8
Monomethylhydrazine1
Acute Exposure Guideline Levels

UPDATE OF MONOMETHYLHYDRAZINE AEGLS

In Volume 1 of the series Acute Exposure Guideline Levels for Selected Airborne Chemicals (NRC 2000), acute exposure guideline level (AEGL) values were developed for 30 minutes (min) and 1, 4, and 8 hours (h). Since that time AEGL values have also been developed for 10-min exposures. This document updates Volume 1 to include 10-min values. The summary below is from Volume 1, reference with additional discussion to address the development of 10-min values.

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 90 ppm of monomethylhydrazine for 10 min reported minor irritation as the only effect (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 respiratory tract, hemolytic re-

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) Committee on Acute Exposure Guideline Levels. The NRC Committee 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, 2001).



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8 Monomethylhydrazine1 Acute Exposure Guideline Levels UPDATE OF MONOMETHYLHYDRAZINE AEGLS In Volume 1 of the series Acute Exposure Guideline Levels for Selected Airborne Chemicals (NRC 2000), acute exposure guideline level (AEGL) values were developed for 30 minutes (min) and 1, 4, and 8 hours (h). Since that time AEGL values have also been developed for 10-min exposures. This document updates Volume 1 to include 10-min values. The summary below is from Vol- ume 1, reference with additional discussion to address the development of 10- min values. SUMMARY Monomethylhydrazine is a clear, colorless liquid used extensively in mili- tary 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 90 ppm of monomethylhydrazine for 10 min reported minor irritation as the only effect (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 respiratory tract, hemolytic re- 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) Committee on Acute Exposure Guideline Levels. The NRC Committee 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 re- ports (NRC 1993, 2001). 209

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210 Acute Exposure Guideline Levels sponses, and some evidence of renal and hepatic toxicity. Lethal exposures are usually preceded by convulsions. Lethal toxicity varies somewhat among spe- cies. One-hour LC50 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 time relationships ap- pear 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-year inhalation bioassay using dogs, rats, mice, and hamsters and monomethylhydrazine concentrations of 2 ppm and 5 ppm, there was no evi- dence of treatment-related carcinogenicity in dogs or rats even after a 1-year postexposure observation period. However, mice exposed to 2 ppm exhibited an increased incidence of lung tumors, nasal adenomas, nasal polyps, nasal osteo- mas, hemangioma, and liver adenomas and carcinomas. In hamsters exposed to 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. Recom- mendation of AEGL-1 values for monomethylhydrazine would be inappropriate. This conclusion was based on the fact that notable toxicity may occur at or be- low the odor threshold. Exposure concentration-exposure duration relationships for monomethylhydrazine indicated little margin between exposures that pro- duce no adverse health effect and those that result in significant toxicity. The AEGL-2 values were derived by a 3-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 thresh- old for lethality is adequate to reach the AEGL-2 threshold level because of the steep dose-response relationship. For AEGL-3, lethality data (1-h LC50 of 82 ppm) for squirrel monkeys (Haun et al. 1970) were downwardly adjusted by a factor of 3 to estimate a le- thality threshold (27.3 ppm). Temporal scaling to obtain time-specific AEGL values was described by C1 × t = k (where C = exposure concentration, t = expo- sure duration, and k = a constant). The lethality data for the species tested indi- cated a near-linear relationship between concentration and time (n = 0.97 and 0.99 for monkeys and dogs, respectively). The derived exposure values were adjusted by a total uncertainty factor of 10. An uncertainty factor of 3 was ap- plied for interspecies variability with the following justification. One-hour LC50s were determined for 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) were used to determine the AEGL-3 because this species appeared to be the most sen- sitive 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 of 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 spe-

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211 Monomethylhydrazine cies tested is very 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. Interaction of the highly reactive monomethylhydrazine with tissues (e.g., pul- monary epithelium) is not likely to vary greatly among individuals. The AEGL values reflect the steep exposure-response relationship exhib- ited by the toxicity data. Additional information regarding the mechanism(s) of action and metabolism of monomethylhydrazine may provide insight into under- standing and defining the threshold between nonlethal and lethal exposures. Inhalation or oral slope factors were not available for monomethylhydra- zine. A cancer assessment based on the carcinogenic potential of dimethylhy- drazine revealed that AEGL values for a 10−4 carcinogenic risk exceeded the AEGL-3 values that were based on noncancer end points. Furthermore, the available data for hydrazine and its methylated derivatives suggest that the tu- morigenic response observed for these compounds results from long-term, re- peated exposures that cause repetitive tissue damage. Because AEGLs are appli- cable to rare events or single once-in-a-lifetime exposures to a limited geographic area and small population, the AEGL values based on noncarcino- genic end points were considered more appropriate. The AEGL values and tox- icity end points are summarized in Table 8-1. TABLE 8-1 Summary of AEGL Values for Monomethylhyrazinea Classification 10 min 30 min 1h 4h 8h End Point (Reference) AEGL-1 NR NR NR NR NR Not recommended due to inadequate data; concentration-response relationships suggest little margin between exposures that cause minor effects and those that result in serious toxicity.b AEGL-2 5.3 ppm 1.8 0.90 0.23 0.11 3-fold reduction in (10 ppm ppm ppm ppm AEGL-3 mg/m3) (3.4 (1.7 (0.43 (0.21 mg/m3) mg/m3) mg/m3) mg/m3) AEGL-3 16 ppm 5.5 2.7 ppm 0.68 0.34 1-h LC50 of 82 ppm 30 ppm 5.1 ppm ppm reduced 3-fold to mg/m3 mg/m3 1.3 10.3 0.64 estimate a lethality mg/m3 mg/m3 mg/m3 threshold; uncertainty factor = 10 a Each uncertainty factor of 3 is the geometric mean of 10, which is 3.16; hence, 3.16 × 3.16 = 10. b Refer to AEGL-1 for hydrazine if hydrazine is also present. (Continued)

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212 Acute Exposure Guideline Levels TABLE 8-1 Continued Note: NR, not recommended. Numerical values for AEGL-1 are not recommended (1) because of the lack of available data, (2) because 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. Absence of an AEGL-1 does not imply that exposure below the AEGL-2 is without adverse effects. REFERENCES Haun, C.C., J.D. MacEwen, E.H. Vernot, and G.F. Egan. 1970. Acute inhalation toxicity of monomethylhydrazine vapor. Am. Ind. Hyg. Assoc. J. 31(6):667-677. MacEwen, J.D., J. Theodore, and E.H. Vernot. 1970. Human exposure to EEL concentra- tions of monomethylhydrazine. Pp. 355-363 in Proceedings of the 1st Annual Con- ference Environmental Toxicology, September 9-11, 1970, Wright-Patterson Air Force Base, OH. AMRL-TR-70-102, Paper No 23. Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, OH. NRC (National Research Council). 2000. Acute Exposure Guideline Levels for Selected Airborne Chemicals, Vol. 1. Washington, DC: National Academy Press.