6
Dimethylhydrazine1
Acute Exposure Guideline Levels

UPDATE OF DIMETHYLHYDRAZINE AEGLS

In Volume 1 of the series Acute Exposure Guideline Levels for Selected Airborne Chemicals (NRC 2000), 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, with additional discussion to address the development of 10-min values.

SUMMARY

Dimethylhydrazine occurs as a symmetrical (1,2-dimethylhydrazine) and an unsymmetrical (1,1-dimethylhydrazine) isomer. Unless otherwise specified, in this document dimethylhydrazine refers to unsymmetrical dimethylhydrazine. Both compounds are clear, colorless liquids. Unsymmetrical dimethylhydrazine is a component of rocket fuel and is also used as an absorbent 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 the symmetrical isomer is limited to small quantities, and it is usually considered a research chemical. Because data are limited for 1,2-dimethylhydrazine, the AEGL values for both isomers are based on 1,1-dimethylhydrazine. Limited data suggest that 1,1-dimethylhydrazine may be somewhat more toxic than 1,2-dimethylhydrazine.

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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6 Dimethylhydrazine1 Acute Exposure Guideline Levels UPDATE OF DIMETHYLHYDRAZINE AEGLS In Volume 1 of the series Acute Exposure Guideline Levels for Selected Airborne Chemicals (NRC 2000), 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, with additional discus- sion to address the development of 10-min values. SUMMARY Dimethylhydrazine occurs as a symmetrical (1,2-dimethylhydrazine) and an unsymmetrical (1,1-dimethylhydrazine) isomer. Unless otherwise specified, in this document dimethylhydrazine refers to unsymmetrical dimethylhydrazine. Both compounds are clear, colorless liquids. Unsymmetrical dimethylhydrazine is a component of rocket fuel and is also used as an absorbent 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 the symmetrical iso- mer is limited to small quantities, and it is usually considered a research chemi- cal. Because data are limited for 1,2-dimethylhydrazine, the AEGL values for both isomers are based on 1,1-dimethylhydrazine. Limited data suggest that 1,1- dimethylhydrazine may be somewhat more toxic than 1,2-dimethylhydrazine. 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). 173

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174 Acute Exposure Guideline Levels Data on acute exposures of humans to both isomers of dimethylhydrazine are limited to case reports of accidental exposures. Signs and symptoms of ex- posure include respiratory irritation, pulmonary edema, nausea, vomiting, and neurological effects. However, definitive exposure data (concentration and dura- tion) were unavailable for these exposures. The limited data for humans suggest that the nonlethal toxic response to acute inhalation of dimethylhydrazine is qualitatively similar to that observed in animals (no information was available regarding lethal responses in humans). In the absence of quantitative data for 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 irri- tation appear to occur at cumulative exposures of less than 100 ppm multiplied by hours. At cumulative exposures at or only slightly greater than 100 ppm-h, more notable effects have been reported, including muscle fasciculation, behav- ioral changes, tremors, and convulsions. At only slightly higher exposures, le- thality has been demonstrated. The available data suggest that there is very little margin between exposures resulting in no significant toxicity and those causing substantial lethality (the lethal concentration for 50% of the animals was .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 oral exposure, and 6-month inhalation to 1,1-dimethyl- hydrazine resulted in an increased tumor response in mice, although these find- ings are compromised by the contaminant dimethylnitrosamine. U.S. Environ- mental Protection Agency (EPA) inhalation slope factors are currently unavail- able 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 that produce no toxic response and those that result in significant toxicity. Behavioral changes and muscle fasciculations in dogs exposed for 15 min to 360 ppm of 1,1-dimethylhydrazine (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, respec- tively). 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). An uncertainty factor of 3 for interspecies variability was applied because the

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175 Dimethylhydrazine toxic response to dimethylhydrazine was similar across the species tested. This was especially true for lethality responses (LC50 values for various time periods ranging from 5 min to 4 h) among rats, mice, dogs, and hamsters. A comparison of LC50 values for the same exposure durations in these species did not vary by more than 3-fold. An uncertainty factor of 10 was retained for intraspecies vari- ability, however, based primarily on the varied toxic responses observed in dogs, from extremely severe (vomiting, tremors, convulsions, and death) to no observ- able effects. Additionally, Weeks et al. indicated that dogs that had been previ- ously stressed (auditory stimuli) may have potentiated their response to di- methylhydrazine. Based on these data, it was assumed that humans may be equally divergent in their response to dimethylhydrazine as a result of similar stresses. The AEGL-3 was 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 downward to estimate the lethality threshold of 327 ppm. An uncer- tainty factor of 3 for interspecies variability was applied for several reasons. The 4-h LC50 values for mice, rats, and hamsters differ by a factor of approximately 2 and were consistent with the dog data when extrapolated from 1 h using n = 1. The more sensitive species, the dog, was used to derive the AEGL-3 values. An uncertainty factor of 10 for intraspecies variability was retained for several rea- sons. A broad spectrum of effects was seen, including behavioral effects, hyper- activity, fasciculations, tremors, convulsions, and vomiting. The mechanism of toxicity is uncertain, and sensitivity among individuals may vary. Following identical exposures, the responses of the dogs varied from one of extreme sever- ity (vomiting, tremors, convulsions, and death) to no observable effects. Tempo- ral scaling as previously described was applied to obtain exposure values for AEGL-specific exposure periods. Verified inhalation and oral slope factors were unavailable from EPA for dimethylhydrazine. A cancer assessment based on the carcinogenic potential (withdrawn cancer slope factors) of dimethylhydrazine revealed that AEGL val- ues for a 10−4 carcinogenic risk exceeded the AEGL- 2 values that were based on noncancer end points. Because the cancer risk for dimethylhydrazine was estimated from nonverified cancer estimates, 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 end points were considered more appropriate. A summary of AEGL values is shown in Table 6-1.

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176 Acute Exposure Guideline Levels TABLE 6-1 Summary of AEGL Values for 1,1- and 1,2-Dimethylhydrazines End Point Classification 10 min 30 min 1h 4h 8h (Reference) AEGL-1 NR NR NR NR NR Not recommended (nondisabling) due to insufficient data; concentration- response relationships suggest little margin between exposures causing minor effects and those resulting in serious toxicity.a AEGL-2 18 ppm 6 ppm 3 ppm 0.75 ppm 0.38 ppm Behavioral changes (disabling) (44 (14.7 (7.4 (2 (1 and muscle mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) fasciculations in dogs exposed to 360 ppm for 15 min (Weeks et al. 1963). AEGL-3 65 ppm 22 ppm 11 ppm 2.7 ppm 1.4 ppm Lethality threshold of (lethal) (159 (54 (27 (6.6 (3.4 327 ppm for 1 h mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) estimated from 1-h LC50 in dogs (Weeks et al. 1963). a Refer to AEGL-1 for hydrazine if hydrazine is also present. 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) because 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 NRC (National Research Council). 2000. Acute Exposure Guideline Levels for Selected Airborne Chemicals, Vol. 1. Washington, DC: National Academy Press. Weeks, M.H., G.C. Maxey, M.E. Sicks, and E.A. Greene. 1963. Vapor toxicity of UDMH in rats and dogs from short exposures. Am. Ind. Hyg. Assoc. J. 24:137- 143.