3

Monomethylhydrazine1
Acute Exposure Guideline Levels

SUMMARY

MONOMETHYLHYDRAZINE is a clear, colorless liquid used extensively in military applications as a missile and rocket propellant, in chemical power sources, and as a solvent and chemical intermediate. Upon contact with strong oxidizers (e.g., hydrogen peroxide, nitrogen tetroxide, chlorine, fluorine) spontaneous ignition may occur.

Human volunteers exposed to monomethylhydrazine at a concentration of 90 parts per million (ppm) for 10 min reported minor ocular and nasopharyngeal irritation as the only consequence of exposure (MacEwen et al. 1970).

Toxicity data are available for multiple laboratory species including, rhesus monkeys, squirrel monkeys, beagle dogs, rats, mice and hamsters. Nonlethal toxic effects include irritation of the upper respiratory tract, hemolysis, and

1  

This document was prepared by AEGL Development Team member Richard Thomas of the National Advisory Committee on Acute Exposure Guideline Levels for Hazardous Substances (NAC) and Robert Young of the Oak Ridge National Laboratory. The NAC reviewed and revised the document, which was then reviewed by the National Research Council (NRC) Subcommittee on Acute Exposure Guideline Levels. The NRC subcommittee concludes that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NAC and are consistent with the NRC guidelines reports (NRC 1993; NRC in press).



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement



Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.

OCR for page 113
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 3 Monomethylhydrazine1 Acute Exposure Guideline Levels SUMMARY MONOMETHYLHYDRAZINE is a clear, colorless liquid used extensively in military applications as a missile and rocket propellant, in chemical power sources, and as a solvent and chemical intermediate. Upon contact with strong oxidizers (e.g., hydrogen peroxide, nitrogen tetroxide, chlorine, fluorine) spontaneous ignition may occur. Human volunteers exposed to monomethylhydrazine at a concentration of 90 parts per million (ppm) for 10 min reported minor ocular and nasopharyngeal irritation as the only consequence of exposure (MacEwen et al. 1970). Toxicity data are available for multiple laboratory species including, rhesus monkeys, squirrel monkeys, beagle dogs, rats, mice and hamsters. Nonlethal toxic effects include irritation of the upper respiratory tract, hemolysis, and 1   This document was prepared by AEGL Development Team member Richard Thomas of the National Advisory Committee on Acute Exposure Guideline Levels for Hazardous Substances (NAC) and Robert Young of the Oak Ridge National Laboratory. The NAC reviewed and revised the document, which was then reviewed by the National Research Council (NRC) Subcommittee on Acute Exposure Guideline Levels. The NRC subcommittee concludes that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NAC and are consistent with the NRC guidelines reports (NRC 1993; NRC in press).

OCR for page 113
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 histopathologic evidence of renal and hepatic toxicity. Lethal exposures are usually preceded by convulsions. Lethal toxicity varies somewhat among species. One-hour LC50 (lethal concentration for 50% of the animals) values of 162, 82, 96, 244, 122, and 991 ppm have been determined for rhesus monkeys, squirrel monkeys, beagle dogs, rats, mice, and hamsters, respectively. Exposure concentration-exposure duration relationships appear to follow a linear relationship, although there appears to be a critical threshold for lethality with little margin between exposures causing only minor, reversible effects, and those resulting in lethality. In a 1-y inhalation bioassay using dogs, rats, mice, and hamsters and monomethylhydrazine concentrations of 2 ppm and 5 ppm, there was no evidence of treatment-related carcinogenicity in dogs or rats even after a 1-y post-exposure observation period. However, mice exposed at 2 ppm exhibited an increased incidence of lung tumors, nasal adenomas, nasal polyps, nasal osteomas, hemangioma, and liver adenomas and carcinomas. In hamsters exposed to monomethylhydrazine at 2 or 5 ppm, there was an increase in nasal polyps and nasal adenomas (5 ppm only), interstitial fibrosis of the kidney, and benign adrenal adenomas. Recommendation of acute exposure guideline level 1 (AEGL-1) values for monomethylhydrazine would be inappropriate. This conclusion was based on the fact that notable toxicity may occur at or below the odor threshold. Exposure concentration-exposure duration relationship for monomethylhydrazine indicated little margin between exposures producing no adverse health effect and those resulting in significant toxicity. The AEGL-2 values were derived by a three-fold reduction of the AEGL-3 values. This approach for estimating a threshold for irreversible effects was used in the absence of exposure-response data related to irreversible or other serious long-lasting effects. It is believed that a 3-fold reduction in the estimated threshold for lethality is adequate to reach the AEGL-2 threshold level because of the steep dose-response relationship. For AEGL-3, the 1-h LC50 of 82 ppm for squirrel monkeys (Haun et al. 1970) was reduced by a factor of 3 to estimate a lethality threshold (27.3 ppm). Temporal scaling to obtain time-specific AEGL values was described by C1× t=k (where C=exposure concentration, t=exposure duration, and k=a constant). The lethality data for the species tested indicated a near linear relationship between concentration and exposure duration (n=0.97 and 0.99 for monkeys and dogs, respectively). The derived exposure value was adjusted by a total uncertainty factor of 10.2 An uncertainty factor of 3 was applied for 2   Each uncertainty factor of 3 is actually the geometric mean of 10, which is 3.16; hence, 3.16×3.16=10.

