NAC Proposed 1: June 2009 1
2
3 

## ACUTE EXPOSURE GUIDELINE LEVELS (AEGLs) 4 

## FOR 5 

## PERCHLORYL FLUORIDE 6 

## (CAS Reg. No. 7616-94-6) 7

8

9

10 

## PROPOSED 11

12PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 2 of 28

1
PREFACE 2
3 Under the authority of the Federal Adviso ry Committee Act (FACA) P. L. 92-463 of 4 1972, the National Advisory Committee for Acut e Exposure Guideline Levels for Hazardous 5 Substances (NAC/AEGL Committee) has been established to identify, review and interpret 6 relevant toxicologic and other sc ientific data and develop AEGLs for high priority, acutely toxic 7
chemicals. 8
9 AEGLs represent threshold exposure limits for the general public a nd are applicable to 10 emergency exposure periods ranging from 10 minutes to 8 hours. Three levels

C AEGL-1, 11
AEGL-2 and AEGL-3

Care developed for each of five e xposure periods (10 and 30 minutes, 1 12 hour, 4 hours, and 8 hours) and are distinguished by va rying degrees of severity of toxic effects. 13
The three AEGLs are defined as follows: 14
15 AEGL-1 is the airborne concentration (expres sed as parts per million or milligrams per 16 cubic meter [ppm or mg/m 3 ]) of a substance above which it is predicted that the general 17 population, including susceptible indi viduals, could experience notab le discomfort, irritation, or 18 certain asymptomatic, non-sensory effects. Ho wever, the effects are not disabling and are 19
transient and reversible upon cessation of exposure. 20
21
AEGL-2 is the airborne concentr ation (expressed as ppm or mg/m 3 ) of a substance above 22 which it is predicted that th e general population, including su sceptible individuals, could 23 experience irreversible or other serious, long-lasting adverse hea lth effects or an impaired ability 24 to escape. 25
26
AEGL-3 is the airborne concentr ation (expressed as ppm or mg/m 3 ) of a substance above 27 which it is predicted that th e general population, including su sceptible individuals, could 28 experience life-threatening health effects or death. 29
30
Airborne concentrations below the AEGL-1 re present exposure levels that could produce 31 mild and progressively increas ing but transient and nondisab ling odor, taste, and sensory 32 irritation or certain asymptomatic , non-sensory effects. With incr easing airborne concentrations 33 above each AEGL, there is a progressive increase in the likelihood of occu rrence and the severity 34
of effects described for each corresponding AEGL. Although the AEGL values represent 35 threshold levels for the general public, including susceptible subpopulations, such as infants, 36 children, the elderly, persons with asthma, and thos e with other illnesses, it is recognized that 37 individuals, subject to unique or idiosyncratic responses, could experience the effects described 38
at concentrations belo w the corresponding AEGL. 39
40
41
42PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 3 of 28

TABLE OF CONTENTS 1

PREFACE........................................................................................................................ .............................2 2

LIST OF TABLES................................................................................................................. .......................5 3

EXECUTIVE SUMMARY .............................................................................................................. ............6 4

1. INTRODUCTION................................................................................................................ ................7 5

2. HUMAN TOXICITY DATA......................................................................................................... ......8 6

2.1. Acute Lethality ........................................................................................................... .................8 7

2.2. Nonlethal Toxicity........................................................................................................ ...............8 8

2.3. Neurotoxicity............................................................................................................. ..................8 9

2.4. Developmental/Reproductive Toxicity....................................................................................... .8 10

2.5. Genotoxicity .............................................................................................................. ..................9 11

2.6. Carcinogenicity........................................................................................................... .................9 12

2.7. Summary................................................................................................................... ...................9 13

3. ANIMAL TOXICITY DATA........................................................................................................ ......9 14

3.1. Acute Lethality ........................................................................................................... .................9 15 3.1.1. Dogs .................................................................................................................... ....................9 16

3.1.2. Rats.................................................................................................................... ......................9 17
3.1.3. Mice .................................................................................................................... ..................10 18 3.1.4. Guinea Pigs ............................................................................................................. .................10 19

3.2. Repeat Exposure........................................................................................................... .............10 20 3.2.1. Dogs .................................................................................................................... ..................10 21

3.2.2. Rats.................................................................................................................... ....................11 22
3.2.3. Mice................................................................................................................... ......................12 23 3.2.4. Guinea Pigs ............................................................................................................. ..............12 24

3.3. Developmental/Reproductive Toxicity......................................................................................1 2 25

