rather than time-dependent, the AEGL-1 is the same for all time periods.

1.
INTRODUCTION

Hydrazine, a simple diamine, is a powerful reducing agent. It acts primarily as an oxygen scavenger and is highly reactive with many other chemicals (WHO 1987). Contact with strong oxidizers (e.g., hydrogen peroxide, nitrogen tetroxide, chlorine, fluorine) will result in immediate ignition or explosions, and contact with catalytic metals may result in flaming decomposition. Hydrazine is used as a chemical intermediate in various manufacturing procedures including the manufacture of pharmaceuticals, plastic blowing agents, dyes, and agricultural chemicals. It is used extensive in military applications as a missile and rocket propellant, and in chemical power sources. (USAF 1989). Hydrazine also occurs naturally as a nitrogen fixation product of Azobacter agile (Raphaelian 1963). U.S. production is estimated at 20 million pounds and world-wide production at 80 million pounds.

The National Research Council Committee on Toxicology (NRC 1985) summarized the toxicologic data for hydrazine for development of Emergency and Continuous Exposure Guidance Levels. Garcia and James (1996) also summarized data regarding the toxicology of hydrazine for the development of Spacecraft Maximum Allowable Concentrations (SMACS).

For derivation of AEGL values, acute exposure studies are preferentially examined. Subchronic and chronic studies generally have not been included in the data analysis for AEGL derivation because of the great uncertainty in extrapolating such data to acute exposure scenarios. Such studies may be addressed when the data provide meaningful insight into understanding toxicity mechanisms or for other special considerations.

The primary physicochemical data for hydrazine are presented in Table 6-2. Hydrazine may also occur as the methylated derivatives, monomethylhydrazine and dimethylhydrazine (symmetrical and unsymmetrical isomers). The reactivity of hydrazine is especially important regarding accurate assessment of

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

exposure concentrations under experimental conditions. Early reports (Comstock et al. 1954) noted such concerns when reporting concentrations of hydrazine in exposure chambers. Because of the extreme reactivity of the compound (up to 99% of the hydrazine would be lost to absorption onto the chamber walls or body surface of the test animals), nominal concentration estimates were found to be a gross overestimation of actual exposure concentrations.

2.
HUMAN TOXICITY DATA

2.1.
Acute Lethality

Definitive information was not available regarding the acute lethality of humans following inhalation exposure to hydrazine. However, Sotaniemi et al. (1971) reported a fatality in a worker exposed to hydrazine once per week for six months. A post-exposure simulation provided an estimated hydrazine concentration of 0.05 ppm (0.071 mg/m3). Possible renal involvement (tubular necrosis, inflammation, hemorrhage, and enlarged kidneys were noted and considered to be a contributing factor to the fatality), neurological effects (tremors), and pulmonary involvement were also noted.

TABLE 6-2 Chemical and Physical Data for Hydrazine

Parameter

Data

Reference

Chemical Name

Hydrazine

Synonyms

Diamide; diamine; hydrazine base; hydrazine anhydrous; levoxine

O’Neil et al. 2001

USAF 1989

CAS Registry No.

302-01-2

O’Neil et al. 2001

Chemical formula

H2NNH2

O’Neil et al. 2001

Molecular weight

32.05

O’Neil et al. 2001

Physical state

Liquid

O’Neil et al. 2001

Odor

ammoniacal and pungent

WHO 1987

Melting/boiling/flash point

2.0°C /113.5°C /37.8°C

Weiss 1980

Specific gravitya

1.011 at 15°C/4°C

O’Neil et al. 2001

Solubility in water

Miscible

O’Neil et al. 2001

Vapor pressure

14.4 mm Hg at 25°C

Schiessl 1985

Relative vapor density

1.1

WHO 1987

Conversion factors in air

1 mg/m3 = 0.76 ppm

1 ppm = 1.3 mg/m3

USAF 1989

aDensity of liquid at 15°C relative to the density of water at 4°C.

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
2.2.
Nonlethal Toxicity

Hydrazine has an irritapting, ammonia-like odor. An odor threshold of 3.0 to 4.0 ppm has been reported (Jacobson et al. 1955). Because of its irritating nature, a level of distinct odor awareness (LOA) was determined for hydrazine. The level of distinct odor awareness (LOA) for hydrazine is 63 ppm (see Appendix E). The odor LOA represents the concentration above which it is predicted that more than half of the exposed population will experience at least a distinct odor intensity, about 10 % of the population will experience a strong odor intensity. The LOA may assist chemical emergency planners and responders in assessing the public awareness of the exposure due to odor perception.

2.2.1.
Case Reports

A single exposure of a 35-year old man to 35% liquid hydrazine (exposure duration was approximately 5 min) was reported by Brooks et al. (1985). The incident involved dermal and oral exposure to liquid hydrazine of unknown dose level and resulted in a pins-and-needles sensation, rash, and disorientation within 2 h. Within 5 h the signs and symptoms included, muscle pain, diarrhea, nausea, abdominal cramping, and respiratory problems (chest tightness, coughing, wheezing). The exposure resulted in a prolonged asthma-like illness (reactive airways dysfunction syndrome) that persisted for 5-6 months.

Cognitive disorders were reported for a worker exposed to hydrazine (concentration unknown). Following removal from the exposure, some improvement in the condition of the individual was observed (Richter et al. 1992).

In an investigation of the role of acetylation phenotype on hydrazine metabolism and excretion by workers involved in the production of hydrazine hydrate, Koizumi et al. (1998) noted that the study population was routinely exposed to hydrazine concentrations of 0.07- 0.12 ppm (8-h TWA). There was no indication that this exposure resulted in signs of toxicity.

2.2.2.
Epidemiologic Studies

Epidemiologic studies regarding nonlethal effects in humans involving exposure to hydrazine were limited to a study of workers in hydrazine manufacturing by Roe (1978), a follow-up study by Wald et al. (1984), a study by Contassot et al. (1987), and study by Morgenstern and Ritz (2001). Generally, the available epidemiological studies on worker populations from different facilities are inconclusive due to small cohort sizes in some studies, compromised record keeping, various confounding factors, and inadequate exposure characterizations.

In both the Roe (1978) study and the follow-up study by Wald et al. (1984), observed worker mortality (facility in the United Kingdom) did not differ significantly from the expected mortality, and no deaths were reported that

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

could be attributed to nasopharyngeal cancers. Because specific exposure concentrations were not available for this study, the exposure groups were categorized as little or no exposure, <1.0 ppm, and 1.0 to 10 ppm.

In the study by Contassot et al. (1987), a cohort of 130 male workers exposed to hydrazine for at least six months were divided into three exposure groups: low level (0.1 ppm), medium level (0.1 to 1.0 ppm) and high level (>1.0 ppm). Although initial conclusions indicated no excess risk of cancer, subsequent analysis suggested that the standard incidence ratio achieved significance for cancers in the high exposure group. A qualifying statement, however, noted that there were problems with record keeping and that the significance was greatly reduced when skin cancers were excluded.

Results of an occupational study of 6107 males (Rocketdyne Corp.) exposed (prior to 1980) to hydrazine and methylated hydrazines (1-methylhydrazine and 1,1-dimethylhydrazine) for at least two years during work associated with rocket propellants was reported by Morgenstern and Ritz (2001). Possible concurrent exposures to pulmonary toxicants such as asbestos, chlorine, fluorine, beryllium, hydrogen peroxide, rocket engine exhaust, and various solvents were noted. Hydrazine exposure was categorized as medium, high or no exposure based upon type of work. Relative to the group with no hydrazine exposure, the low-exposure group was not associated with excess lung cancer mortality but a relative risk of 1.68 (95% confidence interval of 1.12-2.52) was determined for the high exposure group. The investigators concluded that occupational exposure to hydrazine and other chemicals associated with the rocket engine testing increased lung cancer risk and possible risk to other cancers. Cancer risks for lymphopoietic and lung cancer were increased (rel. risk of 2.01 and 2.45, respectively) for earlier time periods (i.e., 1960s vs 1980s). Definitive exposure data were not provided in the study report.

2.3.
Developmental and Reproductive Toxicity

Reports providing information regarding the reproductive and developmental effects of hydrazine exposure in humans were not available.

2.4.
Genotoxicity

Human genotoxicity data relevant to AEGL derivation were not available.

2.5.
Carcinogenicity

Wald et al. (1984) reported no significant increase in mortality (47 deaths reported) due to cancer in 427 workers exposed to an undetermined concentration of hydrazine. The follow-up period used in this study was relatively short and may have compromised the ability to detect a weak carcinogenic response.

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

Epidemiologic studies have also been conducted (see Section 2.2.2.).

2.6.
Summary

Data regarding the effects of acute exposure of humans to hydrazine are lacking. Although anecdotal information (Brooks et al. 1985) is available, the reported situation involved exposure via multiple routes (dermal, oral, and probably inhalation) and no exposure concentration data were reported. Reports by Sotanieme et al. (1971) and Richter et al. (1992) regarding inhalation exposure also lacked definitive exposure data. Therefore, there are no human data available that are acceptable for derivation of AEGL values.

3.
ANIMAL TOXICITY DATA

3.1.
Acute Lethality

Discussions in this section are limited to those studies providing information on acute exposures or to longer-term studies that indicated lethality during the first few days of exposure. For example, MacEwen et al. (1981) conducted a 12-month inhalation exposure study using male and female F344 rats, Syrian golden hamsters, and C57BL/6 mice. Although slight (but statistically insignificant) increases in mortality were noted early during the exposure regimen, these observations could not be attributed to acute exposure but noted only at monthly intervals. Therefore, such data are not considered primary for derivation of AEGL values.

3.1.1.
Nonhuman Primates

House (1964) exposed groups of 10 male Rhesus monkeys to hydrazine at an average concentration of 0.78 ppm (1 mg/m3) (range: 0.25-1.38 ppm [0.33-1.8 mg/m3]) continuously for 90 days. Hydrazine was introduced into the exposure chambers via saturation of a carrier gas (nitrogen) with hydrazine. The exposure of the monkeys was uninterrupted for the duration of the experiment. The hydrazine concentration was measured colorimetrically from samples extracted from the chamber at various times (10-18 samples/day for the first 10 days; 3 times/day thereafter). A 20% mortality was reported following completion of the 90-day exposure. The two deaths occurred during days 21-30 and 81-90.

3.1.2.
Dogs

Acute inhalation exposure data for dogs are limited. In an inhalation study by Comstock et al. (1954), a mongrel dog was exposed to hydrazine at 18 mg/m3 (14 ppm), 6 h/day, 5 days/week. The dog exhibited anorexia and fatigue by the

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

second day of exposure and vomiting ensued after day 2 with the dog becoming progressively weaker until week 13 when it died. Weatherby and Yard (1955) exposed two mongrel dogs to hydrazine (3-6 mg/m3) for 6 h/day, 5 days/week. After 5 days of exposure both dogs exhibited muscular incoordination and weakness. On the seventh day, one dog died and the other was terminated. Pathological examination indicated primarily renal (proximal cortical congestion, capillary damage) and hepatic (central zone fatty changes, hyalinization of hepatocytes, distended bile canaliculi) involvement, with minor pulmonary effects.

An i.v.LD50 of 25 mg/kg was reported for dogs (Witkin 1956). The value is, however, based upon only two dose groups (20 and 30 mg/kg) with only two dogs per group. During a 10-day observation period, both dogs of the low dose group survived while both of the high dose group died within 2 h.

3.1.3.
Rats

Several studies have examined the effect of acute exposure to hydrazine and methylated hydrazine derivatives. The testing protocols and quality of the studies varied considerably, and species variability was evident.

In a study reported by Comstock et al. (1954), groups of six male Wistar rats (150- 250 g) each were exposed to hydrazine vapors at a concentration of ≈ 20,000 mg/m3 (≈ 15,280 ppm) for 0.5, 1, 2, or 4 h. Saturated hydrazine vapor was introduced into the chamber (20L, 25°C) at a rate of 0.002 m3/min. The rats were placed into the chamber after equilibrium was attained. Immediately after introduction into the chamber the rats began scratching and grooming themselves. After 1-2 min, their eyes were partially to completely closed. During the first 2 h of exposure, the rats exhibited alternating periods of restlessness and inactivity. The aforementioned signs are considered normal responses to exposure to a saturated vapor atmosphere. However, shortly thereafter, the rats exhibited pronounced salivation and a red-colored material (porphyrin secreted by the Harderian glands) was observed accumulating around the nares. Such porphyrin secretion is known to be a sensitive indicator of local irritation. The results of this study are shown in Table 6-3. Mortality rates of 33-67% were noted for the 4-h exposure period (latency period not specified). Hyperactivity and/or convulsions were observed in rats that died. No immediate deaths occurred during the 0.5-h exposure period but three of 18 rats had died within the 14-day postexposure period. Necropsy findings included pulmonary edema with localized damage to the bronchial mucosa. Incidence data for these findings were not provided. The results of this study are compromised by the difficulty in assessing chamber concentrations and the resulting extreme variability in the actual concentrations.

Comstock et al. (1954) also conducted an additional test in which the hydrazine concentration was more accurately determined by using a quantitative

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

TABLE 6-3 Acute Inhalation Toxicity of Hydrazine Vapor in Male Rats

Concentration (mg/m3)a

Exposure Period (h)

C × t (mg-h/m3)

Immediate Lethality

14-Day Lethality

20,000

4

80,000

4/6

5/6

20,000

4

80,000

3/6

4/6

20,000

2

40,000

2/6

3/6

20,000

2

40,000

0/6

4/6

21,000

1

21,000

0/6

0/6

20,000

1

20,000

0/6

2/6

20,000

1

20,000

0/6

0/6

21,000

0.5

10,500

0/6

0/6

20,000

0.5

10,500

0/6

2/6

20,000

0.5

10,500

0/6

1/6

aNominal concentration, analytical determination would be considerably lower.

Source: Comstock et al. 1954. Reprinted with permission; copyright 1954, American Medical Association.

analytical method based upon hydrazine’s reactivity with sulfuric acid. The test protocol was the same as for the preceding test. With the exception of one rat each in the 4-h and 1-h groups, exposure to hydrazine vapors did not result in immediate lethality. However, deaths were observed for all exposure durations during the 14-day postexposure period and occurred throughout the 14-day period. The results of this phase of the study are shown in Table 6-4.

Upon analyzing the immediate lethality of hydrazine when exposure is expressed as a concentration × time product (C × t), there does not appear to be any meaningful correlation. For example, deaths were observed at C × t values of 436 and 831 mg-h/m3 while exposure as high as 1,600 mg-h/m3 did not result in immediate death. When considering the lethality rate over a 14-day postexposure period, the highest C × t product (1,600 mg-h/m3) resulted in a substantially higher lethality rate (83%) than lower c × t values (Table 6-5). However, an accurate and meaningful assessment of lethality relative to exposure expressed as a c × t product is compromised by the fact that determination of actual hydrazine concentration in the exposure chambers was highly variable and possibly of questionable accuracy, and that lethality was assessed as both immediate and up to 14 days postexposure. Additionally, these findings are compromised by the low number of animals in each of the exposure groups.

