10
Dimethylhydrazine

Noreen N. Khan-Mayberry, Ph.D.

John T. James, Ph.D., D.A.B.T.

Toxicology Group

Habitability and Environmental Factors Division

Johnson Space Center

National Aeronautics and Space Administration

Houston, Texas

PHYSICAL AND CHEMICAL PROPERTIES

1,1-Dimethylhydrazine (UDMH) is a highly corrosive, clear, colorless, flammable, hygroscopic fuming liquid that gradually turns yellow upon contact with air. It is miscible with water, ethanol, ether, dimethylformamide, and hydrocarbons (EPA 1984). It has an amine-like, ammonia, or fish-like odor, which is characteristic of aliphatic hydrazines (O’Neil et al. 2001). UDMH is highly corrosive and irritating to skin, eyes, and mucous membranes (HSDB 2005). The vapor is flammable in air at concentrations ranging from 2.5% to 95% (Wade 2003), and it may ignite spontaneously when in contact with heat, flame, or oxidizers. Table 10-1 describes UDMH’s physical and chemical properties.

OCCURRENCE AND USE

Dimethylhydrazine occurs as symmetrical (1,2-dimethylhydrazine) and unsymmetrical (1,1-dimethylhydrazine [UDMH]) isomers. UDMH occurs naturally and is synthesized for use in a variety of applications. It can be produced commercially by nitrosation of dimethylamine, followed by reduction of the intermediary to UDMH and ensuing purification (Wade 2003). UDMH has also been used for chemical synthesis and as an intermediate in the manufacture of aminimides; it is still used as an intermediate for organic chemical synthesis.

In plants, UDMH occurs naturally in small amounts (ATDSR 2007). It has been used to control vegetation, flowers, and fruit crops and as an absorbent for acid gases (IARC 1974, EPA 1984). Small amounts of UDMH, up to 147 nanograms per gram (ng/g), have been detected in tobacco products, leading to exposure of persons who chew tobacco, smoke cigarettes, or are exposed to



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10 Dimethylhydrazine Noreen N. Khan-Mayberry, Ph.D. John T. James, Ph.D., D.A.B.T. Toxicology Group Habitability and Environmental Factors Division Johnson Space Center National Aeronautics and Space Administration Houston, Texas PHYSICAL AND CHEMICAL PROPERTIES 1,1-Dimethylhydrazine (UDMH) is a highly corrosive, clear, colorless, flammable, hygroscopic fuming liquid that gradually turns yellow upon contact with air. It is miscible with water, ethanol, ether, dimethylformamide, and hy- drocarbons (EPA 1984). It has an amine-like, ammonia, or fish-like odor, which is characteristic of aliphatic hydrazines (O’Neil et al. 2001). UDMH is highly corrosive and irritating to skin, eyes, and mucous membranes (HSDB 2005). The vapor is flammable in air at concentrations ranging from 2.5% to 95% (Wade 2003), and it may ignite spontaneously when in contact with heat, flame, or oxidizers. Table 10-1 describes UDMH’s physical and chemical properties. OCCURRENCE AND USE Dimethylhydrazine occurs as symmetrical (1,2-dimethylhydrazine) and unsymmetrical (1,1-dimethylhydrazine [UDMH]) isomers. UDMH occurs natu- rally and is synthesized for use in a variety of applications. It can be produced commercially by nitrosation of dimethylamine, followed by reduction of the intermediary to UDMH and ensuing purification (Wade 2003). UDMH has also been used for chemical synthesis and as an intermediate in the manufacture of aminimides; it is still used as an intermediate for organic chemical synthesis. In plants, UDMH occurs naturally in small amounts (ATDSR 2007). It has been used to control vegetation, flowers, and fruit crops and as an absorbent for acid gases (IARC 1974, EPA 1984). Small amounts of UDMH, up to 147 nanograms per gram (ng/g), have been detected in tobacco products, leading to exposure of persons who chew tobacco, smoke cigarettes, or are exposed to 162

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163 Dimethylhydrazine cigarette smoke (NTP 2000). UDMH is also used in the manufacture of N- dimethylaminosuccinamic acid, a plant growth regulator. UDMH is used primarily in military applications, as a storable, high- energy propellant for liquid-fueled rockets, in fuel for thrusters, and in small electrical power-generating units. Development of UDMH started in the Soviet Union in 1949 (Wade 2003) and became the storable liquid fuel of choice by the mid-1950s. It is used, in effect, in all storable liquid rocket engines, with the exception of some orbital maneuvering engines made in the United States, in which monomethylhydrazine is preferred because of its higher density and per- formance (Wade 2003). UDMH has been widely used as the fuel source for a number of Russian, European, and Chinese rockets (Zelnick et al. 2003). TABLE 10-1 Physical and Chemical Properties of UDMH Formula C2H8N2 Chemical name Dimethylhydrazine Synonyms Unsymmetrical dimethylhydrazine U-Dimethylhydrazine UDMH DMH Dimethylhydrazine AS-Dimethylhydrazine Asymmetric dimethylhydrazine ASYM dimethylhydrazine Dimazin Dimazine N,N-Dimethylhydrazine Dimethylhydrazine unsymmetrical CAS number 57-14-7 Physical description Liquid (HSDB 2005) Molecular weight 60.10 (HSDB 2005) Boiling point 63.9°C (HSDB 2005) Freezing/melting point –58°C (HSDB 2005) Flash point (closed cup) –15°C (HSDB 2005) Liquid density at 25oC 0.782 (HSDB 2005) Vapor density 1.94 (HSDB 2005) Vapor pressure 156.8 mm Hg at 25°C Solubility Soluble in water and ethanol; miscible with dimethylformamide, hydrocarbons, alcohol, and ether Specific gravity 0.782 at 25°C Odor threshold 0.3 ppm (Rumsey and Cesta 1970) 1.7 ppm (Amoore and Hautala 1983) 6-14 ppm (Jacobson et al. 1955) 1 ppm = 2.5 mg/m3 (HSDB, 2005) Conversion factor at 25°C, 1 atm