3.4. Genotoxicity .............................................................................................................. ................12 26

3.5. Chronic Toxicity/Carcinogenicity .......................................................................................... ...13 27

3.6. Summary................................................................................................................... .................13 28

4. SPECIAL CONSIDERATIONS ...................................................................................................... ..14 29

4.1. Metabolism and Disposition................................................................................................ ......14 30

4.2. Mechanism of Toxicity..................................................................................................... .........14 31

4.3. Structure Activity Relationships.......................................................................................... ......14 32

4.4. Other Relevant Information................................................................................................ .......14 33 4.4.1. Species Variability ..................................................................................................... ...........14 34 4.4.2. Susceptible Populations ................................................................................................. .......15 35 4.4.3. Concentration-Exposure Duration Relationship ...................................................................15 36PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 4 of 28

5. DATA ANALYSIS FOR AEGL-1 .................................................................................................... 15 1

5.1. Summary of Human Data Relevant to AEGL-1........................................................................15 2

5.2. Summary of Animal Data Relevant to AEGL-1........................................................................15 3

5.3. Derivation of AEGL-1...................................................................................................... .........15 4

6. DATA ANALYSIS FOR AEGL-2 .................................................................................................... 16 5

6.1. Summary of Human Data Relevant to AEGL-2........................................................................16 6

6.2. Summary of Animal Data Relevant to AEGL-2........................................................................16 7

6.3. Derivation of AEGL-2...................................................................................................... .........16 8

7. DATA ANALYSIS FOR AEGL-3 .................................................................................................... 17 9

7.1. Summary of Human Data Relevant to AEGL-3........................................................................17 10

7.2. Summary of Animal Data Relevant to AEGL-3........................................................................17 11

7.3. Derivation of AEGL-3...................................................................................................... .........17 12

8. SUMMARY OF AEGLS ............................................................................................................ .......17 13

8.1. AEGL Values and Toxicity Endpoints......................................................................................17 14

8.2. Comparison with Other Standards and Guidelines....................................................................18 15

8.3. Data Adequa cy and Research ................................................................................................ ....20 16

9. REFERENCES.................................................................................................................. .................20 17

APPENDIX A: Derivation of AEGL Values......................................................................................... ....22 18

APPENDIX B: Category Plot of Toxicity Data and AEGL Values for Perchloryl Fluoride ....................25 19

APPENDIX C: Category Plot of Toxicity Data and AEGL Values for Perchloryl Fluoride ..................25 5 20PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 5 of 28

LIST OF TABLES 1

2 TABLE 1. Summary of AEGL Valu es for Perchloryl Fluoride........................................................................ ...........7 3

TABLE 2. Chemical and Physical Pr operties ...................................................................................... ........................8 4 TABLE 3. Summary of Inhalation Data in Labora tory An imals ...................................................................... .........13 5

TABLE 4. AEGL-1 Values for Perchloryl Fluoride ................................................................................. .................16 6

TABLE 5. AEGL-2 Values for Perchloryl Fluoride ................................................................................. .................16 7

TABLE 6. AEGL-3 Values for Perchloryl Fluoride ................................................................................. .................17 8 TABLE 7. Summary of AEGL Values................................................................................................ .......................18 9 TABLE 8. Extant Standards and Guidelines for Perchloryl fluoride in ppm (mg/m 3 )...............................................19 10PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 6 of 28

