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Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals Appendix E Example of a Summary of A Technical Support Document SUMMARY Dimethylhydrazine occurs as symmetrical (1,2-dimethylhydrazine) and unsymmetrical (1,1-dimethylhydrazine) isomers. Unless otherwise specified, dimethylhydrazine refers to unsymmetrical dimethylhydrazine in this document. Both compounds are clear, colorless liquids. 1,1-Dimethylhydrazine is a component of rocket fuels and is also used as an adsorbent for acid gas, as a plant-growth control agent, and in chemical synthesis. Although it has been evaluated as a high-energy rocket fuel, commercial use of 1,2-dimethylhydrazine is limited to small quantities, and it is usually considered to be a research chemical. Because data are limited for 1,2-dimethylhydrazine, the acute exposure guideline level (AEGL) values for both isomers are based upon 1,1-dimethylhydrazine. Limited data suggest that 1,1-dimethylhydrazine may be somewhat more toxic than 1,2-dimethylhydrazine. Data on acute exposures of humans to both isomers of dimethylhydrazine are limited to case reports of accidental exposures. Signs and symptoms of exposure include respiratory irritation, pulmonary edema, nausea, vomiting, and neurologic effects. However, definitive exposure data (concentration and duration) were unavailable for these accidents. The limited data in humans suggest that the nonlethal toxic response to acute inhalation of dimethylhydra-
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Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals zine is qualitatively similar to that observed in animals. No information was available regarding lethal responses in humans. In the absence of quantitative data in humans, the use of animal data is considered a credible approach for developing AEGL values. Toxicity data of varying degrees of completeness are available for several laboratory species, including, rhesus monkeys, dogs, rats, mice, and hamsters (Weeks et al. 1963). Most of the animal studies were conducted using 1,1-dimethylhydrazine, although limited data suggest that 1,2-dimethylhydrazine exerts similar toxic effects. Minor nonlethal effects such as respiratory tract irritation appear to occur at cumulative exposures of less than 100 parts per million multiplied by hours (ppm·h). At cumulative exposures of 100 ppm·h or slightly greater than this level, more notable effects have been reported, including, muscle fasciculation, behavioral changes, tremors, and convulsions. Lethality has been demonstrated when cumulative exposures exceed these levels only slightly. The available data suggest that there is a very narrow margin between exposures resulting in no significant toxicity and those causing substantial lethality (the lethal concentration for 50% of the animals (LC50)≈900–2,000 ppm·h). Developmental toxicity of dimethylhydrazines has been demonstrated in rats following parenteral administration of maternally toxic doses. Both isomers of dimethylhydrazine have been shown to be carcinogenic in rodents following chronic oral exposure and 6-mon inhalation exposure to 1,1-dimethylhydrazine. Increased tumor incidence was observed in mice, although these findings are compromised by the contaminant exposure to dimethylnitrosamine. An increased incidence of lung tumors and hepatocellular carcinomas was also seen in rats but not in similarly exposed hamsters. The U.S. Environmental Protection Agency (U.S. EPA) inhalation slope factors are currently unavailable for dimethylhydrazine. AEGL-1 values for dimethylhydrazine are not recommended because of inadequate data to develop health-based criteria and because the concentration-response relationship for dimethylhydrazine indicated that a very narrow margin exists between exposures producing no toxic response and those resulting in significant toxicity. Behavioral changes and muscle fasciculations in dogs exposed for 15 min to 1,1-dimethylhydrazine at 360 ppm (Weeks et al. 1963) served as the basis for deriving AEGL-2 values. Available lethality data in dogs and rats indicated a near linear temporal relationship (n=0.84 and 0.80 for dogs and rats, respectively). For temporal scaling (C1×t=k) to derive values for AEGL-specific exposure durations, a linear concentration-response relationship, n=1, was used. (C=exposure concentration, t=exposure duration, and k=a constant.) This value was adjusted by an uncertainty factor of 30. An uncer-
