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5
Perchloryl Fluoride1
Acute Exposure Guideline Levels
PREFACE
Under the authority of the Federal Advisory Committee Act (FACA) P.L.
92-463 of 1972, the National Advisory Committee for Acute Exposure Guide-
line Levels for Hazardous Substances (NAC/AEGL Committee) has been estab-
lished to identify, review, and interpret relevant toxicologic and other scientific
data and develop AEGLs for high-priority, acutely toxic chemicals.
AEGLs represent threshold exposure limits for the general public and are
applicable to emergency exposure periods ranging from 10 minutes (min) to 8
hours (h). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for
each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and are distin-
guished by varying degrees of severity of toxic effects. The three AEGLs are
defined as follows:
AEGL-1 is the airborne concentration (expressed as parts per million or
milligrams per cubic meter [ppm or mg/m3]) of a substance above which it is
predicted that the general population, including susceptible individuals, could
experience notable discomfort, irritation, or certain asymptomatic, nonsensory
1
This document was prepared by the AEGL Development Team composed of Dana
Glass (Oak Ridge National Laboratory), Lisa Ingerman (SRC, Inc.), Chemical Manager
George Cushmac (National Advisory Committee [NAC] on Acute Exposure Guideline
Levels for Hazardous Substances), and Ernest V. Falke (U.S. Environmental Protection
Agency). The NAC reviewed and revised the document and AEGLs as deemed neces-
sary. Both the document and the AEGL values were then reviewed by the National Re-
search Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC com-
mittee has concluded that the AEGLs developed in this document are scientifically valid
conclusions based on the data reviewed by the NRC and are consistent with the NRC
guidelines reports (NRC 1993, 2001).
139
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140 Acute Exposure Guideline Levels
effects. However, the effects are not disabling and are transient and reversible
upon cessation of exposure.
AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a
substance above which it is predicted that the general population, including sus-
ceptible individuals, could experience irreversible or other serious, long-lasting
adverse health effects or an impaired ability to escape.
AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a
substance above which it is predicted that the general population, including sus-
ceptible individuals, could experience life-threatening health effects or death.
Airborne concentrations below the AEGL-1 represent exposure concentra-
tions that could produce mild and progressively increasing but transient and
nondisabling odor, taste, and sensory irritation or certain asymptomatic, nonsen-
sory effects. With increasing airborne concentrations above each AEGL, there is
a progressive increase in the likelihood of occurrence and the severity of effects
described for each corresponding AEGL. Although the AEGL values represent
threshold concentrations for the general public, including susceptible subpopula-
tions, such as infants, children, the elderly, persons with asthma, and those with
other illnesses, it is recognized that individuals, subject to idiosyncratic re-
sponses, could experience the effects described at concentrations below the cor-
responding AEGL.
SUMMARY
Perchloryl fluoride is a colorless, stable gas. It is used as a fluorinating
agent, an oxidant in rocket fuels, and a gaseous dielectric for transformers. It is
prepared by electrolysis of a saturated solution of sodium perchlorate in anhy-
drous hydrofluoric acid. Perchloryl fluoride is a strong oxidizer, and is strongly
irritating to the eyes, mucous membranes, and lungs. Its systemic effects include
induction of methemoglobinemia.
No human data were available for developing AEGL values, and only two
relevant reports of studies in animals were found. Greene et al. (1960) per-
formed several experiments in dogs, rats, mice, and guinea pigs. In acute studies
with dogs, animals were treated with perchloryl fluoride at 224-622 ppm for 4 h,
and hemoglobin and methemoglobin concentrations were evaluated. In studies
with rats and mice, only 4-h LC50 (lethal concentration, 50% lethality) values
were reported. Repeat-exposure studies in dogs, rats, mice, and guinea pigs also
were performed. In the second report, mortality values were presented for rats at
several time points, but details of the exposures to perchloryl fluoride were not
included (Dost et al. 1974). No information relevant to time-scaling AEGL val-
ues for perchloryl fluoride was found.
The AEGL-1 values were derived from a study in which dogs and rats
were exposed to perchloryl fluoride at 24 ppm for 6 h/day, 5 days/week for 26
weeks. All animals survived and no irritation or clinical signs of toxicity were
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Perchloryl Fluoride 141
observed. The only long-term effect was increased fluoride deposition in the
bone and urine. Therefore, 24 ppm was considered a no-effect level for an 8-h
exposure, and was selected as the point of departure. That value was divided by
a total uncertainty factor of 30 (3 for interspecies differences and 10 for intras-
pecies variability). An interspecies uncertainty factor of 3 was selected because
lethality values for dogs, rats, and mice differed by less than a factor of 3. An
intraspecies uncertainty factor of 10 was considered appropriate because infants
are considerably more susceptible to methemoglobinemia than healthy adults. In
the absence of time-scaling information, the 6-h value was scaled using the
equation Cn × t = k, using the default values of n = 3 and n = 1 to extrapolate to
shorter or longer exposure durations, respectively. Because of the uncertainty
associated with scaling a 6-h exposure to 10 min, the 10-min AEGL value was
set equal to the 30-min AEGL value.
No acute studies were available that addressed relevant AEGL-2 effects.
In the absence of appropriate chemical-specific data, AEGL 2 values were set at
one-third of the AEGL-3 values (NRC 2001). This approach is supported by the
apparent steep-concentration response curve for perchloryl fluoride. Two of two
dogs exposed to perchloryl fluoride at 425 ppm survived a 4-h exposure, but one
of two dogs was found moribund after a 4-h exposure at a slightly higher con-
centration of 451 ppm (Green et al. 1960).