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164 SMACs for Selected Airborne Contaminants UDMH is used on the functional cargo block (Russian Funkcionalnij Gru- zovoj Blck [FGB]), service module, Soyuz and Progress thrusters, and reboost engines (Wikipedia, 2008). UDMH should not be present within the spacecraft cabin atmosphere unless it is introduced via contamination of a spacesuit as a consequence of contact during extravehicular activity. The amount of contami- nant that may be introduced by this route is difficult to establish; however, be- cause of the procedural safeguards currently used, theoretically, the amount of UDMH contamination should be less than a few grams (Garcia and James 1996). TOXICOKINETICS Toxicokinetic data are available on the uptake, metabolism, and elimina- tion of UDMH via intraperitoneal (i.p.) and inhalation exposure routes in several species. The weight of evidence (Back et al. 1963) suggests that UDMH is non- selectively distributed throughout the body and metabolized through pathways that have not been fully defined. Absorption Weeks et al. (1963) researched the retention of inhaled UDMH in six anesthetized dogs (mongrel) by using an endotracheal tube or an oronasal mask. They exposed each animal to a known concentration for about 1 h and deter- mined the percent retention of the inhaled dose. They did not describe in detail the method used to do this. Respiratory volumes and electrocardiograms were recorded during the exposure. The reported exposure concentrations ranged from 3 to 20 milligrams per liter (mg/L) (1,200 to 8,000 parts per million [ppm]) and the percent retention ranged from 71% to 93%. Skin absorption of liquid UDMH was studied in anesthetized dogs given 5-30 millimoles of UDMH per kilogram of body weight (mmol/kg) applied to a shaved area of the chest (Smith and Clark 1971). The lower doses were absorbed more rapidly, so that the blood concentrations after the lowest dose peaked 60 min after application, whereas, at a dose of 30 mmol/kg, the peak blood concen- tration occurred 200 min after application. No studies were found that reported dermal absorption of UDMH vapor. Distribution The distribution of UDMH was reported in a limited research study. Back et al. (1963) conducted a study on albino rabbits (1.7 to 4.4 kg), injecting [14C]UDMH intravenously (i.v.) at 50 mg/kg and removing tissue from two rab- bits at each point of sacrifice (eight rabbits). The rabbits were euthanized 2, 4, 18, and 24 h postinjection to determine tissue distribution. They reported that the maximum difference between UDMH concentration in brain tissue, kidney,

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165 Dimethylhydrazine spleen, and liver was approximately 2-fold after a 24-h period. The concentra- tions reported were the average of what was identified in each pair of rabbits. The tissues were not rendered bloodless, and that could account for a portion of the UDMH identified and reported. Within 24 h 10% to 28% of the injected dose was accounted for. UDMH did not preferentially concentrate in any of the vital organs studied. The authors suggested that the bulk of body weight, includ- ing skeletal muscle, bone, and adipose and cutaneous tissues, which were not examined, may represent a reservoir for a good percentage of UDMH not identi- fied in the other tissues. On the other hand, much of the UDMH may have been eliminated by urinary excretion or through metabolism and CO2 exhalation (see Excretion section). Metabolism The metabolism of UDMH has been partially characterized through i.p. and i.v. studies on a variety of species and also by in vitro studies using tissues, cells, or subcellular components. These studies have not led to a complete pic- ture of UDMH metabolism. Dost et al. (1966) administered [14C]UDMH by i.p. injection to rats at doses from 0.013 to 1.33 mmol/kg and found that 30% of the lower doses were converted to CO2, whereas at the highest doses only 13% were converted to CO2 over a much longer time (10 h versus 20 h). At least half the administered radio- activity appeared in the urine during the 2 d after injection. Based on the results reported by Mitz et al. (1962) from rats given UDMH at 40 mg/kg, the urinary metabolites were the glucose hydrazone of UDMH and another hydrazone of UDMH. Clearly, demethylation of UDMH occurs in vivo. Godoy et al. (1983), using rat liver microsomes and S9 fractions under aerobic conditions, identified a nonenzymatic and an enzymatic component in- volved in UDMH metabolism to formaldehyde. The metabolism led to covalent binding to proteins, with the process dominated by nonenzymatic processes; however, UDMH did not produce metabolites that bound covalently to nucleic acids. The reactive metabolites produced by UDMH may be free radical inter- mediates. Albano et al. (1989) studied activation of UDMH in isolated hepato- cytes and liver microsomes of male Wistar rats. Hepatocytes incubated with 2 millimolar (mM) UDMH resulted in the formation of free radical metabolites (measured by spin trapping techniques). The authors noted that the oxidative metabolism of UDMH was largely mediated by FAD-containing monooxy- genase; this study observed that methimazole, a competitive inhibitor of monooxygenase, decreased the free radical activation of UDMH. They also noted that the detection of free radicals suggested that these reactive species could be responsible for the toxic and carcinogenic effects of UDMH and other methylhydrazines (Albano et al. 1989). Using a series of selective inhibitors and copper ions, Tomasi et al. (1987) showed that one nonenzymatic mechanism and two enzymatic pathways were involved in UDMH metabolism.

