B5

Methylhydrazine

Hector D. Garcia, Ph.D.

Johnson Space Center Toxicology Group

Medical Operations Branch

Houston, Texas

PHYSICAL AND CHEMICAL PROPERTIES

Methylhydrazine (MH) is a clear, colorless, hygroscopic, flammable liquid with an ammonia-like odor (ACGIH 1991). It is a strong reducing agent; its vapor is extremely reactive and undergoes rapid autoxidation in air (NAS 1974).

Formula:

CH3HN-NH2

CAS no.:

60-34-4

RTECS no.:

MV5600000

Synonyms:

Hydrazomethane, 1-Methylhydrazine, Monomethylhydrazine.

Molecular weight:

46.09

Boiling point:

87.8°C

Melting point:

-20.9°C

Liquid density at 25°C:

0.874

Vapor density:

1.6

Vapor pressure:

49.63 mmHg at 25°C (36 torr at 20°C) Slightly soluble in water; soluble in

Solubility:

alcohol, ether and hydrocarbons 1-3 ppm (Jacobson et al. 1955)

Odor threshold:

 

Conversion factors

1 ppm = 1.88 mg/m3 and

at 25°C, 1 atm:

1 mg/m3 = 0.53 ppm



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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 B5 Methylhydrazine Hector D. Garcia, Ph.D. Johnson Space Center Toxicology Group Medical Operations Branch Houston, Texas PHYSICAL AND CHEMICAL PROPERTIES Methylhydrazine (MH) is a clear, colorless, hygroscopic, flammable liquid with an ammonia-like odor (ACGIH 1991). It is a strong reducing agent; its vapor is extremely reactive and undergoes rapid autoxidation in air (NAS 1974). Formula: CH3HN-NH2 CAS no.: 60-34-4 RTECS no.: MV5600000 Synonyms: Hydrazomethane, 1-Methylhydrazine, Monomethylhydrazine. Molecular weight: 46.09 Boiling point: 87.8°C Melting point: -20.9°C Liquid density at 25°C: 0.874 Vapor density: 1.6 Vapor pressure: 49.63 mmHg at 25°C (36 torr at 20°C) Slightly soluble in water; soluble in Solubility: alcohol, ether and hydrocarbons 1-3 ppm (Jacobson et al. 1955) Odor threshold:   Conversion factors 1 ppm = 1.88 mg/m3 and at 25°C, 1 atm: 1 mg/m3 = 0.53 ppm

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 OCCURRENCE AND USE MH is used as a solvent, as an organic intermediate, and as a rocket propellant, either singly, or mixed with other hydrazines. It is extremely flammable, but if kept out of contact with air, it is stable up to its boiling point. No MH should be present in the spacecraft cabin atmosphere unless it is introduced as an undetected contaminant on a crew member's spacesuit upon return from extravehicular activity. The amount that may be introduced in that manner is difficult to predict but, given the procedural safeguards currently in use, the amount should be very small. An accident possibly involving entry of MH or nitrogen tetroxide or both into a spacecraft occurred during the descent of an Apollo capsule in 1975 and lasted 8-10 min until the hatch was opened. The crew experienced mild-to-moderate, but spontaneously reversible, pulmonary function deficits (DeJournette 1977). TOXICOKINETICS Absorption No data were found on the toxicokinetics of absorption of inhaled MH vapor by humans or animals. Liquid MH applied to the skin of anesthetized dogs was rapidly absorbed into the bloodstream and could be detected in plasma of blood samples from the femoral artery within 30 sec after application to the shaved chest (Smith and Clark 1969). The plasma level peaked around 60 min (for doses <3 mmol/kg) and decreased slowly thereafter. As the dose increased, the time required to reach peak blood concentrations increased and the rate of subsequent decline decreased until, with doses of 4-6 mmol/kg, no peak was reached in the 6-h observation period. Concentrations of methemoglobin peaked at about 2 h after application of MH to the skin. Distribution No data were found on the distribution of inhaled MH vapor by humans or animals. After intraperitoneal (ip) injections of 22 mg/kg of 14C-MH in mice, 15 mg/kg in rats, and 10 mg/kg in monkeys and dogs, the highest concentrations of 14C were found in liver, kidney, bladder, pancreas, and blood serum (Pinkerton et al. 1967).

