Acute Exposure Guideline Levels for Selected Airborne Chemicals Volume 4 (2004) / Chapter Skim
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Appendix 3: Hydrogen Fluoride: Acute Exposure Guideline Levels
Appendix 3: Hydrogen Fluoride: Acute Exposure Guideline Levels
Pages 123-197
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From page 123... ...
Data on irritant effects in humans and lethal and sublethal effects in six species of mammal (monkey, dog, rat, mouse, guinea pig, and rabbit) were available for developing acute exposure guideline levels (AEGLs)
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From page 124... ...
, and an intraspecies UF of 3 to protect susceptible individuals. The resulting 10-min value clearly is below the serious injury categories of data from tests in monkeys, rats, dogs, mice, guinea pigs, and rabbits.
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From page 125... ...
study in which humane subjects inhaling S.1 ppm intermittently suffered no effects other than slight irritation, the S-h AEGL-2 was set equal to the 4-h AEGL-2. The 10-min AEGL-3 was based on the reported 10-min lethal threshold of 1,764 ppm reported in orally cannulated rats (Dalbey 1996; Dalbey et al.
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From page 126... ...
The acute inhalation toxicity of HF has been studied in several laboratory animal species, and its irritant properties have been studied in human volunteers. Large differences in the concentrations causing the same effects in animal studies indicate that difficulties in measurement techniques were encountered by investigators in some of the early studies, thus limiting the value oftheir quantitative data.
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From page 127... ...
1 963) b Lethality threshold in cannulated rats (Dalbey 1996; Dalbey et al.
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From page 128... ...
An additional study reported on exposures over a period of 10-50 d. Studies of industrial exposures and accidental releases were located, but exposure concentrations either were intermittent or were not measured; furthermore, those studies were confounded by the presence of other chemicals.
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From page 129... ...
for very short exposure periods. Inhalation of HF at 122 ppm produced marked conjunctival and respiratory irritation within 1 min and smarting ofthe exposed skin.
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From page 130... ...
130 Cal an .~ 5 o V]
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From page 132... ...
Exposure concentrations were monitored by an electrochemical sensor. Exact exposures were measured by collecting air samples on cellulose pads impregnated with sodium formate and analyzed with a fluoride selective electrode.
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From page 133... ...
The authors note that the study was not blind and that the symptoms may have been overreported; however, the exposed subjects were unaware of the exposure concentration. In a second publication addressing the same study (Lund et al.
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From page 134... ...
Unfortunately, no monitoring data were available. Estimates of exposure concentrations given by the worker and his coworkers (e.g., a concentration of>25 ppm during acid-tank gauging)
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From page 135... ...
No measurements were taken and no further details of the incident were given. In a third incident, 13 workers at an oil refinery were exposed to hydrofluoric acid mist at a maximum concentration of 150-200 ppm for approxi
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From page 136... ...
The workers were medically evaluated within an hour of exposure, at which time the only symptoms were minor upper respiratory tract irritation.
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From page 137... ...
No deaths occurred at 690, 1,575, or 1,600 ppm; one death occurred in the group exposed at 1,035 ppm; and three deaths occurred in both the group exposed at 1,750 ppm and the group exposed at 2,000 ppm. Using probit analysis, the authors calculated a LC50 of 1,774 ppm (95°/O confidence limit, 1,495-2, 105~.
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From page 138... ...
138 E t~ ~o of D ~ V o ~ ~ ~ Z Ct ~ ·E~ .
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From page 140... ...
They lasted 7 post-exposure and included reddened conjunctivae, pawing at the nose, marked lacrimation, nasal secretion, and sneezing. In addition to some delayed deaths, respiratory distress, body-weight loss (10-15% during days 3-7 post-exposure)
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From page 141... ...
No deaths occurred at 480 ppm. The LC50, calculated by probit analysis, was 1,276 ppm (95°/O confidence limit, 1,036- 1,566~.
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From page 142... ...
Each group of HF-exposed animals was compared with an identical group of sham-exposed controls. End points emphasized effects on the respiratory tract, the anticipated target site, but other organs were also evaluated.
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From page 143... ...
