Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 2 (1996)

Hector D. Garcia, Ph.D., and John T. James, Ph.D.

Johnson Space Center Toxicology Group

Biomedical Operations and Research Branch

Houston, Texas

Hydrazine is a clear, colorless, fuming, oily, hygroscopic, highly polar, flammable liquid with an ammonia-like odor or an extremely irritating gas that is readily adsorbed or condensed onto surfaces and has a high affinity for water (Sevin, 1978).

Hydrazine occurs naturally as a product of nitrogen fixation by Azotobacter agile. It has been identified in tobacco grown without the use of maleic hydrazide (Sevin, 1978). Essentially all commercially used hydrazine is chemically synthesized, usually by one of several processes involving chemical oxidation of ammonia.

Hydrazine is used commercially as a polymerization catalyst, a blowing agent, a reducing agent, and an oxygen scavenger in boiler-water treatment; it is also used commerically in the synthesis of maleic hydrazide and in the manufacture of drugs. In combination with water, it is used in the F-16 aircraft emergency power unit as a source of gas to drive a turbine. The hydrazine bases are used in the production of salts and hydrazones that are used in surfactants, detergents, plasticizers, pharmaceuticals, insecticides, and herbicides (Sevin, 1978).

Hydrazine is used as a rocket propellant and for the auxiliary power unit on the space-shuttle orbiters. Hydrazine might be used on the international space station. It is theoretically possible for a small amount (up to a few grams) to be introduced into the spacecraft atmosphere in the unlikely scenario that, during an extravehicular activity, a cre w member is in the vicinity of an undetected leak leak of a substantial amount of hydrazine, which is deposited unnoticed on the surface of the spacesuit and then is vaporized from the suit after the crew member reenters the spacecraft. During missions in which hydrazine contamination of the airlock is a risk, a real-time chemical monitor using ion-mobility spectrometry has been flown to ensure that unsafe concentrations of propellants, including hydrazine, are not present before the spacecraft is re-entered (Eiceman et al., 1993).

Hydrazine was detectable in the plasma of anesthetized dogs within 30 s after applying concentrated hydrazine solutions to their intact skin (Smith and Clark, 1972). No data were found in the literature on the absorption of hydrazine by inhalation or ingestion.

Hydrazine was distributed rapidly (2 h) to most tissues in mice given single intraperitoneal (i.p.) doses of hydrazine sulfate at 1 mmole/kg of body weight and in rats given 60 mg/kg; the highest concentrations appeared in the kidneys (Dambrauskas and Cornish, 1964).

Anesthetized dogs administered hydrazine sulfate intravenously (i.v.) at a concentration of 50 mg/kg excreted 5-11% as hydrazino nitrogen in the urine within 4 h. Unanesthetized dogs administered hydrazine sulfate i.v. at 15 mg/kg excreted 50% as hydrazino nitrogen within 2 d. Rats given subcutaneous (s.c.) injections of hydrazine at 60 mg/kg excreted it unchanged at the rate of 8% after 2 h, 20% after 20 h, and 50% after 40 h.

Hydrazine injected i.p. into rabbits was shown to undergo a two-step acetylation. Using ¹⁵N-labeled hydrazine to study the metabolic fate of hydrazine in Sprague-Dawley rats, Springer et al. (1981) found that within 48 h, 25% was exhaled as N₂ gas, 30% appeared in the urine as hydrazine, and 20% appeared as a derivative that was acid hydrolyzable to hydrazine. The disappearance of hydrazine from the blood was biphasic, with half-times of 0.74 and 26.9 h.