AEGL-3 values were based on moderate cyanosis and hyperpnea observed
in dogs exposed to perchloryl fluoride at 224 ppm for 4-h. No dogs died at the
next highest concentration of 451 ppm, but that concentration is greater than the
rat 4-h LC50 of 385 ppm in the same study. A total uncertainty factor of 30 was
applied (3 for interspecies differences and 10 for intraspecies variability). An
interspecies uncertainty factor of 3 was selected because lethality values among
dogs, rats, and mice differed by less than a factor of 3, and lethal values for the
rat were considered in selecting the point of departure. An intraspecies uncer-
tainty factor of 10 was considered appropriate because infants are considerably
more susceptible to methemoglobinemia than healthy adults. In the absence of
time-scaling information, the 4-h value was scaled to the shorter- and longer-
exposure durations using the same approach as that for the AEGL-1 values. Be-
cause of uncertainty in time scaling from a 4-h exposure to 10 min, the 10-min
value was set equal to the 30-min AEGL value.
AEGL values for perchloryl fluoride are presented in the Table 5-1.
1. INTRODUCTION
Perchloryl fluoride is a colorless gas with a characteristic sweet odor.
Chemically, it is the acyl fluoride of perchloric acid, and is prepared by elec-
trolysis of a saturated solution of sodium perchlorate in anhydrous hydrofluoric
acid. It is a very stable compound. Perchloryl fluoride is used as a fluorinating
agent, an oxidant in rocket fuels, and a gaseous dielectric for transformers
(Mendiratta et al. 2005). It is a strong oxidizer, and acts as a strong irritant of the
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142 Acute Exposure Guideline Levels
eyes, mucous membranes, and lungs. Absorption of the chemical results in
methemoglobinemia. Dermal contact with the liquid form of perchloryl fluoride
can produce burns.
Production data were not found for perchloryl fluoride. Perchloryl fluoride
does not burn and is not flammable, but it can support combustion. Chemical
and physical properties are provided in Table 5-2.
TABLE 5-1 Summary of AEGL Values for Perchloryl Fluoride
End Point
Classification 10 min 30 min 1h 4h 8h (Reference)
AEGL-1 1.8 ppm 1.8 ppm 1.5 ppm 0.92 ppm 0.60 ppm No effects in dog
(nondisabling) (7.6 (7.6 (6.3 (3.9 (2.5 or rats after 26-wk
mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) exposure (Greene
et al. 1960)
AEGL-2 5.0 ppm 5.0 ppm 4.0 ppm 2.5 ppm 1.2 ppm One-third of the
(disabling) (21 (21 (17 (11 (5.0 AEGL-3 values
mg/m3) mg/m3) mg/m3) mg/m3) mg/m3)
AEGL-3 15 ppm 15 ppm 12 ppm 7.5 ppm 3.7 ppm Highest
(lethal) (63 (63 (50 (32 (16 concentration
mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) causing no deaths
in mice, rats, and
dogs after 4 h
(Greene et al. 1960)
TABLE 5-2 Chemical and Physical Properties of Perchloryl Fluoride
Parameter Value References
Synonyms Trioxychlorofluoride, chlorine oxyfluoride, ACGIH 2008;
chlorine fluoride oxide HSDB 2008
CAS registry no. 7616-94-6 HSDB 2008
Chemical formula Cl-F-O3 HSDB 2008
Molecular weight 102.45 HSDB 2008
Physical state Colorless gas HSDB 2008
Melting point -146°C HSDB 2008
Boiling point -46.8°C HSDB 2008
Density HSDB 2008
Vapor 0.64 (air = 1)
Liquid 1.4 at 20°C (water = 1)
Solubility in water Miscible with water HSDB 2008
Vapor pressure 8,943.9 mm Hg at 25°C HSDB 2008
Flammability limits Not applicable, substance will not burn HSDB 2008
but can support combustion; strong oxidizer
Conversion factors 1 ppm = 4.2 mg/m3 ACGIH 1991
1 mg/m3 = 0.24 ppm
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Perchloryl Fluoride 143
2. HUMAN TOXICITY DATA
2.1. Acute Lethality
No human data were available on the acute lethality of perchloryl fluoride.
2.2. Nonlethal Toxicity
No human data were available on the nonlethal toxicity of perchloryl fluo-
ride. Anecdotal information indicates symptoms of upper respiratory irritation,
headaches, and dizziness after exposure to perchloryl fluoride vapors (HSDB
2008).
Perchloryl fluoride has a characteristic sweet odor. Greene et al. (1960)
used human volunteers (number and gender of participants not specified) to es-
timate the median detectable concentration of perchloryl fluoride gas. The gas,
mixed with air from the room, was metered into an inhalation chamber using a
Fair-Wells osmoscope (no further study details provided). At 41 ppm, 50% of
the volunteers detected the odor and described it as sweet, musty, or similar to
nitric acid.
2.3. Neurotoxicity
No human data were available on the neurotoxicity of perchloryl fluoride.
2.4. Developmental and Reproductive Toxicity
No data human were available on the developmental or reproductive toxic-
ity of perchloryl fluoride.
2.5. Genotoxicity
No human data were available on the genotoxicity of perchloryl fluoride.
2.6. Carcinogenicity
No human data were available on the carcinogenicity of perchloryl fluoride.
2.7. Summary
Data on perchloryl fluoride exposure in humans either by occupational ex-
posure or under experimental conditions were not available. Greene et al. (1960)
conducted an odor-threshold clinical study with human volunteers and reported
that 50% of participants could detect perchloryl fluoride at 41 ppm. However,
details of this study were minimal.
