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6
Hydrazine

This chapter summarizes the relevant epidemiologic and toxicologic studies on hydrazine. Selected chemical and physical properties, toxicokinetic and mechanistic data, and inhalation exposure levels from the National Research Council (NRC) and other agencies are also presented. The subcommittee considered all of that information in its evaluation of the Navy’s proposed 1-hour (h), 24-h, and 90-day exposure guidance levels for hydrazine. The subcommittee’s recommendations for hydrazine exposure levels are provided at the conclusion of this chapter along with a discussion of the adequacy of the data for defining those levels and the research needed to fill the remaining data gaps.

PHYSICAL AND CHEMICAL PROPERTIES

Hydrazine is a base slightly weaker in strength than ammonia that can function as a strong reducing agent or as an oxidizing agent under certain conditions (Schiessl 1995). At ambient temperatures, hydrazine is a fuming, colorless, oily, hygroscopic liquid with an ammonia-like odor (NRC 1996). Hydrazine vapors readily condense on surfaces at ambient temperatures. Odor thresholds of 2-3 parts per million (ppm) (Ruth 1986) and 3.7 ppm (Amoore and Hautala 1983) have been reported. Selected physical and chemical properties are summarized in Table 6-1.

OCCURRENCE AND USE

Hydrazine has numerous industrial applications (Schiessl 1995). It is used in the synthesis of many derivatives, including foaming or blowing



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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants 6 Hydrazine This chapter summarizes the relevant epidemiologic and toxicologic studies on hydrazine. Selected chemical and physical properties, toxicokinetic and mechanistic data, and inhalation exposure levels from the National Research Council (NRC) and other agencies are also presented. The subcommittee considered all of that information in its evaluation of the Navy’s proposed 1-hour (h), 24-h, and 90-day exposure guidance levels for hydrazine. The subcommittee’s recommendations for hydrazine exposure levels are provided at the conclusion of this chapter along with a discussion of the adequacy of the data for defining those levels and the research needed to fill the remaining data gaps. PHYSICAL AND CHEMICAL PROPERTIES Hydrazine is a base slightly weaker in strength than ammonia that can function as a strong reducing agent or as an oxidizing agent under certain conditions (Schiessl 1995). At ambient temperatures, hydrazine is a fuming, colorless, oily, hygroscopic liquid with an ammonia-like odor (NRC 1996). Hydrazine vapors readily condense on surfaces at ambient temperatures. Odor thresholds of 2-3 parts per million (ppm) (Ruth 1986) and 3.7 ppm (Amoore and Hautala 1983) have been reported. Selected physical and chemical properties are summarized in Table 6-1. OCCURRENCE AND USE Hydrazine has numerous industrial applications (Schiessl 1995). It is used in the synthesis of many derivatives, including foaming or blowing

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants TABLE 6-1 Physical and Chemical Properties of Hydrazinea Synonyms and trade names Diamine, diamide, anhydrous hydrazine, hydrazine base, nitrogen hydride CAS registry number 302-01-2 Molecular formula NH2NH2 Molecular weight 32.05 Boiling point 113.5°C Melting point 2.0°C Flash point 52°C (open cup) Explosive limits 4.7% to 100% Specific gravity 1.0036 at 25°C/4°C Vapor pressure 14.4 mmHg at 25°C Solubility Soluble in water and methyl, ethyl, propyl, and isobutyl alcohols Conversion factors 1 ppm = 1.3 mg/m3; 1 mg/m3 = 0.76 ppm aData on explosive limits and vapor pressure are from ACGIH (2001); all other data are from Budavari et al. (1989). Abbreviations: mg/m3, milligrams per cubic meter; mmHg, millimeters of mercury; ppm, parts per million. agents, polymers, antioxidants, fungicides, herbicides, insecticides, plant growth regulators, and pharmaceuticals, such as the antibiotic isoniazid. Because hydrazine is a strong reducing agent, it is used as an oxygen scavenger to prevent corrosion in boiler water and hot-water heating systems. Hydrazine has been used as a principal component of missile and rocket fuels and as a component of fuel cells used primarily for military applications. Hydrazine is a component of tobacco smoke. The quantity of hydrazine in mainstream cigarette smoke ranges from 24 to 43 nanograms (ng) per cigarette and averages 32 ng per cigarette (Liu et al. 1974; Hoffmann and Hecht 1990). The quantity in sidestream smoke (smoke emitted from a smoldering cigarette) might be higher than in mainstream smoke (for example, 94 ng) (Liu et al. 1974). Air samples collected aboard the USS Cavalla (USS Cavalla 1986) indicated a concentration of hydrazine at 0.5 ppm. No information on sampling protocol, location, operations, or duration was available, and no information concerning the sources of hydrazine aboard the USS Cavalla was provided (NRC 1988).

