4

Dimethylhydrazine1
Acute Exposure Guideline Levels

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.

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 155
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 4 Dimethylhydrazine1 Acute Exposure Guideline Levels 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. 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 155
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 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 dimethylhydrazine 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

OCR for page 155
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 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 uncertainty 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 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 divergent 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 sensitive species, the dog, was used to derive the AEGL-3 values. An uncertainty factor of 10 for intraspecies variability was used since a broad spectrum of effects were seen including behavioral effects, hyperactivity, 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 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 expo-

OCR for page 155
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 sures to a limited geographic area and small population, the AEGL values based on noncarcinogenic endpoints were considered to be more appropriate. The derived AEGLs are listed in Table 4–1. 1. INTRODUCTION Dimethylhydrazine occurs as 1,2-dimethylhydrazine and 1,1-dimethylhydrazine isomers. Both compounds are clear, colorless liquids (Trochimowicz 1994). 1,1-Dimethylhydrazine is a component of jet and rocket fuels and is also used as an absorbent for acid gas, as a plant-growth control agent, and as a feedstock in chemical syntheses. 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 (Trochimowicz 1994). Trochimowicz (1994) published a review of the toxicology of dimethylhydrazines with most of the data obtained from studies with 1,1-dimethylhydrazine. Early data on the pharmacologic and toxicologic effects of dimethylhydrazines in laboratory animals by various routes of administration were summarized and noted involvement of the central nervous system, lungs, liver, and kidneys as targets. In the 1950s, additional studies were conducted to assess the acute toxicity of various hydrazines in animals following various routes of exposure. The toxicology of dimethylhydrazines has also been reviewed 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 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 dimethylhydrazines are presented in Table 4–2. 2. HUMAN TOXICITY DATA 2.1. Acute Lethality No information was located regarding the acute lethality to humans following inhalation exposure to dimethylhydrazine.

OCR for page 155
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 TABLE 4–1 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 toxicity.a 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) the lack of available data, (2) data indicate that toxic effects may occur at or below the odor threshold, (3) the inadequate margin of safety that exists between the derived AEGL-1 and the AEGL-2, 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.

OCR for page 155
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 TABLE 4–2 Chemical and Physical Data for Dimethylhydrazines Parameter Value Reference Synonyms 1,1-dimethylhydrazine, unsymmetrical-dimethylhydrazine, asymmetrical-dimethylhydrazine UDMH, N,N-dimethylhydrazine, Dimazine; 1,2-dimethylhydrazine, symmetrical dimethylhydrazine, SDMH, N,N'-dimethylhydrazine Budavari et al. 1989 Chemical formula (CH3)2N-NH2 (1,1-dimethylhydrazine) CH3-NH-NH-CH3 (1,2-dimethylhydrazine) Trochimowicz et al. 1994 Molecular weight 60 U.S. EPA 1987 CAS Registry No. 57–14–7 (1,1-dimethylhydrazine) 540–73–8 (1,2-dimethylhydrazine) Budavari et al. 1989 Physical description liquid U.S. EPA 1987 Solubility soluble in water and alcohol; practically insoluble in ether ACGIH 1996 Vapor pressure 156.8 mm Hg at 25°C (1,1-dimethylhydrazine) 69.6 mm Hg at 25°C (1,2-dimethylhydrazine) Jacobson et al. 1955 Specific gravity 0.782 at 25°C ACGIH 1996 Boiling/melting point/flash point 63.9°C/–58°C/–15°C (closed cup) Budavari et al. 1989 Odor threshold 6–14 ppm; ammonia-like odor ACGIH 1996 Conversion factors in air 1 mg/m3=0.41 ppm (unsymmetrical) 1 ppm=2.45 mg/m3 Trochimowicz et al. 1994 2.2. Nonlethal Toxicity 2.2.1. Acute Exposure Case Reports Information regarding human exposures to dimethylhydrazine are limited to a few case reports. Although case reports provide qualitative data regarding signs and symptoms of exposure, no exposure concentration data or precise exposure duration data were reported. Signs and symptoms of exposure included respiratory effects, nausea, vomiting, neurologic effects, pulmonary edema, and increased serum enzyme levels (reviewed in Trochimowicz et al. 1994).