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144 Acute Exposure Guideline Levels
3. ANIMAL TOXICITY DATA
3.1. Acute Lethality
3.1.1. Dogs
Groups of two adult male beagle dogs were exposed to perchloryl fluoride
at concentrations of 224, 425, or 451 ppm for 4 h (Greene et al. 1960). Two ad-
ditional dogs were exposed at 622 ppm for 2.5 h (see Table 5-3). Perchloryl
fluoride was metered through a calibrated flow meter and was diluted with air
from the room before to entering the exposure chamber. Atmospheric concentra-
tions of the chemical in the chamber were estimated from the weight of the
compound. Blood was collected before and after exposure to determine hemo-
globin and methemoglobin concentrations, and gross and histopathologic ex-
aminations were performed. Two of the eight dogs died; one exposed at 451
ppm for 4 h was moribund when removed from the chamber and one exposed at
622 ppm for 2.5 h was dead, but the time of death was not specified. The re-
maining dogs exposed at 451 or 622 ppm were injected with methylene blue (2
mg/kg) to counteract methemoglobinemia. All dogs experienced concentration-
related cyanosis and hyperpnea. Dogs also exhibited convulsions and motor in-
stability when exposed at 451 or 622 ppm. At 425 ppm, methemoglobin concen-
trations increased to 15.5% immediately after exposure, and decreased to 4.8%
after an 18-h recovery period. Methemoglobin concentrations reached 28.7%
and 70.9% in dogs exposed at 451 and 622 ppm, respectively, before methylene
blue therapy. After methylene-blue therapy was initiated, methemoglobin con-
centrations were reduced to 3.8% and 0.0% in dogs exposed at 451 ppm and 622
ppm, respectively. No further study details were provided.
3.1.2. Rats
Greene et al. (1960) exposed rats to perchloryl fluoride in a manner simi-
lar to that described above for dogs. Groups of 10 adult male rats (derived Wis-
tar CF-1 strain) were exposed to perchloryl fluoride at concentrations of 220-
885 ppm for 4 h (individual concentrations not reported). The gas was metered
through a calibrated flow meter and was diluted with air from the room before to
entering the chamber. Atmospheric concentration of the chemical in the cham-
ber was analyzed by using quantitative hydrolysis of perchloryl fluoride with
10% alcoholic potassium hydroxide in a series of bubblers. Rats that died had
labored breathing, cyanosis, pronounced gasping, and convulsions. Most deaths
occurred during exposure or within 2 days after exposure. Surviving rats were
kept for 7 days postexposure. The 4-h LC50 for rats was 385 ppm (95% confi-
dence limits of 367-404 ppm). Rats that died had moderate discoloration of the
blood with accompanying discoloration of the viscera, especially the lungs. Mi-
croscopic examination showed marked congestion in the pulmonary vasculature
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Perchloryl Fluoride 145
with some areas of hemorrhage in the alveoli. No raw data to confirm the results
were included in the study report.
Dost et al. (1974) exposed male Sprague-Dawley rats to perchloryl fluo-
ride at 5,000 ppm for 15 min, 2,000 ppm for 25 or 40 min, or 1,000 ppm for 60
min (number of rats not specified). Rats were placed in a 3.6-L chamber that
accommodated two rats at a time. Exposure at 5,000 ppm for 15 min and 2,000
ppm for 40 min was lethal to all rats. All rats survived exposure at 2,000 ppm
for 25 min and 1,000 ppm for 60 min. Methemoglobinemia was observed at all
concentrations; at lethal concentrations, methemoglobin exceeded 60% of total
hemoglobin. No further details were available.
3.1.3. Mice
In a mouse lethality study, Greene et al. (1960) exposed groups of 20 fe-
male Carworth Farms CF-1 strain mice to perchloryl fluoride at concentrations
of 220 to 885 ppm for 4 h. The delivery system and concentration analysis were
the same as those described for the rat above. Mice that died had labored breath-
ing, cyanosis, pronounced gasping, and convulsions; most deaths occurred dur-
ing or within 2 days postexposure. Surviving mice were kept for 14-days post-
exposure. The 4-h LC50 for mice was 630 ppm (95% confidence limits of 569 -
697 ppm). The mice that died had the same discoloration of the internal organs
as observed in the rats, but to a lesser degree. No raw data to confirm the results
were included in the study report.
3.1.4. Guinea Pigs
Kushneva (1999) reported an LC50 for perchloryl fluoride of 220 mg/m3
(52 ppm) in guinea pigs, but the exposure duration was not specified.
3.2. Nonlethal Toxicity
Greene et al. (1960) conducted several repeat-exposure studies of perchlo-
ryl fluoride, in which dogs, rats, mice, and guinea pigs were exposed in various
scenarios ranging from 5-26 weeks in duration. Chamber concentrations were
determined analytically with samples collected by quantitative hydrolysis of
perchloryl fluoride with 10% alcoholic potassium hydroxide in a series of three
bubblers. Sample collections were 0.125-0.150 L/min. In all of the studies, data
were reported in graphic format without providing specific values.
3.2.1. Dogs
Groups of three beagles were exposed to perchloryl fluoride at 0 or 24
ppm for 6 h/day, 5 days/week for 26 weeks (Greene et al. 1960). Dogs were
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146 Acute Exposure Guideline Levels
either killed at the end of the exposure period or allowed a 6-week recovery pe-
riod (number of dogs not specified). Fluoride concentrations were measured in
the blood and urine throughout the study and in the bone (femur) at the end of
the exposure period or at the end of the recovery. All dogs survived, and no
clinical signs of toxicity were observed. Urinary fluoride concentrations in-
creased 4-fold over 6 months, but were comparable those of the controls at the
end of the exposure and remained normal during the recovery period. Bone fluo-
ride concentrations in treated dogs were 46% greater than that of control dogs.
However, the investigators stated that the amount of fluoride in the bone did not
reach 4,000 ppm, the concentration thought to cause histopathologic changes.