OCR for page 113
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 interspecies variability with the following justification. One-hour LC50s were determined in the monkey, dog, rat, and mouse. The LC50 values ranged from 82 ppm in the squirrel monkey to 244 ppm in the mouse, differing by a factor of approximately 3. The squirrel monkey data (1-h LC50=82 ppm) was used to determine the AEGL-3, because this species appeared to be the most sensitive to monomethylhydrazine toxicity and because it was the species most closely related to humans. An uncertainty factor of 3 for protection of sensitive individuals was applied to reflect individual variability less than an order of magnitude. Although the mechanism of toxicity is uncertain and sensitivity among individuals may vary, the exposure-response relationship for each species tested is very steep, suggesting limited variability in physiologic response to monomethylhydrazine. Furthermore, it is likely that acute responses are, at least initially, a function of the extreme chemical reactivity of monomethylhydrazine. The interaction of the highly reactive monomethylhydrazine with tissues (e.g., pulmonary epithelium) is not likely to greatly vary among individuals. The AEGL values reflect the steep exposure-response relationship exhibited by the toxicity data. Additional information regarding the mechanism(s) of action and metabolism of monomethylhydrazine may provide further insight into understanding and defining the threshold between nonlethal and lethal exposures. Neither inhalation nor oral carcinogenicity slope factors were available for monomethylhydrazine. A cancer assessment based upon the carcinogenic potential of dimethylhydrazine revealed that AEGL values for a theoretical excess lifetime 10–4 carcinogenic risk exceeded the AEGL-3 values that were based on noncancer endpoints. Furthermore, the available data for hydrazine and its methylated derivatives suggest that the tumorigenic response observed for these compounds is the result of repeated long-term exposures causing repetitive tissue damage. Because AEGLs are applicable to rare events or single once-in-a-lifetime exposures to a limited geographic area and small population, the AEGL values based on noncarcinogenic endpoints were considered more appropriate. Table 3–1 summarizes the AEGL values for monomethylhydrazine.

OCR for page 113
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 TABLE 3–1 Summary of AEGL Values for Monomethylhyrazine Classification 30 min 1 h 4 h 8 h Endpoint (Reference) AEGL-1 (Nondisabling) NR NR NR NR Not recommended due to inadequate data; concentration-response relationships suggest little margin between exposures causing minor effects and those resulting in serious toxicity. AEGL-2 (Disabling) 1.8 ppm 3.4 mg/m3 0.90 ppm 1.7 mg/m3 0.23 ppm 0.43 mg/m3 0.11 ppm 0.21 mg/m3 3-fold reduction in AEGL-3. AEGL-3 (Lethal) 5.5 ppm 10.3 mg/m3 2.7 ppm 5.1 mg/m3 0.68 ppm 1.3 mg/m3 0.34 ppm 0.64 mg/m3 1-h LC50 of 82 ppm reduced 3-fold to estimate a lethality threshold; uncertainty factor=10 Numeric values for AEGL-1 are not recommended, because (1) studies suggest that notable toxic effects may occur at or below the odor threshold or other modes of sensory detection, (2) an inadequate margin of safety exists between the derived AEGL-1 and the AEGL-2, or (3) the derived AEGL-1 is greater than the AEGL-2. The absence of an AEGL-1 does not imply that exposure below the AEGL-2 is without any adverse effects. Abbreviations: NR, not recommended; ppm, parts per million; mg/m3, milligrams per cubic meter.

OCR for page 113
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 1. INTRODUCTION Monomethylhydrazine is a clear, colorless liquid (Trochimowicz 1994). Upon contact with strong oxidizers (e.g., hydrogen peroxide, nitrogen tetroxide, chlorine, fluorine) spontaneous ignition may occur. It is used in military applications as a missile and rocket propellant in chemical power sources (USAF 1989), and is used also as a solvent and chemical intermediate (Trochimowicz 1994). There are are no reports of current commercial production (HSDB 1996) and, therefore, overall production may be considered sporadic (Chemical Economics Handbook 2000). Trochimowicz (1994) provided a review of the toxicology of monomethylhydrazine. Earlier data were summarized regarding the pharmacologic and toxicologic effects of monomethylhydrazine in laboratory animals by various routes of administration, noting involvement of the central nervous system, lungs, liver, and kidneys. Monomethylhydrazine has also been the subject of previous review by the National Research Council (NRC 1985). For derivation of AEGL values, acute exposure studies are preferentially examined. Subchronic and chronic studies generally have not been included in the data analysis for monomethylhydrazine AEGL derivation because of the great uncertainty in extrapolating such data to acute exposure scenarios. Such studies may be addressed when the data provided relate to effects following acute exposures, provide meaningful insight into understanding toxicity mechanisms, or can be used for other special considerations. The primary physical and chemical data for monomethylhydrazine are presented in Table 3–2. 2. HUMAN TOXICITY DATA 2.1. Acute Lethality No information was located regarding acute lethality to humans following inhalation exposure to monomethylhydrazine. 2.2. Nonlethal Toxicity 2.2.1. Acute Exposure Studies A controlled human exposure study provided information regarding non-lethal effects following acute (head-only) exposure to monomethylhydrazine