These same investigators also conducted multiple short-term exposure experiments in which rats were exposed to hydrazine at a average daily concentration of 295 mg/m3 (actual concentration during the Day 1 exposure period was 288 mg/m3) for 6 h/day, 5 days/week for 1 week. None of the 20 rats died following the initial 6-h exposure on day 1 although 16 of 20 rats died following completion of the 5-day exposure regimen. Body weight loss of 10-20 g and

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

signs of pulmonary toxicity (pulmonary edema with localized damage to the bronchial mucosa) were noted for surviving rats. Additional multiple, intermittent exposure experiments using hydrazine concentrations ranging from 26-140 mg/m3 were also conducted and showed that initial exposures did not result in lethality but that signs of toxicity and death did occur following multiple exposures. There were no definitive relationships observed between exposure frequency and lethality.

TABLE 6-4 Acute Inhalation Toxicity in Rats Exposed to Hydrazine Vapor

Concentration (mg/m3)a

Exposure Duration (h)

C × t (mg-h/m3)

Immediate Lethality

14-Day Lethality

352

4

1,408

0/6

2/6

344

4

1,376

0/6

3/6

400

4

1,600

0/6

5/6

109

4

436

1/6

3/6

227

4

908

0/6

1/6

756

2

1,512

0/6

1/6

405

2

810

0/6

1/6

129

2

258

0/6

2/6

128

2

256

0/6

1/6

285

2

570

0/6

2/6

831

1

831

1/6

3/6

151

1

151

0/6

1/6

106

1

106

0/6

1/6

185

1

185

0/6

0/6

aAnalytical determination based upon quantitative relationship of hydrazine/sulfuric acid reaction.

ND: Not determined; exposure time too short for chemical analysis.

Source: Comstock et al. 1954. Reprinted with permission; copyright 1954, American Medical Association.

TABLE 6-5 Lethality in Rats Following 1-Hour Nose-Only Exposure to 64% Hydrazine Aerosola

Exposure Group (mg/L)

Males

Females

Total

Control

0/5

0/5

0/10

0.65

0/5

0/5

0/10

2.04

0/5

0/5

0/10

3.24

1/5

3/5

4/10

4.98

2/5

4/5

6/10

aWith the exception of one female in the 3.24 mg/L exposure group that died 3 days post exposure, all deathsoccurred overnight following the exposure; there was a 14-day post-exposure observation period.

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

Jacobson et al. (1955) assessed the toxicity of hydrazine and the methylated derivatives of hydrazine using several species including male white rats (groups of 10; strain not specified) exposed to hydrazine and observed for up to 14 days. A 4-h LC50 of 750 mg/m3 (570 ppm) was estimated. Based upon a ventilation rate of 0.223 m3/day for rats (0.35 kg) (EPA 1986), this is equivalent to 112 mg/kg/day. Hydrazine appeared to be less toxic than the methylated hydrazine derivatives. These lethality data are summarized in Section 4.3. (see Table 6-9).

Witkin (1956) reported on the acute lethality of hydrazine in several animal species, including rats, following various routes of administration other than inhalation. LD50 values were determined by regression analysis using log-dose probit units from four dose groups of 10 male Wistar rats (100-200 g) administered hydrazine i.v., i.p., or orally. Deaths occurred in the groups given 40 and 70 mg/kg; specific doses for the lower dose groups were not provided. The LD50 determinations were based upon deaths occurring in a 10-day observation period. In rats, the i.v., i.p. and oral LD50 values were estimated at 55 ± 2.7, 59 ± 3.9, and 60 ± 3.8 mg/kg, respectively. Deaths occurred at days 1, 3, and 4 in the 40 mg/kg group (1 death on each day) and on days 1 (5 deaths), 3, 4, and 6 (1 death each day). These data are summarized in Section 7.2. (see Table 6-12).

House (1964) conducted 90-day continuous exposure of male Sprague-Dawley rats to an average concentration of 0.78 ppm (0.25-1.38 ppm) hydrazine. The treatment resulted in 98% mortality with deaths occurring after 41 days of treatment. Although it was noted that the exposed rats were “weak and sick early in the test,” neither specific times nor characterization of the effects were provided.

An acute inhalation study to assess lethality of hydrazine in rats was conducted by Huntingdon Research Centre (HRC 1993). In this study, male and female Sprague-Dawley rats (5/sex/group) were exposed (nose only) for 1 h to an aerosol of hydrazine (64% aqueous solution, mass median aerodynamic diameter ± geometric standard deviation of 5.0 ± 2.56, 1.1 ± 3.56, 1.8 ± 3.04, and 2.4 ± 2.40 for the 0.65, 2.04, 4.98, and 3.24 mg/L exposure atmospheres, respectively). The rats were observed throughout the exposure period (clinical signs recorded at the end of chamber equilibration period and at 0.25, 0.5, 0.75, and 1 h during exposure) and daily (or more frequently as necessary) for an additional 14 days. During the exposure, the rats exhibited exaggerated respiratory movements. During the post-exposure observation period, clinical signs included death (two highest exposures only), exaggerated respiratory movements, noisy respiration, lethargy, secretions from the eyes, brown staining around the snout and jaws, and poorly groomed appearance. The lethality data are summarized in Table 6-5.

Using a log probit method, LC50 values for the 64% hydrazine atmosphere were estimated as: 9.0, 5.3, and 6.5 mg/L, respectively, for males, females, and sexes combined (equivalent to 9,000, 5,300, and 6,500 mg/m3). Based upon hydrazine alone, these respective estimates were 5.8, 3.4, and 4.2 mg/L (equivalent to 5,800, 3,400, and 4,200 mg/m3). Recovery from signs of exposure was ob-

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

served on day 2 for the 0.65 mg/L groups, and on days 3-4 for the 2.04 mg/L groups. For some rats in the higher exposure groups, exaggerated respiratory movements were observed throughout the post-exposure observation period.

3.1.4.
Mice

Comstock et al. (1954) exposed groups of 10 female mice (strain not specified) to hydrazine vapor in various exposure protocols. Exposures (6 h/day for 5 days) to concentrations ranging from 160-611/mg/m3 (average daily exposure of 295 mg/m3) did not result in lethality until day 3. There did not appear to be a definitive concentration-effect relationship; three mice died on Day 3, 5 mice died on Day 4, but no deaths occurred on Day 5. Pathological examination revealed pulmonary edema and localized, unspecified damage to the bronchial mucosa.

Acute toxicity assays using groups of 10 female white mice (strain not specified) and other species were conducted by Jacobson et al. (1955). Based upon 4-h exposures, an LC50 of 330 mg/m3 (252 ppm) was estimated. Based upon a ventilation rate of 0.039 m3/day for a 30 g mouse (EPA 1986), this is equivalent to 17.9 mg/kg/day.

The acute lethality of hydrazine in mice following i.v., i.p., and oral administration was reported by Witkin (1956). LD50 values were determined by regression analysis using log-dose probit units from four dose groups of 10 male Webster-Swiss mice (20-30 g) although the actual doses of each group were not provided in the report. In mice, the i.v., i.p. and oral LD50 values were estimated at 57 ± 7.5, 62 ± 4.0, and 59 ± 7.2 mg/kg, respectively. These data are summarized along with data for other species in Section 7.2. The LD50 determinations were based upon deaths occurring in 10-day observation period. House (1964) conducted 90-day continuous exposure of male ICR Swiss albino mice to hydrazine at concentrations of 0.78 ppm (0.25-1.38 ppm). The treatment resulted in 99% mortality with deaths occurring after 41 days of treatment. Although it was noted that the exposed rats were “weak and sick early in the test”, neither specific times nor characterization of the effects were provided.

3.1.5.
Hamsters

MacEwen and Vernot (1981) exposed groups of 10 male Syrian golden hamsters (whole-body exposure) to hydrazine at concentrations of 2770, 2450, 2140, 1920, 1600, or 1280 ppm for 1 h. The hamsters were observed during the exposure and for 14 days following exposure. Deaths occurring during the exposure and during the 14-day postexposure period were used for estimating the LC50. The lethality data for this experiment are shown in Table 6-6. Probit analysis was used to estimate an LC50 of 2,585 ppm.

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

TABLE 6-6 Lethality in Hamsters Following 1-Hour Inhalation (Whole Body) Exposure to Hydrazinea

Exposure (ppm)

Mortality

Comments

2270

9/10

3 Deaths within 1 h; 4 deaths within 15 h, 1 death at 3 days, and 1 death at 4 days

2450

3/10

1 Death at 12 h, 1 death at 1 day, and 1 death at 3 days

2140

3/10

1 Death at 5 min, 1 death at 1 day, and 1 death at 2 days

1920

3/10

1 Death at 1 day, a death at 3 days, and 1 death at 11 days

1600

2/10

1 Death at 1 h, 1 death at 11 days

1280

2/10

1 Death at 8 days and 1 death at 12 days

a14-Day postexposure observation period.

3.2.
Nonlethal Toxicity
3.2.1.
Nonhuman Primates

No data were located that specifically identified irreversible, nonlethal effects in nonhuman primates following acute exposure to hydrazine. House (1964) exposed groups of 10 male rhesus monkeys to hydrazine continuously at an average concentration of 0.78 ppm (1 mg/m3) (range: 0.25-1.38 ppm [0.33-1.8 mg/m3]) for 90 days. Hydrazine was introduced into the exposure chambers via saturation of a carrier gas (nitrogen) with hydrazine. The exposure of the monkeys was uninterrupted for the duration of the experiment. The hydrazine concentration was measured colorimetrically from samples extracted from the chamber at various times (10-18 samples/day for the first 10 days; 3 times/day thereafter). Although effects of exposure were observed within 24-48 h, the effects (skin flushing and signs of ocular irritation) would be considered reversible. It is important to note that during days 1 through 10, the exposure period of concern for the aforementioned effects, the exposure concentration averaged 0.4 ppm (0.52 mg/m3). The incidences of these effects were not reported but their occurrence provides limited data associating the induction of a non-disabling and assumably reversible effect with exposure to a specific concentration of hydrazine. Pathological examinations at termination of the 90-day treatment period indicated involvement of the kidneys, heart and liver but these were not the result of acute exposure. Because the monkeys were sacrificed upon exposure termination, the reversibility of the pathological findings could not be determined.

3.2.2.
Dogs

Data regarding serious and/or persistent effects in dogs following acute exposure to hydrazine were limited to studies by Comstock et al. (1954) and Weatherby and Yard (1955).

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

In the first study, two mongrel dogs were exposed to hydrazine at a concentration of 6 mg/m3 (4 to 6 ppm), 6 h/day, 5 days/week for up to 28 weeks. During the first week, both dogs were slightly affected (lassitude) and during the middle of the second week refused food and lost weight. After 11 weeks of exposure muscular tremors were observed and additional effects (fatigue, anorexia, vomiting) occurred sporadically through week 27. At the end of week 28 both dogs appeared normal.

In the report by Weatherby and Yard (1955), two male mongrel dogs were exposed to hydrazine at concentrations of 3 to 6 mg/m3 (2 to 5 ppm), 6 h per day, 5 days per week. After 5 days of exposure, the dogs were extremely weak and exhibited muscular incoordination. On the seventh day one dog was moribund and the other dog was terminated. In another experiment one male and one female dog were exposed similarly but to hydrazine concentrations of 4 to 8 mg/m3 (3 to 6 ppm). Within 24 h, the male exhibited muscular incoordination and weakness but improved and remained asymptomatic until terminated. Necropsy of the first pair of dogs indicated extensive hepatic lesions while the second pair of dogs exhibited only minimal hepatic involvement.

3.2.3.
Rats

House (1964) also exposed male Sprague-Dawley rats to hydrazine at an average concentration of 0.78 ppm for 90 days. The exposure resulted in 98% mortality and, although the authors noted that the rats appeared to be weak and sick early in the treatment, no assessment of reversibility of this condition was possible. Clinical chemistry parameters were measured prior to treatment, and at days 30 and 60. Treatment-related alterations were minimal (minor decrease in hematocrit and changes in polymorphonuclear leukocytes and urine specific gravity) but because of the 30-day and 60-day evaluations, could not be attributed to acute exposure. Assessment of reversibility was not possible because of the high mortality rate during the exposure period.

Becker et al. (1981) noted a 6.6% reduction in body weight and histopathologic changes (palor, fatty liver) in the livers of rats given hydrazine intragastrically at dose of 3 mg/kg/day for four days. Methylation of hepatic DNA was also detected.

MacEwen and Vernot (1981) exposed 10 male and 10 female F344 rats and 20 male hamsters to hydrazine at concentrations of 750 ppm for 1 h twice per week for five weeks. Although notable decrease in body weight were observed for the exposed animals, no deaths occurred indicating that a 1-h exposure at 750 ppm is not lethal in this species and strain.

In the study by Comstock et al. (1954), rats exposed to hydrazine at nominal concentrations of 81-630 ppm (106-831 mg/m3) exhibited signs of irritation (restlessness, scratching, lacrimation, eye closure) within 1-2 min. Within 2 h, the rats exhibited alternating periods of hyperactivity and inactivity, and porphyrin secretion from the Harderian gland. Although delayed lethality (17-33% at

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

14 days) was associated with exposures as short as 0.5 h, it is possible that the irritation effects at 1-2 min (probably a response to vapor condensation) would be reversible upon removal from the test atmosphere.

Kulagina (1962) reported alteration of conditioned reflex responses in rats exposed for 2 h to 19 ppm hydrazine (24.7 mg/m3). Adverse effects on motor coordination were observed in rats exposed to 0.74-4 ppm hydrazine (0.9-5.2 mg/m3), 4 h/day, 6 days/week for 7 months. There were no deaths among these rats and the altered responses returned to normal 3-4 weeks after cessation of exposure. Although the exposure duration is subchronic, the report verifies that notable alterations in neurological responses in rats are reversible even after prolonged exposure. Although these data suggest that a C × t product of 3,494 mg-h/m3 is not lethal for intermittent exposures.

