Acute Exposure Guideline Levels for Selected Airborne Chemicals Volume 8 (2010) / Chapter Skim
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6 Hydrazine
6 Hydrazine
Pages 274-326
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From page 274... ...
Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels.
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From page 275... ...
Hydrazine has an ammonia-like odor with an odor threshold of 3.0 to 4.0 ppm. Human data on the toxicity of hydrazine following acute inhalation exposure are limited to anecdotal accounts that lack definitive exposure data.
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From page 276... ...
An uncertainty factor of 3 for interspecies variability was applied to account for uncertainties regarding species variability in the toxic response to inhaled hydrazine. Because the toxic response to acute low-level exposures results from direct contact of the highly reactive hydrazine, the reduction from a default value of 10 is justified.
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From page 277... ...
Cancer inhalation slope factors for hydrazine were derived and compared to AEGL values based upon 10-4, 10-5, and 10-6 cancer risk levels. The assessment revealed that AEGL-2 values derived from noncarcinogenic toxicity end points were greater than the exposure concentrations calculated for the 10-4 excess cancer risk level.
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mg/m3) a Because the contact irritation response to the extremely reactive hydrazine is concentration dependent rather than time-dependent, the AEGL-1 is the same for all time periods.
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Because of the extreme reactivity of the compound (up to 99% of the hydrazine would be lost to absorption onto the chamber walls or body surface of the test animals) , nominal concentration estimates were found to be a gross overestimation of actual exposure concentrations.
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. The odor LOA represents the concentration above which it is predicted that more than half of the exposed population will experience at least a distinct odor intensity, about 10 % of the population will experience a strong odor intensity.
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From page 281... ...
was determined for the high exposure group. The investigators concluded that occupational exposure to hydrazine and other chemicals associated with the rocket engine testing increased lung cancer risk and possible risk to other cancers.
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(1981) conducted a 12-month inhalation exposure study using male and female F344 rats, Syrian golden hamsters, and C57BL/6 mice.
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No immediate deaths occurred during the 0.5-h exposure period but three of 18 rats had died within the 14-day postexposure period. Necropsy findings included pulmonary edema with localized damage to the bronchial mucosa.
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With the exception of one rat each in the 4-h and 1-h groups, exposure to hydrazine vapors did not result in immediate lethality. However, deaths were observed for all exposure durations during the 14-day postexposure period and occurred throughout the 14-day period.
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TABLE 6-4 Acute Inhalation Toxicity in Rats Exposed to Hydrazine Vapor Concentration Exposure C×t Immediate 14-Day (mg/m3)
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During the exposure, the rats exhibited exaggerated respiratory movements. During the post-exposure observation period, clinical signs included death (two highest exposures only)
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There did not appear to be a definitive concentration-effect relationship; three mice died on Day 3, 5 mice died on Day 4, but no deaths occurred on Day 5. Pathological examination revealed pulmonary edema and localized, unspecified damage to the bronchial mucosa.
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From page 288... ...
would be considered reversible. It is important to note that during days 1 through 10, the exposure period of concern for the aforementioned effects, the exposure concentration averaged 0.4 ppm (0.52 mg/m3)
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In another experiment one male and one female dog were exposed similarly but to hydrazine concentrations of 4 to 8 mg/m3 (3 to 6 ppm)
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Another phase of this study exposed rats and hamsters for 10 weeks at 1 h per week to hydrazine at concentrations of 75 or 750 ppm. Male and female rats exposed to 750 ppm and female rats exposed to 75 ppm exhibited significant reductions in body weight (p < 0.05)
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(1995) conducted experiments in which groups of 10 male Syrian golden hamsters were exposed to 750 ppm hydrazine for 1 h.
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Administration of Hydrazine (10 mg/kg) at Various Times During Gestation Gestational Exposure Period Parameter Control (6-15)
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have indicated the genotoxic potential of hydrazine with and without metabolic activation and include methyl DNA adducts in human but not hamster V79 cells, gene mutations in human teratoma cells, and unscheduled DNA synthesis. Hydrazine was positive in the Ames test using TA1535, TA100, TA1537, and TA98 strains of Salmonella typhimurium (Parodi et al.