OCR for page 113
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 TABLE 3–2 Chemical and Physical Data Parameter Value Reference Synonyms methylhydrazine, MMH Trochimowicz et al. 1994 Chemical formula CH6N2 (H2N-NH-CH3) Trochimowicz et al. 1994 Molecular weight 46.07 Trochimowicz et al. 1994 CAS Registry No. 60–34–4 Trochimowicz et al. 1994 Solubility soluble in hydrocarbons; miscible with water and low molecular weight monohydric alcohols Trochimowicz et al. 1994 Physical state liquid Trochimowicz et al. 1994 Vapor density (rel to air) 1.6 Shaffer and Wands 1973 Vapor pressure 49.63 ♂ Hg at 25°C Shaffer and Wands 1973 Specific gravity 0.874 at 25°C Trochimowicz et al. 1994 Boiling/freezing point/flash point 87.5°C/–52.4°C/–8.33°C Trochimowicz et al. 1994 Odor threshold 1–3 ppm; ammonia-like or fishy odor Shaffer and Wands 1973 Conversion factors in air 1 mg/m3=0.53 ppm 1 ppm=1.88 mg/m3   (MacEwen et al. 1970). In a preliminary phase of this study, one subject was exposed at 50 ppm for 10 min and another exposed at 70 ppm for 10 min. Throughout the exposure period and during a 2-w post-exposure period, neither subject complained of adverse signs or symptoms. These subjects and five additional volunteers were then exposed to monomethylhydrazine at 90 ppm (169 mg/m3) for 10 min. All exposures were conducted using Rochester Chambers and male volunteers (23–44 y of age) representing nonsmokers, reformed smokers, and heavy smokers. One of the seven subjects was not included in the final data compilation due to an inability to detect the odor of monomethylhydrazine at any of the exposure atmospheres. The 10-min, 90-ppm exposure (Ct=900 ppm·min) resulted in irritation of the eyes, nose, and throat but did not result in excessive lacrimation or coughing. The subjects experienced irritation ranging from faint (just perceptible, not painful) to moderate in intensity of response. Monitoring of clinical chemistry parameters for 60 d following the exposure revealed no significant findings other than 3–5% increase in Heinz body formation at d 7 that declined after 2 w. Spirometry

OCR for page 113
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 tests revealed no exposure-related effects. The presence of Heinz bodies was not accompanied by anemia or reticulocytosis. 2.2.2. Epidemiologic Studies Epidemiologic studies regarding human exposure to monomethylhydrazine were not available. 2.3. Developmental and Reproductive Toxicity No data are available regarding the potential reproductive and developmental toxicity of monomethylhydrazine in humans. 2.4. Genotoxicity No genotoxicity data specific for AEGL derivation were available for monomethylhydrazine. 2.5. Carcinogenicity No data are available regarding the potential carcinogenicity of monomethylhydrazine in humans. 2.6. Summary The human experience regarding the toxicity of acute exposures to monomethylhydrazine exposure is limited. The study by MacEwen et al. (1970) found that a 10-min exposure to monomethylhydrazine at 169 mg/m3 (90 ppm) resulted in minor ocular and upper respiratory tract irritation. 3. ANIMAL TOXICITY DATA 3.1. Acute Lethality Acute lethality studies in laboratory species are summarized in the following sections. (The LC50 values from these studies are summarized in Table 3–6.)