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 Metabolism MH is metabolized by rat liver to CO2 and to reactive metabolites, including formaldehyde, which bind covalently to nucleic acids and proteins (Hawks and Magee 1974; Diaz Gomez and Castro 1986). In mice, rats, monkeys and dogs injected with 14C-MH, approximately 50% of the total 14C excretion, at all experimental times, appeared to be unchanged MH (Pinkerton et al. 1967). MH vapor is extremely reactive and will auto-oxidize on exposure to air to produce a variety of products, including primarily molecular nitrogen and methane, with traces of carbon monoxide, methanol, acetaldehyde, and various carbon or nitrogen heterocyclic compounds (Vernot et al. 1967; Haun et al. 1969). This oxidation can be catalyzed by a variety of materials including some plastics and formulations of stainless steel (Haun et al. 1969). Excretion The mouse, rat, and monkey excreted twice as much as the dog in the first 2 h after ip injection, but all four species excreted 25-40% of the total dose by 24 h after injection (Pinkerton et al. 1967). TOXICITY SUMMARY MH vapor is extremely toxic in both acute and chronic exposures. Acute exposures can produce nose and eye irritation, anemia, bilirubinemia, methemoglobinemia, vomiting, neurological effects, damage to lungs, liver, kidney, and brain, convulsions, and death. Chronic exposures can produce anemia, methemoglobinemia, liver, spleen, and kidney damage, and cancer. Acute and Short-Term Exposures Noninhalation Exposures Of the methyl-substituted hydrazines, the most acutely toxic is MH (Jacobson et al. 1955), for which the LC50 (lethal concentration for 50% of the animals) by intravenous (iv) injection was reported to be 0.26 mmole/kg for male mongrel dogs observed for a 10-d period (Witkin 1956). Both clinically

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 and pathologically, the dog was much more susceptible than mice, rats, or monkeys to the toxic effects of ip injected MH, especially to severe kidney damage (Pinkerton et al. 1967). The main targets of MH toxicity are the blood (hemolytic anemia with decreased hemoglobin, red cell count, and hematocrit; reticulocytosis; methemoglobinemia; and Heinz body formation) and central nervous system (hyperactivity, tremors, and severe clonic-tonic convulsions), with kidney toxicity possibly associated with hemolytic anemia. The convulsive, toxic, and lethal effects of MH can be prevented by administration of large doses of the vitamin pyridoxine hydrochloride before or after MH (Toth and Erickson 1977). MH administered iv to dogs acts as a weak diuretic by an unknown mechanism (Coe et al. 1967). Even in anesthetized dogs, MH liquid applied to the skin caused convulsions at plasma concentrations of at least 10 mg/mL, with the time of onset of convulsions varying generally with the dose applied and the plasma concentration of MH (Smith and Clark 1969). Acute Inhalation Toxicity MacEwen et al. (1970) exposed human subjects to MH at 90 ppm for 10 min and recorded the subjective irritancy and measurements of clinical chemistry and hematology. The subjects were given pretest physicals, which included nasal and neurological examinations, and were monitored for 60 d post-exposure. To establish a relative irritancy scale, each subject was also exposed to two concentrations of ammonia (30 ppm and 50 ppm), in random order. No changes were seen in any of 14 clinical chemistry tests despite subjective reports of a moderate to strong odor and slight moistening of the eyes and tickling of the nose. No mention was made of any nasal lesions resulting from the MH exposure. Heinz bodies appeared in 3% to 5% of red blood cells (RBCs) by the seventh-day post-exposure, began to decrease after 2 w, and were not detectable 60 d post-exposure. Heinz bodies were not accompanied by any signs of anemia or reticulocytosis. The report did not give any details regarding the method used to establish and check the accuracy of the measurement of the MH concentrations in the exposure chambers except to state that ''The [MH] concentrations, which were continuously monitored, were established and stabilized in the chamber and then the subject inserted his head for 10 min and his sensations were recorded." Subsequent papers from that laboratory showed that the investigators had an appreciation for the difficulty of accurately determining MH concentrations due to humidity and reaction with various materials used in the exposure chambers. Nevertheless, it was not stated whether all of the materials used for human exposure conditions (e.g., the plastic sheet and rubber diaphragm through which the subjects inserted their