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Control animals were exposed to air without hydrazine. Male and female rats exposed to 750 ppm and female rats exposed to 75 ppm exhibited significant reductions in body weight (p < 0.05)
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(1995) conducted experiments in which groups of 10 male Syrian golden hamsters were exposed to 75 or 750 ppm hydrazine for 1 h/week for 10 weeks.
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Definitive exposure-response data regarding non-disabling, reversible health effects in animals following acute inhalation exposure to hydrazine were limited. Muscular incoordination and weakness was observed in dogs (Weatherby and Yard 1955)
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found that 1.7-4% and 4.5-11.4% of the absorbed dose was excreted as urinary acetyl hydrazine and diacetylhydrazine, respectively. The role of metabolism and absorption/excretion kinetics is uncertain regarding immediate port-of-entry toxic effects from acute inhalation exposures.
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From page 298... ...
Results of this study showed that the unsymmetrical isomer of dimethylhydrazine was less acutely toxic than hydrazine or the other hydrazine derivatives. TABLE 6-9 LC50 Values for Rodents Exposed to Monomethylhydrazine and Dimethylhydrazine Isomers LC50 (mg/m3)
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Species Variability The limited available data suggest that the lethal concentration of hydrazine varies somewhat among the species tested. Some of this variability, however, may be attributed to the difficulties in accurately measuring and maintaining the experimental hydrazine concentrations, especially in earlier studies.
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Data from some of the earlier studies were compromised by difficulties in determining the actual hydrazine concentrations in the exposure chambers. Acute exposures (<24 h)
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. An uncertainty factor of 3 was applied for interspecies variability because the surface contact irritation by the highly reactive hydrazine is not likely to vary greatly among species, and because a nonhuman primate was the test species.
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Due to the extreme reactivity of hydrazine, exposure concentration measurements in earlier studies on multiple species were imprecise. An uncertainty factor of 3 for interspecies variability was applied to account for uncertainties regarding species variability in the toxic response to inhaled hydrazine.
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Several studies utilizing inhalation exposures were considered for derivation of an AEGL-3 values. The acute lethality of inhaled hydrazine has been reported by several investigators (Comstock et al.
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(1995) study demonstrated that rats exposed to 750 ppm for 1 h per week for 10 consecutive weeks did not experience mortality.
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An uncertainty factor of 3 for interspecies variability was applied to account for uncertainties regarding species variability in the lethal response to inhaled hydrazine. Because
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This contact irritation is not likely to vary considerably among individuals. A modifying factor of 3 for interspecies variability was applied to account for the high degree of variability in the data.
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For such effects in acute exposure scenarios, the relevance of order-of-magnitude dose/exposure adjustments is questionable because the exposure duration may be insufficient for expression of interspecies and intraspecies variability in toxicodynamics and toxicokinetics. By definition, the AEGLs address "susceptible but not hyper-susceptible individuals".
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From page 308... ...
Although data from the animal studies affirm the carcinogenic potential of hydrazine following inhalation exposure, the observed tumorigenic responses appear to be a function of prolonged tissue irritation resulting from long-term repeated exposures and are unlikely to occur following a single low exposure. This was especially evident in the study by Latendresse et al.
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From page 309... ...
Furthermore, the available animal data suggest that the tumorigenic response to inhaled hydrazine is a function of prolonged tissue irritation resulting from repeated exposures and not the result of a single low exposure. TABLE 6-16 Extant Standards and Guidelines for Hydrazine Exposure Duration Guideline 10 min 30 min 1h 4h 8h AEGL-1 0.1 ppm 0.1 ppm 0.1 ppm 0.1 ppm 0.1 ppm (Nondisabling)
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From page 310... ...
In lieu of definitive exposure-response data for humans, quantitative data in multiple animal species would serve to reduce the uncertainty in interspecies variability and also allow for more precise predictions regarding the toxicologic responses of humans following acute exposure to hydrazine. The use of an adequate numbers of animals in these studies would also assist in reducing the uncertainty regarding individual variability in the toxic response to hydrazine.