Spleen congestion containing iron-bearing pigments was found in treated dogs
killed after the final exposure, but not in treated dogs after a 6-week recovery
period. No effects were observed in the lungs of any dogs.
3.2.2. Rats
Groups of 20 adult male rats (derived Wistar CF-1 strain) were exposed to
perchloryl fluoride at 0, 104 ppm, or 185 ppm for 6 h/day, 5 days/week for 5
weeks (104 ppm) or 7 weeks (185 ppm) (Greene et al. 1960). Groups of three
rats were killed immediately and 18 h after the first and fourth exposure period
of each week. Blood was taken by cardiac puncture and the following hematol-
ogy parameters were measured: red-blood-cell count, white-blood-cell count
(with differential), reticulocyte count, methemoglobin, hemoglobin, fragility,
sedimentation rate, and hematocrit. Select tissues were prepared for histologic
examination. Fluoride deposition in the femur and urinary and blood fluoride
were determined.
Mortality was 90% (18/20) in the 185-ppm group after 35 days and 5%
(1/20) in the 104-ppm group after 25 days. Cyanosis was observed at both con-
centrations, and dyspnea at the highest concentration. After 1 week, rats exposed
at 185 ppm had a 23% increase in methemoglobin concentrations and a 25%
decrease in total hemoglobin compared with controls. Methemoglobin concen-
trations returned to normal after an overnight recovery period. Methemoglobin
and hemoglobin measurements in the treated rats were comparable to those of
controls after the second week. At gross examination, rats exposed at 185 ppm
had darkened organs and splenic weight was increased 4-5 times that of the con-
trols. Histopathologic lesions included splenic, hepatic, and renal hemosiderosis
and pulmonary lesions, including alveolar edema that developed into broncho-
pneumonia. Rats also exhibited stained incisors from fluorosis. At 104 ppm,
similar blood and tissue changes were observed, but were less severe. The only
raw data provided for this study were graphs showing the findings for the rats
exposed at 104 ppm.
Groups of 10 adult male rats (derived Wistar CF-1 strain) were also ex-
posed to perchloryl fluoride at 0 or 24 ppm for 6 h/day, 5 days/week for 26
weeks (Greene et al. 1960). All rats survived the study. Bone (femur) fluoride
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Perchloryl Fluoride 147
concentrations were three times greater than those of the controls at the end of
the study. Urinary fluoride concentrations were not reported. As with dogs, rats
had splenic congestion that disappeared after a recovery period, and no effects
were observed in the lungs.
3.2.3. Mice
Groups of 20 adult female mice (Carworth Farms CF-1 strain) were ex-
posed to perchloryl fluoride at 0 or 185 ppm for 6 h/day, 5 days/week for 7
weeks (Greene et al. 1960). Animals were observed for toxic effects and killed
at the end of the study. Mortality was 51% (20/39) in the mice after 35 days of
exposure, with dyspnea and cyanosis observed.
3.2.4. Guinea Pigs
Groups of 10 adult male guinea pigs (strain not specified) were exposed to
perchloryl fluoride at 0, 104, or 185 ppm for 6 h/day, 5 days/week for 5 weeks
(104 ppm) or 7 weeks (185 ppm) (Greene et al. 1960). Mortality was 100% in
guinea pigs exposed at 185 ppm for 3 days or at 104 ppm for 25 days. Dyspnea
and cyanosis were observed in the animals exposed at 185 ppm. Only cyanosis
was observed at 104 ppm.
Groups of 30 adult male guinea pigs (strain not specified) were exposed to
perchloryl fluoride at 0 or 24 ppm for 6 h/day, 5 days/week for 26 weeks
(Greene et al. 1960). Animals were monitored for toxic effects and 10 animals
per group were killed periodically for blood and tissue samples. Mortality was
3% (1/30) in the controls and 47% (14/30) in the treated animals, but the times
of deaths were not provided. Clinical signs of toxicity were not observed. Al-
though total hemoglobin was consistently lower in treated guinea pigs, the dif-
ferences were not statistically significant. Blood fluoride concentrations were
slightly greater (data not provided) in the treated guinea pigs, but blood volumes
obtained were small making the data unreliable. Urinary fluoride concentrations
increased 5-fold over a 6-month period but were comparable to those of controls
at the end of the exposure and remained normal during the postexposure period.
Bone (femur) fluoride concentrations in treated guinea pigs increased to four
times that of controls at the end of the study. During the recovery period, the
amount of fluoride in the femur did not diminish. Marked changes in the lungs
were observed in both control and treated guinea pigs. Localized damage sug-
gesting a chronic condition was observed in approximately 80-85% of the
guinea pigs in the control and treated groups, indicating a cause other than per-
chloryl fluoride. Bordetella bronchiseptica was isolated in some guinea pigs,
making the results of this study questionable and unreliable for determining
AEGL values. Treated guinea pigs also had congestion of the spleen and a cor-
responding increase in splenic weight, but these effects were reversed after ex-
posure stopped.
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148 Acute Exposure Guideline Levels
3.3. Developmental and Reproductive Toxicity
No animal data were available on the developmental or reproductive toxic-
ity of perchloryl fluoride.
3.4. Genotoxicity
No animal data were available on the genotoxicity of perchloryl fluoride.
3.5. Chronic Toxicity and Carcinogenicity
No animal data were available on the chronic toxicity or carcinogenicity
of perchloryl fluoride.
3.6. Summary
Greene et al. (1960) conducted both acute- and repeat-exposure studies.