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants SUMMARY OF TOXICITY Only data relevant to the derivation of EEGL and CEGL values for hydrazine are discussed below. For comprehensive reviews of hydrazine toxicology, see NRC (1996), the Agency for Toxic Substances and Disease Registry (ATSDR) (1997), the International Agency for Research on Cancer (IARC) (1999), and the American Conference of Governmental Industrial Hygienists (ACGIH) (2001). Hydrazine vapor is a potent ocular and upper respiratory tract irritant in humans and common laboratory animals and is absorbed readily through intact skin, the lungs, and the gastrointestinal tract (Reinhardt and Brittelli 1981). Hydrazine is a convulsant at high doses (Witkin 1956) but can depress the central nervous system (CNS) at lower doses (Back and Thomas 1970). Tremors, pulmonary edema, and hepatotoxicity have been reported in people poisoned with hydrazine (Choudhary and Hansen 1998). The toxicity of multiple low doses is cumulative (NRC 1996). Hydrazine toxicity is concentration-dependent. As inhaled concentrations increased from 14 ppm to 225 ppm, the median time to death in rats decreased from 27 days to 4.5 days (Comstock et al. 1954). Hydrazine has been tested in many experimental systems for genotoxicity. Although many of those tests resulted in negative or equivocal results, positive results were observed in gene mutation studies with bacteria, yeast, and Drosophila melanogaster (IARC 1999). In vivo studies of gene mutation and chromosomal effects have not resulted in consistent positive genotoxic results; however, DNA adducts were reported in three species following hydrazine exposure (IARC 1999). No genotoxicity studies via inhalation have been conducted in laboratory animals, and no data on genotoxicity are available for humans. Nasal tumors have been observed in rats after repeated hydrazine inhalation. Duration of exposure was more significant than concentration in the production of hydrazine-induced nasal cancer in rodents (Latendresse et al. 1995). An epidemiologic study of workers in a hydrazine production plant reported no elevation in cancer risk among men exposed to hydrazine (Wald et al. 1984). A follow-up study of the cohort also failed to show significantly increased cancer risk (Morris et al. 1995). Those studies, however, considered only a small population and lacked rigorous industrial hygiene data. An epidemiologic study of men employed in rocket-engine testing jobs exposed to hydrazine and several other hazardous substances suggested an increased risk for lung and possibly other cancers (Ritz et al.

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants 1999; Morgenstern and Ritz 2001). However, the potential cancer risk from inhalation exposures to hydrazine cannot be determined from the available human studies. Effects in Humans Accidental Exposures Frierson (1965) described the consequences of accidental exposure to hydrazine and unsymmetrical dimethyl hydrazine (UDMH). One case involved a 36-year-old man who discovered a high concentration of hydrazine and UMDH while checking for leaks. He obtained an acid suit and respirator and continued to attempt to identify the source of the leak. He later complained of a burning sensation on his face, a sore throat, and a tight chest. He became pale and developed muscle twitching with clonic movements and pulmonary edema. In another case, a 44-year-old male pipe fabricator received a strong inhalation dose of hydrazine and UMDH and developed severe dyspnea, trembling, muscle weakness, and pulmonary edema. A third case involved the exposure of four men after a liquid hydrazine and UMDH spill. All of the men suffered from severe nausea and vomiting. Sotaniemi et al. (1971) describes the death of a 59-year-old male machinist who handled hydrazine hydrate once each week over a period of 6 months. No account of his work practice or percutaneous hydrazine uptake was provided. He complained of conjunctivitis, tremors, and lethargy after each exposure. On the last day of his employment, he developed gastrointestinal distress and fever. On admission to the hospital, the patient presented with atrial fibrillation; stomatitis; conjunctivitis; upper abdominal pain and enlarged abdomen; jaundice and a tender, palpable liver; elevated bilirubin and creatinine; oligouria with protein and erythrocytes in his urine; and black feces. Chest X-rays revealed pleural effusions and shadowing. He died 15 days after hospitalization. Autopsy revealed tracheitis, bronchitis, and pneumonia; renal tubular necrosis, hemorrhage, and inflammation; and focal hepatocellular necrosis. An enlarged and discolored heart exhibiting degeneration of the cardiac muscle also was noted, but the relationship of that observation to hydrazine exposure was unclear. No empirical hydrazine concentrations were obtained, but subsequent simulations suggested a workplace air concentration of about 0.05 ppm. Richter et al. (1992) described neurobehavioral impairment in many

