Acute Exposure Guideline Levels for Selected Airborne Chemicals Volume 1 (2000) / Chapter Skim
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Monomethylhydrazine: Acute Exposure Guideline Levels
Monomethylhydrazine: Acute Exposure Guideline Levels
Pages 113-154
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From page 113... ...
Nonlethal toxic effects include irritation of the upper respiratory tract, hemolysis, and iThis 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 114... ...
values of 162, 82, 96, 244, 122, and 991 ppm have been determined for rhesus monkeys, squirrel monkeys, beagle dogs, rats, mice, end hamsters, respectively. Exposure concentration-exposure duration relationships appear 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.
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From page 115... ...
A cancer assessment based upon the carcinogenic potential of dimethyThydrazine revealed that AEGL values for a theoretical excess lifetime 10-4 carcinogenic risk exceeded the AEGL-3 values that were based on noncancer endpoints. Furthermore, the available data for hydrazine and its methylated derivatives suggest that the tumorigenic response observed for these compounds is the result of repeated Tong-term exposures causing repetitive tissue damage.
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From page 116... ...
116 .= do C o 3 ~ oo ~ N ~ ~ a ¢ ~ 00 .s ~ O ~ En 0 ~ .~ =~ 3 Ed V ¢ CC ·= o ~ Ce · ~ C', o .
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Acute Exposure Studies A controlled human exposure study provided information regarding nonlethal effects following acute (head-only) exposure to monomethy~hydrazine
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Monitoring of clinical chemistry parameters for 60 ~ following the exposure revealed no significant findings other than 3 -5°/0 increase in Heinz body formation at ~ 7 that declined after 2 w. Spirometry
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ANIMAL TOXICITY DATA 3.~. Acute Lethality Acute lethality studies in laboratory species are summarized in the following sections.
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From page 120... ...
, TABLE 3-3 Lethality in Nonhuman Primates and Dogs Following Inhalation Exposure to Monomethylhydrazine Species Exposure Concentration (C x T) Mortality Ratio 15 min Squirrel monkey 300 ppm (4,500 ppm min)
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From page 121... ...
The reported 15-, 30-, and 60-min LCso values for the squirrel monkeys were 340,145, and 82 ppm, respectively. The cumulative exposure data for various exposure durations suggest a linear relationship within species.
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3.~.4. Mice Acute toxicity assays using groups of 20 mice (strain not specified)
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Histopathologic examination revealed concentrationrelated pulmonary edema and hemorrhage (observed only in hamsters exposed to the two highest concentrations)
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From page 124... ...
These concentrations are, however, only slightly below those resulting in mortality of 250% (e.g., 170 ppm for 60 min in rhesus monkeys, lSO ppm for 30 min or SS ppm for 60 min in squirrel monkeys, see Section 3.1.~. These data affirm the steep exposure-response relationship for monomethy~hydrazine-induced lethality.
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From page 125... ...
exposure 1970 No mortality at 460 ppm; all deaths occurred within 24 h post-exposure Haun et al. 1970 Jacobson et al.
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, moderately severe hemolysis occurred. Intravascular hemolysis was evident in reduced erythrocyte counts, hematocrit, and hemoglobin content.
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Although the data (increased resorptions, moderTABLE 3-7 Developmental Effects of Monomethylhydrazine in Rats Following Intraperitoneal Administration on Gestation Days 6-15 Dose (mg/kg) 0 2.5 Parameter No.
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From page 128... ...
Mice exposed to 2 ppm exhibited an increased incidence of Jung tumors, nasal adenomas, nasal polyps, nasal osteomas, hemangioma, and liver adenomas and carcinomas. At the end ofthe observation period, lung tumor incidences were 13/364, 17/354, 25/347, and 59/360 for the 0, 0.02, 0.2, and 2.0 ppm groups, respectively.
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From page 129... ...
Inhalation of monomethyThydrazine was not carcinogenic in rats or dogs, but mice exposed at 2 ppm for ~ y exhibited an increased incidence of lung tumors, nasal adenomas, nasal polyps, nasal osteomas, hemangioma, and liver adenomas and carcinomas. Hamsters exposed at 2 or 5 ppm exhibited an increased incidence in nasal polyps, interstitial fibrosis ofthe kidney, end benign adrenal adenomas.
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From page 130... ...
in addition to the contact irritant effects, the acute toxicity of dimethy~hydrazine exposure probably involves the central nervous system as exemplified by tremors and convulsions (Shaffer and Wands ~ 973) and behavioral changes at sublethal doses (Streman et al.
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From page 131... ...
Species Variability Based upon the available data, hamsters appear to be more resistant than other tested species to the lethal effects of acute exposure to monomethyIhydrazine. Within similar exposure durations, the data expressed as concentration x time (Ct)
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From page 132... ...
were not consistent with the AEGL-2 and AEGL-3 values derived Tom more robust data sets from laboratory species. The AEGI~-1 values based upon the human data were at or below the odor threshold and above concentrations known to cause notable irritation.
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From page 133... ...
inhalation slope factor for I, ~ -dimethyThydrazine was used to assess carcinogenic risk associated with an acute exposure (see Appendix 3~. The analysis showed that AEGLs based upon acute toxicity were more appropriate.
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From page 134... ...
These reports provided ~ -h LCso values of ~ 62, 82, 96, 244, 122, and 991 ppm for rhesus monkeys, squirrel monkeys, beagle dogs, rats, mice, and hamsters, respectively. Based on these data, the squirrel monkeys and beagle dogs appeared to be the most sensitive species.