OCR for page 155
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 Inhalation (approximately 90-min duration) by two workers of Aerozine-50 (a 1:1 (weight/weight) mixture of hydrazine and 1,1-dimethylhydrazine) resulted in odor detection followed by a complaint of headache, nausea, weakness, burning of the skin, tightness in the chest, and soreness of the throat by one man (Frierson et al. 1965). Pyridoxine successfully ameliorated all symptoms except the tightness in the chest; bilateral pulmonary edema, wet rales, and tachypnea were later detected upon clinical examination. Subsequent examination some weeks later revealed no hematologic, pulmonary, hepatic, or renal sequelae. The second worker, although donning an air supply upon recognition of exposure, suffered severe dyspnea that forced egress from the situation. This individual developed pulmonary edema but recovered after pyridoxine and oxygen therapy and rest. An additional four workers were exposed to high levels of Aerozine-50 (no specific concentration values available) for about 2 h experienced severe nausea and vomiting, which was also successfully treated with intravenous pyridoxine. Shook and Cowart (1957) provided a brief report regarding two individuals exposed during an accidental spillage of 1,1-dimethylhydrazine. Although exposure concentration data were not available, it was noted that the two men were approximately 750 yards from the spill. After being exposed to the release, the men experienced choking and difficulty in breathing. Four hours later both subjects became extremely nauseated and retained the odor and taste of the chemical for an unspecified period of time. This case report also provided evidence of subclinical hepatotoxicity in a group of workers following several months of occupational exposure to low (but unspecified) concentrations of 1,1-dimethylhydrazine. 2.2.2. Epidemiologic Studies Epidemiologic studies regarding human exposure to dimethylhydrazine were not available. 2.3. Developmental and Reproductive No data were available regarding the potential reproductive and developmental toxicity of dimethylhydrazine in humans. 2.4. Genotoxicity Human genotoxicity data applicable to AEGL development for dimethylhydrazine were not available.

OCR for page 155
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 2.5. Carcinogenicity No data are available regarding the potential carcinogenicity of dimethylhydrazine in humans. 2.6. Summary The human experience regarding exposure to dimethylhydrazines is limited to case reports describing severe but nonlethal effects following accidental acute exposures. There are limited data suggesting subclinical hepatotoxicity following subchronic occupational exposure to unspecified low levels of 1,1-dimethylhydrazine. No definite exposure concentrations or durations were available in these reports, and the data are not useful for quantitative derivation of AEGLs. 3. ANIMAL TOXICITY DATA 3.1. Acute Lethality Acute lethality studies in laboratory species are summarized in the following sections. The LC50 and other lethality values from these studies are summarized in Table 4–3. 3.1.1 Nonhuman Primates No data were available regarding lethality in nonhuman primates following acute exposures to dimethylhydrazines. 3.1.2. Dogs Jacobson et al. (1955) reported the deaths of dogs following 4-h exposures to 1,1-dimethylhydrazine at concentrations of 24, 52, or 111 ppm (192-min exposure). Mortality was 0/3, 1/3, and 3/3 for the three exposure groups, respectively. All deaths or terminations (one dog in the high-exposure group was terminated in extremis) occurred within the first day of initiation of exposure. All three dogs in the highest exposure group exhibited vomiting, panting, and convulsions prior to death. The one dog that died in the 52-ppm group also exhibited these signs prior to death, while the two surviving dogs exhibited

OCR for page 155
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 TABLE 4–3 Summary of Lethality Data for Dimethylhydrazine in Laboratory Species Species Toxicity Value (ppm) C×t (ppm·h) Comments Reference Rat 4-h LC50: 252 (1,1-DMH) 1,008   Jacobson et al. 1955 Rat 4-h: 338 (1,2-DMH) 4-h: 285 (1,2-DMH) 4-h: 210 (1,2-DMH) 4-h: 435 (1,2-DMH) 1,352 1,140 840 1,740 50% mortality but not statistically-derived LC50 20% mortality 100% mortality Jacobson et al. 1955 Rat 4-h LC50: 252 (1,1-DMH) 1-h LC50: 1,410 (1,1-DMH) 30-min LC50: 4,010 (1,1-DMH) 15-min LC50: 8,230 (1,1-DMH) 5-min LC50: 24,500 (1,1-DMH) 1,008 1,410 2,005 2,058 2,042 Mortality over 24 h Weeks et al. 1963 Mouse 4-h LC50: 172 (1,1-DMH) 688   Jacobson et al. 1955 Hamster 4-h LC50: 392 (1,1-DMH) 1,568   Dog 192 min: 111 (1,1-DMH) 4-h: 52 (1,1-DMH) 355 208 100% mortality 33% mortality Jacobson et al. 1955 Dog 1-h LC50: 981 (1,1-DMH) 15-min LC50: 3,580 (1,1-DMH) 5-min LC50 22,300 (1,1-DMH) 981 895 1,858 Mortality over 24 h Weeks et al. 1963 Abbreviation: DMH: dimethylhydrazine.