EXECUTIVE SUMMARY 1
2 Perchloryl Fluoride (CAS No. 7616-94- 6) is a colorless, stable ga s. Perchloryl fluoride is 3 used as a fluorinating agent, an oxidant in rocket fuels and a gaseous dielectric for transformers. 4 It is prepared by electrolysis of a saturate d solution of sodium perchlorate in anhydrous 5 hydrofluoric acid. It is a str ong oxidizer and acts as a strong irritant of the eyes, mucus 6 membranes and lungs. Systemic effects can oc cur upon inhalation includ ing the induction of 7 methemoglobinemia. 8
9 Human data were not available for developi ng AEGL values. Animal data were limited 10 to two studies. During 4-hour studies, Greene et al. (1960) exposed dogs to concentrations 11 ranging from 224 to 622 ppm. Only 4-hour LC 50 values were reported for rats and mice. 12 Repeat-exposure data were presented for dogs, rats, mice, and guinea pigs. In a second study, 13 Dost et al. (1974), mortality values were presented for rats at seve ral time points, but details of 14 the exposures were not included. No informa tion relevant to time- scaling AEGL was found. 15
16
The AEGL-1 values were derived from the c oncentration, 24 ppm, at which dogs and rats 17 were exposed for 6 hours/day, 5 days/week for 26 weeks. At this con centration, all animals 18 survived, exhibited no clinical signs, no signs of irritation and the only long-term effect observed 19 was increased fluoride deposition in the bone a nd urine over the course of the 26 weeks. 20 Therefore, this may be considered a no-effect level over an eight hour period. The POD, 24 ppm, 21 was divided by interspecies and intraspecies un certainty factors of 3 and 10, respectively, for a 22 total of 30. An interspecies uncertainty factor of 3 was appropriate as lethality values among 23 dogs, rats, and mice differed by less than a factor of 3. An intraspecies uncertainty factor of 10 24 was considered appropriate because infant s are considerably more susceptible to 25 methemoglobinemia than healthy adults. In th e absence of time-scaling information, the 6-hour 26
value was time-scaled to the shor ter and longer exposure durations (C n x t = k) using the default 27 values of 3 and 1, respectively. Because of un certainty in time-scaling from an 6-hour exposure 28 duration to 10 minutes, the 10-minute value was set equal to the 30-minute value. 29
30
No acute studies addressed effects consistent with the definition of an AEGL-2. In the 31 absence of appropriate chemical-specific data, AEGL 2 values were set at one-third of the 32 AEGL-3 values (NRC 2001). This approach is supported by the steep-concentration-response 33 curve. In a 4-hour study, two of two dogs survived at 425 ppm; whereas, one of two dogs was 34 found moribund at 451 ppm (Green et al. 1960). 35
36
The AEGL-3 values were based on a concen tration of 224 ppm which induced moderate 37 cyanosis and hyperpnea in dogs during a 4-hour e xposure. No dogs died at the next highest 38 concentration of 451 ppm, but this value is above the rat 4-hour LC 50 of 385 ppm in the same 39 study. The 4-hour 224 ppm concen tration was divided by inters pecies and intraspecies 40 uncertainty factors of 3 and 10, respectively, for a total of 30. Lethality values among dogs, rats, 41 and mice differed by less than a factor of 3, and lethal values for the rat were considered in 42 setting the point of departure. An intraspe cies uncertainty factor of 10 was considered 43 appropriate because infants are considerably more susceptible to methemoglobinemia than 44 healthy adults. In the absence of time-scaling information, the 4-hour value was time-scaled to 45 the shorter and longer exposure durations (C n x t = k) using the defa ult values of 3 and 1, 46PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 7 of 28

respectively. Because of uncertainty in tim e-scaling from a 4-hour exposure duration to 10 1 minutes, the 10-minute value was set equal to the 30-minute value. 2
3
Values are summarized in the table below. 4
5
TABLE 1. Summary of AEGL Va lues for Perchloryl Fluoride

Classification 10-min 30-min 1- hr 4-hr 8-hr Endpoint (Reference)

AEGL

B 1 (Nondisabling) 1.8 ppm (7.6 mg/m 3 ) 1.8 ppm (7.6 mg/m 3 ) 1.5 ppm (6.3 mg/m 3 ) 0.92 ppm (3.9 mg/m 3 ) 0.60 ppm (2.5 mg/m 3 ) No effects in dog/rats after 26 week exposure (Greene et al. 1960)

AEGL

B 2 (Disabling) 5.0 ppm (21 mg/m 3 ) 5.0 ppm (21 mg/m 3 ) 4.0 ppm (17 mg/m 3 ) 2.5 ppm (11 mg/m 3 ) 1.2 ppm (5.0 mg/m 3 ) One third of the AEGL-3 values (NRC 2001)

AEGL

B 3 (Lethal) 15 ppm (63 mg/m 3 ) 15 ppm (63 mg/m 3 ) 12 ppm (50 mg/m 3 ) 7.5 ppm (32 mg/m 3 ) 3.7 ppm (16 mg/m 3 ) Highest concentration causing no deaths in mice, rats and dogs after
4 hrs. (Greene et al. 1960)