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1964. Tolerance Criteria for Continuous Inhalation Exposure to Toxic Ma terials.
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1986. Urinary Metabolites of Hydrazine in Male Fischer 344 Rats Following Inhalation or Intravenous exposure.
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2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals.
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1982. Induction of unscheduled DNA synthesis in the germ cells of male mice after treatment with hydrazine or procaba zine.
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exhibited flushing of the face and eye irritation. Uncertainty factors: 3 for interspecies variability (the highly reactive hydrazine appears to be equally irritating to all species)
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Modifying factor: 2 for data inadequacies; definitive exposure-response data specific to AEGL-2 level effects are unavailable for inhalation exposure. An additional modifying factor of 3 has been applied to account for the uncertainties in the measurement of exposure concentrations in earlier studies.
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Modifying factor: 3 for inadequacies regarding measurement of exposure concentrations in earlier studies which compromise a definitive assessment of species variability.
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In the absence of chemical-specific data, temporal scaling was performed using n = 3 when extrapolating to shorter time points and n = 1 when extrapolating to longer time points using the Cn × t = k equation. Calculations: 1064 ppm/30 = 35.5 ppm C3 × t = k (35.5 ppm)
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From page 319... ...
d = 3.2 × 10-7 mg/m3 Calculate 24-h exposure: 24-h exposure = d × 25,600 = (3.2 × 10-7 mg/m3) × 25,600 = 0.008 mg/m3 Adjustment to allow for uncertainties in assessing potential cancer risks under short term exposures under the multistage model [Crump and Howe 1984]
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0.5-h = 6.24 mg/m3 (4.7 ppm) Because the derivation of the cancer slope factor requires conversion of animal doses to human equivalent doses, no reduction of exposure levels is applied to account for interspecies variability.
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0.5 h = 3.8 mg/m3 (2.9 ppm) Because the derivation of the cancer slope factor requires conversion of animal doses to human equivalent doses, no reduction of exposure levels is applied to account for interspecies variability.
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From page 322... ...
Time Scaling: Cn × t = k where n = 3 to scale from 24-h exposure to 4-h and 8-h exposure periods. Due to the extreme reactivity of hydrazine, however, the contact irritant effects were considered to be concentration dependent and, therefore, the 0.1 ppm concentration derived for the 4-h and 8-h periods was applied for all time periods.
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From page 323... ...
Animal to Human Dosimetric Adjustment: Insufficient data Time Scaling: Cn × t = k where n = 1 or 3 (k = 117188 ppm3-min when n = 3 and k = 750 ppm-min when n = 1) ; The concentration exposure time relationship for many irritant and systemically acting vapors and gases may be described by Cn × t = k, where the exponent, n, ranges from 0.8 to 3.5 (ten Berge et al.
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From page 324... ...
Uncertainty Factors/Rationale: Total uncertainty factor: 30 Interspecies: 3-An uncertainty factor of 3 for interspecies variability was applied to account for possible species-dependent uncertainties in the toxic response to inhaled hydrazine. Intraspecies: 3-Hydrazine will be extremely reactive with all biological tissues resulting in irritation and severe tissue damage at high concentrations upon contact.
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From page 325... ...
APPENDIX D Category Plot for Hydrazine AEGLs Chemical Toxicity - TSD All Data Hydrazine 100000 Human - No Effect Human - Discomfort 10000 Human - Disabling 1000 Animal - No Effect Animal - Discomfort 100 ppm Animal - Disabling 10 AEGL-3 AEGL-2 Animal - Some Lethality 1 Animal - Lethal AEGL-1 AEGL 0 0 60 120 180 240 300 360 420 480 Minutes FIGURE D 1 Category plot for hydrazine.
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From page 326... ...
represents the concentration above which it is predicted that more than half of the exposed population will experience at least a distinct odor intensity, about 10 % of the population will experience a strong odor intensity. The LOA should help chemical emergency planners and responders in assessing the public awareness of the exposure due to odor perception.
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