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166 SMACs for Selected Airborne Contaminants Excretion Back et al. (1963) reported that 30% to 50% of UDMH is excreted in urine in its original form in dogs and cats, respectively, within 5 h. Both i.p. and i.v. doses of UDMH ranging from 10 to 50 mg/kg were injected into the test ani- mals. In some experiments in this study, they observed urinary concentrations of considerable magnitude as early as 3 min after administration of the compound, regardless of the route of administration. Back et al. (1963) also noted that uri- nary UDMH concentration is the most sensitive biomarker of exposure, because urine concentrations can be found at doses that do not produce detectable con- centrations in blood. However, when urine is used as evidence of exposure, con- centrations would not be considered an absolute indicator of the dose received because an unknown amount of drug administered would be lost to various transformation pathways within the body. TOXICITY SUMMARY Information on acute exposures to UDMH in humans is generally limited to case reports of accidental exposures. Most animal toxicity research on UDMH was conducted in military laboratories from the 1950s to the 1970s. These stud- ies were published in peer-reviewed journals or in technical reports, in some cases without peer review. Furthermore, they were conducted before good labo- ratory practices became widely accepted in toxicity studies, so they typically lack the detail and organization of more recent toxicity studies. Toxicity data of different degrees of completeness are available for numerous species of labora- tory animals, including rhesus monkeys, dogs, rats, mice, and hamsters (Weeks et al. 1963). Acute Toxicity (≤1 d) Lethality in Humans Review of research indicates that lethal exposures of UDMH have caused death by respiratory arrest, and postmortem examinations reveal pulmonary edema. Authoritative data on these lethal exposures, including concentration and duration of exposure, were not available for these incidents (NRC 2000). Lethality in Animals Several studies characterized the lethal concentrations of UDMH in a vari- ety of species. These studies reported consistent signs of convulsive activity, other central nervous system (CNS) effects, and respiratory effects before death, regardless of species. Dogs exposed to UDMH at 24, 52, or 111 ppm for 4 h had mortality rates of 0/3, 1/3, and 3/3 for the three exposure groups, respectively

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167 Dimethylhydrazine (Jacobson et al. 1955). The authors noted that all deaths or terminations occurred within the first day of exposure. All three dogs in the highest exposure group displayed vomiting, panting, and convulsions before death. The sole dog that expired in the 52-ppm exposure group also exhibited the aforementioned signs before death, while the remaining two dogs exhibited nausea, panting, or lack of coordination. One dog in the low-exposure (24 ppm) group also exhibited vom- iting and convulsions but did not die. No hematologic changes were observed in any of the surviving dogs. The surviving dogs were sacrificed for examination after 14 d. Necropsy revealed pulmonary edema and patchy hemorrhage in ani- mals that had convulsions; according to the authors, these observations possibly resulted as a secondary consequence from seizures as opposed to being a direct result of UDMH exposure. Weeks et al. (1963) exposed male rats (100 to 120 g), 10 per group, to UMDH at concentrations ranging from 252 to 24,500 ppm for 5, 15, 30, 60, and 240 min. They were observed for signs of toxicity 7 days postexposure. The authors conducted histopathologic studies on rats sacrificed immediately and 1, 3, and 7 d after exposure. Rats exposed to UDMH demonstrated signs of irrita- tion, including sneezing, eye closure, and restlessness. Deaths occurred within 24 h postexposure and were preceded by alternating episodes of tonic-clonic convulsions and depressed activity. The median lethal concentration (LC50) val- ues for this study are given in Table 10-2. The purity of UDMH and recovery in the chamber were not reported. Several physiological tests were done on ex- posed animals, but the extent of any pathologic study was unclear. TABLE 10-2 LC50 Values for UDMH (95% Confidence Interval) Exposure Concentration, ppm Duration Species, Sex, Strain Reference 52a 4h Dog, N/A, mongrel Weeks et al. 1963 172 (150-194) 4h Mouse, N/A, N/A Jacobsen et al. 1955 252 (219-290) 4h Rat, male, N/A Weeks et al. 1963, Jacobsen et al. 1955 392 (376-413) 4h Hamster, N/A Jacobsen et al. 1955 981 (862-1,120) 1h Dog, N/A, mongrel Weeks et al. 1963 1,410 (1,300-1,530) 1h Rat, male, N/A Weeks et al. 1963 3,580 (2,330-5,500) 15 min Dog, N/A, mongrel Weeks et al. 1963 4,010 (3,730-4,310) 30 min Rat, male, N/A Weeks et al. 1963 8,230 (6,930-9,780) 15 min Rat, male, N/A Weeks et al. 1963 18,315 12 min Rat, N/A Chevrier and Pfister 1974 22,300 (22,000-22,600) 5 min Dog, N/A, mongrel Weeks et al. 1963 24,500 (23,400-25,500) 5 min Rat, male N/A Weeks et al. 1963 a Approximate lethal concentration = lowest concentration producing mortality.

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168 SMACs for Selected Airborne Contaminants CNS Effects Most studies have demonstrated that exposures to elevated concentrations of UDMH produce signs and symptoms originating in the CNS. CNS effects are expected to be the greatest acute hazard to crews. The mechanism of initiation of CNS effects is uncertain. In rats, the i.p. median lethal dose (LD50), which is the dose where the highest frequency of convulsions occurs, can be increased approximately 2-fold by i.p. injection of pyridoxine at 0.15 mmol/kg, 5 min after injection of the neurotoxicant (O’Brien et al. 1964). A study of brain, plasma, and erythrocyte cholinesterase concentra- tions in rats injected i.p. with UDMH showed that cholinesterase inhibition is not a factor in causing convulsions (Cornish et al. 1965). In the same study, a comparison of latency times to convulsions between i.p. and intracerebral injec- tion suggested that metabolism outside the brain may not be important. Back and Thomas (1962) studied the convulsive threshold of UDMH, not- ing that they did not discover the cause of the latency between dosage (i.p.) and ensuing CNS effects. Latency periods varied by species and dosage; mice showed CNS effects 50 to 120 min postdosing (131 mg/kg, i.p.), dogs ranged from 30 to 120 min (100 mg/kg, i.p. and i.v.) and 2 to 4 h (50 mg/kg, i.p. and i.v.), and Macaca iris monkeys had effects within 2 to 4 h (30 mg/kg, threshold dose, i.p.).Weeks et al. (1963) conducted a study similar to that of Back and Thomas (1962) in which they observed subdued behavior, muscle fasciculations, tremors, and convulsions in exposed dogs. All dogs in the Weeks et al. (1963) study survived the low dose (50 mg/kg) and symptoms occurred at the same time regardless of the route of administration (i.p. or i.v.). The M. iris monkey test subjects, in the same study, had no more than two convulsive episodes. UDMH did not affect the appetites of these animals, and the authors noted that some ate within 5 min after experiencing a convulsion (Weeks et al. 1963). Accidental human exposures to UDMH caused dizziness, lack of coordi- nation, headaches, and convulsions (ACGIH 1991). Dhennin et al. (1988, as cited in HSDB 2005) reported a case history of a 31-year-old man with exten- sive UDMH burns whose symptoms were predominantly neurological. Although the relative susceptibilities of various species are unknown, CNS symptoms caused by UDMH exposure appear qualitatively consistent across the species tested. Respiratory Effects Shook and Cowart (1957) as summarized by the National Research Coun- cil (NRC) (2000) reported that two people exposed to an undetermined concen- tration of UDMH first exhibited choking and breathing difficulty. The research- ers suggested that some of these respiratory consequences may be an indirect result of CNS toxicity such as tonic-clonic convulsions leading to respiratory arrest (Back and Thomas 1962). However, evidence that the respiratory toxicity