. No deaths occurred in orally cannulated rats inhaling 20 ppm or 48 ppm for 1 h.
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From page 144... ...
No deaths were observed in rats exposed at 593 ppm or 1,589 ppm for 2 mini no effects were observed at 593 ppm. A concentration-response effect was also observed in orally cannulated rats exposed to HF for 10 min.
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From page 145... ...
No deaths occurred at the two lower exposure concentrations. Two groups of rats were exposed at 33 ppm (30 animals)
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(1934) exposed guinea pigs to concentrations ranging from 30 ppm to 9,760 ppm for exposure times of 5 min to 41 h.
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No deaths occurred in guinea pigs exposed at 122 ppm for 5 h. In a follow-up study, MachIe and Kitzmiller (1935)
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From page 148... ...
148 ·_I o an 5 sit ~ ~O o C)
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150 a O au .
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(Stokinger 1949~. No deaths occurred in either group.
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From page 152... ...
To evaluate respiratory tract effects, two groups of four rats were exposed for 1 h to HF at 1,630 ppm under conditions of low humidity or at 1,910 ppm under conditions high relative humidity. Groups of four were sacrificed at 1 ~ post-exposure and at 14 ~ post-exposure, and the respiratory tracts were examined histologically (Haskell Laboratory 1990~.
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From page 153... ...
3.2.5. Guinea pigs Groups of three guinea pigs were exposed to concentrations of HE ranging from 30 ppm to 9,760 ppm for exposure durations of 5 min to 41 h (MachIe et al.
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From page 154... ...
caused no deaths within a year following exposure, but lesions were present. Guinea pigs were exposed to HF at either 33 ppm or S.6 ppm for 6 hid for a period of 5 wk (166 h)
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From page 155... ...
No deaths occurred with either exposure regime. Slight pulmonary hemorrhage was observed in four of 10 rabbits at the higher exposure regime.
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From page 156... ...
Because inhaled HE would exert its systemic effects as fluoride ion, oral studies of fluoride administration may be relevant. A chronic oral carcinogenicity study in which sodium fluoride was administered to male and female rats and mice via drinking water resulted in equivocal evidence of bone cancer in male rats, but not in female rats or in mice of either gender (NIP 1990)
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From page 157... ...
One of 20 orally cannulated rats exposed at 1,764 ppm for 10 min died, whereas one of 10 nose-breathing rats exposed at 2,039 ppm for 1 h died. Severe irritant effects but no deaths occurred in nose-breathing rats exposed at 1,224 ppm for 1 h (Dalbey 1996; Dalbey et al.
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From page 158... ...
No deaths occurred in the nose-breathing rats, whereas 25% of orally cannulated rats died within 24 h of exposure. Effects in nosebreathing rats were limited to the anterior nasal passages; no changes were observed in the trachea.
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From page 159... ...
At two other plants, average S-h exposure concentrations ranged from 2.4 mg/m3 to 6.0 mg/m3 (2.9-7.3 ppm) , and average fluoride concentrations in the urine ranged from S.7 ppm to 9.
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From page 160... ...
The form of fluorine in both lung and plasma was primarily ionic, with a small amount being bound or nonexchangeable. Plasma fluoride concentrations in guinea pigs exposed at 1.S,3.7, 6.1, or 12.2 ppm were increased in a concentration-dependent manner (Dousset et al.
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From page 161... ...
4.2. Mechanism of Toxicity The available studies indicate that HF is a severe irritant to the skin, eyes, and respiratory tract, particularly the anterior nasal passages where, depending on species and concentration, it appears to be effectively scrubbed from the inhaled air.
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From page 162... ...
also showed that at concentrations up to 226 ppm, >99.7°/O of inspired HF may be scrubbed in the upper respiratory tract of the rat.
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From page 163... ...
To some extent, this increased susceptibility may be due to less effective scrubbing of HCl in the upper respiratory tract" (NRC 1991~. Quantitative data for HBr were limited to one study, but that study also showed that HF was more toxic than either HCl or HBr.
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From page 164... ...