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 heads into the Rochester chambers, and the aircraft radio headset worn by the subjects during exposures) had been tested for their compatibility with MH and their effect on MH concentrations. It seems unlikely, however, that these factors would be sufficient to account for the differences between the MacEwen study findings and the subsequent findings of a NASA odor panel described below. In 1975, NASA conducted an odor panel test at NASA's White Sands Testing Facility. In this study (Hoffman and Schluter 1976), designed to determine if personnel were capable of detecting the odor of MH at the current Theshold Limit Value of 0.2 ppm, 42 NASA and Lockheed Electronics employees sniffed a single 30-cc airborne bolus of MH at 0.2 ppm injected into a face mask. Approximately two-thirds of the subjects were able to detect the odor. The major complaint was a feeling of irritation comparable to inhaling something strong. Two hours after the odor test, the subjects were medically examined for any signs of injury of the nose or throat. Most employees checked showed an increased appearance of dryness, and 75% of the subjects complained of a tingling, irritating sensation of their noses after the test. Twelve of the 42 showed marked injury with clear blisters or cavitation of the mucosa, 4 of those showed signs of slight bleeding, and 3 showed white patches and had sinus congestion. There was no correlation between those signs and symptoms and the subjects' previous or recent routine exposure to MH, nor to the ability to detect the odor of MH in this study. In evaluating the disparity between the results from the NASA study and those of the MacEwen study, the level of detail reported was a major consideration. The NASA report included a detailed description of the preparation and dilution of the MH samples and the methods used to calculate nominal and determine analytical concentrations, whereas the MacEwen report did not provide that information. A careful examination of the NASA methods revealed no problems or errors that would allow one to disregard the study or consider the results suspect. Haun et al. (1969) studied the acute inhalation toxicity of MH in rats, mice, beagles, squirrel monkeys, and rhesus monkeys at a range of MH concentrations from 25 ppm to about 500 ppm. Squirrel monkeys were the most sensitive and rats the least sensitive to the lethal effects of MH. The cause of death after exposure to lethal concentrations of MH was attributed to CNS damage, which was commonly accompanied by pulmonary, renal, and hepatic congestion and hemorrhage, and, in dogs, bloodless spleens. The most common and persistent pathological finding, however, was renal damage, which ranged from mild swelling of the tubular epithelium to vacuolization and coagulative necrosis of the epithelial cells. As the MH concentration was increased for each series of experiments, the number and degree of toxic signs in mice and rats

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 increased from mild to severe, in the following sequence: (1) irritation of nose and eyes; (2) diarrhea, abnormally frequent urination, and more rapid and labored breathing; (3) increased alertness, piloerection, hyperactivity, and interrupted by periods of inactivity characterized by rigid posture and exophthalmos; and (4) tonoclonic convulsions and tremors, mucous discharge from mouth and nose and frequent biting. The last two categories of toxic signs occurred either during exposure or within a few hours post-exposure. The rodents that developed all of the toxic signs except convulsions survived, whereas those that convulsed died during or following exposure. The mice that succumbed to MH usually died immediately after a single convulsive seizure. The general pattern of signs observed in dogs and monkeys was similar to that seen in rodents. However, some additional signs were noted in the larger animals. In the general order of occurrence during and after exposure, the signs were as follows: (1) eye irritation; (2) salivation and licking; (3) emesis (occurred earliest in dogs, but was more severe and reoccurred frequently in monkeys); (4) diarrhea, frequent urination, pupil dilation, and ataxia in dogs; (5) hyperactivity, tremors and cyanosis (dogs only), and convulsions, which did not inevitably lead to death; and (6) prostration and apparent unconsciousness. Convulsions were produced in rhesus and squirrel monkeys as late as 10 and 24 h after exposure, respectively, and in squirrel monkeys at all doses, but the frequency of episodes was greatest at the highest MH doses tested. Blood was observed in the urine and feces of two dogs, one exposed to MH at 92 ppm for 60 min, the other to MH at 180 ppm for 30 min. RBC hemolysis was induced in dogs and monkeys, with moderate to severe anemia in all surviving dogs and mild to moderate hemolytic effects in all surviving rhesus monkeys. Some evidence for development of tolerance to repeated exposures was seen in rhesus monkeys, but the evidence is inconclusive. A summary of the LC50 values for MH are presented in Table 5-1. TABLE 5-1 LC50 Values for MH Species 1-h Exposure, ppm 4-h Exposure, ppm Squirrel monkeys 82 — Dogs (beagles) 96 — Mice 122 56 Rhesus monkeys 162 — Rats 244 74 Hamsters — 143