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169 Dimethylhydrazine is only a secondary manifestation has not been demonstrated. An acute toxicity study of groups of 20 mice, utilizing 4-h UDMH exposure assays at doses of 24, 52, and 111 ppm, was conducted by Jacobson et al. (1955). For the exposure period of 4 h, the mice displayed restlessness, dyspnea, convulsions, clonic but in some cases tonic-clonic, and exophthalmos at 52 and 111 ppm. Postmortem examination revealed no significant histopathologic findings with the exception of pulmonary edema and occasional localized pulmonary hemorrhage; the au- thors did not specify the concentrations at which these findings were noted. Hemorrhage was noted only in animals that had convulsions but was not noted in every animal that convulsed. Short-Term Toxicity (2 to 10 d) We did not find any studies using exposures in the above range. Subchronic Toxicity (11 to 100 d) Back (1963) reported no visible signs of toxicity or body weight changes in surviving ICR Swiss mice, Sprague-Dawley rats, and rhesus monkeys after inhalation exposure to 0.56 ppm of UDMH continuously for 90 d. One monkey died on day 41, three rats died between days 59 and 82, and six mice died be- tween days 3 and 41. Back noted some long-term exposure effects, which in- cluded degenerative lesions in the liver of rhesus monkeys, and the cytoplasm in central zones appeared swollen and reticulated. The authors note that the heart was dilated in all monkeys except one; calcium deposits were noted in the myo- cardium of two monkeys, including the one that died on day 41, which also had necrosis of muscle fibers. Calcification was indicated in the adrenal gland of one monkey. Mite infestation of the lung was identified in six monkeys, including the one that died on day 41. The infestation does not appear to be attributable to the UDMH exposure. Hemosiderin deposits in the Kuppfer and liver cells of mice and lesions in rat kidney (vacuolization of renal tubular epithelium) and heart (cardiac fibrosis in one and cardiac necrosis in six others) were also noted. It is difficult to attribute the concentration of 0.56 ppm as a true effect level based on the findings noted. We also note that the report was not peer reviewed. Weeks et al. (1963) exposed groups of dogs to UDMH at 50, 200, or 600 ppm for 60, 15, or 5 min, respectively, twice weekly for 6 wk. The authors ex- pected the dogs not to produce any signs of toxicity based on results previously obtained from acute exposures of three groups of four mixed-breed dogs to the same concentrations and exposure sessions twice weekly for 6 wk (50, 200, and 600 ppm for 60, 15, and 5 min, respectively). All these animals were observed for general health, characteristic behavioral signs, coordination, and reflex reac- tions for 2 months before exposures. Baseline values for white blood cells, re- ticulocyte counts, hematocrit, nonprotein nitrogen, glucose, bilirubin, and choli- nesterase levels were also determined. Two dogs from each group were trained

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170 SMACs for Selected Airborne Contaminants to perform a conditioned avoidance test. During the exposure period, each trained dog’s behavior was recorded. The trials were recorded on each nonexpo- sure day, except weekends and 15 min before and after exposure. No effects attributable to the exposures were found at these concentrations. After 6 wk of exposure the three groups of dogs were scheduled to be ex- posed twice weekly for 2 wk at twice the previous concentrations (100, 400, and 1,200 ppm for 60, 15, and 5 min, respectively). Responses in the conditioned avoidance test remained unchanged, and the clinical laboratory parameters were unchanged (except possibly red blood cell (RBC) count and hematocrit); how- ever, severe toxic signs developed even during the first exposures. Exposures were discontinued during the second week because of the continued appearance of severe toxic signs, including convulsion, tremors, vomiting, depressed behav- ior, salivating, apprehensive behavior, and death. Chronic Toxicity (>101 d) Chronic inhalation exposures to UDMH using conventional protocols in use today have not been published; however, one peer-reviewed study in dogs was published some time ago. Rinehart et al. (1960) set out to expose three dogs per group to UDMH concentrations of 5 and 25 ppm for 26 wk (6 h/d, 5 d/w). A control group was not used; however, they conducted preexposure hematologic assessments on dogs exposed to UDMH. Results from the exposed dogs were compared with preexposure values. At the higher concentration, one dog died on the third day, but the other two were exposed for a total of 13 wk. During this time, signs of depression, salivation, emesis, diarrhea, ataxia, convulsions, con- junctival injection, bradycardia, and fever were noted. No severe signs were noted in the lower concentration group. Blood was drawn weekly or monthly from the dogs to determine hematologic parameters. The two dogs surviving the 13-wk exposure to UDMH at 25 ppm showed a large decrease in RBC count (9.8 to 5.9 × 106/mm2) and in hematocrit (50.8% to 45.0 %). The three dogs exposed to 5 ppm showed a decreased RBC count (7.2 to 6.0 × 106/mm2), decreased hemoglobin (15.4% to 11.4 gm%), and de- creased hematocrit (52.9% to 46.0 %). Serum bilirubin was also measured in these animals and was found to increase from 0.2 mg% before the study to 0.7 mg% after 26 wk. Pathology for this group revealed only hemosiderosis of the spleen. These data may reflect a hemolytic process giving rise to the modest anemia observed at 13 wk. Other organs examined and found to be devoid of lesions included the brain, heart, kidney, stomach, intestines, pancreas, trachea, adrenals, testes, bladder, and trachea. The protocol for this examination was not clearly defined; however, a microscopic examination of stained sections from each of these organs was likely performed, as reporting of tissue section exami- nations included detail such as pigment in lymph nodes, bone marrow, and Kupffer cells.