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants parameters, including mood, memory, learning, comprehension, and concentration, in a water treatment technician occupationally exposed to hydrazine-containing mixtures. His condition improved over several years with the cessation of exposure. There are at least three reports that describe the consequences of hydrazine ingestion (Drews et al. 1960; Reid 1965; Harati and Niakan 1986). Clinical signs and symptoms included vomiting, weakness, dyspnea, confusion, lethargy, ataxia, restlessness, and loss of consciousness. Experimental Studies No controlled experimental studies of hydrazine and its potential health effect were identified. Occupational and Epidemiologic Studies Contassot et al. (1987) provided an abstract summary of workplace exposures to hydrazine at <0.1, 0.1-1.0, or >1.0 ppm among 130 men. These men had been employed for at least 6 months. Analyses suggested that the standardized incidence ratio (the ratio of the number of cases observed to the number of new cases expected on the basis of age-specific rates) achieved statistical significance for an excess of all cancers in the high-exposure group, but that ratio was reduced when skin cancers were excluded from consideration. Wald et al. (1984) studied 427 men who experienced varying levels of hydrazine exposure at a plant in the United Kingdom. The facility produced 700 tons of hydrazine per year from 1945 to 1971. Hydrazine exposures were estimated on the basis of simulated spills. Airborne hydrazine concentrations in the general plant environment were estimated to be 1-10 ppm, whereas the concentrations near storage vessels were estimated to be up to 100 ppm. Workers were categorized by severity of exposure. Exposures at 1-10 ppm were considered high, and exposures at <1 ppm were considered moderate to low. There were 1,565 man-years in the high-exposure group and 6,786 man-years in the moderate-to-low exposure group. Overall mortality among hydrazine-exposed employees was lower than expected (49 vs 61.47 expected). Mortality rates from lung cancer (5 vs 6.65 expected), other types of cancer (7 vs 9.27 expected), and all other causes (37 vs 45.55 expected) were similar to the expected values.

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants Morris et al. (1995) provided a follow-up of 95% of the 427 workers initially evaluated by Wald et al. (1984) and Roe (1978), adding 10 years of observation time for this population. There were no increases in mortality from all causes (86 total deaths; standardized mortality ratio [SMR] = 0.75), from lung cancer (8 deaths; SMR = 0.66), from digestive tract cancers (9 deaths; SMR = 0.95), or from cancers at other sites (8 deaths; SMR = 0.76) compared with rates for England and Wales. Among workers with the highest levels of exposure, there were three deaths from lung cancer (SMR = 1.08) and 20 total deaths (SMR = 0.74). Of the three lung cancer deaths, two occurred in workers who were exposed to hydrazine for less than 2 years. None of the SMR values were significantly different from 1. Morgenstern and Ritz (2001) and Ritz et al. (1999) described an occupational cohort of 6,107 men involved in rocket-engine fueling and testing who were potentially exposed to hydrazine, 1-methylhydrazine, and 1,1-dimethylhydrazine for at least 2 years. Mean follow-up time was 29 years; only 23% of the cohort died in that time. Workplace exposures might also have included asbestos, beryllium, chlorine, fluorine, hydrogen peroxide, isopropyl alcohol, kerosenes, nitric acid, rocket-engine exhaust, and chlorinated solvents (Ritz et al. 1999). Workers were assigned to exposure groups on the basis of exposure severity. Propulsion or test mechanics or technicians involved in hydrazine pumping were in the high-exposure category; propulsion or test inspectors, test or research engineers, and instrumentation mechanics were in the medium-exposure category; and workers with little opportunity for direct hydrazine exposure were in the low-exposure category. All subjects had engaged in at least 6 months of service in their job category. The data showed reduced mortality rates from all cancers and from all causes compared with rates for white males in the United States. The all-cause SMR also was consistent with that observed for other high-socioeconomic-status workers. No excess lung cancer mortality was seen in the medium-exposure group, but the lung cancer rate ratio (RR) for the high-exposure group compared with unexposed workers ranged from 1.68 (95% confidence interval [CI] = 1.12-2.52) to 2.10 (95% CI = 1.36-3.25) depending on exposure duration and lag time for hydrazine exposure. Rate ratios for lymphopoietic cancers and urinary tract cancers increased with exposure. When examined by decade of employment, lung (RR = 2.01; 95% CI = 1.21-3.33) and lymphopoietic (RR = 2.45; 95% CI = 0.91-6.58) cancer risks were increased for those who were working during the 1960s, a time when rocket-engine test firings and hydrazine fuel consumption were at their highest levels. Despite the study limitations (collapsing heterogeneous cancers by organ system, exposure estimated by job title,