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 Subchronic and Chronic Exposures In a study at Wright-Patterson Air Force Base, dogs, monkeys, rats and mice were exposed 6 h/d, 5 d/w for 6 mo to MH vapors at 0, 2, and 5 ppm (Haun 1970). Signs of toxicity observed at 5 ppm included photophobia and prominent nictitating membranes in dogs and rough, yellowed fur coats, lethargy, increased mortality, and enlarged spleens in mice. No signs of ocular effects were seen in dogs at 2 ppm. Rats showed dose related depressed body weight gains and splenic hemosiderosis. Dogs had black livers, dose related decreased hematocrit, hemoglobin, and RBC counts and showed Heinz body formation and abnormal bone marrows. Monkeys had similar, but less severe dose-related hematologic effects. In another study at Wright-Patterson Air Force Base, dogs, hamsters, rats, and mice were exposed 6 h/d, 5 d/w for 1 y to MH vapors at 0, 0.02, 0.2, 2.0, and 5.0 ppm (Kroe 1971). Non-neoplastic lesions observed at statistically significant frequencies included: at 0.02 ppm, nasal inflammation and plasmacytosis of the mandibular lymph node in mice; at 0.2 ppm, liver cysts in mice and hamsters, kidney cysts and angiectasis in mice, and rhinitis and submucosal cysts of the nares in hamsters; at 2 ppm, nasal polyps, kidney interstitial fibrosis and lung atelectasis in hamsters, and, in mice, bile duct hyperplasia, hepatocyte pleomorphism, gall bladder crystals, and kidney hydronephrosis. In further studies at Wright-Patterson Air Force Base, Darmer and MacEwen (1973) reported the results of a 90-d continuous exposure of dogs, monkeys, and rats to MH at 0.04 and 0.10 ppm. No significant hematologic or growth rate effects were reported at 0.04 ppm, but at 0.1 ppm, rat growth rate was depressed and, in dogs, increased osmotic fragility of RBCs and increases in serum phosphorus and alkaline phosphatase were noted. No effects were seen in monkeys at either tested dose. Another set of experiments showed that a single continuous 24-h exposure at 1 ppm was a no-observed-effect level (NOEL) and 2 ppm was a lowest-observed-effect level (LOEL) for hemolysis of RBCs (involving methemoglobin formation and Heinz body production) in dogs, monkeys, and rats monitored for 30 d post-exposure. Carcinogenicity In an Air Force study not subjected to peer review, chronic inhalation of MH at concentrations of 0, 0.02, 0.2, 2, and 5 ppm by rats, mice, and hamsters, and up to 2 ppm by beagles for 6 h/d, 5 d/w for 1 y produced significant increases in lung tumors, nasal adenomas, nasal polyps, nasal osteomas, hemangiomas,

