w ANY) S. Toxicological (ell a for br EAL 5 RN Rand: pr Q WP 1,000 — ® ir " un 2r 3m wm 100 — am ® 5d & 6d 10 [— Key 1— r Rat Hl Lcso The number next to each m Mouse @ LOAEL for serious effects (animals) Poi conssaons 10 6nitries k Monkey (D LOAEL for less serious effects (animals) d Dog O NOAEL (animals) ' Minimal risk level for effects 5 Hamster ¢ CEL-C . , other than cancer - Cancer Effect Level (animals) W *Doses represent the lowest dose tested per study that produced a tumorigenic response and do not imply the existence of a threshold for the cancer end point. S103443 HLV3H 2 S3NIZVHAAH 4 Figure 2-1. Levels of Significant Exposure to Hydrazines - Inhalation (continued) Intermediate (15-364 days) Systemic Gp : \ 8 LL 8 P oO 9” «QO o N N & OQ OF © \ ® oO? ¢ (ppm) o 0.0 3 >» > & © &* 2 O98 SL RK 8 S$ od Ss Q > CO 4 oN = Q << oO 1,000 — 7m 100 .. 25m ® 21d 21d se em @ ®@ 00 ® ® O re | 10d 21d 21d 21d 21d 27d 10 14r 20s 22d 18m 22d 12k 12k 17m 224 26d F Q ®@ CO 0 O 000 OO 21d 12k 15r 21d 18m 21d 21d 27d 5 12k 15r 11 © @ O O oOo 20 Od O00 0 O o» 30m 9m 11d (J 13k 16r 23d @ 19m 23d 13k 13k 16r 23d 28d ¢ 17m 17m 01 O 0 » O 0 O : 17m 23d 13k 17m 19m 23d 13k 16r 23d 28d zon ad 0 *® 14r 14r | 20r 0.01 Ey LW | 0.001 |— | vv 0.0001 = Key r Rat LC50 The number next to each 0.00001 L- . oint corresponds to entries m Mouse @ LOAEL for serious effects (animals) point co 2 a k Monkey LOAEL for less serious effects (animals) d Dog O NOAEL (animals) | Minimal risk level for effects $ Womstor } ; other than cancer $ CEL - Cancer Effect Level (animals) Ww “Doses represent the lowest dose tested per study that produced a tumorigenic response and do not imply the existence of a threshold for the cancer end point. S103443 H1V3H 2 S3NIZVHAAH 92 Figure 2-1. Levels of Significant Exposure to Hydrazines - Inhalation (continued) (ppm) 10 0.1 0.01 d Dog O NOAEL (animals) s Hamster $ CEL - Cancer Effect Level (animals) do not imply the existence of a threshold for the cancer end point. *Doses represent the lowest dose tested per study that produced a tumorigenic response and Chronic (>365 days) Systemic > ed a NZ x @ QS & 8 iS © © & © \ > S N Q aN) © o @ $$ N) $ 2 & 2 WF oR & & $ RX Q Lu 3 a * Q Q <& dD ad dD & 32r 33m 33m 33m 37r o 06 0 0 a oO oO 0 ° — d 32r 34m 34m 34m 32r 34m 36d 34m 34m 38s ® oO d O dD d 0 31s 32r 35s 36d 35s 35s 38s Key r Rat HB cso The number next to each m Mouse @ LOAEL for serious effects (animals) Pains conesponss to entries k Monkey (D LOAEL for less serious effects (animals) } '" Minimal risk level for effects , other than cancer \/ S103443 H1TVAH 2 SANIZVHAAH LZ Figure 2-1. Levels of Significant Exposure to Hydrazines - Inhalation (continued) (ppm) 10 1 0.1 0.01 0.001 0.0001 0.00001 0.000001 0.0000001 0.00000001 0.000000001 0.0000000001 0.00000000001 0.000000000001 0.0000000000001 0.00000000000001 Chronic (>365 days) < & oo ® ¢ oo 39r 40m 41s 104 — Estimated Upper- 4 10-5 — Bound Human 10° 10 Estimated Upper- Cancer Risk 105 Estimated Upper- 10-5 —| Bound Human ~~ 1096 —{ Levels for Bound Human Cancer Risk 7 _| 11DMH 106 Cancer Risk 106 — Levels for 10 107 Levels for H 12DMH } 1077 Key r Rat HM cso The number next to each m Mouse @ LOAEL for serious effects (animals) Dear Ss ponas to entries k Monkey (D LOAEL for less serious effects (animals) d Dog O NOAEL (animals) | Minimal risk level for effects ) , other than cancer s Hamster $ CEL - Cancer Effect Level (animals) W “Doses represent the lowest dose tested per study that produced a tumorigenic response and do not imply the existence of a threshold for the cancer end point. S3NIZVHAAH S103443 H1IIV3H 2 8c HYDRAZINES 29 2. HEALTH EFFECTS No adverse effects were noted on the cardiovascular system of dogs exposed intermittently to 25 ppm 1,1-dimethylhydrazine for 13-26 weeks (Rinehart et al. 1960). In mice exposed to 0.05-5 ppm 1,1-dimethylhydrazine for 6 months to 1 year, the blood vessels were abnormally dilated (angiectasis) (Haun et al. 1984). However, no clinical or histopathological effects were noted on the cardiovascular system of mice exposed intermittently to 1 ppm hydrazine for 1 year (Vernot et al. 1985). The findings of the animal studies are inconsistent with the effects reported in the human case study and suggest that effects noted may not have been related to exposure. However, this is not certain. Gastrointestinal Effects. No studies were located regarding gastrointestinal effects in humans after inhalation exposure to hydrazines. No histopathological changes were observed in the gastrointestinal tract of dogs intermittently exposed to 25 ppm 1,1-dimethylhydrazine for 13-26 weeks (Rinehart et al. 1960) or in mice intermittently exposed to 1 ppm hydrazine for 1 year (Vernot et al. 1985). Although these data are limited, they suggest that the gastrointestinal system is not a primary target of the noncarcinogenic effects of hydrazine or 1,1-dimethylhydrazine. Hematological Effects. No studies were located regarding the hematological effects in humans after inhalation exposure to hydrazines. Mild anemia (17-26% decreases in red blood cell count, hemoglobin, and hematocrit) was observed in dogs intermittently exposed (5 days/week, 6 hours/day) to 5 ppm 1,1-dimethylhydrazine for 24 weeks (Rinehart et al. 1960). Anemia was more pronounced (28-60% decreases in above described parameters) at a higher concentration (25 ppm) of 1,1-dimethylhydrazine after 4 weeks of intermittent exposure. In dogs exposed continuously to 1 ppm hydrazine for 6 months, hemoglobin, hematocrit, and red blood cell count were all significantly reduced (approximately 25-30%) (Haun and Kinkead 1973). These effects were not observed in dogs exposed to 0.2 ppm hydrazine in this study. Hematological effects were not observed in rats, dogs, and hamsters exposed to 0.5 and 5 ppm 1,1-dimethylhydrazine for 6 months (Haun et al. 1984). The lack of an anemic effect of purified 1,1- dimethylhydrazines in the dogs of this study is inconsistent with the observations made by Rinehart et al. (1960) in dogs exposed to the same concentration for a shorter duration. It is possible that impurities of the 1,1-dimethylhydrazine (for example, dimethylnitrosamine) used by Rinehart et al. (1960) contributed to the anemic response. Alternatively, the anemic effects of hydrazine and HYDRAZINES 30 2. HEALTH EFFECTS 1,1-dimethylhydrazine may be related to their ability to react with pyridoxine (see Section 2.3.5); a deficiency of this vitamin results in anemia (NAS 1989). No adverse effects were reported for a large number of hematological parameters in rats or monkeys exposed to 1 ppm hydrazine continuously for 6 months (Haun and Kinkead 1973). In dogs, the anemic effects of hydrazine in this study and 1,1-dimethylhydrazine in the Rinehart et al. (1960) study appear to be fairly similar, and the data suggest that dogs may be particularly sensitive to the hematological effects of these compounds. However, some questions remain, considering the results with dogs seen by Haun et al. (1984), cited above. Rats (Haun and Kinkead 1973; Haun et al. 1984), monkeys (Haun and Kinkead 1973), and hamsters (Haun et al. 1984) appear to be relatively insensitive to the hematological effects of these compounds. Musculoskeletal Effects. No studies were located regarding musculoskeletal effects in humans after inhalation exposure to hydrazines. No studies were located regarding musculoskeletal effects in animals after inhalation exposure to 1,1-dimethylhydrazine. No musculoskeletal effects were observed in mice exposed intermittently to 1 ppm hydrazine for 1 year (Vernot et al. 1985). Hepatic Effects. A single case study reported areas of focal necrosis and cell degeneration in the liver of a worker exposed to an undetermined concentration of hydrazine in air once a week for 6 months (Sotaniemi et al. 1971). Studies of workers exposed to 1,1-dimethylhydrazine have reported changes indicative of a hepatic effect including elevated serum alanine aminotransferase activity, fatty degeneration, and a positive cephalin flocculation test (Petersen et al. 1970; Shook and Cowart 1957). Although the levels of hydrazine and 1,1-dimethylhydrazine exposure were not determined, these studies indicate qualitatively that the liver is a target for both hydrazines. In dogs exposed intermittently to 5 ppm 1,1-dimethylhydrazine for 8.5 weeks, cytoplasmic degeneration of the liver was observed (Haun 1977). Hemosiderosis of the spleen was observed in dogs exposed intermittently to 5 ppm 1,1-dimethylhydrazine for 26 weeks, and the same effect was observed in the Kupffer cells of the liver after exposure to 25 ppm for 13 weeks (Rinehart et al. 1960). Dogs exposed to 5 ppm 1,1-dimethylhydrazine for 6 months showed transitory increases in serum glutamic pyruvic transaminase (SGPT) levels which returned to normal during the postexposure HYDRAZINES 31 2. HEALTH EFFECTS recovery period (Haun et al. 1984). This study also found impaired liver function at the same dose level as measured by retention of injected bromosulphalein after a 6-month exposure to 1,1-dimethylhydrazine. Fatty changes were observed in the livers of mice, dogs, and monkeys exposed continuously to 0.2-1 ppm hydrazine for 6 months (Haun and Kinkead 1973). The hepatotoxic effects of hydrazine were notably more severe in mice than in dogs or monkeys and were responsible for the increased mortality observed in this species. Based on a LOAEL of 0.2 ppm for liver effects in mice, an intermediate inhalation MRL of 4x10 ppm was calculated for hydrazine as described in footnote "c" in Table 2-1. Intermittent exposure to 0.25-1 ppm hydrazine for 1 year resulted in a number of hepatic effects in rats, dogs, and hamsters including focal cellular change, vacuolated cells, elevated serum transaminases, amyloidosis, hemosiderosis, and bile duct hyperplasia (Vernot et al. 1985). The NOAEL values for hepatic effects range from 0.25 to 1 ppm for rats, mice, and dogs in this study. In addition, hamsters appeared to be the most sensitive species to hydrazine- induced hepatic effects, whereas mice appeared to be the most resistant. In rats and mice, exposure to 0.05-5 ppm 1,1-dimethylhydrazine for 6 months to 1 year produced fatty changes, angiectasis, hyaline degeneration of the gall bladder, and congestion in the liver (Haun et al. 1984). Based on a LOAEL of 0.05 ppm, an intermediate inhalation MRL of 2x10 ppm was calculated for 1,1-dimethylhydrazine as described in footnote "b" in Table 2-1. Collectively, these data clearly indicate that the liver is a target for hydrazine and 1,1-dimethylhydrazine toxicity. Furthermore, species differences are apparent in the sensitivity to hepatotoxicity. However, these data are inconsistent (mice were the most sensitive in one study but the most resistant in another) and suggest that strain differences in sensitivity may also exist in mice. It should be noted that dimethylnitrosamine, a potent liver toxin, occurs as a contaminant of technical grades of 1,1-dimethylhydrazine and may contribute to the hepatotoxic effects observed in animals following exposure to this compound (Haun 1977). A single study reported hyaline degeneration of the gall bladder in mice exposed to 0.05 ppm 1,1-dimethylhydrazine for 6 months (Haun et al. 1984). Renal Effects. No studies were located regarding renal effects in humans after inhalation exposure to 1,1-dimethylhydrazine. A single case study reported renal effects including tubular necrosis, hemorrhaging, inflammation, discoloration, and enlargement in a worker exposed to 0.07 mg/m’ (0.05 ppm) hydrazine once a week for 6 months (Sotaniemi et al. 1971). These renal effects were severe and were a contributing factor in the death of this worker. HYDRAZINES 32 2. HEALTH EFFECTS Renal effects were not observed in dogs exposed intermittently to 25 ppm 1,1-dimethylhydrazine for 13-26 weeks (Rinehart et al. 1960). Mild renal effects including amyloidosis and mineralization were observed in hamsters exposed intermittently to 0.25 ppm hydrazine for 1 year (Vernot et al. 1985); however, no effects were noted in the kidneys of mice exposed intermittently to 1 ppm hydrazine for 1 year (Vernot et al. 1985). The findings of these animal studies are inconsistent with the severe effects observed in the human case study. However, more severe effects on the kidney have been observed in animals exposed to hydrazines by other routes (see Sections 2.2.2.2 and 2.4). Ocular Effects. No studies were located regarding ocular effects in humans after inhalation exposure to 1,1-dimethylhydrazine. A single case of a worker exposed to an undetermined concentration of hydrazine once a week for 6 months reported conjunctivitis (Sotaniemi et al. 1971). Since the conjunctivitis was repeatedly observed on each day the worker was exposed, continuing through to the following day, this effect is clearly related to hydrazine exposure. No studies were located regarding ocular effects in animals after inhalation exposure to 1,1-dimethylhydrazine. Minimal irritation of the eyes was noted in monkeys during the first few weeks of exposure to 1 ppm hydrazine (Haun and Kinkead 1973). This effect was not observed in monkeys exposed to 0.2 ppm hydrazine (Haun and Kinkead 1973), or in mice exposed intermittently to 1 ppm hydrazine for 1 year (Vernot et al. 1985). Although these data are internally inconsistent, the data from monkeys are consistent with the human data which suggest that hydrazine acts as an irritant to the eyes. Body Weight Effects. No studies were located regarding body weight effects in humans after inhalation exposure to hydrazine or 1,1-dimethylhydrazine. Several studies in animals have reported decreased body weight gain. Male and female rats and male hamsters experienced significantly decreased body weight gains compared to controls during a 10-week period of exposure to 750 ppm hydrazine (1 hour/week) (Latendresse et al. 1995). Weight gains returned to normal during the subsequent recovery period. Body weight gain was reduced in rats and dogs exposed continuously to 1 ppm hydrazine for 6 months (Haun and Kinkead 1973), and in dogs exposed to 5 ppm 1,1-dimethylhydrazine 6 hours/day, 5 days/week, for 26 weeks (Rinehart et al. 1960), or 5 ppm hydrazine for the same dosing regimen (Comstock et al. 1954). No effects in body weight gain were observed in several species exposed to concentrations of 0.2-1 ppm hydrazine or HYDRAZINES 33 2. HEALTH EFFECTS 5 ppm 1,1-dimethylhydrazine for 6 months (Haun and Kinkead 1973; Haun et al. 1984). Chronic exposure to 0.25 ppm hydrazine caused a 14% loss of body weight in hamsters (Vernot et al. 1985). A similar decrease in body weight gain was noted in mice exposed to 5 ppm 1,1-dimethylhydrazine for 1 year (Haun et al. 1984). 2.2.1.3 Immunological and Lymphoreticular Effects No studies were located regarding immunological and lymphoreticular effects in humans or animals after inhalation exposure to hydrazines. 2.2.1.4 Neurological Effects Data regarding the neurological effects of hydrazines in humans are limited to several case studies. Acute exposure to an undetermined concentration of a hydrazine/ 1,1-dimethylhydrazine mixture in air resulted in trembling, twitching, clonic movements, hyperactive reflexes, and weakness in two cases (Frierson 1965). Nausea, vomiting, and tremors were observed in a worker exposed to an undetermined levels of hydrazine in air once a week for 6 months (Sotaniemi et al. 1971). Difficulties in concentration, comprehension, memory, and task performance, as well as changes in mood status were noted in a water technician occupationally exposed to an undetermined concentration of hydrazine in air (Richter et al. 1992). Slow, gradual improvement was noted in the latter case after the subject was removed from exposure. Although limited, these studies suggest that inhalation exposure to hydrazine and 1,1-dimethylhydrazine can adversely affect the central nervous system in humans. In dogs exposed intermittently to 25 ppm 1,1-dimethylhydrazine, depression, ataxia, salivation, emesis, and seizures were noted after 3 days (Rinehart et al. 1960). These effects were not observed in dogs exposed to 5 ppm for 26 weeks. Tonic convulsions were noted in one of eight dogs exposed continuously to 1 ppm hydrazine for 6 months but were not observed in any dogs exposed to 0.2 ppm (Haun and Kinkead 1973). Tremors were observed occasionally in rats and mice exposed continuously to 75 ppm 1,1-dimethylhydrazine (Rinehart et al. 1960). These data confirm the observations from human studies and indicate that the central nervous system is a target for the toxicity of inhaled hydrazine or 1,1-dimethylhydrazine. The highest NOAEL values and all LOAEL HYDRAZINES 34 2. HEALTH EFFECTS values from each reliable study for neurological effects resulting from inhalation exposure to hydrazines are recorded in Table 2-1 and plotted in Figure 2-1. 2.2.1.5 Reproductive Effects No studies were located regarding reproductive effects in humans after inhalation exposure to hydrazines. Endometrial cysts were noted in female mice exposed to 0.05 ppm 1,1-dimethylhydrazine for 6 months (Haun et al. 1984). The incidence of endometrial cysts were also elevated in female mice exposed to 5 ppm 1,1-dimethylhydrazine for 1 year (Haun et al. 1984); however, this increase was not statistically significant. Furthermore, this type of lesion is common to aged female mice and therefore may not be related to treatment. In female rats exposed intermittently to 5 ppm hydrazine for 1 year, atrophy of the ovaries and inflammation of the endometrium and fallopian tube were noted (Vernot et al. 1985). Senile testicular atrophy was observed in male hamsters exposed to 1 ppm hydrazine for 1 year but not in hamsters exposed to 0.25 ppm hydrazine (Vernot et al. 1985). An absence of sperm production was observed in hamsters exposed to 5 ppm. The study authors noted that the changes observed in male hamsters are normally associated with aging and that exposure to hydrazine seemed to accelerate these changes. However, available studies suggest that hydrazine and 1,1-dimethylhydrazine can produce serious reproductive effects. A complete assessment of the reproductive toxicity of hydrazines cannot be made since reproductive function was not determined in these studies. The highest NOAEL values and all LOAEL values from each reliable study for reproductive effects resulting from inhalation exposure to hydrazines are recorded in Table 2-1 and plotted in Figure 2-1. 2.2.1.6 Developmental Effects No studies were located regarding developmental effects in humans or animals after inhalation exposure to hydrazines. 2.2.1.7 Genotoxic Effects No studies were located regarding genotoxic effects in humans or animals after inhalation exposure to hydrazines. HYDRAZINES 35 2. HEALTH EFFECTS Genotoxicity studies are discussed in Section 2.5. 2.2.1.8 Cancer A single epidemiological study reported no significant increase in cancer mortality in a group of men (n=427) occupationally exposed to an undetermined concentration of hydrazine in air (Wald et al. 1984). Although this study reported no evidence of a carcinogenic effect for hydrazine, the follow-up period was relatively short and only 49 deaths were observed. However, when the workers were observed for another 10 years, there was still no significant increase in cancer mortality (Morris et al. 1995). Exposure to 0.05-0.5 ppm 1,1-dimethylhydrazine for 6 months produced an increased incidence of leukemia and tumors of the pancreas, pituitary, blood vessels, liver, and thyroid in mice and/or rats (Haun et al. 1984). Tumors of the lung, liver, nasal cavity, bone, and blood vessels were observed in mice exposed to 5 ppm 1,1-dimethylhydrazine for 1 year (Haun et al. 1984). A significantly increased incidence (p<0.05) of nasal tumors and thyroid carcinomas was observed in male rats exposed intermittently to 1 and 5 ppm hydrazine, respectively, for 1 year (Vernot et al. 1985). Hamsters and rats exposed to 750 ppm hydrazine once for 1 hour, or 1 hour per week for 10 weeks, exhibited increased incidences of squamous metaplasia, hyperplasia, and neoplasia in the nose (Latendresse et al. 1995). Nasal tumors were also noted in hamsters and female rats intermittently exposed to 5 ppm hydrazine for 1 year (Vernot et al. 1985). Tumor incidence was not significantly increased in mice and dogs exposed intermittently to 1 ppm hydrazine for 1 year (Vernot et al. 1985). The studies suggest that hydrazine and 1,1-dimethylhydrazine are carcinogenic by the inhalation route. All CEL values from each reliable study resulting from inhalation exposure to hydrazines are recorded in Table 2-1 and plotted in Figure 2-1. The EPA has derived an inhalation unit risk of 0.0049 (ug/m®)" for hydrazine based on nasal cavity tumors, and an inhalation unit risk of 0.001 (ug/m’)" for 1,1-dimethylhydrazine based on tumor of the respiratory system (HEAST 1992; IRIS 1995). Although no studies were located regarding the carcinogenic effects of 1,2-dimethylhydrazine following inhalation exposures, EPA has derived an inhalation unit risk of 0.011 (ug/m®)" for 1,2-dimethylhydrazine (HEAST 1992), based on extrapolation of cancer data for oral exposures (see Section 2.2.2.8). The concentrations of hydrazine, HYDRAZINES 36 2. HEALTH EFFECTS 1,1-dimethylhydrazine, and 1,2-dimethylhydrazine corresponding to excess cancer risks of 10 to 107 are shown in Figure 2-1. 2.2.2 Oral Exposure 2.2.2.1 Death No studies were located regarding lethal effects in humans after oral exposure to hydrazines. Acute oral LDj, values of 11.7 and 27.1 mg/kg have been reported for 1,2-dimethylhydrazine in male and female mice, respectively (Visek et al. 1991). Mortality was 100% in mice given a single dose of 90 mg/kg 1,2-dimethylhydrazine (Visek et al. 1991) and in mice given 133 mg/kg/day hydrazine or 533 mg/kg/day 1,1-dimethylhydrazine for 5 days (Roe et al. 1967). Death occurred in two of two dogs administered weekly doses of 60 mg/kg 1,2-dimethylhydrazine for 2 weeks (Wilson 1976). For intermediate exposures, doses of 2.3 and 4.9 mg/kg/day hydrazine for 15-25 weeks increased mortality in mice and hamsters, respectively (Biancifiori 1970). Exposure to 33 mg/kg/day 1,1-dimethylhydra- zine killed two of five mice exposed for 4-21 weeks (Roe et al. 1967). Mortality was 62.5-100% following intermediate-duration exposures to 1,2-dimethylhydrazine in rats given 13.6 mg/kg/day (Teague et al. 1981), guinea pigs given 60 mg/kg/day (Wilson 1976), dogs administered 15 mg/kg/day (Wilson 1976), pigs administered 60 mg/kg/day (Wilson 1976), and in mice given 4.5-5.1 mg/kg/day (Visek et al. 1991). Mortality in mice was 100% after chronic exposure to 0.95 mg/kg/day via the drinking water (Toth and Patil 1982). These data indicate that large doses of hydrazines are lethal by the oral route. Furthermore, male mice were 2-3 times more sensitive to the acutely lethal effects of 1,2-dimethylhydrazine than female mice (Visek et al. 1991), suggesting that there may be important sex differences. However, this was only observed in a single study. All LOAEL values from each reliable study for lethality are recorded in Table 2-2 and plotted in Figure 2-2. 2.2.2.2 Systemic Effects No studies were located regarding any systemic effects in humans after oral exposure to hydrazines. Also, no studies were located regarding the hematological effects in animals after oral exposure to hydrazines. The available studies regarding systemic effects in animals after oral exposure to hydrazines are described below. The highest NOAEL values and all LOAEL values for systemic HYDRAZINES 37 2. HEALTH EFFECTS effects in animals resulting from oral exposure to hydrazines are recorded in Table 2-2 and plotted in Figure 2-2. Respiratory Effects. No adverse histological effects were observed in the lungs of mice exposed to 9.5 mg/kg/day hydrazine via the drinking water for 2 years (Steinhoff et al. 1990). No other studies were located regarding respiratory effects in animals ingesting hydrazines. Cardiovascular Effects. Focal myocytolysis, fibrosis, and calcification of the heart were observed in mice receiving 1.6 mg/kg/day 1,2-dimethylhydrazine in the feed for 5 months (Visek et al. 1991). These effects were not observed in mice receiving 0.75 mg/kg/day. No adverse histological effects were observed in the hearts of mice receiving 9.5 mg/kg/day hydrazine in the drinking water for 2 years (Steinhoff et al. 1990). These data are too limited to make firm conclusions regarding the cardiovascular effects of hydrazines. Gastrointestinal Effects. Although oral exposure to hydrazine has produced nausea in humans, this effect is probably due to effects on the central nervous system and is therefore discussed in Section 2.2.2.4. Proliferative foci were noted in the colons of rats receiving two doses of 25 mg/kg 1,2-dimethylhydrazine within a 4-day period (Caderni et al. 1991). No adverse histological effects were observed in the gastrointestinal tracts of mice receiving 9.5 mg/kg/day hydrazine in the drinking water for 2 years (Steinhoff et al. 1990). These data are too limited to make firm conclusions regarding the gastrointestinal effects of hydrazines. Musculoskeletal Effects. No adverse effects were observed in the muscle tissue of mice receiving 9.5 mg/kg/day hydrazine in the drinking water for 2 years (Steinhoff et al. 1990). No other studies were located regarding the effects of hydrazines on the musculoskeletal system. Hepatic Effects. A number of studies in animals have reported effects on the liver after oral exposure to hydrazines. In rats and mice, relatively mild effects on the liver such as megamitochondria formation, increased lipogenesis, and fatty changes occurred following acute exposure to 49-650 mg/kg/day hydrazine (Marshall et al. 1983; Preece et al. 1992b; Wakabayashi et al. 1983). More notable effects, including degeneration, hemorrhage, and necrosis of the liver, were TABLE 2-2 Levels of Significant Exposure to Hydrazines - Oral Exposure/ Key * Duration/ to Species/ Frequency NOAEL Less Serlous Serious Reference figure (Strain) (Specific Route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form ACUTE EXPOSURE Death 1 Mouse Once 11.7 M (LD50) Visek et al. 1991 (B6C3F1) (GW) 12DMH 27.1 F (LD50) 2 Mouse Once 90 B (100% mortality) Visek et al. 1991 (B6C3F1) (GW) 12DMH 3 Mouse 1 wk 533 F (5/5 deaths) Roe et al. 1967 (Swiss) 5 x/wk 11DMH (GW) 4 Mouse 1 wk 133 F (5/5 deaths) Roe et al. 1967 (Swiss) 5 x/wk H (GW) 5 Dog 2 wk 60 M (2/2 deaths) Wilson 1976 (NS) 1 x/wk 12DMH (GW) Systemic 6 Rat 4d Gastro 25 F (proliferative foci in colon) Caderni et al. (Sprague- 2x 1991 Dawley) (G) 12DMH 7 Rat Once Hepatic 27 M 81 M (fatty liver) Preece et al. (Sprague- (GW) 1992a Dawley) HS 8 Rat Once Hepatic 49 F (increased lipogenesis) Marshall et al. (Wistar) (GW) 1983 HS S103443 H1TV3H 2 S3ANIZVHAAH 8g TABLE 2-2 Levels of Significant Exposure to Hydrazines - Oral (continued) Exposure/ LOAEL Key * Duration/ to Specles/ Frequency NOAEL Less Serious Serious Reference figure (Strain) (Specific Route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 9 Dog 2 wk Hepatic 60 M (hepatic degeneration and ~~ Wilson 1976 (NS) 1 x/wk hemorrhagic necrosis) 12DMH GW) Bd Wt 60 M (unspecified decrease in weight loss) Developmental 10 Hamster Once 166 F Schiller et al. (Syrian Gd 12 1979 Golden) (GW) H 11 Hamster Once 68 F Schiller et al. (Syrian Gd 12 1979 Golden) (GW) 12DMH Cancer 12 Rat Once 15.8 M (CEL: colonic epithelial Schiller et al. (Fischer) (GW) polypoid tumors) 1980 12DMH 13 Rat Once 30 M (CEL: colon Craven and (Sprague- ~~ (G) adenocarcinomas) DeRubertis 1992 Dawley) 12DMH 14 Rat Once 15.8 M (CEL: colonic Watanabe et al. (Sprague- (GW) adenocarcinomas or 1985 Dawley) mucinous adenocarcinomas 12DMH INTERMEDIATE EXPOSURE Death 15 Rat 10 wk 13.6 B (100% mortality) Teague et al. (DA, HS, 1 x/wk 1981 AS2) (GW) 12DMH S103443 H1V3aH © S3ANIZVHAAH 6€ TABLE 2-2 Levels of Significant Exposure to Hydrazines - Oral (continued) Exposure/ Key * Duration/ to Species/ Frequency NOAEL Less Serious Serious Reference figure (Strain) (Specific Route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 16 Mouse 6 wk M (100% mortality in males) Visek et al. 1991 (B6C3F1) ad libitum 12DMH (F) F (100% mortality in females) 17 Mouse 25 wk 1.1B B (38/50 deaths by 80 weeks) Biancifiori 1970 (CBA) 150 x HS (GW) 18 Mouse 4-21 wk F (2/5 deaths) Roe et al. 1967 (Swiss) 5 x/wk 11DMH (GW) 19 Hamster 15-20 wk B (32/35 deaths by week 50) Biancifiori 1970 (Syrian 60-100 x HS golden) (GW) 20 Dog 4-10 wk M (9/10 deaths) Wilson 1976 (NS) 1 x/wk 12DMH (GW) 21 Pig 10 wk M (5/8 deaths) Wilson 1976 (Miniature) 1 x/wk 12DMH (GW) 22 Gn pig 7-10 wk M (5/6 deaths) Wilson 1976 (Hartley) 1 x/wk 12DMH (GW) Systemic 23 Rat <10 mo Hepatic M (hepatic DNA alteration) Bedell et al. (Fischer-344) ad libitum 1982 Ww) 12DMH 24 Rat 9 wk Bd Wt 15 B 30 B (10% decrease in body Barbolt and (Sprague- 1 x/wk weight gain) Abraham 1980 Dawley) (GW) 12DMH S103443 H1IV3H 2 S3ANIZVHAAH ov TABLE 2-2 Levels of Significant Exposure to Hydrazines - Oral (continued) Exposure/ LOAEL Key * Duration/ to Species/ Frequency NOAEL Less Serious Serious Reference figure (Strain) (Specific Route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 25 Mouse 5 mo Cardio 0.75M 1.6 M (myocytolysis, fibrosis, and Visek etal. 1991 (B6C3F1) ad libitum calcification 12DMH (F) Hepatic 0.75% M (mild hepatitis) 1.6 M (hepatitis, centrilobular necrosis, and hepatocellular hypertrophy) Renal 0.75M 1.6 M (interstitial nephritis and pyelonephritis) 26 Mouse 6 wk Hepatic 1.4 B (decrease of 1.3% in Visek et al. 1991 (B6C3F1) ad libitum relative liver weight) 12DMH (F) 27 Mouse 25 wk Endocr 1 F (brown degeneration of Biancifiori 1970 (CBA) 150 x the adrenals) HS (aw) 28 Hamster 15-20 wk Hepatic 4.9 B (cirrhosis, cell proliferation, Biancifiori 1970 (Golden) 60-100 x degenerative changes) HS (GW) Endocr 53 B 29 Dog 4-10 wk Hepatic 5 M (mild hepatic fibrosis, Wilson 1976 (NS) 1 x/wk hemosiderosis, and ascites) 12DMH (GW) 15 M (hepatic failure) 30 Pig 10 wk Hepatic 30 M (focal megalocytosis and ~~ Wilson 1976 (Miniature) 1 x/wk postfibrotic necrosis of the ~~ 12DMH (GW) liver) 31 Gn pig 7-10 wk Hepatic 30 M (hepatic necrosis and Wilson 1976 (Hartley) 1 x/wk ascites) 12DMH (GW) Bd Wt 30 M (severe but unspecified decrease in body weight gain) S103443 H1TV3aH 2 S3ANIZVHAAH Iv TABLE 2-2 Levels of Significant Exposure to Hydrazines - Oral (continued) Exposure/ LOAEL Key * Duration/ to Species/ Frequency NOAEL Less Serious Serious Reference figure (Strain) (Specific Route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form Immunological/Lymphoreticular 32 Rat 5 wk 271 M Locniskar et al. (Sprague- 1 x/wk 1986 Neurological 33 Human 1-47 d 0.6 B (dizziness) Spremulli et al. 3 x/d 1979 (©) HS 34 Human 1-6 mo 0.6 B (nausea, vomiting, Gershanovich et 3 x/d dizziness, excitement, al. 1981 (©) insomnia, and polyneuritic ~~ HS syndrome) 35 Human 30d 0.7 B (nausea, transient Chlebowski et al. 3 x/d dizziness) 1984 (©) HS Reproductive 36 Mouse 25 wk 93 B Biancifiori 1970 (CBA) 150 x HS GW) 37 Hamster 15-20 wk 53 B Biancifiori 1970 (Golden) 60-100 x HS (GW) Cancer 38 Rat 10 wk 4.5 B (CEL: liver angiosarcoma, Teague et al. (DA, HS, 1 x/wk cholangioma, hepatocellular 1981 AS2) (GW) carcinoma, bowel 12DMH adenocarcinoma) 13.6 B (CEL: ear canal papilloma) S103443 H1TV3H 2 S3NIZVHAAH cy TABLE 2-2 Levels of Significant Exposure to Hydrazines - Oral (continued) Exposure/ LOAEL Key * Duration/ to Species/ Frequency NOAEL Less Serious Serious Reference figure (Strain) (Specific Route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 39 Rat 5 wk 30 M (CEL: adenomas and Calvert et al. (Fischer-344) 1 x/wk adenocarcinomas of the 1987 (GO) small intestine and colon) ~~ 12DMH 40 Rat <10 mo 4.2 M (CEL: angiosarcoma of the Bedell et al. (Fischer-344) ad libitum liver and lung, 1982 Ww) hepatocellular carcinoma, ~~ 12DMH renal adenoma and mesenchymal tumors) 41 Rat 11 wk 3 NS (CEL: hemangioendo- Druckrey 1970 (NS) 1 x/wk theliomas of the liver) 12DMH or 5 d/wk 21 NS(CEL: carcinomas of the @) colon, small intestine, and rectum) 42 Rat 10 wk 30 B (CEL: gastrointestinal Asano and (S-D, Lobund- 1 x/wk adenocarcinomas) Pollard 1978 Wistar, (GW) 12DMH Buffalo) 43 Rat 4-8 wk 30 M (CEL: colon and squamous Wilson 1976 (Sprague- 1 x/wk cell carcinoma of the ear) 12DMH Dawley) (GW) 44 Rat 5 wk 27.1 M (CEL: carcinomas of the Locniskar et al. (Sprague- 1 x/wk colon and small intestine) ~~ 1986 Dawley) (GW) 12DMH 45 Rat 9 wk 30 M (CEL: gastrointestinal Abraham et al. (Sprague- 1 x/wk adenomas and 1980 Dawley) (GW) adenocarcinomas) 12DMH S103443 H1IV3aH ¢ S3ANIZVHAAH ey TABLE 2-2 Levels of Significant Exposure to Hydrazines - Oral (continued) Exposure/ LOAEL Key * Duration/ to Specles/ Frequency NOAEL Less Serious Serious Reference figure (Strain) (Specific Route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 46 Rat 9 wk 15 B (CEL: colon adenoma and Barbolt and (Sprague- 1 x/wk adenocarcinoma) Abraham 1980 Dawley) (GW) 12DMH 30 B (CEL: duodenal adenocarcinoma) 47 Rat 10 wk 9 M (CEL: colorectal adenoma, Thorup etal. (Wistar) 1 x/wk adenocarcinoma, and signet 1992 (GW) ring cell carcinoma) 12DMH 48 Mouse 33-48 wk 0.46 M (CEL: lung adenomas and Yamamoto and (AN) ad libitum adenocarcinomas) Weisburger 1970 W) HS 49 Mouse 24 wk 30 F (CEL: angiosarcomas Izumi et al. 1979 (BALB/c) 1 x/wk predominantly in the liver, ~~ 12DMH (GW) adenomas and adenocarcinomas of the lungs and large intestines, and squamous cell carcinomas of the anus) 50 Mouse 46 wk 93 F (CEL: pulmonary adenomas Biancifiori and (Balb/c) 1 xd and adenocarcinomas) Ribacchi 1962 (GW) HS S103443 HITV3H ¢ S3ANIZVHAAH Exposure/ TABLE 2-2 Levels of Significant Exposure to Hydrazines - Oral (continued) . LOAEL Key Duration/ to Species/ Frequency NOAEL Less Serious Serious Reference figure (Strain) (Specific Route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 51 Mouse 10-48 wk 19 B (CEL: hemangiomas and Izumi et al. 1979 (BALB/c) ad libitum hemangioendotheliomas 12DMH (W) predominantly in the liver, adenomas and adenocarcinomas of the lungs) 15.2 (CEL: adenomas and adenocarcinomas of the large intestine and squamous cell carcinomas of the anus) 52 Mouse 25 wk 2.3 (CEL: hepatomas) Biancifiori 1970 (CBA) 150 x HS (GW) 53 Mouse 36 wk 9.2 (CEL: lung adenomas Biancifiori et al. (CBA) 7 d/wk adenocarcinomas, 1964 1 xd hepatomas) HS (GW) 54 Mouse 40 wk 16.7 (CEL: lung adenomas and ~~ Roe etal. 1967 (Swiss) 5 x/wk adenocarcinomas) H (GW) 55 Mouse 40 wk 33 F (CEL: lung adenomas and Roe et al. 1967 (Swiss) 5 x/wk adenocarcinomas) 11DMH (GW) 56 Mouse 4-11 mo 9 B (CEL: adenocarcinomas of Bhide et al. 1976 (Swiss, A, 6 x/wk the lungs and breast) HS C17, (G) ICRCXC3H) 57 Gn pig 7-10 wk 30 M (CEL: hepatomas and bile ~~ Wilson 1976 (Hartley) 1 x/wk duct cell carcinomas) 12DMH (GW) S103443 HITV3H ¢ SANIZVHAAH 14 TABLE 2-2 Levels of Significant Exposure to Hydrazines - Oral (continued) Exposure/ LOAEL Key * Duration/ to Species/ Frequency NOAEL Less Serious Serious Reference figure (Strain) (Specific Route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form CHRONIC EXPOSURE Death 58 Mouse Lifetime 0.95 B (100% mortality by week 70) Toth and Patil (Swiss) ad libitum 1982 WwW) 12DMH Systemic 59 Mouse 2yr Resp 95 B Steinhoff et al. (NMR) ad libitum 1990 (W) HH Cardio 95 B Gastro 95 B Musc/skel 95 B Hepatic 95 B Renal 95 B Derm 95 B Bd Wt 1.9 B 9.5 B (reduced body weight gain by 10%, and ruffled coats) Cancer 60 Rat 68 wk 12 B (CEL: lung adenomas and ~~ Biancifiori et al. (CBRI/SE) 215x carcinomas) 1966 (GW) HS 61 Mouse 55 wk 9 B (CEL: lung tumors) Maru and Bhide (Swiss) 5 d/wk 1982 1 x/d HS (GW) 62 Mouse Lifetime 1.9 B (CEL: lung adenomas) Toth 1972b (Swiss) ad libitum H Ww) S103443 H1V3H 2 S3ANIZVHAAH av TABLE 2-2 Levels of Significant Exposure to Hydrazines - Oral (continued) Exposure/ LOAEL Key * Duration/ to Species/ Frequency NOAEL Less Serious Serious Reference figure (Strain) (Specific Route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 63 Mouse Lifetime 19 B (CEL: angiosarcomas Toth 1973a (Swiss) ad libitum predominantly in the liver, ~~ 11DMH Ww) hepatomas, adenomas and adenocarcinomas of the lungs, and adenomas of the kidneys) 64 Mouse Lifetime 0.059 B (CEL: angiomas and Toth and Patil (Swiss) ad libitum angiosarcomas) 1982 (W) 12DMH 65 Mouse 13-18 mo 9 B (CEL: adenocarcinomas of ~ Bhide etal. 1976 (Swiss, A, 6 x/wk the lungs and breast) HS C17, (G) ICRCxC3H) 66 Mouse Lifetime 56 B (CEL: lung adenomas and Toth 1969 (Swiss, C3H, ad libitum adenocarcinomas) HS AKR) Ww) 67 Hamster 2yr 8.3 M (CEL: hepatocellular Bosan et al. (Syrian ad libitum carcinoma, adrenal cortical 1987 Golden) (W) adenoma) HS 68 Hamster Lifetime 1.1 B (CEL: angiosarcomas Toth 1972 (Syrian (W) predominantly in the liver) ~~ 12DMH Golden) *The number corresponds to entries in Figure 2-2. Used to derive an intermediate oral miminimal risk level (MRL) of 8X10-* mg/kg/d dose 1,2-dimethylhydrazine; dose divided by an uncertainty factor of 1,000 (10 for use of a LOAEL, 10 for extrapolation from animals to humans, and 10 for human variability). 