Hydrazine vapor is extremely irritating to the eyes, nose, and throat. Quantitative information on worker exposure, however, can only be estimated from the existing published data (Santodonato et al., 1985). The median concentration of hydrazine detectable by odor is 3-4 ppm (Jacobson et al., 1955). Inhalation can cause dizziness, anorexia (MacEwen et al., 1974), and nausea. Hydrazine can be absorbed dermally

(Smith and Clark, 1972) or orally and can induce contact dermatitis (Evans, 1958; van Ketel, 1964; Høvding, 1967), neurological impairment (Kulagina, 1962; Reid, 1965), and kidney, lung, and liver damage at an i.p. dose of 20 mg/kg for 3 d in rodents (Scales and Timbrell, 1982). Hydrazine is fetotoxic in rats and mice at i.p. doses of 5 mg/kg and is teratogenic in mice at 12 mg/kg.

The summary of the toxic effects of hydrazine given below applies also to the salts of hydrazine, such as sulfate and hydrochloride, because they differ in toxicity from the free base only when the development of toxicity is related to differences in pH, solubility, volatility, or mass (in expression of doses) (Sevin, 1978).

The LD₅₀ for hydrazine injected i.p. into rats is 80-100 mg/kg of body weight. Rats administered 200 mg/kg went into convulsions within 5 min and died within 3 h of dosing (Scales and Timbrell, 1982). A 2-h exposure to hydrazine vapors at a concentration of 1.0-2.0 mg/L (7600-15,200 ppm) has been reported to induce convulsions, respiratory arrest, and death in mice and rats (Kulagina, 1962). The toxicity of multiple lower doses was cumulative, but surviving animals recovered and lived normal life spans if exposure was discontinued. The LC₅₀ for a 4-h exposure to hydrazine is 750 mg/m³ (570 ppm) for rats and 330 mg/m³ (250 ppm) for mice (Jacobson et al., 1955). Continuous inhalation exposure to hydrazine at 0.8 ppm was highly lethal to mice within 1-4 w (House, 1964).

Rats given i.p. injections of hydrazine at 20 mg/kg exhibited vacuolization of liver cells within 24 h of exposure, and those given 10 mg/kg showed no histopathology (Scales and Timbrell, 1982), but they did show increases in triglyceride levels (Timbrell et al., 1982). Those given hydrazine at 60 mg/kg exhibited ultrastructural changes in liver

cells 30 min after exposure (Scales and Timbrell, 1982). Methylation of liver DNA has been shown in rats given oral doses of hydrazine at 30-90 mg/kg (Becker et al., 1981).

Continuous inhalation exposure to hydrazine at 0.8 ppm was highly lethal to rats within 7-10 w and moderately lethal (20%) to monkeys within 3-13 w (House, 1964). Dogs, rats, mice, and guinea pigs exposed at 14 ppm for 6 h/d, 5d/w, for up to 6 mo showed varying mortalities, mice being the most sensitive species (Comstock et al., 1954). Rats that survived the exposures were found to have completely recovered with no observable pathology about 6 mo after the last day of exposure (Comstock et al., 1954).

There are a few literature reports of accidental human exposures to high, but unspecified, doses of hydrazine. In one case, a man drank between a swallow and half a cup of liquid hydrazine, which induced vomiting and unconsciousness, followed in a few hours by violent behavior and in a few days by ataxia, nystagmus, and paraesthesia (Roe, 1978). No followup report was found. Another case involving 6 mo of occupational contact exposure once a week to hydrazine by a machinist culminated in conjunctivitis, tremor, cough, fever, vomiting, diarrhea, and death (Sotaniemi et al., 1971). There were no deaths due to acute exposure to hydrazine vapor at a hydrazine factory among all 78 workers exposed for at least 6 mo at an estimated 1-10 ppm (54 of them were exposed for over 2 y) (Wald et al., 1984).

Fatty changes in the liver have been reported in rats, mice, dogs, and monkeys exposed by inhalation at 0.8 ppm for 90 d (Weatherby and Yard, 1955; House, 1964). Prominent fat vacuoles and pigmentation of liver Kupffer cells were reported in dogs exposed at 14 ppm, for 6 h/d, 5 d/w, for 39 w (Comstock et al., 1954). Exposure at 1 ppm for 6

h/d, 5 d/w, for 1 y produced no hepatotoxicity in mice and male rats but did cause a statistically significant increase (to 60% from an incidence of »40%) in focal liver-cell hyperplasia in female rats (MacEwen et al., 1981). ''Fatty livers'' were induced in rats given hydrazine orally (Weatherby and Yard, 1955).