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171 Dimethylhydrazine Carcinogenicity Cancer in Humans No information is available regarding carcinogenicity to humans after in- halation exposure to UDMH (NRC 2000). Cancer in Animals UDMH was reported to be carcinogenic in mice after lifetime drinking water exposures (Toth 1973, NRC 2000). A concentration of 1,000 mg/L was linked to elevated incidences of angiosarcomas, pulmonary adenomas, malig- nant lymphoma, kidney adenomas, and hepatomas. Toth (1977) conducted a similar study in hamsters that identified excessive numbers of tumors in the cecum and blood vessels. Mice administered 0.5 mg of UDMH (dosage in mg/kg not given) daily for 40 wk exhibited a marginal increase in lung tumors. Rats and mice developed liver tumors after a 2-year exposure to UDMH in drinking water (Toth 1977; NRC 2000). U.S. Air Force inhalation studies reported an increase in hemangiosarco- mas and Kupffer cell sarcomas in mice exposed to UDMH at 5 ppm for 6 h/d, 5 d/wk for 6 months (Haun et al. 1979, 1984). Similarly, rat exposures to UDMH at 5 ppm caused an increase in the incidence of squamous cell carcino- mas of the lung and hepatocellular carcinomas. The study used relevant test spe- cies and an adequate number of animals (total number of animals: 400 C571B1/6 mice, 200 Fischer rats, 200 golden Syrian hamsters, and 8 beagle dogs). The UDMH used in these studies contained 0.12% or 6 parts per billion of dimethylnitrosamine (DMNA). However, Haun et al. (1984) tested the puri- fied UDMH along with the DMNA-contaminated UDMH and concluded that the UDMH caused the oncogenic tumors. The results of the Haun et al. (1984) 6-month study demonstrated that UDMH is tumorigenic in rats and mice, mainly at the highest concentration (5 ppm) studied. Tumors were not produced in ham- sters and dogs through inhalation. Lesions in hamsters were not hepatotoxic, and in no case were lesions that were identified statistically different from those in control animals. The liver was the primary target of UDMH-induced neoplastic and pre- neoplastic changes in rats and mice. An indication of hepatotoxicity in dogs was demonstrated by transitory elevations of serum enzyme levels and liver function values in test subjects exposed to 5 ppm of UDMH. Six- to 12-month exposures resulted in a significantly increased oncogenic response to purified UDMH; this proved particularly true for lung adenomas (rarely seen) and for nasal tumors and liver adenomas not previously reported in dogs (Haun et al. 1984). These findings confirm the authors’ contention that the toxicity of UDMH is not inten- sified by the 0.12% DMNA contained in the UDMH studied. However, in cer- tain cases (6- to 12-month studies) purified UDMH had greater toxicity (in- creased oncogenic response) than the DMNA-contaminated UDMH.

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172 SMACs for Selected Airborne Contaminants We examined the technical report of Haun et al. (1984) to determine whether a defensible cancer risk can be gleaned from the information presented. The authors reported a dose-related increase in tumors in female mice for the following tumors: hemangiosarcomas, thyroid carcinomas, and Kupffer cell sarcomas. However, our inspection of the data does not support this conclusion (Table 10-3). A statistical trend analysis was not done on the data. Although several of the exposed-group incidences are statistically higher than control incidences, there is not a clear dose response for any of the cancers. The situation is no different for male rats exposed to DMNA-contaminated UDMH for 6 months. The results from female mice exposed to purified UDMH for 6 months do not clarify the situation. This study used only a single dose (5 ppm) and a con- trol group. Thyroid carcinomas and Kupffer cell sarcomas were not reported as increased in the exposed group. The incidence of hemangiosarcomas was 0.053 in exposed mice, and in controls it was 0.021. Although the incidence in the exposed group is a good match to the previous result (0.053 versus 0.047), the incidence in controls is much higher than in the earlier experiment (0.021 versus 0.007). We conclude that there are no dose-response data suitable for a cancer risk assessment. If cancers are caused by UDMH, then it is only at the highest dose of 5 ppm. Haun et al. (1984) reported an array of nonmalignant tumors in the noses of mice exposed to purified UDMH. These lesions were not reported in mice from the DMNA-contaminated exposures, presumably because they were not looked for. The incidences of papillomas and adenomatous polyps were statisti- cally higher than in controls; however, the rodent nares are well known to be a poor model of the human nasal cavities. This background, along with the fact that the purified UDMH study involved a single dose, precludes a defensible cancer risk assessment, even if one were to consider the nonmalignant lesions as cancer harbingers. Furthermore, none of the data has been peer reviewed, and the study was completed before good laboratory practices were the norm for inhalation toxicology studies. TABLE 10-3 Incidence of Cancers in Female Mice Exposed 6 Months to DMNA-Contaminated UDMH Lesion/Exposure Group Control 0.05 ppm 0.5 ppm 5.0 ppm 0.024a 0.047a Hemangiosarcomas 0.007 0.008 (5/701) (9/374) (3/368) (17/360) 0.029a 0.017a Thyroid carcinomas 0.004 0.003 (2/551) (1/311) (8/278) (5/286) 0.010a 0.022a Kupffer cell sarcomas 0.001 0.000 (1/701) (4/374) (0/368) (8/360) a Incidence statistically different from control group at P = 0.01. Source: Haun et al. 1984