OCR for page 113
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 3.1.1. Nonhuman Primates In a study by Haun et al. (1970), male and female rhesus monkeys (three to five per group, sex ratio per exposure varied) and male squirrel monkeys (two to four per exposure group) were exposed to monomethylhydrazine for 60 min (rhesus monkeys) and 15, 30, or 60 min (squirrel monkeys) (Table 3–3). For the rhesus monkeys (three males and two females), there were no deaths following a 60-min exposure to a mean concentration of 160 ppm (range, 145–170 ppm), TABLE 3–3 Lethality in Nonhuman Primates and Dogs Following Inhalation Exposure to Monomethylhydrazine Species Exposure Concentration (C×T) Mortality Ratio   15 min   Squirrel monkey 300 ppm (4,500 ppm·min) 1/4   340 ppm (5,100 ppm·min) 1/2   376 ppm (5,640 ppm·min) 3/3 Beagle dog 380 ppm (5,700 ppm·min) 0/2   390 ppm (5,850 ppm·min) 1/2   400 ppm (6,000 ppm·min) 3/5   30 min   Squirrel monkey 130 ppm (3,900 ppm·min) 0/3   150 ppm (4,500 ppm·min) 2/3   170 ppm (5,100 ppm·min) 2/2 Beagle dog 180 ppm (5,400 ppm·min) 0/2   190 ppm (5,700 ppm·min) 1/3   200 ppm (6,000 ppm·min) 2/2   60 min   Rhesus monkey 160 ppm (9,600 ppm·min) 0/5   170 ppm (10,200 ppm·min) 2/3 Squirrel monkey 75 ppm (4,500 ppm·min) 0/2   85 ppm (5,100 ppm·min) 2/4   90 ppm (5,400 ppm·min) 2/2 Beagle dog 92 ppm (5,520 ppm·min) 0/3   104 ppm (6,240 ppm·min) 3/3   Source: Haun et al. 1970.

OCR for page 113
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 but at a mean concentration of 170 ppm (range, 138–180 ppm), mortality was 2/3 (two males of two males and one female). Although no time-to-death values were reported for the rhesus monkeys, it was stated that no deaths occurred during the exposure period. A 60-min LC50 of 162 ppm was reported for the rhesus monkeys. For the squirrel monkeys, deaths occurred as early as 2 h post-exposure, although most deaths occurred between 10 and 24 h post-exposure. The reported 15-, 30-, and 60-min LC50 values for the squirrel monkeys were 340, 145, and 82 ppm, respectively. The cumulative exposure data for various exposure durations suggest a linear relationship within species. 3.1.2. Dogs Jacobson et al. (1955) reported on the lethality of monomethylhydrazine in dogs exposed for 4 h. Groups of dogs (three per group) exposed to three different concentrations of monomethylhydrazine developed hyperactivity, salivation, vomiting, respiratory distress, and convulsions. Dogs exposed to monomethylhydrazine experienced elevated body temperatures (as high as 106°F vs 102°F for controls) immediately following exposure, but body temperatures returned to normal within 1 d after cessation of treatment. The mortality for the 15-, 21-, and 29-ppm exposure levels was 0/3, 2/3, and 2/3, respectively. This mortality data included all animals that died within 14 d of exposure and those that were terminated due to morbidity. Postmortem examination revealed pulmonary edema and hemorrhagic foci in the lungs. The latter was observed only in dogs that convulsed and was considered a secondary effect rather than a direct effect of the test substance. The acute toxicity of monomethylhydrazine in dogs was also studied by Haun et al. (1970). Three groups of male and female beagle dogs (two to five per exposure group) were exposed to monomethylhydrazine for 15 min (380– 400 ppm), 30 min (180–200 ppm), or 60 min (92–104 ppm) (Table 3–3). Deaths occurred within 2 h following termination of the exposure. The study authors calculated 15-min, 30-min, and 1-h LC50 values of 390, 195, and 96 ppm, respectively. 3.1.3. Rats Jacobson et al. (1955) assessed the lethality of monomethylhydrazine in rats (10 per exposure group; strain not specified) following a single 4-h exposure to various unspecified concentrations. An LC50 of 74 ppm (139 mg/m3) was reported. Based upon the exposure-response data, an LC20 of ≈70 ppm (≈132

OCR for page 113
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 mg/m3) can be estimated. The exposure-response curve was very steep (slope =28.5), suggesting very little variability in the response. Haun et al. (1970) also assessed the acute lethal toxicity of rats. Groups of 10 Sprague-Dawley rats were exposed to monomethylhydrazine (30, 60, 120, or 240 ppm) for 30, 60, 120, or 240 min. Similar to the results of Jacobson et al. (1955) the exposure-response curve was steep. The study authors calculated 30-, 60-, 120-, and 240-min LC50 values of 427, 244, 127, and 78 ppm, respectively. 3.1.4. Mice Acute toxicity assays using groups of 20 mice (strain not specified) exposed to various unspecified concentrations of monomethylhydrazine for 4 h were conducted by Jacobson et al. (1955). During the exposure, the mice were restless and exhibited dyspnea, convulsions, and exophthalmos. An LC50 of 56 ppm (105 mg/m3) was reported. Postmortem examination of the mice revealed no significant histopathologic findings other than pulmonary edema and occasional, localized hemorrhage. The hemorrhaging was, however, considered to be secondary to the observed convulsions and not considered a direct effect of monomethylhydrazine. Based upon the exposure-response data, an LC20 of ≈36 ppm (≈68 mg/m3) can be estimated. The exposure-response curve was steep (slope = 4.96), suggesting little variability in the response. Analytical concentrations of monomethylhydrazine averaged 77% of nominal, suggesting some difficulty with accurate measurement of the test material. In a study by Haun et al. (1970), groups of 20 male ICR mice were exposed to a range of monomethylhydrazine concentrations for 30, 60, 120, or 240 min. LC50 values for 30, 60, 120, and 240 min were 272, 122, 92, and 65 ppm, respectively. Additional experiments in which groups of 20 mice were exposed to various monomethylhydrazine concentrations (Table 3–4) were also conducted to assure reproducibility of the mortality findings. 3.1.5. Hamsters Jacobson et al. (1955) assessed the lethality of monomethylhydrazine in hamsters exposed for 4 h. Based on the estimated LC50 (143 ppm, or 270 mg/m3), hamsters were somewhat less sensitive to inhaled monomethylhydrazine. Similar to mice and rats, the slope of the exposure-response curve was steep (2.46), suggesting little variability in the response. In a study reported by MacEwen and Vernot (1975), groups of 10 male