More recently, Latendresse et al. (1995) conducted experiments in which groups of five male and five female F-344 rats and 10 male Syrian golden hamsters were exposed to 750 ppm hydrazine for 1 h. Control animals were exposed to air without hydrazine. Gross and histopathological examinations were conducted on the animals following euthanasia at 24 h after exposure. The 1-h exposure to hydrazine resulted in lesions of the nasal transitional epithelium. These lesions were characterized as minimal necrosis, mild to moderate exfoliation, minimal to moderate acute inflammation, and mild apoptosis. Another phase of this study exposed rats and hamsters for 10 weeks at 1 h per week to hydrazine at concentrations of 75 or 750 ppm. Male and female rats exposed to 750 ppm and female rats exposed to 75 ppm exhibited significant reductions in body weight (p < 0.05). Hamsters in the 750-ppm group also exhibited significant reductions (p < 0.05) in body weight gain compared to controls. Exposure-induced lesions including desquamation, necrosis, apoptosis, and squamous metaplasia were observed in the nasal transitional epithelium during the exposure period. Although apoptosis and squamous metaplasia were observed after the exposure, the alterations appeared to revert back to normal-appearing transitional epithelium with incidences of lesions at 24 months being low: epithelial hyperplasia (4/99 males, 1/95 females); polyploid adenomas (4/99 males, 6/95 females) and; squamous cell carcinoma (1/99 males) were also observed in rats held up to 28 months postexposure. Hamsters exposed to 750 ppm hydrazine (1 h/week for 10 weeks) exhibited similar incidences of hyperplasia (2/94) and neoplasia (5/94). However, none of the lesions observed in the exposed animals were seen in the control animals.

3.2.4.
Mice

House (1964) also conducted inhalation exposure studies in male ICR Swiss mice. The protocol was identical as for rats (see Section 3.2.3.). A high mortality early in the exposure period (98% within 4 weeks) precluded the evaluation of reversibility of effects. There were no findings in mice relevant to non-disabling, reversible effects following acute exposure to hydrazine.

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

Kulagina (1962) noted alteration of conditioned reflex responses in mice exposed for 2 h to 19 ppm hydrazine (24.7 mg/m3).

3.2.5.
Hamsters

MacEwen and Vernot (1981) exposed 20 male Syrian golden hamsters to hydrazine at concentrations of 750 ppm for 1 h twice per week for five weeks. Although no deaths occurred, notable decreases (no statistical analysis performed) in body weight were observed for the exposed animals.

Latendresse et al. (1995) conducted experiments in which groups of 10 male Syrian golden hamsters were exposed to 750 ppm hydrazine for 1 h. Control animals were exposed to air without hydrazine. Gross and histopathological examinations were conducted on the animals following euthanasia at 24 h after exposure. The 1-h exposure to hydrazine resulted in lesions of the nasal transitional epithelium. These lesions were characterized as minimal necrosis, mild to moderate exfoliation, minimal to moderate acute inflammation, and mild apoptosis.

3.3.
Developmental and Reproductive Toxicity
3.3.1.
Rats

Developmental toxicity of parenterally administered hydrazine has been reported. Lee and Aleyassine (1970) reported fetal toxicity (reduced size, pallor, edema and petachiae) and lethality in rats following subcutaneous administration of hydrazine (8 mg/kg) during days 11-21 of gestation. The administered dose also resulted in marked maternal toxicity characterized by body weight loss.

In a study by Keller et al. (1982), pregnant Fischer 344 rats were administered hydrazine in physiologic saline i.p. at doses of 2.5 (n = 17), 5.0 (n = 19), or 10.0 (n = 6) mg/kg, on days 6 through 15 of gestation. Controls (n = 27) were given equivalent volumes of saline, i.p. A dose-response in no. of resorptions/litter was observed. This response was statistically significant (p≤0.05) at doses of 5.0 or 10 mg/kg. Maternal toxicity (body weight loss) was also observed in these groups during the treatment period. Pregnant rats were also exposed to hydrazine percutaneously (30-min, covered exposure of 2.5 cm square area) at doses of 5.0 or 50.0 g/kg on day 9 of gestation. The higher dose also resulted in a high incidence of embryolethality. Results of the i.p. injection experiment are shown in Table 6-7.

In a second experiment reported by Keller et al. (1982), pregnant F344 rats were given hydrazine (10 mg/kg, i.p.) on gestation days 7-9, 10-12, or 13-15. This protocol was used because the former dosing protocol resulted in excessive embryolethality that precluded meaningful assessment of possible developmental effects during later developmental periods. Based upon resorptions/litter,

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

fetal weight, and incidence of anomalies, exposure during gestation days 7-9 appeared to be the most critical. However, similar to the preceding experiment, dams exhibited body weight loss during the treatment period. The results of this experiment are shown in Table 6-8.

TABLE 6-7 Developmental Effects of Hydrazine in Rats Following i.p. Administration on Gestation Days 6-15

Parameter

Dose (mg/kg)

0

2.5

5.0

10

Number of litters

27

17

19

6

Implants/littera

8.2 ± 0.6

8.1 ± 0.7

6.5 ± 0.7

7.0 ± 1.9

Resorptions/littera

1.5 ± 0.4

1.8 ± 0.4

3.3 ± 0.7b

6.0 ± 2.3b

No. litters with >50% resorption

4

1

10

5

Fetal wta

3.1 ± 0.04

3.1 ± 0.04

2.9 ± 0.1b

3.1 ± 0.3

No. fetuses examined

27(181)

17(107)

15(60)

1(6)

Litters (fetuses) affected

8(11)

4(5)

7(8)

1(3)

Anomaliesc

6

3

4

3

Major malformations

7d,e

3d

4f

3

aValues are means ± S.E.

bSignificantly different from control, p ≤ 0.05.

cSupernumerary ribs, fused ribs, delayed ossification, moderate hydronephrosis, moderate dilation of brain ventricles, other similar but less frequently occurring abnormalities.

dMajor malformation was anophthalmia.

eThree fetuses with anophthalmia in one litter.

fMajor malformations were anophthalmia (2), right side aorta (1), and monorchid (1).

Source: Keller et al. 1982.

TABLE 6-8 Developmental Effects in Rats Following i.p. Administration of Hydrazine (10 mg/kg) at Various Times During Gestation

Parameter

Gestational Exposure Period

Control (6-15)

7-9

10-12

13-15

Number of litters

27

11

1

10

Implants/littera

8.2 ± 0.6

7.5 ± 1.1

8.9 ± 1.0

7.7 ± 1.4

Resorptions/littera

1.5 ± 0.4

6.1 ± 1.10b

0.8 ± 0.4

1.0 ± 0.3

Litters with >50% resorption

4

8

0

0

Fetal wta

3.1 ± 0.04

2.7 ± 0.1b

3.1 ± 0.1

2.9 ± 0.5b

No. fetuses examined

27(181)

8(16)

10(81)

10(57)

Litters (fetuses) affected

8(11)

6b(8)

4(4)

4(4)

Anomalies

6

8c

2

4

Major malformations

7

0

2d

4

aValues are means ± S.E.

bSignificantly different from control, p ≤ 0.05.

cMajor malformations were anophthalmia and adrenal agenesis.

dAnomalies detected were supernumerary ribs (2), moderate hydronephrosis (2), and moderate hydrocephalus (4).

Source: Keller et al. 1982.

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

An inhalation exposure (nose-only) study, Keller (1988) exposed pregnant rats (strain not specified) on gestation day 9 to 500 or 50 ppm of hydrazine for 1 h. Although no teratogenic effects were observed, exposure to 500 ppm hydrazine resulted in 48% embryolethality that was concurrent with maternal toxicity. Embryolethality at 50 ppm hydrazine was similar to that observed for unexposed controls; 3% and 4%, respectively. However, data were lacking regarding exposure atmosphere analysis, characterization of the maternal toxicity, and protocol details.

3.4.
Genotoxicity

There were no inhalation genotoxicity data available for hydrazine. Hydrazine has been shown to be mutagenic in various microbial tests and evidence of genotoxic potential in mammals has been shown following oral and parenteral administration (reviewed by NRC 1985; Garcia and James 1996). This review concluded that hydrazine has the potential for inducing somatic mutations. Intraperitoneal injection of hydrazine (10 to 120 mg/kg) in mice during the early stages of spermatogenesis did not induce unscheduled DNA synthesis (Sotomayor et al. 1982), and Epstein and Shafner (1968) reported negative results in mouse dominant-lethal test. However, positive results in sister chromatid exchange in various murine tissues have been reported (Couch et al. 1986; Neft and Conner 1989). In vitro studies (summarized in ATSDR 1997) have indicated the genotoxic potential of hydrazine with and without metabolic activation and include methyl DNA adducts in human but not hamster V79 cells, gene mutations in human teratoma cells, and unscheduled DNA synthesis. Hydrazine was positive in the Ames test using TA1535, TA100, TA1537, and TA98 strains of Salmonella typhimurium (Parodi et al. 1981) and mutagenicity was demonstrated in strain WP2 of Escherichia coli (Noda et al. 1986).

Leakakos and Shank (1994) reported that DNA methylation (presumably a requirement for oral and parenteral hydrazine-induced liver cancer in rodents) was detectable only when the dose of hydrazine was necrogenic (25 or 50 mg/kg). This conclusion was based upon findings of methylguanine adducts (7-methylguanine and O6-methylguanine) in hepatic DNA of neonatal rats given subcutaneous injections of hydrazine. Inhibition of restriction at specific sites following necrogenic doses was provided as evidence of a hydrazine-specific genotoxic response.

3.5.
Carcinogenicity
3.5.1.
Dogs

There were no treatment related effects observed in male or female beagle dogs (four per group) exposed to hydrazine at concentrations of 0.25-5.0 ppm

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

(0.35-6.55 mg/m3) 6 h per day, 5 days per week for one year (MacEwen et al. 1981).

Vernot et al. (1985) conducted 1-year inhalation exposure of dogs to hydrazine at concentrations of 0.25 or 1.0 ppm for 6 h/day, 5 days/week. The dogs were maintained an additional 38 months postexposure. No tumors attributed to hydrazine were observed in any of the dogs.

3.5.2.
Rats

MacEwen et al. (1981) exposed groups of 100 rats of both sexes to 0.05-5.0 ppm (0.07-6.55 mg/m3) hydrazine for one year (6 h/day, 5 days/week). Evidence of inflammatory changes in the respiratory tract were observed at the lowest exposure but were more prevalent and more severe at the highest exposure. The histopathologic changes included squamous cell metaplasia of the nasal cavity, larynx, and trachea. Hyperplastic changes were observed in the nasal and pulmonary epithelia, and inflammatory changes were observed in the larynx and trachea. At the highest exposure tested, male rats exhibited a significant increase in squamous metaplastic changes in the nasal region (47/99; p ≤ 0.001), nasal epithelial hyperplasia (21/99; p ≤ 0.001), squamous metaplasia of the larynx (18/29; p ≤ 0.001) and trachea (10/97; p ≤ 0.001), inflammatory changes in the larynx (72/92; p ≤ 0.001) and trachea (52/97; p ≤ 0.001), and pulmonary epithelia hyperplasia (6/99; p ≤ 0.001). What appears to be a published report of this study is described below.

Vernot et al. (1985) reported on a 1-year inhalation exposure of rats to hydrazine at concentrations of 0.05, 0.25, 1.0, or 5.0 ppm for 6 h/day, 5 days/week. The rats were maintained an additional 18 months postexposure. A dose-dependent increased incidence was noted for benign nasal adenomatous polyps (58/98 treated vs 1/146 control in males, and 28/95 treated vs 0/145 control in females; p ≤ 0.01) and villous polyps (12/98 vs 0/146 in males only; p ≤ 0.01), and thyroid carcinomas (13/98 vs 1/146 males only; p ≤ 0.05). The nasal tumors were often associated with chronic irritation. The increased incidence of thyroid carcinoma was significant (13/98 vs 7/146; p ≤ 0.5) in the 5.0 ppm males at the end of the 18-month observation period. Squamous cell carcinomas and bronchial carcinomas were also increased in males but significantly so.

Latendresse et al. (1995) conducted experiments in which groups of five male and five female F-344 rats were exposed to 75 or 750 ppm hydrazine for 1 h/week for 10 weeks. Control animals were exposed to air without hydrazine. Male and female rats exposed to 750 ppm and female rats exposed to 75 ppm exhibited significant reductions in body weight (p < 0.05). Hamsters in the 750-ppm group also exhibited significant reductions (p < 0.05) in body weight gain compared to controls. Exposure-induced lesions including desquamation, necrosis, apoptosis, and squamous metaplasia were observed in the nasal transitional

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

epithelium during the exposure period. Although apoptosis and squamous metaplasia were observed after the exposure, the alterations appeared to revert back to normal-appearing transitional epithelium with incidences of lesions at 24 months being low: epithelial hyperplasia [4/99 males, 1/95 females]; polyploid adenomas [4/99 males, 6/95 females] and; squamous cell carcinoma [1/99 males]) were also observed in rats held up to 28 months postexposure. However, none of the lesions observed in the exposed animals were seen in the control animals.

3.5.3.
Mice

Groups of 400 female C57BL/6 mice were exposed to hydrazine (0.05, 0.25, or 1.0. ppm) 6 h/day, 5 days/week for up to one year (MacEwen et al. 1981). A group of 800 female mice exposed to clean air served as controls. The mice appeared to be resistant to the oncogenic effects of hydrazine. The only significant response was 3% incidence (12/379; p ≤ 0.05) in pulmonary adenomas in the highest exposure tested. A published report of this study appeared as Vernot et al. (1985).

The 1-year inhalation study by Vernot et al. (1985) also examined mice (400 females per group) exposed to hydrazine at concentrations of 0.05, 0.25, or 1.0 ppm for 6 h/day, 5 days/week. The mice were maintained an additional 15 months postexposure. As described above, pulmonary adenomas were slightly increased in mice of the 1.0 ppm group.

3.5.4.
Hamsters

Latendresse et al. (1995) conducted experiments in which groups of 10 male Syrian golden hamsters were exposed to 75 or 750 ppm hydrazine for 1 h/week for 10 weeks. Control animals were exposed to air without hydrazine. Gross and histopathological examinations were conducted on the animals following euthanasia at 24 h after exposure. Hamsters exposed to 750 ppm hydrazine (1 h/week for 10 weeks) exhibited hyperplasia (2/94) and neoplasia (5/94). None of the lesions observed in the exposed animals were seen in the control animals.

Vernot et al. (1985) and MacEwen et al. (1981) also utilized hamsters in their 1-year inhalation exposure studies of hydrazine. Groups of 200 males hamsters were exposed to hydrazine at concentrations of 0.25, 1.0, or 5.0 ppm for 6 h/day, 5 days/week. The hamsters were maintained an additional year. Evidence of degenerative changes, including amyloidosis, was observed in hamsters exposed to 0.25 ppm hydrazine and higher. The incidence of nasal adenomatous polyps was significantly increased (16/160 vs 1/181; p ≤ 0.05) in the 5.0-ppm group relative to unexposed controls.

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
3.6.
Summary

Acute lethality data for inhalation exposure to hydrazine were available for dogs, rats, mice and hamsters, although the data for dogs are compromised by the small numbers of animals and the use of mongrels rather than a fixed breed. Some data from earlier studies are also compromised by inadequacies in accuracy of exposure concentration measurements, highly variable concentrations during the testing period, and variabilities in observation periods for assessing lethality. Acute lethality data following parenteral routes (i.e., iv, i.p.) and oral administration are available for dogs, rats, and mice. These data were discussed with reference to route-dependent variability in lethality. The route of administration does not appear to significantly affect the qualitative nature of hydrazine toxicity (Krop 1954; Witkin 1956; NRC 1985), although dose-response alterations are observed and nasal lesions appear to be more prominent in inhalation exposures. Some studies have also shown that hydrazine may induce embryolethality at maternally toxic doses.