There are conflicting reports on the carcinogenicity of hydrazine. The National Institute of Environmental Health Sciences finds that there is sufficient evidence for the carcinogenicity of hydrazine in experimental animals but inadequate evidence for its carcinogenicity in humans (NTP, 1989). Inhaled hydrazine has been reported to induce alveolargenic carcinomas in three of eight mice exposed at 0.2 ppm (MacEwen et al., 1974), malignant nasal tumors in 6 of 99 male rats and 5 of 98 female rats exposed at 5 ppm (MacEwen et al., 1981), and benign nasal polyps in 16 of 160 hamsters exposed at 5 ppm (Carter et al., 1981). Unequivocally toxic doses (up to 50 mg/L), however, administered in drinking water for the lifetime of rats were only weakly carcinogenic (Steinhoff and Mohr, 1988). In male rats (the most sensitive species and sex) exposed by inhalation, tumors, which were predominantly benign, occurred only late in life in animals showing many other chronic toxic effects, including a greatly increased inflammatory response of the upper airways (Carter et al., 1981).

The epidemiological data available on hydrazine-related cancers in humans (Karstadt and Bobal, 1982) indicates no excess risk of cancer in workers occupationally exposed to hydrazine vapors, but the number of workers having substantial exposure has been too few to detect anything other than gross carcinogenic hazards (Roe, 1978; Wald et al., 1984). A NASA-sponsored followup study of the Wald cohort of occupationally exposed workers failed to show any increase in cancer-induced mortality 20 y after exposures ended (Morris et al., 1995).

Hydrazine has been reported to be mutagenic in several test systems

(Jain and Shukla, 1972; Herbold and Buselmaier, 1976; Kimball, 1977), including the Escherichia coli and Ames Salmonella (+S9) assays, the Drosophila-melanogaster-specific locus test, and L5178Y cultured mouse lymphoma cells. Hydrazine induces sister chromatid exchanges in vitro (MacRae and Stich, 1979). Hydrazine has been shown to saturate the 5,6 double bond and degrade the pyrimidine bases in DNA. DNA from the livers of hydrazine-exposed rats, but not control rats, has been demonstrated to have methylated guanine bases.

Hydrazine induces abnormally shaped spermatocytes in treated male mice (Wyrobek and London, 1973). In the mouse dominant lethal test, hydrazine did not induce early fetal deaths or preimplantation losses at single i.p. doses of 42 mg/kg or 52 mg/kg.

No information was found on the effects of hydrazine exposure on developing embryos.

No reports of toxicologically relevant interactions with other chemicals were found.

Hydrazine induces a variety of toxic effects including irritation of the eyes, nose, and throat, contact dermatitis, and, at higher concentrations, dizziness, anorexia, nausea, vomiting, cough, fever, diarrhea, temporary blindness, hepatotoxicity, tremors, hyperexcitability, convulsions, and death. Prolonged exposures to relatively low concentrations have been reported to induce hepatotoxicity and carcinogenicity (Comstock et al., 1954; House, 1964; Haun and Kinkead, 1973; MacEwen et al., 1974; Carter et al., 1980; MacEwen et al., 1981; Vernot et al., 1985). Of these end points, quantitative data are available only for hepatotoxicity, carcinogenicity, and lethality. SMACs were determined following the guidelines of the National Research Council for exposure durations

of 1 h, 24 h, 7 d, 30 d, and 180 d by establishing acceptable concentrations (ACs) for each adverse effect at each exposure duration and selecting the lowest AC at each exposure duration to be the SMAC (NRC, 1992).