OCR for page 113
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 TABLE 3–4 Mortality in Mice Following Inhalation Exposure to Monomethylhydrazine for 240 Min Mean concentration (ppm) Concentration range (ppm) Mortality (no. of dead per no. of exposed) Total Mortality 27 (10–35) 0/20 0/40 25 (23–30) 0/20   50 (48–53) 0/20 0/40 50 (45–55) 0/20   55 (50–58) 0/20 1/40 55 (50–58) 1/20   63 (55–70) 5/20 7/40 60 (50–68) 2/20   63 (48–68) 13/20 23/40 63 (58–68) 10/20   68 (63–75) 18/20 31/40 66 (60–70) 13/20   83 (60–113) 19/20 37/40 83 (65–88) 18/20   Source: Haun et al. 1970. Syrian golden hamsters were exposed to monomethylhydrazine at concentrations of 460, 620, 810, 910, 1,110, or 1,380 ppm for 1 h followed by a 14-d observation period. Immediate irritation of the eyes and nose followed by labored breathing and gasping were observed in all exposure groups. The onset of these signs appeared to be concentration-dependent; signs appeared more rapidly as the concentration increased. Coordination was affected, although the hamsters did not become prostrate. Convulsions were observed during the last few minutes of exposure in hamsters of the highest exposure group. These convulsions continued as long as 1 h post-exposure. Mortality ratios are shown in Table 3–5. Hamsters that died did so within 24 h post-exposure, and all survivors exhibited notable body-weight loss. A 1-h LC50 of 991 ppm (95% confidence interval=870–1,130 ppm) was reported based upon these data. Gross examination revealed lung and liver congestion, and concentration-related alveolar irritation. Histopathologic examination revealed concentration-related pulmonary edema and hemorrhage (observed only in hamsters exposed to the two highest concentrations). Hamsters from the highest exposure groups exhibited cuboidal atrophy, erosion and ulcerations in tracheobronchial epithe-

OCR for page 113
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 Toxicity endpoint: 1-h LC50 of 82 ppm in female squirrel monkeys; lethality threshold estimated as a 3-fold reduction of the LC50 (82 ppm/3=27.3 ppm) Uncertainty factors: Interspecies: A factor of 3 was used. One-hour LC50s were determined in the monkey, dog, rat, and mouse. The LC50 values ranged from 82 ppm in the squirrel monkey to 244 ppm in the mouse, differing by a factor of approximately 3. The squirrel monkey estimated threshold value of 27.3 ppm calculated above was used to determine the AEGL-3 value. Because the species used was the most sensitive to monomethylhydrazine toxicity and the most closely related to humans, an uncertainty factor of 3 is justified. Intraspecies: A factor of 3 was used. Although the mechanism of toxicity is uncertain and sensitivity among individuals may vary, the exposure-response relationship is steep, suggesting limited variability in the toxic response to methylhydrazine. Furthermore, it is likely that acute toxic responses are, at least initially, a function of the extreme reactivity of methylhydrazine. The interaction of the highly reactive monomethylhydrazine with tissues (e.g., pulmonary epithelium) is not likely to greatly vary among individuals. Calculations: 27.3 ppm/10=2.73 ppm C1×t=k 2.73 ppm×60 min=163.8 ppm·min Time scaling: C1×t=k (ten Berge et al. 1986) (27.3 ppm)1×60 min=163.8 ppm·min; regression analysis of the squirrel monkey lethality data suggested a near linear relationship 30-min AEGL-3: C1×30 min=163.8 ppm·min C=5.5 ppm 1-h AEGL-3: C1×60 min=163.8 ppm·min C=2.7 ppm 4-h AEGL-3: C1×240 min=163.8 ppm·min C=0.68 ppm 8-h AEGL-3: C1×480 min=163.8 ppm·min C=0.34 ppm