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants possible exposure to solvents and other materials, reliance on mortality instead of cancer incidence data, and the inability to control completely for tobacco smoking), Ritz et al. (1999) reached the following conclusion: “occupational exposure to hydrazine or other chemicals associated with rocket-engine testing jobs increased the risk of dying from lung cancer and possibly other cancers.” Effects in Animals Acute Toxicity The 1-h LC50 (concentration lethal to 50% of subjects) for hydrazine in hamsters (whole-body exposure) was 2,585 ppm (Back et al. 1978). Hydrazine exposures induced alopecia and lung, liver, and kidney damage in the exposed animals. The 4-h LC50 for hydrazine in rats (570 ppm) was somewhat greater than that in mice (252 ppm) (Jacobson et al. 1955). After a single 1-h exposure at an average concentration of 80 ppm, male Wistar rats salivated, some developed convulsions, and one of six rats died (Comstock et al. 1954). However, the subcommittee questions the accuracy of the reported hydrazine concentration because Latendresse et al. (1995) found a maximum 1-h nonlethal concentration in five male and five female Fischer 344 rats at 750 ppm. When 10 adult male hamsters and five adult male and five adult female Fischer 344 rats inhaled hydrazine at 750 ppm for 1 h, the transitional, respiratory, and olfactory epithelium in the anterior nasal passages showed bilateral necrosis and exfoliation (Latendresse et al. 1995). Apoptosis in the posterior olfactory epithelium was also noted in some rats. CMA (1993) exposed Sprague-Dawley rats to an aqueous aerosolized 64% solution of hydrazine for 1-h. The 1-h LC50 values estimated for hydrazine alone were 4,420 ppm for males and 2,590 ppm for females. Topical hydrazine can produce chemical burns, and it is absorbed through the skin in amounts sufficient to precipitate systemic intoxication and death (Smith and Clark 1972). The rat single-dose oral LD50 (60 milligram per kilogram [mg/kg]) (Witkin 1956) is similar to a lethal dose observed in dogs following dermal exposure (96 mg/kg) (Smith and Clark 1972) and the dermal LD50 values reported in rabbits and guinea pigs (93-190 mg/kg) (Rothberg and Cope 1956). Thienes et al. (1948) investigated the ocular toxicity of hydrazine and reported that one drop instilled in rat or rabbit eyes caused permanent damage. Six drops of an aqueous 25% solu-

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants tion applied at a rate of 1 drop per 10 minutes (min) also caused permanent damage, but a 1% solution produced no visible reaction. Repeated Exposures and Subchronic Toxicity Weatherby and Yard (1955) exposed eight male guinea pigs to hydrazine at 2-5 ppm for 6 h per day, 5 days per week for 9 days. During that time, no signs of hydrazine intoxication were observed. From day 10 until day 69, hydrazine concentrations were increased to 3-6 ppm. Six of the eight guinea pigs survived and appeared in good health at study termination. Necropsy revealed pulmonary lymphoid hyperplasia, diffuse atelectasis, and evidence of an inflammatory infiltrate. Weatherby and Yard (1955) exposed two male mongrel dogs to hydrazine at 2-5 ppm for 6 h per day, 5 days per week for up to 7 days. Both dogs became lethargic and lost coordination by day 5. At day 7, one died, and the other was killed in extremis. When one male and one female dog were exposed at 3-6 ppm for 6 h, the male showed signs of hydrazine poisoning within 24 h. After 19 days of hydrazine exposure, the study was terminated and tissues were collected. The dogs’ livers showed marked fatty infiltration into the central zone with areas of hepatocellular necrobiotic hyalinization and distention of the biliary canaliculi. The proximal renal cortex was congested, and capillary endothelium showed moderate hyperplasia. Haun and Kinkead (1973) conducted inhalation studies with 97% anhydrous hydrazine using 50 male Sprague-Dawley rats, 40 female ICR mice, eight male beagles, and four female rhesus monkeys per exposure group. The protocol used two designs: (1) continuous exposures at 0.2 or 1 ppm for 24 h per day, 7 days per week (33.6 or 168 ppm-h per week) for 6 months and (2) intermittent exposures at 1 or 5 ppm for 6 h per day, 5 days per week (30 or 150 ppm-h per week) for 6 months. Minimal eye irritation was noted in monkeys continuously exposed at 1 ppm and intermittently exposed at 5 ppm during the first few weeks of the study and periodically thereafter. None of the primates died under either protocol. One of the dogs continuously exposed at 1 ppm developed tonic convulsions—one episode after 3 months of exposure and two episodes on the same day after 5 months of exposure. Two dogs died after 16 weeks of continuous exposure at 1 ppm. Within 8 weeks, 2-7% of the mice exposed intermittently at 1 ppm or continuously at 0.2 ppm died, and 35-40% exposed intermittently at 5 ppm or continuously at 1 ppm died. No clinical signs or hydrazine-related mortality was reported for the rats. Body weights