Liver effects induced by inhalation of airborne hydrazine include fatty changes in the liver in several species after 90 d of continuous exposure at 0.8 ppm (House, 1964). In calculating an AC, these data were used rather than data on hyperplasia because the fatty changes were seen at a much earlier time for similar concentrations of hydrazine.

AC values for liver toxicity were calculated for 180-d and 30-d exposures by using Haber's rule on data for fatty changes induced in 7 of 10 monkeys exposed continuously at 0.8 ppm for 90 d (also seen in 2 of 10 control monkeys). An uncertainty factor of 10 was applied for extrapolation from animals to humans, and another factor of 10 was applied for extrapolation from an effect level to a no effect level. The use of Haber's rule to extrapolate from a 90-d exposure to exposure durations of 7 d or less (i.e., ≤12-fold extrapolation) was deemed inappropriate.

An AC for a 24-h exposure can be derived from the data of Timbrell et al. (1982), which showed that an i.p. dose of 10 mg/kg in rats induced the lowest-observed-adverse-effect level (LOAEL) for increased liver triglycerides when examined 24 h after dosing. For a 70-kg man inhaling 20 m³/d, assuming 100% absorption, one can convert from an i.p. dose to an equivalent inhalation dose and derive a 24-h AC as follows:

An AC for a 7-d exposure can be calculated from the 24-h AC by using Haber's rule. Thus,

Liver effects induced by inhalation of hydrazine include a significant increase in the incidence of focal-liver-cell hyperplasia in female rats (but not in male rats, mice, hamsters, or dogs) exposed at 1 ppm or 5 ppm for 6 h/d, 5 d/w, for 1 y (Vernot et al., 1985). (Hyperplasia occurred in 58 of 97 exposed female rats compared with 57 of 147 controls.) Female rats exposed at 0.25 ppm under the same conditions had no significant increase in focal-liver-cell hyperplasia (36 of 100). Thus, 0.25 ppm is a NOAEL for focal-liver-cell hyperplasia for an exposure of 1560 h or 65 d. ACs can be calculated for 30 d and 180 d by using a factor of 10 for species differences and Haber's rule for extrapolating from 65 d to 180 d. The concentration is not increased for extrapolating from 65 d to 30 d:

Hydrazine has been found to be carcinogenic in animal model systems (MacEwen et al., 1981; Carter et al., 1981; Vernot et al., 1985). The oncogenic changes were mostly benign and observable only at the microscopic level, producing little or no impairment of respiratory function and no effect on life expectancy. The nononcogenic toxicities of hydrazine exposure in animals were more severe in producing debilitation and lethal effects. There are, moreover, no known reports of hydrazine-induced human tumors. Most human exposures to hydrazine have been accidental or job-related, and dose-response data are not available. The only clearly demonstrated effect induced by inhalation of hydrazine is nasal polyps in rodents and, at higher exposures, nasal adenocarcinomas. The most sensitive species for this effect is rats;

hence, they are used to make the risk estimate at a risk level of 10^-4. ACs were calculated by using the linearized multistage model described below (NRC, 1992).

Based on the data of MacEwen et al. (1981) and using linearized multistage extrapolation, the NRC Committee on Toxicology (COT) calculated that the lower 95 % confidence limit on the inhalation dose of hydrazine that would produce a 1 % lifetime tumor incidence in rats is 0.055 ppm for a 6 h/d, 5 d/w, 52 w/y for a 1-y exposure (NRC, 1985). This dose extrapolates to 0.005 ppm for a continuous 2-y exposure:

Extrapolating from the 1 % tumor incidence for a continuous 2-y exposure at 0.005 ppm to calculate the expected incidence for a 24-h exposure at the same concentration (0.005 ppm), the COT estimated that the tumor risk for rats should be less than 10^-6 (NRC, 1985, 1992).