OCR for page 113
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 APPENDIX B TIME SCALING CALCULATIONS FOR MONOMETHYLHYDRAZINE AEGLS The relationship between dose and time for any given chemical is a function of the physical and chemical properties of the substance and the unique toxicologic and pharmacologic properties of the individual substance. Historically, the relationship according to Haber (1924), commonly called Haber’s law (NRC 1993) or Haber’s rule (i.e., C×t=k, where C=exposure concentration, t= exposure duration, and k=a constant), has been used to relate exposure concentration and duration to effect (Rinehart and Hatch 1964). This concept states that exposure concentration and exposure duration may be reciprocally adjusted to maintain a cumulative exposure constant (k) and that this cumulative exposure constant will always reflect a specific quantitative and qualitative response. This inverse relationship of concentration and time may be valid when the toxic response to a chemical is equally dependent upon the concentration and the exposure duration. However, an assessment by ten Berge et al. (1986) of LC50 data for certain chemicals revealed chemical-specific relationships between exposure concentration and exposure duration that were often exponential. This relationship can be expressed by the equation Cn×t=k, where n represents a chemical-specific exponent and even a toxic endpoint-specific exponent. The relationship described by this equation is basically the form of a linear regression analysis of the log-log transformation of a plot of C vs t. ten Berge et al. (1986) examined the airborne concentration (C) and short-term exposure duration (t) relationship relative to death for approximately 20 chemicals and found that the empirically derived value of n ranged from 0.8 to 3.5 among this group of chemicals. Hence, these workers showed that the value of the exponent n in the equation Cn×t=k quantitatively defines the relationship between exposure concentration and exposure duration for a given chemical and for a specific health effect endpoint. Haber’s rule is the special case where n=1. As the value of n increases, the plot of C vs t yields a progressive decrease in the slope of the curve. Two data sets of LC50 values for different time periods of exposure were analyzed using a linear regression analysis of the log-log transformation of a plot of C vs t to derive values of n for monomethylhydrazine. Monomethylhydrazine monkey data from Haun et al. 1970 The LC50 values for 15, 30, and 60 min were 340, 145, and 82 ppm, respectively.

OCR for page 113
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 Time Conc. Log Time Log Conc. 15 340 1.1761 2.5315 30 145 1.4771 2.1614 60 82 1.7782 1.9138 n=0.97 Calculated LC50 values: Min Conc. 30 159.30 60 78.23 240 18.87 480 9.27

OCR for page 113
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 Monomethylhydrazine dog data from Haun et al. 1970 The LC50 values for 15, 30, and 60 min were 390, 195, and 96 ppm, respectively. Time Conc. Log Time Log Conc. 15 390 1.1761 2.5911 30 195 1.4771 2.2900 60 96 1.7782 1.9823 n=0.99 Calculated LC50 values: Min Conc. 30 193.99 60 96.25 240 23.69 480 11.75

OCR for page 113
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 APPENDIX C CARCINOGENICITY ASSESSMENT FOR MONOMETHYLHYDRAZINE AEGLS Neither an inhalation nor an oral slope factor is currently available for monomethylhydrazine. Slope factors for 1,1-dimethylhydrazine and 1,2-dimethylhydrazine were available but have been withdrawn from the U.S. EPA Integrated Risk Information System (IRIS) (U.S. EPA 1986). For a preliminary carcinogenicity assessment, the withdrawn inhalation slope factor for 1,1-dimethylhydrazine (cited in ATSDR 1994) will be used as a surrogate for monomethylhydrazine. The assessment follows previously described methodologies (NRC 1985; Henderson 1992). The withdrawn slope factor for 1,1-dimethylhydrazine was 3.5 (mg/kg·d)–1, which, based upon a human inhalation rate of 20 m3/d and a body weight of 70 kg, is equivalent to 1 (mg/m3)–1. To convert to a level of monomethylhydrazine that would cause an excess cancer risk of 10–4: Risk of 1×10–4=(1×10–4/1)×1 mg/m3=1×10–4 mg/m3 (virtually safe dose). To convert a 70-y exposure to a 24-h exposure: 24-h exposure=d×25,600 =(1×10–4 mg/m3)×25,600 d =2.56 mg/m3. Adjustment to allow for uncertainties in assessing potential cancer risks for short-term exposures under the multistage model (Crump and Howe 1984): (2.56 mg/m3)/6=0.4 mg/m3 (0.2 ppm). Therefore, based upon the potential carcinogenicity of monomethylhydrazine, an acceptable 24-h exposure would be 0.4 mg/m3 (0.2 ppm). If the exposure is limited to a fraction (f) of a 24-h period, the fractional exposure becomes 1/f×24 h (NRC 1985). 24-h exposure=0.4 mg/m3 (0.2 ppm) 8-h=1.2 mg/m3 (0.5 ppm) 4-h=2.4 mg/m3 (1 ppm)