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From page 135... ...
This estimate can be justifiedby the known steep exposureresponse relationship for the toxic effects of monomethyThydrazine, and the fact that the resulting 27.3-ppm value represents an exposure concentration that does not produce overt toxicity in test animals. The derived lethality threshold value of 27.3 ppm was adjusted by a total uncertainty factor of ~ 0 (each uncertainty factor of 3 is the geometric mean of 10, which is 3.16; hence, 3.16.
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From page 136... ...
For the development of AEGL values for monomethy~hydrazine, toxicity endpoints specific for each of the three AEGL levels were not available, thereby necessitating the adjustment of available exposures to estimate AEGL-specific effect levels (e.g., adjustment of LCso values to estimate a lethality threshold for AEGL-3~. For monomethyIhydrazine, an AEGL-l was not considered to be appropriate, because notable toxicity may occur at or below the odor threshold.
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From page 137... ...
Available animal data also suggested that there may be little margin between nonlethal and lethal effects, and this was reflected in the uncertainty factor adjustments used in the development of the AEGL values. The available data for hydrazine and its methylated derivatives suggest that a tumorigenic response may occur following repeated Tong-term exposures that cause repetitive tissue damage.
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From page 138... ...
Numeric values for AEGL- 1 are not recommended because (1) studies suggest that notable toxic effects may occur at or below the odor threshold or other modes of sensory detection, (2)
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From page 139... ...
The acute toxicity of the vapors of some methylated hydrazine derivatives.
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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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Appendixes
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From page 143... ...
Time scaling: Not directly applicable; AEGL-2 values derived from 3-fold downward adjustment of AEGL-3 values.
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From page 144... ...
(27.3 ppm) ~ x 60 min = 163.8 ppm mini regression analysis ofthe squirrel monkey lethality data suggested a near linear relationship 1-h AEGL-3: 4-h AEGL-3: S-h AEGL-3: 30-min AEGL-3: C' x 30 min = 163.8 ppm min C = 5.5 ppm C' x 60 min = 163.8 ppm min C =2.7 ppm C' x 240 min = 163.8 ppm min C=0.68ppm C'x480min=~63.8ppmmin C = 0.34 ppm .
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From page 145... ...
, 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)
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From page 147... ...
MONOME THYLHYDRA ZINE Monomethylhydrazine dog data from Haun et al. 1970 147 The LCso values for 15,30, and 60 min were 390, 195, and 96 ppm, respect~vely.
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EPA ~986~. For a preliminary carcinogenicity assessment, the withdrawn inhalation slope factor for I,1dimethy~hydrazine (cited in ATSDR 1994)
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From page 149... ...
0.5-h = 19.2 mg/m3 (10 ppm) 149 Because the AEGEs based upon acute toxicity were equivalent to or lower than the values derived based upon potential carcinogenicity, the acute toxicity data were used for the proposed AEGEs for monomethy~hydrazine.
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From page 150... ...
43.2 mg/m3 (23 ppm) Because the AEGEs based upon acute toxicity were equivalent to or Tower than the values derived based on potential carcinogenicity, the acute toxicity data were used for the proposed AEGEs for monomethyThydrazine.
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From page 151... ...
Time Scaling: Not applicable Data Adequacy: Both animal and human data affirm that low level exposure will cause mild irritation of the respiratory tract and that there is likely to be little margin between AEGL-1 type effects and more serious effects. Numeric values for AEGL-1 are not recommended because (1)
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From page 152... ...
31:667-677 Test Species/Strain/Sex/Number: Squirrel monkeys, 2-4 males/group Exposure Route/Concentrations/Durations: Inhalation; exposure at 300, 340, or 376 ppm for 15 mini 130, 150, or 170 ppm for 30 mini 75, 85, or 90 ppm for 60 min Effects: Data specifically identifying serious, irreversible effects consistent with the AEGL-2 definition were not available. The lethality data are shown in the summary table for AEGI~-3.
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From page 153... ...
31:667-677 Test Species/Strain/Sex/Number: Squirrel monkeys, 2-4 males/group Exposure Route/Concentrations/Durations: Inhalation; exposure at 300, 340, or 376 ppm for 15 mini 130, 150, or 170 ppm for 30 mini 75, 85, or 90ppmfor60min Effects: Exposure Lethality ratio 15min 300 ppm 1/4 340 ppm 1/2 376 ppm 3/3 30 min 130 ppm 0/3 150 ppm 2/3 170 ppm 2/2 60 min 75 ppm 0/2 85 ppm 2/4 60-min LCso = 82 ppm 90 ppm 2/2 Endpoint/Concentration/Rationale: The 60-min LCso of 82 ppm was reduced to 27.3 ppm by using a 3-fold adjustment as an estimate of the lethality threshold; the available data indicated the squirrel monkey to be the most sensitive species tested. That is a reasonable estimate of the lethality threshold, because monomethylhydrazine has a steep exposureresponse curve, and data on other chemicals with similar dose response curves indicate that this approach represents a likely estimate of the threshold for lethaTity.
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From page 154... ...
Data Adequacy: Adequate lethality data were available for several species including nonhuman primates. Although the variability in response to the lethal effects of monomethylhydrazine among all species tested appeared to be relatively small (2- to 3-fold difference)
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