OCR for page 155
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 nausea, panting, and incoordination, or no signs of toxicity. One dog in the low-exposure group also exhibited vomiting and convulsions but did not die. No changes were observed in hematologic values (hemoglobin level, red-blood-cell counts, leukocyte counts, prothrombin times) in any of the surviving dogs. Necropsy revealed pulmonary edema and patchy hemorrhage only in animals that had convulsions, possibly resulting from the seizures rather than direct test-article action. An LC50 was not estimated by the investigators. In a study reported by Rinehart et al. (1960), three male beagle dogs were exposed to 1,1-dimethylhydrazine at 25 ppm 6 h/d, 5 d/w for 26 w. Although one dog died after the third exposure (equivalent to a Ct of 450 ppm·h), the exposure was discontinuous, making application of that result to AEGL development difficult. One of the other two dogs exhibited similar signs of toxicity without death and the other exhibited no sign of toxicity (see Section 3.2.2). Weeks et al. (1963) studied the outcome of 1,1-dimethylhydrazine inhalation on mongrel dogs (groups of three) exposed for 5, 15, or 60 min to various concentrations. During exposure, signs of toxicity were limited to licking of the lips and nose, and vomiting. After the exposure, all dogs appeared dazed and depressed, and sharp noises induced shivering and cowering. Intermittent tonicoclonic convulsions (2–15 min duration) were observed in dogs just prior to death and in some dogs that survived. Dogs that survived appeared to be completely recovered by 48 h post-exposure, and all deaths occurred within 24 h. The LC50 values for the 5, 15, and 60-min exposures were 22,300, 3,580, and 981 ppm, respectively (Table 4–3). The slope of the exposure-response curve for 5-min exposures was steep (221.0, standard error (SE)=207.0); for 15 and 60 min, the slopes were 3.9 (SE=2.2) and 14.7 (SE=7.8), respectively). Because external auditory stimuli appeared to affect the response of dogs exposed to 1,1-dimethylhydrazine, additional experiments were carried out using dogs that were stressed by auditory, visual, and/or electrical stimuli. Generally, neurobehavioral responses were observed at exposure concentrations that previously had caused no response. For the 5-min exposure, one of two dogs that died was exposed to 1,1-dimethylhydrazine at 4,230 ppm. No dogs exposed for 15 min died, but tremors and vomiting occurred in two of four dogs exposed at 610 ppm, and one of three dogs exposed at 360 ppm exhibited muscle fasciculations. For the 60-min exposures, two of three dogs exposed at 400–500 ppm died, one of three dogs exposed at 200–250 ppm died, and one of four dogs exposed at 80–120 ppm exhibited slight tremors. Minimal response resulted from exposures to 1,1-dimethylhydrazine at 1,200, 400, and 100 ppm for 5, 15, and 60 min, respectively. A 1-h exposure at 96 ppm represents a no-observed-effect level for mongrel dogs. There were no gross or histopathologic changes observed in any dogs that could be attributed to exposure to the test article.

