Acute Exposure Guideline Levels for Selected Airborne Chemicals Volume 1 (2000) / Chapter Skim
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Dimethylhydrazine: Acute Exposure Guideline Levels
Dimethylhydrazine: Acute Exposure Guideline Levels
Pages 155-201
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From page 155... ...
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 ofthe Oak Ridge National Laboratory.
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From page 156... ...
AEGL-l values for dimethy~hydrazine are not recommended because of inadequate data to develop health-based criteria and because the concentrationresponse relationship for dimethyThydrazine 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 ~ 5 min to I,1-dimethyThydrazine at 360 ppm (Weeks et al.
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From page 157... ...
A cancer assessment based upon the carcinogenic potential (withdrawn cancer slope factors) of dimethyThydrazine revealed that AEGL values for a theoretical excess lifetime 10-4 carcinogenic risk exceeded the AEGL- 2 values that were based on noncancer endpoints.
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From page 158... ...
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.
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159 .~ o · =N =^ ~ Z ._ > ~ Z ¢ to ~ E o Z ~ _~ lo .= ~ ._ ARC Cq .^ Ct ~ ct be ._ ._ C)
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From page 160... ...
Acute Exposure Case Reports Info~ ~ation regarding human exposures to dimethyThydrazine are limited to a few case reports. Although case reports provide quaTitative data regarding signs and symptoms of exposure, no exposure concentration data or precise exposure duration data were reported.
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1965~. Pyridoxine successfully ameliorated all symptoms except the tightness in the chest; bilateral pulmonary edema, wet rates, and tachypnea were later detected upon clinical examination.
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2.6. Summary The human experience regarding exposure to dimethy~hydrazines is limited to case reports describing severe but nonlethal effects following accidental acute exposures.
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163 _ Ct o Cal o l,, ~ _ sol Cal ._ ~ b o o o V .= .= b4 X ~ V .s o En' ~~ so Ce ~ en ~ ~ - ^ ~ ~ ____ ....
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From page 164... ...
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 ofthree dogs exposed at 400-500 ppm died, one ofthree dogs exposed at 200-250 ppm died, and one of four dogs exposed at 80-120 ppm exhibited slight tremors.
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From page 165... ...
An LCso 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.
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From page 166... ...
Although one monkey died at 41 6, there were no deaths or clinical signs of toxicity during the exposure period. Additionally, there were no significant alterations in clinical chemistry parameters throughout the exposure period; however, clinical data were obtained only at 30,60, and 90 during exposure, and no definitive observations were provided for acute exposure durations.
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From page 167... ...
For this study, mongrel dogs were first stressed by auditory, visual, and/or electrical stimuli and subsequently subjected to varying concentrations of 1,1-dimethy~hydrazine for 5, 15, or 60 min. Five-minute exposures oftwo dogs at concentrations as high as ~ ,200 ppm produced no signs of toxicity, while exposure at 1,550 ppm resulted in behavioral changes (depression)
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From page 168... ...
. Because laboratory data were recorded only at 30, 60, and 90 6, no inferences could be made regarding potential effects of acute exposures.
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From page 169... ...
reported that 1 ,1 -dimethyThydrazine failed to increase reversions in Salmonella typhimurium or Saccharomyces cerevisiae gene mutation assays with or without metabolic activation. A concentrationrelated response was observed in the mouse lymphoma assay (with activation)
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From page 170... ...
Included were the Ames' Salmonelia/microsome assay, a microbial suspension assay, mutation induction at the TK locus in L5178Y mouse lymphoma cells, stimulation of UDS in WI-38 cells, and a dominant lethal assay in mice. 1,1-Dimethy~hydrazine was active in all of the tests except the dominant lethal assay.
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From page 171... ...
3.6. Summary Inhalation lethality data are available for several laboratory species, including dogs, rats, mice, and hamsters.
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Cumulative exposures of <90 ppm h were not associated with clinical signs oftoxicity, although there is little margin between such exposures and those that induce significant toxic responses; e.g., notable but nonlethal effects have been reported for exposures of 90 ppm h. An assessment of the limited data for dogs suggests that this species may be somewhat more sensitive than other species and that hamsters are the least sensitive.
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From page 173... ...
In addition to the contact irritant effects, the acute effects of dimethy~hydrazine exposure may involve the central nervous system as exemplified by tremors and convulsions (Shaffer and Wands 1973) and behavioral changes at sublethal doses (Streman et al.
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Species Variability Compared with other tested species, hamsters appear to be resistant to the lethal effects of acute exposure to monomethyThydrazine. Within similar exposure durations, the cumulative exposure data (exposure concentration x time)
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5.2. Summary of Animal Data Relevant to AEGL-1 Continuous exposure of rhesus monkeys to I, 1-dimethyThydrazine at 0.43 ppm resulted in no reported signs of toxicity during the first 30 ~ of a 90-d exposure period, thereby implying that this exposure caused no notable signs of toxicity (House 1964~.
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From page 176... ...