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0.56 90 d, continuous Monkey, M, rhesus One fatality at day 41; degenerative Back et al. 1963 lesions in liver; heart dilation; calcium deposits in myocardium of 2; necrosis of muscle fibers in fatality; calcification of adrenal in 1; mite infestation of lung in 6 5 8.5 wk, daily Hamster, N/A NOAEL MacEwen and Vernot Golden Syrian 1970 6 h/d, 5 d/wk, 6 mo Mice, N/A Increase in tumor response, Haun et al. 1979 5a hemangiosarcomas, Kupffer cell sarcomas 5a 6 h/d, 5 d/wk, 6 mo Rat, N/A Increase in squamous cell carcinomas, Haun et al. 1979 lung tumors, and hepatocellular carcinomas 0.5a 6 h/d, 5 d/wk, 6 mo Rat, N/A Islet cell adenomas of pancreas, slight Haun et al. 1979 increase in fibrous histiocytomas 5 6 h/d, 5 d/wk, 6 mo Dog, M & F, beagle 1 fatality 15 mo postexposure, neoplastic Haun et al. 1984 lesions in heart & lung; reticulum cell sarcoma; increased SGPT levels in all dogs; BSP levels high 0.5 6 h/d, 5 d/wk, 6 mo Dog, M & F, beagle No toxic effects Haun et al. 1984 0.05 6 h/d, 5 d/wk, 6 mo Dog, M & F, beagle No toxic effects Haun et al. 1984 5 6 h/d, 5 d/wk, 6 mo Mice, F, C57BL Increase in tumor response, Haun et al. 1984 hemangiosarcomas, Kupffer cell sarcomas, thyroid sarcomas; increased uterine cysts 0.5 6 h/d, 5 d/wk, 6 mo Mice, F, C57BL Increased uterine cysts Haun et al. 1984 0.05 6 h/d, 5 d/wk, 6 mo Mice, F, C57BL Increased uterine cysts Haun et al. 1984 (Continued) 179

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TABLE 10-4 Continued 180 Concentration, ppm Exposure Duration Species, Sex, Strain Effects Reference 5 6 h/d, 5 d/wk, 6 mo Rat, M, CDF Bronchiolar adenomas; pituitary Haun et al. 1984 chromophobe adenomas 0.5 6 h/d, 5 d/wk, 6 mo Rat, M, CDF Pancreatic islet cell adenomas; pituitary Haun et al. 1984 chromophobe adenomas 0.05 6 h/d, 5 d/wk, 6 mo Rat, M, CDF Hepatocellular adenomas; pituitary Haun et al. 1984 chromophobe adenomas 5 6 h/d, 5 d/wk, 6 mo Hamster, M, No toxic effects Haun et al. 1984 Golden Syrian 0.5 6 h/d, 5 d/wk, 6 mo Hamster, M, No toxic effects Haun et al. 1984 Golden Syrian 0.05 6 h/d, 5 d/wk, 6 mo Hamster, M, No toxic effects Haun et al. 1984 Golden Syrian a UDMH contained 0.12% of the known carcinogen DMNA. Abbreviations: F, female; M, male; N/A, not applicable.

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181 Dimethylhydrazine TABLE 10-5 Exposure Limits Set by Other Organizations Organization, Standard Exposure Limit Reference ACGIH HSDB 2005 TLV-TWA, skin 0.01 ppm OSHA HSDB 2005 PEL, skin 0.5 ppm NIOSH HSDB 2005 REL, 2-h ceiling 0.06 ppm IDLH 50 ppm NRC NRC 2000 AEGL-2, 1 h 3 ppm AEGL-2, 8 h 0.38 ppm AEGL-3, 1 h 11 ppm AEGL-3, 8 h 1.4 ppm ATSDR ATSDR 2007 MRL 0.0002 ppm Abbreviations: ACGIH, American Conference of Governmental Industrial Hygienists; AEGL-2, acute exposure guideline level (disabling); AEGL-3, acute exposure guideline level (life-threatening); Agency for Toxic Substances & Diseases Registry minimum risk level (inhalation); ATSDR MRL; IDLH, immediately dangerous to life or health concen- tration; NIOSH, National Institute of Occupational Safety and Health; OSHA, Occupa- tional Safety and Health Administration; PEL, permissible exposure limit; REL, recom- mended exposure limit; TLV, threshold limit value; TWA, time-weighted average. TABLE 10-6 Spacecraft Maximum Allowable Concentrations Concentration, mg/m3 Duration Concentration, ppm Target Toxicity 1h 3 7.5 CNS effects 24 h 0.12 0.3 CNS effects 7d 0.03 0.075 Anemia 30 d 0.017 0.0425 Anemia 180 d 0.003 0.0075 Hepatotoxicity To set SMACs for UDMH, ACs were calculated for the induction of each adverse effect (CNS effects, anemia, or hepatotoxicity) using the guidelines es- tablished by the NRC (1992). Five key inhalation studies were identified. These studies show fairly good consistency over a wide range of exposure times and species. For every putative astronaut exposure time (1 h, 24 h, 7 d, 30 d, and 180 d), the lowest AC was selected as the SMAC value (Table 10-7).