There is evidence that long-term exposure of rats to hydrazine may cause an increased incidence in nasal tumors or histopathologic changes indicative of a possible tumorigenic response (Vernot et al. 1985; Latendresse et al. 1995). Based upon the animal data, however, it appears that repeated exposures resulting in long-term tissue irritation is instrumental in the observed tumorigenic responses.

Definitive exposure-response data regarding non-disabling, reversible health effects in animals following acute inhalation exposure to hydrazine were limited. Muscular incoordination and weakness was observed in dogs (Weatherby and Yard 1955), alteration of conditioned response behaviors was noted for rats (Kulagina 1962), and nasal lesions observed in rats following a single exposure (Latendresse et al. 1995).

4.
SPECIAL CONSIDERATIONS

4.1.
Metabolism and Disposition

Studies with animals have shown that hydrazine may be metabolized to acetylhydrazine, diacetylhydrazine, ammonia, and urea, and may form hydrazones with pyruvate and 2-oxoglutarate (Wright and Timbrell 1978; Timbrell et al. 1982; Preece et al. 1991; Timbrell 1992). These studies also indicated that urinary excretion to be a major route of elimination following various administration routes. The biotransformation of hydrazine is mediated, at least in part, by hepatic monooxygenases and acetyltransferases (Timbrell 1992; Koizumi et al. 1998).

Differential rates of hydrazine metabolism by humans and the role of acetylation phenotype was investigated by Koizumi et al. (1998). Acetylation phenotype was determined for 297 workers involved in the production of hydrazine

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

hydrate. Based on analysis of 12 individuals from this study population, the mean biological half-life of hydrazine among individual workers of various acetylation phenotype varied about 2-fold (p < 0.05); 3.94 ± 1.70 h, 2.25 ± 0.37 h, and 1.86 ± 0.67 h, respectively, for slow, intermediate and rapid acetylators. Exposure to hydrazine was reportedly 0.07-0.12 ppm (8-h TWA).

Timbrell (1992) reported that hepatic uptake of hydrazine by rats following intraperitoneal administration appeared to be a saturable process. In experiments with rats exposed via inhalation to hydrazine at concentrations of 10-500 ppm for 1 h, Llewellyn et al.(1986) found that 1.7-4% and 4.5-11.4% of the absorbed dose was excreted as urinary acetyl hydrazine and diacetylhydrazine, respectively.

The role of metabolism and absorption/excretion kinetics is uncertain regarding immediate port-of-entry toxic effects from acute inhalation exposures. The highly reactive nature of hydrazine may be instrumental in the manifestation of acute port-of-entry toxic effects. However, the systemic effects (e.g., convulsions, cardiovascular collapse) and delayed lethality attributed to hepatic and renal effects, may be affected by absorption, distribution and excretion kinetics, as well as metabolism processes. This is consistent with early reports of lipid accumulation in the liver and kidneys of experimental animals following single and repeated doses of hydrazine (Comstock et al. 1954).

4.2.
Mechanism of Toxicity

Although the acute lethality of hydrazine has been demonstrated in several species following multiple routes of administration, time to lethality following inhalation exposure appears to be extremely variable. As exemplified in the studies by Comstock et al. (1954) and Witkin (1956), inhalation exposure to hydrazine for exposure periods (0.5 to 4 h) may result in lethality as long as 14 days following cessation of exposure. Such latency complicates the estimation of acute exposure values and their possible resultant effects. Additionally, some consideration must also be given to the steep slope of the concentration effect curve for lethal effects of hydrazine. Jacobson et al. (1955) noted the slope of the exposure concentration/lethality curve to be 7.32 ± 1.8 and 3.79 ± 1.6 (±SE) for rats and mice, respectively. The steep slope generated by the rat lethality data implies a relatively smaller ratio between the dose causing low mortality and that causing a high mortality. This is a relevant point of concern regarding establishing an effect level based upon hydrazine lethality. The available data suggest that there may be little margin between lethal effects and nonlethal effects following inhalation exposure to hydrazine.

4.3.
Structure-Activity Relationships

The toxicity of methylated derivatives of hydrazine (monomethylhydrazine and the symmetrical and unsymmetrical isomers of dimethylhydrazine [1,1-

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

dimethylhydrazine and 1,2-dimethylhydrazine, respectively]) have also been studied. Jacobson et al. (1955) reported excessive salivation, vomiting, respiratory distress and convulsions in dogs exposed to monomethylhydrazine and unsymmetrical dimethylhydrazine. Fourteen day mortality in three groups of dogs (three dogs/group) exposed for 4 h to monomethylhydrazine at concentrations of 29, 21, and 15 ppm were 2/3, 2/3, and 0/3, respectively. Fourteen day mortality in three groups of dogs (three dogs/group) exposed for 4 h to unsymmetrical dimethylhydrazine at concentrations of 111, 52, and 24 ppm were 3/3, 1/3, and 0/3, respectively. In studies reported by Rinehart et al. (1960), 29/30 mice exposed continuously to symmetrical dimethylhydrazine (140 ppm) died within two weeks and 8/30 mice exposed to 75 ppm died within five weeks. Rinehart et al. (1960) also reported that 1/3 dogs exposed intermittently to symmetrical hydrazine (25 ppm) died within three days. For rodents, estimated LC50 values for monomethylhydrazine, unsymmetrical dimethylhydrazine and symmetrical dimethylhydrazine are shown in Table 6-9.

Jacobson et al. (1955) noted that the toxic actions of hydrazine and its methylated derivatives were similar; all are respiratory irritants and convulsants. However, it was observed that monomethylhydrazine also induced severe intravascular hemolysis in dogs.

Witkin (1956) reported i.v., i.p., and oral LD50 values for mice and rats, and i.v. LD50 values for dogs. Similar to hydrazine, the route of administration had minimal effect on the LD50 within species. Generally, monomethylhydrazine and symmetrical dimethylhydrazine appeared to be somewhat more toxic in mice than was hydrazine. Results of this study showed that the unsymmetrical isomer of dimethylhydrazine was less acutely toxic than hydrazine or the other hydrazine derivatives.

TABLE 6-9 LC50 Values for Rodents Exposed to Monomethylhydrazine and Dimethylhydrazine Isomers

Species

LC50 (ppm)

LC50 (mg/m3)

Monomethylhydrazine

Rat

74

139

Mouse

56

10

Hamster

143

270

Unsymmetrical dimethylhydrazine

Rat

252

618

Mouse

172

423

Hamster

392

962

Symmetrical dimethylhydrazine

Rat

280-400

364-520

Source: Jacobson et al. 1955. Reprinted with permission; copyright 1955, American Medical Association.

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

House (1964) reported unsymmetrical dimethylhydrazine to be less toxic to monkeys, rats, and mice. Mortality rates over a 90-day inhalation exposure to 0.56 ppm (0.73 mg/m3) were 20, 98, and 99% for monkeys, rats, and mice, respectively.

The database on hydrazine derivatives provides no additional information that would be applicable to deriving AEGL values for hydrazine.

4.4.
Other Relevant Information
4.4.1.
Species Variability

The limited available data suggest that the lethal concentration of hydrazine varies somewhat among the species tested. Some of this variability, however, may be attributed to the difficulties in accurately measuring and maintaining the experimental hydrazine concentrations, especially in earlier studies. As shown in Tables 6-12 and 6-13 in Section 7.2, both the LC50 and the LD50 values are very similar for rats and mice. The estimated LD50 for the dog suggests greater sensitivity but this value is based upon only two doses and two test animals per dose. Overall, there still appears to be uncertainty regarding species variability in the toxic response to hydrazine and, more importantly from the standpoint of AEGL development, uncertainty regarding the sensitivity of humans relative to laboratory species. Furthermore, definitive data were not available regarding species variability in irreversible, nonlethal effects of acute exposure to hydrazine.

4.4.2.
Physical and Chemical Properties

The extreme reactivity of hydrazine also deserves special attention with regard to accurate assessment of experimental exposure concentrations. As shown in the studies of Jacobson et al. (1955) and Comstock et al. (1954), accurate and consistent measurement of hydrazine concentrations even under experimental conditions is difficult and subject to many variabilities (size of chamber, number and size of animals, chamber construction material, etc.). The highly reactive nature of hydrazine per se is a plausible determinant of acute port-of-entry toxic effects.

4.4.3.
Concurrent Exposure Issues

Although data analyzing the adverse effects of concurrent exposure to hydrazine and other chemicals are not available, this may be an important issue, especially for those chemicals with irritant properties. Furthermore, hydrazine is a highly reactive reducing agent that may react with many other chemicals (especially oxidizers), thereby altering their effects on physiologic systems.

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

5.
DATA ANALYSIS FOR AEGL-1

5.1.
Human Data Relevant to AEGL-1

Human data were not available for deriving an AEGL-1. The odor threshold for hydrazine is 3 to 4 ppm.

5.2.
Animal Data Relevant to AEGL-1

Data regarding the nonlethal, reversible effects of hydrazine on animals following acute exposures were limited. Data from some of the earlier studies were compromised by difficulties in determining the actual hydrazine concentrations in the exposure chambers. Acute exposures (<24 h) of animals to hydrazine resulted in irritation at various exposures. A cumulative exposure as low as 106 mg/m3 for 1-2 min was reported to cause irritation in rats while exposure to 975 mg/m3 for 1 h produced nasal lesions in rats. Eye and facial irritation in monkeys was noted following an exposure of 0.52 mg/m3 for ≈24 h, and neurological effects (alteration of conditioned responses) were observed in mice following exposure to 24.7 mg/m3 for 2 h. Repeated 8 h/day occupational exposure of rocket plant workers was without signs of acute toxicity (Koizumi et al. 1998).

5.3.
Derivation of AEGL-1

The data from the study by House (1964) in which male monkeys were continuously exposed to hydrazine at 0.52 mg/m3 (equivalent to 0.4 ppm average concentration for the first 10 days of the 90-day exposure period) resulting in skin flushing and swollen eyes after 24 h of exposure was used as the basis for the AEGL-1. Based upon the available data, this exposure represents the lowest exposure resulting in a definitive effect that could be considered consistent with the definition of an AEGL-1. Exponential scaling with the equation, Cn × t = k (ten Berge et al. 1986), was used to derive exposure duration-specific values. Data were unavailable for an empirical derivation of n in the equation, Cn × t = k. It has been shown that the concentration-exposure time relationship for many irritant and systemically acting vapors and gases may be described by Cn × t = k, where the exponent n ranges from 0.8 to 3.5. In the absence of chemical specific data, an n of 3 was applied to extrapolate the 24-h 0.4 ppm exposure from the House (1964) study to the 8-h AEGL -1 time frame (k = 0.4 ppm3 × 24 h = 1.54 ppm3-h). Because hydrazine is extremely reactive and the sensory-irritation effects are considered to be concentration dependent rather than time dependent, 0.1 ppm (the 30-min, 1-h, 4-h, and 8-h values were all approximately 0.1 ppm) was considered appropriate for all AEGL-1 durations. (Table 6-10 and Appendix A).

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

TABLE 6-10 AEGL-1 Values for Hydrazine

Classification

10-min

30-min

1-h

4-h

8-h

AEGL-1

0.1 ppm (0.1 mg/m3)

0.1 ppm (0.1 mg/m3)

0.1 ppm (0.1 mg/m3)

0.1 ppm (0.1 mg/m3)

0.1 ppm (0.1 mg/m3)

A total uncertainty factor of 10 was applied to derive the AEGL-1 values (each uncertainty factor of 3 is actually the geometric mean of 1 and 10 [i.e., 3.16], hence; 3.16 × 3.16 = 10). An uncertainty factor of 3 was applied for interspecies variability because the surface contact irritation by the highly reactive hydrazine is not likely to vary greatly among species, and because a nonhuman primate was the test species. An uncertainty factor of 3 was applied for intraspecies variability because the contact irritation from the highly reactive hydrazine is not expected to vary greatly among individuals, including susceptible individuals.

6.
DATA ANALYSIS FOR AEGL-2

6.1.
Summary of Human Data Relevant to AEGL-2

Human data were not available for deriving an AEGL based upon nonlethal, irreversible effects of hydrazine exposure.

6.2.
Summary of Animal Data Relevant to AEGL-2

Data were limited regarding irreversible, nonlethal effects of acute exposure to hydrazine. AEGL-2 values were first derived based upon several studies. Using the data from Weatherby and Yard (1955) showing muscular incoordination and weakness in one of two dogs exposed for 6 h, results in the most conservative AEGL-2 estimates. These data, however, are greatly compromised by the use of only two animals (only one of which responded) and the use of mongrel dogs. The developmental toxicity data of Keller (1988) provides a reasonable data set for AEGL-2 derivation but results in AEGL-2 values that are somewhat higher than those derived using the other data sets. The data of Kulagina (1962) is of questionable use for AEGL derivation because of the subjective nature of assessing alterations in behavioral responses.

Results of a study in rats by Becker et al. (1981) identified long-term deleterious effects but not immediately disabling effects. The toxicity end points reported included body weight reduction, fatty liver and methylation of hepatic DNA following intragastric administration of hydrazine at a dose of 3 mg/kg/day for up to 4 days. These effects are considered severe enough to result in serious and irreversible impairment of health over time, especially if one considers the methylation of hepatic DNA to represent a possible precursor to a carcinogenic response. However, the use of route-to-route extrapolation may be

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

tenuous due to the uncertainties in toxicokinetics between inhalation and oral routes.

The study by Latendresse et al. (1995) appeared to provide the best data for AEGL-2 derivation. Results of this study showed the induction of nasal lesions in rats following a single 1-h exposure to 750 ppm hydrazine. The nasal lesions were characterized by histopathologic analysis and were shown to be reversible upon removal from exposure. This toxicologic response is indicative of an initial response that is part of a continuum of tissue damage resulting from hydrazine exposure. It is the highest tested exposure that did not lead to lethality and, due to its reversibility and a severity that is less than that consistent with AEGL-2 tier definition, is considered as the critical effect for AEGL-2 development. The experiments also utilized the inhalation exposure route, and measurement of hydrazine concentrations did not appear to be a confounding factor regarding the validity of the experimental results.

6.3.
Derivation of AEGL-2

The data from the Latendresse et al. (1995) study showing nasal lesions (minimal necrosis, mild to moderate exfoliation, minimal to moderate acute inflammation, mild apoptosis) in rats following a 1-h exposure to 750 ppm was considered to be appropriate for setting AEGL-2 values. The study protocol and analytical techniques were superior to earlier studies and histopathologic data were available. The toxicity end point involved a specific region of the respiratory tract (nasopharyngeal region) and, although toxicologically and physiologically serious, was reversible upon removal from exposure.