Considering the greater water solubility of HF compared with HCI, it is possible that the more effective scrubbing of HF in the nasal passages is responsible for the apparent decrease in the relative toxicities of HF and HCl at lower concentrations associated with longer exposure durations. Conversely, the greater toxicity of HF at higher concentrations associated with shorter exposure durations might be due to saturation ofthe scrubbing mechanism and higher concentrations in the lower respiratory system.
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From page 165... ...
l 963~. Responses of rabbits and guinea pigs to sublethal and lethal exposures appeared to be similar, except that guinea pigs were more likely than rabbits to suffer delayed deaths.
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From page 166... ...
In both studies, concentrations that produced effects confined to the nasal passages in nose-breathing rats resulted in serious lower respiratory tract effects or deaths in orally cannulated rats. These results indicate that the site of injury and resultant toxicologic effects will differ with oral and nasal breathing, the former mode resulting in more severe responses under similar exposure situations.
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From page 167... ...
For 60-min exposures, mild and occasional signs of eye, nose, or respiratory irr~tation were observed in the dog at 157 ppm and in the rat at 103 and 126 ppm (Rosenholtz et al.1963~. For guinea pigs and rabbits, a concentration at 61 ppm for 5 h resulted in only mild irr~tation to the respiratory tract, but histologic studies were not performed at that exposure concentration.
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From page 168... ...
Their approach employed a log-probit extrapolation of concentration-response data to the 95°/O lower confidence limit on the toxic concentration producing a benchmark dose of 1 % response called a practical threshold. Species-specific and chemical-specif~c adjustment factors were applied to develop exposure levels applicable to the general public.
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From page 169... ...
provide information on sublethal effects from acute exposures. The 5-min exposure periods of
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From page 170... ...
In those studies, l 0-min exposures of orally cannulated rats (a conservative model for the human breathing pattern under irritant conditions, because HE would not be scrubbed by the mouth and upper respiratory tract) resulted in a NOAEL of 950 ppm for the AEGL-2 definition (the next highest exposure, l ,764 ppm, resulted in death in one of 20 rats)
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From page 171... ...
The 10-min AEGL-2 is clearly below the serious injury category of data from tests in monkeys, rats, dogs, mice, guinea pigs, and rabbits, as shown in Figure 3-1. Therefore, a total UF of 10 applied to the orally cannulated rat data should be protective of susceptible populations.
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From page 172... ...
172 ~ o $ o o 0 Z E ~ E I I t ~ W ~ o lo ~ C)
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From page 173... ...
The AEGL-2 values are clearly below the serious injury category of data from tests in monkeys, rats, dogs, mice, guinea pigs, and rabbits. According to Alarie (1981)
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From page 174... ...
In those studies, 10-min exposures to HE in orally cannulated rats (a potentially realistic model for the human breathing pattern under irritant conditions) resulted in serious effects including lethality at 1,764 ppm (1/20)
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From page 175... ...
Therefore, a combined factor of 6 is reasonable. The AEGL-3 values are clearly below the levels that cause death in monkeys, rats, dogs, mice, guinea pigs, and rabbits (Figure 3-1~.
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From page 176... ...
Because of the 6-h exposure duration of the supporting study, and because adaptation to mild sensory irritation occurs, the 1 ppm value was applied to all AEGL- 1 exposure durations. The 10-min AEGL-2 value was based on the 10-min NOAEL of 950 ppm for serious lung effects in orally cannulated rats; that value was considered the threshold for serious effects.
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From page 177... ...
On the basis of repeated exposures in animal studies and the well-known scrubbing capacity of the mammalian nose at low concentrations, the S-h AEGL-3 was set equal to the 4-h value. Values are summarized in Table 3-11, above.
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From page 178... ...
bCEEL (community emergency exposure levels) (Clement International Corp., unpublished material)
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From page 179... ...
X.3. Data Adequacy and Research Needs The database for human exposures is relatively good both short-term and long-term studies with human volunteers are available.
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From page 180... ...
Therefore, the S-h AEGL-2 and AEGL-3 values were set equal to the respective 4-h values. Sampling and analytical methods used in the human and animal studies conducted in the 1960s and 1970s were not as sensitive as those perfected by the late l980s and l990s end may have under- or overestimated concentrations.