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 and liver adenomas and carcinomas in female mice at 2 ppm compared with controls (Kinkead et al. 1985). Also, a significant increase in benign nasal tumors was observed in hamsters at 2 and 5 ppm compared with controls. Those effects follow the administration of toxic doses that are irritating to the sensitive nasal epithelium of the rodent over most of its lifetime. The main target organs are the liver, lungs, and the nasal epithelium (following inhalation). Rats and beagles showed no exposure-related tumors. CDF1 mice given eight weekly doses of MH at 0.46 mg by gavage or 0.23 mg by ip injection, one dose per week, and observed for 20-24 w had no increase in the incidence of tumors compared with controls (Kelly et al. 1969). Genotoxicity MH does not appear to be strongly genotoxic (Brusick and Matheson 1976; Rogers and Back 1981; Rogan et al. 1982). It is not mutagenic to cultured mouse cells (Brusick and Matheson 1976; Rogers and Back 1981), nor does it cause unscheduled DNA synthesis in cultured human cells (Brusick and Matheson 1976), although it is mutagenic in the Ames bacterial assay if performed in suspension rather than in plates (Brusick and Matheson 1976; Rogan et al. 1982). Reproductive Toxicity Aqueous MH solutions injected ip daily for 5 d at 0.26, 0.86, or 2.6 mg/kg in 7- to 8-w-old male ICR mice and 0.215, 0.72, and 2.15 mg/kg in 10- to 12-w-old male Sprague-Dawley rats 2 d before mating with virgin females did not induce significant dominant lethality in either rats or mice (Brusick and Matheson 1976). Developmental Toxicity MH administered ip on d 6-15 of pregnancy was not selectively embryotoxic or teratogenic in Fischer 344 rats at doses that induced a dose-related decrease in maternal weight gain. (Keller et al. 1984). Interaction with Other Chemicals MH is believed to react with pyridoxal in rodent brain, producing the convulsant agent pyridoxal methylhydrazone and inhibiting the activity of pyridoxal

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 dependent enzymes such as DOPA decarboxylase and glutamic acid decarboxylase (Furst et al. 1969). Those enzymes are essential for the formation and metabolism of a number of brain biogenic amines like seritonin, norepinephrine, dopamine and GABA (Furst et al. 1969). The development of convulsions after exposure to MH can be reduced or prevented by ip administration of large doses of vitamin B6 (pyridoxine hydrochloride) (Toth and Erickson 1977). A summary of the toxicity data on MH is presented in Table 5-2.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 TABLE 5-2 Inhalation Toxicity Summary Concentration, ppm Exposure Duration Species Effects Reference 0.2 30 cc, 1 sniff Human Nasal injury Hoffman et al. 1976 90 10 min Human Heinz bodies MacEwen et al. 1970 0.02 6 h/d, 5 d/w, 1 y Mouse Nasal inflammation and plasmacytosis of the mandibular lymph node Kroe 1971 0.04 90 d, continuous Rat, dog, monkey NOAEL for all signs Darmer and MacEwen 1973 0.1 90 d, continuous Dog Hemolytic effects; liver pathology Darmer and MacEwen 1973 0.1 90 d, continuous Monkey NOAEL Darmer and MacEwen 1973 0.1 90 d, continuous Rat Depressed growth rate Darmer and MacEwen 1973 0.2 6 h/d, 5 d/w, 1 y Mouse Kidney cysts; angiectasis; liver cysts Kroe 1971 0.2 6 h/d, 5 d/w, 1 y Hamster Submucosal cysts in nares; liver cysts Kroe 1971 1 24 h Dog, monkey, rat NOEL for methemoglobin and Heinz body formation Darmer and MacEwen 1973 2 24 h Dog, monkey, rat LOEL for methemoglobin and Heinz body formation Darmer and MacEwen 1973 2 6 h/d, 5 d/w, 6 mo Dog NOAEL for ocular effects Haun 1970 2 6 h/d, 5 d/w, 1 y Mouse Lung tumors, hemangiomas Kinkead et al. 1985 2 6 h/d, 5 d/w, 1 y Mouse Bile duct hyperplasia, hydronephrosis; hepatocyte pleomorphism; gall bladder crystals Kroe 1971 2 6 h/d, 5 d/w, 1 y Hamster Nasal polyps, kidney interstitial fibrosis; lung atelectasis Kroe 1971

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 Concentration, ppm Exposure Duration Species Effects Reference 5 6 h/d, 5 d/w, 6 mo Dog Black livers, photophobia; prominent nictitating membranes; dose-related decreased hematocrit, hemoglobin, and RBC counts; Heinz bodies; abnormal bone marrows Haun 1970 5 6 h/d, 5 d/w, 6 mo Monkey Decreased hematocrit, hemoglobin, and RBC counts; Heinz bodies; abnormal bone marrows (all less severe than for dogs) Haun 1970 5 6 h/d, 5 d/w, 6 mo Mouse Rough, yellowed fur coats; lethargy; increased mortality; enlarged spleens Haun 1970 5 6 h/d, 5 d/w, 6 mo Rat Splenic hemosiderosis; dose-related depressed body weight gains Haun 1970 85 1 h Monkey Death in 2 of 4 exposed Haun et al. 1969 130 30 min Monkey No deaths in 3 exposed Haun et al. 1969