OCR for page 155
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 3.1.3. Rats Jacobson et al. (1955) assessed the lethality of 1,2-dimethylhydrazine and 1,1-dimethylhydrazine in rats following a 4-h exposure. Lethality was assessed over a 14-d post-exposure variability in the response. For 1,1-dimethylhydrazine, an LC50 of 252 ppm was calculated, and an LC20 of 210 ppm (515 mg/m3) was estimated from the exposure-response graphs in the report. The exposure-response curve was steep (slope = 8.65; SE = 2.8), suggesting very little variability among the test groups. Preliminary studies with 1,2-dimethylhydrazine were also reported: 2/10, 5/10, and 5/5, rats died respectively, after a single 4-h exposure at 285, 338, or 435 ppm (Jacobson et al. 1955). During the exposure, the rats were restless and exhibited dyspnea, convulsions, and exophthalmos. Although an LC50 was not estimated, review of these data suggest that 1,2-dimethylhydrazine is somewhat less toxic under these experimental conditions in this species and strain. For 1,2-dimethylhydrazine, lethality was assessed over a 7-d period. Weeks et al. (1963) exposed male rats (10 per group) to various concentrations of 1,1-dimethylhydrazine for periods of 5, 15, 30, 60, and 240 min. Rats exposed to 1,1-dimethylhydrazine showed signs of irritation (sneezing, eye closure, restlessness). In animals that died, deaths occurred within 24 h post-exposure and were preceded by alternating periods of tonicoclonic convulsions and depressed activity. For the 5-, 15-, 30-, 60-, and 240-min exposure periods, LC50 values of 24,500, 8,230, 4,010, 1,410, and 252 ppm were reported by the study authors (Table 4–3). 3.1.4. Mice Acute toxicity assays using groups of 20 mice (strain not specified) exposed to 1,1-dimethylhydrazine 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 172 ppm was reported and an LC20 of 140 ppm was estimated from the exposure-response curve presented by the study authors. Post-mortem examination of the mice revealed no significant histopathologic findings other than pulmonary edema and occasional, localized pulmonary hemorrhage. The hemorrhaging was, however, considered to be secondary to the observed convulsions and not a direct effect of dimethylhydrazine in those tissues. The exposure-response curve was steep (slope=8.52; SE=1.9), suggesting little variability among the test groups. Analytical concentrations of 1,1-dimethylhydrazine averaged 75% of nominal, which suggested that there were difficulties in accurately maintaining or measuring test article concentrations.

OCR for page 155
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1   was similar across the species tested. This was especially true for lethality responses (LC50 values for varying 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 more than 3-fold. An uncertainty factor of 10 was retained for intraspecies variability (protection of sensitive populations). A broad spectrum of effects were seen that included behavioral effects, hyperactivity, fasciculations, tremors, convulsions, and vomiting. The mechanism of toxicity is uncertain and sensitivity among individuals regarding these effects 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. A factor of 10 was also retained because experiments by Weeks et al. (1963) indicated that dogs that had been previously stressed (auditory stimuli) were more sensitive to the adverse effects of dimethylhydrazine. Calculations: 327 ppm/30=10.9 ppm C1×t=k 11.9 ppm×60 min=654 ppm-min Time scaling: C1×t=k (ten Berge et al. 1986) 11.9 ppm1×60 min=654 ppm-min LC50 data were available for 5, 15, 30, 60, and 240-min exposures in rats and 5, 15, and 60 min in dogs. Exposure-response data indicated a near linear concentration-response relationship (n=0.84 for rats, n=0.80 for dogs). For time-scaling, a linear relationship was assumed and a value of n =1 was selected. 30-min AEGL-2: C1×30 min=654 ppm·min C=22 ppm 1-h AEGL-2: C1×60 min=654 ppm·min C=11 ppm 4-h AEGL-2: C1×240 min=654 ppm-min C=2.7 ppm 8-h AEGL-2: C1×480 min=654 ppm-min C=1.4 ppm

OCR for page 155
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 APPENDIX B TIME SCALING CALCULATIONS FOR DIMETHYLHYDRAZINE 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 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 concentration vs time 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 dimethylhydrazine. Dimethylhydrazine dog data from Weeks et al. 1963 The LC50 values for 5-, 15-, and 60-min exposures were 22,300, 3,580, and 981 ppm, respectively.