11DMH = 1,1-dimethylhydrazine; 12DMH = 1,2-dimethylhydrazine; Bd Wt = body weight; (C) = capsule; Cardio = cardiovascular; CEL = cancer effect level; d = day(s); Derm = dermal; Endocr = endocrine; (F) = feed: (G) = gavage (not specified); Gastro = gastrointestinal; GD = gestation day(s); Gn pig = guinea pig; (GO) = gavage (oil); (GW) = gavage (water); H = hydrazine; HS = hydrazine sulfate; HH = hydrazine hydrate; LD50 = lethal dose (50% kill); LOAEL = lowest-observed-adverse-effect level; mg/kg/d = milligram per kilogram per day; mo = month(s); Musc/skel = musculoskeletal; NOAEL = no-observed-adverse-effect level; NS = not specified; Resp = respiratory; (W) = drinking water; wk = week(s); x = times(s); yr = year(s) S103443 H1TV3H ¢ S3ANIZVHAAH Ly (mg/kg/day) 1,000 100 10 Figure 2-2. Levels of Significant Exposure to Hydrazines - Oral Acute (<14 days) Systemic AN (eg N oO Na aN x Ns P . $ S . & . CO > $$ * > oO 3 {D RX < & * & SY & ¢ ® 3m O ° ° 10s 2m & ? ® a O Qo 11s 5d 9d 9d 8r B® ad 9 * im 6r r $ 13r * Hn 12r 14r im Key r Rat HB LD50 Mouse @ LOAEL for serious effects (animals) The number next to each d Dog (PD LOAEL for less serious effects (animals) point corresponds to entries s Hamster O NOAEL (animals) in Table 2-2. p Pig A LOAEL for serious effects (humans) ' Minimal risk level for effects g Guinea pig A LOAEL for less serious effect (humans) , other than cancer 4 CEL - Cancer Effect Level (animals) wv “Doses represent the lowest dose tested per study existence of a threshold for the cancer end point. that produced a tumorigenic response and do not imply the S103443 HITV3H 2 S3INIZVHAAH 8y Figure 2-2. Levels of Significant Exposure to Hydrazines - Oral (continued) Chronic (>365 days) Systemic $2 a S$ xO > 2 S° & * (mg/kg/day) @ FTE NL & FF FSR N o FRE FoR oF of rd QV © WRT QT O 100 — * 66m 10 O O O ¢ 2 3 2 = 59m 59m 59m 3 O or 4 63m * eo ¢ 1H—@ oon 61m @ m 67s 0.1 58m 62M cam 68s Co ¢ 0.01 — 0.001 — 0.0001 — , - | 10° Estimated Estimated 0.00001 «| Upper \ 5 | Upper 10° Bound 10° Estimated Bound Human 0.000001 — Human 5 | Upper 6 __| Cancer Risk 0.0000001 — 106 — Cancer 10% — Bound 107° Levels for . 107 Risklsuets 6 Human Riek 107 11DMH or - ancer Ris 0.00000001 — 10 ,_] Levels or % 12DMH 0.000000001 [— : 10 0 e 0.0000000001 |— ’ Rat IB LD50 0.00000000001 — 5 MOUSE & LOAEL for serious effects (animals) The number next to each 0.000000000001 d Do (D LOAEL for less serious effects (animals) point corresponds to entries 0.0000000000001 — ¢ Hamster OQ NOAEL (animals) nee p Pig A LOAEL for serious effects (humans) ' Minimal risk level for effects g Guinea pig A LOAEL for less serious effect (humans) , other than cancer 4 CEL - Cancer Effect Level (animals) v *Doses represent the lowest dose tested per study that produced a tumorigenic response and do not imply the existence of a threshold for the cancer end point. S103443 HLIVaH ¢ S3ANIZVHAAH 6 Figure 2-2. Levels of Significant Exposure to Hydrazines - Oral (continued) Intermediate (15-364 days) Systemic N \ FP WY 2 oO» S A” > nN &F FEES : (mg/kg/day) & 5S & @ Ss SE & © & » Q 2 N PC) > 160 i PR FER TIF & o fe — 21p 39 43 55m 30 24r go; r I 44r 46r 49m oe I 60 ay 4000.000 , 100 ® 5m @® ® 31g O3ig Bm @ a2r 51 $$ 5g 10 |= 20d 29d 2ar 0 41r 51m & 3 28s 0 38r sr @@ $$ 41r 47r 50m 56m 16m - 25m 25m 29d 25m 288 7 ® ®o o I O 17m ® 0 ® A 40 ® 17 O ® 26m O27m AA 51m 52m 25m 25m 25m 33 35 & 1 48m 0.1 — | | I | 0.01 — | | I 0.001 — W Key 0.0001 r Rat Ws | m Mouse @ LOAEL for serious effects (animals) The number next to each d Dog (D LOAEL for less serious effects (animals) point corresponds to entries . in Table 2-2. 8 Hamster O NOAEL (aniriats) p Pig A LOAEL for serious effects (humans) Minimal risk level for effects g Guinea pig A LOAEL for less serious effect (humans) , other than cancer @ CEL - Cancer Effect Level (animals) wv “Doses represent the lowest dose tested per study that produced a tumorigenic response and do not imply the existence of a threshold for the cancer end point. S103443 H1TV3H 2 S3ANIZVHAAH 0S HYDRAZINES 51 2. HEALTH EFFECTS observed in dogs administered weekly doses of 60 mg/kg 1,2-dimethylhydrazine for 2 weeks (Wilson 1976). Intermediate-duration exposure to 1,2-dimethylhydrazine produced liver damage (hemosiderosis, necrosis, hepatitis, fibrosis, ascites and/or failure) in rats receiving 4.2 mg/kg/day (Bedell et al. 1982), guinea pigs receiving 30 mg/kg/day or more (Wilson 1976), mice receiving 0.75 mg/kg/day or more (Visek et al. 1991), dogs receiving 5 mg/kg/day or more (Wilson 1976), and pigs receiving 30 mg/kg/day (Wilson 1976). Cirrhosis, reticuloendothelial cell proliferation, bile duct proliferation, and degenerative fibrous cells were observed in the livers of hamsters exposed to 4.9 mg/kg/day hydrazine for 15-20 weeks (Biancifiori 1970). No adverse effects were observed in the livers of mice receiving 9.5 mg/kg/day hydrazine for 2 years (Steinhoff et al. 1990). Collectively, these data indicate that hydrazine and 1,2-dimethylhydrazine are hepatotoxic by the oral route. Based on a LOAEL of 0.75 mg/kg/day for hepatic effects in mice (Visek et al. 1991), an intermediate oral MRL of 8x10 mg/kg/day was calculated for 1,2-dimethylhydrazine as described in footnote "b" in Table 2-2. Renal Effects. Interstitial nephritis and pyelonephritis were observed in mice receiving 1.6 mg/kg/day 1,2-dimethylhydrazine in feed for 5 months (Visek et al. 1991). These effects were not observed in mice similarly exposed to 0.75 mg/kg/day 1,2-dimethylhydrazine. No adverse effects were noted in the kidneys of mice receiving 9.5 mg/kg/day hydrazine in the drinking water for 2 years (Steinhoff et al. 1990). These data are too limited to make firm conclusions but suggest that 1,2-dimethylhydrazine is toxic to the kidneys and hydrazine is not. Endocrine Effects. Degeneration of the adrenals was noted in female mice exposed to 1.1 mg/kg/day or more hydrazine for 25 weeks (Biancifiori 1970). No adverse effects were noted in the thyroid of mice exposed to 9.3 mg/kg/day hydrazine for 25 weeks. Similarly, no effects were observed in the thyroid or adrenals of hamsters exposed to 5.3 mg/kg/day hydrazine for 15-20 weeks (Biancifiori 1970). Dermal Effects. No adverse effects were observed in the skin of mice receiving 9.5 mg/kg/day hydrazine in their drinking water for 2 years (Steinhoff et al. 1990). No other studies were located regarding dermal effects in animals after oral exposure to hydrazines. HYDRAZINES 52 2. HEALTH EFFECTS Ocular Effects. No adverse effects were observed in the eyes of mice receiving 9.5 mg/kg/day hydrazine in their drinking water for 2 years (Steinhoff et al. 1990). No other studies were located regarding ocular effects in animals after oral exposure to hydrazines. Body Weight Effects. Body weight loss and decreased body weight gain were reported in animals exposed orally to 1,2-dimethylhydrazine and hydrazine. Weight loss was noted in dogs receiving 2 weekly doses of 60 mg/kg/day (Wilson 1976). Decreased body weight gains were reported for intermediate-duration exposure to 1,2-dimethylhydrazine for rats receiving 30 mg/kg/day (Barbolt and Abraham 1980), guinea pigs receiving 30 mg/kg/day (Wilson 1976), and in mice receiving 0.75 mg/kg/day or more (Visek et al. 1991). Decreased body weight gain was also noted in mice chronically exposed to 9.5 mg/kg/day hydrazine in the drinking water for 2 years (Steinhoff et al. 1990). No significant effect on body weight gain was noted in mice receiving 1.9 mg/kg/day. Decreases in body weight were often accompanied by decrements in food intake, organ weights, and altered physical appearance and therefore probably represent signs of general toxicity. In some cases, decreased body weight gain may be secondary to an underlying disease (e.g., cancer). 2.2.2.3 Immunological and Lymphoreticular Effects No studies were located regarding immunological and lymphoreticular effects in humans after oral exposure to hydrazines. A single study in rats reported that splenic natural killer cell activity was not affected after exposure to 27.1 mg/kg/day 1,2-dimethylhydrazine once a week for 5 weeks (Locniskar et al. 1986). This NOAEL value is recorded in Table 2-2 and plotted in Figure 2-2. 2.2.2.4 Neurological Effects Ingestion of hydrazine (estimated between a mouthful and a cupful) resulted in several neurological effects including episodes of violent behavior, ataxia, coma, convulsions, hypesthesia of the hands, and paraesthesia of the arms and legs (Reid 1965). Confusion, lethargy, restlessness, paresthesia, and neurogenic atrophy were observed in a 24-year-old male who swallowed a mouthful of hydrazine (Harati and Niakan 1986). Hydrazine has been used as a chemotherapeutic agent in human cancer patients. Neurological side effects have been observed in some human cancer patients (4-50%) treated HYDRAZINES 53 2. HEALTH EFFECTS with 0.2-0.7 mg/kg/day hydrazine as hydrazine sulfate for intermediate durations (Chlebowski et al. 1984; Gershanovich et al. 1976, 1981; Ochoa et al. 1975; Spremulli et al. 1979). For the most part, the neurological effects were relatively mild (lethargy, nausea, vomiting, dizziness, excitement, insomnia); however, two studies reported more serious effects (paresthesia, sensorimotor abnormalities, polyneuritis) (Gershanovich et al. 1976; Ochoa et al. 1975). The appearance of more serious effects in these two studies may be related to increased exposure duration. For example, Gershanovich et al. (1976, 1981) noted that polyneuritis developed only in patients receiving uninterrupted treatment with hydrazine for 2-6 months. The treatment duration used by Chlebowski et al. (1984) and Spremulli et al. (1979), which was less than 2 months in both studies, may have been sufficiently short enough to prevent the development of more serious neurological effects. Limitations in the findings of these studies lie in the fact that the test subjects were generally not healthy prior to hydrazine exposure. Therefore it is possible that some of the observed effects may be attributable to the underlying disease. However, collectively these studies strongly suggest that the central nervous systems is a target of hydrazine in humans after oral exposure. The highest NOAEL values and all LOAEL values for neurological effects resulting from oral exposure to hydrazines are recorded in Table 2-2 and plotted in Figure 2-2. No studies were located regarding neurological effects in animals after oral exposure to hydrazines. 2.2.2.5 Reproductive Effects No studies were located regarding reproductive effects in humans after oral exposure to hydrazines. A single animal study reported no histopathological lesions in the ovaries of mice and hamsters exposed to 9.3 or 5.3 mg/kg/day hydrazine, respectively, for 15-25 weeks (Biancifiori 1970). However, the findings of this study are limited since reproductive function was not assessed. These NOAEL values for reproductive effects are recorded in Table 2-2 and plotted in Figure 2-2. 2.2.2.6 Developmental Effects No studies were located regarding developmental effects in humans after oral exposure to hydrazines. HYDRAZINES 54 2. HEALTH EFFECTS A single study in hamsters reported no evidence of developmental toxicity or teratogenicity following exposure to a single dose of 166 mg/kg hydrazine or 68 mg/kg 1,2-dimethylhydrazine on day 12 of gestation (Schiller et al. 1979). Although these data are limited, they suggest that fetal development is not adversely affected by hydrazine or 1,2-dimethylhydrazine. These NOAEL values for developmental effects resulting from oral exposure to hydrazines are recorded in Table 2-2 and plotted in Figure 2-2. 2.2.2.7 Genotoxic Effects No studies were located regarding genotoxic effects in humans after oral exposure to hydrazines. Alkylation of liver DNA was reported in rats acutely exposed to 30-90 mg/kg hydrazine for 1-3 days (Becker et al. 1981; Bosan et al. 1986). Micronuclei were observed in the bone marrow of mice exposed to a single oral dose of 10-50 mg/kg 1,2-dimethylhydrazine (Albanese et al. 1988; Ashby and Mirkova 1987). However, micronuclei were not observed in the bone marrow of rats after a single oral dose of 50-80 mg/kg 1,2-dimethylhydrazine (Ashby and Mirkova 1987). These data indicate that hydrazine and 1,2-dimethylhydrazine are genotoxic by the oral route. Furthermore, species differences may exist between rats and mice regarding their sensitivity to the genotoxic effects of 1,2-dimethylhydrazine. Other genotoxicity studies are discussed in Section 2.5. 2.2.2.8 Cancer No studies were located regarding carcinogenic effects in humans after oral exposure to hydrazines. Adenomas and adenocarcinomas of the colon have been observed in rats following a single oral exposure to 15.8-30 mg/kg 1,2-dimethylhydrazine (Craven and DeRubertis 1992; Schiller et al. 1980; Watanabe et al. 1985). Colon tumors are not common to rats and were not observed in the control animals of these studies. Several tumor types have been observed in animals after intermediate-duration exposure to hydrazines. Exposure to 0.46-16.7 mg/kg/day hydrazine for 24-48 weeks produced a statistically significant HYDRAZINES 55 2. HEALTH EFFECTS increase in the incidence of lung, liver, and breast tumors in mice (Bhide et al. 1976; Biancifiori 1970; Biancifiori and Ribacchi 1962; Biancifiori et al. 1964; Roe et al. 1967; Yamamoto and Weisburger 1970). A single study reported an increased incidence of lung tumors in mice after daily administra- tion of 0.25 mg hydrazine or 0.5 1,1-dimethylhydrazine (0.8 or 1.7 mg/kg/day, respectively), 5 times per week for 40-50 or 50-60 weeks (Roe et al. 1967). A large number of studies have reported tumors in rodents after intermediate exposure to 1,2-dimethylhydrazine. Statistically significant increases were reported for tumor incidences of the blood vessels (Bedell et al. 1982; Druckrey 1970; Izumi et al. 1979; Teague et al. 1981), liver (Bedell et al. 1982; Teague et al. 1981; Wilson 1976), lung (Izumi et al. 1979), kidney (Bedell et al. 1982), ear duct (Teague et al. 1981; Wilson 1976), and most notably the intestines, colon, and anus (Abraham et al. 1980; Asano and Pollard 1978; Barbolt and Abraham 1980; Calvert et al. 1987; Druckrey 1970; Izumi et al. 1979; Locniskar et al. 1986; Teague et al. 1981; Thorup et al. 1992: Wilson 1976). Doses of 1,2-dimethylhydrazine resulting in increased tumor incidence ranged from 1.9 mg/kg/day to 30 mg/kg/day. Chronic oral exposure to hydrazines has also resulted in statistically significant increases in the incidence of tumors in rodents. Exposure to 1.9-12 mg/kg/day hydrazine resulted in lung tumor formation in rats and mice (Biancifiori et al. 1966; Bhide et al. 1976; Maru and Bhide 1982; Toth 1969, 1972b). In hamsters, exposure to 8.3 mg/kg/day hydrazine produced an increased incidence of liver and kidney tumors (Bosan et al. 1987). The difference in target organ specificity for the carcinogenic effects of hydrazine may represent an important species difference between hamsters and other laboratory rodents. Several tumor types, including those of the blood vessels, lung, kidney, and liver were noted at elevated incidences in mice chronically exposed to 19 mg/kg/day 1,1-dimethylhydrazine in the drinking water (Toth 1973a). Studies have reported a statistically significant increase in the incidence of blood vessel tumors in mice exposed to 0.059 mg/kg/day 1,2-dimethylhydrazine (Toth and Patil 1982) and in hamsters exposed to 1.1 mg/kg/day 1,2-dimethylhydrazine in the drinking water for life (Toth 1972c¢). Collectively, these data indicate that hydrazines are carcinogenic by the oral route following acute, intermediate, or chronic exposure, and are capable of producing tumors in multiple tissue sites in several different animal species. Clearly, 1,2-dimethylhydrazine is the most potent carcinogen of the three hydrazines, since significant tumor incidences have been reported following single doses (Craven and DeRubertis 1992; Schiller et al. 1980; Watanabe et al. 1985) and at very low chronic doses (Toth and Patil 1982). Hydrazine and 1,1-dimethylhydrazine are less potent carcinogens, producing tumors HYDRAZINES 56 2. HEALTH EFFECTS primarily in the lungs (Bhide et al. 1976; Biancifiori et al. 1966; Maru and Bhide 1982; Roe et al. 1967). All CEL values from each reliable study resulting from oral exposure to hydrazines are recorded in Table 2-2 and plotted in Figure 2-2. The EPA has derived oral slope factors of 30 (mg/kg/day) for hydrazine based on liver tumors, 2.6 (mg/kg/day) for 1,1-dimethylhydrazine based on tumors of the cardiovascular system, and 37 (mg/kg/day) for 1,2-dimethylhydrazine based on tumors of the cardiovascular system (HEAST 1992; IRIS 1993). Doses of hydrazine, 1,1-dimethylhydrazine, and 1,2-dimethylhydrazine corresponding to excess cancer risks of 10 to 107 are shown in Figure 2-2. 2.2.3 Dermal Exposure 2.2.3.1 Death No studies were located regarding lethal effects in humans after dermal exposure to hydrazines. In rabbits and guinea pigs, the dermal LD, values ranged from 93 to 190 mg/kg, 1,341 to 1,680 mg/kg, and 158 to 563 mg/kg for hydrazine, 1,1-dimethylhydrazine, and 1,2-dimethylhydrazine, respectively (Rothberg and Cope 1956). One out of four dogs administered a single dermal dose of 300 mg/kg 1,1-dimethylhydrazine died 6 hours after exposure (Smith and Clark 1971). All dogs (three out of three) exposed to a single dermal dose of 1,800 mg/kg 1,1-dimethylhydrazine died within 6 hours. In dogs exposed to hydrazine, two of three died following exposure to a single dermal dose of 96 mg/kg (Smith and Clark 1972). Additional deaths were noted in this study at higher dermal doses of hydrazine. These data indicate that acute dermal exposure to large doses of hydrazines can be lethal. These LOAEL values are recorded in Table 2-3. The lack of repeat dermal exposure studies in animals is probably due to the corrosiveness of hydrazines and their ability to induce dermal sensitization reactions. 2.2.3.2 Systemic Effects No studies were located regarding respiratory, cardiovascular, gastrointestinal, musculoskeletal, hepatic, or renal effects in humans or animals after dermal exposure to hydrazines. All LOAEL values for hematological, dermal, and ocular effects from each reliable study are recorded in Table 2-3. TABLE 2-3. Levels of Significant Exposure to Hydrazines - Dermal Exposure/ Duration/ Specles/ Frequency/ (Strain) (Specific Route) System ACUTE EXPOSURE Death Dog Once (Mongrel) Dog Once (Mongrel) Rabbit Once (Albino) Rabbit Once (Albino) Rabbit Once (Albino) Gn pig Once (NS) Gn pig Once (NS) Gn pig Once (NS) NOAEL (mg/kg/day) Less Serious (mg/kg/day) 300 M (1/4 deaths) 96 M (2/3 deaths) 467 NS (LD50) 1059 NS (LD50) 93 NS (LD50) 190 NS (LD50) 1327 NS (LD50) 131 NS (LD50) Reference Chemical Form Smith and Clark 1971 11DMH Smith and Clark 1972 H Rothberg and Cope 1956 12DMH Rothberg and Cope 1956 11DMH Rothberg and Cope 1956 H Rothberg and Cope 1956 H Rothberg and Cope 1956 11DMH Rothberg and Cope 1956 12DMH S103443 H1TV3H 2 S3ANIZVHAAH LS TABLE 2-3. Levels of Significant Exposure to Hydrazines - Dermal (continued) Exposure/ LOAEL Duration/ Specles/ Frequency/ NOAEL Less Serious Serious Reference (Strain) (Specific Route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form Systemic Dog Once Derm 300 M (slight irritation of the skin) Smith and Clark (Mongrel) 1971 11DMH Dog Once Derm 96 M (discoloration and edema Smith and Clark (Mongrel) of the skin) 1972 H Dog Once Hemato 300 NS (decreased Smith and (NS) thromboplastin generation Castaneda 1970 time) 11DMH Ocular 300 NS (corneal swelling) 11DMH = 1,1-dimethylhydrazine; 12DMH = 1,2-dimethylhydrazine; Derm = dermal; Gn pig - guinea pig; H = hydrazine; Hemato = hematological; LD50 = lethal dose (50% kill); LOAEL = lowest-observed-adverse-effect level; mg/kg = milligram per kilogram; NOAEL = no-observed-adverse-effect level; NS = not specified. S103443 H1IV3H 2 S3NIZVHAAH 8S HYDRAZINES 59 2. HEALTH EFFECTS Hematological Effects. No studies were located regarding hematological effects in humans after dermal exposure to hydrazines. Data in animals regarding hematological effects are limited to a single study. A decreased thromboplastin generation time was noted in dogs exposed to a single dose of 300 mg/kg 1,1-dimethylhydrazine (Smith and Castaneda 1970). No other blood coagulation parameters were significantly affected. Dermal Effects. Dermal exposure to hydrazine produces contact dermatitis. A number of studies have reported contact dermatitis in humans after dermal exposure to solutions containing 0.00005% to 1% hydrazine (Frost and Hjorth 1959; Hovding 1967; Suzuki and Ohkido 1979; Van Ketel 1964; Wrangsjo and Martensson 1986). These studies clearly indicate that hydrazine is a sensitizing agent. Exposure to a single dermal dose of 93-190 mg/kg hydrazine resulted in discoloration of the exposed area in rabbits and guinea pigs (Rothberg and Cope 1956). Dermal discoloration and edema of the skin (application area) were observed in dogs dermally exposed to a single dose of 96 mg/kg hydrazine or more (Smith and Clark 1972). Discoloration was also observed in dogs after dermal exposure to a single dose of 300 mg/kg 1,1-dimethylhydrazine (Smith and Clark 1971). Ocular Effects. No studies were located regarding ocular effects in humans after dermal exposure to hydrazines. A single application of 3 pL of hydrazine, 1,1-dimethylhydrazine, or 1,2-dimethylhydrazine directly to the eyes produced conjunctivitis and erythema of the eyelids in rabbits (Rothberg and Cope 1956). Corneal damage was also noted in rabbits exposed to hydrazine but not in rabbits exposed to 1,1-dimethylhydrazine or 1,2-dimethylhydrazine. Dermal exposure to a single dose of 5 mmole/kg 1,1-dimethylhydrazine produced corneal swelling in dogs (Smith and Castaneda 1970). Although the ocular effects observed in this study may have resulted from hydrazine that was absorbed systemically, it is also possible that direct exposure of the eyes to hydrazine vapors was responsible for this effect. These data indicate that all three hydrazines can produce effects on the eyes. HYDRAZINES Ls 2. HEALTH EFFECTS 2.2.3.3 Immunological and Lymphoreticular Effects Data regarding the immunological or lymphoreticular effects of hydrazines in humans after dermal exposure are limited to a single case study. A female laboratory worker intermittently exposed to an undetermined amount of hydrazine developed a lupus erythematosus-like disease (Reidenberg et al. 1983). Symptoms included a photosensitive rash, fatigue, anthragias, and a breaking off of frontal hair. The subject also possessed antinuclear antibodies and antibody to DNA. A positive skin patch test response was obtained after a dermal challenge to hydrazine was administered. The study authors concluded that hydrazine can induce a lupus erythematosus-like disease in predisposed persons. In support of this view, a number of other hydrazine derivatives have been linked to the induction of lupus erythematosus in humans (Pereyo 1986). As discussed in Section 2.2.3.2, dermal exposure to hydrazine also produces allergic contact dermatitis in humans. No data were located regarding the immunological or lymphoreticular effects in animals after dermal exposure to hydrazines. 2.2.3.4 Neurological Effects Data regarding neurological effects in humans after dermal exposure to hydrazines are limited to two case studies. A man who suffered burns during an industrial hydrazine explosion became comatose 14 hours after the explosion (Kirklin et al. 1976). Rapid recovery from the coma was facilitated by pyridoxine treatment. Another man who suffered burns during an industrial 1,1-dimethylhydrazine explosion exhibited abnormal EEG readings and narcosis within 40 hours after exposure (Dhennin et al. 1988). Recovery from these symptoms was also facilitated by pyridoxine treatment. Several months after the incident the latter worker developed polyneuritis. The findings from these studies are limited because the subjects were burn patients. The trauma from the burns may have played a role in some of the neurological effects observed. In addition, pyridoxine is also known to produce neurological effects at high doses, and may have been partially responsible for the delayed polyneuritis. Mild convulsions were noted in 3 of 13 dogs receiving a single dermal dose of 300-1,800 mg/kg 1,1-dimethylhydrazine (Smith and Clark 1971). Similarly, convulsions were noted in 3 of 25 dogs administered a single dermal dose of 96-480 mg/kg hydrazine (Smith and Clark 1972). The data from HYDRAZINES 61 2. HEALTH EFFECTS animal studies support the findings of the human case studies which indicate that hydrazine and 1,1-dimethylhydrazine adversely affect the central nervous system following large dermal exposures. No studies were located regarding the following effects in humans or animals after dermal exposure to hydrazines: 2.2.3.5 Reproductive Effects 2.2.3.6 Developmental Effects 2.2.3.7 Genotoxic Effects Genotoxicity studies are discussed in Section 23. 2.2.3.8 Cancer No studies were located regarding cancer effects in humans or animals after dermal exposure to hydrazines. 2.3 TOXICOKINETICS No data were located regarding the toxicokinetics of hydrazines in humans after inhalation, oral, or dermal exposure to hydrazines. Inhalation, oral, and dermal studies in animals indicate that hydrazines are rapidly absorbed into the blood. Animal studies also indicate that hydrazines readily distribute to tissues without preferential accumulation at any specific site. Hydrazines with a free amino group are able to react with endogenous alpha-keto acids and in so doing produce a variety of adverse health effects. In vivo and in vitro studies indicate that hydrazines are metabolized by several pathways, both enzymatic and nonenzymatic. Free radical and carbonium ion intermediates are produced during the metabolism of hydrazines and may also be involved in adverse health effects produced by exposure to hydrazines. Limited data from animal studies indicate that metabolites of hydrazines are excreted principally in the urine and expired air. Although the data are limited, animal studies appear to indicate that the toxicokinetics of hydrazines may vary among animal species. HYDRAZINES 62 2. HEALTH EFFECTS 2.3.1 Absorption 2.3.1.1 Inhalation Exposure No studies were located regarding absorption in humans after inhalation exposure to hydrazines. A single animal study was located which investigated the absorption of hydrazine in the lungs. Groups of eight rats were exposed to concentrations of 10, 60, or 500 ppm hydrazine in a nose-only chamber for 1 hour (Llewellyn et al. 1986). Based on the levels of hydrazine and its metabolites excreted in the urine within 48 hours, the absorption of hydrazine was estimated to be at least 8.4-29.5%. However, because a large percentage of the dose may have been retained in the body or excreted by fecal or pulmonary routes, absorption in the lungs is probably significantly higher than 8.4-29.5%. 2.3.1.2 Oral Exposure No studies were located regarding absorption in humans after oral exposure to hydrazines. It should be noted, however, that the drug isoniazid, which is used to treat tuberculosis, is metabolized to hydrazine, and thus patients administered isoniazid exhibit elevated levels of hydrazine in their blood plasma (Blair et al. 1985). A single animal study was located which investigated the oral absorption of hydrazine. Groups of 15 rats were administered a single dose of hydrazine, ranging from 2.9 to 81 mg/kg (Preece et al. 1992a). Based on the levels of hydrazine and its metabolites excreted in the urine within 24 hours, at least 19-46% of the administered dose was absorbed. However, since the analytical method employed in this study cannot detect certain metabolites of hydrazine, and since 24 hours may have been too short a time period to collect all urinary metabolites, the absorption of hydrazine in the gastrointestinal tract is most likely higher than 19-46%. In a more detailed description of presumably the same study, Preece et al. (1992b) reported dose saturation effects with respect to urinary excretion and liver concentration of hydrazine. Both the ratio of plasma to liver hydrazine levels and the proportion of hydrazine and acetylhydrazine excreted in the urine declined with the dose. These authors also reported that evidence of fatty liver and reduction in liver and body weights occurred only at the highest dose examined (81 mg/kg). HYDRAZINES 63 2. HEALTH EFFECTS 2.3.1.3 Dermal Exposure No studies were located regarding absorption in humans after dermal exposure to hydrazines. Two studies in dogs reported that hydrazine and 1,1-dimethylhydrazine were detected in the blood within 30 seconds of exposure to a single dermal dose (Smith and Clark 1971, 1972). In dogs exposed to a single dermal dose of 96-480 mg/kg hydrazine, maximum levels of hydrazine in the blood (approximately 70 pg/L) were detected 3 hours after exposure (Smith and Clark 1972). Similarly, in dogs exposed to a single dermal dose of 300-1,800 mg/kg 1,1-dimethylhydrazine, the highest levels of 1,1-dimethylhydrazine (approximately 130 pg/mL) were detected 3 hours after exposure (Smith and Clark 1971). These data indicate that hydrazine and 1,1-dimethylhydrazine are rapidly absorbed from the skin into the blood. However, these studies do not provide enough information to estimate the extent to which hydrazine and 1,1-dimethylhydrazine are absorbed. The lack of repeat dermal exposure studies in animals is probably due to the corrosiveness of hydrazines and their ability to induce dermal sensitization reactions. 2.3.2 Distribution 2.3.2.1 Inhalation Exposure No studies were located regarding distribution in humans or animals after inhalation exposure to hydrazines. 2.3.2.2 Oral Exposure No studies were located regarding distribution in humans after oral exposure to hydrazines. A single study in animals reported limited information on the distribution of hydrazine after oral exposure. Following a single oral dose of 2.9-81 mg/kg hydrazine, peak levels of hydrazine in the plasma and liver of rats were achieved within 30 minutes (Preece et al. 1992a). These levels ranged from approximately 0.0003 to 0.01 mg/mL in the plasma and from 0.0006 to 0.006 mg/kg in the liver. The levels of hydrazine in other tissues were not reported. In a more detailed description of presumably the same study, Preece et al. (1992b) found that there was a fivefold greater amount of HYDRAZINES 64 2. HEALTH EFFECTS hydrazine in the liver than in blood plasma 24 hours after dosing. No acetylhydrazine was found at that time. The concentration of hydrazine in the liver (other organs were not examined) did not increase proportionately with the dose, suggesting saturation effects. Similarly, the urinary excretion was dose-dependent, with a greater portion of hydrazine and acetylhydrazine being excreted at lower doses than at higher doses. 2.3.2.3 Dermal Exposure No studies were located regarding distribution in humans or animals after dermal exposure to hydrazines. 2.3.2.4 Other Routes of Exposure No studies were located regarding distribution in humans after exposure to hydrazines. In rats administered a single dose of 9.9 mg/kg hydrazine by subcutaneous injection, hydrazine was observed to rapidly distribute to tissues (Kaneo et al. 1984). Maximum tissue levels were observed within 30 minutes in the liver, lung, plasma, and particularly the kidney. Hydrazine was detected in the brain of rats at levels of 0.5-1 ug/g following intravenous injection of 5.1 mg/kg hydrazine (Matsuyama et al. 1983). The levels of hydrazine in various tissues in rats were reported to decrease with half-times ranging from 2.3 to 3.3 hours (Kaneo et al. 1984). In a series of experiments, groups of rats, rabbits, cats, dogs, and monkeys were administered a single intraperitoneal dose of 1,1-dimethylhydrazine ranging from 10 to 50 mg/kg (Back et al. 1963). The plasma levels of 1,1-dimethylhydrazine in all species reached maximum values within 1 hour of the injection, accounting for up to 14.3% of the dose in dogs and 8.7% of the dose in cats. Plasma levels were not detectable in rats after 2-24 hours, indicating that 1,1-dimethylhydrazine was rapidly distributed to tissues or was excreted. Plasma levels in monkeys tended to drop off after 1 hour and were not detectable after 24 hours. In a limited study, male rats were subcutaneously injected with 50 mg/kg 1,1-dimethylhydrazine or 100 mg/kg 1,2-dimethylhydrazine (Fiala and Kulakis 1981). Plasma levels of these two hydrazines decreased rapidly after exposure, with half-lives of approximately 1 hour for each chemical. HYDRAZINES 65 2. HEALTH EFFECTS In rats administered a single dose of 0.78-80 mg/kg 1,1-dimethylhydrazine by intraperitoneal injection, approximately 71.1% of the dose was retained in the body after 4 hours (Mitz et al. 1962), and approximately 7.1-38.7% of the dose was retained in the body after 53 hours (Dost et al. 1966). Low levels of 1,1-dimethylhydrazine (approximately 0.1-3.1% of the dose) were detected in tissues (brain, liver, kidney, heart, blood) of rats administered a single dose of 11-60 mg/kg 1,1-dimethylhydrazine by intraperitoneal injection (Mitz et al. 1962: Reed et al. 1963). Preferential accumulation of 1,1-dimethylhydrazine was not observed in any organ. Although higher concentrations of 1,1-dimethylhydrazine were detected in the liver and colon of rabbits within 2 hours after receiving a single intravenous or intraperitoneal dose (Back et al. 1963), this was not judged to be evidence of preferential accumulation by the study authors. The highest levels in these rabbits were detected in the liver (8.9%) and colon (11.6%) after 2 hours, whereas other tissue levels ranged from 0.02 to 4.18% of the dose. These data indicate that hydrazines distribute rapidly to all tissues without preferential accumulation following injection of a single dose. Furthermore, tissue levels of hydrazine and 1,1-dimethylhydrazine tend to reach maximal values within 1 hour and are generally not detectable after 24 hours. 