Dogs exposed for 4 h to perchloryl fluoride at 224 or 425 ppm survived,
whereas 4-h exposures at 451 and 622 ppm were partially lethal. The 4-h LC50
values for rats and mice were 385 and 630 ppm, respectively. In repeat-exposure
studies, dogs and rats survived a 26-week exposure to perchloryl fluoride at 24
ppm for 6 h/day, 5 days/week. Evidence of contact irritation (dyspnea, labored
breathing) and of systemic absorption leading to methemoglobinemia (cyanosis)
and fluoride deposition were observed in all species. Dost et al. (1974) reported
that perchloryl fluoride at 2,000 ppm for 25 min or at 1,000 ppm for 60 min was
not lethal to rats. A summary of the available animal data on perchloryl fluoride
is presented in Table 5-3.
4. SPECIAL CONSIDERATIONS
4.1. Metabolism and Disposition
There were no studies available on the metabolism and disposition of per-
chloryl fluoride. In the longer-term repeat studies by Greene et al. (1960), rats,
guinea pigs, and dogs had fluoride deposition in the bone (femur) and in the
urine of dogs and guinea pigs, indicating that the molecule is broken down and
fluoride is released. Enamel fluorosis was also observed in rats.
4.2. Mechanism of Toxicity
No studies were identified describing the mechanism of toxicity for per-
chloryl fluoride. Two mechanisms of action might be present. The oxidative
properties of perchloryl fluoride might lead to direct-contact lung damage. For-
mation of methemoglobin in all species studied indicates that perchloryl fluoride
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TABLE 5-3 Summary of Inhalation Data on Perchloryl Fluoride in Laboratory Animals
Species Concentration (ppm) Exposure Duration Effect Reference
Acute Lethality Studies
Doga 224 4h Moderate cyanosis, hyperpnea. Greene et al. 1960
Dog 425 4h Severe cyanosis, hyperpnea, emesis. Greene et al. 1960
Dog 451 4h Severe cyanosis, hyperpnea, motor instability, Greene et al. 1960
convulsions; one dog moribund in chamber, other
dog treated with methylene blue and survived.
Dog 622 2.5 h Severe cyanosis, hyperpnea, salivation, motor Greene et al. 1960
instability; convulsions; one dog died, other dog
treated with methylene blue and survived.
Rat 384 4h LC50 Greene et al. 1960
Rat 5,000 15 min 100% mortality Dost et al. 1974
Rat 2,000 25 min No mortality Dost et al. 1974
40 min 100% mortality
Rat 1,000 60 min No mortality Dost et al. 1974
Mouse 630 4h LC50 Greene et al. 1960
Repeat-Exposure Studiesb
Dog 0, 24 6 h/d, 5 d/wk for 26 wk All survived; no clinical signs; increased fluoride Greene et al. 1960
in femur after 6 mos
Rat 0, 104, 185 6 h/d, 5 d/wk for 5 wk 104 ppm: 1/20 died (>25 exposure days), cyanosis, Greene et al. 1960
(104 ppm) or 7 wk increased methemoglobin, decreased hemoglobin,
(185 ppm) histopathologic changes (liver, spleen, kidney)
185 ppm: 18/20 died (>35 exposure days), dyspnea,
same effects as 104 ppm but more severe
(Continued)
149
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156 Acute Exposure Guideline Levels
TABLE 5-8 Extant Standards and Guidelines for Perchloryl Fluoride
Exposure Duration
Guideline 10 min 30 min 1h 4h 8h
AEGL-1 1.8 ppm 1.8 ppm 1.5 ppm 0.92 ppm 0.60 ppm
(7.6 mg/m3) (7.6 mg/m3) (6.3 mg/m3) (3.9 mg/m3) (2.5 mg/m3)
AEGL-2 5.0 ppm 5.0 ppm 4.0 ppm 2.5 ppm 1.2 ppm
(21 mg/m3) (21 mg/m3) (17 mg/m3) (11 mg/m3) (5.0 mg/m3)
AEGL-3 15 ppm 15 ppm 12 ppm 7.5 ppm 3.7 ppm
(63 mg/m3) (63 mg/m3) (50 mg/m3) (32 mg/m3) (16 mg/m3)
IDLH (NIOSH)a 100 ppm
(420 mg/m3)
TLV-TWA 3 ppm
(ACGIH)b (14 mg/m3)
PEL-TWA 3 ppm
(OSHA)c (14 mg/m3)
REL-TWA 3 ppm
(NIOSH)d (14 mg/m3)
TLV-STEL 6 ppm
(ACGIH)e (25 mg/m3)
(15 min)
REL-STEL 6 ppm
(NIOSH)f (25 mg/m3)
(15 min)
MAC (MSZW)g 3 ppm
(14 mg/m3)
a
IDLH (immediately dangerous for life or health, National Institute for Occupational
Safety and Health) (NIOSH 1994) represents the maximum concentration from which
one could escape within 30 min without any escape-impairing symptoms, or any irre-
versible health effects.
b
TLV-TWA (threshold limit value-time weighted average, American Conference of Gov-
ernmental Industrial Hygienists) (ACGIH 1991, 2008) is the time-weighted average con-
centration for a normal 8-h workday and a 40-h workweek, to which nearly all workers
may be repeatedly exposed, day after day, without adverse effect.
c
PEL-TWA (permissible exposure limit-time weighted average, Occupational Safety and
Health Administration) (29 CFR Part 1910 [2005]) is defined analogous to the ACGIH
TLV-TWA, but is for exposures of no more than 10 h/day, 40 h/week.
d
REL-TWA (recommended exposure limit-time weighted average, National Institute for
Occupational Safety and Health) (NIOSH 2010) is defined analogous to the ACGIH
TLV-TWA.
e
TLV-STEL (threshold limit value-short term exposure limit, American Conference of
Governmental Industrial Hygienists) (ACGIH 2008) is defined as a 15-min TWA expo-
sure which should not be exceeded at any time during the workday even if the 8-h TWA
is within the TLV-TWA. Exposures above the TLV-TWA up to the STEL should not be
longer than 15 min and should not occur more than four times per day. There should be at
least 60 min between successive exposures in this range.