OCR for page 113
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 1-h=9.6 mg/m3 (5 ppm) 0.5-h=19.2 mg/m3 (10 ppm) Because the AEGLs based upon acute toxicity were equivalent to or lower than the values derived based upon potential carcinogenicity, the acute toxicity data were used for the proposed AEGLs for monomethylhydrazine. Additionally, available data on monomethylhydrazine and hydrazine suggest that long-term, repeated exposures may be necessary for tumorigenic effects. There are no data available that demonstrate a tumorigenic response following acute inhalation exposure. For 10–5 and 10–6 risk levels, the 10–4 values are reduced by 10-fold or 100-fold, respectively. An alternate cancer assessment was performed using the data of Kinkead et al. (1985). In this study, mice exposed to monomethylhydrazine (0, 0.02, 0.2, or 2.0 ppm) 6 h/d, 5 d/w for 1 y followed by a 1-y observation period. At the end of the observation period, lung tumor incidences were 13/364, 17/354, 25/347, and 59/360 for the 0, 0.02, 0.2, and 2.0 ppm groups, respectively. The assessment follows previously described methodologies (NRC 1985; Henderson 1992). GLOBAL86 was used to obtain a virtually safe dose (VSD) of 2.1×10–6 mg/m3. VSD=2.1×10–6 mg/m3. To convert a 70-y exposure to a 24-h exposure: 24-h exposure=d×25,600 =(2.1×10–6 mg/m3)×25,600 d =5.4×10–2 mg/m3. Adjustment to allow for uncertainties in assessing potential cancer risks for short-term exposures under the multistage model (Crump and Howe 1984): (5.4×10–2 mg/m3)/6=0.9 mg/m3. Therefore, based upon the potential carcinogenicity of monomethylhydrazine, an acceptable 24-h exposure would be 0.9 mg/m3. If the exposure is limited to a fraction (f) of a 24-h period, the fractional exposure becomes 1/f×24 h (NRC 1985). 24-h exposure=0.9 mg/m3 (0.5 ppm) 8-h=2.7 mg/m3 (1 ppm) 4-h=5.4 mg/m3 (3 ppm)

OCR for page 113
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 1-h=21.6 mg/m3 (11 ppm) 0.5-h=43.2 mg/m3 (23 ppm) Because the AEGLs based upon acute toxicity were equivalent to or lower than the values derived based on potential carcinogenicity, the acute toxicity data were used for the proposed AEGLs for monomethylhydrazine. Additionally, available data on monomethylhydrazine and hydrazine suggest that long-term, repeated exposures may be necessary for tumorigenic effects. There are no data available that demonstrate a tumorigenic response following acute inhalation exposure. For 10–5 and 10–6 risk levels, the 10–4 values are reduced by 10-fold or 100-fold, respectively.

OCR for page 113
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 APPENDIX D DERIVATION SUMMARY FOR ACUTE EXPOSURE GUIDELINES FOR MONOMETHYLHYDRAZINE (CAS No. 60–34–4) AEGL-1 Values-Monomethylhydrazine 30 min 1 h 4 h 8 h Not Not Not Not recommended recommended recommended recommended Reference: Not applicable Test Species/Strain/Number: Not applicable Exposure Route/Concentrations/Durations: Not applicable Effects: Not applicable Endpoint/Concentration/Rationale: Not applicable Uncertainty Factors/Rationale: Not applicable Modifying Factor: Not applicable Animal to Human Dosimetric Adjustment: Not applicable Time Scaling: Not applicable Data Adequacy: Both animal and human data affirm that low level exposure will cause mild irritation of the respiratory tract and that there is likely to be little margin between AEGL-1 type effects and more serious effects. Numeric values for AEGL-1 are not recommended because (1) studies suggest that notable toxic effects may occur at or below the odor threshold or other modes of sensory detection, (2) an inadequate margin of safety exists between the derived AEGL-1 and the AEGL-2, or (3) the derived AEGL-1 is greater than the AEGL-2. The absence of an AEGL-1 does not imply that exposure below the AEGL-2 is without any adverse effects.