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Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals tainty factor of 3 for interspecies variability was applied, because the toxic response to dimethylhydrazine was similar across the species tested. This was especially true for lethality among rats, mice, dogs, and hamsters with LC50 values for time periods ranging from 5 min to 4 h. A comparison of LC50 values for the same exposure durations in these species did not vary more than 3-fold. An uncertainty factor of 10 was used for intraspecies variability. This factor was based primarily on the variability observed in dogs in which responses varied from one of extreme severity (vomiting, tremors, convulsions, and death) to no observable effects. Additionally, Weeks et al. (1963) indicated that dogs previously stressed by auditory stimuli may have potentiated their response to dimethylhydrazine. Based on these data, it was assumed that humans may be equally variable in their response to dimethylhydrazine as a result of similar stresses. The AEGL-3 values were derived from the 1-h LC50 (981 ppm) for 1,1-dimethylhydrazine in dogs (Weeks et al. 1963). Because of the steep slope of the dose-response curve of 1,1-dimethylhydrazine, the 1-h LC50 of 981 ppm was adjusted to estimate the lethality threshold of 327 ppm. An uncertainty factor of 3 for interspecies variability was applied for several reasons. The 4-h LC50 values for mouse, rat, and hamster differ by a factor of approximately 2 and were consistent with the dog data when extrapolated from 1 h using n=1. The more susceptible species, the dog, was used to derive the AEGL-3 values. An uncertainty factor of 10 for intraspecies variability was used because a broad spectrum of effects were seen including behavioral effects, hyperactivity, fasciculations, tremors, convulsions, and vomiting. The mechanism of toxicity is uncertain, and susceptibility among individuals may vary. Following identical exposures, the responses of the dogs varied from one of extreme severity (vomiting, tremors, convulsions, and death) to no observable effects. Temporal scaling as previously described was applied to obtain exposure values for AEGL-specific exposure periods. Verified inhalation and oral slope factors were unavailable from U.S. EPA for dimethylhydrazine. A cancer assessment based upon the carcinogenic potential (withdrawn cancer slope factors) of dimethylhydrazine revealed that AEGL values for a theoretical excess lifetime 10−4 carcinogenic risk exceeded the AEGL-2 values that were based on noncancer endpoints. Because the risk for dimethylhydrazine exposure was estimated from nonverified sources and 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 to be more appropriate.
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Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals Summary of AEGL Values for 1,1- and 1,2-Dimethylhydrazines Classification 30 min 1 h 4 h 8 h Endpoint (Reference) AEGL-1 (Nondisabling) NR NR NR NR Not recommended due to insufficient data; concentration-response relationships suggest little margin between exposures causing minor effects and those resulting in serious toxicitya AEGL-2 (Disabling) 6 ppm (14.7 mg/m3) 3 ppm (7.4 mg/m3) 0.75 ppm (2 mg/m3) 0.38 ppm (1 mg/m3) Behavioral changes and muscle fasciculations in dogs exposed at 360 ppm for 15 min (Weeks et al. 1963) AEGL-3 (Lethal) 22 ppm (54 mg/m3) 11 ppm (27 mg/m3) 2.7 ppm (6.6 mg/m3) 1.4 ppm (3.4 mg/m3) Lethality threshold of 327 ppm for 1 h estimated from 1-h LC50 in dogs (Weeks et al. 1963) Numeric values for AEGL-1 are not recommended because (1) available data are lacking, (2) data indicate that toxic effects may occur at or below the odor threshold, (3) the margin of safety that exists between the derived AEGL-1 and the AEGL-2 is inadequate, or (4) 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. Abbreviations: NR, not recommended; ppm, parts per million; mg/m3, milligrams per cubic meter. Reference: Weeks, M.H., Maxey, G.C., Sicks, Greene, E.A. 1963. Vapor toxicity of UDMH in rats and dogs from short exposures. American Industrial Hygiene Association Journal 24:137–143.
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