Due to the extreme reactivity of hydrazine, exposure concentration measurements in earlier studies on multiple species were imprecise. An uncertainty factor of 3 for interspecies variability was applied to account for uncertainties regarding species variability in the toxic response to inhaled hydrazine. Because much of the toxic response to acute low-level exposures is likely a function of the extreme reactivity of hydrazine, the reduction from a default value of 10 is justified. An uncertainty factor of 3 was applied for intraspecies variability because the port-of-entry effect of the extremely reactive hydrazine is likely attributed to direct interaction with respiratory tract tissues. This contact irritation is not likely to vary considerably among individuals. Additionally, variability in acetylation phenotypes among humans and the subsequent effect on at least one aspect of hydrazine metabolism has been shown to vary approximately 2-fold. A modifying factor of 2 was applied to account for data inadequacies regarding the identification of toxic responses consistent with AEGL-2 level effects (i.e., serious or irreversible, but nonlethal, effects of acute inhalation exposure to hydrazine). Although the more recent studies such as those by Latendresse et al.(1995) and HRC (1993) appear to have more reliable determinations of hydrazine concentrations, the overall data set for hydrazine is compromised by uncertainties regarding the variability in response among species. At least some

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

of this variability may be the results of inaccurate exposure concentration measurements due to the reactivity of hydrazine with the surfaces of the exposure apparatus. Therefore, an additional modifying factor of 3 has been applied to account for the impact of these data deficiencies. This resulted in a total adjustment of 60-fold for derivation of AEGL-2 values (Table 6-11).

Because data were unavailable for an empirical derivation of n in the equation, Cn × t = k, temporal scaling was performed using n = 3 when extrapolating to shorter time points and n = 1 when extrapolating to longer time points using the Cn × t = k equation (Appendix A).

As previously noted, the data on nonlethal, irreversible effects resulting from acute exposure to hydrazine are limited. The key study (Latendresse et al. 1995) used to derive the AEGL-2 values appears to provide the highest confidence among the data available for AEGL-2 type effects or an estimation of a threshold for such effects.

7.
DATA ANALYSIS FOR AEGL-3

7.1.
Human Data Relevant to AEGL-3

Although there is a report on one human fatality resulting from hydrazine exposure, the case involved repeated exposure to approximately 0.05 ppm(estimated from a post-exposure simulation) over a 6-month period (Sotaniemi et al. 1971). The confounding effects of a repeated exposure scenario (e.g., compromised tissue repair in the presence of repeated insults, excretion and detoxication kinetic considerations, etc.), and uncertainties regarding the estimate derived from a simulated exposure prevent the use of this report in deriving a defensible AEGL Level 3 value.

7.2.
Animal Data Relevant to AEGL-3

Developmental toxicity of hydrazine by i.p. and percutaneous routes has been demonstrated in rats (Lee and Aleyassine 1970; Keller et al. 1982, Keller 1988). Because the significant findings (increased resorptions/litter, decreased fetal weight, embryolethality, increased incidences of anomalies) were concurrent with maternal toxicity (decreased body weight during gestational treatment period), it is difficult to attribute the developmental effects directly to hydrazine exposure per se and to consider hydrazine a selective developmental toxicant. Because of the route of administration and the inherent uncertainties of route-to-route extrapolation, the data from Lee and Aleyassine (1970) and Keller et al. (1982) were not used for deriving the AEGL-3 levels. Several studies utilizing inhalation exposures were considered for derivation of an AEGL-3 values.

The acute lethality of inhaled hydrazine has been reported by several investigators (Comstock et al. 1954; Jacobson et al. 1955; Keller 1988; HRC 1993). Keller (1988) reported embryolethality following 1-h exposure to 500

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

ppm hydrazine but experimental protocol details and analytical data are lacking. Although Keller (1988) reported maternal toxicity and embryolethality resulting from a 1-h exposure to 500 ppm hydrazine, Latendresse et al. (1995) reported only nasal lesions (necrosis, exfoliation, and acute inflammation) in rats and hamsters exposed to 750 ppm for 1 h but did not note any overt clinical signs of toxicity in exposed animals (body weight was decreased in those animals receiving multiple exposures but did not appear to be significant in those subjected to 1-h exposure). LC50 values of considerable variability have also been reported by several investigators (Comstock et al. 1954; Jacobson et al. 1955; MacEwen and Vernot 1981; HRC 1993). For comparison, summaries of LD50 and LC50 values are shown in Table 6-12 and 6-13, respectively.

7.3.
Derivation of AEGL-3

Although several inhalation studies are available that provide data showing lethality or life-threatening effects acute exposure to hydrazine, the quality of the studies varies considerably. Earlier studies tended to be compromised to varying degrees by analytical deficiencies in determining the hydrazine concentration of the experimental exposures. Several studies were identified for derivation of AEGL-3 values (Appendix A). These included the acute exposure studies by Jacobson et al. (1955), Keller (1988), HRC (1993).

A notable range of values were obtained depending upon the study used. Although AEGL-3 values derived from the embryolethality data reported by Keller (1988) provide the most conservative AEGL-3 values, this study was compromised by the absence of details for experimental protocol and results (see Section 3.4.1). The AEGL-3 values derived from the Jacobson et al. (1955) data were similar although slightly lower.

The AEGL-3 values were derived based upon the data from the HRC study that provided a 1-h LC50 of 4.2 mg/L (3,192 ppm) in rats (both sexes). Although a 1-h LC01 of 334 ppm was estimated from the HRC data using the method of Litchfield and Wilcoxon (1949), it was considered to be inappropriate for derivation of AEGL-3 values because it was not consistent with the recent data from Latendresse et al. (1995) that showed 1-h exposure of rats to 750 ppm did not result in any lethalities. It is believed that a 3-fold reduction of the 1-h LC50 (3,192 ppm/3 = 1,064 ppm) provides an estimate of the lethality threshold that is consistent with the available data. For example, the Latendresse et al. (1995) study demonstrated that rats exposed to 750 ppm for 1 h per week for 10 consecutive weeks did not experience mortality.

TABLE 6-11 AEGL-2 Values for Hydrazine

Classification

10-min

30-min

1-h

4-h

8-h

AEGL-2

23 ppm (30 mg/m3)

16 ppm (21 mg/m3)

13 ppm (17 mg/m3)

3.1 ppm (4.0 mg/m3)

1.6 ppm (2.1 mg/m3)

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

TABLE 6-12 Summary of LD50 Values for Hydrazine in Studies by Witkin (1956) and Jacobson et al. (1955)

Species

LD50 (mg/kg)

Route of Administration

Time of Death

Reference

Rat

55

I.V.

10 da

Witkin 1956

59

I.P.

10 d

Witkin 1956

60

Oral

10 da

Witkin 1956

112

Inhalation

4 hb

Jacobson et al. 1955

Mouse

57

I.V.

10 da

Witkin 1956

62

I.P.

10 da

Witkin 1956

59

Oral

10 da

Witkin 1956

18

Inhalation

4 hb

Jacobson et al. 1955

Dog

25

I.V.

10 da

Witkin 1956

aObservation period.

bDuration of exposure; conversion to internal dose (mg/kg) based upon default values for body weight and ventilation rate for rats (EPA 1986).

TABLE 6-13 Summary of LC50 Values for Hydrazine in Studies by Jacobson et al. (1955), Comstock et al. (1954), HRC (1993), and MacEwen and Vernot (1981)

Species

LC50 (mg/m3 [ppm])

Exposure Duration (h)

C × t (mg-h/m3)

Reference

Rat

750 [570]

4

3,000

Jacobson et al. 1955

Rat

344 [260]a

4

1,376

Comstock et al. 1954

Rat

831 [630]b

4

3,324

Comstock et al. 1954

Rat

4,200 [3,192]c

1

4,200

HRC 1993

Hamster

3,360 [2,585]d

1

3,360

MacEwen and Vernot 1981

Mouse

330 [252]

4

1,320

Jacobson et al. 1955

a50% lethality at 8 days postexposure.

b50% lethality at 13 days postexposure.

cValue is for males and female combined (males 1-h LC50: 5,800 mg/m3; females 1-h LC50 3,400 mg/m3.

d14-day postexposure observation.

Additionally, the concentration-exposure time relationship for many irritant and systemically acting vapors and gases may be described by Cn × t = k, where the exponent, n, ranges from 0.8 to 3.5. To obtain AEGL values, temporal scaling was performed using n = 3 when extrapolating to shorter time points (10 min and 30 min) and n = 1 when extrapolating to longer time points (4 and 8 h) using the Cn × t = k equation (Appendix A).

Uncertainty factors were applied as described for AEGL-2. An uncertainty factor of 3 for interspecies variability was applied to account for uncertainties regarding species variability in the lethal response to inhaled hydrazine. Because

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

much of the toxic response to acute low-level exposures is likely a function of the extreme reactivity of hydrazine and resulting direct-contact damage to tissues, the reduction from a default value of 10 is justified. An uncertainty factor of 3 was applied for intraspecies variability because the port-of-entry effect of the extremely reactive hydrazine is likely attributed to direct interaction with respiratory tract tissues. This contact irritation is not likely to vary considerably among individuals. A modifying factor of 3 for interspecies variability was applied to account for the high degree of variability in the data. As previously described in Section 6.3, the more recent studies by Latendresse et al. (1995) and HRC (1993) utilized more sophisticated exposure chambers assuring more reliable hydrazine exposures. However, the overall data set for hydrazine is still somewhat deficient in reliably determining species variability in the toxic response to inhaled hydrazine. The AEGL-3 values are shown in Table 6-14.

8.
SUMMARY OF AEGLS

8.1.
AEGL Values and Toxicity End Points

A summary of the AEGLs for hydrazine and their relationship to one another are shown in Table 6-15. For AEGL development, an effort was made to identify exposures and toxicity end points specific for the three AEGL levels thereby avoiding the uncertainty involved in extrapolating severity of effects from one effect level (e.g. extrapolation of reversible, nondisabling effects from effects that are clearly lethal). For hydrazine three different data sets and toxic end points were used for derivation of the three AEGL tiers.

The values for the three AEGL tiers appear to be relationally valid, both among the exposure periods for a given AEGL tier as well as across the exposure durations of three AEGL tiers. Furthermore, exposure to AEGL-1 or AEGL-2 values for any of the specified durations, would not result in doses known to induce developmental toxicity in laboratory animals (5 mg/kg, Keller et al. 1982, see Section 3.4.1). It must be noted that the AEGL-1 values are very close to current detection limits (0.05-0.6 ppm) for hydrazine (OSHA 2003).

TABLE 6-14 AEGL-3 Values for Hydrazine

Classification

10-min

30-min

1-h

4-h

8-h

AEGL-3

64 ppm (83 mg/m3)

45 ppm (59 mg/m3)

35 ppm (46 mg/m3)

8.9 ppm (12 mg/m3)

4.4 ppm (5.7 mg/m3)

TABLE 6-15 Relational Comparison of AEGL Values for Hydrazine

Classification

10-min

30-min

1-h

4-h

8-h

AEGL-1 (Nondisabling)

0.1 ppm

0.1 ppm

0.1 ppm

0.1 ppm

0.1 ppm

AEGL-2 (Disabling)

23 ppm

16 ppm

13 ppm

3.1 ppm

1.6 ppm

AEGL-3 (Lethality)

64 ppm

45 ppm

35 ppm

8.9 ppm

4.4 ppm

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

The AEGL-1 was developed based upon skin flushing and swollen eyes in rhesus monkeys after 24 h continuous exposure to 0.5 mg hydrazine/m3 (0.4 ppm) (House 1964). The exposure continued for 90 days and resulted in a 20% mortality although the first death did not occur until days 21-30. Pathological findings in the hydrazine-exposed monkeys were most notable in the heart, kidneys, and liver. It is assumed that the effects of concern regarding the AEGL-1 would have been reversible and not life-threatening. The data based upon effects in a nonhuman primate were considered to be more relevant than data from rodent species (Comstock et al. 1954; Kulagina 1962; Latendresse et al. 1995) described in Section 3.2.3. The AEGL-1 was further adjusted (to 0.1 ppm for all time periods) due to the extreme reactivity and potential for irritation below the odor threshold. Furthermore, an analysis of occupational exposure to hydrazine by Koizumi et al. (1998) indicated that repeated 8 h/day exposure to hydrazine at 0.1 ppm did not result in signs of toxicity.

The AEGL-2 was based upon data showing the induction of nasal lesions following a single 1-h exposure of rats to 750 ppm hydrazine (Latendresse et al. 1995). The lesions were reversible upon removal from the exposure. Although this end point is not consistent with the severity of effect routinely identified for AEGL-2 development, it represents the only definitive nonlethal end point associated with definitive exposure. The end point, albeit a conservative estimate for AEGL-2 type effects, does represent an important effect consistent with the continuum of hydrazine toxicity (i.e., respiratory tract irritation, tissue damage, and potential tumorigenicity). Therefore, it is considered an appropriate basis for AEGL-2 development.

The AEGL-3 is based upon lethality data in rats exposed by nose-only inhalation to hydrazine at concentrations of 0.65, 2.04, 3.24, and 4.98 mg/L (HRC 1993). The HRC report identified a 1-h LC50 of 3,192 ppm. This reported 1-h LC50 was reduced three-fold as an estimate of the lethality threshold and used in the development of the AEGL-3 values.

The divergence from order-of-magnitude uncertainty factor application in AEGL derivations was adopted for several reasons. For the AEGL-1 type effects that are of rapid onset (e.g., skin flushing eye irritation) and that may more be appropriately considered surface contact effects, interspecies variability may be small and, therefore, an uncertainty factor of 3 appeared to be justified. For such effects in acute exposure scenarios, the relevance of order-of-magnitude dose/exposure adjustments is questionable because the exposure duration may be insufficient for expression of interspecies and intraspecies variability in toxicodynamics and toxicokinetics. By definition, the AEGLs address “susceptible but not hyper-susceptible individuals”. Therefore, a 3-fold adjustment was considered appropriate to account for some level of individual variability without being unrealistically conservative in the AEGL derivation. The order-of-magnitude adjustments are more likely to be relevant and appropriate in long-term exposures.

Because long-term inhalation exposure to hydrazine has been shown to be tumorigenic in several species, a cancer assessment was also performed (Appendix B).

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

Following the methods of NRC (1986), AEGL-2 values were derived based on two available data sets. Both data sets identified nasal tumors in rats following 1-year inhalation exposure to hydrazine. Although data from the animal studies affirm the carcinogenic potential of hydrazine following inhalation exposure, the observed tumorigenic responses appear to be a function of prolonged tissue irritation resulting from long-term repeated exposures and are unlikely to occur following a single low exposure. This was especially evident in the study by Latendresse et al. (1995) that showed repeated exposures were necessary for reversible histopathologic changes in rat nasal epithelium. Additionally, the work reported by Leakakos and Shank (1994) showed that showed DNA methylation (presumably a requirement for oral and parenteral hydrazine-induced liver cancer in rodents) was detectable only when the dose of hydrazine was necrogenic. Therefore, it would appear that hydrazine AEGL values that address rare, or single once-in-a-lifetime exposures should not be based upon cancer risk.