2.3.3 Metabolism Several enzymatic and nonenzymatic pathways are involved in the metabolism of hydrazines. Humans with a slow acetylator genotype may accumulate more hydrazine in the plasma because of an impaired ability to metabolize and excrete the compound (Blair et al. 1985). Although the extent to which each pathway contributes to total metabolism may depend somewhat on the route of exposure (a first-pass metabolic effect for oral exposure, for example), the types of pathways involved and metabolites formed do not appear to be dependent on route. Therefore this section discusses the data without reference to route of exposure. While the metabolic pathways of hydrazine, 1,1-dimethylhydrazine, and 1,2-dimethylhydrazine are similar in some ways, there are some important differences. Therefore, data from in vivo and in vitro studies regarding the metabolism of hydrazine, 1,1-dimethylhydrazine, and 1,2-dimethylhydrazine are discussed separately below. Hydrazine. In rats exposed to 10-500 ppm hydrazine for 1 hour, approximately 2-10% of the inhaled dose was excreted in the urine unchanged, 1.7-4% as acetyl hydrazine, and 4.5-11.4% as diacetyl HYDRAZINES 66 2. HEALTH EFFECTS hydrazine (Llewellyn et al. 1986). In rats exposed to a single dose of 16-64 mg/kg hydrazine, approximately 20% was excreted in the urine as an unspecified hydrazine derivative, 30% was excreted in the urine unchanged, and 25% of the nitrogen in hydrazine was released in expired air as nitrogen gas (Springer et al. 1981). In rats administered a single dose of 2-81 mg/kg hydrazine, a small percentage of the dose (1-19%) was recovered in the urine as acetyl hydrazine and/or diacetyl hydrazine within 24-48 hours of exposure (Kaneo et al. 1984; Llewellyn et al. 1986; Preece et al. 1992a). Following exposure to larger doses of 427 mg/kg hydrazine, a number of metabolites were excreted in the urine, including acetyl hydrazine, diacetyl hydrazine, pyruvate hydrazone, urea, and a cyclic compound (1,4,5,6-tetrahydro-6-oxo-3-pyridazine carboxylic acid, a product of the reaction between 2-oxoglutarate and hydrazine) (Preece et al. 1991). These data indicate that hydrazine undergoes acetylation and can react with cellular molecules in vivo. Hydrazine is rapidly metabolized by rat liver microsomes in vitro (Timbrell et al. 1982). Oxygen, nicotinamide-adenine dinucleotide phosphate (NADPH), and active enzyme were required for maximal activity. Metabolism of hydrazine by rat liver hepatocytes was increased when rats were pretreated with cytochrome P-450 inducers (phenobarbital and rifampicin) and was decreased by the addition of cytochrome P-450 inhibitors (metyrapone and piperonyl butoxide) (Noda et al. 1987). Cytochrome P-450 inhibitors and inducers were also reported to increase and decrease hydrazine toxicity, respectively, indicating a relationship between metabolism and toxicity (Timbrell et al. 1982). Free radical formation was reported to occur when hydrazine was incubated with purified NADPH- cytochrome P-450 reductase (Noda et al. 1988). This reaction required NADPH and oxygen, was stimulated by FAD, inhibited by superoxide dismutase, and was unaffected by carbon monoxide. Free radicals were also noted when hydrazine was metabolized in perfused rat livers (Sinha 1987). These free radicals included acetyl, hydroxyl, and hydrogen radicals, the type of which was dependent upon the addition of an activating system (horseradish peroxidase or copper ion) to the perfusate. The occurrence of an acetyl radical suggests that hydrazine is acetylated prior to radical formation. These data indicate that hydrazine is metabolized by cytochrome P-450 but that transformation via other enzyme systems (peroxidases) or nonenzymatic reactions (copper ion-mediated) may occur as well. The formation of free radicals during the metabolism of hydrazine may be important to the mechanism of action of hydrazine toxicity. 1,1-Dimethylhydrazine. In rats administered a single dose of 0.78-60 mg/kg 1,1-dimethylhydrazine, approximately 12-27% of the dose was detected in expired air as carbon dioxide (Dost et al. 1966; HYDRAZINES 67 2. HEALTH EFFECTS Reed et al. 1963). Four hours after receiving a single dose of 40 mg/kg 1,1-dimethylhydrazine, less than 2% of the dose was released in expired air (Mitz et al. 1962). Approximately 3-10% and 20-25% of the dose was recovered in the urine as the glucose hydrazone of 1,1-dimethylhydrazine and an unidentified metabolite (Mitz et al. 1962). The study authors speculated that the unidentified metabolite was another hydrazone of 1,1-dimethylhydrazine. These data indicate that 1,1-dimethyl- hydrazine undergoes demethylation and can react with cellular molecules in vivo. N-demethylation of 1,1-dimethylhydrazine by rat and hamster liver microsomes in vitro required the presence of NADPH and oxygen and was decreased by the addition of flavin-containing monooxygenase inhibitor (methimazole) but not by the addition of cytochrome P-450 inhibitors (Prough et al. 1981). 1,1-Dimethylhydrazine was also noted to be a good substrate for N-oxidation by amine oxidase (Prough 1973). In rat liver microsomes and S-9 fractions, both a nonenzymatic and an enzymatic component were identified for the metabolism of 1,1-dimethylhydrazine (Godoy et al. 1983). Formaldehyde was produced by both components, although the nonenzymatic component dominated the formation of a reactive protein-binding species. In contrast, rat liver slices metabolized 1,1-dimethylhydrazine to carbon dioxide and did not generate any reactive protein-binding species (Godoy et al. 1983), suggesting that in vitro metabolic studies may not be presenting an accurate picture of 1,1-dimethylhydrazine metabolism as it occurs in vivo. The formation of formaldehyde by rat colon microsomes was decreased by the addition of lipoxygenase and cyclooxygenase inhibitors (indomethacin and eicosatetranoic acid) and was stimulated by the addition of fatty acids, suggesting that lipoxygenase and cyclooxygenase may be involved in the colonic metabolism of 1,1-dimethylhydrazine (Craven et al. 1985). Several studies have shown that the reactive binding species generated by 1,1-dimethylhydrazine metabolism may be free radical intermediates. Rat liver microsomes and rat hepatocytes are capable of metabolizing 1,1-dimethylhydrazine to form methyl radical intermediates (Albano et al. 1989; Tomasi et al. 1987). The formation of these radicals was inhibited by the addition of inhibitors of cytochrome P-450 (SKF 525A, metyrapone, and carbon monoxide) and inhibitors of the flavin- containing monooxygenase system (methimazole). The formation of free radicals could also be supported nonenzymatically by the presence of copper ion (Tomasi et al. 1987). These data indicate that at least two independent enzyme systems and one nonenzymatic pathway may be involved in the metabolism of 1,1-dimethylhydrazine. HYDRAZINES 68 2. HEALTH EFFECTS 1,2-Dimethylhydrazine. In vivo studies indicate that 1,2-dimethylhydrazine is metabolized to form azomethane, azoxymethane, methylazoxymethanol, ethane, and carbon dioxide. In rats administered a single dose of 20-200 mg/kg 1,2-dimethylhydrazine, approximately 4-24% and 14-23% of the dose was detected in expired air as carbon dioxide and azomethane, respectively (Fiala et al. 1976; Harbach and Swenberg 1981). Azoxymethane and methylazoxymethanol were detected in the urine of rats injected with 21 mg/kg 1,2-dimethylhydrazine (Fiala et al. 1977). It has been proposed that 1,2-dimethylhydrazine undergoes sequential oxidations to form azomethane, which in turn is metabolized to form azoxymethane and then methylazoxymethanol (Druckrey 1970). Ethane was detected in the expired air of rats exposed to a single dose of 9-91 mg/kg 1,2-dimethylhydrazine (Kang et al. 1988). The study authors proposed that ethane was formed by a dimerization of methyl radicals originating from 1,2-dimethylhydrazine metabolism. These data indicate that oxidation can occur at both the nitrogen and the carbon of 1,2-dimethylhydrazine in vivo and suggest that free radicals may be formed as well. Human colon microsomes and human colon cancer cells were capable of generating formaldehyde from 1,2-dimethylhydrazine in vitro (Newaz et al. 1983). The formation of formaldehyde was decreased by the addition of cytochrome P-450 inhibitors and was increased by the pretreatment of cancer cells with cytochrome P-450 inducers. Interestingly, the study authors noted a gradient with respect to 1,2-dimethylhydrazine metabolism activity in the colon (ascending < transverse < descending). Other studies have reported that the greatest capacity to produce DNA-binding intermediates from 1,2-dimethylhydrazine is in the ascending colon of humans (Autrup et al. 1980a). Rat colon epithelial cells were found to metabolize 1,2-dimethylhydrazine to azoxymethane, methylazoxymethanol, and a reactive binding species (Glauert and Bennink 1983). In the hamster colon cells, surface columnar epithelial cells were found to metabolize 1,2-dimethylhydrazine 2-3 times as well as crypt cells (Sheth-Desai et al. 1987). In addition, metabolism was inhibited by an alcohol dehydrogenase inhibitor (pyrazole). In a rat liver perfusion study, the metabolites of 1,2-dimethylhydrazine were identified as azomethane, azoxymethane, and methylazoxymethanol (Wolter et al. 1984). Rat liver microsomes were found to metabolize 1,2-dimethylhydrazine to azomethane (N-N oxidation) and formaldehyde (C-N oxidation) (Erikson and Prough 1986). These activities were increased in rats pretreated with cytochrome P-450 inducers (phenobarbital) indicating the involvement of this enzyme. Mitochondrial amine oxidase demonstrated considerable activity as well (Coomes and Prough 1983; Erikson and Prough 1986), although 1,2-dimethylhydrazine was not as good a substrate for this enzyme as was 1,1-dimethylhydrazine (Prough 1973). Likewise, HYDRAZINES 69 2. HEALTH EFFECTS 1,2-dimethylhydrazine was not as good a substrate as 1,1-dimethylhydrazine for flavin-containing monooxygenase-mediated metabolism (Prough et al. 1981) or colonic cyclooxygenase and lipoxygenase (Craven et al. 1985). Since 1,2-dimethylhydrazine is a potent colon carcinogen while 1,1-dimethylhydrazine is not carcinogenic for the rodent colon, the significance of these findings is uncertain. Reactive intermediates are formed during the metabolism of 1,2-dimethylhydrazine. In vitro studies indicate that methylazoxymethane can form a reactive species (probably a methyldiazonium ion) either spontaneously (Nagasawa and Shirota 1972) or enzymatically by alcohol dehydrogenase and/or cytochrome P-450 (Feinberg and Zedeck 1980; Sohn et al. 1991). Other in vitro studies suggest that free radicals are formed during the metabolism of 1,2-dimethylhydrazine. For example, as observed with 1,1-dimethylhydrazine, the formation of methyl free radicals from 1,2-dimethylhydrazine in rat liver microsomes and rat hepatocytes was inhibited by cytochrome P-450 inhibitors (SKF 525A, metyrapone, and carbon monoxide) (Albano et al. 1989; Tomasi et al. 1987). However, unlike 1,1-dimethylhydrazine, the formation of methyl radicals was not decreased by the addition of a flavin- containing monooxygenase inhibitor (methimazole), suggesting that this enzyme is not involved in the production of free radicals from 1,2-dimethylhydrazine. Carbon-centered radicals were observed when 1,2-dimethylhydrazine was metabolized by horseradish peroxidase (Augusto et al. 1985; Netto et al. 1987). These data indicate differences exist between the enzyme systems involved in metabolism of 1,2-dimethylhydrazine and 1,1-dimethylhydrazine to reactive intermediates. Reactive intermediates produced during the metabolism of 1,2-dimethylhydrazine are most likely responsible for DNA adducts observed in vivo (Becker et al. 1981; Netto et al. 1992; Pozharisski et al. 1975) and in vitro (Autrup et al. 1980a; Harris et al. 1977; Kumari et al. 1985). There is evidence for both the methyldiazonium and methyl radical as reactive species derived from 1,2-dimethylhydrazine, and it is clear that metabolism of the compound is required for its carcinogenicity. Inhibition of metabolism by disulfiram and other thiono sulfur compounds (Fiala et al. 1977) resulted in inhibition of DNA alkylation (Swenberg et al. 1979) and colon carcinogenicity (Wattenberg 1975). Moreover, azoxymethane and methylazoxymethanol, two metabolites of 1,2-dimethylhydrazine, are also potent colon and liver carcinogens (Williams and Weisburger 1991). HYDRAZINES 70 2. HEALTH EFFECTS 2.3.4 Excretion 2.3.4.1 Inhalation Exposure No studies were located regarding excretion in humans after inhalation exposure to hydrazines. Forty-eight hours after a 1-hour exposure to 10-500 ppm hydrazine, approximately 8.4-29.5% of the inhaled dose was excreted in the urine of rats (Llewellyn et al. 1986). Most of the recovered dose was excreted during the first 24 hours. Three metabolites were identified in the urine as unchanged hydrazine, acetyl hydrazine, and diacetyl hydrazine. No other studies were located regarding excretion in animals after inhalation exposure to hydrazine. 2.3.4.2 Oral Exposure No studies were located regarding excretion in humans after oral exposure to hydrazines. A single study was located that reported excretion in animals after oral exposure to hydrazine. Twenty-four hours after a single oral dose of 2.9-81 mg/kg hydrazine, approximately 19-46% of the dose was recovered in the urine of exposed rats (Preece et al. 1992a). Two metabolites were identified in the urine as unchanged hydrazine and acetyl hydrazine. Fecal excretion and release of the compound in expired air were not investigated in this study. 2.3.4.3 Dermal Exposure No studies were located regarding excretion in humans after dermal exposure to hydrazines. Data in animals regarding the excretion of hydrazines are limited to two studies. In dogs administered a single dermal dose of 300-1,800 mg/kg 1,1-dimethylhydrazine, levels of up to 600 pg/mL 1,1-dimethylhydrazine were detected in the urine within 5 hours (Smith and Clark 1971). Similarly, in dogs administered a single dermal dose of 96-480 mg/kg hydrazine, levels of up to 70 pg/mL were detected in the urine within 3 hours (Smith and Clark 1972). However, neither of these studies examined fecal excretion nor did they provide sufficient information to estimate the fraction of the dose excreted in the urine. HYDRAZINES 71 2. HEALTH EFFECTS 2.3.4.4 Other Exposure No studies were located regarding excretion in humans after other exposures to hydrazines. The levels of hydrazine in the blood were reported to decrease in a biphasic manner in rats administered 16-64 mg/kg hydrazine via indwelling catheters, with half-times of 0.74 and 26.9 hours (Springer et al. 1981). In dogs administered a single dose of 16-64 mg/kg hydrazine via an indwelling cannula, approximately 25% and 50% of the dose was recovered within 48 hours in the expired air and urine, respectively (Springer et al. 1981). Forty-eight hours after receiving a single intravenous dose of 2-12 mg/kg hydrazine, rats excreted approximately 13.8-37.3% of the dose in the urine (Llewellyn et al. 1986). Approximately 29.2% of a single subcutaneous dose of 9.9 mg/kg hydrazine was excreted in the urine of rats after 48 hours (Kaneo et al. 1984). Although these data are limited by the lack of information on fecal excretion, they suggest that the majority of an absorbed dose of hydrazine is excreted in the urine but that a significant fraction of the dose may be released in expired air. In rats administered a single dose of 0.78-80 mg/kg 1,1-dimethylhydrazine, approximately 18.9-76% of the carbon dose was recovered in the urine and 2-23% of the carbon dose was excreted in expired air within 4-53 hours (Dost et al. 1966; Mitz et al. 1962; Reed et al. 1963). Approximately 34.8-39.1% of the carbon dose was excreted in the urine within 5 hours in dogs intraperitoneally injected with 50 mg/kg 1,1-dimethylhydrazine (Back et al. 1963). Approximately 37.2-51.2% of the carbon dose was recovered in the urine within 6 hours in cats intraperitoneally injected with 10-50 mg/kg 1,1-dimethylhydrazine (Back et al. 1963). These studies typically employed a carbon radiolabel (**C-1,1-dimethylhydrazine). This radiolabel can become separated from the rest of the molecule during the demethylation of 1,1-dimethylhydrazine; therefore, these studies may not accurately depict the metabolic fate of the nitrogen contained within the dose. In addition, fecal excretion of 1,1-dimethylhydrazine was not determined in these studies. Despite these limitations, these data suggest that the majority of the carbon from an absorbed dose of 1,1-dimethylhydrazine is excreted in the urine but that a significant fraction of the carbon dose may be released in expired air. In rats treated subcutaneously with 21 mg/kg “C-labelled 1,2-dimethylhydrazine, approximately 13-16% of the radioactivity was released in expired air as CO, within 24 hours, while 14-15% was expired as azomethane and 17% was released in urine (Fiala et al. 1977). A similar rat study found HYDRAZINES 72 2. HEALTH EFFECTS that the levels of radiolabel in expired CO, and azomethane after 24 hours were 11% and 14%, respectively, when the dose was 21 mg/kg 1,2-dimethylhydrazine, and 4% and 23%, respectively, when the dose was 200 mg/kg (Fiala et al. 1976). Likewise, rats injected with 20 mg/kg 1,2-dimethylhydrazine expired about 22% of the radioactive dose as azomethane and about 16% as CO, after 12 hours (Harbach and Swenberg 1981). By quantitating the radioactivity released as azomethane, which contains both nitrogens from the 1,2-dimethylhydrazine, the metabolic fate of these nitrogens can be followed, in contrast to studies which only measure expired CO,. Female mice injected with 15 mg/kg “C-labelled 1,2-dimethylhydrazine expired about 24% of the radioactivity as CO, within 24 hours, while 10% was excreted in the urine (Hawks and Magee 1974). This same study found that 0.9% of the radioactivity was excreted in the bile after a dose of 200 mg/kg. These data suggest that a significant fraction of the carbon dose of 1,2-dimethylhydrazine may be released in expired air and urine, whereas fecal excretion is relatively low. 2.4 MECHANISMS OF ACTION Studies in animals indicate that hydrazines are rapidly absorbed through the skin (Smith and Clark 1971, 1972), and presumably in the lungs and gastrointestinal tract as well. Although the mechanism by which hydrazines are absorbed into the blood has not been studied, this most likely does not occur by passive diffusion because of the polar nature of these compounds. A number of studies have investigated the mechanisms by which hydrazines produce adverse health effects. These data suggest there are at least two distinct mechanisms of action for hydrazines: one involving the direct binding of those hydrazines with a free amino group (hydrazine and 1,1-dimethylhydrazine) to key cellular molecules, and the other involving the generation of reactive species such as free radical intermediates or methyldiazonium ions as a result of metabolism. Studies which support the existence of these mechanisms are discussed below. In vitro studies have shown that hydrazine reacts with alpha-keto acids to form hydrazone compounds (O'Leary and Oikemus 1956). By binding to keto acids and forming hydrazones, hydrazine inhibited oxygen consumption with mitochondrial substrates in vitro (Fortney 1967). This mechanism may well account for the hyperlactemic and hypoglycemic effects of hydrazine observed in humans (Ochoa et al. 1975) and dogs in vivo (Fortney 1967). Hydrazine and 1,1-dimethylhydrazine can form hydrazones with vitamin Bg derivatives (Cornish 1969). By binding to vitamin By derivatives, hydrazine and HYDRAZINES 73 2. HEALTH EFFECTS 1,1-dimethylhydrazine are able to inhibit reactions that require vitamin Bg as a cofactor. These reactions include transamination reactions, decarboxylation and other transformations of amino acids, the metabolism of lipids and nucleic acids, and glycogen phosphorylation (NRC 1989). Deficiency of vitamin B can produce convulsions, dermatitis, and anemia. These data suggest that the convulsions and anemia observed in animal studies are the result of the formation of hydrazone derivatives of vitamin B,. In addition, some authors have proposed that a free amino group, as found in hydrazine and 1,1-dimethylhydrazine, is required for hydrazone formation (Cornish 1969). This would explain why convulsions are associated with exposures to hydrazine and 1,1-dimethylhydrazine, and not 1,2-dimethylhydrazine. It should be noted that pyridoxine (one of the forms of vitamin By) is commonly used to treat humans exposed to hydrazine or 1,1-dimethylhydrazine. A number of in vitro studies have reported the production of reactive intermediates during the metabolism of hydrazines (see Section 2.3.3). Evidence for the production of radicals including methyl, acetyl, hydroxyl, and hydrogen radicals has been observed during the metabolism of hydrazine (Ito et al. 1992; Noda et al. 1988; Runge-Morris et al. 1988; Sinha 1987), 1,1-dimethylhydrazine (Albano et al. 1989; Tomasi et al. 1987), and 1,2-dimethylhydrazine (Albano et al. 1989; Augusto et al. 1985; Netto et al. 1987; Tomasi et al. 1987). Multiple pathways, both enzymatic and nonenzymatic, appear to be involved in free radical generation. Free radicals have been implicated in protein (hemoglobin) damage associated with hydrazine in human erythrocytes (Runge-Morris et al. 1988), suggesting that free radicals may be involved in the anemic effects of hydrazines observed in animals in vivo (Haun and Kinkead 1973; Rinehart et al. 1960). It has also been proposed that metabolism of 1,2-dimethylhydrazine yields a reactive, methyldiazonium ion (Feinberg and Zedeck 1980; Sohn et al. 1991). The production of reactive species during the metabolism of hydrazines may also explain their genotoxic effects, such as the formation of DNA and RNA adducts in vivo (Becker et al. 1981; Beranek et al. 1983; Bolognesi et al. 1988; Bosan et al. 1986; Netto et al. 1992; Pozharisski et al. 1975; Quintero-Ruiz et al. 1981). DNA and RNA adducts may well be responsible for gene mutations observed in a number of in vitro studies (DeFlora and Mugnoli 1981; Hawks and Magee 1974; Kang 1994; Kerklaan et al. 1983; Levi et al. 1986; Malaveille et al. 1983; Noda et al. 1986; Oravec et al. 1986; Parodi et al. 1981; Rogers and Back 1981; Sedgwick 1992; Wilpart et al. 1983) and may also serve as the initiating event for cancers induced by hydrazines in vivo. HYDRAZINES 74 2. HEALTH EFFECTS 2.5 RELEVANCE TO PUBLIC HEALTH Data regarding the toxic effects of hydrazines in humans are limited to a few case studies of accidental exposure and chemotherapy trials in cancer patients. Studies consistently indicate that the central nervous system is the primary target for hydrazine and 1,1-dimethylhydrazine following inhalation, oral, and dermal exposures. In some cases, neurological effects were delayed, but most effects were observed either during exposure or soon after. Quantitative data on human exposures are available only for oral exposures of intermediate durations. Studies in animals, which support the findings from human studies, report neurological effects following inhalation, dermal, and parenteral exposures to hydrazine and 1,1-dimethylhydrazine. Neurological effects do not appear to be of concern following exposure to 1,2-dimethylhydrazine. Effects on the liver have been consistently reported in animal studies following exposure to all three hydrazines. Limited studies in animals suggest that exposure to hydrazines by the inhalation, oral, and parenteral routes may cause reproductive and developmental effects. A number of species-, sex-, and strain-specific differences have been observed for sensitivity to the toxic effects of hydrazines. All three hydrazines are carcinogenic in animals following oral and inhalation exposures. 1,2-Dimethyl- hydrazine is a potent carcinogen in animals and can induce tumors following single oral or parenteral doses. Data regarding the toxicokinetics of hydrazines are limited but suggest that in animals hydrazines are rapidly absorbed and distributed to all tissues and that metabolites are excreted largely in the urine or released in expired air. Limited data in humans suggest that people with a slow acetylator genotype do not clear hydrazine from the body as well as those who are fast acetylators and therefore may be more susceptible to the toxic effects of hydrazine. Minimal Risk Levels for Hydrazines Inhalation MRLs * An MRL of 4x10” ppm has been derived for intermediate-duration inhalation exposure to hydrazine. This MRL is based on a LOAEL of 0.2 ppm for moderate fatty liver changes observed in female mice (Haun and Kinkead 1973). In this study, groups of 40 female ICR HYDRAZINES 75 2. HEALTH EFFECTS mice were exposed for 6 months to either 0, 0.2, or 1 ppm hydrazine continuously, or to 0, 1, or 5 ppm intermittently (6 hours/day, 5 days/week). The study authors also investigated the effects of inhaled hydrazine in other species. In support of this MRL, fatty liver changes were also observed in dogs exposed to 1 ppm hydrazine for 6 months and in monkeys exposed to 0.2 ppm for 6 months. An MRL of 2x10 ppm has been derived for intermediate inhalation exposure to 1,1-dimethylhydrazine. This MRL is based on a LOAEL of 0.05 ppm for hepatic effects (hyaline degeneration of the gall bladder) in female mice (Haun et al. 1984). In this study, female C57BL/6 mice were exposed for 6 months to 0, 0.05, 0.5, or 5 ppm 1,1-dimethylhydrazine for 6 hours/day, 5 days/week. The MRL is supported by other studies in humans (Petersen et al. 1970; Shook and Cowart 1957), rats (Haun et al. 1984), and dogs (Haun 1977; Rinehart et al. 1960), which indicate that the liver is a target of 1,1-dimethylhydrazine after inhalation exposure. No inhalation MRLs were derived for exposures to hydrazines for acute or chronic durations. Although data from animal studies indicate that inhalation exposures to hydrazines produce adverse effects on the liver and central nervous system following acute (Rinehart et al. 1960) and chronic exposures (Vernot et al. 1985), these studies do not define the threshold exposure level for these effects with confidence. Oral MRLs An MRL of 8x10 mg/kg/day has been derived for intermediate oral exposure to 1,2-dimethylhydrazine. This MRL is based on a LOAEL of 0.75 mg/kg/day for mild hepatitis in mice (Visek et al. 1991). In this study, groups of 25 male mice were administered 0, 0.75, 1.6, or 2.7 mg/kg/day 1,2-dimethylhydrazine in the diet for 5 months. This MRL is supported by studies reporting LOAELS for hepatic effects ranging from 4.2-30 mg/kg/day 1,2-dimethylhydrazine in several other species, including rats (Bedell et al. 1992), guinea pigs (Wilson 1976), dogs (Wilson 1976), and pigs (Wilson 1976). No oral MRLs were derived for exposures to hydrazine or for exposure to 1,1-dimethylhydrazine for acute and chronic durations. Although data are available for neurological effects in humans after HYDRAZINES 76 2. HEALTH EFFECTS intermediate-duration exposure to hydrazine (Chlebowski et al. 1984; Gershanovich et al. 1976, 1981; Ochoa et al. 1975; Spremulli et al. 1979), the effects levels were inconsistent among studies. Studies in animals have reported effects on the liver following acute-duration (Marshall et al. 1983; Wakabayashi et al. 1983; Wilson 1976) and intermediate-duration exposures (Biancifiori 1970). However, these data do not define the threshold dose for hepatic effects with confidence. No acute-, intermediate-, or chronic-duration dermal MRLs were derived for hydrazines because of the lack of an appropriate methodology for the development of dermal MRLs. Death. Data regarding the lethal effects of hydrazines in humans are limited to a single case study involving inhalation exposure to hydrazine. Death was reported in a male worker exposed to an undetermined concentration of hydrazine once a week for 6 months (Sotaniemi et al. 1971). Death in this case was due to lesions of the kidneys and lungs with complicating pneumonia. The effects on the kidneys and lungs, as well as effects in other tissues, were comparable to those observed in animals exposed to hydrazine. Therefore, death in this case is most likely attributed to hydrazine exposure. A number of animal studies have reported acute lethality after exposure by most routes to hydrazines. For inhalation exposures, deaths were observed in dogs and mice after acute exposure to 25-140 ppm 1,1-dimethylhydrazine (Rinehart et al. 1960). No studies were located that examined lethality after acute-duration inhalation exposure to hydrazine or 1,2-dimethylhydrazine. For oral exposures, doses of 133 mg/kg hydrazine, 533 mg/kg/day 1,1-dimethylhydrazine, and 11.7-90 mg/kg 1,2-dimethyl- hydrazine caused deaths in mice and/or dogs (Roe et al. 1967; Visek et al. 1991; Wilson 1976). For dermal exposures, LDj, values ranging from 93 to 1,680 mg/kg were reported for all three hydrazines in rabbits and guinea pigs (Rothberg and Cope 1956). Deaths were noted in dogs after application of a single dose of 96 mg/kg hydrazine or 300 mg/kg 1,1-dimethylhydrazine (Smith and Clark 1971, 1972). A large number of studies have reported deaths in several animal species following injections of 8-400 mg/kg/day hydrazine (Bodansky 1923; Lee and Aleyassine 1970; O’Brien et al. 1964; Roberts and Simonsen 1966; Rothberg and Cope 1956; Wakebayashi et al. 1983), 71-125 mg/kg/day 1,1-dimethylhydrazine (Back and Thomas 1962; Furst and Gustavson 1967; Geake et al. 1966; O’Brien et al. 1964; Rothberg and Cope 1956), and 44-60 mg/kg 1,2-dimethylhydrazine (Rothberg and Cope 1956; Wilson 1976). These doses are comparable to those producing death following oral exposure, suggesting that hydrazines are absorbed fairly well by the oral route. Limited information HYDRAZINES 77 2. HEALTH EFFECTS from a single oral study suggests that male animals are more sensitive to the lethal effects of hydrazine than females (Visek et al. 1991). A number of studies have reported increased mortality following exposure to hydrazines for intermediate durations. Following inhalation exposures, increased mortality was noted in mice and dogs exposed to 1 ppm hydrazine (Haun and Kinkead 1973), and in mice exposed to 75 ppm 1,1-dimethylhydrazine (Rinehart et al. 1960), but not in several species following intermediate exposure to 0.05-5 ppm 1,1-dimethylhydrazine (Haun et al. 1984). Oral exposures of 2.3-4.9 mg/kg/day hydrazine (Biancifiori 1970), 33 mg/kg/day 1,1-dimethylhydrazine (Roe et al. 1967), and 4.5-60 mg/kg/day 1,2-dimethylhydrazine (Teague et al. 1981; Visek et al. 1991; Wilson 1976) caused deaths in a number of animal species. Increased mortality was observed in several animal species after injections of 20-21.8 mg/kg/day hydrazine (Bodansky 1923; Patrick and Back 1965), 30 mg/kg/day 1,1-dimethylhydrazine (Cornish and Hartung 1969), and 15-60 mg/kg/day 1,2-dimethylhydrazine (Wilson 1976). Data regarding lethality effects in animals after chronic exposure to hydrazines are limited to two studies. Mortality was significantly increased in hamsters exposed to 0.25 ppm hydrazine in air for 1 year (Vernot et al. 1985), and in mice exposed to 0.95 mg/kg/day hydrazine via the drinking water (Toth and Patil 1982). These exposures are notably lower than those producing fatalities after acute- and intermediate-duration exposure to hydrazine. Systemic Effects Respiratory Effects. Pneumonia, tracheitis, and bronchitis were observed in a man occupationally exposed to an undetermined concentration of hydrazine in air once a week for 6 months (Sotaniemi et al. 1971). Dyspnea and pulmonary edema were observed in two men exposed to a mixture of hydrazine and 1,1-dimethylhydrazine (Frierson 1965). Hyperplasia was observed in the lungs of rats and mice exposed to 0.05 ppm 1,1-dimethylhydrazine for 6 months (Haun et al. 1984). Lung irritation and damage has been noted in dogs after intermediate-duration exposure to 25 ppm 1,1-dimethyl- hydrazine but not 5 ppm 1,1-dimethylhydrazine (Rinehart et al. 1960). Similarly, pulmonary effects were observed in rats chronically exposed to 5 ppm hydrazine but not in mice chronically exposed to 1 ppm hydrazine (Vernot et al. 1985). Effects on the nasal mucosa, including inflammation, hyperplasia, and dysplasia were noted in mice chronically exposed to 5 ppm 1,1-dimethylhydrazine HYDRAZINES 78 2. HEALTH EFFECTS (Haun et al. 1984). Pulmonary edema, congestion, and pneumonia were observed in rats injected with 20 mg/kg/day hydrazine but not in rats injected with 10 mg/kg/day hydrazine (Patrick and Back 1965). No adverse effects were observed in the lungs of mice exposed to 9.5 mg/kg/day hydrazine via the drinking water for 2 years (Steinhoff et al. 1990). These data suggest that effects on the lungs and upper respiratory tract are of concern primarily following inhalation exposures to hydrazines. Cardiovascular Effects. Data regarding the cardiovascular effects of hydrazines in humans are limited to a single case study involving inhalation exposure to hydrazine. Intermittent exposure of a worker to an undetermined concentration of hydrazine in air for 6 months produced atrial fibrillation, enlargement of the heart, and degeneration of heart muscle fibers (Sotaniemi et al. 1971). The findings from animal studies have been inconsistent. No adverse effects were noted on the cardiovascular system of dogs exposed to 25 ppm 1,1-dimethylhydrazine or mice exposed to 1 ppm hydrazine for intermediate and chronic durations (Rinehart et al. 1960; Vernot et al. 1985). Mice exposed to 0.05-5 ppm 1,1-dimethylhydrazine for 6 months to 1 year had abnormally dilated blood vessels (angiectesis) (Haun et al. 1984). Focal myocytolysis, fibrosis, and calcification of the heart were noted in mice receiving 1.6 mg/kg/day 1,2-dimethylhydrazine in the feed for 5 months (Visek et al. 1991). Slight accumulation of fat was observed in the myocardium of monkeys receiving 5 mg/kg/day hydrazine by intraperitoneal injection for 1-4 weeks (Patrick and Back 1965). Changes in blood pressure were noted in dogs following a single injection of 100 mg/kg 1,1-dimethylhydrazine (Back and Thomas 1962). Cardiovascular effects were not observed in mice receiving 0.75 mg/kg/day 1,2-dimethylhydrazine (Visek et al. 1991). No adverse effects were observed in the hearts of rats injected with 20 mg/kg/day hydrazine for 5 weeks (Patrick and Back 1965) or in mice receiving 9.5 mg/kg/day hydrazine in the drinking water for 2 years (Steinhoff et al. 1990). The findings of the animal studies, although inconsistent, suggest that the cardiovascular effects observed in the human case study are related to hydrazine exposure. Gastrointestinal Effects. Oral exposure to hydrazine has produced nausea and vomiting in human cancer patients. These effects could be due to direct irritation of the gastrointestinal tract but could also be due to effects on the central nervous system. Studies in animals generally have not reported effects on the gastrointestinal system following intermediate and chronic inhalation exposures to 25 ppm 1,1-dimethylhydrazine (Rinehart et al. 1960) or 1 ppm hydrazine (Vernot et al. 1985). Similarly, chronic oral exposure to 9.5 mg/kg/day hydrazine were without effect on the gastrointestinal system of mice (Steinhoff et al. 1990). Proliferation, dysplasia, and hyperplasia of the colon mucosa HYDRAZINES 79 2. HEALTH EFFECTS have been observed in rats orally exposed to 25 mg/kg 1,2-dimethylhydrazine or injected with 15-20 mg/kg 1,2-dimethylhydrazine (Caderni et al. 1991; Decaens et al. 1989; Wargovich et al. 1983). These effects are most likely precursors of carcinogenic lesions induced by 1,2-dimethylhydrazine in this tissue site. Although these data suggest that the gastrointestinal system is not a primary target of the noncarcinogenic effects of hydrazines, this is not certain, particularly for 1,2-dimethylhydrazine. Hematological Effects. No studies were located regarding hematological effects in humans after exposure to hydrazines. Studies in dogs indicate that inhalation exposure for intermediate durations to relatively high concentrations of hydrazine (1-5 ppm), but not 1,1-dimethylhydrazine, produces anemia (Haun and Kinkead 1973; Haun et al. 1984; Rinehart et al. 1960). Signs of anemia were not observed in dogs exposed to 0.2 ppm hydrazine. Hematological effects (decreased thromboplastin generation time) were also noted in dogs exposed to a single dermal dose of 5 mmol/kg 1,1-dimethylhydrazine (Smith and Castaneda 1970). However, hematological effects have not been observed in other species. For example, rats, hamsters, and monkeys exposed to 1 ppm hydrazine or 5 ppm 1,1-dimethyl- hydrazine for 6 months (Haun and Kinkead 1973; Haun et al. 1984) and rats and monkeys injected with 10-50 mg/kg/day 1,1-dimethylhydrazine (Cornish and Hartung 1969; Patrick and Back 1965) did not exhibit any hematological effects. These data suggest that dogs may be