1963) resulted in cumulative exposures of 96 ppm h that produced no significant toxic effects in two of three dogs examined, although, as previously described, notable effects were seen in one dog.
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An uncertainty factor of ~ O was retained for intraspecies variability, however, based primariTy upon the variability in the response observed in dogs. This variability was especially demonstrated in dogs wherein responses varied from one of extreme severity (vomiting, tremors, convulsions, and death)
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From page 178... ...
Based upon the available data, dogs appeared to be the most sensitive species tested. Although LCso values for various exposure periods were available for rats and dogs, and 4-h LCsoS were available for mice and hamsters, available data did not identify a definitive lethal threshold for inhalation exposure to dimethy~hydrazine.
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From page 179... ...
The more sensitive species, the dog, was used to derive the AEGL-3 values. An uncertainty factor of 10 was retained for intraspecies variability, and it was based primarily on the variability of response observed in dogs; this variability was demonstrated in dogs whereinresponses varied from one of extreme severity (vomiting, tremors, convulsions, and death)
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From page 180... ...
No AEGL-1 values were developed because data indicated that overt toxicity may become manifest at or below the odor threshold and because the exposure-response relationship for dimethy~hydrazine suggest little margin between exposures resulting in no observable effects and those producing significant toxicity. The AEGL-2 is based upon data showing only behavioral changes and moderate neuromuscular involvement, but these exposures were very close to those inducing tremors, convulsions, and death.
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From page 181... ...
Case reports, although lacking definitive exposure terms, indicate that acute exposure to dimethyThydrazines may cause nasal and respiratory tract irritation, breathing difficulties, and nausea. Quantitative data in animals have shown concentration-dependent effects ranging from respiratory tract irritation, pulmonary edema and neurologic effects to lethality.
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From page 182... ...
Abbreviations: NR, Not recommended; EEL, emergency exposure levels; IDLH, immediately dangerous to life and health; PEL, permissible exposure limit; TLV-TWA, Threshold Limit Value-time-weighted average. The most notable database deficiencies were the absence of quantitative exposure data regarding the human experience, the absence of a well-defined exposure-response curve relationship in animals, end understanding of individual variability in response to inhaTed dimethy~hydrazines.
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1996. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices.
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Standing Operating Procedures for Developing Acute Exposure Guideline Levels for airborne Chemicals. Washington, DC: National Academy Press.
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From page 185... ...
1981. Comparative mutagenicity of hydrazine and 3 methylated derivatives in L5178Y mouse lymphoma cells.
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Appendixes
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1963 Toxicity endpoint: Dogs exposed to 1,1-dimethyThydrazine at 360 ppm for 15 min exhibited behavioral changes and muscle fasciculations Uncertainty factors: An uncertainty factor of 3 for interspecies variability was applied because the toxic response to dimethy~hydrazine was similar across the species tested. This was especially true for lethality responses (LCso values for varying time periods ranging from 5 min to 4 h)
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From page 190... ...
(1963) provided data showing that 15-min exposure of dogs at 36-400 ppm produced only minor, reversible effects (behavioral changes and miTd muscle fasciculations)
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among rats, mice, dogs, and hamsters. A comparison of LCso values for the same exposure durations in these species did not vary more than 3-fold.
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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.
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DIMETHYLHYDRAZINE 193 Log Log Time Concentration Time 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 LCso values: Men Concentration 30 60 240 480 2036.15 860.12 153.48 64.83 Best Flt Concentra'don x nme Cone 4.4 ~ ~ 3.8 \ 3.2 ~ \ 2.8 0.6 0.8 1 1.2 1.4 1.6 1.8 Log nme
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From page 194... ...
194 A CUTE EXPOSURE GUIDELINE LEVELS FOR SELECTED AIRBORNE CHEMICA LS Dimethylhydrazine rat data from Weeks et al. 1963 The LCso values for 5-, 15-, 30-, 60-, and 240-min exposures were 24,500, 8,230, 4,010, 1,410, and 252 ppm, respectively.
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EPA 1986~. For a preliminary carcinogenicity assessment, the withdrawn inhalation slope factor for I ,1 -dimethy~hydrazine (cited in ATSDR 1994)
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96 ACUTE EXPOSURE GUIDELINE LEVELS FOR SELECTED AIRBORNE CHEMICALS Because the AEGL-2 values based upon acute toxicity were equivalent to or Tower than the i0-4 risk values derived based on potential carcinogenicity, the acute toxicity data were used for the AEGEs for dimethyThydrazine. For lo-s and lo-6 risk levels, the 10-4 values are reduced by 10-fold or 100-fold, respectively.
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From page 197... ...
data are not available, (2) data indicate that toxic effects may occur at or below the odor threshold, (3)
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From page 198... ...
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 (LCso values)
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From page 199... ...
Data Adequacy: Information regarding the human experience for acute inhalation exposure to dimethyThydrazine 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.
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From page 200... ...
This variability was especially demonstrated in dogs wherein responses varied from one of extreme severity (vomiting, tremors, convuIsions, and death) to no observable effects.
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From page 201... ...
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.
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