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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).
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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-
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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-
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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.
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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
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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.
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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
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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.
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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
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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
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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
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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.
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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.
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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
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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:
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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 × 10−7 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).
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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.
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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.
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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.
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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.
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APPENDIX D
Category Plot for Hydrazine AEGLs
FIGURE D 1 Category plot for hydrazine.
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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.