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Perchloryl Fluoride 157
f
REL-STEL (recommended exposure limit-short term exposure limit, National Institute
for Occupational Safety and Health) (NIOSH 2010) is defined analogous to the ACGIH
TLV-STEL.
g
MAC (maximaal aanvaarde concentratie [maximal accepted concentration], Ministry of
Social Affairs and Employment, The Hague, The Netherlands [MSZW 2004]) is defined
analogous to the ACGIH TLV-TWA.
9. REFERENCES
ACGIH (American Conference of Government and Industrial Hygienists). 1991. Perchlo-
ryl Fluoride (CAS Reg. No. 7616-94-6). Documentation of the Threshold Limit
Values and Biological Exposure Indices. American Conference of Government
and Industrial Hygienists, Cincinnati, OH.
ACGIH (American Conference of Government and Industrial Hygienists). 2008. Perchlo-
ryl Fluoride (CAS Reg. No. 7616-94-6). P. 47 in Documentation of the Threshold
Limit Values and Biological Exposure Indices. American Conference of Govern-
ment and Industrial Hygienists, Cincinnati, OH.
Da-Silva, S., I.S. Sajan, and J. Underwood, III. 2003. Congenital methemoglobinemia: A
rare cause of cyanosis in the newborn - a case report. Pediatrics 112(2):158-161.
Dost, F.N., D.J. Reed, V.N. Smith, and C.H. Wang. 1974. Toxic properties of chlorine
trifluoride. Toxicol. Appl. Pharmacol. 27(3):527-536.
Greene, E.A., J.L. Colbourn, E. Donati, and M.H. Weeks. 1960. The Inhalation Toxicity
of Perchloryl Fluoride. U.S. Army Chemical Research and Development Laborato-
ries Technical Report CRDLR 3010. Army Chemical Center, Edgewood, MD.
HSDB (Hazardous Substances Databank). 2008. Trioxychlorofluoride (CAS Reg. No.
7616-94-6). TOXNET, Specialized Information Services, U.S. National Library of
Medicine, Bethesda, MD [online]. Available: http://toxnet.nlm.nih.gov/cgi-bin/sis/
htmlgen?HSDB [accessed Oct. 31, 2008].
Kiese, M. 1974. Methemoglobinemia: A Comprehensive Treatise. Cleveland, OH: CRC
Press.
Kushneva. 1999. Handbook of Toxicological and Hygienic Standards (PDK) of Poten-
tially Hazardous Substances. Developed by the Institute of Biophysics and its (as-
sociated) branches.
Mendiratta, S.K., R.L. Dotson, and R.T. Brooker. 2005. Perchloric acid and perchlorates.
In Kirk-Othmer Encyclopedia of Chemical Technology. New York: John Wiley
and Sons.
MSZW (Ministerie van Sociale Zaken en Werkgelegenheid). 2004. Nationale MAC-lijst
2004: Perchlorylfluoride Den Haag: SDU Uitgevers [online]. Available: http://
www.lasrook.net/lasrookNL/maclijst2004.htm [accessed Aug. 28, 2012].
NIOSH (National Institute for Occupational Safety and Health). 1994. Documentation for
Immediately Dangerous to Life or Health Concentrations (IDLH): Perchloryl fluo-
ride. U.S. Department of Health and Human Services, Centers for Disease Control
and Prevention, National Institute for Occupational Safety and Health, Cincinnati,
OH [online]. Available: http://www.cdc.gov/niosh/idlh/7616946.html [accessed
Aug. 22, 2012].
NIOSH (National Institute for Occupational Safety and Health). 2010. NIOSH Pocket
Guide to Chemical Hazards: Perchloryl fluoride. U.S. Department of Health and
Human Services, Centers for Disease Control and Prevention, National Institute
OCR for page 158
158 Acute Exposure Guideline Levels
for Occupational Safety and Health, Cincinnati, OH [online]. Available: http://
www.cdc.gov/niosh/npg/default.html [accessed Aug. 22, 2012].
NRC (National Research Council). 1993. Guidelines for Developing Community Emer-
gency Exposure Levels for Hazardous Substances. Washington, DC: National
Academy Press.
NRC (National Research Council). 2001. Standard Operating Procedures for Developing
Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: Na-
tional Academy Press.
Seger, D.L. 1992. Methemoglobin-forming chemicals. Pp. 800-806 in Hazardous Materi-
als Toxicology: Clinical Principles of Environmental Health, J.B. Sullivan, and
G.R. Krieger, eds. Baltimore, MD: Williams & Wilkins.
ten Berge, W.F., A. Zwart, and L.M. Appelman. 1986. Concentration-time mortality
response relationship of irritant and systemically acting vapours and gases. J. Haz-
ard. Mater. 13(3):301-309.
Wilburn-Goo, D., and L. Lloyd. 1999. When patients become cyanotic: Acquired
methemoglobinemia. J. Am. Dent. Assoc. 130(6):826-831.
OCR for page 159
Perchloryl Fluoride 159
APPENDIX A
DERIVATION OF AEGL VALUES FOR PERCHLORYL FLUORIDE
Derivation of AEGL-1 Values
Key study: Greene, E.A., J.L. Colbourn, E. Donati, and
M.H. Weeks. 1960. The Inhalation Toxicity
of Perchloryl Fluoride. U.S. Army Chemical
Research and Development Laboratories
Technical Report CRDLR 3010. Army
Chemical Center, Edgewood, MD.
Toxicity end point: No treatment-related adverse effects.