OCR for page 155
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 Time Concentration Log Time Log Concentration 5 22,300 0.6990 4.3483 15 3,580 1.1761 3.5539 60 981 1.7782 2.9917 n=0.8 Calculated LC50 values: Min Concentration 30 2036.15 60 860.12 240 153.48 480 64.83

OCR for page 155
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 Dimethylhydrazine rat data from Weeks et al. 1963 The LC50 values for 5-, 15-, 30-, 60-, and 240-min exposures were 24,500, 8,230, 4,010, 1,410, and 252 ppm, respectively. Time Concentration Log Time Log Concentration 5 24,500 0.6990 4.3892 15 8,230 1.1761 3.9154 60 4,010 1.4771 3.6031 240 252 2.3802 2.4014 n=0.84 Calculated LC50 values: Min Concentration 30 3,323.28 60 1,449.93 240 276.00 480 120.42

OCR for page 155
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 APPENDIX C CARCINOGENICITY ASSESSMENT OF DIMETHYLHYDRAZINE 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. EPA1986). For a preliminary carcinogenicity assessment, the withdrawn inhalation slope factor for 1,1-dimethylhydrazine (cited in ATSDR 1994) will be used. 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 a theoretical 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 To account for uncertainty regarding the variability in the stage of the cancer process at which monomethylhydrazine or its metabolites may act, a multistage factor of 6 is applied (Crump and Howe 1984): (2.56 mg/m3)/6=0.43 mg/m3 (0.18 ppm) Therefore, based upon the potential carcinogenicity of monomethylhydrazine, an acceptable 24-h exposure would be 0.9 mg/m3 (0.5 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=0.43 mg/m3 (0.18 ppm) 8-h=1.3 mg/m3 (0.5 ppm) 4-h=2.6 mg/m3 (1.1 ppm) 1-h=10.3 mg/m3 (4.2 ppm) 0.5h=20.6 mg/m3 (8.5 ppm)

OCR for page 155
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 Because the AEGL-2 values based upon acute toxicity were equivalent to or lower than the 10–4 risk values derived based on potential carcinogenicity, the acute toxicity data were used for the AEGLs for dimethylhydrazine. For 10–5 and 10–6 risk levels, the 10–4 values are reduced by 10-fold or 100-fold, respectively.

OCR for page 155
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 APPENDIX D DERIVATION SUMMARY FOR ACUTE EXPOSURE GUIDELINE LEVELS FOR DIMETHYLHYDRAZINE (CAS No. 57–14–7; 1,1-Dimethylhydrazine) (CAS No. 540–73–8; 1,2-Dimethylhydrazine) AEGL-1 Values 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: Numeric values for AEGL-1 are not recommended because (1) data are not available, (2) data indicate that toxic effects may occur at or below the odor threshold, (3) an inadequate margin of safety exists between the derived AEGL-1 and the AEGL-2, 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.

OCR for page 155
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 AEGL-2 Values 30 min 1 h 4 h 8 h 6.0 ppm 3.0 ppm 0.75 ppm 0.38 ppm Reference: Weeks, M.H., G.C.Maxey, M.E.Sicks, and E.A.Greene. 1963. Vapor toxicity on UDMH in rats and dogs from short exposures. Am. Ind. Hyg. Assoc. J. 24:137–143 Test Species/Strain/Sex/Number: mongrel dogs, 2–4/group, sex not specified Exposure Route/Concentrations/Durations: Inhalation; 1,200–4,230 ppm for 5 min; 360, 400, or 1,530 ppm for 15 min; 80–250 ppm for 60 min Effects: Exposure (15 min) Effect 360 ppm muscle fasciculations in 1 of 4 dogs (determinant for AEGL-2) 400 ppm behavioral changes in 2 of 4 dogs 1,530 ppm tremors, convulsions, vomiting in 2 of 2 dogs Endpoint/Concentration/Rationale: 15-min exposure at 360 ppm considered a threshold for potentially irreversible effects or effects that would impair escape. At this exposure, muscle fasciculations were observed in 1 of 4 exposed dogs, and at 400 ppm, behavioral changes were observed. Uncertainty Factors/Rationale: Total uncertainty factor: 30 Interspecies: 3—The toxic response to dimethylhydrazine (LC50 values) was similar across species. 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 sensitive species, the dog, was used to derive the AEGL-2 values. Intraspecies: 10—A broad spectrum of effects were seen, including behavioral effects, hyperactivity, fasciculations, tremors, convulsions, and vomiting. The mechanism of toxicity is uncertain and sensitivity among individuals regarding these effects may vary. This variability was especially demonstrated in dogs wherein responses varied from one of extreme severity (vomiting, tremors, convulsions, and death) to no observable effects. Therefore, a factor of 10 was retained. A factor of 10 was also retained because experiments by Weeks et al. (1963) indicated that dogs had been previously stressed (auditory stimuli), which may have affected their response to dimethylhydrazine. Based upon these data, it was assumed that humans may be equally divergent in their response to dimethylhydrazine.