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants of exposed monkeys were not significantly different from those of controls. Body weights were depressed in dogs continuously exposed at 1 ppm, and a dose-dependent decrease in the body weights of rats was observed. In rats exposed continuously at 0.2 ppm, the decrease was not statistically significant after 10 weeks of exposure. Mice were not weighed. Hematologic and clinical chemistry measurements were normal in monkeys and rats; reduced erythrocyte count, hematocrit, and hemoglobin developed within 8 weeks in dogs exposed either continuously at 1 ppm or intermittently at 5 ppm but returned to normal within 2 weeks post-exposure in the two dogs evaluated from those exposure groups. Hematology and clinical chemistry parameters were not evaluated in the mice. Hepatic fatty infiltration was evident in mice at all exposure concentrations, which is consistent with observations of dogs that inhaled hydrazine at 3-6 ppm for 19 days reported in Weatherby and Yard (1955). Slight to moderate hepatic fat accumulation was found in exposed monkeys, but that accumulation was also observed to some degree in the control monkeys. Dogs exposed continuously at 1 ppm or intermittently at 5 ppm also developed fatty livers. Bronchopneumonia was reported in rats exposed intermittently at 5 ppm. It was not clear whether the finding had any relationship to hydrazine exposure. House (1964) conducted a 90-day continuous (24 h per day, 7 days per week) inhalation study with hydrazine (95%) in 10 male rhesus monkeys, 50 male Sprague-Dawley rats, and 100 male ICR mice. Animals were exposed to an average hydrazine concentration of 0.78 ppm (range, 0.25-1.38 ppm). Separate groups of equal numbers of animals were housed in an adjacent room and served as concurrent controls throughout the exposure period. After the first day, the treated monkeys developed reddish faces and swollen eyes. They became weak and thin throughout the exposure period and exhibited reduced food and water consumption. Two of the treated monkeys died, one on day 30 and the other on day 85; a control monkey died on day 30. The body weights of the treated monkeys began to decrease after day 45. Clinical chemistry and urinalysis parameters appeared normal. Necropsy demonstrated hepatic fatty infiltration in 7 of the 10 treated monkeys; two of the concurrent controls showed similar changes. Two treated monkeys also exhibited mild congestion of the liver, and one of them developed fatty liver. Calcification in the adrenal glands (2 of 10), kidney (3 of 10), and heart (3 of 10) were observed in treated monkeys. Renal congestion and nephritis, adrenal calcification, and cardiac dilatation were observed similarly in both exposed and control monkeys. Whole-body exposures of male Sprague-Dawley rats and male ICR mice killed 98-99% of those animals; the majority of the rats died between days 46 and 64, and

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants the majority of the mice died within the first 30 days of exposure. Animals were “weak and sick early in the test,” and water and food consumption declined obviously until death. Ten weeks of 1-h exposures, one per week at 750 ppm produced a significant reduction in body weights in adult male and female Fischer 344 rats and male Syrian hamsters (Latendresse et al. 1995). No hydrazine-induced mortality occurred in rats or hamsters. Inhaled hydrazine induced acute inflammation, exfoliation, desquamation, necrosis, and squamous metaplasia in the nasal transitional epithelia. At 28-30 months after cessation of exposure, polypoid adenomas (in 4 of 99 males and 6 of 95 females) and a squamous cell carcinoma (in 1 of 99 males) were found in rats. The authors considered the apoptosis found in the olfactory epithelium and the squamous metaplastic transitional epithelium to be an adaptive response. Hamsters exhibited nasal transitional hyperplasia in 2 of 94 and frank neoplastic transformation (polypoid adenomas) in 3 of 94. No such changes were observed in any of the concurrent controls. Latendresse et al. (1995) also exposed adult male and female Fischer 344 rats and male Syrian hamsters to hydrazine at 75 ppm for 1 h each week for 10 weeks and held them post-exposure for 24 to 30 months. The body weights of female rats were significantly reduced during the exposure period. Proliferative lesions (focal squamous epithelial hyperplasia and squamous cell carcinoma) were observed in 2.2% of male rats (2 of 93). A nasal polypoid adenoma was observed in one hamster. Chronic Toxicity MacEwen et al. (1981) and Vernot et al. (1985) published the results of a hydrazine inhalation study conducted in male and female Fischer 344 rats, female C57BL/6 mice, male Syrian hamsters, and 6-month-old male and female beagle dogs. Groups of 100 rats were exposed to hydrazine at 0.05, 0.25, 1.0, or 5.0 ppm for 6 h per day, 5 days per week for 52 weeks and were maintained for an additional 18 months post-exposure. Rat mortality at termination of the study was similar in all groups. Body weights of rats were decreased compared with controls; the most significant effect was observed in male rats exposed at 5 ppm. Significantly increased incidences of non-neoplastic lesions primarily were observed in the nasal cavity (squamous metaplasia and epithelial hyperplasia), larynx (squamous metaplasia and inflammation), and trachea (squamous metaplasia and inflammation) of male and