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TABLE 10-7 End Point and Acceptable Concentrations 182 Uncertainty Factor Acceptable Concentration, ppm Selected End Species, Reference Space- End Point Point Data Test Group Size NOAEL Time Species flight 1h 24 h 7d 30 d 180 d Lethality Dogs, n = 3 30 1 10 1 3 -- -- -- -- 860 ppm = LL LC50 1 h exposure (Weeks et al. 1963) CNS 5 ppm NOAEL Dogs, n = 3 1 6 10 1 -- 0.12 -- -- -- 6 h/d, (Rinehart et al. 5 d/wk, 6 wk 1960) Anemia 5 ppm LOAEL Dogs, n = 3 5 1 10 3 -- -- 0.03 -- -- 6 h/d, (Rinehart et al. 5 d/wk, 6 wk 1960) Anemia 5 ppm LOAEL Dogs, n = 3 10 1 10 3 -- -- -- 0.017 -- 6 h/d, 5 d/wk, 24 (Rinehart et al. wk 1960) Hepatotoxicity 5 ppm LOAEL Dogs, n = 8 10 1 10 1 -- -- -- 0.05 -- 6 h/d, 5 d/wk, 26 (Haun et al. 1984) wk Hepatotoxicity 0.5 ppm NOAEL Dogs, n = 8 1 6 10 1 -- -- -- -- 0.01 6 h/d, 5 d/wk, 26 (Haun et al. 1984) wk Anemia 5 ppm LOAEL Dogs, n = 3 10 6 10 3 -- -- -- -- 0.003 6 h/d, 5 d/wk, 24 (Rinehart et al. wk 1960) SMAC 3 0.12 0.03 0.017 0.003 Abbreviation: --, not calculated.

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183 Dimethylhydrazine 1-h AC A 1-h AC can be estimated from the inhalation study by Weeks et al. (1963). They exposed rats (n = 10 rats per group) and mongrel dogs (n = 3 dogs per group) to UDMH vapor in a dynamic flow gassing chamber for 1 h or less. Dogs were more sensitive than rats. From another study, it is clear that, at least for 4-h exposures, dogs are more sensitive than mice (Jacobsen et al. 1955); therefore, we use dog data even though the number of test animals was small. From the Weeks et al. study, the lower limit (LL) of the 95% confidence interval of the 1-h LC50 value in dogs was found to be 860 ppm. One can roughly esti- mate a safe concentration as follows: AC(lethality) = 860 ppm (LL of LC50) ×1/3 (to LOAEL) × 1/10 (LOAEL to NOAEL) × 1/10 (species) = 3 ppm where the factor 1/3 is used for the LC50 to LOAEL, which is reasonable to ap- ply based on Table 10-5 of Weeks et al. (1963) showing that a 1-h exposure under added stress to dogs yields an LC50 of 300 to 350 ppm and a LOAEL of 80 to 120 ppm; a default factor of 1/10 is applied for LOAEL to no-observed- adverse-effect level (NOAEL). An additional default species extrapolation fac- tor of 1/10 is applied. Benchmark estimation was not attempted because of the small number of animals in each group. Alternatively, one can estimate an AC for CNS effects from the observa- tion of Weeks et al. (1963) in nine stressed dogs exposed for 1 h to a concentra- tion of 80 to 120 ppm. One of the nine dogs showed slight tremors from which it recovered in 1 h. The calculation is as follows: AC (CNS effects) = 100 ppm (average LOAEL) × 1/3 (LOAEL to NOAEL) × 1/10 (species) = 3 ppm The reduced factor for extrapolation for a LOAEL to a NOAEL was due to the fact that the dogs were already stressed before their exposure. Additionally, we note that the odor threshold may be exceeded by concen- trations in this range (3 ppm); therefore, an odor may be experienced or noted by crewmembers exposed to 3 ppm. 24-h AC A 24-h AC can be estimated from the inhalation study by Rinehart et al. (1960) This peer-reviewed study exposed three dogs to UDMH at 5 and 25 ppm for 6 h/d, 5 d/wk for 26 wk. The authors observed some hemolytic anemia, slight bilirubinemia, and some lethargy, but the effects were very minimal. The minimal anemia effects at this level would not be expected to enhance space- flight anemia and are not a concern for the 24-h short-term contingency SMAC.

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184 SMACs for Selected Airborne Contaminants None of the CNS effects noted at the high dose (25 ppm) was observed at the low dose (5 ppm). This is considered a NOAEL for CNS effects. The AC can be calculated as follows: AC (CNS effects) = 5 ppm (NOAEL) × 1/10 (species) = 0.5 ppm Assuming exposure is not cumulative = 0.5 ppm × 6 h/24 h = 0.12 ppm. 7-d AC For the longer-term ACs we also used the studies by Rinehart et al. (1960). They exposed dogs, rats, and mice 6 h/d, 5 d/wk to UDMH concentra- tions ranging from 5 to 140 ppm, and for times ranging from 6 to 26 wk. In three dogs exposed to UDMH at 5 ppm for 26 wk, they observed weight loss, mild anemia, splenic hemosiderosis, and an increase in serum bilirubin. However, 6 wk into the study there were minimal, if any, changes to the blood and there was no evidence of hepatotoxicity (see Table III of the paper). The 7-d AC to protect against anemia was estimated as follows: AC(anemia) = 5 ppm (LOAEL) × 1/10 (species) × 1/3 (spflt anemia) × 1/3 (LOAEL to NOAEL) = 0.05 ppm where the factors were 10 for species extrapolation, 3 for anemia of spaceflight, and 3 to extrapolate to a true NOAEL because the degree of anemia was mar- ginal at most. By marginal, we mean that at the 6-wk point the RBC count had dropped from 7.2 to 7.0 × 106/mm3, the hemoglobin was unchanged, and the hematocrit decreased from 53% to 48%. 30-d AC The 30-d AC for hematologic effects can be estimated from the data on dogs used for the 7-d AC; however, we turn to the data on the dogs after 24 wk of exposure. At this time, the RBC count had dropped from 7.2 to 6.0 × 106/mm3, the hemoglobin dropped from 15.4 to 11.4 gram %, and the hematocrit decreased from 53% to 43%. We take 5 ppm for 24 wk of exposure for 6 h/d 5 d/wk (30 d cumulative) to be a LOAEL. Using the same calculation as in the equation above, with a LOAEL to NOAEL factor of 10 instead of 3, gives the following: AC(anemia) = 5 ppm (LOAEL)× 1/10 (species)× 1/3 (spflt anemia) × 1/10 (LOAEL to NOAEL) = 0.017 ppm