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 RATIONALE FOR ACCEPTABLE CONCENTRATIONS Table 5-3 presents exposure limits for MH set by other organizations and Table 5-4 presents the SMACs established by NASA. MH can induce a variety of toxic effects. The initial overt signs of acute MH toxicity in mice, rats, dogs, and monkeys include irritation of nose and eyes and methemoglobiniemia (seen as hemolytic anemia and Heinz bodies in humans, monkeys and dogs and black or mottled liver in dogs). In addition, chronic exposure to low concentrations of MH has been shown to induce methemoglobiniemia in dogs and cancer in mice and hamsters. Exposure to higher doses produces salivation, emesis, diarrhea, hyperactivity, tremors and severe tonicclonic convulsions, which precede death. To set SMAC values for MH, acceptable concentrations (ACs) were calculated for the induction of each adverse TABLE 5-3 Exposure Limits Set by Other Organizations Organization Exposure Limit, ppm Reference ACGIH's TLV-TWA 0.01 (skin) ACGIH 1998 NIOSH's 2-h STEL 0.04 (ceiling) (lowest detectable level for 2 h air sample) ACGIH 1991 OSHA's PEL 0.2 (ceiling) (skin) ACGIH 1991 NRC's 1-h SPEGL 0.24 NRC 1985 NRC's 24-h SPEGL 0.01 NRC 1985 TLV, Theshold Limit Value; TWA, time-weighted average; STEL, short-term exposure limit; PEL, permissible exposure limit; SPEGL, short-term public emergency guidance level. TABLE 5-4 Spacecraft Maximum Allowable Concentrations Duration Concentration, ppm Concentration, mg/m3 Target Toxicity 1 h 0.002 0.004 Nasal injury 24 h 0.002 0.004 Nasal injury 7 da 0.002 0.004 Nasal injury 30 d 0.002 0.004 Nasal injury 180 d 0.002 0.004 Nasal injury a Previous 7-d SMAC = 0.04 ppm (0.08 mg/m3).

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 effect (nasal irritation and injury, nasal tumors, and methemoglobinemia) using the guidelines established by the NRC (1992). No ACs were calculated for effects seen only at high doses, because such effects would be prevented by protecting against the effects seen at lower doses. For each exposure time (1 h, 24 h, 7 d, 30 d, and 180 d), the lowest AC was selected as the SMAC value (Table 5-5). Nasal Injury The most sensitive end point for toxicity at concentrations greater than or equal to the odor threshold is nasal injury. Because the data for injury were obtained from human subjects, no species conversion is required. Nevertheless, because 75% of the subjects complained of irritating odor and 28% developed significant nasal pathology under the test conditions, the tested concentration of 0.2 ppm must be lowered to a concentration that would be anticipated to produce no adverse effects. Because there are no dose-response data for nasal injury, a safety factor of 10 was used to estimate the NOAEL. An additional safety factor of 10 is warranted to account for the fact that a single sniff caused the observed effects, whereas the AC must be set to protect during continuous, much longer term potential exposures. The resulting concentration of 0.002 ppm is less than or equal to even the 180-d ACs for all other end points. Because the end point is injury of the nasal mucosa and because no epidemiological data are available to indicate that long term exposure to sub-irritating (short-term) concentrations of MH would lead to cumulative effects, the AC for MH-induced nasal injury is set at 0.002 ppm for all exposure durations. Carcinogenesis The NRC (1985) used the data of Kinkead et al. (1985) as input to the multistage model of Crump and Howe (1984) to obtain a 95% lower confidence limit of 0.116 ppm for a lung tumor risk in mice of 0.01, based on a work-week exposure schedule. Using Haber's rule to convert to a continuous lifetime exposure yielded the value of 0.01 ppm corresponding to a lifetime tumor risk of 0.01. In another document, the NRC (1992) used the model of Crump and Howe (1984) to derive an equation, simplified here for k = 3 stages, for estimating the constant exposure concentration, D, during the time interval between t0 and t1,