Time scaling: Cn × t = k
n = 3 for extrapolating to the 30-min and
1- and 4-h durations
(24 ppm)3 × 6 h = 8.3 × 104 ppm-h
n = 1 for extrapolating to the 8-h duration
(24 ppm)1 × 6 h = 144 ppm-h
Uncertainty factors: 3 for interspecies differences
10 for intraspecies variability
10-min AEGL-1: 1.8 ppm (set equal to the 30-min value
because of the long exposure duration of
the key study)
30-min AEGL-1: C3 × 0.5 h = 8.3 × 104 ppm-h
C3 = 1.7 × 105 ppm
C = 55.4 ppm
55.4 ppm ÷ 30 = 1.8 ppm
1-h AEGL-1: C3 × 1 h = 8.3 × 104 ppm-h
C3 = 8.3 × 104 ppm
C = 43.6 ppm
43.6 ppm ÷ 30 = 1.5 ppm
4-h AEGL-1: C3 × 4 h = 8.3 × 104 ppm-h
C3 = 20,750 ppm
C = 27.5 ppm
27.5 ppm ÷ 30 = 0.92 ppm
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160 Acute Exposure Guideline Levels
8-h AEGL-1: C1 × 8 h = 144 ppm-h
C1 = 18 ppm
18 ppm ÷ 30 = 0.60 ppm
Derivation of AEGL-2 Values
Key study: NRC (National Research Council).
2001. Standard Operating Procedures
for Developing Acute Exposure Guideline
Levels for Hazardous Chemicals.
Washington, DC: National Academy Press.
Toxicity end point: For chemicals with a steep concentration-
response curve, AEGL-2 values may be
calculated by dividing AEGL-3 values by 3
(NRC 2001).
Time scaling: See derivation of AEGL-3
Uncertainty factors: See derivation of AEGL-3
10-min AEGL-2: 15 ppm ÷ 3 = 5.0 ppm
30-min AEGL-2: 15 ppm ÷ 3 = 5.0 ppm
1-h AEGL-2: 12 ppm ÷ 3 = 4.0 ppm
4-h AEGL-2: 7.5 ppm ÷ 3 = 2.5 ppm
8-h AEGL-2: 3.7 ppm ÷ 3 = 1.2 ppm
Derivation of AEGL-3 Values
Key study: Greene, E.A., J.L. Colbourn, D. Donati, and
M.H. Weeks. 1960. The Inhalation Toxicity
of Perchloryl Fluoride. U.S. Army Chemical
Research and Development Laboratories
Technical Report CRDLR 3010. Army
Chemical Center, Edgewood, MD.
Toxicity end point: Highest 4-h concentration causing no
mortality in dogs, but below the LC50
value for rats in the same study.
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Perchloryl Fluoride 161
Scaling: Cn × t = k
n = 3 for extrapolating to the 30-min and
1-h durations
(224 ppm)3 × 4 h = 4.5 x 107 ppm-h
n = 1 for extrapolating to the 8-h duration
(224 ppm)1 × 4 h = 896 ppm-h
Uncertainty factors: 3 for interspecies variability
10 for intraspecies variability
10-min AEGL-3: 15 ppm (set equal to the 30-min value
because of the long exposure duration of
the key study)
30-min AEGL-3: C3 × 0.5 h = 4.50 × 107 ppm-h
C3 = 9.0 x 107 ppm
C = 448 ppm
448 ppm ÷ 30 = 15 ppm
1-h AEGL-3: C3 × 1 h = 4.50 × 107 ppm-h
C3 = 4.50 x 107 ppm
C = 356 ppm
356 ppm ÷ 30 = 12 ppm
4-h AEGL-3 C = 224 ppm ÷ 30
C = 7.5 ppm
8-h AEGL-3: C1 × 8 h = 896 ppm-h
C1 = 112 ppm
112 ppm ÷ 30 = 3.7 ppm
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162 Acute Exposure Guideline Levels
APPENDIX B
Chemical Toxicity - TSD Animal Data
Perchloryl Fluoride
10000
1000
No Effect
Discomfort
100
Disabling
ppm
AEGL-3
10 Some Lethality
AEGL-2
Lethal
AEGL-1
1
AEGL
0
0 60 120 180 240 300 360 420 480
Minutes
FIGURE B-1 Category plot of animal toxicity data on perchloryl fluoride compared with
AEGL values.
TABLE B-1 Data Used in Category Plot of AEGL Values for Perchloryl Fluoride
Concentration Duration
Source Species (ppm) (min) Category
NAC/AEGL-1 1.8 10 AEGL
NAC/AEGL-1 1.8 30 AEGL
NAC/AEGL-1 1.5 60 AEGL
NAC/AEGL-1 0.92 240 AEGL
NAC/AEGL-1 0.60 480 AEGL
NAC/AEGL-2 5 10 AEGL
NAC/AEGL-2 5 30 AEGL
NAC/AEGL-2 4 60 AEGL
NAC/AEGL-2 2.5 240 AEGL
NAC/AEGL-2 1.2 480 AEGL
NAC/AEGL-3 15 10 AEGL
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Perchloryl Fluoride 163
NAC/AEGL-3 15 30 AEGL
NAC/AEGL-3 12 60 AEGL
NAC/AEGL-3 7.5 240 AEGL
NAC/AEGL-3 3.7 480 AEGL
Greene et al. 1960 Dog 224 240 2 (moderate cyanosis,
hyperpnea)
Dog 425 240 2 (severe cyanosis,
hyperpnea, emesis)
Dog 451 240 SL (severe cyanosis,
hyperpnea, motor
instability, convulsions,
death of one of two
dogs)
Dog 622 150 SL (severe cyanosis,
hyperpnea, salivation,
motor instability,
convulsions; death of
one of two dogs)
Rat 384 240 SL (LC50)
Mouse 630 240 SL (LC50)
Dost et al. 1974 Rat 5,000 15 3 (100% mortality)
Rat 2,000 25 2 (no mortality)
Rat 2,000 40 3 (100% mortality)
Rat 1,000 60 2 (no mortality)
For category: 0 = no effect; 1 = discomfort; 2 = disabling; SL = some lethality; and 3 =
lethal.