A graphic representation of the AEGL values and their relationship to one another and to available data are shown in the category plot in Appendix D.

8.2.
Comparison with Other Standards and Criteria

Exposure standards and guidelines for hydrazine have been established by several organizations. All currently available values are shown in Table 6-16. Because most of these standards are derived to be protective against any adverse health effects and in certain cases intended for repeated or prolonged exposure durations, they are comparable only to the AEGL-1 values. Hydrazine is a suspected human carcinogen (A2) based upon the formation of nasal tumors in rats exposed to hydrazine for one year (MacEwen et al. 1981), and the NRC SPEGLs were derived with respect to this carcinogenic potential. Although the AEGLs were not derived based upon carcinogenic potential, the AEGL-1 values vary by less than an order of magnitude relative to the NRC SPEGLs and the ACGIH TLV.

8.3.
Data Adequacy and Research Needs

Definitive exposure-response data for hydrazine toxicity in humans are not available. However, qualitative information on the human experience affirms that hydrazine vapor is highly irritating. Animal data from earlier studies were often compromised by uncertain quantitation of exposure atmospheres, use of exposure durations that were not consistent with those of interest for AEGL development, poor exposure-response relationships for acute exposures, and imprecise characterization of toxicologic end points relative to acute exposures.

More recent studies in laboratory animals, however, utilized accurate and reliable methods for characterizing exposure concentrations and provided more focus on specific toxicologic end points (e.g., contact irritation, nasal lesions,

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

and lethality) resulting from acute exposures. Data from these studies enabled the development of AEGL values consistent with the methodologies described in the Standing Operating Procedures of the National Advisory Committee for AEGLs (NRC 2001).

Because the AEGL values are applicable to rare events or single once-in-a-lifetime exposures to a limited geographic area and small population, the AEGL values based on noncarcinogenic end points were considered to be more appropriate than those based upon a potential carcinogenic response. Furthermore, the available animal data suggest that the tumorigenic response to inhaled hydrazine is a function of prolonged tissue irritation resulting from repeated exposures and not the result of a single low exposure.

TABLE 6-16 Extant Standards and Guidelines for Hydrazine

Guideline

Exposure Duration

10 min

30 min

1 h

4 h

8 h

AEGL-1 (Nondisabling)

0.1 ppm

0.1 ppm

0.1 ppm

0.1 ppm

0.1 ppm

AEGL-2 (Disabling)

23 ppm

16 ppm

13 ppm

3.1 ppm

1.6 ppm

AEGL-3 (Lethal)

64 ppm

45 ppm

35 ppm

8.9 ppm

4.4 ppm

ERPG-1(AIHA)a

 

 

0.5 ppm

 

 

ERPG-2 (AIHA)

 

 

5 ppm

 

 

ERPG-3 (AIHA)

 

 

30 ppm

 

 

SPEGL (NRC)b

 

 

0.12 ppm

0.03 ppm

0.015 ppm

SMAC (NRC)c

 

 

4 ppm

 

 

STPL(NRC)d

15 ppm

10 ppm

5 ppm

 

 

IDLH (NIOSH)e

REL-TWA (NIOSH)f

 

50 ppm

0.03 ppm (2-h ceiling)

 

 

PEL-TWA (NIOSH)g

 

 

 

 

1 ppm

TLV-TWA(ACGIH)h

 

 

 

 

0.01 ppm

MAK (Germany)i

 

 

 

 

-

MAC (The Netherlands)j

 

 

 

 

0.1ppm

aERPG (Emergency Response Planning Guidelines, American Industrial Hygiene Association) (AIHA 2002).

The ERPG-1 is the maximum airborne concentration below which it is believed nearly all individuals could be exposed for up to 1 h without experiencing other than mild, transient adverse health effects or without perceiving a clearly defined objectionable odor.

The ERPG-2 is the maximum airborne concentration below which it is believed nearly all individuals could be exposed for up to 1 h without experiencing or developing irreversible or other serious health effects or symptoms that could impair an individual's ability to take protection action.

The ERPG-3 is the maximum airborne concentration below which it is believed nearly all individuals could be exposed for up to 1 h without experiencing or developing life-threatening health effects.

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

bSPEGL (Short-term Public Emergency Guidance Level, National Research Council). (NRC 1985)

cSMAC (Spacecraft Maximum Allowable Concentration, National Research Council ) (Garcia and James 1996)

dSTPL (Short-Term Public Exposure Limit, National Research Council). (Shaffer and Wands 1973)

eIDLH (Immediately Dangerous to Life and Health, National Institute of Occupational Safety and Health) (NIOSH 1996) represents the maximum concentration from which one could escape within 30 min without any escape-impairing symptoms, or any irreversible health effects.

fREL-TWA (National Institute of Occupational Safety and Health, Recommended Exposure Limits-Time Weighted Average, National Institute of Occupational Safety and Health) (NIOSH 2005) is defined analogous to the-TLV-TWA, with cancer notation.

gPEL-TWA (Occupational Health and Safety Administration, Permissible Exposure Limits Time Weighted Average, Occupational Health and Safety Administration) (OSHA 2003, 29 CFR 1910.1000 [2006]) is defined analogous to the ACGIH-TLV-TWA, but is for exposures of no more than 10 h/day, 40 h/week.

hTLV-TWA (Threshold Limit Value-Time Weighted Average, American Conference of Governmental Industrial Hygienists) (ACGIH 2002) is the time-weighted average concentration for a normal 8-h workday and a 40-h workweek, to which nearly all workers may be repeatedly exposed, day after day, without adverse effect.

iMAK (Maximale Arbeitsplatzkonzentration [Maximum Workplace Concentration]) (Deutsche Forschungsgemeinschaft [German Research Association] (DFG 2002) is defined analogous to the ACGIH-TLV-TWA.

jMAC (Maximaal Aanvaarde Concentratie [Maximal Accepted Concentration] Dutch Expert Committee for Occupational Standards, The Netherlands) (MSZW 2000) is defined analogous to the ACGIH-TLV-TWA.

In lieu of definitive exposure-response data for humans, quantitative data in multiple animal species would serve to reduce the uncertainty in interspecies variability and also allow for more precise predictions regarding the toxicologic responses of humans following acute exposure to hydrazine. The use of an adequate numbers of animals in these studies would also assist in reducing the uncertainty regarding individual variability in the toxic response to hydrazine. Studies addressing toxic end points consistent with those of AEGL-1 and AEGL-2 type effects would allow for more precisely defining the thresholds for these levels.

9.
REFERENCES

ACGIH (American Conference of Governmental Hygienists). 2002. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. American Conference of Governmental Hygienists, Cincinnati, OH.

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

AIHA (American Industrial Hygiene Association). 2002. Emergency Response Planning Guidelines and Workplace Environmental Exposure Level Guides Handbook. Fairfax, VA: AIHA Press.

ATSDR (Agency for Toxic Substances and Disease Registry). 1997. Toxicological Profile for Hydrazines. U.S. Department of Health and Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry, Atlanta, GA [online]. Available: http://www.atsdr.cdc.gov/toxprofiles/tp100.pdf [accessed Nov. 5, 2008].

Becker, R.A., L.R. Barrows, and R.C. Shank. 1981. Methylation of liver DNA guanine in hydrazine hepatotoxicity: Dose-response and kinetic characteristics of 7-methylguanine and O6-methylguanine formation and persistence in rats. Carcinogenesis 2(11):1181-1188.

Brooks, S.M., M.A. Weiss, and I.L. Bernstein. 1985. Reactive airways dysfunction syndrome (RADS). Persistent asthma syndrome after high level irritant exposures. Chest 88(3):376-384.

Comstock, C.C., L.H. Lawson, E.A. Greene, and F.W. Oberst. 1954. Inhalation toxicity of hydrazine vapor. A.M.A. Arch. Ind. Hyg. Health 10(6):476-490.

Contassot, J.C., B. Saint-Loubert, R.J. Millischer, S. Cordier, and D. Hemon. 1987. Epidemiological study of cancer: Morbidity among workers exposed to hydrazine. XXII International Congress on Occupational Health, 27 September-2 October 1987, Sydney, Australia.

Couch, D.B., J.D. Gingerich, E. Stuart, and J.A. Heddle. 1986. Induction of sister chromatid exchanges in murine colonic tissue. Environ. Mutagen 8(4):579-587.

Crump, K.S., and R.B. Howe. 1984. The multistage model with a time-dependent dose pattern: Applications to carcinogenic risk assessment. Risk Anal. 4(3):163-176.

DFG (Deutsche Forschungsgemeinschaft). 2002. List of MAK and BAT Values 2002. Maximum Concentrations and Biological Tolerance Values at the Workplace Report No. 38. Weinheim, Federal Republic of Germany: Wiley VCH.

EPA (U.S. Environmental Protection Agency). 1986. Reference Values for Risk Assessment. Prepared by Environmental Criteria and Assessment Office, Cincinnati, OH, for Office of Solid Waste, U.S. Environmental Protection Agency, Washington, DC.

EPA (U.S. Environmental Protection Agency). 2002. Hydrazine/Hydrazine Sulfate (CASRN 302-01-2). Integrated Risk Information System, U.S. Environmental Protection Agency [online]. Available: http://www.epa.gov/iris/subst/0352.htm [accessed Nov. 12, 2008].

Epstein, S.S., and H. Shafner. 1968. Chemical mutagens in the human environment. Nature 219(5152):385-387.

Garcia, H.D., and J.T. James. 1996. Hydrazine. Pp. 213-233 in Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Vol. 2. Washington, DC: National Academy Press.

House, W.B. 1964. Tolerance Criteria for Continuous Inhalation Exposure to Toxic Materials. III. Effects on Animals of 90-day Exposure to Hydrazine, Unsymmetrical Dimethylhydrazine (UMDH), Decaborane, and Nitrogen Dioxide. ASD-TR-61-519 (III). Wright-Patterson Air Force Base, OH.

HRC (Huntingdon Research Centre, Ltd.). 1993. Hydrazine 64% Aqueous Solution: Acute Inhalation Toxicity in Rats 1-hour Exposure. Huntingdon Research Centre, Cambridge, England. CMA 8/930523. Chemical Manufacturers’ Association, Washington, DC.

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

Jacobson, K.H., J.H. Clem, H.J. Wheelwright, Jr., W.E. Rinehart, and N. Mayes. 1955. The acute toxicity of the vapors of some methylated hydrazine derivatives. A.M.A. Arch. Ind. Health 12(6):609-616.

Keller, W.C. 1988. Toxicity assessment of hydrazine fuels. Aviat. Space Environ. Med. 59(11 Pt 2):A100-A106.

Keller, W.C., C.T. Olson, K.C. Back, and C.L. Gaworski. 1982. Evaluation of the Embryotoxicity of Hydrazine in Rats. AFAMRL-TR-82-29, Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, OH.

Koizumi, A., T. Nomiyama, M. Tsukada, Y. Wada, K. Omae, S. Tanaka, H. Miyauchi, S. Imamiya, and H. Sakurai. 1998. Evidence on N-acetyltransferase allele-asssociated metabolism of hydrazine in Japanese workers. J. Occup. Environ. Med. 40(3):217-222.

Krop, S. 1954. Toxicology of hydrazine: A review. A.M.A. Arch. Ind. Hyg. Occup. Med. 9(3):199-204.

Kulagina, N.K. 1962. The toxicologic characteristics of hydrazine. Toxicology of new industrial chemical substances. Acad. Med. Sci. USSR 4:65-81 (as cited in Garcia and James 1996).

Latendresse, J.R., G.B. Marit, E.H. Vernot, C.C. Haun, and C.D. Flemming. 1995. Oncogenic potential of hydrazine in the nose of rats and hamsters after 1 or 10 1-hr exposures. Fundam. Appl. Toxicol. 27(1):33-48.

Leakakos, T, and R.C. Shank. 1994. Hydrazine genotoxicity in the neonatal rat. Toxicol. Appl. Pharmacol. 126(2):295-300.

Lee, S.H., and H. Aleyassine. 1970. Hydrazine toxicity in pregnant rats. Arch. Environ. Health 21(5):615-619.

Llewellyn, B.M., W.C. Keller, and C.T. Olson. 1986. Urinary Metabolites of Hydrazine in Male Fischer 344 Rats Following Inhalation or Intravenous exposure. AAMRL-TR-86-025. NTIS/AD-A170743/9. Harry G. Armstrong Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, OH.

Litchfield, J.T., and F. Wilcoxon. 1949. Simplified method of evaluating dose-effect experiments. J. Pharmacol. Exp. Ther. 96(26):99-113.

MacEwen, J.D., and E.H. Vernot. 1981. Toxic Hazards Research Unit Annual Technical Report: 1981. AFAMRL-TR-81-126. Aerospace Medical Research Laboratory, Wright Patterson Air Force Base, OH..

MacEwen, J.D., E.H. Vernot, C.C. Haun, E.R. Kinkead, and A. Hall. 1981. Chronic Inhalation Toxicity of Hydrazine: Oncogenic Effects. AFAMRL-TR-81-56. NTIS/AD-A101 847/2. Air Force Aerospace Medical Research Laboratory, Wright-Patterson AFB, OH.

Morgenstern, H., and B. Ritz. 2001. Effects of radiation and chemical exposures on cancer mortality among Rocketdyne workers: A review of three cohort studies. Occup. Med. 16(2):219-237.

MSZW (Ministerie van Sociale Zaken en Werkgelegenheid). 2000. Nationale MAC-lijst 2000. Den Haag: SDU Uitgevers.

Neft, R.E., and M.K. Conner. 1989. Induction of sister chromatid exchange in multiple murine tissue in vivo by various methylating agents. Teratogen. Carcinogen. Mutagen. 9(4):219-237.

NIOSH (National Institute of Occupational Safety and Health). 1996. Documentation for Immediately Dangerous to Life or Health Concentrations (IDLH): NIOSH Chemical Listing and Documentation of Revised IDLH Values (as of 3/1/95)-Hydrazine. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute of Occupational Safety and Health

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

[online]. Available: http://www.cdc.gov/niosh/idlh/302012.html [accessed Nov. 6, 2008].

NIOSH (National Institute of Occupational Safety and Health). 2005. NIOSH Pocket Guide to Chemical Hazards: Hydrazine. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute of Occupational Safety and Health, Cincinnati, OH. September 2005 [online]. Available: http://www.cdc.gov/niosh/npg/npgd0329.html [accessed Oct. 16, 2008].

Noda, A., M. Ishizawa, K. Ohno, T. Sendo, and H. Noda. 1986. Relationship between oxidative metabolites of hydrazine and hydrazine-induced mutagenicity. Toxicol. Lett. 31(2):131-137.