6
7
1. INTRODUCTION 8
9 Perchloryl fluoride is a colorless gas with a characteristic sweet odor. Chemically, it is 10 the acyl fluoride of perchloric acid and is prepar ed by electrolysis of a saturated solution of 11 sodium perchlorate in anhydrous hydrofluoric acid. It is a very stable compound. Perchloryl 12 fluoride is used as a fluorinating agent, an oxida nt in rocket fuels and a gaseous dielectric for 13 transformers (Mendiratta et al. 2005 ). It is a strong oxidizer, a nd acts as a strong irritant of the 14 eyes, mucous membranes and lungs. Absorption re sults in methemoglobinemia. Dermal contact 15 with the liquid form of perchloryl fluoride can also produce burns. 16
17 Production data were not identified for perchlor yl fluoride. Perchloryl fluoride does not 18 burn and is not flammable, but it can support co mbustion. Chemical and physical properties are 19 provided in Table 2. 20
21PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 8 of 28

TABLE 2. Chemical and Physical Properties

Parameter Value References

Synonyms Trioxychlorofluoride; chlorine oxyfluoride; chlorine fluoride oxide HSDB 2008;
ACGIH 2008
Chemical formula Cl-F-O 3 HSDB 2008 Molecular weight 102.45 HSDB 2008 CAS Reg. No. 7616-94-6 HSDB 2008 Physical state Colorl ess gas HSDB 2008 Solubility in water Miscible with water HSDB 2008 Vapor pressure 8943.9 mm Hg @ 25 °C HSDB 2008 Vapor density (air =1) 0.64 HSDB 2008 Liquid density (water =1) 1.4 @ 20 °C HSDB 2008 Melting point -146 °C HSDB 2008 Boiling point -46.8 °C HSDB 2008

Flammability limits Not applicable- substance will not burn but can support combustion; strong
oxidizer HSDB 2008

Conversion factors 1 ppm = 4.2 mg/m 3 1 mg/m 3 = 0.24 ppm ACGIH 1991

1
2
2. HUMAN TOXICITY DATA 3 2.1. Acute Lethality 4
5
There are no data available. 6
7 2.2. Nonlethal Toxicity 8
9
There are no data available th at address the nonlethal toxicity of perchloryl fluoride in 10 humans. Anecdotal information about human expo sure to perchloryl fluoride vapor describes 11 symptoms of upper respiratory irritation, as we ll as headaches and dizziness (HSDB 2008). 12
13 Perchloryl fluoride has a char acteristic sweet odor. Green e et al. (1960) used human 14 volunteers (number and gender of participants no t provided) to estimate the median detectable 15 concentration of perchloryl fluoride gas. The gas, mixed with room air was metered into an 16 inhalation chamber using a Fair-Wells Osmoscop e (no further study details provided). At 41 17 ppm, 50% of the volunteers detected the odor and de scribed it as sweet, musty or nitric acid-like. 18
19 2.3. Neurotoxicity 20
21
There are no data available. 22
23 2.4. Developmental/Reproductive Toxicity 24
25
There are no data available. 26
27PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 9 of 28

2.5. Genotoxicity 1
2
There are no data available. 3
4 2.6. Carcinogenicity 5
6
There are no data available. 7
8 2.7. Summary 9
10 Data on perchloryl fluoride exposure in humans either by occupational exposure or 11 experimental exposure are not available. Greene et al. (1960) conducted an odor threshold 12 clinical study with human volunt eers and reported that 50% of participants could detect 13 perchloryl fluoride at 41 ppm, alt hough study details were minimal. 14
15
3. ANIMAL TOXICITY DATA 16 3.1. Acute Lethality 17 3.1.1. Dogs 18
19 Two adult male beagle dogs/group were e xposed for 4 hours to concentrations of 224, 20 425, or 451 ppm. Two additional dogs inhale d 622 ppm for 2.5 hours (Greene et al. 1960) 21 (Table 3). The gas was metered through a calibra ted flow meter and was diluted with room air 22 prior to entering the exposure chamber. Atmo spheric concentration of the chemical in the 23 chamber was estimated from the weight of the compound used. Blood was collected before and 24 after exposure for hemoglobin and methemoglob in levels; gross and histopathological 25 examinations were performed. Out of the eight study dogs, there were tw o deaths; one exposed 26 to 451 ppm for 4 hours was moribund upon removal from the chamber and one exposed to 622 27 ppm for 2.5 hours died, although the time of d eath was not provided. The remaining dogs 28 exposed to 451 or 622 ppm were injected w ith methylene blue to counteract increased 29 methemoglobin. All dogs experien ced concentration-related cyanos is and hyperpnea. Dogs also 30
exhibited convulsions and motor instability when exposed to 451 or 622 ppm. At 425 ppm, 31 methemoglobin levels increased to 15.5 % immediately after expos ure, decreasing to 4.8% after 32 an 18-hour recovery period. Methemoglobin leve ls reached 28.7 and 70.9% in dogs exposed to 33 451 and 622 ppm, respectively, prior to methylene bl ue therapy. After met hylene blue therapy (2 34 mg/kg) was initiated as a treatment, the meth emoglobin levels dropped to 3.8 and 0.0% in the 35 dogs exposed to 451 ppm and 622 ppm, respectivel y. No further study details were provided. 36
37
3.1.2. Rats 38
39 Greene et al. (1960) exposed ra ts to perchloryl fluoride in a manner similar to that 40 described above for dogs. Groups of 10 adult male rats (derived Wistar CF-1 strain) were 41 exposed to perchloryl fluoride at concentr ations of 220 to 885 ppm for 4 hours (individual 42 concentrations not reported). The gas was metered through a calibrated flow meter and was 43 diluted with room air prior to entering the cham ber. Atmospheric concen tration of the chemical 44 in the chamber was analyzed by collecting sa mples of the chamber air using quantitative 45 hydrolysis of perchloryl fluoride with 10% alcoholic potassium hydroxide in a series of bubblers. 46PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 10 of 28