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 which gives the lifetime (t hours) excess risk equivalent to the constant lifetime dose rate, d, for a model having k stages: That model assumes that the carcinogen affects only the first stage of a process having three to six stages and that the risk of carcinogenesis is a function of the age at exposure. The NRC (1992) stated that for a 3-6 stage process (with only the first stage dose-related), the worst case (highest risk) would occur with a 3-stage process, with exposure at the earliest age possible. To calculate MH AC values, k in the equation above was set to 3 and a minimum astronaut age of 30 y was assumed. ACs were calculated using a continuous lifetime exposure at 0.01 ppm for which the NRC Committee on Toxicology calculated an upper 95% risk of 0.01. Because the model is conservative, no safety factor was used to convert animal test data to human exposure limits. Therefore, the following equation, based on Crump and Howe's multistage model with only the first stage dose-related, was used to calculate the exposure concentrations, D, which would yield a tumor risk of 10-4 for exposure durations of 24 h, 7 d, 30 d, and 180 d: where d is the concentration during a lifetime exposure (0.01 ppm in this case) 25,600 is the number of days in a 70-y human lifetime k is the number of stages in the model (three in this case) 10-4 is the acceptable risk level age is the minimum age of an astronaut, in years (30 in this case) t is the exposure duration, in days (1, 7, 30, or 180) risk is the risk of tumor for lifetime exposure to d (10-2 in this case) That equation yields values of D24h = 2.6 ppm. D7d = 0.37 ppm. D30d = 0.087 ppm. D180d = 0.015 ppm.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 Microgravity-induced physiological changes are not anticipated to affect the carcinogenic potency of concentration. Effects on Red Blood Cells Humans exposed for 10 min to MH at 90 ppm showed no increase in methemoglobin but did have a delayed appearance of Heinz bodies in 3-5% of RBCs with no signs of anemia or reticulocytosis (Darmer and MacEwen 1973). Starting with that as a LOAEL, an AC for a 1-h exposure was calculated by applying a factor of 10 to estimate a NOAEL, using Haber's rule to extrapolate to a 1-h exposure, and applying a spaceflight factor of 3 for blood toxicants. Thus, 1-h AC = 90 ppm ( LOAEL) ÷ 6 (exposure duration) ÷ 3 (spaceflight) = 5 ppm. In continuous, 90-d low-dose inhalation exposures of rats, dogs and monkeys at 0.04 pm and 0.1 ppm, dogs showed significant decreases in hematocrit, hemoglobin levels and RBC count at 0.1 ppm but no effects at 0.04 ppm (Darmer and MacEwen 1973). According to the authors, methemoglobin formed during the exposures is rapidly converted back to oxyhemoglobin (mainly by methemoglobin reductase) during chronic exposure conditions. The methemoglobinemia reaches an equilibrium level unique to the exposure concentration and is accompanied by Heinz body formation (Darmer and MacEwen 1973). Thus, the AC value, based on the 0.04-ppm NOAEL, is not adjusted for exposure duration for durations of at least 24 h. Because dogs and humans have equivalent levels of methemoglobin reductase activity (Smith 1996), the default species extrapolation factor of 10 was not applied. A spaceflight factor of 3 for blood toxicants was applied. Thus, the calculated ACs are 24-h, 7-d, 30-d, 180-d AC = 0.04 ppm (NOAEL) ÷ 3 (spaceflight)   = 0.01 ppm.