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants female rats exposed at 5 ppm; however, squamous metaplasia of the nasal cavity was not significantly increased in the females. Lymph node hyperplasia was significantly increased in females exposed at 5 ppm, and hepatic focal cell hyperplasia was significantly increased in females exposed at 1 and 5 ppm. Statistically significant changes in tumor incidence included increases in nasal adenomatous polyps in females exposed at 5 ppm and in males exposed at 1 and 5 ppm; increases in nasal villous polyps in males exposed at 5 ppm; and increases in thyroid carcinomas in males exposed at 5 ppm. The nasal tumors were associated with chronic local irritation, and most of the rat nasal tumors were seen at 12 months post-exposure. The first appearance of nasal tumors in male and female rats occurred at 20 and 23 months, respectively, following initiation of exposure. Groups of 400 female C57BL/6 mice were exposed to hydrazine at 0.05, 0.25, or 1.0 ppm and maintained for 15 months post-exposure. No non-neoplastic pathology could be detected after hydrazine exposure. An increase in pulmonary adenomas observed in mice exposed at the highest concentration was marginal compared with concurrent controls. When those results were compared with data from an additional control group of 385 female C57BL/6 mice, there were no significant differences. Vernot et al. (1985) noted that the historical control incidence of pulmonary adenomas in C57BL/6 mice was 2-3% and considered the 3.2% increase observed at 1.0 ppm to be consistent with the background rate in that strain. Higher concentrations could not be assessed due to the high mortality indicated in previous studies (Haun and Kinkead 1973; MacEwen et al. 1974). Groups of 200 hamsters exposed to hydrazine at 0.25, 1.0, or 5.0 ppm experienced increased mortality during the early phase of the study. All groups exhibited decreased body weights compared with controls; however, only animals exposed at 5 ppm showed significantly decreased body weights in the final months of the study. Hepatic, renal, and adrenal amyloidosis were increased significantly in all exposed groups, but 22-23% of the concurrent controls exhibited the same conditions. Amyloidosis was also significantly increased in the spleens of animals exposed at 1 and 5 ppm and in the thyroids of animals exposed at 0.25 and 5 ppm. Exposure-related amyloidosis, hemosiderosis, testicular senile atrophy, and bile duct hyperplasia appeared to reflect accelerated age-related degeneration. The only significant increase in tumors was restricted to the 16 hamsters in the 5.0-ppm exposure group (n = 160) that had nasal adenomatous polyps. Dogs were exposed to hydrazine by inhalation at 0.25 and 1.0 ppm and were maintained for 38 months post-exposure. Hematology and clinical chemistry parameters appeared normal during the exposures. Although liver

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants 1-Hour EEGL NRC (1996) discussed the difficulties of deriving a 1-h hydrazine exposure limit. No rigorous exposure data from workplace studies (Morris et al. 1995; Ritz et al. 1999) or accounts of human intoxication (Frierson 1965; Sotaniemi et al. 1971) are available. Percutaneous uptake of hydrazine through intact dog skin is rapid (30 seconds) (Smith and Clark 1972) and confounds the estimation of total dose in reports of acute inhalation toxicity. No physiologically based pharmacokinetic (PBPK) model for hydrazine is available, and no pulmonary absorption data are available to assist in determining absorbed dose. Therefore, the 1-h EEGL was by necessity, based on chamber air concentrations used in controlled inhalation studies in animals. House (1964) indicated that the eyelids of adult male rhesus monkeys became swollen during the initial 24 h of exposure to hydrazine at 0.4 ppm (the mean concentration for the first 10 days of a 90-day study that had an overall concentration range of 0.25-1.38 ppm). A similar inhalation study involving continuous exposure at 1 ppm for 24 h per day, 7 days per week for 6 months or intermittent exposure at 5 ppm for 6 h per day, 5 days per weeks for 6 months in four female rhesus monkeys resulted in minimal ocular irritation during the first few weeks of the study (Haun and Kinkead 1973). In the absence of controlled ocular and nasal irritation data for human beings, the data from controlled inhalation studies in monkeys were considered to be the most relevant. The House (1964) study describes difficulties in maintaining constant exposure concentrations, and the controlled conditions used by Haun and Kinkead (1973) are considered more reliable than those reported by House (1964). Thus, the continuous hydrazine exposure concentration of about 1 ppm associated with eye irritation in rhesus monkeys was considered appropriate for deriving the 1-h EEGL. Although the 1-ppm concentration was associated with ocular irritation, those changes were reversible and were not life-threatening. No uncertainty factors were applied because the primary acute effect of hydrazine is the result of direct contact irritation, which should be similar for both monkeys and humans, and because this irritation is not likely to vary among individuals of the same species. Therefore, the recommended 1-h EEGL is 1.0 ppm.

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants TABLE 6-2 Selected Inhalation Exposure Levels for Hydrazine from NRC and Other Organizationsa Organization Type of Level Exposure Level (ppm) Reference Occupational       ACGIH TLV-TWA 0.01 ACGIH 2000 NIOSH REL-Ceiling 0.03 NIOSH 2004 OSHA PEL-TWA 1 29 CFR 1910.1000 Spacecraft       NASA SMAC   NRC 1996   1 h 4     24 h 0.3     30 days 0.02     180 days 0.004   General Public       ATSDR Intermediate MRL 0.004 ATSDR 1997 NAC/NRC Proposed AEGL-1 (1 h) 0.1 EPA 2004   Proposed AEGL-2 (1 h) 13     Proposed AEGL-1 (8 h) 0.1     Proposed AEGL-2 (8 h) 1.6   NRC SPEGL   NRC 1985   1 h 0.12     24 h 0.005   aThe comparability of EEGLs and CEGLs with occupational and public health standards or guidance levels is discussed in Chapter 1, section “Comparison to Other Regulatory Standards or Guidance Levels.” Abbreviations: ACGIH, American Conference of Governmental Industrial Hygienists; AEGL, acute exposure guideline level; ATSDR, Agency for Toxic Substances and Disease Registry; h, hour; MRL, minimal risk level; NAC, National Advisory Committee; NASA, National Aeronautics and Space Administration; NIOSH, National Institute for Occupational Safety and Health; NRC, National Research Council; OSHA, Occupational Health and Safety Administration; PEL, permissible exposure limit; ppm, parts per million; REL, recommended exposure limit; SMAC, spacecraft maximum allowable concentration; SPEGL, short-term public emergency guidance level; TLV, Threshold Limit Value; TWA, time-weighted average. 24-Hour EEGL Continuous 24-h hydrazine exposures at 0.2 or 1.0 ppm in groups of four female rhesus monkeys, lasting 24 h per day 7 days per week for 6 months failed to increase mortality (Haun and Kinkead 1973; MacEwen et