NRC (National Research Council), 1985. Hydrazine. Pp. 5-21 in Emergency and Continuous Exposure Guidance Levels for Selected Airborne Contaminants, Vol. 5. Washington, DC: National Academy Press.

NRC (National Research Council). 1986. Appendix F. EEGLS for carcinogens. Pp. 25-27 in Criteria and Methods for Preparing Emergency and Exposure Guidance Level (EEGL), Short-Term Public Emergency Guidance Level (SPEGL), and Continuous Exposure Guidance Level (CEGL) Documents. Washington, DC: National Academy Press.

NRC (National Research Council). 1993. Guidelines for Developing Community Emergency Exposure Levels for Hazardous Substances. Washington, DC: National Academy Press.

NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: National Academy Press.

O’Neil, M.J., A. Smith, P.E. Heckelman, J.R. Obenchain, Jr., J. Gallipeau, and M.A. D’Arecca. 2001. Hydrazine. Pp. 851-852 in The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals, 13th Ed. Whitehouse Station, NJ: Merck.

OSHA (Occupational Safety and Health Administration). 2003. Safety and Health Topic: Hydrazine. U.S. Department of Labor, Occupational Safety and Health Administration [online]. Available: http://www.osha.gov/dts/chemicalsampling/data/CH_245900.html [accessed Nov. 6, 2008].

Parodi, S., S. De Flora, M. Cavanna, A. Pino, L. Robbiano, C. Bennicelli, and G. Brambilla. 1981. DNA-damaging activity in vivo and bacterial mutagenicity of sixteen hydrazine derivatives as related quantitatively to their carcinogenicity. Cancer Res 41(4):1469-1482.

Preece, N.E., J.K. Nicholson, and J.A. Timbrell. 1991. Identification of novel hydrazine metabolites by 15N NMR. Biochem. Pharmacol. 41(9):1319-1324.

Raphaelian, L.A. 1963. Hydrazine and its derivatives. Pp. 762-806 in Kirk-Othmer Encyclopedia of Chemical Technology, 2nd. Ed, H.F. Mark, J.J. Mcketta, D.F. Othmer, and A. Stander, eds. New York: Interscience.

Richter, E.D., A. Gal, E. Bitchatchi, and A. Reches. 1992. Residual neurobehavioral impairment in a water technician exposed to hydrazine-containing mixtures. Isr. J. Med. Sci. 28(8-9):598-602.

Rinehart, W.E, E. Donati, and E.A. Green. 1960. The sub-acute and chronic toxicity or 1,1-dimethylhydrazine vapor. Am. Ind. Hyg. Assoc. J. 21(3):207-210.

Roe, F.J. 1978. Hydrazine. Ann. Occup. Hyg. 21(3):323-326.

Schiessl, H.W. 1985. Hydrazine and its derivates. Pp. 609-610 in Kirk-Othmer Concise Encyclopedia of Chemical Technology, H.F. Mark, D.F. Othmer, C.G. Overberger, and G.T. Seaborg, eds. New York: John Wiley and Sons.

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

Shaffer, C.B., and R.C. Wands. 1973. Guides for short-term exposure limits to hydrazines. Pp. 235-242 in Proceedings of the 4th Annual Conference on Environmental Toxicology. AMEL-TR-73-125. Aerospace Medical research laboratory, Wright-Patterson Air Force Base, OH.

Sotaniemi, E., J. Hirvonen, H. Isomaki, J. Takkunen, and J. Kaila. 1971. Hydrazine toxicity in the human. Report of a fatal case. Ann. Clin. Res. 3(1):30-33.

Sotomayor, R.E., P.S. Chauhan, and U.H. Ehling. 1982. Induction of unscheduled DNA synthesis in the germ cells of male mice after treatment with hydrazine or procabazine. Toxicology 25(2-3):201-211.

ten Berge, W.F., A. Zwart, and L.M. Appelman. 1986. Concentration-time mortality response relationship of irritant and systemically acting vapours and gases. J. Hazard. Mater. 13(3):301-309.

Timbrell, J.A. 1992. U.S. Air Force Funded Study of Hydrazine Metabolism and Toxicity. ADA245 755. Toxicology Unit, School of Pharmacy, University of London.

Timbrell, J.A., M.D. Scales, and A.J. Streeter. 1982. Studies on hydrazine hepatotoxicity. 2. Biochemical findings. J. Toxicol. Environ. Health 10(6):955-968.

USAF (U.S. Air Force). 1989. Hydrazine. Pp. 55-1 to 55-29 in The Installation Restoration Program Toxicology Guide, Vol. 4. AD-A215 002. Prepared by Biomedical and Environmental Information Analysis, Oak Ridge National Laboratory, Oak Ridge, TN, for Harry G. Armstrong Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, OH.

van Doorn, R., M. Ruijten and T. Van Harreveld. 2002. Guidance for the Application of Odor in 22 Chemical Emergency Response, Version 2.1, August 29, 2002. Public Health Service of Rotterdam, The Netherlands.

Vernot, E.H., J.D. MacEwen, R.H. Bruner, C.C. Haun, E.R. Kinkead, D.E. Prentice, A. Hall, III, R.E. Schmidt, R.L. Eason, G.B. Hubbard, and J.T. Young. 1985. Long-term inhalation toxicity of hydrazine. Fundam. Appl. Toxicol. 5(6 Pt. 1):1050-1064.

Wald, N., J. Boreham, R. Doll, and J. Bonsall. 1984. Occupational exposure to hydrazine and subsequent risk of cancer. Br. J. Ind. Med. 41(1):31-34.

Weatherby, J.H., and A.S. Yard. 1955. Observations on the subacute toxicity of hydrazine. A.M.A. Arch. Ind. Health 11(5):413-419.

Weiss G. 1980. Hazardous Chemicals Data Book. Park Ridge, NJ: Noyes Data Corp.

WHO (World Health Organization). 1987. Hydrazine. Environmental Health Criteria 68. Geneva: World Health Organization [online]. Available: http://www.inchem.org/documents/ehc/ehc/ehc68.htm [accessed Nov. 10, 2008].

Witkin, L.B. 1956. Acute toxicity of hydrazine and some of its methylated derivatives. A.M.A. Arch. Ind. Health 13(1):34-36.

Wright, J.M., and J.A. Timbrell. 1978. Factors affecting the metabolism of 14C-acetylhydrazine in rats. Drug Metab. Disp. 6(5):561-566.

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

APPENDIX A
Derivation of AEGL Values

Derivation of AEGL-1

Key Study:

House (1964). Monkeys exposed continuously by inhalation to 0.4 ppm (0.52 mg/m3) exhibited flushing of the face and eye irritation.

Uncertainty factors:

3 for interspecies variability (the highly reactive hydrazine appears to be equally irritating to all species); 3 represents the geometric mean of 10 (3.16)

 

3 for intraspecies variability (the contact irritation due to the extreme reactivity of hydrazine is not likely to vary among individuals); 3 represents the geometric mean of 10

Total uncertainty factor adjustment:

3.16 × 3.16 = 10

Time scaling:

C3 × t = k (ten Berge et al. 1986)

Calculations:

0.4 ppm/10 = 0.04 ppm

C3 × t = k

(0.04 ppm)3 × 1440 min = 0.09216 ppm3-min

10-min AEGL-1

(0.04 ppm)3 × 1440 min = 0.09216 ppm3-min

C3 × 10 min = 0.09216 ppm3-min

C = 0.21 ppm

30-min AEGL-1

(0.04 ppm)3 × 1440 min = 0.09216 ppm3-min

C3 × 30 min = 0.09216 ppm3-min

C = 0.15 ppm

1-h AEGL-1

(0.04 ppm)3 × 1440 min = 0.09216 ppm3-min

C3 × 60 min = 0.09216 ppm3-min

C = 0.12 ppm

4-h AEGL-1

(0.04 ppm)3 × 1440 min = 0.09216 ppm3-min

C3 × 240 min = 0.09216 ppm3-min

C = 0.07 ppm

8-h AEGL-1

(0.04 ppm)3 × 1440 min = 0.09216 ppm3-min

C3 × 480 min = 0.09216 ppm3-min

C = 0.06 ppm

Note: The above represents the basis for the initial AEGL-1 derivations. Because of the extreme reactivity of hydrazine and its great capacity as a direct-contact irritant, 0.1 ppm was adopted as the AEGL-1 for all time periods (the calculated values for 30 min, 1 h, 4 h, and 8 h are all approximately 0.1 ppm).

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Derivation of AEGL-2

Key Study:

Latendresse et al. (1995). Rats exposed for 1 h to 750 ppm hydrazine exhibited nasal lesions. The lesions were reversible following cessation of exposure. Compared to unexposed controls, there was no significant increase in lethality in males exposed to a single 1-h exposure to 750 ppm or following 10 weekly 1-h exposures. Although a significant increased mortality (p > 0.05) was observed in female rats at 30 months, there was no increased lethality at 14.5 months following the single 1-h exposure. Furthermore, there were no deaths in rats following 10 consecutive weekly 1-h exposures. There was no significant difference in mortality of similarly exposed male and female hamsters at any time point. Therefore, the 750 ppm exposure represents an exposure that will result in notable irritation and histopathological changes.

Uncertainty factors:

3 for interspecies variability; available data disallow a definitive assessment of species variability although the direct-contact reactivity of hydrazine would limit dosimetric variability.

 

3 for intraspecies variability; available data (clinical signs and histopathologic correlates) indicate that hydrazine toxicity is a port-of-entry toxicant and acts by direct-contact mechanisms due to the extreme reactivity of hydrazine. The irritation and resulting tissue damage are not likely to vary among individuals. Additionally, variability in acetylation phenotypes among humans reportedly varies by approximately 2-fold thereby implying minimal variability in this aspect of hydrazine metabolism.

Modifying factor:

2 for data inadequacies; definitive exposure-response data specific to AEGL-2 level effects are unavailable for inhalation exposure.

 

An additional modifying factor of 3 has been applied to account for the uncertainties in the measurement of exposure concentrations in earlier studies. While not an issue for recent studies such as Latendresse et al. (1995) and HRC (1993), this deficiency compromises the incorporation of older data into assessing species variability.

Time scaling:

Cn × t = k; data were unavailable for empirical derivation of a scaling factor. The concentration-exposure time relationship for many irritant and systemically acting vapors and gases may described by Cn × t = k, where the exponent n ranges from 0.8 to 3.5. In the absence of chemical-specific data, temporal scaling was performed using n = 3 when extrapolating to shorter time points and n = 1 when extrapolating to longer time points using the Cn × t = k equation.

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

Calculations:

750 ppm/60 = 12.5 ppm

C3 × t = k

(12.5 ppm)3 × 60 min = 117188 ppm3-min

 

C1 × t = k

(12.5 ppm)1 × 60 min = 750 ppm-min

10-min AEGL-2

C3 × 10 min = 117188 ppm3-min

C = 23 ppm

30-min AEGL-2

C3 × 30 min = 117188 ppm3-min

C = 16 ppm

1-h AEGL-2

C = 12.5 ppm (rounded to 13 ppm)

4-h AEGL-2

C1 × 240 min = 750 ppm1-min

C = 3.1 ppm

8-h AEGL-2

C1 × 480 min = 750 ppm1-min

C = 1.6 ppm

Derivation of AEGL-3

Key Study:

HRC 1993. Lethality in rats following 1-h nose-only inhalation exposure. A 3-fold reduction in the reported LC50 of 4.2 mg/L (3,192 ppm) is used as an estimate of the lethality threshold (3,192 ppm/3 = 1,064 ppm). The rat data from the recent Latendresse et al. (1995) study indicated that this exposure would not be lethal to rats exposed for 1 h. The steep exposure-response curve for hydrazine also suggests derivation of an LC0 1(3,192 ppm) derived by a Litchfield and Wilcoxon analysis may represent an exposure below the lethality threshold. Data from recent studies such as the HRC (1993) report and Latendresse et al. (1995) are also more reliable than older studies due to improved analytical techniques (older studies likely underestimated hydrazine concentrations due to its extreme reactivity).

Uncertainty factors:

3 for interspecies variability; the extreme reactivity of hydrazine resulted in compromised and variable exposure concentration data; the order-of-magnitude adjustment is considered adequate for to account for dosimetry differences among species.

 

3 for intraspecies variability; available data (clinical signs and histopathologic correlates) indicate that hydrazine toxicity is a port-of-entry toxicant and acts by direct-contact mechanisms that are not likely to vary by an order of magnitude across species.

Modifying factor:

3 for inadequacies regarding measurement of exposure concentrations in earlier studies which compromise a definitive assessment of species variability.

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

Time scaling:

Cn × t = k ; data were unavailable for empirical derivation of a scaling factor. The concentration-exposure time relationship for many irritant and systemically acting vapors and gases may described by Cn × t = k, where the exponent n ranges from 0.8 to 3.5. In the absence of chemical-specific data, temporal scaling was performed using n = 3 when extrapolating to shorter time points and n = 1 when extrapolating to longer time points using the Cn × t = k equation.

Calculations:

1064 ppm/30 = 35.5 ppm

C3 × t = k

(35.5 ppm)3 × 60 min = 2684333 ppm3-min

 

C1 × t = k

(35.5 ppm)1 × 60 min = 2130 ppm-min

10-min AEGL-3

C3 × 10 min = 2684333 ppm3-min

C = 64 ppm

30-min AEGL-3

C3 × 30 min = 2684333 ppm3-min

C = 45 ppm

1-h AEGL-3

C = 35 ppm

4-h AEGL-3

C1 × 240 min = 2130 ppm-min

C = 8.9 ppm

8-h AEGL-3

C1 × 480 min = 2130 ppm-min

C = 4.4 ppm

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

APPENDIX B
Carcinogenicity Assessment for Hydrazine AEGLs

Key Study:

Vernot et al. 1985

Administered Dose (ppm)

Human Equivalent Dosea (mg/kg/day)

Tumor Incidenceb

0

0

0/146

0.05

0.0009

2/96

0.25

0.004

1/94

1.0

0.017

9/97

5.0

0.084

58/98

aTransformed animal dose (TAD) converted to human equivalent dose (HED): TAD × 20 m3/day × 1/70 kg.HED entered into GLOBAL86; unit risk converted back to mg/m3.

bNasal adenomatous polyps, male rats (female rats and hamsters exhibited lower but statistically significant incidences [p≤0.01] as well).

The cancer assessment for acute inhalation exposure to hydrazine was conducted following the NRC methodology for EEGLs, SPEGLs and CEGLs (NRC 1986). The value derived from the animal data and GLOBAL86 was divided by 2.4 to adjust for dose and study duration ([24 mos/18 mos]3 = 2.4). This adjustment accounts for the proportional effect of age on the tumorigenic response and provides the following VSD:

Adjustment to allow for uncertainties in assessing potential cancer risks under short term exposures under the multistage model [Crump and Howe 1984]):

If the exposure is limited to a fraction (f) of a 24-h period, the fractional exposure becomes 1/f × 24 h (NRC 1985). For a 1 × 10−4 risk:

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

Because the derivation of the cancer slope factor requires conversion of animal doses to human equivalent doses, no reduction of exposure levels is applied to account for interspecies variability. For 10−5 and 10−6 risk levels, the 10−4 values are reduced by 10-fold or 100-fold, respectively.