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 TABLE 5-5 Acceptable Concentrations End Point, Exposure   Uncertainty Factors Acceptable Concentrations, ppm Data, Reference Species NOAEL Time Species Spaceflight 1 h 24 h 7 d 30 d 180 d Nasal injury Human 10 10 1 1 0.002 0.002 0.002 0.002 0.002 12/42 exposed to 0.2 ppm, 30 cc, single sniff (Hoffman and Schluter 1976)                     Carcinogenesis Mice LMS LMS 1 1 NS 2.6 0.37 0.087 0.015 2 ppm, 1 y, intermittent (Kinkead et al. 1985)                     Effects on RBCs (5% of red cells) Human — 1 1 3 5 NS NS NS NS LOAEL, 90 ppm for 10 min (MacEwen et al. 1970)                     Effects on RBCs Dogs 1 1 1 3 NS 0.01 0.01 0.01 0.01 NOAEL, 0.04 ppm for 90 d, continuous (Darmer and MacEwen 1973)                     SMACs           0.002 0.002 0.002 0.002 0.002 —, not applicable. LMS, linearized multistage model. NS, not set.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 REFERENCES ACGIH. 1991. Methylhydrazine. Pp. 1009-1012 in Documentation of the Threshold Limit Values and Biological Exposure Indices, 6th Ed. American Conference of Governmental Industrial Hygienists, Cincinnati, Ohio. ACGIH. 1998. TLVs and BEIs. American Conference of Governmental Industrial Hygienists, Cincinnati, Ohio. Brusick, D. and D. W. Matheson. 1976. P. 38 in Mutagen and Oncogen Study of Methylhydrazine. Final Report. Report No. AMRL-TR-76-80. Report prepared by Litton Bionetics, Kensington, Md., for the Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, Ohio. Coe, F.L., R. W. Howe and J.A. Goetting. 1967. The Effects of Monomethylhydrazine on Renal Function. Report No. SAM-TR-67-61. USAF School of Aerospace Medicine, Brooks Air Force Base, Texas. Crump, K.S. and R.B. Howe. 1984. The multistage model with a time-dependent dose pattern: Applications to carcinogenic risk assessment. Risk Anal. 4:163-176. Darmer, K.I., Jr., and J.D. MacEwen. 1973. Monomethylhydrazine—Chronic Low Level Exposures and 24-hour Emergency Limits. Report No. AMRL-TR-73-125. Aerospace Medical Research Laboratory, Air Force Systems Command, Wright-Patterson Air Force Base, Ohio. DeJournette, R.L. 1977. Rocket propellant inhalation in the Apollo-Soyuz astronauts. Radiology 125:21-24. Diaz Gomez, M.I., and J.A. Castro. 1986. Effect of inhibitors of the FAD-containing monooxygenase system from rat liver microsomes on monomethylhydrazine metabolism and activation to reactive metabolites. Arch. Toxicol. 59:64-66. Furst, A., W.R. Gustavson, and R.S. deRopp. 1969. Biochemical Pharmacology of Hydrazines Toxicity. Report No. AMRL-TR-68-132, Aerospace Medical Research Laboratory, Air Force Systems Command, Wright-Patterson Air Force Base, Ohio. Haun, C.C., J.D. MacEwen, E.H. Vernot, and G.F. Egan. 1969. The Acute Inhalation Toxicity of Monomethylhydrazine Vapor. Report No. AMRL-TR-68-169. Aerospace Medical Research Laboratory, Air Force Systems Command, Wright-Patterson Air Force Base, Ohio. Haun, C.C. 1970. Chronic Exposure to Low Concentrations of Monomethylhydrazine. Report No. AMRL-TR-70-102. Aerospace Medical Research Laboratory, Air Force Systems Command, Wright-Patterson Air Force Base, Ohio. Hawks, A., and P.N. Magee. 1974. The alkylation of nucleic acids of rat and mouse in vivo by the carcinogen 1, 2-dimethylhydrazine. Br. J. Cancer 30:440-447. Hoffman, E.J. and L.A. Schluter. 1976. Test Report: Olfactory Response to Monomethylhydrazine . Report No. TR-WSTF-140. NASA Johnson Space Center, White Sands Test Facility, Las Cruces, N.M. Jacobson, K.H., J.H. Clem, H.J. Wheelwright, Jr., W.E. Rinehart, and N. Mayes. 1955. The acute toxicity of the vapors of some methylated hydrazine derivatives. AMA Arch. Ind. Health 12:609-616. Keller, W.C., C.T. Olson, K.C. Back and C.L. Gaworski. 1984. Teratogenic assess

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