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants TABLE 6-3 Emergency and Continuous Exposure Guidance Levels for Hydrazine (ppm) Exposure Level U.S. Navy Values NRC Recommended Current Proposed Values EEGL           1 h — 4 1   24 h — 0.3 1 CEGL           90 days — 0.01 0.03 Abbreviations: CEGL, continuous exposure guidance levels; EEGL, emergency exposure guidance level; h, hour; NRC, National Research Council; ppm, parts per million. al. 1974). Minimal eye irritation was observed in monkeys exposed at 1.0 ppm. There were no significant differences in hematologic parameters (hemocrit, hemoglobin, erythrocyte and leukocyte counts, differential count and reticulocyte counts), clinical chemistry profiles (sodium, potassium, cholesterol, calcium, phosphorus, total bilirubin, alubumin:globulin ratios, total protein, blood urea nitrogen [BUN], serum glutamic-oxaloacetic transaminase [SGOT], serum glutamic-pyruvic transaminase [SGTP], chloride, creatinine, triglycerides, glucose, alkanine phosphatase), or body weights between control and hydrazine-treated monkeys. At termination of the 6-month study, the livers of the control monkeys showed “some degree of fatty liver change” (MacEwen et al. 1974). The livers from hydrazine-treated monkeys showed slight to moderate hepatic fat infiltration. Organ weights (organs not specified) from monkeys exposed to hydrazine were not statistically different from those of the controls (Haun and Kinkead 1973). The 24-h EEGL was based on the results of the 6-month continuous exposure study in rhesus monkeys conducted by Haun and Kinkead (1973). The primary treatment-related consequence of continuous exposure to hydrazine at 1.0 ppm was ocular irritation judged to be “minimal” by the authors. The process of identifying the inter- and intraspecies uncertainty factors for the 24-h EEGL was identical to that described for the 1-h EEGL. Therefore, the recommended 24-h EEGL is 1.0 ppm. 90-Day CEGL A 90-day CEGL for hydrazine exposure for noncancer effects can be derived from the hydrazine inhalation data from monkeys. The subcommit-

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants tee found that the size, anatomy, and physiology of the respiratory tract of the monkey made it an appropriate model for humans. Continuous exposure, as would occur during a 3-month operational tour aboard an Ohio class submarine, is best represented by the 90-day (House 1964) to 180-day (Haun and Kinkead 1973; MacEwen et al. 1974) exposures employed in the monkey studies. The 1.0-ppm concentration from the 6-month continuous-exposure study by Haun and Kinkead (1973) was considered to be a minimal lowest-observed-adverse-effect level (LOAEL) for the monkeys because the slight to moderate fat accumulation in the livers of exposed animals was also observed to some degree in the controls, and there were no abnormal findings in clinical chemistry, hematology, or organ or body weights. The authors did not specify any difference in hepatic fat accumulation between rhesus monkeys that inhaled hydrazine at 0.2 ppm compared with those that inhaled hydrazine at 1.0 ppm. Application of an interspecies uncertainty factor of 3 to the monkey 6-month continuous exposure no-observed-adverse-effect level (NOAEL) or possibly minimal LOAEL of 0.2 ppm was considered appropriate. An intraspecies uncertainty factor of 2 was applied on the basis of the differential rates of hydrazine acetylation measured in slow and fast acetylators in a group of Japanese hydrazine workers (Koizumi et al. 1998). Thus, a total uncertainty factor of 6 was applied to yield a 90-day CEGL of 0.03 ppm. CARCINOGENICITY ASSESSMENT The current EPA (1991) inhalation unit risk factor used in estimating the theoretical excess cancer risk of hydrazine (4.9 × 10-3 per micrograms per cubic meter [g/m3]) is based on Global 82 linearized multistage fitting to the combined incidence of nasal adenoma and adenocarcinoma in male Fischer 344 rats (MacEwen et al. 1981). Assuming that the EPA unit risk value is an accurate reflection of hydrazine carcinogenic potency in humans, theoretical excess cancer risk at the 90-day CEGL of 0.03 ppm exceeds 1 × 10-4. EPA qualified the inhalation value: “The unit risk should not be used if the [hydrazine] air concentration exceeds 2 g/m3 [2 ppb], since above this concentration the unit risk may not be appropriate.” However, no explanation is supplied to support that statement. NRC (1986) recognized that assuming all carcinogenic responses are directly proportional to the total dose over the entire exposure range “is likely not to hold for all materials and all tissues that these materials affect. Knowledge of mechanisms that produce different dose-response curves should, in the future, lead to better material/mechanism-specific risk assessment computations.”