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From page 181... ...
1987. Fatality due to acute hydrofluoric acid exposure.
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From page 182... ...
1986. Effects of inhaled HE on cholesterol metabolism in guinea pigs.
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From page 183... ...
1989. Relative acute toxicities in the respiratory tract of inhaled hydrogen fluoride, hydrogen bromide, and hydrogen chloride.
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From page 184... ...
2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals.
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From page 185... ...
1991. Hydrofluoric acid exposures: Long-term effects [draft]
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From page 186... ...
1991. Acute health effects in a community after a release of hydrofluoric acid.
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From page 187... ...
HYDROGEN FLUORIDE APPENDIX A Time-Scaling Calculations for Hydrogen Fluoride AEGLs Best Fit Concentration x Time Curve 3.7 3.6 Q o ~ 3.5 a) it' 3.4 o 0 3.3 3.2 3.1 0.6 0.8 1 1.2 Log Time (minutes)
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From page 188... ...
the 10-min NOAEL of 950 ppm in orally cannulated rats (Dalbey 1996) Irritation (30-min and 1-,4-, and S-h values)
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From page 189... ...
UP = 10, and n=2 C2/10 x t = k k= 35429.4 ppm2 min Uncertainty factors: 10-min AEGL-2 Combined uncertainty factor of 10 3 for interspecies (effects are unlikely to differ be tween species; LC50 values were similar among spe cies; oral cannulation maximizes the dose to the lower respiratory tract) 3 forintraspecies (oral cannulation maximizes the dose to the lower respiratory tract and is a potentially realis tic model for human response to corrosive gases)
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From page 190... ...
UF/MF = 6, end n =2 (263 ppm/6~2 x 60 min = 115,281.67 ppm2 min Uncertainty factors: 10-min AEGL-3 Combined uncertainty factor of 10 3 for interspecies (effects are unlikely to differ greatly among species; LC50 values were similar among species; oral cannulation maximizes the dose to the lower respiratory tract) 3 forintraspecies (oral cannulation maximizes the dose to the lower respiratory tract and is a potentially realistic model for human response to corrosive gases)
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From page 191... ...
1990~. No deaths occurred in groups of four male and female rhesus monkeys inhaling 690 ppm for 1 h (MacEwen and Vernot 1970~.
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From page 192... ...
. At 0.85-2.9 ppm, no to low sensory irritation; no change in FVC, FEW; increase in the percentage of CD3 cells and myeloperoxidase in bronchial portion of BAL; no increases in neutrophils, eosinophils, protein, or methyl histamine in BAL.
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From page 193... ...
AEGL-1 values were calculated by adjusting the 1-h concentration of 3 ppm by a UP of 3. Because the response to slight irritation would be similar at shorter exposure durations, the 10- and 30-min values were set equal to the 1-h concentration.
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From page 194... ...
1963) Exposure route/concentrations/duration: 10-min inhalation exposures of orally cannulated rats to 135, 271, 950, or 1,764 ppm (Dalbey, 1996~; 60-min inhalation exposures of mongrel dogs to 157 ppm or 243 ppm (Rosenholtz et al.
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From page 195... ...
Uncertainty factors/rationale: 10-min AEGL-2 values Total uncertainty factor: 10 Interspecies: 3. A sensitive model was used (orally cannulated rats)
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From page 196... ...
60-min inhalation exposures of female mice at 263, 278, 324, 381, or 458 ppm Effects: In the 10-min inhalation exposures of orally cannulated rats, at 135 ppm there were no effects; at 271 ppm there was no effect; 950 ppm was set as a no-observed-adverse-effect level (NOAEL) (increase in myeloperoxidase and polymorphonuclear leukocytes in BAL)
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From page 197... ...
Because the time-scaled 8-h AEGL-3 value of 15 ppm was inconsistent with results of longer-term studies with monkeys and rodents, the 8-h value was set equal to the 4-h value. Data adequacy: There is considerable support for the AEGL-3 values as the database for hydrogen fluoride is extensive with multiple studies of lethality conducted at several exposure durations and involving five species of mammals (monkey, rat, mouse, guinea pig, and rabbit)
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