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185 Dimethylhydrazine Note that 24 wk of intermittent exposure at a rate of 30 h/wk is the same cumulative time as 30 d of continuous exposure for 24 h/d. This is not an ideal approach to converting intermittent exposures to continuous ones, but it is com- monly used. The 30-d AC for hepatotoxicity can be estimated from the study of Haun et al. (1984). They found significant transitory hepatotoxic effects of inhaled UDMH at 5 ppm for 6 h/d, 5 d/wk for 6 months in dogs, mice, rats, and ham- sters. The dogs showed elevated serum glutamic pyruvic transaminase (SGPT) by week 4 of exposure. At 6 wk, the average SGPT value was 3 times the level in the control group. Through the remaining 20 wk of exposure, SGPT values stabilized at 3 to 4 times that of the control group. Recovery was noted to be 50% at 2 wk postexposure; however, there was no further reduction at 4, 8, and 11 wk postexposure. Sampling at weeks 27 and 47 showed a return to normal values. Bromsulphalein (BSP) concentrations were used to measure for liver function. BSP concentrations in blood after a 10-mg/kg injection showed sig- nificant retention at exposure termination 4 and 8 wk postexposure. The BSP measurements for liver function returned to normal at 11 wk postexposure. With UDMH at 0.5 ppm, Haun et al. (1984) found no observable adverse effects. The AC for hepatotoxicity was calculated from the NOAEL of 0.5 ppm using a factor of 10 for species extrapolation: AC (hepatotoxicity) = 0.5 ppm (LOAEL) × 1/10 (species) = 0.05 ppm 180-d AC The 180-d ACs for anemia and hepatotoxicity were estimated by multiply- ing the 30-d ACs by the time default extrapolation factor of 30 d/180 d which is Haber’s rule. Thus, the ACs were as follows: AC(anemia) = 0.017 ppm (30-d AC, anemia) × 30 d/180 d (time extrapolation) = 0.003 ppm AC(hepatotoxicity) = 0.05 ppm (30-d AC, hepatotoxicity) × 30 d/180 d (time extrapolation) = 0.01 ppm COMPARISON WITH OTHER LIMITS The SMACs compare reasonably well with other exposure guidelines (see Table 10-5) where comparisons are possible. The 1-h SMAC of 3 ppm matches the NRC acute exposure guideline level “above which it is predicted that the general population, including susceptible individuals, could experience irre- versible or other serious, long-lasting adverse health effects or an impaired abil- ity to escape” (AEGL-2) (NRC 2000). The 24-h SMAC of 0.12 ppm is almost 3- fold lower than the NRC AEGL-2 for 8 h of exposure at 0.38 ppm. The AEGL-2

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186 SMACs for Selected Airborne Contaminants was derived from the data of Weeks et al. (1963) starting with the exposure of 360 ppm for 15 min, which caused reversible effects (behavioral changes and mild muscular fasciculations) in dogs. This was divided by a factor of 30 (3 for interspecies variability and 10 for intraspecies variability) to give a 15-min AEGL-2 of 12 ppm. Using Haber’s rule (Cn × t = k) where n = 1, the AEGL-2 for a 1-h exposure was estimated at 3 ppm; likewise, the AEGL-2 for 8 h was estimated at 0.38 ppm. From the Weeks et al. (1963) study, we elected to start with 100 ppm, a mild lowest-observed-adverse-effect level (LOAEL) for expo- sure to dogs that were stressed before exposure; one of nine dogs displayed slight tremors and experienced full recovery within 1 h, which calculates to a 1- h AC of 3 ppm. The long-term SMACs of 0.017 and 0.003 ppm for 30 and 180 d of con- tinuous exposure compare favorably with the threshold limit value of 0.010 ppm set by the American Conference of Governmental Industrial Hygienists. The 1-h SMAC of 3 ppm is substantially higher than the National Institute of Occupa- tional Safety and Health (NIOSH) 2-h ceiling value of 0.06 ppm; however, the Occupational Safety and Health Administration permissible exposure limit of 0.5 ppm for long-term worker protection seems inconsistent with the NIOSH value. The SMACs are somewhere in the middle of the array of values set by other organizations. RECOMMENDATIONS We are confident that the values used to set ACs for astronaut crew health are moderately sound, but current peer-reviewed studies are needed to update inhalation exposure data on UDMH. Most descriptive toxicity studies were con- ducted from the late 1950s to the 1970s. Several of the published reports were not peer reviewed. A limited number of inhalation studies were identified in the 1980s. An updated study on the carcinogenic effects of UDMH inhalation and dermal exposure would aid in determining the potential increased risk of car- cinogenesis. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 1991. Documen- tation of the Threshold Limit Values and Biological Exposure Indices, 6th Ed. American Conference of Governmental Industrial Hygienists, Cincinnati, OH. Albano, E., A. Tomasi, L. Goria-Gatti, and A. Iannone. 1989. Free radical activation of monomethyl and dimethyl hydrazines in isolated hepatocytes and liver micro- somes. Free Radic. Biol. Med. 6(1):3-8. Amoore, J.E., and E. Hautala. 1983. Odor as an aid to chemical safety: Odor thresholds compared with threshold limit values and volatiles for 214 industrial chemicals in air and water dilution. J. Appl. Toxicol. 3(6):272-290.

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