Because long-term inhalation exposure to hydrazine has been shown to be tumorigenic in several species, a cancer assessment was also performed (Appendix B). Following the methods of NRC (1986), AEGL-2 values were derived based on two available data sets. Both data sets identified nasal tumors in rats following 1-year inhalation exposure to hydrazine. Although data from the animal studies affirm the carcinogenic potential of hydrazine following inhalation exposure, the observed tumorigenic responses appear to be a function of prolonged tissue irritation resulting from long-term repeated exposures and are unlikely to occur following a single low exposure. This was especially evident in the study by Latendresse et al.(1995) that showed repeated exposures were necessary for reversible histopathologic changes in rat nasal epithelium. This contention is also supported by the work of Leakakos and Shank (1994) that showed DNA methylation (presumably a requirement for oral and parenteral hydrazine-induced liver cancer in rodents) was detectable only when the dose of hydrazine was necrogenic. Therefore, it would appear that hydrazine AEGL values that address rare, or single once-in-a-lifetime exposures should not be based upon cancer risk.

Key Study:

MacEwen et al. (1981) significant increased tumor incidence in mice (pulmonary adenomas), rats (nasal adenomas, adenocarcinomas), and hamsters (nasal cavity polyps) exposed to highest concentration. Exposure protocol: male and female rats exposed to hydrazine at 0, 0.05, 0.25, 1.0, or 5.0 ppm, 6 h/day, 5 days/week for one year; 12- to 38-month postexposure observation.

The cancer assessment for acute inhalation exposure to hydrazine was conducted following the NRC methodology for EEGLs, SPEGLs and CEGLs (NRC 1986).


Virtually safe dose (VSD) exposure level (d) of 2 × 10−4 ug /m3 (2 × 107 mg/m3) for a 1 × 10−6 risk level for hydrazine was selected (EPA 2002). This risk level was based upon an inhalation unit risk of 4.9 × 10−3 per ug /m3 derived from the MacEwen et al. (1981) data using the linearized multistage procedure.

Assuming the carcinogenic effect to be a linear function of cumulative dose, a single-day exposure is equivalent to d × 25,600 days (average lifetime).

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

Adjustment to allow for uncertainties in assessing potential cancer risks under short term exposures under the multistage model [Crump and Howe 1984]).

For a 1 × 10−4 risk, the extent of risk based on the 24-h exposure concentration becomes:

If the exposure is limited to a fraction (f) of a 24-h period, the fractional exposure becomes 1/f × 24 h (NRC 1985). For a 1 × 10−4 risk:

Because the derivation of the cancer slope factor requires conversion of animal doses to human equivalent doses, no reduction of exposure levels is applied to account for interspecies variability. For 10−5 and 10−6 risk levels, the 10−4 values are reduced by 10-fold or 100-fold, respectively.

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

APPENDIX C
Derivation Summary for Hydrazine AEGLs
DERIVATION SUMMARY

AEGL-1 VALUES

10 min

30 min

1 h

4 h

8 h

0.1 ppm

0.1 ppm

0.1 ppm

0.1 ppm

0.1 ppm

Key Reference: House, W.B. 1964. Tolerance Criteria for Continuous Inhalation Exposure to Toxic Materials. III. Effects on Animals of 90-day Exposure to Hydrazine, Unsymmetrical Dimethylhydrazine (UMDH), Decaborane, and Nitrogen Dioxide. ASD-TR-61-519 (III). Wright-Patterson Air Force Base, OH.

Test Species/Strain/Number: 10 male rhesus monkeys.

Exposure Route/Concentrations/Durations:

Inhalation: average of 0.78 ppm (range: 0.25-1.38 ppm) continuous (24 h/day, 7 days/week) exposure for 90 days; 0.4 ppm for first 10 days (determinant for AEGL-1)

Effects: Eye and facial irritation within 24 h.

End Point/Concentration/Rationale:

0.4 ppm for the first 24 h resulted in mild irritation which is a defined AEGL-1 end point.

Uncertainty Factors/Rationale:

Total uncertainty factor: 10

Interspecies: 3: Contact irritation is not likely to vary greatly among species because hydrazine is a highly reactive and direct acting irritant. Also, a nonhuman primate was the test species.

Intraspecies: 3: Hydrazine will be extremely reactive with all biological tissues resulting in irritation and reversible tissue damage upon contact. This process, especially for port-of-entry effects, is not expected to differ greatly among individuals.

Modifying Factor: Not applicable.

Animal to Human Dosimetric Adjustment: Not applied; insufficient data.

Time Scaling: Cn × t = k where n = 3 to scale from 24-h exposure to 4-h and 8-h exposure periods. Due to the extreme reactivity of hydrazine, however, the contact irritant effects were considered to be concentration dependent and, therefore, the 0.1 ppm concentration derived for the 4-h and 8-h periods was applied for all time periods.

Data Adequacy:

Quantitative data pertaining to AEGL-1 type effects are limited. The data provided by House (1964) for nonhuman primates, however, are consistent with the human experience regarding the irritant effects of low level hydrazine exposure.

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

AEGL-2 VALUES

10 min

30 min

1 h

4 h

8 h

23 ppm

16 ppm

13 ppm

3.1 ppm

1.6 ppm

Reference: Latendresse, J.R., G.B. Marit, E.H. Vernot, C.C. Haun, and C.D. Flemming. 1995. Oncogenic potential of hydrazine in the nose of rats and hamsters after 1 or 10 1-h exposures. Fundam. Appl. Toxicol. 27(1): 33-48.

Test Species/Strain/Sex/Number:

5 male and 5 female Fischer-344 rats and 10 Syrian golden hamsters, 10/exposure group.

Exposure Route/Concentrations/Durations: Inhalation: 750 ppm for 1 h.

Effects:

Exposure Effect:

750 ppm for 1 h Nasal lesions (minimal necrosis, mild to moderate exfoliation, minimal to moderate acute inflammation, mild apoptosis; determinant for AEGL-2).

End Point/Concentration/Rationale:

750 ppm for 1 h resulted in nasal lesions (minimal necrosis, mild to moderate exfoliation, minimal to moderate acute inflammation, mild apoptosis) that were considered to be an estimate of a threshold for an AEGL-2 effect.

Uncertainty Factors/Rationale:

Total uncertainty factor: 10

Interspecies:

3: An uncertainty factor of 3 for interspecies variability was applied to account for possible species-dependent uncertainties in the toxic response to inhaled hydrazine.

Intraspecies:

3: Hydrazine is extremely reactive with all biological tissues resulting in irritation and tissue damage upon contact. This process, especially for port-of-entry effects, is not expected to differ greatly among individuals. Additionally, variability in acetylation phenotypes among humans and the subsequent effect on at least one aspect of hydrazine metabolism has been shown to vary approximately 2-fold.

Modifying Factor: 2 for inadequacies in the database pertaining to AEGL-2 effects 3 for the uncertainties in the measurement of exposure concentrations in earlier studies. While not an issue for recent studies such as Latendresse et al. (1995) and HRC (1993), this deficiency compromises the use of older data for assessing species variability.

Animal to Human Dosimetric Adjustment: Insufficient data

Time Scaling:

Cn × t = k where n = 1 or 3 (k = 117188 ppm3-min when n = 3 and k = 750 ppm-min when n = 1); The concentration exposure time relationship for many irritant and systemically acting vapors and gases may be described by Cn × t = k, where the exponent, n, ranges from 0.8 to 3.5 (ten Berge et al. 1986). Temporal scaling was performed using n = 3 when extrapolating to shorter exposure durations points and n = 1 when extrapolating to longer time points using the Cn × t = k equation.

Data Adequacy:

Although the toxicity end points selected for AEGL-2 derivation are not consistent with an effect severity consistent with the AEGL-2 definition, they are consistent with the continuum of effects known to occur as a result of hydrazine exposures that could result in more serious responses. Because of the know toxicity of hydrazine and its carcinogenic potential, the somewhat conservative approach was justified. Species variability is poorly defined due primarily to data deficiencies.

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

AEGL-3 VALUES

10 min

30 min

1 h

4 h

8 h

64 ppm

45 ppm

35 ppm

8.9 ppm

4.4 ppm

Key Reference: Huntingdon Research Centre 1993. Hydrazine 64% Aqueous Solution: Acute Inhalation Toxicity in Rats 1-h Exposure. Huntingdon Research Centre, Cambridge, England. CMA 8/930523. Chemical Manufacturers’ Association, Washington, DC.

Test Species/Strain/Sex/Number: Male and female Sprague-Dawley rats, 5/sex/group.

Exposure Route/Concentrations/Durations:

Inhalation: 0, 0.65, 2.04, 3.24, 4.9 mg/L for 1 h (nose-only exposure to 64% aerosol)

Effects

 

Concentration

Mortality

2.04 mg/L (1556 ppm)

0/10

3.24 mg/L (2472 ppm)

4/10

4.98 mg/L (6596 ppm

6/1

Reported LC50: 4959 ppm (64% aerosol); 3192 ppm (hydrazine alone)

End Point/Concentration/Rationale:

When compared to the data from Latendresse et al. (1995), where rats survived multiple 1-h exposures to 750 ppm, the calculated 1-h LC01 of 334 ppm appeared to be unrealistically low and not scientifically defensible as an estimated lethality threshold. Therefore, a three-fold reduction in the 1-h LC50 (3192 ppm/3 = 1064 ppm) was determined to be an estimate of the lethality threshold for a 1-h exposure duration that is consistent with the currently available data.

Uncertainty Factors/Rationale:

Total uncertainty factor: 30

Interspecies:

3-An uncertainty factor of 3 for interspecies variability was applied to account for possible species-dependent uncertainties in the toxic response to inhaled hydrazine.

Intraspecies:

3-Hydrazine will be extremely reactive with all biological tissues resulting in irritation and severe tissue damage at high concentrations upon contact. This process, especially for port-of-entry effects, is not expected to differ greatly among individuals.

Modifying Factor: 3 for inadequacies regarding measurement of exposure concentrations in earlier studies which compromise a definitive assessment of species variability

Animal to Human Dosimetric Adjustment: Insufficient data

Time Scaling: Cn × t = k where n = 1 or 3 (k=2684333 ppm3-min when n = 3 and k = 2130 ppm-min when n = 1); The concentration exposure time relationship for many irritant and systemically acting vapors and gases may be described by Cn × t = k, where the exponent, n, ranges from 0.8 to 3.5 (ten Berge et al. 1986). Temporal scaling was performed using n = 3 when extrapolating to shorter time points and n = 1 when extrapolating to longer time points using the Cn × t = k equation.

Data Adequacy:

Lethality data are available for several animal species. Lethality values quantitatively derived from a recent study were considered appropriate as the basis for AEGL-3 derivation. Species variability is poorly defined.

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

APPENDIX D
Category Plot for Hydrazine AEGLs

FIGURE D 1 Category plot for hydrazine.

FIGURE D 1 Category plot for hydrazine.

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

APPENDIX E
Level of Distinct Odor Awareness (LOA) for Hydrazine
DERIVATION OF THE LOA: HYDRAZINE

The level of distinct odor awareness (LOA) represents the concentration above which it is predicted that more than half of the exposed population will experience at least a distinct odor intensity, about 10 % of the population will experience a strong odor intensity. The LOA should help chemical emergency planners and responders in assessing the public awareness of the exposure due to odor perception. The LOA derivation follows the guidance given by van Doorn et al. (2002).

The odor detection threshold (OT50) for hydrazine was calculated to be 4 ppm (van Doorn et al. 2002).

The concentration (C) leading to an odor intensity (I) of distinct odor detection (I = 3) is derived using the Fechner function:

For the Fechner coefficient, the default of kw = 2.33 will be used due to the lack of chemical-specific data:

The resulting concentration is multiplied by an empirical field correction factor. It takes into account that in every day life factors, such as sex, age, sleep, smoking, upper airway infections and allergy as well as distraction, increase the odor detection threshold by a factor of 4. In addition, it takes into account that odor perception is very fast (about 5 seconds) which leads to the perception of concentration peaks. Based on the current knowledge, a factor of 1/3 is applied to adjust for peak exposure. Adjustment for distraction and peak exposure lead to a correction factor of 4 / 3 = 1.33.

The LOA for hydrazine is 63 ppm.

Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 274
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 275
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 276
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 277
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 278
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 279
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 280
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 281
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 282
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 283
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 284
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 285
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 286
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 287
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 288
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 289
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 290
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 291
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 292
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 293
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 294
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 295
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 296
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 297
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 298
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 299
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 300
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 301
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 302
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 303
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 304
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 305
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 306
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 307
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 308
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 309
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 310
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 311
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 312
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 313
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 314
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 315
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 316
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 317
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 318
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 319
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 320
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 321
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 322
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 323
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 324
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 325
Suggested Citation:"6 Hydrazine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Page 326
Next: 7 Peracetic Acid »
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8 Get This Book
×
Buy Paperback | $90.00 Buy Ebook | $69.99
MyNAP members save 10% online.
Login or Register to save!
Download Free PDF

This book is the eighth volume in the series Acute Exposure Guideline Levels for Selected Airborne Chemicals, and reviews AEGLs for acrolein, carbon monoxide, 1,2-dichloroethene, ethylenimine, fluorine, hydrazine, peracetic acid, propylenimine, and sulfur dioxide for scientific accuracy, completeness, and consistency with the NRC guideline reports.

  1. ×

    Welcome to OpenBook!

    You're looking at OpenBook, NAP.edu's online reading room since 1999. Based on feedback from you, our users, we've made some improvements that make it easier than ever to read thousands of publications on our website.

    Do you want to take a quick tour of the OpenBook's features?

    No Thanks Take a Tour »
  2. ×

    Show this book's table of contents, where you can jump to any chapter by name.

    « Back Next »
  3. ×

    ...or use these buttons to go back to the previous chapter or skip to the next one.

    « Back Next »
  4. ×

    Jump up to the previous page or down to the next one. Also, you can type in a page number and press Enter to go directly to that page in the book.

    « Back Next »
  5. ×

    Switch between the Original Pages, where you can read the report as it appeared in print, and Text Pages for the web version, where you can highlight and search the text.

    « Back Next »
  6. ×

    To search the entire text of this book, type in your search term here and press Enter.

    « Back Next »
  7. ×

    Share a link to this book page on your preferred social network or via email.

    « Back Next »
  8. ×

    View our suggested citation for this chapter.

    « Back Next »
  9. ×

    Ready to take your reading offline? Click here to buy this book in print or download it as a free PDF, if available.

    « Back Next »
Stay Connected!