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants The EPA calculation from 1991 does not directly consider the mode of action of hydrazine. Hydrazine is a reliable rodent carcinogen at chronic oral doses, producing hepatic and lung tumors. Chronic hydrazine inhalation studies in rats and mice yield concentration-related nasal and lung tumors. Hydrazine is clearly genotoxic in rats, mice, hamsters, and guinea pigs, inducing dose-dependent increases in hepatic O6-methylguanine and 7-methylguanine (Bosan and Shank 1983; Lambert and Shank 1988). Hydrazine-induced rodent liver tumors arise only after repeated exposures sufficient to produce hepatocellular necrosis (Leakakos and Shank 1994). It must be noted that methylguanines are detectable in rat hepatic DNA only after necrogenic doses and that hydrazine-induced DNA alkylation at cytotoxic doses is directed at or near specific genes (Leakakos and Shank 1994; Zheng and Shank 1996). Jenner and Timbrell (1994) reported the initial depletion of reduced hepatic glutathione (GSH) after hydrazine exposure. That finding was later confirmed by Hussain and Frazier (2002) who also reported the commensurate increase in oxidized GSH. Those changes are followed by generation of free methyl, acetyl, hydroxyl, and hydrogen radicals; increased reactive oxygen species; and inhibition of catalase activity sufficient to overwhelm cellular antioxidant defense mechanisms (Hussain and Frazier 2002). Increased cellular lipid peroxidation follows. Hydrazine cytotoxicity appears to be inextricably linked with the oxidative stress and damage observed after exposures sufficient to saturate and overwhelm normal defense mechanisms. Given the dependence of the response on exposure time, Hussain and Frazier (2002) concluded that hydrazine heptocellular toxicity is a highly nonlinear function of dose. Latendresse et al. (1995) found that the induction of rodent nasal tumors by hydrazine also is a nonlinear function of dose. Vernot et al. (1985) described the similarities between hydrazine-induced and formaldehyde-induced rodent nasal cancers. Although the rigorous molecular dosimetry available for formaldehyde does not exist for hydrazine, the available data support the conclusion that the carcinogenic potential of inhaled hydrazine, like that of formaldehyde (Conolly et al. 2003), is a threshold phenomenon that is associated with local cytotoxicity and regenerative hyperplasia. The subcommittee concluded that preventing upper respiratory tract irritation and associated cytotoxicity should eliminate, for all practical purposes, any excess carcinogenic risk posed by occupational hydrazine exposures. Although theoretical risk values can be generated using published linear potency factors, the subcommittee concluded that those values are unreliable given the uncertainty associated with them. Because the 90-day CEGL is far lower than the hydrazine concentra-

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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants tions associated with respiratory tract irritation and its consequences in primates, the health risk to submariners posed by hydrazine exposures less than or equal to the 90-day CEGL of 0.03 ppm can be considered de minimis. DATA ADEQUACY AND RESEARCH NEEDS Sufficient data were available for deriving the submarine guidance levels for hydrazine. However, fundamental mechanistic studies of hydrazine tumorigenesis in the rat nasal epithelium recommended by Latendresse et al. (1995) have not been conducted. Although similarities to formaldehyde carcinogenesis have been noted in this profile, such as the association with pronounced necrosis and regenerative hyperplasia, the subcommittee concludes that data are needed to determine the relationship between overt cytotoxicity induced in rodent respiratory tract tissues and carcinogenic response. Data are also needed to elucidate the contribution of the genotoxic activity of hydrazine at doses and exposures that elicit a significant carcinogenic response, given the overt tissue damage observed at those doses. These data would improve the confidence of the 90-day CEGL value and its protectiveness for longer-term exposures to hydrazine. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 2000. TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. American Conference of Governmental Industrial Hygienists, Cincinnati, OH. ACGIH (American Conference of Governmental Industrial Hygienists). 2001. Documentation of the Threshold Limit Values and Biological Exposure Indices, 7th Ed. American Conference of Governmental Industrial Hygienists, Cincinnati, OH. Amoore, J.E., and E. Hautala. 1983. Odor as an aid to chemical safety: Odor thresholds compared with threshold limit values and volatilities for 214 industrial chemicals in air and water dilution. J. Appl. Toxicol. 3(6):272-290. ATSDR (Agency for Toxic Substances and Disease Registry). 1997. Toxicological Profile for Hydrazines. Agency for Toxic Substances and Disease Registry, U.S. Department of Health and Human Services, Atlanta, GA. Back, K.C., and A.A. Thomas. 1970. Aerospace problems in pharmacology and toxicology [review]. Annu. Rev. Pharmacol. 10:395-412. Back, K.C., V.L. Carter, Jr., and A.A. Thomas. 1978. Occupational hazards of missile operations with special regard to the hydrazine propellants. Aviat. Space Environ. Med. 49(4):591-598.

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