particularly sensitive to the hematological effects of hydrazines. Currently, it is not known if dogs are good animal models for the hematological effects of hydrazines in humans; therefore, it is uncertain if this effect is of concern to humans exposed to hydrazines. Musculoskeletal Effects. No studies were located regarding musculoskeletal effects in humans after exposure to hydrazines. Data in animals are limited to a single study. No adverse effects were observed in the muscle tissue of mice chronically exposed to 9.5 mg/kg/day hydrazine (Steinhoff et al. 1990). These data are too limited to determine if effects on the musculoskeletal system are of concern for humans exposed to hydrazines. Hepatic Effects. Areas of focal necrosis and cell degeneration were noted in the liver of a worker exposed to an undetermined concentration of hydrazine in air once a week for 6 months (Sotaniemi et al. 1971). These effects on the liver, however, were not contributing factors in the worker’s death. Elevated serum alanine aminotransferase activity, fatty degeneration, and a positive cephalin flocculation test were seen in workers exposed to 1,1-dimethylhydrazine (Petersen et al. 1970; Shook and Cowart 1957). A large number of studies in animals were located regarding the hepatotoxic HYDRAZINES 80 2. HEALTH EFFECTS effects of hydrazines. Multiple effects on the liver (hemosiderosis, degeneration, fatty changes, elevated serum enzymes, hyperplasia) have been observed in a number of species following inhalation exposure to 0.25-5 ppm hydrazine (Haun and Kinkead 1973; Vernot et al. 1985) or 0.05-25 ppm 1,1-dimethylhydrazine (Haun 1977; Haun et al. 1984; Rinehart et al. 1960). Hepatotoxic effects (fatty changes, degeneration, necrosis, hemosiderosis, hepatitis, fibrosis) were also observed in animals following oral exposure to 4.9-650 mg/kg/day hydrazine (Biancifiori 1970; Marshall et al. 1983; Preece et al. 1992a; Wakabayashi et al. 1983) and 0.75-60 mg/kg/day 1,2-dimethylhydrazine (Bedell et al. 1982; Visek et al. 1991; Wilson 1976). Similar effects were observed in animals receiving injections of 5-45 mg/kg/day hydrazine (Bodansky 1923; Patrick and Back 1965; Reinhardt et al. 1965b; Warren et al. 1984) or 3-333 mg/kg/day 1,2-dimethylhydrazine (Dixon et al. 1975; Pozharisski et al. 1976; Wilson 1976). Species differences in sensitivity were noted in individual studies, but these were not consistently observed across studies. Although data are lacking on the hepatic effects of 1,2-dimethylhydrazine by the inhalation route and 1,1-dimethylhydrazine by the oral route, these data clearly indicate that the liver is an important target organ and that hepatic effects are of potential concern for humans exposed to hydrazines. Renal Effects. Data regarding the renal effects of hydrazines in humans are limited to a single case study. This study reported severe renal effects (tubular necrosis, hemorrhaging, inflammation, discoloration, enlargement) in a worker after exposure to an undetermined concentration of hydrazine (Sotaniemi et al. 1971). The renal effects were a significant factor in the worker’s death. Renal effects have been observed in several animal studies. Following inhalation exposure to 0.25 ppm hydrazine, mild effects were noted in the kidneys of hamsters (Vernot et al. 1985). Similarly, signs of mild renal toxicity were observed in rats and dogs injected with 16-64 mg/kg/day hydrazine (Dominguez et al. 1962; Van Stee 1965) or 50 mg/kg/day 1,1-dimethylhydrazine (Cornish and Hartung 1969). More severe effects (nephritis) were noted in the kidneys of mice orally exposed to 1.6 mg/kg/day 1,2-dimethylhydrazine (Visek et al. 1991) and in dogs and monkeys injected with 20-28 mg/kg/day hydrazine (Bodansky 1923; Patrick and Back 1965). However, no effects were observed in the kidneys of dogs exposed to 25 ppm 1,1-dimethylhydrazine by the inhalation route (Rinehart et al. 1960), in mice exposed to 0.75 mg/kg/day 1,2-dimethylhydrazine or 9.5 mg/kg/day hydrazine by the oral route (Steinhoff et al. 1990; Visek et al. 1991), or in rats injected with 20 mg/kg/day hydrazine (Patrick and Back 1965). These animal studies support the findings of the human case study and suggest that the kidney is an important target organ, at least following exposure to high doses of hydrazines. HYDRAZINES 81 2. HEALTH EFFECTS Endocrine Effects. Mice exposed to hydrazine for 25 weeks exhibited degeneration of the adrenals, but no adverse effects in the thyroid, while exposed hamsters exhibited no effects in either organ (Biancifiori 1970). Overall, there is little evidence that the endocrine system is a major target of hydrazines. Dermal Effects. Contact dermatitis has been observed in humans after dermal exposure to dilute solutions containing hydrazine (Hovding 1967; Suzuki and Ohkido 1979; Wrangsjo and Martensson 1986). Dermal effects (discoloration, irritation) and ocular effects (corneal swelling) were also observed in dogs, rabbits, and guinea pigs after dermal exposure to hydrazine, 1,1-dimethylhydrazine, and 1,2-dimethylhydrazine (Rothberg and Cope 1956; Smith and Castaneda 1970; Smith and Clark 1971, 1972). However, by the oral route, no effects were observed in the skin of mice exposed to 9.5 mg/kg/day hydrazine (Steinhoff et al. 1990). These data indicate that direct contact with hydrazines causes irritation of the skin. Ocular Effects. Conjunctivitis was consistently observed in a worker repeatedly exposed to an undetermined concentration of hydrazine (Sotaniemi et al. 1971). Eye irritation was noted in monkeys exposed to 1 ppm hydrazine in air but not in monkeys exposed to 0.2 ppm hydrazine (Haun and Kinkead 1973). Thus direct contact with hydrazine may cause irritation of the eyes. Body Weight Effects. A large number of studies in animals exposed orally or by injection to hydrazines have reported decreased body weight gain. For example, oral exposure to 0.75-60 mg/kg/day 1,2-dimethylhydrazine (Barbolt and Abraham 1980; Visek et al. 1991; Wilson 1976), 5 mg/kg/day 1,1-dimethylhydrazine (Haun et al. 1984), or 9.5 mg/kg/day hydrazine (Steinhoff et al. 1990) decreased body weight gain in a number of animal species. Similarly, injection of 5-10 mg/kg/day hydrazine (Patrick and Back 1965), 10 mg/kg/day 1,1-dimethylhydrazine (Patrick and Back 1965), or 60 mg/kg/day 1,2-dimethylhydrazine (Wilson 1976) decreased animal body weight gain. These decreases in body weight gain are most likely due, at least in part, to decreased food intake. The decreased food intake may be due to taste aversion in feed studies; however, the appearance of this effect in animals exposed by other routes suggests that appetite may be decreased. Alternatively, decreases in body weight gain may be secondary to an underlying disease (e.g., cancer). HYDRAZINES 82 2. HEALTH EFFECTS Immunological and Lymphoreticular Effects. Very little information is available regarding immunological and lymphoreticular effects of hydrazines. Several studies in humans indicate that dermal exposure to hydrazine produces contact dermatitis (Hovding 1967; Suzuki and Ohkich 1979; Wrangsjo and Martensson 1986). In addition, there are some data from case studies in humans which suggest that exposure to hydrazine and other hydrazine derivatives can produce a lupus erythematosus- like disease (Pereyo 1986; Reidenberg et al. 1983). However, this possibility warrants further investigation before firm conclusions can be made. A single study in animals reported no effect in the splenic natural killer cell activity in rats orally exposed to 27.1 mg/kg/day 1,2-dimethylhydrazine (Locniskar et al. 1986). However, in mice injected with 75 mg/kg/day 1,1-dimethylhydrazine, a decreased T helper cell count was observed (Frazier et al. 1991). In vitro studies have reported that 1,1-dimethylhydrazine induces immunomodulation (enhancing some immune functions while diminishing others) in mouse lymphocytes and splenocytes (Bauer et al. 1990; Frazier et al. 1992). These data are limited, but suggest that humans exposed to hydrazines may be at risk of developing immunological effects. Neurological Effects. Neurological effects have been noted in humans after inhalation, oral, and dermal exposure to hydrazines. For inhalation exposure, these effects included nausea, vomiting, tremors, and impairment of cognitive functions (Richter et al. 1992; Sotaniemi et al. 1971). Neurological symptoms of nausea, vomiting, dizziness, excitement, lethargy, and neuritis have been reported in some cancer patients treated orally with 0.2-0.7 mg/kg/day hydrazine (Chlebowski et al. 1984; Gershanovich et al. 1976, 1981; Ochoa et al. 1975; Spremulli et al. 1979). Dermal exposure to hydrazine or 1,1-dimethylhydrazine as a result of an industrial explosion produced narcosis, coma, and polyneuritis in two workers (Dhennin et al. 1988; Kirklin et al. 1976). Neurological effects (depression, seizures, convulsions, tremors, lethargy, behavioral changes) have also been observed in a number of animal species following inhalation exposure to 1 ppm hydrazine (Haun and Kinkead 1973), and 25-75 ppm 1,1-dimethylhydrazine (Rinehart et al. 1960). Effects on the central nervous system were also observed in dogs after dermal exposure to 96-480 mg/kg hydrazine (Smith and Clark 1972) or 300-1,800 mg/kg 1,1-dimethylhydrazine (Smith and Clark 1971). Similar neurological effects were noted in animals after injection of 16-350 mg/kg/day hydrazine (Floyd 1980; Mizuno et al. 1989; Patrick and Back 1965) or 4-125 mg/kg/day 1,1-dimethylhydrazine (Furst and Gustavson 1967; Geake et al. 1966; Goff et al. 1967, 1970; Minard and Mushahwar 1966: O’Brien et al. 1964; Reynolds et al. 1964; Segerbo 1979; Sterman and Fairchild 1967). The studies in humans and animals HYDRAZINES 83 2. HEALTH EFFECTS convincingly demonstrate that the central nervous system is a target for persons exposed to hydrazine or 1,1-dimethylhydrazine. However, based on the mechanism by which hydrazine and 1,1-dimethylhydrazine affect the central nervous system, neurological effects do not appear to be of concern for humans exposed to 1,2-dimethylhydrazine. Reproductive Effects. Data regarding the reproductive effects of hydrazines are limited to a few animal studies. Reproductive effects (ovarian and testicular atrophy, endometrial inflammation, aspermatogenesis) were observed in hamsters exposed to 1-5 ppm hydrazine by the inhalation route (Vernot et al. 1985). The incidence of endometrial cysts was significantly elevated in female mice exposed to 0.05 ppm 1,1-dimethylhydrazine (Haun et al. 1984). Sperm abnormalities and decreased caudal epididymal sperm counts were noted in mice injected with 8 mg/kg/day hydrazine or 12.5-68.8 mg/kg/day 1,1-dimethylhydrazine (Wyrobek and London 1973). These effects were not observed in hamsters exposed to 0.25 ppm hydrazine by the inhalation route (Vernot et al. 1985) or in mice and hamsters exposed to 5.3-9.5 mg/kg/day hydrazine by the oral route (Biancifiori 1970). No studies were located regarding the reproductive effects of 1,2-dimethylhydrazine. In addition, no studies were located which investigated effects of hydrazines on reproductive function. Despite the inconsistency of the findings from animal studies, the serious nature of the reproductive effects observed in the positive studies makes them one of concern for humans exposed to hydrazine. Developmental Effects. Signs of developmental toxicity or teratogenicity were not observed in hamsters exposed to a single dose of 166 mg/kg hydrazine or 68 mg/kg 1,2-dimethylhydrazine on day 12 of gestation (Schiller et al. 1979). Likewise, Keller et al. (1984) examined the effects of 1,1-dimethylhydrazine (10-60 mg/kg/day) and 1,2-dimethylhydrazine (2-10 mg/kg/day) given intra- peritoneally to pregnant rats on days 6-15 of gestation, and found no dose-related teratogenic effects. Embryotoxicity, manifested as reduced fetal weight, occurred only in the animals treated with the highest dose levels of either chemical. However, in another study increased prenatal and perinatal mortality was reported in rats injected with 8 mg/kg/day hydrazine during gestation days 11-21 (Lee and Aleyassine 1970). The data in animals are inconsistent between routes of exposure and are too limited to permit firm conclusions regarding the potential for developmental effects in humans exposed to hydrazines. HYDRAZINES 84 2. HEALTH EFFECTS Genotoxic Effects. No studies were located regarding genotoxic effects in humans after exposure to hydrazines. Studies regarding the genotoxic effects in animals after oral or injection exposure to hydrazines are summarized in Table 2-4, while in vitro studies are presented in Table 2-5. These findings are discussed below. Data from in vivo studies indicate that hydrazines are alkylating agents. The methylation of tissue DNA was reported in animals exposed orally to hydrazine (Becker et al. 1981; Bosan et al. 1986) or by injection to hydrazine (Bosan et al. 1986; Quintero-Ruiz et al. 1981) or 1,2-dimethylhydrazine (Beranek et al. 1983; Bolognesi et al. 1988; Hawks and Magee 1974; Netto et al. 1992; Pozharisski et al. 1975; Rogers and Pegg 1977). The mechanism by which adducts are formed may involve the generation of reactive species (methyldiazanium ions or methyl free radicals) (Albano et al. 1989; Augusto et al. 1985; Feinberg and Zedeck 1980; Netto et al. 1987, 1992). The formation of methyl adducts with DNA bases in vivo may be one of the mechanisms by which hydrazines have produced DNA damage (Parodi et al. 1981), gene mutations (Jacoby et al. 1991; Winton et al. 1990; Zeilmaker et al. 1991; Zijlstra and Vogel 1988), micronuclei (Albanese et al. 1988; Ashby and Mirkova 1987), and sister chromatid exchange (Couch et al. 1986; Neft and Conner 1989). In vivo studies on the genotoxicity of hydrazines have largely reported positive results, although hydrazine did not induce unscheduled DNA synthesis in mouse sperm cells (Sotomayor et al. 1982). In addition, 1,2-dimethylhydrazine failed to induce micronuclei in rat bone marrow cells, even though this effect has been observed in mouse bone marrow cells (Albanese et al. 1988; Ashby and Mirkova 1987). A large number of in vitro studies have reported genotoxic effects for all three hydrazines. Hydrazines produced methyl adducts in DNA from human cells (Autrup et al. 1980a; Harris et al. 1977; Kumari et al. 1985) and in free DNA (Bosan et al. 1986; Lambert and Shank 1988), but adducts were not noted in Chinese hamster V79 cells (Boffa and Bolognesi 1986). Gene mutations have been observed in human teratoma cells (Oravec et al. 1986), mouse lymphoma cells (Rogers and Back 1981), and in several strains of bacteria (DeFlora and Mugnoli 1981; Kerklaan et al. 1983; Levi et al. 1986; Malaveille et al. 1983; Noda et al. 1986; Parodi et al. 1981; Sedgwick 1992; Wilpart et al. 1983). Other genotoxic effects observed in mammalian cells exposed to hydrazines include sister chromatid exchange (MacRae and Stich 1979), transformation (Kumari et al. 1985), and unscheduled DNA synthesis (Mori et al. 1988). The administration of 25 or 50 mg/kg hydrazine subcutaneously to neonatal rats was necrogenic to the liver (Leakakos and Shank 1994). Liver DNA isolated from these animals was shown to have site-specific damage in that one or more Mspl sites were lost or blocked. TABLE 2-4. Genotoxicity of Hydrazines In Vivo Species (test system) End point Results Reference Form Mammalian cells: Rat liver and colon Rat liver and colon Rat liver and colon Rat liver Rat liver, colon, and kidney Rat liver, kidney and intestines Rat liver Rat liver Mouse liver Mouse liver and colon Rat liver and colon Rat liver, kidney, and colon Mouse liver and lung Mouse liver and lung Mouse liver and lung Mouse lung, liver, and kidney Mouse intestine Rat colon Rat colon Rat colon Mouse colon Rat bone marrow Mouse bone marrow Mouse bone marrow Mouse colon Mouse bone marrow, lung, liver, and kidney Mouse blood and spleen lymphocytes Mouse sperm Mouse sperm DNA alkylation DNA alkylation DNA alkylation DNA alkylation DNA alkylation DNA alkylation DNA alkylation DNA alkylation DNA alkylation DNA alkylation RNA alkylation DNA damage DNA damage DNA damage DNA damage Decreased DNA content Gene mutation Gene mutation Gene mutation Gene mutation Inhibition of DNA repair Micronuclei Micronuclei Micronuclei Sister chromatid exchange Sister chromatid exchange Sister chromatid exchange Unscheduled DNA synthesis Dominant lethal mutation + +++ FFF +++ + Netto et al. 1992 Hawks and Magee 1974 Netto et al. 1992 Bosan et al. 1986 Rogers and Pegg 1977 Pozharisski et al. 1975 Becker et al. 1981 Beranek et al. 1983 Quintero-Ruiz et al. 1981 Hawks and Magee 1974 Kang 1994 Bolognesi et al. 1988 Parodi et al 1981 Parodi et al 1981 Parodi et al 1981 D’Souza and Bhide 1975 Winton et al. 1990 Jacoby et al. 1991 Jacoby et al. 1991 Llor et al. 1991 Koval 1984 Albanese et al. 1988 Albanese et al. 1988 Ashby and Mirkova 1987 Couch et al. 1986 Neft and Conner 1989 Neft and Conner 1989 Sotomayor et al. 1982 Brusick and Matheson 1976 12DMH 12DMH 12DMH 12DMH 12DMH 12DMH HS 12DMH 12DMH 12DMH 11DMH 12DMH HH HS 12DMH 12DMH 12DMH 12DMH 12DMH 12DMH 12DMH 12DMH 12DMH 12DMH 12DMH 11DMH S103443 H1TV3H 2 SANIZVHAAH G8 TABLE 2-4. Genotoxicity of Hydrazines In Vivo (continued) Species (test system) End point Results Reference Form Nonmammalian cells: Drosophila melanogaster Gene mutation - Zijlstra and Vogel 1988 11DMH Drosophila melanogaster Gene mutation - Zijlstra and Vogel 1988 12DMH Host-mediated assays: Mouse Gene mutation (Escherichia coli) + Zeilmaker et al. 1991 12DMH — = negative result; + = positive result 11DMH = 1,1-dimethylhydrazine; 12DMH = 1,2-dimethylhydrazine; DNA = deoxyribonucleic acid; H = hydrazine; HH = hydrazine hydrate; HS = hydrazine sulfate S103443 HLV3H 2 S3ANIZVHAAH 98 TABLE 2-5. Genotoxicity of Hydrazines In Vitro With Without Species (test system) End point activation activation Reference Form Prokaryotic organisms: Salmonella typhimurium Gene mutation + + Parodi et al 1981 HH S. Typhimurium Gene mutation + + DeFlora and Mugnoli 1981 HH S. Typhimurium Gene mutation + + Wilpart et al. 1983 12DMH S. Typhimurium Gene mutation No data - Pence 1985 12DMH S. Typhimurium Gene mutation + + Parodi et al 1981 12DMH S. Typhimurium Gene mutation + - Malaveille et al. 1983 12DMH S. Typhimurium Gene mutation + - Kerklaan et al. 1983 12DMH S. Typhimurium Gene mutation + + DeFlora and Mugnoli 1981 12DMH S. Typhimurium Gene mutation + + DeFlora and Mugnoli 1981 11DMH S. Typhimurium Gene mutation + + Parodi et al 1981 11DMH S. Typhimurium Gene mutation - - Brusick and Matheson 1976 11DMH Saccharomyas cerevisiae Gene mutation - - Brusick and Matheson 1976 11DMH Photobacterium leiognathi Gene mutation No data + Levi et al. 1986 H Escherichia coli Gene mutation + No data Noda et al. 1986 H E. coli Gene mutation No data + Sedgwick 1992 12DMH E. coli Gene mutation No data + Sedgwick 1992 11DMH E. coli Gene mutation - - Brusick and Matheson 1976 11DMH Mammalian cells: Human colon DNA alkylation No data + Autrup et al. 1980a 12DMH Human bronchi DNA alkylation + No data Harris et al. 1977 12DMH Human fibroblasts DNA alkylation No data + Kumari et al. 1985 12DMH Human fibroblasts DNA alkylation No data + Kumari et al. 1985 11DMH Human teratoma Gene mutation + No data Oravec et al. 1986 12DMH Human fibroblasts Transformation No data + Kumari et al. 1985 12DMH Human fibroblasts Transformation No data + Kumari et al. 1985 11DMH V79 Chinese hamster DNA alkylation + - Boffa and Bolognesi 1986 12DMH Mouse lymphoma Gene mutation No data + Rogers and Back 1981 H Mouse lymphoma Gene mutation No data + Rogers and Back 1981 12DMH Mouse lymphoma Gene mutation No data + Rogers and Back 1981 11DMH Mouse lymphoma Gene mutation + + Brusick and Matheson 1976 11DMH S103443 HLTV3H ¢ S3ANIZVHAAH 18 TABLE 2-5. Genotoxicity of Hydrazines In Vitro (continued) Results With Without Species (test system) End point activation activation Reference Form Chinese hamster ovary Sister chromatid No data + MacRae and Stich 1979 H exchange Chinese hamster ovary Sister chromatid + + MacRae and Stich 1979 12DMH exchange Mouse hepatocytes Unscheduled DNA No data + Mori et al. 1988 HS synthesis Mouse hepatocytes Unscheduled DNA No data + Mori et al. 1988 HH synthesis Mouse hepatocytes Unscheduled DNA No data + Mori et al. 1988 12DMH synthesis Rat hepatocytes Unscheduled DNA No data + Mori et al. 1988 12DMH synthesis Human diploid W1-38 Unscheduled DNA - +) Brusick and Matheson 1976 11DMH synthesis Mouse hepatocytes Unscheduled DNA No data + Mori et al. 1988 11DMH synthesis Noncellular assays: Calf thymus DNA DNA alkylation + - Bosan et al. 1986 H Calf thymus DNA DNA alkylation + - Lambert and Shank 1988 H Plasmid DNA DNA damage No data + Yamamoto and Kawanishi H 1991 Plasmid DNA DNA damage No data + Kawanishi and Yamamoto 11DMH 1991 Plasmid DNA DNA damage No data + Kawanishi and Yamamoto 12DMH 1991 — = negative result; + = positive result; (+) = weakly positive result 11DMH = 1,1-dimethylhydrazine; 12DMH = 1,2-dimethylhydrazine; DNA = deoxyribonucleic acid; H = hydrazine; HH = hydrazine hydrate; HS = hydrazine sulfate S103443 H1IV3H 2 S3ANIZVHAAH 88 HYDRAZINES 89 2. HEALTH EFFECTS In vitro studies regarding the genotoxic effects of hydrazines have generally reported positive results, with and without metabolic activation. Taken together with the in vivo studies discussed above, these data clearly indicate that all three forms of hydrazine are genotoxic. Cancer. No significant increase in cancer mortality was observed in a single epidemiology study of workers exposed to hydrazine (Morris et al. 1995; Wald et al. 1984), or in a U.S. Public Health Service survey of tuberculosis patients with isoniazid (Glassroth et al. 1977), which is metabolized to hydrazine. However, a large number of studies in animals have reported increased tumor incidence following inhalation, oral, and parenteral exposures to hydrazines. Following inhalation exposures to 5 ppm hydrazine, increased nasal and thyroid tumor incidences were reported in mice and hamsters (Vernot et al. 1985). Tumors of the lung, nasal passageways, bone, pancreas, pituitary, blood vessels, liver, and thyroid, and leukemia were observed at an increased incidence in mice or rats exposed to 0.05-5 ppm 1,1-dimethylhydrazine (Haun et al. 1984). It is possible that some of the carcinogenic effects of impure grades of 1,1-dimethylhydrazine may be attributable to the presence of dimethylnitrosamine, a potent carcinogen, as a contaminant (Haun 1977). Following oral exposures, doses of 0.46-16.7 mg/kg/day hydrazine increased the incidence of liver, kidney, breast, and particularly lung tumors in several animal species (Bhide et al. 1976; Biancifiori 1970; Biancifiori and Ribacchi 1962; Biancifiori et al. 1964, 1966; Bosan et al. 1987; Maru and Bhide 1982: Roe et al. 1967; Yamamoto and Weisburger 1970). Oral exposure to 33 mg/kg/day 1,1-dimethylhydrazine increased the incidence of lung tumors in mice (Roe et al. 1967). Multiple tumor types, but most notably colon and blood vessel tumors, were induced in several animal species exposed to oral doses of 0.059-30 mg/kg/day 1,2-dimethylhydrazine (Abraham et al. 1980; Asano and Pollard 1978; Barbolt and Abraham 1980; Bedell et al. 1982; Calvert et al. 1987; Izumi et al. 1979; Locniskar et al. 1986; Teague et al. 1981; Thorup et al. 1992: Toth and Patil 1982; Wilson 1976). Colon tumors were also induced after single oral doses of 15.8-30 mg/kg 1,2-dimethylhydrazine (Craven and DeRubertis 1992; Schiller et al. 1980; Watanabe et al. 1985). A large number of studies have reported the carcinogenic effects of 1,2-dimethylhydrazine by the injection route. These studies have reported an induction of tumor types similar to those reported for oral exposure following single injections of 15-143 mg/kg 1,2-dimethylhydrazine (Barnes et al. 1983; Decaens et al. 1989; Fujii and Komano 1989; Glauert and Weeks 1989; Karkare et al. 1991; Sunter and Senior 1983; Toth et al. 1976; Wargovich et al. 1983) and repeated injections of 3-40 mg/kg/day HYDRAZINES 90 2. HEALTH EFFECTS (Andrianopoulos et al. 1990; Barsoum et al. 1992; Decaens et al. 1989; Druckrey 1970; Hagihara et al. 1980; James et al. 1983; Nelson et al. 1992; Pozharisski et al. 1976; Shirai et al. 1983; Vinas-Salas et al. 1992). Peripheral nerve sheath tumors were observed in hamsters injected with 32.5 mg/kg/day 1,1-dimethylhydrazine (Ernst et al. 1987). Several government departments and regulatory offices have evaluated the evidence regarding the carcinogenicity of hydrazines. The Department of Health and Human Services has determined that hydrazine and 1,1-dimethylhydrazine are reasonably anticipated to be carcinogens (NTP 1994). The International Agency for Research on Cancer has determined that hydrazine, 1,1-dimethylhydrazine, and 1,2-dimethylhydrazine are probably carcinogenic to humans (Group 2B) (IARC 1987). The EPA has determined that hydrazine, 1,1-dimethylhydrazine, and 1,2-dimethylhydrazine are probable human carcinogens (Group B2) (HEAST 1992; IRIS 1995). The American Conference of Governmental Industrial Hygienists (ACGIH) currently lists hydrazine and 1,1-dimethylhydrazine as suspected human carcinogens (ACGIH 1994a). However, it has recently been recommended that the listing of hydrazine be changed to that of animal carcinogen, not likely to cause cancer in humans under normal exposure conditions (ACGIH 1994b). 2.6 BIOMARKERS OF EXPOSURE AND EFFECT Biomarkers are broadly defined as indicators signaling events in biologic systems or samples. They have been classified as markers of exposure, markers of effect, and markers of susceptibility (NAS/NRC 1989). Due to a nascent understanding of the use and interpretation of biomarkers, implementation of biomarkers as tools of exposure in the general population is very limited. A biomarker of exposure is a xenobiotic substance or its metabolite(s), or the product of an interaction between a xenobiotic agent and some target molecule(s) or cell(s) that is measured within a compartment of an organism (NAS/NRC 1989). The preferred biomarkers of exposure are generally the substance itself or substance-specific metabolites in readily obtainable body fluid(s) or excreta. However, several factors can confound the use and interpretation of biomarkers of exposure. The body burden of a substance may be the result of exposures from more than one source. The substance being measured may be a metabolite of another xenobiotic substance (e.g., high urinary levels of phenol can result from exposure to several different aromatic compounds). Depending on the properties of the substance HYDRAZINES 91 2. HEALTH EFFECTS (e.g., biologic half-life) and environmental conditions (e.g., duration and route of exposure), the substance and all of its metabolites may have left the body by the time samples can be taken. It may be difficult to identify individuals exposed to hazardous substances that are commonly found in body tissues and fluids (e.g., essential mineral nutrients such as copper, zinc, and selenium). Biomarkers of exposure to hydrazines are discussed in Section 2.6.1. Biomarkers of effect are defined as any measurable biochemical, physiologic, or other alteration within an organism that, depending on magnitude, can be recognized as an established or potential health impairment or disease (NAS/NRC 1989). This definition encompasses biochemical or cellular signals of tissue dysfunction (e.g., increased liver enzyme activity or pathologic changes in female genital epithelial cells), as well as physiologic signs of dysfunction such as increased blood pressure or decreased lung capacity. Note that these markers are not often substance specific. They also may not be directly adverse, but can indicate potential health impairment (e.g., DNA adducts). Biomarkers of effects caused by hydrazines are discussed in Section 2.6.2. A biomarker of susceptibility is an indicator of an inherent or acquired limitation of an organism’s ability to respond to the challenge of exposure to a specific xenobiotic substance. It can be an intrinsic genetic or other characteristic or a preexisting disease that results in an increase in absorbed dose, a decrease in the biologically effective dose, or a target tissue response. If biomarkers of susceptibility exist, they are discussed in Section 2.8, "Populations That Are Unusually Susceptible." 26.1 Biomarkers Used to Identify or Quantify Exposure to Hydrazines Methods exist for measuring the levels of hydrazines and their metabolites in the plasma of humans (Blair et al. 1985) and in tissues, urine, and expired air of animals (Alvarez de Laviada et al. 1987; Back et al. 1963; Dost et al. 1966; Fiala and Kulakis 1981; Fiala et al. 1976; Harbach and Swenberg 1981; Kaneo et al. 1984; Kang et al. 1988; Matsuyama et al. 1983; Preece et al. 1991; Reed et al. 1963; Springer et al. 1981). These studies have employed colorimetric, chromatographic, and nuclear magnetic resonance techniques. Such methods require the use of expensive equipment and skilled technicians, which may limit the availability of facilities capable of monitoring exposure on a routine basis. The levels of hydrazines or their metabolites in tissues and excreta cannot presently be used to quantify past exposures. The detection of hydrazines and some of their metabolites (for example, azomethane and azoxymethane from 1,2-dimethylhydrazine) is a fairly specific biomarker of exposure. HYDRAZINES 92 2. HEALTH EFFECTS However, hydrazine is a metabolite of drugs such as isoniazid and hydralazine (Blair et al. 1985). Therefore, care must be taken to ensure that exposure to these drugs has not occurred. Other metabolites of hydrazines (for example, carbon dioxide and nitrogen) are endogenous to the body, and therefore, cannot be used as specific biomarkers of exposure. 2.6.2 Biomarkers Used to Characterize Effects Caused by Hydrazines Effects on the liver are associated with exposure to hydrazines in humans (Sotaniemi et al. 1971) and animals (Haun and Kinkead 1973; Rinehart et al. 1960; Vernot et al. 1985; Wilson 1976). Therefore, assessment of serum transaminase activities may be useful in revealing liver damage in people exposed to hydrazines. Neurological effects are often observed following exposure to hydrazine and 1,1-dimethylhydrazine in humans (Chlebowski et al. 1984: Gershanovich et al. 1976; Ochoa et al. 1975; Richter et al. 1992; Sotaniemi et al. 1971) and animals (Haun and Kinkead 1973; Rinehart et al. 1960). The mechanism by which hydrazine and 1,1-dimethylhydrazine produce neurological effects involves binding to vitamin Bg derivatives. Therefore, assessment of vitamin Bg status either by direct measurement in the blood, tryptophan load tests, or measurements of vitamin Bg-dependent activities in plasma or erythrocytes may serve to indicate if vitamin Bg status has been compromised by hydrazine or 1,1-dimethylhydrazine. DNA adducts have been observed in animals exposed to hydrazines in vivo (Becker et al. 1991; Beranek et al. 1983; Bolognesi et al. 1988; Bosan et al. 1986; Netto et al. 1992; Pozharisski et al. 1975; Quintero-Ruiz et al. 1981; Rogers and Pegg 1977). RNA base adducts have also been observed in liver and colon after treatment of rats with 1,2-dimethylhydrazine (Hawks and Magee 1974; Kang 1994). However, these are somewhat difficult to detect and quantitate, and therefore, may not be useful as biomarkers of effect. An increased incidence of colon tumors is the most consistent effect observed following exposure to 1,2-dimethylhydrazine in animals (Abraham et al. 1980; Asano and Pollard 1978; Barbolt and Abraham 1980; Calvert et al. 1987; Izumi et al. 1979; Locniskar et al. 1986; Teague et al. 1981; Thorup et al. 1992; Wilson 1976). Simple tests for occult blood in the stools can be used as a preliminary screen for intestinal tumors. However, these types of effects can be caused by exposures to a large number of agents, and in no way are these biomarkers specific for the effects of hydrazines. HYDRAZINES 93 2. HEALTH EFFECTS 2.7 INTERACTIONS WITH OTHER SUBSTANCES No studies were located regarding interactions in humans or animals after exposure to hydrazine or 1,1-dimethylhydrazine. On the other hand, a large number of studies are available in animals regarding the interactions of various treatments on 1,2-dimethylhydrazine-induced colon cancer. For example, high-fat diets, high-cholesterol diets, potassium chloride, caffeine, vitamin C, iron, ethoxyquin, and colorectal surgery were all found to increase the incidence, multiplicity, or malignancy of 1,2-dimethylhydrazine-induced intestinal tumors (Balansky et al. 1992; Bansal et al. 1978; Cruse et al. 1982; Locniskar et al. 1986; Nelson et al. 1992; Shirai et al. 1985; Siegers et al. 1992), whereas aspirin, bran, pectin, calcium, vitamin D, vitamin E, carbon tetrachloride, carbon disulfide, sodium selenate, butylated hydroxytoluene, corn oil, and calcium chloride were all found to decrease the incidence of these tumors (Balansky et al. 1992; Barnes et al. 1983; Barsoum et al. 1992; Belleli et al. 1992: Calvert et al. 1987; Colacchio et al. 1989; Craven and DeRubertis 1992; Heitman et al. 1992; Shirai et al. 1985). Other studies have reported that bran, beta-carotene, butylated hydroxyanisole, propyl gallate, and stress had no significant effect on tumors of the colon induced by 1,2-dimethylhydrazine (Andrianopoulos et al. 1990: Barbolt and Abraham 1980; Colacchio et al. 1989; Shirai et al. 1985; Thorup et al. 1992). A number of mechanisms are possible for these interactions including but not limited to interference with the metabolism of 1,2-dimethylhydrazine (Fiala et al. 1977), action as a scavenger for free radicals produced during 1,2-dimethylhydrazine metabolism, and influences at the post-initiation stage of colon carcinogenesis. 2.8 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE A susceptible population will exhibit a different or enhanced response to hydrazines than will most persons exposed to the same level of hydrazines in the environment. Reasons include genetic make- up, developmental stage, age, health and nutritional status (including dietary habits that may increase susceptibility, such as inconsistent diets or nutritional deficiencies), and substance exposure history (including smoking). These parameters may result in decreased function of the detoxification and excretory processes (mainly hepatic, renal, and respiratory) or the pre-existing compromised function of target organs (including effects or clearance rates and any resulting end-product metabolites). For these reasons we expect the elderly with declining organ function and the youngest of the population with immature and developing organs will generally be more vulnerable to toxic substances than HYDRAZINES 94 2. HEALTH EFFECTS healthy adults. Populations who are at greater risk due to their unusually high exposure are discussed in Section 5.6, "Populations With Potentially High Exposure." Data from a single human study indicate that people with a slow acetylator genotype may be unusually susceptible to the effects of hydrazine. A pronounced accumulation of hydrazine was noted in the plasma of slow acetylator patients treated with isoniazid compared to those patients that were rapid acetylators (Blair et al. 1985). With 1,1-dimethylhydrazine, similar results may be observed. However, no information is available on humans for 1,1-dimethylhydrazine. Further investigation of this mechanism is warranted. In animals, a number of studies have reported differences in susceptibility to the toxic effects of hydrazines with respect to species (Haun and Kinkead 1973; Rinehart et al. 1960; Vernot et al. 1985; Wilson 1976), strain (Asano and Pollard 1978; Bhide et al. 1976; Teague et al. 1981; Toth 1969), sex (Bhide et al. 1976; Biancifiori 1970; Teague et al. 1981; Visek et al. 1991), and age (Wakabayashi et al. 1983). Some of the differences in susceptibility may be related to differences in ability to metabolize hydrazines; however, many other differences still lack a satisfactory explanation. 