OCR for page 155
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 Modifying Factor: None Animal to Human Dosimetric Adjustment: None applied, insufficient data Time Scaling: Cn×t=k, where n=1 and k=180 ppm·min; LC50 data were available for 5-, 15-, 30-, 60-, and 240-min exposures in rats and 5-, 15-, and 60-min in dogs. Exposure-response data indicated a near linear concentration-response relationship (n=0.84 for rats; n=0.80 for dogs). For time-scaling, a linear relationship was assumed and a value where n= 1 was selected. Data Adequacy: Information regarding the human experience for acute inhalation exposure to dimethylhydrazine are limited to qualitatively case reports indicating nasal and respiratory tract irritation, breathing difficulties, and nausea. Data in animals have shown concentration-dependent effects ranging from respiratory tract irritation, pulmonary edema and neurologic effects to lethality. Because the nonlethal effects in humans and animals are qualitatively similar, the animal data were considered relevant and appropriate for development of AEGL values. The AEGL values for dimethylhydrazine reflect the steep exposure-response relationship suggested by available data.

OCR for page 155
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 AEGL-3 Values 30 min 1 h 4 h 8 h 22 ppm 11 ppm 2.7 ppm 1.4 ppm Reference: 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 Test Species/Strain/Sex/Number: mongrel dogs, 3–4/group; sex not specified Exposure Route/Concentrations/Durations: Inhalation; exposure to various concentrations (80–22,300 ppm) for 5, 15, or 60 min Effects: 1-h LC50 981 ppm (reduction by 1/3 was basis for AEGL-3 derivation) 15-min LC50 3,580 ppm 5-min LC50 22,300 ppm Endpoint/Concentration/Rationale: 1-h LC50 (981 ppm) reduced by 1/3 was considered an estimate of the lethality threshold (327 ppm). Based on the available exposure-response data for this chemical (Jacobson et al. 1955), a 3-fold reduction in LC50 values results in exposures that would not be associated with lethality. Uncertainty Factors/Rationale: Total uncertainty factor: 30 Interspecies: 3—The toxic response to dimethylhydrazine (LC50 values) was similar across species. 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 sensitive species, the dog, was used to derive the AEGL-3 values. Intraspecies: 10—A broad spectrum of effects were seen, including behavioral effects, hyperactivity, fasciculations, tremors, convulsions, and vomiting. The mechanism of toxicity is uncertain, and sensitivity among individuals regarding these effects may vary. This variability was especially demonstrated in dogs wherein responses varied from one of extreme severity (vomiting, tremors, convulsions, and death) to no observable effects. Therefore, a factor of 10 was used. A factor of 10-fold was also used because experiments by Weeks et al. (1963) indicated that dogs previously stressed by auditory stimuli may have a potentiated response to dimethylhydrazine. Based upon these data, it was assumed that humans may be equally divergent in their response to dimethylhydrazine subsequent to similar stresses.

OCR for page 155
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 Modifying Factor: None Animal to Human Dosimetric Adjustment: None applied, insufficient data Time Scaling: Cn×t=k, where n=1 and k=654 ppm-min; LC50 data were available for 5-, 15-, 30-, 60-, and 240-min exposures in rats and 5-, 15-, and 60-min in dogs. Exposure-response data indicated a near linear concentration-response relationship (n=0.84 for rats; n=0.80 for dogs). For time-scaling, a linear relationship was assumed and a value where n= 1 was selected by the National Advisory Committee. Data Adequacy: Information regarding the lethality of dimethylhydrazine in humans were not available. Lethality data for several animal species allowed for a defensible development of the AEGL-3 values but uncertainties remain regarding individual variability in the toxic response to dimethylhydrazines.