OCR for page 113
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 AEGL-2 Values-Monomethylhydrazine 30 min 1 h 4 h 8 h 1.8 ppm 0.90 ppm 0.23 ppm 0.11 ppm Reference: Haun, C.C., J.D.MacEwen, E.H.Vernot, and G.F.Egan. 1970. Acute inhalation toxicity of monomethylhydrazine vapor. Am. J. Ind. Hyg. Assoc. 31:667–677 Test Species/Strain/Sex/Number: Squirrel monkeys, 2–4 males/group Exposure Route/Concentrations/Durations: Inhalation; exposure at 300, 340, or 376 ppm for 15 min; 130, 150, or 170 ppm for 30 min; 75, 85, or 90 ppm for 60 min Effects: Data specifically identifying serious, irreversible effects consistent with the AEGL-2 definition were not available. The lethality data are shown in the summary table for AEGL-3. Endpoint/Concentration/Rationale: In the absence of data specifically identifying AEGL-2 endpoints, the AEGL-2 was based upon a 3-fold reduction of the AEGL-3 values for all time periods. Given the steepness of the exposure-dose curve, it is believed that a 3-fold downward adjustment would be protective against serious long-term, irreversible effects, or the inability to escape. Uncertainty Factors/Rationale: Total uncertainty factor: 10 Interspecies: 3 Intraspecies: 3 Modifying Factor: None Animal to Human Dosimetric Adjustment: None applied, insufficient data Time Scaling: Cn×t=k, where n=1; see discussion for AEGL-3, because AEGL-2 values were derived by 3-fold reduction of AEGL-3 values Data Adequacy: In the absence of relevant data, the AEGL-2 values were derived by downward adjustment of the AEGL-3 values. The narrow margin between the AEGL-2 and AEGL-3 values for monomethylhydrazine reflect the steep exposure-response relationship suggested by available data. The absence of toxicologic data regarding AEGL-2 specific toxic endpoints is a notable deficiency.

OCR for page 113
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 AEGL-3 Values-Monomethylhydrazine 30 min 1 h 4 h 8 h 5.5 ppm 2.7 ppm 0.68 ppm 0.34 ppm Reference: Haun, C.C., J.D.MacEwen, E.H.Vernot, and G.F.Egan. 1970. Acute inhalation toxicity of monomethylhydrazine vapor. Am. J. Ind. Hyg. Assoc. 31:667–677 Test Species/Strain/Sex/Number: Squirrel monkeys, 2–4 males/group Exposure Route/Concentrations/Durations: Inhalation; exposure at 300, 340, or 376 ppm for 15 min; 130, 150, or 170 ppm for 30 min; 75, 85, or 90 ppm for 60 min Effects: Exposure Lethality ratio   15 min 300 ppm 1/4     340 ppm 1/2     376 ppm 3/3   30 min 130 ppm 0/3     150 ppm 2/3     170 ppm 2/2   60 min 75 ppm 0/2     85 ppm 2/4 60-min LC50=82 ppm   90 ppm 2/2   Endpoint/Concentration/Rationale: The 60-min LC50 of 82 ppm was reduced to 27.3 ppm by using a 3-fold adjustment as an estimate of the lethality threshold; the available data indicated the squirrel monkey to be the most sensitive species tested. That is a reasonable estimate of the lethality threshold, because monomethylhydrazine has a steep exposure-response curve, and data on other chemicals with similar dose response curves indicate that this approach represents a likely estimate of the threshold for lethality. For the 1-h exposure, 2/2 monkeys died at 90 ppm, 2/4 at 85 ppm, and 0/2 at 75 ppm. A similar spectrum of response is seen with the rhesus monkey and dog. Uncertainty Factors/Rationale: Total uncertainty factor: 10 Interspecies: 3—1-h LC50s were determined in the monkey, dog, rat, and mouse. The LC50 values ranged from 82 ppm in the squirrel monkey to 244 ppm in the mouse, differing by a factor of approximately 3. The squirrel monkey value of 82 ppm was used to determine the AEGL-3 value. Because the species used was the most sensitive to

OCR for page 113
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 monomethylhydrazine toxicity, and the most closely related to humans, an uncertainty factor of 3 is justified. Intraspecies: 3—Although the mechanism of toxicity is uncertain and sensitivity among individuals may vary, the exposure-response relationship is steep, suggesting limited variability in the toxic response to monomethylhydrazine. Furthermore, it is likely that acute toxic responses are, at least initially, a function of the extreme reactivity of monomethylhydrazine. The interaction of the highly reactive monomethylhydrazine with tissues (e.g., pulmonary epithelium) is not likely to greatly vary among individuals. Modifying Factor: None Animal to Human Dosimetric Adjustment: None applied, insufficient data Time Scaling: Cn×t=k, where n=1 and k=163.8 ppm·min. A regression analysis of data from squirrel monkeys and dogs (Haun et al. 1970) for 15, 30, and 60-min indicated a near-linear relationship (n=0.97 and 0.99, respectively, for the monkey and dog data). It was the consensus of the National Advisory Committee to assume linearity (n=1). Data Adequacy: Adequate lethality data were available for several species including nonhuman primates. Although the variability in response to the lethal effects of monomethylhydrazine among all species tested appeared to be relatively small (2- to 3-fold difference), the squirrel monkey appeared to be somewhat more sensitive. The AEGL values for monomethylhydrazine reflect the steep exposure-response relationship suggested by available data.