2.9 METHODS FOR REDUCING TOXIC EFFECTS This section describes clinical practice and research concerning methods for reducing toxic effects of exposure to hydrazines. However, because some of the treatments discussed may be experimental and unproven, this section should not be used as a guide for treatment of exposures to hydrazines. When specific exposures have occurred, poison control centers and medical toxicologists should be consulted for medical advice. 2.9.1 Reducing Peak Absorption Following Exposure No data were located regarding methods for reducing absorption after inhalation exposure to hydrazines. There are several methods by which the absorption of hydrazines can be reduced in the gastrointestinal tract. Induced emesis, gastric lavage, use of saline cathartics, or activated charcoal are all methods which are commonly used to decrease the gastrointestinal absorption of compounds such as hydrazines HYDRAZINES 95 2. HEALTH EFFECTS (Bronstein and Currance 1988; Sittig 1991; Stutz and Janusz 1988). In general, these treatments are most effective when used within a few hours after oral exposure. In some cases, these treatments may be contraindicated. For example, some authors contend that emesis should not be induced (Bronstein and Currance 1988). In addition, emesis should not be induced in obtunded, comatose, or convulsing patients. Oils should not be used as a cathartic, since they may enhance the gastrointestinal absorption of hydrazines. Following dermal or ocular exposures to hydrazines, there are several methods by which absorption can be reduced. All contaminated clothing should be removed, and contacted skin should be washed immediately with soap and water (Bronstein and Currance 1988; Haddad and Winchester 1990; Sittig 1991; Stutz and Janusz 1988). Eyes that have come in contact with hydrazines should be flushed with copious amounts of water. Contact lenses should be removed prior to flushing with water. Proparacaine hydrochloride may be used to assist eye irrigation (Bronstein and Currance 1988). 2.9.2 Reducing Body Burden Elimination of hydrazines in the urine may be enhanced by forced diuresis and acidification of the urine (Haddad and Winchester 1990). Hemodialysis and peritoneal dialysis may also be helpful, but this has not been fully studied. Activated charcoal is sometimes administered in serial doses to minimize the enterohepatic recirculation of persistent chemicals. Data regarding the enterohepatic recirculation of hydrazines were not located. However, available data suggest that hydrazines are readily cleared from the body since the levels in various tissues in animals are usually not detectable after 24 hours. In addition, studies in rats indicate that only a small percentage of a dose of 1,2-dimethylhydrazine (0.4-0.9%) is excreted in the bile (Hawks and Magee 1974). Therefore, it is not likely that efforts to minimize enterohepatic recirculation of hydrazines would be of much use. 2.9.3 Interfering with the Mechanism of Action for Toxic Effects There are at least two distinct mechanisms by which hydrazines produce adverse health effects. Methods for interfering with these mechanisms are discussed below. The first mechanism involves the reaction of hydrazine or 1,1-dimethylhydrazine with endogenous alpha-keto acids such as vitamin Bg (pyridoxine). The formation of hydrazones of pyridoxine is the proposed mechanism by which hydrazine and 1,1-dimethylhydrazine produce neurological effects. Several studies have reported HYDRAZINES 96 2. HEALTH EFFECTS successful treatment of neurological effects in humans exposed to hydrazine and 1,1-dimethylhydrazine with pyridoxine (Dhennin et al. 1988; Ellenhorn and Barceloux 1988; Haddad and Winchester 1990; Kirklin et al. 1976). In addition, several animal studies reported that pyridoxine diminished, and in some cases completely abolished, the lethal and neurological effects of hydrazine and 1,1-dimethylhydrazine (Geake et al. 1966; Lee and Aleyassine 1970; O’Brien et al. 1964; Segerbo 1979). However, treatment with pyridoxine is not without risk. For example, some authors suggested that pyridoxine is also capable of producing neuropathy (Harati and Niakan 1986). This effect has been noted in humans exposed to hydrazines and treated with pyridoxine (Dhennin et al. 1988; Harati and Niakan 1986; Ochoa et al. 1975), but it is difficult to ascribe this effect to exposure to either hydrazines or pyridoxine alone. It is possible that the adverse effects of pyridoxine treatment may be associated with treatments using large doses. Evidence of a therapeutic window has been reported in animal studies (Geake et al. 1966). Studies in animals have also reported that the hydrazones of pyridoxine are more toxic than the corresponding hydrazine (Furst and Gustavson 1967). These data indicate that pyridoxine should be used with caution and that all potential risks and benefits should be considered prior to treatment. In any case, treatment with pyridoxine would not be expected to be beneficial for exposures to 1,2-dimethylhydrazine since this compound, unlike hydrazine and 1,1-dimethylhydrazine, does not form hydrazones. The second mechanism by which hydrazines produce adverse health effects involves the generation of free radical intermediates. Free radicals have been detected during the metabolism of hydrazines in vitro (Albano et al. 1989; Augusto et al. 1985; Ito et al. 1992; Netto et al. 1987; Noda et al. 1988; Runge-Morris et al. 1988; Sinha 1987; Tomasi et al. 1987). Therefore, treatment with agents that act as free radical scavengers could offer a protective effect. In vitro studies have shown that glutathione is an effective scavenger of the free radicals produced from the metabolism of 1,1-dimethylhydrazine and 1,2-dimethylhydrazine (Tomasi et al. 1987). A number of animal studies have reported that aspirin, vitamin C, vitamin E, and butylated hydroxytoluene decreased the incidence, multiplicity, or malignancy of 1,2-dimethylhydrazine-induced intestinal tumors (Belleli et al. 1992; Colacchio et al. 1989; Cook and McNamara 1980; Craven and DeRubertis 1992; Shirai et al. 1985). It is possible that this protective effect may occur via inhibition of metabolic activation or a free radical scavenging mechanism, and if so, treatment would be most effective if administered relatively soon after exposure; however, the mechanism is not known conclusively and warrants further investigation. HYDRAZINES 97 2. HEALTH EFFECTS Since reactive intermediates are produced as a result of the metabolism of hydrazines, the administra- tion of inhibitors of the cytochrome P-450 or the flavin-containing monooxygenase system may offer some protective effect. For example, disulfiram, an inhibitor of cytochrome P45011E1 (Guengerich et al. 1991), decreased the oxidation of azomethane (a metabolite of 1,2-dimethylhydrazine) to azoxy- methane, and the further oxidation of azoxymethane to methylazoxymethanol (Fiala et al. 1977). The inhibition of the activation pathway of 1,2-dimethylhydrazine by disulfiram resulted in decreased DNA methylation in the liver and colon of rats (Swenberg et al. 1979), and inhibition of 1,2-dimethyl- hydrazine-induced colon carcinogenesis (Wattenberg 1975). Although disulfiram is a toxic compound which is known to inhibit other enzyme systems, it has been used in humans as an alcohol deterrent (Ellenhorn and Barceloux 1988). In cases of significant exposure to 1,2-dimethylhydrazine, the potential benefits of disulfiram in preventing colon cancer may outweigh the potential risk of adverse toxic effects. 2.10 ADEQUACY OF THE DATABASE Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the Administrator of EPA and agencies and programs of the Public Health Service) to assess whether adequate information on the health effects of hydrazines is available. Where adequate information is not available, ATSDR, in conjunction with the National Toxicology Program (NTP), is required to assure the initiation of a program of research designed to determine the health effects (and techniques for developing methods to determine such health effects) of hydrazines. The following categories of possible data needs have been identified by a joint team of scientists from ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would reduce the uncertainties of human health assessment. This definition should not be interpreted to mean that all data needs discussed in this section must be filled. In the future, the identified data needs will be evaluated and prioritized, and a substance-specific research agenda will be proposed. 2.10.1 Existing Information on Health Effects of Hydrazines The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to hydrazines are summarized in Figure 2-3. The purpose of this figure is to illustrate the existing information concerning the health effects of hydrazines. Each dot in the figure indicates that one or HYDRAZINES 98 2. HEALTH EFFECTS more studies provide information associated with that particular effect. The dot does not necessarily imply anything about the quality of the study or studies, nor should missing information in this figure be interpreted as a "data need." A data need, as defined in ATSDR’ Decision Guide for Identifying Substance-Specific Data Needs Related to Toxicological Profiles (ATSDR 1989), is substance-specific information necessary to conduct comprehensive public health assessments. Generally, ATSDR defines a data gap more broadly as any substance-specific information missing from the scientific literature. As shown in Figure 2-3, data are available in humans regarding lethal, neurological, and carcinogenic effects after inhalation exposure to hydrazines. Data are also available for the systemic effects observed in humans exposed to hydrazines by the inhalation route for intermediate durations. By the oral route, information is only available for the neurological effects in humans exposed to hydrazines. Acute systemic, immunological, and neurological effects have been reported in humans after dermal exposure to hydrazines. Considerably more information on the health effects of hydrazines is available from animal studies. These are data for all effect categories from animal studies for oral exposure to hydrazines. The lethal, neurological, reproductive, carcinogenic, and systemic effects for all exposure durations are available from studies in animals exposed to hydrazines by the inhalation route. For dermal exposures to hydrazines, animal data are available regarding the lethal, neurological, and acute systemic effects. 2.10.2 Identification of Data Needs Acute-Duration Exposure. Data are available for the acute toxicity of hydrazine in humans after inhalation and dermal exposures, and in several animal species after oral and dermal exposures. Although a human case study suggests neurological effects are of concern following inhalation exposure to hydrazine (Frierson 1965), quantitative data are not available for the acute toxicity of hydrazine after inhalation exposure. Data from animal studies (rats, dogs) indicate that the liver is the primary target organ after oral exposures (Marshall et al. 1983; Preece et al. 1992a; Wakabayashi et al. 1983), and that the skin is the most sensitive target in humans and animals (rabbits, guinea pigs, dogs) following dermal exposures (Hovding 1967; Suzuki and Ohkido 1979). These data do not sufficiently define the threshold dose for these effects and do not support the derivation of an MRL. HYDRAZINES 99 2. HEALTH EFFECTS FIGURE 2-3. Existing Information on Health Effects of Hydrazines NO 5) & $ SYSTEMIC S . xQ L >» < © &° 2 “© S pg 4 Q RY) QO o X FY J¢ = & > © S oS > &° EEE SSE SEE Inhalation | © | ® | © . . Oral Dermal ° LI Human < £ eo SS KL SYSTEMIC 4D AN \ NZ > & 3 o 557 SAE Ge : 0 < 50S SSS 5 &/&E REESE EF eX SP Inhalation | © | ®| ® | ® ° ° Oral ® eo | © ° » ° oe | © Dermal ° ° ® Animal ® Existing Studies HYDRAZINES 100 2. HEALTH EFFECTS Data are available for the acute toxicity of 1,1-dimethylhydrazine after inhalation exposure in humans, and inhalation, oral, and dermal exposures in animals. A human case study suggests that neurological effects are of concern following acute inhalation exposure to 1,1-dimethylhydrazine (Frierson 1965). Data from a study in dogs indicate that the central nervous system is affected following inhalation of 1,1-dimethylhydrazine (Rinehart et al. 1960). This finding is supported by data in rats, mice, cats, and monkeys acutely exposed to 1,1-dimethylhydrazine by injection (Furst and Gustavson 1967; Furst et al. 1969; Geake et al. 1966; Goff et al. 1967, 1970; Minard and Mushahwar 1966; O’Brien et al. 1964; Reynolds et al. 1963, 1964; Segerbo 1979; Sterman and Fairchild 1967). Data regarding the effects of acute oral exposure to 1,1-dimethylhydrazine are limited to a lethality study in mice (Roe et al. 1967). Animal studies (rabbits, dogs) have reported hematological and ocular effects following dermal exposure to 1,1-dimethylhydrazine (Rothberg and Cope 1956; Smith and Castaneda 1970; Smith and Clark 1971). These studies do not define the threshold for effect with confidence, and do not support the derivation of an MRL. Data are available for the acute toxicity of 1,2-dimethylhydrazine in animals after acute oral and dermal exposures. No human studies were located regarding the acute toxicity of 1,2-dimethylhydrazine. Two studies in rats and dogs were located which reported effects on the colon, liver, and body weight after oral exposure (Caderni et al. 1991: Wilson 1976). Studies in rabbits and guinea pigs indicate that acute dermal exposure to 1,2-dimethylhydrazine can produce irritation and death (Rothberg and Cope 1956). These studies do not define the effect level for 1,2-dimethyl- hydrazine with confidence and do not support the derivation of an MRL. Studies are also available on the carcinogenic effects of 1,2-dimethylhydrazine after acute oral exposure (Craven and DeRubertis 1992; Schiller et al. 1980; Watanabe et al. 1985). No animal studies were located regarding the effects of acute inhalation exposure to 1,2-dimethylhydrazine. Additional animal studies to investigate the acute effects of hydrazines after inhalation, oral, and dermal exposures would better define the threshold dose for adverse health effects. Such studies would be useful in predicting adverse health effects in humans following acute exposures. Intermediate-Duration Exposure. Data are available on the toxicity of hydrazine and 1,1-dimethylhydrazine in humans and several animal species after intermediate-duration exposure by the inhalation and oral routes. These studies reported effects on the central nervous system in humans following oral exposure (Chlebowski et al. 1984; Gershanovich et al. 1976, 1981; Ochoa et al. 1975) HYDRAZINES 101 2. HEALTH EFFECTS and in animals (rats, mice, dogs) after inhalation exposure (Haun and Kinkead 1973), and effects on the liver in animals (mice, dogs, monkeys, rats) after inhalation exposure (Biancifiori 1970; Haun and Kinkead 1973; Haun et al. 1984; Rinehart et al. 1960). The data were sufficient to support the derivation of inhalation MRLs of 4x10” ppm for hydrazine and 2x10 ppm for 1,1-dimethylhydrazine based on hepatic effects. No data were located regarding the toxicity of hydrazine or 1,1-dimethylhydrazine following dermal exposure for an intermediate duration. Studies are also available for the carcinogenic effects of hydrazine and 1,1-dimethylhydrazine after intermediate- duration exposures (Haun et al. 1984; Roe et al. 1967). No studies were located regarding the toxicity of 1,2-dimethylhydrazine in humans after intermediate- duration exposure. Data on the toxicity of 1,2-dimethylhydrazine in animals after intermediate- duration exposure are limited to those regarding the oral route. These studies have generally reported hepatic effects in rats, guinea pigs, mice, and pigs (Bedell et al. 1982; Visek et al. 1991; Wilson 1976), and support the derivation of an intermediate oral MRL of 8x10™* mg/kg/day for 1,2-dimethylhydrazine. In addition, a large number of studies report the carcinogenic effects of 1,2-dimethylhydrazine after intermediate exposures (Izumi et al. 1979; Teague et al. 1981; Wilson 1976). Additional studies in animals to investigate the effects of hydrazines after intermediate-duration inhalation, oral, and dermal exposures would better define the threshold dose for adverse health effects. Such studies would be useful in predicting adverse health effects in humans exposed for intermediate-durations to hydrazines. Chronic-Duration Exposure and Cancer. Data are available on the toxicity of hydrazine and 1,1-dimethylhydrazine in animals after chronic-duration exposure by the inhalation and oral routes. Effects on the liver, lung, and body weight gain are the most consistent findings observed in rats, mice, dogs, and hamsters (Haun et al. 1984; Steinhoff et al. 1990; Vernot et al. 1985). However, these studies do not define the threshold dose level for these effects with confidence, and therefore do not support the derivation of an MRL. Data regarding the noncarcinogenic effects of 1,2-dimethylhydrazine after chronic exposures are largely lacking. Additional studies which investigate the effects of hydrazines in animals after chronic inhalation, oral, and dermal exposures would help define the threshold dose for adverse health effects. Such studies would be useful in predicting adverse health effects in humans chronically exposed to hydrazines. HYDRAZINES 102 2. HEALTH EFFECTS As discussed in the previous sections, hydrazines can cause cancer in animals following acute- or intermediate-duration exposure by the oral and inhalation route. In addition, several studies reported carcinogenic effects in a number of animal species exposed to hydrazine (Bhide et al. 1976; Bosan et al. 1987; Maru and Bhide 1982; Toth 1969, 1972b; Vernot et al. 1985), 1,1-dimethylhydrazine (Haun et al. 1984; Toth 1973a), and 1,2-dimethylhydrazine (Toth and Patil 1982), following chronic oral and inhalation exposures. These studies demonstrate that hydrazines are carcinogenic in animals following chronic oral and inhalation exposures. Epidemiological studies which investigate the carcinogenic effects in humans exposed occupationally or therapeutically to hydrazine would confirm whether or not the cancer effects observed in animal studies also occur in humans. Genotoxicity. Data regarding the genotoxicity of hydrazines in humans are not available. A large number of studies are available that report the genotoxic effects of hydrazines in animals in vivo (Albanese et al. 1988; Ashby and Mirkova 1987; Becker et al. 1981; Beranek et al. 1983; Bolognesi et al. 1988; Bosan et al. 1986; Couch et al. 1986; Jacoby et al. 1991; Netto et al. 1992; Parodi et al. 1981; Pozharisski et al. 1975; Quintero-Ruiz et al. 1981; Winton et al. 1990; Zeilmaker et al. 1991; Zijlstra and Vogel 1988) and in a number of cell lines in vitro (Autrup et al. 1980a; Bosan et al. 1986; DeFlora and Mugnoli 1981; Harris et al. 1977; Kerklaan et al. 1983; Kumari et al. 1985; Lambert and Shank 1988; Levi et al. 1986; Malaveille et al. 1983; Noda et al. 1986; Oravec et al. 1986; Parodi et al. 1981; Rogers and Back 1981; Sedgwick 1992; Wilpart et al. 1983). These studies convincingly demonstrate that all three hydrazines are genotoxic. Additional genotoxicity studies in humans exposed to hydrazines, either occupationally or therapeutically would determine whether or not the effects observed in animals and in cells are also observed in humans. Reproductive Toxicity. Data regarding the reproductive toxicity of hydrazines in humans are not available. Data regarding the reproductive effects of hydrazines are limited to a few animal studies regarding inhalation, oral, and parenteral exposure to hydrazine (Biancifiori 1970; Vernot et al. 1985; Wyrobek and London 1973) and inhalation exposure to 1,1-dimethylhydrazine (Haun et al. 1984). The serious nature of the effects caused by the inhalation of hydrazines suggests they may be of concern in humans similarly exposed. Studies that investigate the reproductive effects of 1,2-dimethylhydrazine, hydrazine, and 1,1-dimethylhydrazine, particularly those which also evaluate reproductive function over several generations, would be valuable in determining if the reproductive system is adversely affected in humans exposed to hydrazines. HYDRAZINES 103 2. HEALTH EFFECTS Developmental Toxicity. Data regarding the developmental toxicity of hydrazines in humans are not available. Data regarding the developmental effects of hydrazines in animals are limited to a study which reported increased fetal and neonatal mortality following exposure to hydrazine by the parenteral route (Lee and Aleyassine 1970). No apparent developmental effects were seen after oral exposure of pregnant hamsters to 1,2-dimethylhydrazine dihydrochloride (Schiller et al. 1979). Studies that investigate the developmental effects of 1,1-dimethylhydrazine for any exposure route, as well as studies that better define the dose-response relationship for the developmental effects of hydrazine and 1,2-dimethylhydrazine for any exposure route, would be useful in determining whether developmental effects are of concern in humans exposed to hydrazines. Immunotoxicity. The data regarding the immunological effects of hydrazines are limited. There is some suggestive evidence from human studies that exposure to hydrazine and other hydrazine derivatives can produce a lupus erythematosus-like disease (Pereyo 1986; Reidenberg et al. 1983). Data in animals reported immunological effects in mice with parenteral exposure to 1,1-dimethylhydrazine (Frazier et al. 1991) but not in rats with oral exposure to 1,2-dimethylhydrazine (Locniskar et al. 1986). In vitro studies suggest 1,1-dimethylhydrazine produces immunomodulatory effects (Bauer et al. 1990; Frazier et al. 1992). Additional case studies in humans and studies in animals which better define the dose-response relationship for the immunological effects of all three hydrazines would help determine if these effects are of concern to humans exposed to hydrazines. Neurotoxicity. Data are available for the neurological effects of hydrazines in humans following inhalation, oral, and dermal exposures to hydrazine (Chlebowski et al. 1984; Gershanovich et al. 1976, 1981; Haun and Kinkead 1973; Ochoa et al. 1975; Richter et al. 1992; Sotaniemi et al. 1971; Spremulli et al. 1979) and 1,1-dimethylhydrazine (Dhennin et al. 1988; Kirklin et al. 1976; Rinehart et al. 1960). Effects on the central nervous system were also observed in animals following dermal and parenteral exposures to hydrazine (Floyd 1980; Mizuno et al. 1989; Patrick and Back 1965; Smith and Clark 1972) and 1,1-dimethylhydrazine (Furst and Gustavson 1967; Geake et al. 1966; Goff et al. 1970; Minard and Mushahwar 1966; O’Brien et al. 1964; Reynolds et al. 1964; Segerbo 1979; Smith and Clark 1971). Although these studies convincingly demonstrate that the central nervous system is a primary target of hydrazine and 1,1-dimethylhydrazine, these data do not define the threshold dose and more fully characterize neurological effects with confidence. Additional studies which better define the threshold dose for the neurological effects of hydrazine and 1,1-dimethylhydrazine would be useful in determining the risk of neurological effects in humans exposed to these hydrazines. Preliminary HYDRAZINES 104 2. HEALTH EFFECTS neurological screening studies on 1,2-dimethylhydrazine in animals may determine if neurological effects are of concern for humans exposed to this chemical. Epidemiological and Human Dosimetry Studies. Only one epidemiological study was located regarding the effects of hydrazine. This study showed no significant increase in cancer mortality in 427 hydrazine workers (Wald et al. 1984). However, the number of deaths examined was relatively small and the follow-up period may not have been sufficient for detecting a weak carcinogenic effect. Additional epidemiological studies investigating the neurological, hepatic, renal, and carcinogenic effects of hydrazines, particularly studies which also provide quantitative information on exposure, would be valuable in estimating the risk of adverse health effects in persons exposed to hydrazines in the workplace or therapeutically. Biomarkers of Exposure and Effect Exposure. Methods are available for determining the levels of hydrazine in the plasma of humans (Blair et al. 1985), and the levels of all three hydrazines and their metabolites and in tissues, urine, and expired air of animals (Alvarez de Laviada et al. 1987; Back et al. 1963; Dost et al. 1966; Fiala et al. 1976; Harbach and Swenberg 1981; Kaneo et al. 1984; Kang et al. 1988; Matsuyama et al. 1983; Preece et al. 1991; Reed et al. 1963; Springer et al. 1981). The detection of hydrazines and some of their metabolites (for example, the metabolites of 1,2-dimethylhydrazine—azoxymethane and methylazoxymethanol) are fairly specific for exposures to hydrazines. However, it should be kept in mind that treatment with certain drugs such as isoniazid or hydralazine can result in the presence of hydrazine in human plasma (Blair et al. 1985); therefore, care should be taken to ensure subjects have not been exposed to these drugs. Other metabolites of hydrazines (for example, carbon dioxide and nitrogen) are endogenous to the body, and therefore, cannot be used as specific biomarkers of exposure. Studies which investigate the quantitative relationship between exposure intensity, time since exposure, and the levels of hydrazines or their unique metabolites detected in biological samples, particularly in the urine, would be useful for estimating human exposures to hydrazines. Studies that identify biomarkers of exposure that are specific to 1,1-dimethylhydrazine and hydrazine could lead to the development of a reliable method for estimating recent exposures to hydrazines. Effect. Exposure to hydrazine and 1,1-dimethylhydrazine is associated with the development of neurological and hepatic effects in humans (Chlebowski et al. 1984; Gershanovich et al. 1976; Ochoa HYDRAZINES 105 2. HEALTH EFFECTS et al. 1975; Richter et al. 1992; Sotaniemi et al. 1971) and animals (Haun and Kinkead 1973; Rinehart et al. 1960; Vernot et al. 1985; Wilson 1976). Studies which investigate if serum transaminase levels or vitamin By status could be used to predict effects of hydrazines could be useful, if they are coupled with confirmed exposures to hydrazines. The carcinogenic effects of hydrazines have also been amply demonstrated in animal studies (Abraham et al. 1980; Asano and Pollard 1978; Barbolt and Abraham 1980; Calvert et al. 1987; Izumi et al. 1979; Locniskar et al. 1986; Teague et al. 1981; Thorup et al. 1992; Wilson 1976). Studies which investigate if tests for occult blood in stools could be used to predict intestinal tumors induced by 1,2-dimethylhydrazine could be useful. However, the etiology of colon cancer is multifactional and may not be related to exposures to 1,2-dimethylhydrazine. Studies which identify biomarkers of effect that are specific to exposures to hydrazines could lead to the development of a reliable method for predicting past exposures to hydrazines. Absorption, Distribution, Metabolism, and Excretion. Data regarding the toxicokinetics of hydrazines are limited to in vitro metabolic assays (Albano et al. 1989; Augusto et al. 1985; Coomes and Prough 1983; Craven et al. 1985; Erikson and Prough 1986; Glauert and Bennink 1983; Godoy et al. 1983; Netto et al. 1987; Newaz et al. 1983; Noda et al. 1987, 1988; Prough 1973; Prough et al. 1981; Sheth-Desai et al. 1987; Sinha 1987; Timbrell et al. 1982; Tomasi et al. 1987; Wolter et al. 1984) and in vivo studies in rats exposed via inhalation (Llewellyn et al. 1986), rats exposed orally (Preece et al. 1992b), dogs exposed dermally (Smith and Clark 1971, 1972), and in several species exposed by parenteral routes (Back et al. 1963; Dost et al. 1966; Fiala et al. 1976; Harbach and Swenberg 1981; Kaneo et al. 1984; Mitz et al. 1962; Reed et al. 1963; Springer et al. 1981). These studies invariably employed a single radiolabel (either *C or *N), and therefore, in the case of 1,1-dimethylhydrazine and 1,2-dimethylhydrazine, the metabolic fate data (expressed as a carbon or nitrogen dose) were often incomplete. Studies which investigate the toxicokinetics of hydrazines for all routes and durations, particularly those which employ both a carbon and nitrogen label, would enhance the current understanding of the metabolic fate of hydrazines in humans exposed at hazardous waste sites. Comparative Toxicokinetics. Studies in humans (Dhennin et al. 1988; Kirklin et al. 1976; Sotaniemi et al. 1971) and several animal species (Biancifiori 1970; Haun and Kinkead 1973; Marshall et al. 1983; Rinehart et al. 1960; Vernot et al. 1985; Wakabayashi et al. 1983) indicate that the liver and central nervous system are the primary target organs affected following oral, inhalation, and dermal exposures to hydrazine and 1,1-dimethylhydrazine. Studies in several animal species indicate HYDRAZINES 106 2. HEALTH EFFECTS that the intestinal tract and liver are the primary target organs affected following oral exposure to 1,2-dimethylhydrazine (Bedell et al. 1992; Wilson et al. 1976). Data regarding the toxicokinetics of hydrazines are lacking in humans and are limited in animals. These data are not sufficient to conclude which animal species is best for modeling human exposures. Similarly, these data do not reveal the basis of species differences in the toxicokinetics or pharmacodynamics of hydrazines which may underlie the species differences in toxicity. For example, dogs appear to be particularly sensitive to the hematological effects of hydrazine and 1,1-dimethylhydrazine (Haun and Kinkead 1973; Haun et al. 1984; Rinehart et al. 1960; Smith and Castaneda 1970). Additional studies which investigate the toxicokinetics in multiple species, including humans or human tissues, would be useful in developing an appropriate animal model for humans exposed to hydrazines at hazardous waste sites. Methods for Reducing Toxic Effects. General methods exist for reducing the absorption of chemicals from the eyes, skin, and gastrointestinal tract (Bronstein and Currance 1988; Sittig 1991; Stutz and Janusz 1988). However, none of these methods are specific for exposures to hydrazines. No data were located for reducing body burden after exposure to hydrazines. Pyridoxine, which interferes with the mechanism of action of hydrazine and 1,1-dimethylhydrazine, is often administered to humans exposed to these hydrazines (Dhennin et al. 1988; Kirklin et al. 1976). However, exposure to pyridoxine may also be associated with adverse health effects. Additional studies that investigate the threshold dose for adverse effects of pyridoxine, and studies that investigate alternative agents that interfere with the mechanism of action of hydrazines could lead to a safer method of treatment. Inhibitors of metabolic activation (Fiala et al. 1977) and free radical scavengers may also be useful in interfering with the mechanism of action of hydrazines (Belleli et al. 1992; Colacchio et al. 1989: Cook and McNamara 1980; Craven and DeRubertis 1992; Shirai et al. 1985; Tomasi et al. 1987). Additional studies that investigate the effects of metabolic inhibitors and various free radical scavengers in humans occupationally exposed to hydrazines and in animals could lead to other methods of interfering with the mechanism of action of hydrazines. 2.10.3 On-going Studies A number of researchers are continuing to investigate the toxicity and toxicokinetics of 1,2-dimethylhydrazine. Table 2-6 summarizes studies sponsored by agencies of the U.S. federal government. HYDRAZINES 107 2. HEALTH EFFECTS TABLE 2-6. On-going Studies on the Health Effects of Hydrazines* Investigator Affiliation Research description Sponsor Brasitus, TA University of Chicago Colonic epithelial cell plasma membranes NIH, NCI in rats treated with 1,2-dimethylhydrazine Goldman, P Harvard School of Metabolism of 1,2-dimethylhydrazine by rat NIH, NCI Public Health intestinal bacteria Kazarinoff, MN Cornell University Induction of ornithine decarboxylase by USDA 1,2-dimethylhydrazine McGarrity, TJ Milton S Hershey Cellular changes in 1,2-dimethylhydrazine- NIH, NCI Medical Center induced colon tumors in the rat Pretlow, TP Case Western Reserve Colonic putative preneoplastic foci in NIH, NCI University rats by metabolite, azoxymethane Shank, RC University of California Environmental hydrazines and methylation of NIH, NIEHS DNA in rats and hamsters Strobel, HW University of Texas Identification of cytochrome P-450 isozymes NIH, NCI Medical School involved in the metabolism of 1,2-dimethylhydrazine *Source: CRISP (1993) NCI = National Cancer Institute; NIEHS = National Institute of Environmental Health Sciences; NIH = National Institute of Health; USDA = U.S. Department of Agriculture HYDRAZINES 109 3. CHEMICAL AND PHYSICAL INFORMATION 3.1 CHEMICAL IDENTITY Information regarding the chemical identity of hydrazines is located in Table 3-1. 3.2 PHYSICAL AND CHEMICAL PROPERTIES Information regarding the physical and chemical properties of hydrazines is located in Table 3-2. TABLE 3-1. Chemical Identity of Hydrazines Characteristic Hydrazine 1,1-Dimethylhydrazine 1,2-Dimethylhydrazine References Synonym(s) Diamine; diamide; Hydrazine, 1,1-dimethyl; Hydrazine, 1,2-dimethyl; HSDB 1993 anhydrous hydrazine; DMH; unsymmetrical DMH; symmetrical hydrazine base dimethylhydrazine; dimethylhydrazine; SDMH; UDMH; dimazine; and others hydrazomethane; and others Registered trade name(s) Levoxin®; SCAV-OX; No data No data HSDB 1993; Zerox; Oxytreat 35 WHO 1987 Chemical formula H,N, C,HgN, C,HgN, HSDB 1993 H,C \ Chemical structure H,N-NH, N—NH, CH, - NH - NH - CH, IARC 1974 / H,C Identification numbers: CAS registry 302-01-2 57-14-7 540-73-8 HSDB 1993 NIOSH RTECS MU7175000 MV2450000 MV2625000 HSDB 1993 EPA hazardous waste U133 u098 u099 HSDB 1993 OHM/TADS No data No data No data DOT/UN/NA/IMCO shipping UN2029, UN2030 UN1163 UN2382 HSDB 1993 IMCO 3.1 IMCO 3.2 IMCO 3.1 IMCO 8.2 NA 9188 HSDB 544 528 4039 HSDB 1993 NCI No data No data No data CAS = Chemical Abstracts Services; DOT/UN/NA/IMCO = Department of Trans Code; EPA = Environmental Protection Agency; HSDB = Hazardous Substance Occupational Safety and Health; OHM/TADS = Oil and Hazardous Materials/Technical Assistance D. Substances portation/United Nations/North America/International Maritime Dangerous Goods s Data Bank; NCI = National Cancer Institute; NIOSH = National Institute for ata System; RTECS = Registry of Toxic Effects of Chemical NOILYWHOLNI TVOISAHd ANV TVOINIHO © S3ANIZVHAAH Okt TABLE 3-2. Physical and Chemical Properties of Hydrazines Property Hydrazine 1,1-Dimethylhydrazine 1,2-Dimethylhydrazine Reference Molecular weight 32.05 60.10 60.10 HSDB 1993 Color Colorless Colorless Colorless HSDB 1993 Physical state Liquid Liquid Liquid HSDB 1993 Melting point 2°C -58°C -9°C HSDB 1993 Boiling point 113.5°C 63.9°C 81°C WHO 1987 Density 1.0036 g/mL at 25°C 0.7914 g/mL at 25°C 0.8274 g/mL at 20°C HSDB 1993; WHO 1987 Odor Ammoniacal, Ammoniacal, Ammoniacal HSDB 1993; WHO 1987 pungent, fishy fishy Odor threshold: Water 160 mg/L No data No data Amoore and Hautala 1983 Air 34 mgm’ 12-20 mg/m’ No data Ruth 1986 Solubility: Water Miscible Miscible Miscible Budavari et al. 1989; HSDB 1993 Organic solvent(s) Partition coefficients: Log K,,, Log K,. Vapor pressure Henry's law constant Autoignition temperature Flashpoint Flammability limits Conversion factors Explosive limits Miscible with alcohol, insoluble in chloroform and ether -3.08 -1.07 No data 10.4-16 mmHg at 20°C No data No data 38°C (open cup) 1.8-100% 1 ppm = 1.31 mg/m’ 1 mg/m® = 0.76 ppm 4.7-100% Miscible with alcohol, ether, dimethyl formamide and hydrocarbons No data No data 157 mmHg at 25°C No data 249°C -15°C (closed cup) No data 1 ppm = 2.5 mg/m’ 1 mg/m® = 0.407 ppm 2-95% Miscible with alcohol, ether, dimethyl formamide and hydrocarbons No data No data 68 mmHg at 24°C No data No data <23°C (closed cup) No data 1 ppm = 2.5 mg/m’ 1 mg/m’ = 0.407 ppm No data ACGIH 1991a, 1991b; Budavari et al. 1989 Radding et al. 1977; Poitrast et al. 1988 HSDB 1993; Verschueren 1983; WHO 1987 HSDB 1993; WHO 1987 WHO 1987 HSDB 1993; Verschueren 1983; WHO 1987 ACGIH 1991a, 1991b NOILVWHO4NI TVOISAHd ANV TVOIN3HO '€ S3NIZVHAAH LEE HYDRAZINES 113 4. PRODUCTION, IMPORT, USE, AND DISPOSAL 4.1 PRODUCTION For most uses, hydrazine is produced as hydrazine hydrate in a formulation with water. The hydrate may be produced commercially by three methods: the Raschig process, the ketazine process, and the peroxide process. The Raschig process, the original commercial production process for hydrazine, involves oxidation of ammonia to chloramine with sodium hypochlorite, then further reaction of the chloramine with excess ammonia and sodium hydroxide to produce an aqueous solution of hydrazine with sodium chloride as a by-product. Fractional distillation of the product yields hydrazine hydrate solutions. Currently, most hydrazine is produced by the ketazine process, which is a variation of the Raschig process. Ammonia is oxidized by chlorine or chloramine in the presence of an aliphatic ketone, usually acetone. The resulting ketazine is then hydrolyzed to hydrazine. In the peroxide process, hydrogen peroxide is used to oxidize ammonia in the presence of a ketone. Anhydrous hydrazine is the formulation used in rocket fuels and is produced by dehydration of the hydrate by azeotropic distillation with aniline as an auxiliary fluid (Budavari et al. 1989; IARC 1974; Schmidt 1988; WHO 1987). 