The linearized multistage model is considered sufficiently conservative so that an additional species extrapolation factor is unnecessary (J. Doull, Committee on Toxicology, personal commun., 1989). Therefore, the following equation, based on Crump and Howe's (1984) multistage model with only the first stage dose-related, was used to calculate the exposure concentrations, D, which would yield a tumor risk of 10^-4 for exposure durations of 24 h, 7 d, 30 d, and 180 d:

where d is the concentration during a lifetime exposure (0.005 ppm in this case); 25,600 is the number of days in a 70-y human lifetime; k is the number of stages in the model (three in this case); 10^-4 is the acceptable risk level; age is the minimum age of an astronaut in years (30 y in this case); t is the exposure duration in days (1, 7, 30, or 180); risk is the risk of tumor for lifetime exposure to d (10^-2 in this case).

This equation yields values of

D_24h = 1.0 ppm.

D_7d = 0.2 ppm.

D_30d = 0.04 ppm.

D_180d = 0.007 ppm.

Analysis of the lethality data is a difficult and frustrating process. The data for repeated exposures to hydrazine are highly scattered. A major factor in the poor reproducibility of results between laboratories might be the propensity of hydrazine to adhere to surfaces. An early report (Comstock et al., 1954) showed that, at a nominal concentration of 20,000 ppm, the recovery of hydrazine vapor from the chamber atmosphere decreases from 26% to 4% with dead rats in the chamber; if the rats are alive, the recovery is decreased to 2%. This clearly indicates that a large fraction of the airborne hydrazine adheres to the rat fur, probably about 10 times the amount retained in the respiratory system. Examination of the methods used for many of the experiments reveals serious shortcomings in some of the study designs (number of animals tested; not sham-exposing control animals, etc.). Despite these potential problems in experimental designs and highly scattered rodent data, the conservative approach would be to use the data for the most sensitive species (mice). Epidemiological data on workers occupationally exposed to hydrazine vapors over periods of months to years lead to the conclusion that humans are much less susceptible to hydrazine toxicity than are mice (Wald et al., 1984). Personal communication with Dr. Nick Wald (April 1992) confirmed that there were no deaths seen in his epidemiological study among the 78 factory workers exposed to hydrazine at 1-10 ppm over a period of at least 6 mo. ACs can be calculated from these data as follows:

For a 1-h exposure: The assumption is made that if the hydrazine concentrations were between 1 and 10 ppm for ≥6 mo, it would be highly likely that there would be at least one period during those ≥6 mo when the hydrazine concentration was 5 ppm for at least 1 h. Thus, multiplying 5 ppm by the square root of 78 divided by 10 to adjust for the use of less than 100 subjects,

is a NOAEL for lethality.

For exposures of 24 h, 7 d, and 30 d: AC values were calculated

using the lower end of the concentration range (1 ppm) and assuming a work schedule of 6 h/d, 5 d/w, for 6 mo (equivalent to 32.5 d continuous exposure) and not increasing the 30-d AC for exposure durations shorter than 30 d. Thus,

For exposures of 180 d: Using Haber's rule, the AC is

The susceptibility of astronauts to the toxic effects of hydrazine would not be expected to be affected by the physiological changes induced by spaceflight.

Studies are needed to definitively determine the fate of the large fraction of the hydrazine vapor that disappears during controlled laboratory exposures. This determination would help eliminate the uncertainty in the total dose received by exposed animals. Currently, it is not known whether hydrazine vapor might be undergoing some reaction in the air or on surfaces that converts it to a form that, although not measured as hydrazine in analytical measurements of airborne concentrations, might be the ultimate toxin or carcinogen or that might be metabolized by the body to the ultimate toxin or carcinogen.

A study on the relative absorption rates for dermal versus inhalation absorption of hydrazine vapor would aid in estimating the total absorbed dose during exposures.

A carcinogenicity study using a continuous exposure protocol including concentrations that do not produce nasal inflammation or necrosis would be helpful.

A carcinogenicity study in which animals are continuously exposed to

high concentrations of hydrazine vapor for 1 h, 24 h, or 7 d and then observed for their lifetime would be useful.

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