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164 Acute Exposure Guideline Levels
APPENDIX C
ACUTE EXPOSURE GUIDELINE LEVELS
FOR PERCHLORYL FLUORIDE
Derivation Summary
AEGL-1 VALUES
10 min 30 min 1h 4h 8h
1.8 ppm 1.8 ppm 1.5 ppm 0.92 ppm 0.60 ppm
Key reference: Greene, E.A., J.L. Colbourn, D. Donati, and M.H. Weeks. 1960.
The Inhalation Toxicity of Perchloryl Fluoride. U.S. Army Chemical Research and
Development Laboratories Technical Report CRDLR 3010. Army Chemical Center,
Edgewood, MD.
Test species/Strain/Number: Beagle dogs, 2 per group; Sprague-Dawley rats,
10 per group
Exposure route/Concentrations/Durations: Inhalation, 24 ppm for 6 h/day,
5 days/week for 26 weeks
Effects:
0 ppm: No effects observed
24 ppm: No clinical signs observed; some increases in fluoride deposition but
only after long-term exposure.
End point/Concentration/Rationale: No effect except for increased fluoride
deposition in bones after 26 weeks
Uncertainty factors/Rationale:
Total uncertainty factor: 30
Interspecies: 3, because the 4-h concentration at which 1 of 2 dogs were moribund
(451 ppm) and the LC50 concentrations for rats (385 ppm) and mice (630 ppm) are
within 3-fold of each other, and all species developed similar symptoms (dyspnea
and cyanosis).
Intraspecies: 10, because perchloryl fluoride is systemically absorbed and the
possible increased sensitivity of some humans, especially infants, for developing
methemoglobinemia.
Modifying factor: Not applied
Animal-to-human dosimetric adjustment: Not applicable
Time scaling: Extrapolation to different exposure durations was performed using the
equation Cn × t = k (ten Berge et al. 1986), where n = 3 for extrapolation to durations
of 30-min, 1 h, and 4 h, and n = 1 for extrapolation to 8 h. The 30-min value was
adopted as the 10-min value because extrapolating from 4 h to 10 min is not
recommended (NRC 2001).
Data adequacy: Adequate
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Perchloryl Fluoride 165
AEGL-2 VALUES
10 min 30 min 1h 4h 8h
5.0 ppm 5.0 ppm 4.0 ppm 2.5 ppm 1.2 ppm
Key reference: NRC (National Research Council). 2001. Standard Operating
Procedures for Developing Acute Exposure Guideline Levels for Hazardous
Chemicals. National Research Council, National Academy Press: Washington, DC.
Test species/Strain/Number: See derivation of AEGL-3
Exposure route/Concentrations/Durations: See derivation of AEGL-3
Effects: See derivation of AEGL-3
End point/Concentration/Rationale: In the absence of chemical-specific data, NRC
(2001) recommends taking one-third of AEGL-3 values when there is evidence of a
steep concentration-response curve.
Uncertainty factors/Rationale: See derivation of AEGL-3
Modifying factor: See derivation of AEGL-3
Animal-to-human dosimetric adjustment: See derivation of AEGL-3
Time scaling: See derivation of AEGL-3
Data adequacy: Not adequate
AEGL-3 VALUES
10 min 30 min 1h 4h 8h
15 ppm 15 ppm 12 ppm 7.5 ppm 3.7 ppm
Key reference: Greene, E.A., J.L. Colbourn, D. Donati, and M.H. Weeks. 1960.
The Inhalation Toxicity of Perchloryl Fluoride. U.S. Army Chemical Research
and Development Laboratories Technical Report CRDLR 3010. Army Chemical
Center, Edgewood, MD.
Test species/Strain/Number: Male beagle dogs, 2 per group
Exposure route/Concentrations/Durations: Inhalation, 224, 425, or 451 ppm for 4-h.
Effects:
Rat: LC50 = 385 ppm
Mouse: LC50 = 630 ppm
Dogs: 224 ppm, both dogs had cyanosis and hyperpnea; 425 ppm, both dogs had
severe cyanosis and hyperpnea; 451 ppm, 1 of 2 dogs moribund
End point/Concentration/Rationale: 224 ppm was highest nonlethal concentration
in dogs with no projected mortality in rats and mice.
Uncertainty factors/Rationale:
Total uncertainty factor: 30
Interspecies: 3, because the 4-h concentration at which 1 of 2 dogs were moribund
(451 ppm) and the LC50 concentrations for rats (385 ppm) and mice (630 ppm) are
within 3-fold of each other, and all species developed similar symptoms (dyspnea
and cyanosis).
(Continued)
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166 Acute Exposure Guideline Levels
AEGL-3 VALUES Continued
Intraspecies: 10, because perchloryl fluoride is systemically absorbed and the
possible increased sensitivity of some humans, especially infants, for developing
methemoglobinemia.
Modifying factor: Not applied
Animal-to-human dosimetric adjustment: Not applicable
Time scaling: Extrapolation to different exposure durations was performed using
the equation Cn × t = k (ten Berge et al. 1986), where n = 3 for extrapolation to
durations of 30-min, 1 h, and 4 h, and n = 1 for extrapolation to 8 h. The 30-min
value was adopted as the 10-min value because extrapolating from 4 h to 10 min
is not recommended (NRC 2001).
Data adequacy: Adequate