1,1-Dimethylhydrazine is currently prepared commercially by a modified Raschig process: reacting dimethylamine with the chloramine produced from ammonia and sodium hypochlorite. Formerly, it was prepared by the reduction of dimethylnitrosamine or by the reductive catalytic alkylation of carboxylic acid hydrazides with formaldehyde and hydrogen, followed by basic hydrolysis (Budavari et al. 1989; EPA 1984a, 1992b; IARC 1974; Schmidt 1988). 1,2-Dimethylhydrazine may be prepared from dibenzoylhydrazine or by electrosynthesis from nitromethane (Budavari et al. 1989). The two current chemical producers of hydrazine in the United States are the Olin Corporation in Lake Charles, Louisiana, and Miles Inc. in Baytown, Texas. The chemical was also produced by Fairmount Chemical Company, Inc., Newark, New Jersey, as recently as 1987. 1,1-Dimethylhydrazine is produced by Olin and Uniroyal Chemical Company, Inc., Geismar, Louisiana. Estimates of past production (based on anhydrous hydrazine, although most production was of the hydrate) indicate that U.S. production volume was about 7,000 metric tons (15 million pounds) per year in the mid-1960s and increased to 17,000 metric tons (37 million pounds) per year in the mid-1970s. Production HYDRAZINES 114 4. PRODUCTION, IMPORT, USE, AND DISPOSAL capacity in the United States was estimated at 17,240 metric tons (38 million pounds) in 1979 and about 14,000 metric tons (30 million pounds) in 1984, the most recent year for which information was located. 1,1-Dimethylhydrazine production volume was estimated to be at least 45 metric tons (99,000 pounds) in 1977 and more than 4.5 metric tons (9,900 pounds) in 1982 (HSDB 1995; Schmidt 1988; SRI 1987, 1988, 1992; WHO 1987). Information on current production volume is not publicly available for either hydrazine or 1,1-dimethylhydrazine (EPA 1991d). Tables 4-1 and 4-2 list information on U.S. companies that reported the manufacture and use of hydrazine and 1,1-dimethylhydrazine, respectively, in 1993 (TRI93 1995). The data listed in the Toxics Release Inventory (TRI) should be used with caution since only certain types of facilities are required to report. This is not an exhaustive list. 4.2 IMPORT/EXPORT There is some indication that hydrazine was imported into the United States from Japan during the 1970s (IARC 1974), but no data were located on past or current U.S. import or export quantities of hydrazine or 1,1-dimethylhydrazine. 4.3 USE Hydrazine (anhydrous or as the hydrate) has numerous commercial uses. The principal current use for hydrazine is as an intermediate in the production of agricultural chemicals such as maleic hydrazide. It is also used as an intermediate in the manufacture of chemical blowing agents which are used in the production of plastics such as vinyl flooring and automotive foam cushioning, as a corrosion inhibitor and water treatment agent, as a rocket propellant, and, to a lesser extent, as a reducing agent, in nuclear fuel reprocessing, as a polymerization catalyst, as a scavenger for gases, and several other uses. It has also been used as a medication for sickle cell disease and cancer. From the late 1950s through the 1960s, the primary use of hydrazine was as a rocket propellant. In 1964, 73% of the hydrazine consumed in the United States was used for this purpose. By 1982, other commercial uses dominated the market; 40% of the hydrazine consumed was used in agricultural Table 4-1. Facilities That Manufacture or Process Hydrazine Facility Location® Range of maximum amounts on site in pounds Activities and uses OCCIDENTAL CHEMICAL CORP. HALL CHEMICAL CO. OLIN CORP. GREAT LAKES CHEMICAL CORP. GREAT LAKES CHEMICAL CORP. NA DEEPWATER IODIDES INC. AEROJET SACRAMENTO OPS. HERCULES INC. AMOCO 3M SUNDSTRAND AEROSPACE ALLIED-SIGNAL INC. VANDERBILT CHEMICAL CORP. UNIROYAL CHEMICAL CO. INC. OLIN CORP. SHELL OIL PRODS. NA ZENECA RESINS BF GOODRICH BAYER CORP. FAIRMOUNT CHEMICAL CO. INC. JOHNSON MATTHEY INC. DEGUSSA CORP. E. |. DU PONT DE NEMOURS & CO. PROCTER & GAMBLE OLIN CORP. HALL CHEMICAL CO. LUBRIZOL CORP. BF GOODRICH MUSCLE SHOALS, AL ARAB, AL MCINTOSH, AL EL DORADO, AR EL DORADO, AR AZ CARSON, CA SACRAMENTO, CA BRUNSWICK, GA WOOD RIVER, IL IL ROCKFORD, IL PITTSBURG, KS MURRAY, KY GEISMAR, LA WESTLAKE, LA NORCO, LA MA WILMINGTON, MA LEOMINSTER, MA KANSAS CITY, MO NEWARK, NJ WEST DEPTFORD, NJ SOUTH PLAINFIELD, NJ NJ NORWICH, NY ROCHESTER, NY WICKLIFFE, OH PAINESVILLE, OH AVON LAKE, OH 10,000-99,999 10,000-99,999 10,000-99,999 10,000-99,999 10,000-99,999 100-999 10,000-99,999 100,000-999,999 10,000-99,999 10,000-99,999 10,000-99,999 1,000-9,999 10,000-99,999 10,000-99,999 100,000-999,999 100,000-999,999 1,000-9,999 100-999 1,000-9,999 1,000-9,999 100,000-999,999 10,000-99,999 1,000-9,999 10,000-99,999 10,000-99,999 10,000-99,999 10,000-99,999 1,000-9,999 10,000-99,999 10,000-99,999 As a chemical processing aid As a chemical processing aid In repackaging only As a chemical processing aid As a formulation component Ancillary uses As a reactant Ancillary uses As a reactant As a reactant As a reactant Ancillary uses As a reactant As a reactant As a reactant Produce; For sale/distribution; Ancillary uses As a chemical processing aid As a reactant As a reactant As a reactant As a reactant As a reactant As a chemical processing aid As a reactant; As a chemical processing aid As a chemical processing aid As a reactant As a reactant; As a formulation component As a chemical processing aid As a reactant As a reactant IvSOdSIA ANY ‘3SN ‘LHOdWI ‘NOLLONAOHd “¥ S3INIZVHAAH Ski Table 4-1. Facilities That Manufacture or Process Hydrazine (continued) Range of 2 maximum amounts Facility Location on site in pounds Activities and uses DOWELL SCHLUMBERGER INC. TULSA, OK 10,000-99,999 As a reactant BILCHEM LTD. PONCE, PR 10,000-99,999 As a reactant GREAT LAKES CHEMICAL CORP. NEWPORT, TN 10,000-99,999 As a chemical processing aid NA TN 10,000-99,999 As a reactant DREXEL CHEMICAL CO. MEMPHIS, TN 10,000-99,999 As a reactant MILES INC. BAYTOWN, TX 1,000,000-9,999,999 Produce; For sale/distribution PHELPS DODGE CORP. TX 1,000-9,999 As a reactant LUBRIZOL CORP. PASADENA, TX 10,000-99,999 As a reactant HOECHST-CELANESE CHEMICAL GROU LBS 1,000-9,999 Ancillary uses SHELL OIL CO. DEER PARK, TX 10,000-99,999 Ancillary uses ASHLAND CHEMICAL CO. HOUSTON, TX 100,000-999,999 Import; For sale/distribution; As a formulation component; As a product component; In repackaging only MOBIL OIL BEAUMONT REFINERY BEAUMONT, TX 10,000-99,999 As a manufacturing aid MERCK & CO. INC. ELKTON, VA 10,000-99,999 As a reactant SPECIALTYCHEM PRODS. CORP. MARINETTE, WI 10,000-99,999 As a reactant BAYER CORP. NEW MARTINSVILLE, WV 100,000-999,999 As a reactant Source: TRI93 1995 2 Post office state abbreviations used NA = not available T¥SOdSIA ANY ‘ISN ‘LHOdWI ‘NOILONAOHd + S3ANIZVHAAH 9k Table 4-2. Facilities That Manufacture or Process 1,1-Dimethylhydrazine Range of maximum amounts Facility Location” on site in pounds Activities and uses OLIN CORP. AL 10,000-99,999 In repackaging only AEROJET SACRAMENTO OPS. SACRAMENTO, CA 100,000-999,999 Ancillary uses UNIROYAL CHEMICAL CO. INC. GEISMAR, LA 100,000-999,999 Import; For on-site use/processing; As a reactant OLIN CORP. WESTLAKE, LA 100,000-999,999 Produce; For sale/distribution Source: TRI93 1995 a Post office state abbreviations used IV¥SOdSIA ANY ‘3SN ‘LHOdWI ‘NOILONAOHd 'v S3NIZVHAAH Li HYDRAZINES 118 4. PRODUCTION, IMPORT, USE, AND DISPOSAL chemicals, about 33% for blowing agents, 15% as a corrosion inhibitor in boiler water and only 5% as an aerospace propellant (Budavari et al. 1989; Fajen and McCammon 1988; HSDB 1995; Schmidt 1988; WHO 1987). 1,1-Dimethylhydrazine is used mainly as a component of jet and rocket fuels. Other uses include an adsorbent for acid gases, a stabilizer for plant growth regulators, an intermediate for organic chemical synthesis, and in photography. 1,2-Dimethylhydrazine is used only as a research chemical and has no known commercial uses (ACGIH 1991a; Budavari et al. 1989; HSDB 1995). 4.4 DISPOSAL Hydrazine, 1,1-dimethylhydrazine, 1,2-dimethylhydrazine, and wastes containing these chemicals are classified as hazardous wastes by EPA. Generators of waste containing these contaminants must conform to EPA regulations for treatment, storage, and disposal (see Chapter 7). Liquid injection or fluidized bed incineration methods are acceptable disposal methods for these wastes. Oxidation of spills of hydrazine fuels with sodium or calcium hypochlorite or hydrogen peroxide prior to disposal has been recommended. However, incomplete reaction of 1,1-dimethylhydrazine with hypochlorite leads to formation of several by-products, including carcinogenic N-nitrosoalkylamines. Ozonation of wastewater containing hydrazine fuels has been shown to reduce concentrations of the fuels, their associated impurities, and oxidation products to environmentally acceptable levels. Biodegradation is also an acceptable treatment for wastewaters containing hydrazine wastes (Brubaker 1988; EPA 1991a; HSDB 1995; Jody et al. 1988; WHO 1987). According to the TRI, about 106,000 pounds of hydrazine and 3,000 pounds of 1,1-dimethylhydrazine were transferred to landfills and/or treatment/disposal facilities in 1993 (see Section 5.2) (TRI93 1995). Of this quantity, about 1,400 pounds of hydrazine were discharged to publicly owned treatment works. HYDRAZINES 119 5. POTENTIAL FOR HUMAN EXPOSURE 5.1 OVERVIEW Hydrazine and 1,1-dimethylhydrazine are industrial chemicals that enter the environment primarily by emissions from their use as aerospace fuels and from industrial facilities that manufacture, process, or use these chemicals. Treatment and disposal of wastes containing these chemicals also contribute to environmental concentrations. These chemicals may volatilize to the atmosphere from other media and may sorb to soils. These chemicals degrade rapidly in most environmental media. Oxidation is the dominant fate process, but biodegradation occurs in both water and soil at low contaminant concentrations. The half-lives in air range from less than 10 minutes to several hours, depending on ozone and hydroxyl radical concentrations. Half-lives in other media range up to several weeks, under various environmental conditions. Bioconcentration does occur, but biomagnification through the food chain is unlikely. Human exposure to hydrazine and 1,1-dimethylhydrazine is mainly in the workplace or in the vicinity of aerospace or industrial facilities or hazardous waste sites where contamination has been detected. These chemicals have not been detected in ambient air, water, or soil. Humans may also be exposed to small amounts of these chemicals by using tobacco products. Hydrazine has been found in at least 4 of the 1,430 current or former EPA National Priorities List (NPL) hazardous waste sites (HazDat 1996). 1,1-Dimethylhydrazine and 1,2-dimethylhydrazine have been identified in at least 3 and 1 of these sites, respectively. However, the number of sites evaluated for these chemicals is not known. The frequency of these sites within the United States can be seen in Figure 5-1. 5.2 RELEASES TO THE ENVIRONMENT Hydrazine occurs naturally as a product of nitrogen fixation by some algae and in tobacco and tobacco smoke (IARC 1974). However, the major environmental sources of hydrazine are anthropogenic. There are no known natural sources of dimethylhydrazines. The estimated total annual environmental release of hydrazine and 1,1-dimethylhydrazine from manufacture and processing reported to the FIGURE 5-1. FREQUENCY OF NPL SITES WITH HYDRAZINES CONTAMINATION * FREQUENCY EER 1 sI1TE BFF H 2 SITES ¥Derived from HazDat 1995 3HNSOdX3 NVIWNH HOH TVILNILOd °S S3ANIZVHAAH oct HYDRAZINES 121 5. POTENTIAL FOR HUMAN EXPOSURE TRI were about 30,000 and 4,000 pounds, respectively, in 1988 (EPA 1991d). However, more recent data reported to the TRI indicate that environmental releases from manufacture and use of these chemicals total about 17,000 and 200 pounds, respectively (TRI93 1995). 1,1-Dimethylhydrazine may also be released to the environment from the application of daminozide (Alar®), a growth enhancer which contains about 0.005% 1,1-dimethylhydrazine as a contaminant to nonfood plants (EPA 1992c). 5.2.1 Air The major sources of hydrazine releases to air are expected to be from its use as an aerospace propellant and boiler water treatment agent (HSDB 1995). However, hydrazine released as a boiler water treatment agent is present only briefly since it would oxidize rapidly in water (HSDB 1995). Burning of rocket fuels containing hydrazine and/or 1,1-dimethylhydrazine reportedly produces exhaust gases containing trace amounts of unchanged fuel (IARC 1974). Emissions are also expected from the production and processing of hydrazine (EPA 1991d; WHO 1987). It has been estimated, based on data from Germany, that 0.06-0.08 kg of hydrazine are emitted to the air for every metric ton produced, and an additional 0.02-0.03 kg are emitted for every metric ton subjected to handling and further processing (WHO 1987). On this basis, assuming production volume of about 14,000 metric tons (30 million pounds) (see Section 4.1) and handling or processing of the product, emissions to the air may range from 1,100 to 1,500 kg (500-680 pounds) annually. Atmospheric releases of hydrazine may also occur from tobacco smoking (see Section 5.4.4) and from hazardous waste sites at which this chemical has been detected (HSDB 1995; WHO 1987). Release of 1,1-dimethylhydrazine to the atmosphere is expected to occur primarily from its use as an aerospace propellant (HSDB 1995). Release of this chemical and 1,2-dimethylhydrazine may also occur from hazardous waste sites at which they have been detected. As shown in Tables 5-1 and 5-2, an estimated total of 16,452 pounds of hydrazine and 194 pounds of 1,1-dimethylhydrazine, amounting to about 95% and 100% of the total environmental releases, respectively, were discharged to the air from manufacturing and processing facilities in the United States in 1993 (TRI93 1995). The TRI data should be used with caution since only certain types of facilities are required to report. This is not an exhaustive list. Table 5-1. Releases to the Environment from Facilities That Manufacture or Process Hydrazine Reported amounts released in pounds per year State® City Facility Air Water Land Underground Total POTW Off-site injection environment® transfer waste transfer AL MUSCLE SHOALS OCCIDENTAL CHEMICAL 75 33 108 CORP. AL ARAB HALL CHEMICAL CO. 250 250 AL MCINTOSH OLIN CORP. 6 6 AR EL DORADO GREAT LAKES 24 24 CHEMICAL CORP. AR EL DORADO GREAT LAKES 18 18 CHEMICAL CORP. AZ NA NA CA CARSON DEEPWATER IODIDES 5 5 INC. CA SACRAMENTO AEROJET SACRAMENTO 9 9 2,874 OPS. GA BRUNSWICK HERCULES INC. 30 30 IL WOOD RIVER AMOCO 19 19 1,400 IL NA 3M IL ROCKFORD SUNDSTRAND 500 500 AEROSPACE KS PITTSBURG ALLIED-SIGNAL INC. 15 15 KY MURRAY VANDERBILT CHEMICAL 1 1 CORP. LA GEISMAR UNIROYAL CHEMICAL 222 222 CO. INC. LA WESTLAKE OLIN CORP. 690 690 2,802 LA NORCO SHELL OIL PRODS. 933 933 4,500 MA NA NA MA WILMINGTON ZENECA RESINS 1 1 491 3HNSOdX3 NVWNH HOA TVILNILOd °S S3NIZVYHAAH cl Table 5-1. Releases to the Environment from Facilities That Manufacture or Process Hydrazine (continued) Reported amounts released in pounds per year State® City Facility Air Water Land Underground Total POTW Off-site injection environment transfer waste transfer MA LEOMINSTER BF GOODRICH 332 332 MO KANSAS CITY BAYER CORP. 439 1 440 NJ NEWARK FAIRMOUNT CHEMICAL 2,500 2,500 CO. INC. NJ WEST DEPTFORD JOHNSON MATTHEY INC. 5 5 NJ SOUTH DEGUSSA CORP. 1,360 1,360 PLAINFIELD NJ NA E. |. DU PONT DE NEMOURS & CO. NY NORWICH PROCTER & GAMBLE 130 130 NY ROCHESTER OLIN CORP. 161 161 3 OH WICKLIFFE HALL CHEMICAL CO. 5 5 OH PAINESVILLE LUBRIZOL CORP. 50 50 OH AVON LAKE BF GOODRICH 3 3 OK TULSA DOWELL 5 5 SCHLUMBERGER INC. PR PONCE BILCHEM LTD. 255 255 TN NEWPORT GREAT LAKES 1 1 CHEMICAL CORP. TN NA NA TN MEMPHIS DREXEL CHEMICAL CO. 10 5 15 5 TX BAYTOWN MILES INC. 500 750 1,250 92,000 ™ NA PHELPS DODGE CORP. TX PASADENA LUBRIZOL CORP. 6,131 6,131 3,617 IRS NA HOECHST-CELANESE CHEMICAL GROUP TX DEER PARK SHELL OIL CO. 914 914 3HNSOdX3 NVWNH HOA TVILN3LOd 'S S3INIZVHAAH ech Table 5-1. Releases to the Environment from Facilities That Manufacture or Process Hydrazine (continued) Reported amounts released in pounds per year State® City Facility Air Water Land Underground Total POTW Off-site injection environment® transfer waste transfer ™ HOUSTON ASHLAND CHEMICAL CO. 31 31 27 TX BEAUMONT MOBIL OIL BEAUMONT 14 14 REFINERY VA ELKTON MERCK & CO. INC. 50 50 Wi MARINETTE SPECIALTYCHEM 1 1 PRODS. CORP. NEW BAYER CORP. 757 757 MARTINSVILLE Totals 16,452 784 5 17,241 1,408 106,311 Source: TRI93 1995 . Post office state abbreviations used The sum of all releases of the chemical to air, land, water, and underground injection wells by a given facility NA = not available; POTW = publicly owned treatment works IHNSOdX3 NVIWNH HOH TVILN3LOd °S S3NIZVYHAAH vel Table 5-2. Releases to the Environment from Facilities That Manufacture or Process 1,1-Dimethylhydrazine Reported amounts released in pounds per year State® City Facility Air Water Land Underground Total POTW Off-site injection environment transfer waste transfer AL NA OLIN CORP. CA SACRAMENTO AEROJET SACRAMENTO 65 65 2,851 OPS. GEISMAR UNIROYAL CHEMICAL 104 104 CO. INC. WESTLAKE OLIN CORP. 25 25 74 Totals 194 194 2,925 Source: TRI93 1995 2 post office state abbreviations used The sum of all releases of the chemical to air, la NA = not available; POTW = publicly owned treatment works nd, water, and underground injection wells by a given facility 3HNSOdX3 NYWNH HO4 TVILN3LOd 'S S3ANIZVHAAH sch HYDRAZINES 126 5. POTENTIAL FOR HUMAN EXPOSURE 5.2.2 Water Releases of hydrazine and 1,1-dimethylhydrazine to water may occur during production, processing, use, or disposal of the chemical. Hydrazine was detected at a concentration of 0.01 mg/L in effluent from one industrial facility (EPA 1984b). However, since these chemicals are rapidly oxidized in water (see Section 5.3.2.2), the unreacted compounds are not likely to persist in detectable concentrations. As shown in Tables 5-1 and 5-2, an estimated total of 784 pounds of hydrazine amounting to about 4.5% of the total environmental releases and no 1,1-dimethylhydrazine were discharged to surface water from manufacturing and processing facilities in the United States in 1993 (TRI93 1995). An additional 423 pounds of hydrazine (1% of the total) were discharged by underground injection. The TRI data should be used with caution since only certain types of facilities are required to report. This is not an exhaustive list. 5.23 Soil No data were located documenting release of hydrazine or dimethylhydrazines to soil. However, releases to soil may occur from spills and leakage of underground storage tanks during the use of hydrazine and 1,1-dimethylhydrazine as rocket propellants (Street and Moliner 1988). Deposition from air is not expected to be significant (see Section 5.3.1). Hydrazine and dimethylhydrazines may be released to soil from hazardous waste sites at which these chemicals have been detected. 1,1-Dimethylhydrazine may also be released to soil from the application of daminozide (Alar®) as a growth enhancer on nonfood plants. The use of this chemical on food products was voluntarily cancelled in 1989 by the manufacturer (Uniroyal Chemical Company) (EPA 1992c). Daminozide contains about 0.005% 1,1-dimethylhydrazine as an impurity and about 0.012% of a daminozide solution that hydrolyzes to 1,1-dimethylhydrazine after 24 hours (EPA 1992c). No data were located on the amount of daminozide used annually, but it is estimated that, in 1989, 90% of potted chrysanthemums and 40-50% of 65 million square feet of bedding plants were treated with this chemical. HYDRAZINES 127 5. POTENTIAL FOR HUMAN EXPOSURE As shown in Tables 5-1 and 5-2, 5 pounds of hydrazine (<0.1% of the total environmental release) and Z no 1,1-dimethylhydrazine were reported discharged to land from manufacturing and processing $ facilities in the United States in 1993 (TRI93 1995). The data listed in the TRI should be used with caution since only certain types of facilities are required to report. This is not an exhaustive list. 5.3 ENVIRONMENTAL FATE 5.3.1 Transport and Partitioning Hydrazine or dimethylhydrazines released to water or soil may volatilize into air or sorb onto soil. These chemicals have low vapor pressures and are miscible in water (see Table 3-2). Therefore, volatilization is not expected to be an important removal process. Reported evaporation rates from aqueous solutions under laboratory conditions were 0.49 mg/cm’ minute for hydrazine and 13 mg/cm’ minute for 1,1-dimethylhydrazine (EPA 1984a). The significance of these values to environmental conditions is unknown. Data from other studies indicate that volatilization of these chemicals from water increases with higher concentrations of the chemical and in the presence of sunlight (due to increased temperature of the hydrazine pool). Based on air dispersion modeling, volatilization of hydrazine from surface soil following a spill is expected to be sufficient (16-100 mg/cm’* hour) to generate a short-term ambient air concentration of 4 mg/m’ up to 2 km downwind of the spill under worst-case meteorological conditions (MacNaughton et al. 1981). Degradation of hydrazine would likely reduce the concentration within several hours (see Section 5.3.2.1). Atmospheric transport of hydrazine or dimethylhydrazines may occur, but transport will be limited by the high reactivity of the chemicals in the atmosphere (see Section 5.3.2.1). No data were located on deposition of hydrazine or dimethylhydrazines from air to water or soil, but deposition would also be limited by their high reactivity. Hydrazine undergoes complex interactions with soils, including both reversible physical sorption and irreversible chemisorption to colloids (Mansell et al. 1988). In a study on the adsorption and leaching characteristics of hydrazine fuels, no adsorption of 1,1-dimethylhydrazine was observed on sand, with almost 100% of the chemical leaching with water (Braun and Zirrolli 1983). In three other soils, adsorption ranged from 26% to 80%. No correlation between adsorption and soil organic content or pH was observed. The mechanisms of attenuation in soil materials were not reported. However, HYDRAZINES 128 5. POTENTIAL FOR HUMAN EXPOSURE reported results of additional hydrazine adsorption studies with clays and soils indicate that adsorption may be correlated with soil organic matter and clay content and is highly dependent on pH; hydrazine appears to be adsorbed by different mechanisms under acidic and alkaline conditions (Moliner and Street 1989b). In a study of hydrazine in aqueous systems, the chemical was reported to be absorbed by guppies from a 0.5 mg/L solution (Slonim and Gisclard 1976). After 96 hours, the hydrazine concentration in fish was 144 ng/g, indicating a moderate tendency to bioconcentrate. However, the bioconcentration of hydrazine and dimethylhydrazines is not expected to be important in aquatic systems because of the rapid degradation of these chemicals in water (see Section 5.3.2.2) as well as their low octanol-water partition coefficients. 5.3.2 Transformation and Degradation 5.3.2.1 Air Hydrazine and dimethylhydrazines degrade rapidly in air through reactions with ozone, hydroxyl (OH) radicals, and nitrogen dioxide (WHO 1987). The reaction of hydrazine and 1,1-dimethylhydrazine with ozone is probably the major fate of these chemicals in the atmosphere. The reaction rate constant for hydrazine, derived from its decay rate in the presence of excess ozone, was about 3x10" cm? molecules” and for 1,1-dimethylhydrazine the rate was greater than 1x10" ¢cm® molecules’! (Atkinson and Carter 1984). Major reaction products were hydrogen peroxide for the hydrazine reaction and dimethylnitrosamine (about 60%) for the 1,1-dimethylhydrazine reaction. Estimated atmospheric half-lives ranged from less than 10 minutes for hydrazine during an ozone pollution episode to less than 2 hours under usual conditions, with a half-life about one-tenth that time for 1,1-dimethylhydrazine (Tuazon et al. 1981). Reported results of additional studies indicate a reaction rate constant for hydrazine of 2.5x10' cm® molecules”, resulting in an estimated half-life of less than 1 minute (Stone 1989). The reported measured rate constant for reaction of hydrazine with atmospheric hydroxyl (OH) radicals producing ammonia and nitrogen gas was 6.110"! cm? molecule’'s” (Harris et al. 1979). The rate constant for 1,1-dimethylhydrazine was not measured since the chemical decomposed rapidly in the test system, but the value was estimated at 5x10" cm’ molecules! Assuming an average OH radical HYDRAZINES 129 5. POTENTIAL FOR HUMAN EXPOSURE concentration of about 10° molecule/cm’, the tropospheric half-lives of both chemicals due to reaction with OH were estimated to be about 3 hours. The half-lives are expected to range from less than 1 hour in polluted urban air to 3—6 hours in less polluted atmospheres (Tuazon et al. 1981). Hydrazine and 1,1-dimethylhydrazine react rapidly with nitrogen oxides in both the light and dark, with a half-life of about 2 hours for hydrazine and less than 10 minutes for 1,1-dimethylhydrazine (Pitts et al. 1980). Hydrazine and 1,1-dimethylhydrazine may also be removed from the atmosphere by autoxidation. In a dark reaction chamber, the approximate half-lives of hydrazine ranged from 1.8 to 5 hours, with the lower value measured at higher humidity. Reported values for 1,1-dimethylhydrazine under similar conditions were 5.9-9 hours. Surface interactions are important in controlling the rates of these reactions (Stone 1989). Although data were not located for 1,2-dimethylhydrazine, this chemical is expected to be degraded in the atmosphere by undergoing the same reactions as hydrazine and 1,1-dimethylhydrazine, although the rate and extent of degradation may be different. 5.3.2.2 Water Hydrazine and 1,1-dimethylhydrazine degrade in aqueous systems, but the rate of degradation is dependent on specific aquatic environmental factors, including pH, hardness, temperature, oxygen concentration, and the presence of organic matter and metal ions (Moliner and Street 1989a; Slonim and Gisclard 1976; WHO 1987). Oxidation and biodegradation are the primary removal mechanisms. Reaction of hydrazine with dissolved oxygen is catalyzed by metal ions, particularly copper (EPA 1984a). The reaction rate is strongly influenced by pH; degradation proceeds more rapidly in alkaline solutions. Hydrazine is rapidly removed from polluted waters, with less than one-third of the original concentration remaining in dirty river water after 2 hours (Slonim and Gisclard 1976). More than 90% of the hydrazine added to pond or chlorinated, filtered county water disappeared after 1 day. However, chlorinated, filtered, and softened city water contained almost the original amount of hydrazine after 4 days. Organic matter in the water and hardness were reported to be the major factors in the differing rates of degradation. HYDRAZINES 130 5. POTENTIAL FOR HUMAN EXPOSURE The primary reaction pathway for hydrazine degradation in water produces nitrogen gas and water (Moliner and Street 1989a). In oxygen-deficient waters or in the presence of metal ions which serve as catalysts, ammonia may also be produced. The reaction of 1,1-dimethylhydrazine with dissolved oxygen in water may proceed by a process catalyzed by copper ions or by an uncatalyzed reaction (Banerjee et al. 1984). The products include dimethylnitrosamine, formaldehyde, dimethylamine, and other related chemicals. Dimethylnitrosamine did not form in dilute solutions, which might be encountered in ambient waters, but was reported in concentrated solutions, which could be present in the vicinity of spills (EPA 1984a). The reported half-life of 1,1-dimethylhydrazine in ponds and seawaters ranged from 10 to 14 days, presumably because of reaction with oxygen and other free radicals (EPA 1984a). Biodegradation may be a significant removal process at low hydrazine concentrations in ambient waters, but at higher concentrations the chemical is toxic to microorganisms. In the presence of bacterial cells, more than 90% of the hydrazine was degraded in six water samples containing 11 pg/mL of the chemical within 2 hours (Ou and Street 1987b). Lower degradation rates were reported with increasing hydrazine concentrations. No degradation was reported for incubation of these waters without bacteria. Additional studies indicate that hydrazine and 1,1-dimethylhydrazine are toxic to bacterial populations. Concentrations of hydrazine and 1,1-dimethylhydrazine that reduced bacterial metabolism by 50% ranged from 14.6 to 145 mg/L and from 19.2 to 9,060 mg/L, respectively (Kane and Williamson 1983). Thus, biological treatment would not be useful for spills of these chemicals into the aquatic environment. 5.3.2.3 Sediment and Soil Hydrazine appears to degrade more rapidly in soil than in water, with oxidation and biodegradation as the main removal processes. Hydrazine applied to nonsterile Arredondo soil (fine sand) at concentrations of 10, 100, and 500 Hg/g was completely degraded in 1.5 hours, 1 day, and 8 days, respectively (Ou and Street 1987a). In this study, comparison to degradation rates in sterile soils indicated that autoxidation appeared to be the major factor contributing to disappearance of the chemical, but the study authors attributed about 20% of removal to biodegradation. Several heterotrophic soil bacteria were reported to degrade hydrazine, indicating that microbial degradation may contribute to removal of the chemical from soil (Ou 1987). HYDRAZINES 131 5. POTENTIAL FOR HUMAN EXPOSURE 5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 5.4.1 Air No monitoring data were located for hydrazine or dimethylhydrazines in ambient air. Since these chemicals are readily degraded in the atmosphere (see Section 5.3.2.1), they are not expected to be present measurable levels, except in the vicinity of production or processing facilities or spills. 5.4.2 Water No monitoring data were located for hydrazine or dimethylhydrazines in ambient water. Since these chemicals are readily degraded in aquatic systems (see Section 5.3.2.2), they are not expected to be present at measurable levels, except in the vicinity of production or processing facilities, spills, or possibly, hazardous waste sites. 5.4.3 Sediment and Soil No data were located documenting hydrazine or dimethylhydrazine concentrations in ambient soil or sediments. Since these chemicals are readily degraded in soil (see Section 5.3.2.3), they are not expected to be present at measurable levels, except in the vicinity of production or processing facilities, spills, or hazardous waste sites. 5.4.4 Other Environmental Media Hydrazine and 1,1-dimethylhydrazine have been detected in tobacco. 1,1-Dimethylhydrazine was reported at concentrations ranging from not detected to 147 ng/g in various types of tobacco in the United States (Schmeltz et al. 1977). Mainstream smoke from blended U.S. cigarettes contained an average of 31.5 ng of hydrazine per cigarette (Liu et al. 1974). Sidestream smoke may have higher hydrazine concentrations. The authors reported 94.2 ng of hydrazine in sidestream smoke from one cigarette. Although hydrazine may be an impurity in maleic hydrazide, a pesticide formerly used on tobacco plants, reports on studies of tobacco from both treated and untreated plants indicate that the application of maleic hydrazide is not the major source of hydrazine in tobacco. It has been suggested HYDRAZINES 132 5. POTENTIAL FOR HUMAN EXPOSURE that these chemicals may be produced in tobacco by bacterial or enzymatic processes which occur during curing (Schmeltz et al. 1977). 1,1-Dimethylhydrazine has been detected in several food products because of its presence as an impurity (about 0.005%) in daminozide (Alar)®, a plant growth enhancer. 1,1-Dimethylhydrazine was detected in several processed fruits at maximum levels ranging from 0.007 to 0.60 ppm (Saxton et al. 1989). The fruits had been treated with, and contained residues of, daminozide. It appears that during thermal processing, some of the daminozide degrades to 1,1-dimethylhydrazine, adding to the quantity of 1,1-dimethylhydrazine already present. However, daminozide is no longer used on food plants in the United States since its registered uses for food products were voluntarily cancelled in 1989 (EPA 1992c). Therefore, 1,1-dimethylhydrazine is no longer expected to be present in foods prepared from food plants grown in the United States. 5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE Exposure of the general population to hydrazine and dimethylhydrazines is expected to be extremely low (WHO 1987). Because of the high reactivity of these chemicals, they are unlikely to remain in environmental media for extended periods. These chemicals have not been detected in ambient air, water, or soil. Occupational exposures to hydrazine and 1,1-dimethylhydrazine may occur in facilities that manufacture, process, transport, or use these chemicals. The National Institute for Occupational Safety and Health (NIOSH) conducted a National Occupational Exposure Survey (NOES) during 1981-1983 and estimated that 59,675 and 2,197 workers were potentially exposed to hydrazine and 1,1-dimethylhydrazine, respectively, at that time (EPA 1991d). Since most hydrazine production processes involve closed systems, the potential for exposure is generally low (Fajen and McCammon 1988). The greatest potential for exposure probably occurs during process stream sampling, with measured time-weighted average (TWA) concentrations ranging from 0.04 to 0.27 ppm and excursions up to 0.91 ppm. Workplace breathing zone air levels of hydrazine and 1,1-dimethylhydrazine ranged from 0.22 to 1.98 ppm and from 0.23 to 4.61 ppm, respectively, in a rocket propellant plant (Cook et al. 1979). Workers in facilities where exposure to these chemicals is possible are required to wear protective respirators. Analysis of samples from within the respirators indicated that these chemicals HYDRAZINES 133 5. POTENTIAL FOR HUMAN EXPOSURE are not usually present at detectable levels. Thus, routine exposure to these levels is not expected, but respirator failures and other accidental exposures may occur. Occupational exposures may also occur to military and civilian personnel during the use of these chemicals as aerospace propellants. Exposure to workers may occur during loading or unloading of propellants, transfer operations, or testing of spacecraft components that use hydrazine fuels (Fajen and McCammon 1988). Although full-body supplied-air suits are usually worn during these operations, spills and other accidents may lead to short-term, high-level exposures, rather than longer-term, low- level exposures. Exposure may also result from the use of hydrazine as an oxygen scavenger in boiler systems (Fajen and McCammon 1988). Long-term concentrations in areas where hydrazine was added to the boiler systems were generally below 0.1 ppm, but short-term concentrations ranged up to 0.23 ppm. In addition, those individuals who work as daminozide applicators in greenhouses may be exposed to 1,1-dimethylhydrazine (EPA 1992c). 5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES Populations with potential exposures to hydrazines above ambient levels include those exposed occupationally (see Section 5.5), such as during the manufacture or agricultural application of hydrazines, people living or working near military or aerospace installations using these chemicals as fuels, or people living near hazardous waste sites where these chemicals have been detected. Others who may be exposed to these chemicals at above ambient levels include individuals who chew or smoke tobacco and those exposed to sidestream smoke (see Section 5.4.4). Furthermore, hydrazine is a metabolite of several drugs (e.g., hydralazine, isoniazid), and it has been suggested that individuals taking these drugs may be exposed to hydrazine, based on the detection of hydrazine in the urine of patients taking hydralazine (Timbrell and Harland 1979) and the blood plasma of patients taking isoniazid (Blair et al. 1985). 5.7 ADEQUACY OF THE DATABASE Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the Administrator of EPA and agencies and programs of the Public Health Service) to assess whether HYDRAZINES 134 5. POTENTIAL FOR HUMAN EXPOSURE adequate information on the health effects of hydrazines is available. Where adequate information is not available, ATSDR, in conjunction with the NTP, is required to assure the initiation of a program of research designed to determine the health effects (and techniques for developing methods to determine such health effects) of hydrazines. The following categories of possible data needs have been identified by a joint team of scientists from ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would reduce the uncertainties of human health assessment. This definition should not be interpreted to mean that all data needs discussed in this section must be filled. In the future, the identified data needs will be evaluated and prioritized, and a substance-specific research agenda will be proposed. 5.7.1 Identification of Data Needs Physical and Chemical Properties. The physical and chemical properties of hydrazine and dimethylhydrazines are sufficiently well characterized to allow estimation of their environmental fate (see Table 3-2) (HSDB 1993; IARC 1975; Verschueren 1983). On this basis, it does not appear that further research in this area is required. Production, Import/Export, Use, Release, and Disposal. Hydrazine is produced at one facility and 1,1-dimethylhydrazine is produced at two locations (SRI 1992). However, production volume and import and export information are not available. This information would be useful in assessing potential exposure to workers and the general population. Since 1,2-dimethylhydrazine is produced only in gram quantities for research, additional information is not required. According to the Emergency Planning and Community Right-to-Know Act of 1986, 42 U.S.C. Section 11023, industries are required to submit substance release and off-site transfer information to the EPA. The Toxics Release Inventory (TRI), which contains this information for 1993, became available in May of 1995. This database will be updated yearly and should provide a list of industrial production facilities and emissions. HYDRAZINES 135 5. POTENTIAL FOR HUMAN EXPOSURE Environmental Fate. The environmental fate of hydrazine and 1,1-dimethylhydrazine has been well defined (Atkinson and Carter 1984; EPA 1984a; Moliner and Street 1989a, 1989b; Ou and Street 1987a, 1987b; Stone 1989; WHO 1987). These chemicals are highly reactive and degrade readily in environmental media. Thus, they are not likely to be present in air or water and it is not likely that exposure to the general population is of concern. Nevertheless, because these chemicals may migrate to groundwater, additional studies might be useful to assess the potential for transport of these chemicals from hazardous waste sites and their fate in closed water systems such as groundwater. Bioavailability from Environmental Media. Hydrazine is known to be absorbed following inhalation (Llewellyn et al. 1986), oral (dissolved in water) (Preece et al. 1992a), and dermal (Smith and Clark 1971, 1972) exposures. Little is known about the absorption of 1,1-dimethylhydrazine and 1,2-dimethylhydrazine, but based on their chemical properties, the absorption is most likely similar to that of hydrazine. No information was located on the bioavailability of hydrazine or dimethyl- hydrazines from environmental media. This information would be helpful in evaluating the impact of environmental exposures on human health. Food Chain Bioaccumulation. Hydrazine in water may bioconcentrate in aquatic organisms to a moderate degree (Slonim and Gisclard 1976), but because of its high reactivity, the chemical is rapidly degraded in aquatic systems. This property, as well as the low octanol-water partition coefficient of hydrazine, makes food chain bioaccumulation unlikely. Exposure Levels in Environmental Media. Hydrazine and dimethylhydrazines have not been detected in ambient air, water, or soil, since they are highly reactive and degrade readily in environmental media. Hydrazine and 1,1-dimethylhydrazine have been detected in workplace air and in tobacco (Cook et al. 1979; Schmeltz et al. 1977). Since these chemicals are highly reactive and exposure of the general population is not expected to be of concern, monitoring of ambient environmental media does not appear to be required. However, monitoring of workplace air would help to determine potential sources and magnitude of exposure. Exposure Levels in Humans. Hydrazine and dimethylhydrazines have not been detected in human tissues as a result of exposure to these chemicals from environmental media. Hydrazine has been detected in the urine of individuals taking medication (hydralazine) which may metabolize to hydrazine (Timbrell and Harland 1979). Since hydrazine and dimethylhydrazines are rapidly HYDRAZINES 136 5. POTENTIAL FOR HUMAN EXPOSURE metabolized in vivo, it is unlikely that any free chemical would be present in biological tissues within a few days after environmental exposure. Studies that investigate the levels of hydrazines in humans within the first few days after exposure, along with their relationship to exposure levels, would be useful. This information is necessary for assessing the need to conduct health studies on these populations. Exposure Registries. No exposure registries for hydrazines were located. These substances are not currently in a subregistry of the National Exposure Registry. These substances will be considered in the future when chemical selection is made for subregistries to be established. The information that is amassed in the National Exposure Registry facilitates the epidemiological research needed to assess adverse health outcomes that may be related to exposure to these substances. 5.7.2 On-going Studies No information was located regarding on-going studies on the environmental fate or exposure levels of hydrazine or dimethylhydrazines. HYDRAZINES 137 6. ANALYTICAL METHODS The purpose of this chapter is to describe the analytical methods that are available for detecting, and/or measuring, and/or monitoring hydrazines, their metabolites, and other biomarkers of exposure and effect to hydrazines. The intent is not to provide an exhaustive list of analytical methods. Rather, the intention is to identify well-established methods that are used as the standard methods of analysis. Many of the analytical methods used for environmental samples are the methods approved by federal agencies and organizations such as EPA and the National Institute for Occupational Safety and Health (NIOSH). Other methods presented in this chapter are those that are approved by groups such as the Association of Official Analytical Chemists (AOAC) and the American Public Health Association (APHA). Additionally, analytical methods are included that modify previously used methods to obtain lower detection limits, and/or to improve accuracy and precision. 6.1 BIOLOGICAL MATERIALS Spectrophotometric methods, high-performance liquid chromatography (HPLC), and gas chromatography (GC) may be used to detect and measure hydrazine and dimethylhydrazines in biological materials (Alvarez de Laviada et al. 1987; Amlathe and Gupta 1988; Fiala and Kulakis 1981; Preece et al. 1992a; Reynolds and Thomas 1965; Timbrell and Harland 1979). The spectrophotometer measures the absorbance of light at a particular wavelength, thereby identifying and quantifying a compound that absorbs at that wavelength. The chromatograph separates complex mixtures of organics and allows individual compounds to be identified and quantified by a detector. An electrochemical detector (ED), in the case of HPLC, and a nitrogen phosphorus detector (NPD) or flame ionization detector (FID), in the case of GC, may be used to identify hydrazine or dimethylhydrazine or their derivatives. When unequivocal identification is required, a mass spectrometer (MS) coupled to the GC column may be employed. Prior to GC or spectrophotometric analysis, hydrazine and dimethylhydrazines must be separated from the biological sample matrix and derivatives of the compounds must be prepared. Separation is usually effected by precipitation of residual protein with acid and extraction of interfering lipids with methylene chloride (Alvarez de Laviada et al. 1987; Preece et al. 1992a; Reynolds and Thomas 1965; Timbrell and Harland 1979). Hydrazine and 1,1-dimethylhydrazine, but not 1,2-dimethylhydrazine, HYDRAZINES 138 6. ANALYTICAL METHODS may then be derivatized with an aldehyde such as pentafluorobenzaldehyde or p-dimethylamino- benzaldehyde. 1,2-Dimethylhydrazine, which has no free-NH, group, cannot be derivatized in this way but may be quantified by chromatographic methods that do not require derivatization (Fiala and Kulakis 1981). Details of selected analytical methods for hydrazine and dimethylhydrazines in biological samples are summarized in Table 6-1. Accurate analysis of hydrazine and dimethylhydrazines in biological samples is complicated by the tendency of these chemicals to autoxidize during storage (Preece et al. 1992a). Thus, derivatization should be completed as rapidly as possible, before autoxidation can occur. 6.2 ENVIRONMENTAL SAMPLES Determination of hydrazine and dimethylhydrazines in air, water, soil, food, and tobacco is also carried out by spectrophotometry, GC, or HPLC analysis (Amlathe and Gupta 1988; ASTM 1991b; Holtzclaw et al. 1984; Leasure and Miller 1988; Liu et al. 1974; NIOSH 1977a, 1977b, 1984; Rutschmann and Buser 1991; Schmeltz et al. 1977; Wright 1987). Several representative methods for quantifying these chemicals in each of these media are summarized in Table 6-2. EPA-validated methods are not available for analysis of hydrazine or dimethylhydrazines in any environmental medium. Two EPA methods (8250 and 8270) are recommended for analysis of 1,1-dimethylhydrazine in wastes (EPA 1990e). However, these methods do not list 1,1-dimethylhydrazine as an analyte (EPA 1990c, 1990d) and do not appear to be suitable methods for analysis of this compound since 1,1-dimethylhydrazine is likely to degrade during the GC analysis unless it has been derivatized. Separation of hydrazine and dimethylhydrazines from environmental samples is by acid extraction when necessary. Air samples are usually collected in a bubbler with acid or on an acid-coated silica gel (NIOSH 1977a, 1977b, 1984). When GC is employed, detection may be by electron capture detector (ECD), FID, nitrogen-specific detector (NSD), thermionic ionization detector (TID), and/or MS as described above (Section 6.1). Accurate determination of hydrazine and dimethylhydrazines in environmental samples is also complicated by the susceptibility of these chemicals to oxidization. Air samples must be analyzed immediately after collection (Cook et al. 1979). Degradation of hydrazine in aqueous samples can be prevented by acidification with sulfuric acid (WHO 1987). TABLE 6-1. Analytical Methods for Determining Hydrazine, 1,1-Dimethylhydrazine, and 1,2-Dimethylhydrazine in Biological Samples* Sample detection Percent Sample matrix Preparation method Analytical metod limit recovery Reference Urine Precipitate residual protein with GC/NPD 8 umol® 79+14 Preece et al. hydrochloric acid and ammonium 1992 sulfate; extract interfering lipids with methylene chloride; derivatize aqueous fraction with pentafluoro- benzaldehyde; extract with ethyl acetate. Urine Extract with methylene chloride; GC/NPD 0.05 pg/mL No data Timbrell and discard extract; derivatize aqueous Harland 1979 fraction with p-chlorobenzaldehyde; extract with methylene chloride; dry and dissolve in ethyl acetate. Urine Deproteinate with trichloroacetic Spectrophotometry 0.065 pg/mL 99.4-100 Amlathe and acid; derivatize with vanillin in Gupta 1988 ethanol; acidify with sulfuric acid. Urine’ Dilute with deionized water. Ion-exchange 8 ng®sample No data Fiala and HPLC/ECD Kulakis 1981 Plasma Precipitate residual protein GC/MS =20 nmol/mL® 1039 Preece et al. Liver Tissue with hydrochloric acid and 1992 ammonium sulfate; extract interfering lipids with methyl- ene chloride; derivatize aqueous fraction with pentafluoro- benzaldehyde; extract with chloroform. SAOHLIN TVOILATVNY 9 SANIZVHAAH 6El TABLE 6-1. Analytical Methods for Determining Hydrazine, 1,1-Dimethylhydrazine, and 1,2-Dimethylhydrazine in Biological Samples (continued) Sample detection Percent Sample matrix Preparation method Analytical metod limit recovery Reference Plasma*® None Ion-exchange 8 ng’/sample No data Fiala and HPLC/ED Kulakis 1981 Serum Acidify; derivatize with p-dimethyl- Spectrophotometry 0.025 pg’/sample No data Alvarez Liver/brain aminobenzaldehyde in ethanol. de Laviada tissue et al. 1987 Serum Treat with trichloroacetic acid; Spectrophotometry 0.05 pg/mL® No data Reynolds and centrifuge; derivatize supernatant with p-dimethylaminobenzaldehyde in ethanol. Thomas 1965 * Applicable to hydrazine only unless otherwise noted. ® Lowest detected amount. © Method applicable to 1,1-dimethylhydrazine and 1,2-dimethylhydrazine as well as hydrazine. ED = electrochemical detector; GC = gas chromatography; HPLC = high performance liquid chromatography; MS = mass spectroscopy; NPD = nitrogen-phosphorus detector. SAOHL3N TVOILATVYNY ‘9 S3ANIZVHAAH ovi TABLE 6-2. Analytical Methods for Determining Hydrazine, 1,1-Dimethylhydrazine, and 1,2-Dimethylhydrazine in Environmental Samples® Sample detection Percent Sample matrix Preparation method Analytical metod limit recovery Reference Air Collect in bubbler with hydrochloric Spectrophotometry 0.9 pg/sample No data NIOSH 1984 acid; neutralize with sodium hydroxide; derivatize with p-dimethylaminobenz- aldehyde; dilute with glacial acetic acid. Air® Adsorb on sulfuric acid-coated silica GC/FID 0.002 mg/m*¢ No data NIOSH 1977b gel; elute with water; derivatize with (hydrazine) 2-furaldehyde; extract with ethyl 0.04 mg/m*¢ acetate (1,1-dimethyl- hydrazine) Air Collect in bubbler with hydrochloric Spectrophotometry 0.02 mg/m’ No data NIOSH 1977a acid; derivatize with phosphomolybdic acid Air’ Collect in a microimpinger containing GC/NSD 4 ppb 97-104 Holtzclaw acetone and glacial acetic acid to (5 pg/m?) et al. 1984 trap and derivatize in one step Water Acidify with hydrochloric acid; Spectrophotometry 5 pg/L 97.5-100.3 ASTM 1991b derivatize with p-dimethylamino- benzaldehyde Water Derivatize with vanillin in ethanol; Spectrophotometry 0.065 ppm 99.2-100.4 Amlathe and acidify with sulfuric acid Gupta 1988 SAOHLINW TVOILATVYNY 9 S3ANIZVHAAH Ly TABLE 6-2. Analytical Methods for Deter oe mining Hydrazine, 1,1-Dimethylhydrazine, and 1,2-Dimethylhydrazine in Environmental Samples (continued) Sample detection Percent Sample matrix Preparation method Analytical metod limit recovery Reference Soil® Extract with sulfuric acid; derivatize GC/TID 0.1 ppm 98-100 Leasure and with 2,4-pentanedione (hydrazine) (hydrazine) Miller 1988 0.5 ppm 94-101 (1,1-dimethyl- (1,1-dimethyl- hydrazine) hydrazine) Food* Extract with L-ascorbic acid; GC/ECD 10 ppb 72-122 Wright 1987 derivatize with 2-nitrobenzaldehyde; cleanup on alumina column Food“ Derivatize with pentafluorobenzoyl GC/MS 0.01 ppm 24-100 Rutschmann and chloride; extract with methylene Buser 1991 chloride Tobacco/ Derivatize with pentafluorobenzaldehyde; GC/ECD 0.1 ng/cigarette No data Liu et al. 1974 tobacco smoke enrich the resulting decafluorobenz- aldehyde azine by thin layer chromatrography; extract with ether * Applicable to hydrazine only unless otherwise noted. ® Applicable to hydrazine and 1,1-dimethylhydrazine. ¢ Lower limit of range. ¢ Applicable to 1,1-dimethylhydrazine only. ECD = electron capture detection; FID = flame ionization detector; GC = gas chromatography; MS = mass spectroscopy; NSD = nitrogen specific detector; TID = thermionic ionization detector SAOHLIN TVOILATVYNY 9 S3ANIZVHAAH cri HYDRAZINES 143 6. ANALYTICAL METHODS 6.3 ADEQUACY OF THE DATABASE Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the Administrator of EPA and agencies and programs of the Public Health Service) to assess whether adequate information on the health effects of hydrazines is available. Where adequate information is not available, ATSDR, in conjunction with the NTP, is required to assure the initiation of a program of research designed to determine the health effects (and techniques for developing methods to determine such health effects) of hydrazines. The following categories of possible data needs have been identified by a joint team of scientists from ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would reduce the uncertainties of human health assessment. This definition should not be interpreted to mean that all data needs discussed in this section must be filled. In the future, the identified data needs will be evaluated and prioritized, and a substance-specific research agenda will be proposed. 6.3.1 Identification of Data Needs Methods for Determining Biomarkers of Exposure and Effect. Methods are available for determining the levels of hydrazine, 1,1-dimethylhydrazine, and 1,2-dimethylhydrazine in biological samples, including urine, plasma, serum, liver tissue, and brain tissue (Alvarez de Laviada et al. 1987; Amlathe and Gupta 1988; Fiala and Kulakis 1981; Preece et al. 1992a; Reynolds and Thomas 1965; Timbrell and Harland 1979). These methods generally employ standard chromatographic and spectrophotometric procedures with detection limits ranging from 0.02 to 0.065 pg/mL, and therefore, most likely are sufficiently sensitive to measure levels at which biological effects occur following recent exposures. The limited data available indicate that these methods are accurate and reliable if analyses are performed rapidly, before autoxidation can occur. The background levels of hydrazines in biological samples in the general population have not been determined; if hydrazines are present at all, they are most likely present at levels below current detection limits. The detection limits for current methods are sufficiently sensitive to detect levels at which effects occur. Since hydrazines can occur in the body following exposure to drugs such as isoniazid and hydralazine (Timbrell and Harland 1979), and many of the metabolites of hydrazines are ubiquitous or may occur following exposure to other chemicals, measures should be taken to ensure exposure to these confounding chemicals has not HYDRAZINES 144 6. ANALYTICAL METHODS occurred. Other metabolites such as azomethane, azoxymethane, and methylazoxymethanol are unique to exposure to 1,2-dimethylhydrazine. Studies which identify specific biomarkers for past exposure to hydrazines, in conjunction with the development of accurate and reliable methods for detecting such biomarkers, would be useful in estimating exposure to hydrazines at hazardous waste sites. The effects of hydrazines have been fairly well characterized in humans and animals, and include neurological, hepatic, and carcinogenic effects (Chlebowski et al. 1984; Gershanovich et al. 1976; Haun and Kinkead 1973; Rinehart et al. 1960; Thorup et al. 1992; Wilson 1976). Methods exist for measuring serum transaminase levels, vitamin By status, and occult blood in stool samples, all of which may serve as biomarkers of effect for hydrazines. Although these methods are fairly accurate and reliable, none of them are specific for effects of hydrazines. Studies which identify biomarkers of effect that are specific to hydrazines, in conjunction with the development of accurate and reliable methods for detecting such biomarkers, would be useful in determining if individuals have been exposed to predicting recent exposures to hydrazines at hazardous waste sites. Methods for Determining Parent Compounds and Degradation Products in Environmental Media. Analytical methods are available to detect and quantify hydrazine and dimethylhydrazines in air, water, soil, food, and tobacco (Amlathe and Gupta 1988; ASTM 1991b; Holtzclaw et al. 1984; Leasure and Miller 1988; Liu et al. 1974; NIOSH 1977a, 1977b, 1984: Rutschmann and Buser 1991; Wright 1987). Air is the medium of most concern for human exposure to this chemical. Exposure may also occur from water, especially in the vicinity of hazardous waste sites or industrial sources. The existing analytical methods can provide determinations for these chemicals at levels sufficiently low to meet regulatory requirements (NIOSH 1977a, 1977b, 1984). Assuming that an adequate quantity of air is passed through the collector (for example: a volume of at least 41 m’ is required to detect a level equivalent to the intermediate inhalation MRL of 2x10 ppm for 1,1-dimethylhydrazine, assuming a detection limit of 0.9 pg/sample), current methods are sufficiently sensitive to measure levels near the MRL value for 1,1-dimethylhydrazine. However, their tendency to degrade and their chemical reactivity limit the accuracy of analyses of these chemicals in all media. Improved methods of extraction and analysis that minimize these reactions would enhance recovery of these chemicals from environmental samples and provide a better estimate of environmental levels, especially in drinking water and soil at hazardous waste sites. HYDRAZINES 145 6. ANALYTICAL METHODS In addition, methods are available to measure degradation products of hydrazine and dimethylhydrazines (see Section 5.3.2) in environmental samples and can be used to determine the environmental impact of these chemicals. 6.3.2 On-going Studies On-going studies to improve analytical methods for hydrazine and dimethylhydrazines includes continuing research to improve HPLC columns and EDs. In addition, the Naval Research Laboratory has been investigating pattern recognition techniques using microsensors capable of measuring hydrazine in air at ppb concentrations (Anon 1987). These improvements are designed to overcome sampling problems and increase sensitivity and reliability of the analyses. HYDRAZINES 147 7. REGULATIONS AND ADVISORIES Because of its potential to cause adverse health effects in exposed people, numerous regulations and advisories have been established for hydrazines by various international, national and state agencies. Major regulations and advisories pertaining to hydrazine, 1,1-dimethylhydrazine, and 1,2-dimethylhydrazine are summarized in Tables 7-1, 7-2, and 7-3, respectively. ATSDR has derived an intermediate-duration inhalation MRL of 4x10” ppm for hydrazine, as described in Appendix A. The MRL is based on a LOAEL of 0.2 ppm for fatty liver changes in female mice (Haun and Kinkead 1973). The LOAEL was adjusted for intermittent exposure (6 hours/day, 5 days/week), converted to a Human Equivalent Concentration (HEC), and divided by an uncertainty factor of 300 (10 for use of a LOAEL, 3 for extrapolation from animals to humans, and 10 for human variability). ATSDR has derived an intermediate-duration inhalation MRL of 2x10 ppm for 1,1-dimethylhydrazine, as described in Appendix A. The MRL is based on a LOAEL of 0.05 ppm for hepatic effects (hyaline degeneration of the gall bladder in female mice) (Haun et al. 1984). The LOAEL was adjusted for intermittent exposure (6 hours/day, 5 days/week), converted to an HEC, and divided by an uncertainty factor of 300 (10 for use of a LOAEL, 3 for extrapolation from animals to humans, and 10 for human variability). ATSDR has derived an intermediate-duration oral MRL of 8x10 mg/kg/day for 1,2-dimethylhydrazine, as described in Appendix A. The MRL is based on a LOAEL of 0.75 mg/kg/day for mild hepatitis in male mice (Visek et al. 1991). The LOAEL was divided by an uncertainty factor of 1,000 (10 for use of a LOAEL, 10 for extrapolation from animals to humans, and 10 for human variability). HYDRAZINES 7. REGULATIONS AND ADVISORIES 148 TABLE 7-1. Regulations and Guidelines Applicable to Hydrazine Proposed TLV TWA carcinogen, 0.1 ppm (0.13 mg/m’), skin Animal carcinogen, 0.01 ppm (0.013 mg/m’), skin Agency Description Information References INTERNATIONAL IARC Carcinogenic classification Group 2B* IARC 1994 NATIONAL Regulations: a. Air EPA OAQPS Hazardous Air Pollutant Yes Public Law 101-549 Section 112 High-risk Pollutant (proposed) Yes EPA 1991c List of Regulated Substances and 5,000 pounds EPA 1993 Threshold for Accidental Release Prevention - Proposed OSHA PEL TWA 0.1 ppm NIOSH 1994 (0.1 mg/m’), skin® b. Food: FDA Boiler water additive-limits for 0 21 CFR 173.310 steam that will contact food c. Other: EPA OERR Reportable quantity 1 pound EPA 1989 (40 CFR 302.4) Extremely Hazardous Substance TPQ 1,000 pounds EPA 1987 (40 CFR 355) EPA OSW Hazardous Waste Constituent Yes EPA 1980 (Appendix VIII) (40 CFR 261) Land Disposal Restrictions Yes EPA 1990b, 1991a (40 CFR 268) Burning of Hazardous Waste in 1x10 mg/kg EPA 1991b Boilers and Industrial Furnaces- Residue Concentration Limit EPA OTS Toxic Chemical Release Reporting Rule Yes EPA 1988b (40 CFR 372) Priority Testing List (Section 4E) Yes EPA 1991d Guidelines: a. Air ACGIH TLV TWA Suspected human ACGIH 19%4a HYDRAZINES 149 7. REGULATIONS AND ADVISORIES TABLE 7-1. Regulations and Guidelines Applicable to Hydrazine (continued) Agency Description Information References NIOSH REL Ceiling (120 minutes) Potential NIOSH 1994 occupational carcinogen 0.03 ppm (0.04 mg/m’) b. Other: EPA Carcinogenic Classification Group B2° IRIS 1995 Cancer slope factor (q,*) q,* (oral) q,* (inhalation) DHHS Carcinogenic Classification STATE Regulations and Guidelines: a. Air Acceptable ambient air concentrations Connecticut Florida Kansas Louisiana Maine Massachusetts Michigan Nevada New York North Carolina North Dakota Oklahoma Pennsylvania Rhode Island South Carolina 3.0 (mg/kg-day)’ 1.7x10' (mg/kg-day)” May reasonably be NTP 1994 anticipated to be a carcinogen NATICH 1995 1.0 pg/m® (8 hour) 1.0 x 10° mg/m’ (8 hour) 3.1 x 10° pg/m’ (24 hour) 1.3 x 10" pg/m® (8 hour) 3.4 x 10 pg/m® (1 year) 2.0 x 10* pg/m® (1 year) 2.0 x 10? pg/m’ (1 year) 2.0 x 10* pgm’ (1 year) 7.0 x 10° pg/m® (24 hour) 2.0 x 10° pg/m’® (anuual) 2.0 x 10 pg/m® (1 year) 2.0 x 10” mg/m’ (8 hour) 3.3 x 10" pg/m® (1 year) 6.0 x 10 mg/m’ (24 hour) 0 (best available control technology) 3.93 x 10" pg/m® (24 hour) 2.4 x 10" pgm’ (1 year) 2.4 x 10" ppb (1 year) 3.0 x 10* pg/m® (annual) 5.0 x 10" pg/m*® (24 hour) HYDRAZINES 150 7. REGULATIONS AND ADVISORIES TABLE 7-1. Regulations and Guidelines Applicable to Hydrazine (continued) Agency Description Information References Texas 1.3 x 10" pg/m® (30 minute) 1.3 x 10”? pg/m’ (annual) Virginia 1.3 pg/m’ (24 hour) * Group 2B: Possible human carcinogen ® Due to a Federal court decision, not enforceable as of March 22, 1993 (Hanson 1993). © Group B2: Probable human carcinogen ACGIH = American Conference of Governmental Industrial Hygienists; DHHS = Department of Health and Human Services; EPA = Environmental Protection Agency; FDA = Food and Drug Administration; IARC = International Agency for Research on Cancer; NIOSH = National Institute for Occupational Safety and Health; NTP = National Toxicology Program; OAQPS = Office of Air Quality Planning and Standards; OERR = Office of Emergency and Remedial Response; OSHA = Occupational Safety and Health Administration; OSW = Office of Solid Waste; OTS = Office of Toxic Substances; PEL = Permissible Exposure Limit; REL = Recommended Exposure Limit; TLV = Threshold Limit Value; TPQ = Threshold Planning Quantity; TWA = Time-Weighted Average HYDRAZINES 7. REGULATIONS AND ADVISORIES TABLE 7-2. Regulations and Guidelines Applicable to 1,1-Dimethylhydrazine Agency Description Information References INTERNATIONAL IARC Carcinogenic classification Group 2B* IARC 1994 NATIONAL Regulations: a. Air EPA OAQPS Hazardous Air Pollutant Yes Public Law 101-549 List of Regulated Substances and 5,000 pounds EPA 1993 Threshold for Accidental Release Prevention - Proposed NESHAP for Source Categories: Yes EPA 1992a Organic HAPs from Synthetic Organic Chemical Manufacturing Industry - Proposed OSHA Skin PEL TWA .5 ppm (1 mg/m’) NIOSH 1994 b. Other: EPA OERR Reportable quantity 10 pounds EPA 1989 (40 CFR 302.4) Extremely Hazardous Substance TPQ 1,000 pounds EPA 1987 (40 CFR 355) EPA OSW Hazardous Waste Constituent Yes EPA 1980 (Appendix VIII) (40 CFR 261) Land Disposal Restrictions Yes EPA 1990b EPA 1991a EPA 1992b (40 CFR 268) EPA OTS Toxic Chemical Release Reporting Rule Yes EPA 1988b (40 CFR 372) Priority Testing List (Section 4E) Yes EPA 1991d Guidelines: a. Air ACGIH TLV TWA Suspected human ACGIH 19%4a carcinogen, 0.5 ppm (1.2 mg/m’), skin Proposed TLV TWA Animal carcinogen, 0.01 ppm (0.25 mg/m’) skin HYDRAZINES 152 7. REGULATIONS AND ADVISORIES TABLE 7-2. Regulations and Guidelines Applicable to 1,1-Dimethylhydrazine (continued) Agency Description Information References NIOSH REL Ceiling (120 minutes) Potential NIOSH 1994 occupational carcinogen 0.06 ppm (0.15 mg/m’) b. Other: EPA Carcinogenic Classification Group B2° HEAST 1992 Cancer slope factor (q,*) q,* (oral) 2.6 (mg/kg-day)’ q,* (inhalation) 3.5 (mg/kg-day)’! DHHS Carcinogenic Classification May reasonably be NTP 1994 anticipated to be a carcinogen STATE Regulations and Guidelines: a. Air Acceptable ambient air concentrations NATICH 1995 Connecticut 11 pg/m’® (8 hour) Florida 1.0 x 10? mg/m’ (8 hour) 6.0 x 10? pg/m’ (24 hour) 2.5 x 10" pg/m* (8 hour) Nevada 2.4 x 10? mg/m® (8 hour) New York 3.3 pg/m’ (1 year) North Dakota 0 (best available control technology) Oklahoma 1.5 pg/m® (24 hour) Pennsylvania 2.4 pg/m’ (1 year) South Carolina 1.2 ppb (1 year) 5.0 pg/m® (24 hour) Texas 2.5 x 10" pg/m® (30 minute) 2.5 x 10? pgm’ (annual) Virginia 12 pg/m* (24 hour) Washington 3.3 pgm? (24 hour) * Group 2B: Possible human carcinogen ® Due to a Federal court decision, not enforceable as of March 22, 1993 (Hanson 1993). © Group B2: Probable human carcinogen ACGIH = American Conference of Governmental Industrial Hygienists; EPA = Environmental Protection Agency; DHHS = Department of Health and Human Services; HAP = Hazardous Air Pollutants; IARC = International Agency for Research on Cancer; NESHAP = National Emission Standards for Hazardous Air Pollutants; NIOSH = National Institute for Occupational Safety and Health; NTP = National Toxicology Program; OAQPS = Office of Air Quality Planning and Standards; OERR = Office of Emergency and Remedial Response; OSHA = Occupational Safety and Health Administration; OSW = Office of Solid Waste; OTS = Office of Toxic Substances; PEL = Permissible Exposure Limit; REL = Recommended Exposure Limit; TLV = Threshold Limit Value; TPQ = Threshold Planning Quantity; TWA = Time-Weighted Average. HYDRAZINES 153 7. REGULATIONS AND ADVISORIES TABLE 7-3. Regulations and Guidelines Applicable to 1,2-Dimethylhydrazine Agency Description Information References INTERNATIONAL IARC Carcinogenic classification Group 2B* IARC 1994 NATIONAL Regulations: a. Other: EPA OERR Reportable quantity 1 pound EPA 1989 (40 CFR 302.4) EPA OSW Hazardous Waste Constituent Yes EPA 1980 (Appendix VIII) (40 CFR 261) Land Disposal Restrictions Yes EPA 1990b EPA 1991a (40 CFR 268) EPA OTS Toxic Chemical Release Reporting Yes EPA 1992d Rule - Proposed (40 CFR 372) Guidelines: a. Other: EPA Carcinogenic Classification Group B2° HEAST 1992 Cancer slope factor (q,*) q,* (oral) q,* (inhalation) STATE Regulations and Guidelines: a. 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Influence of inhibition of the metabolic activation on the mutagenicity of some nitrosamines, triazenes, hydrazines and seniciphylline in Drosophila melanogaster. Mutat Res 202:251-267. Zusman I, Madar Z, Nyska A. 1992a. Individual variability of pathological parameters in chemically induced rat colon tumors. Acta Anat 145:106-111. Zusman I, Zimber A, Madar Z, et al. 1992b. Morphological, histochemical and immunohistochemical differences between tumorous and adjacent tissues in chemically induced colon cancer in rats. Acta Anat 145:29-34, HYDRAZINES 183 9. GLOSSARY Acute Exposure -- Exposure to a chemical for a duration of 14 days or less, as specified in the Toxicological Profiles. Adsorption Coefficient (K,) -- The ratio of the amount of a chemical adsorbed per unit weight of organic carbon in the soil or sediment to the concentration of the chemical in solution at equilibrium. Adsorption Ratio (Kd) -- The amount of a chemical adsorbed by a sediment or soil (i.e., the solid phase) divided by the amount of chemical in the solution phase, which is in equilibrium with the solid phase, at a fixed solid/solution ratio. It is generally expressed in micrograms of chemical sorbed per gram of soil or sediment. Bioconcentration Factor (BCF) -- The quotient of the concentration of a chemical in aquatic organisms at a specific time or during a discrete time period of exposure divided by the concentration in the surrounding water at the same time or during the same period. Cancer Effect Level (CEL) -- The lowest dose of chemical in a study, or group of studies, that produces significant increases in the incidence of cancer (or tumors) between the exposed population and its appropriate control. Carcinogen -- A chemical capable of inducing cancer. Ceiling Value -- A concentration of a substance that should not be exceeded, even instantaneously. Chronic Exposure -- Exposure to a chemical for 365 days or more, as specified in the Toxicological Profiles. Developmental Toxicity -- The occurrence of adverse effects on the developing organism that may result from exposure to a chemical prior to conception (either parent), during prenatal development, or postnatally to the time of sexual maturation. Adverse developmental effects may be detected at any point in the life span of the organism. Embryotoxicity and Fetotoxicity -- Any toxic effect on the conceptus as a result of prenatal exposure to a chemical; the distinguishing feature between the two terms is the stage of development during which the insult occurred. The terms, as used here, include malformations and variations, altered growth, and in utero death. EPA Health Advisory -- An estimate of acceptable drinking water levels for a chemical substance based on health effects information. A health advisory is not a legally enforceable federal standard, but serves as technical guidance to assist federal, state, and local officials. Immediately Dangerous to Life or Health (IDLH) -- The maximum environmental concentration of a contaminant from which one could escape within 30 min without any escape-impairing symptoms or irreversible health effects. Intermediate Exposure -- Exposure to a chemical for a duration of 15-364 days, as specified in the Toxicological Profiles. HYDRAZINES 184 9. GLOSSARY Immunologic Toxicity -- The occurrence of adverse effects on the immune system that may result from exposure to environmental agents such as chemicals. In Vitro -- Isolated from the living organism and artificially maintained, as in a test tube. In Vivo -- Occurring within the living organism. Lethal Concentration o, (LC,,) -- The lowest concentration of a chemical in air which has been reported to have caused death in humans or animals. Lethal Concentration, (LCs) -- A calculated concentration of a chemical in air to which exposure for a specific length of time is expected to cause death in 50% of a defined experimental animal population. Lethal Dose, (LD, ,) -- The lowest dose of a chemical introduced by a route other than inhalation that is expected to have caused death in humans or animals. Lethal Doses, (LDyy) -- The dose of a chemical which has been calculated to cause death in 50% of a defined experimental animal population. Lethal Time, (LT) -- A calculated period of time within which a specific concentration of a chemical is expected to cause death in 50% of a defined experimental animal population. Lowest-Observed-Adverse-Effect Level (LOAEL) -- The lowest dose of chemical in a study, or group of studies, that produces statistically or biologically significant increases in frequency or severity of adverse effects between the exposed population and its appropriate control. Malformations -- Permanent structural changes that may adversely affect survival, development, or function. Minimal Risk Level -- An estimate of daily human exposure to a dose of a chemical that is likely to be without an appreciable risk of adverse noncancerous effects over a specified duration of exposure. Mutagen -- A substance that causes mutations. A mutation is a change in the genetic material in a body cell. Mutations can lead to birth defects, miscarriages, or cancer. Neurotoxicity -- The occurrence of adverse effects on the nervous system following exposure to chemical. No-Observed-Adverse-Effect Level (NOAEL) -- The dose of chemical at which there were no statistically or biologically significant increases in frequency or severity of adverse effects seen between the exposed population and its appropriate control. Effects may be produced at this dose, but they are not considered to be adverse. Octanol-Water Partition Coefficient (Kow) == The equilibrium ratio of the concentrations of a chemical in n-octanol and water, in dilute solution. Permissible Exposure Limit (PEL) -- An allowable exposure level in workplace air averaged over an 8-hour shift. HYDRAZINES 185 9. GLOSSARY q,* -- The upper-bound estimate of the low-dose slope of the dose-response curve as determined by the multistage procedure. The g,* can be used to calculate an estimate of carcinogenic potency, the incremental excess cancer risk per unit of exposure (usually pg/L for water, mg/kg/day for food, and pg/m® for air). Reference Dose (RfD) -- An estimate (with uncertainty spanning perhaps an order of magnitude) of the daily exposure of the human population to a potential hazard that is likely to be without risk of deleterious effects during a lifetime. The RfD is operationally derived from the NOAEL (from animal and human studies) by a consistent application of uncertainty factors that reflect various types of data used to estimate RfDs and an additional modifying factor, which is based on a professional judgment of the entire database on the chemical. The RfDs are not applicable to nonthreshold effects such as cancer. Reportable Quantity (RQ) -- The quantity of a hazardous substance that is considered reportable under CERCLA. Reportable quantities are (1) 1 pound or greater or (2) for selected substances, an amount established by regulation either under CERCLA or under Sect. 311 of the Clean Water Act. Quantities are measured over a 24-hour period. Reproductive Toxicity -- The occurrence of adverse effects on the reproductive system that may result from exposure to a chemical. The toxicity may be directed to the reproductive organs and/or the related endocrine system. The manifestation of such toxicity may be noted as alterations in sexual behavior, fertility, pregnancy outcomes, or modifications in other functions that are dependent on the integrity of this system. Short-Term Exposure Limit (STEL) -- The maximum concentration to which workers can be exposed for up to 15 min continually. No more than four excursions are allowed per day, and there must be at least 60 min between exposure periods. The daily TLV-TWA may not be exceeded. Target Organ Toxicity -- This term covers a broad range of adverse effects on target organs or physiological systems (e.g., renal, cardiovascular) extending from those arising through a single limited exposure to those assumed over a lifetime of exposure to a chemical. Teratogen -- A chemical that causes structural defects that affect the development of an organism. Threshold Limit Value (TLV) -- A concentration of a substance to which most workers can be exposed without adverse effect. The TLV may be expressed as a TWA, as a STEL, or as a CL. Time-Weighted Average (TWA) -- An allowable exposure concentration averaged over a normal 8-hour workday or 40-hour workweek. Toxic Dose (TDs) -- A calculated dose of a chemical, introduced by a route other than inhalation, which is expected to cause a specific toxic effect in 50% of a defined experimental animal population. Uncertainty Factor (UF) -- A factor used in operationally deriving the RfD from experimental data. UFs are intended to account for (1) the variation in sensitivity among the members of the human population, (2) the uncertainty in extrapolating animal data to the case of human, (3) the uncertainty in extrapolating from data obtained in a study that is of less than lifetime exposure, and (4) the uncertainty in using LOAEL data rather than NOAEL data. Usually each of these factors is set equal to 10. HYDRAZINES A-1 APPENDIX A ATSDR MINIMAL RISK LEVEL The Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) [42 US.C. 9601 et seq.], as amended by the Superfund Amendments and Reauthorization Act (SARA) [Pub. L. 99-499], requires that the Agency for Toxic Substances and Disease Registry (ATSDR) develop jointly with the U.S. Environmental Protection Agency (EPA), in order of priority, a list of hazardous substances most commonly found at facilities on the CERCLA National Priorities List (NPL); prepare toxicological profiles for each substance included on the priority list of hazardous substances; and assure the initiation of a research program to fill identified data needs associated with the substances. The toxicological profiles include an examination, summary, and interpretation of available toxicological information and epidemiologic evaluations of a hazardous substance. During the development of toxicological profiles, Minimal Risk Levels (MRLs) are derived when reliable and sufficient data exist to identify the target organ(s) of effect or the most sensitive health effect(s) for a specific duration for a given route of exposure. An MRL is an estimate of the daily human exposure to a hazardous substance that is likely to be without appreciable risk of adverse noncancer health effects over a specified duration of exposure. MRLs are based on noncancer health effects only and are not based on a consideration of cancer effects. These substance-specific estimates, which are intended to serve as screening levels, are used by ATSDR health assessors to identify contaminants and potential health effects that may be of concern at hazardous waste sites. It is important to note that MRLs are not intended to define clean-up or action levels. MRLs are derived for hazardous substances using the no-observed-adverse-effect level/uncertainty factor approach. They are below levels that might cause adverse health effects in the people most sensitive to such chemical-induced effects. MRLs are derived for acute (1-14 days), intermediate (15-364 days), and chronic (365 days and longer) durations and for the oral and inhalation routes of exposure. Currently, MRLs for the dermal route of exposure are not derived because ATSDR has not yet identified a method suitable for this route of exposure. MRLs are generally based on the most sensitive chemical-induced end point considered to be of relevance to humans. Serious health effects (such as irreparable damage to the liver or kidneys, or birth defects) are not used as a basis for establishing MRLs. Exposure to a level above the MRL does not mean that adverse health effects will occur. HYDRAZINES A-2 APPENDIX A MRLs are intended only to serve as a screening tool to help public health professionals decide where to look more closely. They may also be viewed as a mechanism to identify those hazardous waste sites that are not expected to cause adverse health effects. Most MRLs contain a degree of uncertainty because of the lack of precise toxicological information on the people who might be most sensitive (e.g., infants, elderly, nutritionally or immunologically compromised) to the effects of hazardous substances. ATSDR uses a conservative (i.e., protective) approach to address this uncertainty consistent with the public health principle of prevention. Although human data are preferred, MRLs often must be based on animal studies because relevant human studies are lacking. In the absence of evidence to the contrary, ATSDR assumes that humans are more sensitive to the effects of hazardous substance than animals and that certain persons may be particularly sensitive. Thus, the resulting MRL may be as much as a hundredfold below levels that have been shown to be nontoxic in laboratory animals. Proposed MRLs undergo a rigorous review process: Health Effects/MRL Workgroup reviews within the Division of Toxicology, expert panel peer reviews, and agencywide MRL Workgroup reviews, with participation from other federal agencies and comments from the public. They are subject to change as new information becomes available concomitant with updating the toxicological profiles. Thus, MRLs in the most recent toxicological profiles supersede previously published levels. For additional information regarding MRLs, please contact the Division of Toxicology, Agency for Toxic Substances and Disease Registry, 1600 Clifton Road, Mailstop E-29, Atlanta, Georgia 30333. HYDRAZINES APPENDIX A MINIMAL RISK LEVEL WORKSHEETS Chemical Name: Hydrazine CAS Number: 302-01-2 Date: September 5, 1996 Profile Status: Draft 3 Route: [X] Inhalation [ ] Oral Duration: [1 Acute [X] Intermediate [ ] Chronic Graph Key: 19 Species: mouse Minimal Risk Level: 4 x 10° ppm [ ] mg/kg/day [X] ppm Reference: Haun and Kinkead 1973 Experimental design:(human study details or strain, number of animals per exposure/control groups, sex, dose administration details): 40 female ICR mice per group, exposed by inhalation to 0, 0.2, or 1.0 ppm continuously for 6 months. Effects noted in study and corresponding doses: Moderate to severe fatty liver changes were seen at both exposure levels. Calculations: LOAEL yc, = LOAEL x [(V/BW), + (VA/BW),l LOAEL jc, = 0.2 ppm x [(V/BW), + (VA/BW),l LOAEL yc, = 0.2 ppm x [(0.043 m*/day + 0.026 kg) + (20 m*/day + 70 kg)] LOAEL gc, = 1.154 ppm MRL = LOAEL , + Uncertainty Factor MRL = 1.154 ppm + 300 MRL = 4 x 10° ppm Dose and endpoint used for MRL derivation: [ ] NOAEL [X] LOAEL Uncertainty Factors used in MRL derivation: [X] 10 for use of a LOAEL [X] 3 for extrapolation from animals to humans following conversion to HEC [X] 10 for human variability Was a conversion used from ppm in food or water to a mg/body weight dose? If so, explain: No If an inhalation study in animals, list the conversion factors used in determining human equivalent dose: V, mouse = 0.043 m’/day, BW = 0.026 kg A-3 HYDRAZINES A-4 APPENDIX A V, human = 20 m*day, BW = 70 kg Other additional studies or pertinent information which lend support to this MRL: The authors (Haun and Kinkead 1973) also investigated the effects of inhaled hydrazine in other species. Fatty liver changes were also observed in dogs exposed to 1 ppm hydrazine for 6 months and in monkeys exposed to 0.2 ppm for 6 months. Agency Contact (Chemical Manager): Hugh Hansen Agency Review Date: 1° review: 2° review: HYDRAZINES A-5 APPENDIX A Chemical Name: 1,1-Dimethylhydrazine CAS Number: 57-14-7 Date: September 5, 1996 Profile Status: Draft 3 Route: [X] Inhalation [ ] Oral Duration: [ ] Acute [X] Intermediate [] Chronic Graph Key: 17 Species: mouse Minimal Risk Level: 2 x 10* [ ] mg/kg/day [X] ppm Reference: Haun et al. 1984 Experimental design:(human study details or strain, number of animals per exposure/control groups, sex, dose administration details): Groups of 400 female C57BL/6 mice per group, exposed by inhalation to 0, 0.05, 0.5, or 5 ppm for 6 months, 5 days per week, 6 hours per day. Effects noted in study and corresponding doses: Hyaline degeneration in the gallbladder was significantly increased in the 0.05, 0.5, and 5 ppm groups compared to controls. Thus, the LOAEL is set at 0.05 ppm. Calculations: LOAEL gc) = LOAEL (upp) x [(V ABW), + (V/BW)yl LOAEL yc, = (0.05 ppm X 6 hr/24 hr x 5 d/7 d) x [(VJ/BW), + (V/BW)yl LOAEL zc, = 0.0089 ppm X [(0.043 m’/day + 0.026 kg) + (20 m®/day + 70 kg)] LOAEL jc, = 0.05 ppm MRL = LOAEL , + Uncertainty Factor MRL = 0.05 ppm + 300 MRL = 2 x 10“ ppm Dose and endpoint used for MRL derivation: [ ] NOAEL [X] LOAEL Uncertainty Factors used in MRL derivation: [X] 10 for use of a LOAEL [X] 3 for extrapolation from animals to humans following conversion to HEC [X] 10 for human variability Was a conversion used from ppm in food or water to a me/body weight dose? If so, explain: No If an inhalation study in animals, list the conversion factors used in determining human equivalent dose: V, mouse = 0.043 m’/day, BW = 0.026 kg V, human = 20 m’/day, BW = 70 kg HYDRAZINES A-6 APPENDIX A Other additional studies or pertinent information which lend support to this MRL: Studies of workers exposed to 1,1-dimethylhydrazine have reported changes indicative of a hepatic effect (elevated serum alanine aminotransferase activity, positive cephalin flocculation test) (Petersen et al. 1970; Shook and Cowart 1957). Angiectasis was observed in the livers of all exposed mice. Hepatic congestion was noted in mice exposed to 0.5 or 5 ppm 1,1-dimethylhydrazine (Haun et al. 1984). No NOAEL was identified. Agency Contact (Chemical Manager): Hugh Hansen Agency Review Date: 1° review: 2° review: HYDRAZINES A-7 APPENDIX A Chemical Name: 1,2-Dimethylhydrazine CAS Number: 540-73-8 Date: September 5, 1996 Profile Status: Draft 3 Route: [ ] Inhalation [X] Oral Duration: [1 Acute [X] Intermediate [ ] Chronic Graph Key: 25 Species: mouse Minimal Risk Level: 8 x 10* [X] mg/kg/day [ ] ppm Reference: Visek et al. 1991 Experimental design:(human study details or strain, number of animals per exposure/control groups, sex, dose administration details): 25 male mice per group, exposed to 0, 0.75, 1.6, or 2.7 mg/kg/day in the diet for 5 months. Although 2 diet preparations were administered (one containing 10% protein, the other containing 40% protein), the doses of 1,2-dimethylhydrazine were judged not to differ significantly between the two groups. Effects noted in study and corresponding doses: Mild hepatitis and small decreases in body weight gain and relative organ weights were observed in mice exposed to the lowest dose (0.75 mg/kg/day). These effects were more severe in animals exposed to higher doses. For example, doses of 1.6 mg/kg/day produced frank toxic hepatitis, as characterized by lobular disorganization, hepatocellular hypertrophy, and centrilobular necrosis. Portal fibrosis and bile duct hyperplasia, two effects noted in only a few animals exposed to 1.6 mg/kg/day, were more frequently observed in animals receiving the highest dose (2.7 mg/kg/day). Calculations: MRL = LOAEL + Uncertainty Factor MRL = 0.75 mg/kg/day + 1000 MRL = 8 x 10* mg/kg/day Dose and endpoint used for MRL derivation: [ ] NOAEL [X] LOAEL Uncertainty Factors used in MRL derivation: [X] 10 for use of a LOAEL [X] 10 for extrapolation from animals to humans [X] 10 for human variability Was a conversion used from ppm in food or water to a mg/body weight dose? If so, explain: 0.058 mg/day (daily food intake provided by authors) + 0.035 kg (body weight provided by authors) x 0.45 (molecular weight adjustment for use of dihydrochloride salt) = 0.75 mg/kg/day. HYDRAZINES A-8 APPENDIX A If an inhalation study in animals, list the conversion factors used in determining human equivalent dose: N/A Other additional studies or pertinent information which lend support to this MRL: Hepatic effects (hepatotoxicity, necrosis, fibrosis, hemosiderosis, ascites, cirrhosis, degeneration) have been observed in rats (Bedell et al. 1982), guinea pigs (Wilson 1976), dogs (Wilson 1976), and pigs (Wilson 1976) subchronically exposed to 4.2-30 mg/kg/day 1,2-dimethylhydrazine by the oral route. Agency Contact (Chemical Manager): Hugh Hansen Agency Review Date: 1° review: 2° review: HYDRAZINES B-1 APPENDIX B USER'’S GUIDE Chapter 1 Public Health Statement This chapter of the profile is a health effects summary written in non-technical language. Its intended audience is the general public especially people living in the vicinity of a hazardous waste site or chemical release. If the Public Health Statement were removed from the rest of the document, it would still communicate to the lay public essential information about the chemical. The major headings in the Public Health Statement are useful to find specific topics of concern. The topics are written in a question and answer format. The answer to each question includes a sentence that will direct the reader to chapters in the profile that will provide more information on the given topic. Chapter 2 Tables and Figures for Levels of Significant Exposure (LSE) Tables (2-1, 2-2, and 2-3) and figures (2-1 and 2-2) are used to summarize health effects and illustrate graphically levels of exposure associated with those effects. These levels cover health effects observed at increasing dose concentrations and durations, differences in response by species, minimal risk levels (MRLs) to humans for noncancer end points, and EPA’s estimated range associated with an upper- bound individual lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. Use the LSE tables and figures for a quick review of the health effects and to locate data for a specific exposure scenario. The LSE tables and figures should always be used in conjunction with the text. All entries in these tables and figures represent studies that provide reliable, quantitative estimates of No-Observed-Adverse- Effect Levels (NOAELSs), Lowest-Observed-Adverse-Effect Levels (LOAELS), or Cancer Effect Levels (CELs). The legends presented below demonstrate the application of these tables and figures. Representative examples of LSE Table 2-1 and Figure 2-1 are shown. The numbers in the left column of the legends correspond to the numbers in the example table and figure. LEGEND See LSE Table 2-1 (1) Route of Exposure One of the first considerations when reviewing the toxicity of a substance using these tables and figures should be the relevant and appropriate route of exposure. When sufficient data exists, three LSE tables and two LSE figures are presented in the document. The three LSE tables present data on the three principal routes of exposure, i.e., inhalation, oral, and dermal (LSE Table 2-1, 2-2, and 2-3, respectively). LSE figures are limited to the inhalation (LSE Figure 2-1) and oral (LSE Figure 2-2) routes. Not all substances will have data on each route of exposure and will not therefore have all five of the tables and figures. HYDRAZINES B-2 2) 3) “ 3) (6) (7) ®) ® APPENDIX B Exposure Period Three exposure periods - acute (less than 15 days), intermediate (15-364 days), and chronic (365 days or more) are presented within each relevant route of exposure. In this example, an inhalation study of intermediate exposure duration is reported. For quick reference to health effects occurring from a known length of exposure, locate the applicable exposure period within the LSE table and figure. Health Effect The major categories of health effects included in LSE tables and figures are death, systemic, immunological, neurological, developmental, reproductive, and cancer. NOAELSs and LOAELs can be reported in the tables and figures for all effects but cancer. Systemic effects are further defined in the "System" column of the LSE table (see key number 18). Key to Figure Each key number in the LSE table links study information to one or more data points using the same key number in the corresponding LSE figure. In this example, the study represented by key number 18 has been used to derive a NOAEL and a Less Serious LOAEL (also see the 2 "18r" data points in Figure 2-1). Species The test species, whether animal or human, are identified in this column. Section 2.5, "Relevance to Public Health," covers the relevance of animal data to human toxicity and Section 2.3, "Toxicokinetics," contains any available information on comparative toxicokinetics. Although NOAELs and LOAELS are species specific, the levels are extrapolated to equivalent human doses to derive an MRL. Exposure Frequency/Duration The duration of the study and the weekly and daily exposure regimen are provided in this column. This permits comparison of NOAELs and LOAELSs from different studies. In this case (key number 18), rats were exposed to 1,1,2,2-tetrachloroethane via inhalation for 6 hours per day, 5 days per week, for 3 weeks. For a more complete review of the dosing regimen refer to the appropriate sections of the text or the original reference paper, i.e., Nitschke et al. 1981. System This column further defines the systemic effects. These systems include: respiratory, cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, renal, and dermal/ocular. "Other" refers to any systemic effect (e.g., a decrease in body weight) not covered in these systems. In the example of key number 18, 1 systemic effect (respiratory) was investigated. NOAEL A No-Observed-Adverse-Effect Level (NOAEL) is the highest exposure level at which no harmful effects were seen in the organ system studied. Key number 18 reports a NOAEL of 3 ppm for the respiratory system which was used to derive an intermediate exposure, inhalation MRL of 0.005 ppm (see footnote "b"). LOAEL A Lowest-Observed-Adverse-Effect Level (LOAEL) is the lowest dose used in the study that caused a harmful health effect. LOAELs have been classified into "Less Serious" and "Serious" effects. These distinctions help readers identify the levels of exposure at which adverse health effects first appear and the gradation of effects with increasing dose. A brief description of the specific endpoint used to quantify the adverse effect accompanies the LOAEL. The respiratory effect reported in key number 18 (hyperplasia) is a Less serious LOAEL of 10 ppm. MRLs are not derived from Serious LOAELSs. (10) Reference The complete reference citation is given in chapter 8 of the profile. HYDRAZINES B-3 APPENDIX B (11) CEL A Cancer Effect Level (CEL) is the lowest exposure level associated with the onset of carcinogenesis in experimental or epidemiologic studies. CELs are always considered serious effects. The LSE tables and figures do not contain NOAELSs for cancer, but the text may report doses not causing measurable cancer increases. (12) Footnotes Explanations of abbreviations or reference notes for data in the LSE tables are found in the footnotes. Footnote "b" indicates the NOAEL of 3 ppm in key number 18 was used to derive an MRL of 0.005 ppm. LEGEND See Figure 2-1 LSE figures graphically illustrate the data presented in the corresponding LSE tables. Figures help the reader quickly compare health effects according to exposure concentrations for particular exposure periods. (13) Exposure Period The same exposure periods appear as in the LSE table. In this example, health effects observed within the intermediate and chronic exposure periods are illustrated. (14) Health Effect These are the categories of health effects for which reliable quantitative data exists. The same health effects appear in the LSE table. (15) Levels of Exposure concentrations or doses for each health effect in the LSE tables are graphically displayed in the LSE figures. Exposure concentration or dose is measured on the log non scale "y" axis. Inhalation exposure is reported in mg/m’ or ppm and oral exposure is reported in mg/kg/day. (16) NOAEL In this example, 18r NOAEL is the critical endpoint for which an intermediate inhalation exposure MRL is based. As you can see from the LSE figure key, the open-circle symbol indicates to a NOAEL for the test species-rat. The key number 18 corresponds to the entry in the LSE table. The dashed descending arrow indicates the extrapolation from the exposure level of 3 ppm (see entry 18 in the Table) to the MRL of 0.005 ppm (see footnote "b" in the LSE table). (17) CEL Key number 38r is 1 of 3 studies for which Cancer Effect Levels were derived. The diamond symbol refers to a Cancer Effect Level for the test species-mouse. The number 38 corresponds to the entry in the LSE table. (18) Estimated Upper-Bound Human Cancer Risk Levels This is the range associated with the upper-bound for lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. These risk levels are derived from the EPA’s Human Health Assessment Group's upper-bound estimates of the slope of the cancer dose response curve at low dose levels (q,*). (19) Key to LSE Figure The Key explains the abbreviations and symbols used in the figure. S3ANIZVHAAH TABLE 2-1. Levels of Significant Exposure to [Chemical x] — Inhalation Exposure LOAEL (effect) Key to frequency/ NOAEL - - figure Species duration System (ppm) Less serious (ppm) Serious (ppm) Reference INTERMEDIATE EXPOSURE 1 l Systemic 18 3 10 (hyperplasia) Nitschke et al. 1981 > TU = —_— mo CHRONIC EXPOSURE S x @ Cancer 38 Rat 18 mo 20 (CEL, multiple Wong et al. 1982 5d/wk organs) 7hr/d 39 Rat 89-104 wk 10 (CEL, lung tumors, NTP 1982 5d/wk nasal tumors) 6hr/d 40 Mouse 79-103 wk 10 (CEL, lung tumors, NTP 1982 5d/wk hemangiosarcomas) 6hr/d ® The number corresponds to entries in Figure 2-1. ® Used to derive an intermediate inhalation Minimal Risk Level (MRL) of 5 x 10° ppm; dose adjusted for intermittent exposure and divided by an uncertainty factor of 100 (10 for extrapolation from animal to humans, 10 for human variability). CEL = cancer effect level; d = days(s); hr = hour(s); LOAEL = lowest-observed-adverse-effect level; mo = month(s); NOAEL = no- observed-adverse-effect level; Resp = respiratory; wk = week(s) @ —————> Figure 2-1. Levels of Significant Exposure to [Chemical X] — Inhalation Acute Intermediate (<14 days) (15-364 days) Systemic Systemic N » > 4 < © 5 & & o> & eR & * ” @ 0 & 0 © SO & XS Q @ Q & @ £ © Ry & & & & & oR RK SS Q <& 4 Q Qs > x << oO 1000 |— oO @ 37m 1) 100 — @9® o ® s0r 34r & 17r Dp 20mP Boom 3ir @® 35m d 16r 24918: ® 229211 O 28m® 20r O o7r 40m * 10 | — - 33r 22m 34r Q er | 1 — | | 104 — | . 01 | 10°5 Estimated <— v Upper Bound 0.01 }— | Human Cancer Key 10 Risk Levels 0.001 — r Rat @ LOAEL for serious effects (animals) , Minimal risk level for effects 1077 m Mouse (P LOAEL for less serious effects (animals) | other than cancer 0.0001 — h Rabbit (QO NOAEL (animals) g Guinea Pig CEL - Cancer Effect Level The number next to each point 0.00001 k Monkey * corresponds to entries in the accompanying table. 0.000001 — a . * Doses represent the lowest dose tested per study that produced a tumorigenic response and do not imply mn the existence of a threshold for the cancer end point. 0.0000001 g XIAN3ddV S3ANIZVHAAH S-d HYDRAZINES B-6 APPENDIX B Chapter 2 (Section 2.5) Relevance to Public Health The Relevance to Public Health section provides a health effects summary based on evaluations of existing toxicologic, epidemiologic, and toxicokinetic information. This summary is designed to present interpretive, weight-of-evidence discussions for human health end points by addressing the following questions. 1. What effects are known to occur in humans? 2. What effects observed in animals are likely to be of concern to humans? 3. What exposure conditions are likely to be of concern to humans, especially around hazardous waste sites? The section covers end points in the same order they appear within the Discussion of Health Effects by Route of Exposure section, by route (inhalation, oral, dermal) and within route by effect. Human data are presented first, then animal data. Both are organized by duration (acute, intermediate, chronic). In vitro data and data from parenteral routes (intramuscular, intravenous, subcutaneous, etc.) are also considered in this section. If data are located in the scientific literature, a table of genotoxicity information is included. The carcinogenic potential of the profiled substance is qualitatively evaluated, when appropriate, using existing toxicokinetic, genotoxic, and carcinogenic data. ATSDR does not currently assess cancer potency or perform cancer risk assessments. Minimal risk levels (MRLs) for noncancer end points (if derived) and the end points from which they were derived are indicated and discussed. Limitations to existing scientific literature that prevent a satisfactory evaluation of the relevance to public health are identified in the Data Needs section. Interpretation of Minimal Risk Levels Where sufficient toxicologic information is available, we have derived minimal risk levels (MRLs) for inhalation and oral routes of entry at each duration of exposure (acute, intermediate, and chronic). These MRLs are not meant to support regulatory action; but to acquaint health professionals with exposure levels at which adverse health effects are not expected to occur in humans. They should help physicians and public health officials determine the safety of a community living near a chemical emission, given the concentration of a contaminant in air or the estimated daily dose in water. MRLs are based largely on toxicological studies in animals and on reports of human occupational exposure. MRL users should be familiar with the toxicologic information on which the number is based. Chapter 2.5, "Relevance to Public Health," contains basic information known about the substance. Other sections such as 2.7, "Interactions with Other Substances,” and 2.8, "Populations that are Unusually Susceptible” provide important supplemental information. MRL users should also understand the MRL derivation methodology. MRLs are derived using a modified version of the risk assessment methodology the Environmental Protection Agency (EPA) provides (Barnes and Dourson 1988) to determine reference doses for lifetime exposure (RfDs). HYDRAZINES B-7 APPENDIX B To derive an MRL, ATSDR generally selects the most sensitive endpoint which, in its best judgement, represents the most sensitive human health effect for a given exposure route and duration. ATSDR cannot make this judgement or derive an MRL unless information (quantitative or qualitative) is available for all potential systemic, neurological, and developmental effects. If this information and reliable quantitative data on the chosen endpoint are available, ATSDR derives an MRL using the most sensitive species (when information from multiple species is available) with the highest NOAEL that does not exceed any adverse effect levels. When a NOAEL is not available, a lowest-observed- adverse-effect level (LOAEL) can be used to derive an MRL, and an uncertainty factor (UF) of 10 must be employed. Additional uncertainty factors of 10 must be used both for human variability to protect sensitive subpopulations (people who are most susceptible to the health effects caused by the substance) and for interspecies variability (extrapolation from animals to humans). In deriving an MRL, these individual uncertainty factors are multiplied together. The product is then divided into the inhalation concentration or oral dosage selected from the study. Uncertainty factors used in developing a substance-specific MRL are provided in the footnotes of the LSE Tables. HYDRAZINES ACGIH ADME AML atm ATSDR BCF BEI BSC C CDC CEL CERCLA CFR Ci CLP cm CML CNS d DHEW DHHS DOL ECG EEG EPA EKG F F, FAO FEMA FIFRA fpm ft FR g GC gen HPLC hr IDLH IARC ILO in Kd C-1 APPENDIX C ACRONYMS, ABBREVIATIONS, AND SYMBOLS American Conference of Governmental Industrial Hygienists Absorption, Distribution, Metabolism, and Excretion acute myeloid leukemia atmosphere Agency for Toxic Substances and Disease Registry bioconcentration factor Biological Exposure Index Board of Scientific Counselors Centigrade Centers for Disease Control Cancer Effect Level Comprehensive Environmental Response, Compensation, and Liability Act Code of Federal Regulations curie Contract Laboratory Program centimeter chronic myeloid leukemia central nervous system day Department of Health, Education, and Welfare Department of Health and Human Services Department of Labor electrocardiogram electroencephalogram Environmental Protection Agency see ECG Fahrenheit first filial generation Food and Agricultural Organization of the United Nations Federal Emergency Management Agency Federal Insecticide, Fungicide, and Rodenticide Act feet per minute foot Federal Register gram gas chromatography generation high-performance liquid chromatography hour Immediately Dangerous to Life and Health International Agency for Research on Cancer International Labor Organization inch adsorption ratio HYDRAZINES RR £ LOAEL LSE m MA mCi mg min mL mm mm Hg mmol mo mppcf MRL MS NCE NIEHS NIOSH NIOSHTIC ng nm NHANES nmol NOAEL NOES NOHS NPL NRC NTIS NTP OSHA PEL PCE pg pmol PHS PMR ppb ppm APPENDIX C kilogram metric ton organic carbon partition coefficient octanol-water partition coefficient liter liquid chromatography lethal concentration, low lethal concentration, 50% kill lethal dose, low lethal dose, 50% kill lowest-observed-adverse-effect level Levels of Significant Exposure meter trans, trans-muconic acid millicurie milligram minute milliliter millimeter millimeters of mercury millimole month millions of particles per cubic foot Minimal Risk Level mass spectrometry normochromatic erythrocytes National Institute of Environmental Health Sciences National Institute for Occupational Safety and Health NIOSH’s Computerized Information Retrieval System nanogram nanometer National Health and Nutrition Examination Survey nanomole no-observed-adverse-effect level National Occupational Exposure Survey National Occupational Hazard Survey National Priorities List National Research Council National Technical Information Service National Toxicology Program Occupational Safety and Health Administration permissible exposure limit polychromatic erythrocytes picogram picomole Public Health Service proportionate mortality ratio parts per billion parts per million C-2 HYDRAZINES ppt REL RfD RTECS sec SCE SIC SMR STEL STORET TLV TSCA TRI TWA UMDNJ U.S. UF yr WHO wk RR KIAA IVY = 3 = a APPENDIX C parts per trillion recommended exposure limit Reference Dose Registry of Toxic Effects of Chemical Substances second sister chromatid exchange Standard Industrial Classification standard mortality ratio short term exposure limit STORAGE and RETRIEVAL threshold limit value Toxic Substances Control Act Toxics Release Inventory time-weighted average University of Medicine and Dentistry New Jersey United States uncertainty factor year World Health Organization week greater than greater than or equal to equal to less than less than or equal to percent alpha beta delta gamma micrometer microgram C-3 # U.S. GOVERNMENT PRINTING OFFICE: 1997-538-073 1 6121 BERKELEY LIBRARIES C08LA&9313k