Rats that died showed labored breathing, cya nosis, pronounced gasping and convulsions. Most 1 deaths occurred during the exposure or within 2 days post-exposure. Surviving rats were kept 2 for 7 days post-exposure. The 4-hour LC 50 for rats was 385 ppm (95% confidence limits of 367- 3 404 ppm). Rats that died had moderate di scoloration of the blood with accompanying 4 discoloration of the viscera, especially the lungs. Microsc opic examination showed marked 5 congestion in the pulmonary vasculature with some areas of hemorrhage in the alveoli. No raw 6
data to confirm the results were included in the study report. 7
8 Dost et al. (1974) exposed male Sprague-Dawle y rats to 5000 ppm perc hloryl fluoride for 9 15 minutes; 2000 ppm for 25 or 40 minutes; or 1000 ppm for 60 mi nutes (number of rats/group 10 not provided). Exposures were whole body in a 3.6-L chamber that accommodated two rats at a 11 time. Exposure to 5000 ppm for 15 minutes and 2000 ppm for 40 minutes was lethal to all rats. 12 All rats survived exposure to 2000 ppm fo r 25 minutes and 1000 ppm for 60 minutes. 13 Methemoglobin was observed at all exposure concen trations, and in lethal exposures exceeded 14 60% of total hemoglobin. No further details were available. 15
16
3.1.3. Mice 17
18 In the mouse lethality study, Greene et al. ( 1960) exposed 20 female Carworth Farms CF19 1 strain mice/group to perchloryl fluoride at concentrations of 220 to 885 ppm for 4 hours. The 20 delivery system and concentration an alysis were as described for th e rat, above. Mice that died 21 showed labored breathing, cyanosis, pronounced ga sping and convulsions; most deaths occurred 22 during or within 2 days post-exposure. Surviving mice were kept for 14 days post-exposure. The 23
4-hour LC 50 for mice was 630 ppm (95% confidence lim its of 569-697 ppm) with the mice that 24 died having the same discoloration of the internal organs as observ ed in the rats, but to a lesser 25 degree. No raw data to confirm the re sults were included in the study report. 26
27 3.1.4. Guinea Pigs 28
29 Kushneva (1999) provided an LC 50 of 220 mg/m 3 (52 ppm) for guinea pigs. An exposure 30 duration was not provided. 31
32 3.2. Repeat Exposure 33
34 All repeat exposure studies were performed by the same laboratory (Greene et al. 1960). 35 In these studies, dogs, rats, mice, and guinea pi gs were exposed in va rious scenarios ranging 36 from 5 weeks up to 26 weeks. Chamber concentr ations were determined analytically with 37 samples collected by quantitative hyd rolysis of perchloryl fluoride with 10% alcoholic potassium 38 hydroxide in a series of thr ee bubblers. Collections of sa mples were 0.125 L/min to 0.150 39 L/min. In all of the studies, data were reporte d in graphic format without actual values listed. 40
41 3.2.1. Dogs 42
43 Three beagles/group were exposed to 0 (c ontrols) or 24 ppm perchloryl fluoride by 44 inhalation for 6 hours/day, 5 days/week for 26 week s (Greene et al. 1960). Dogs were either 45 sacrificed at the end of the exposure period or allowed a 6-7 week recovery period (number of 46PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 11 of 28

dogs allowed to recover not provi ded). Fluoride levels were m easured in the blood and urine 1 throughout the study and in the bone (femur) at the end of the exposure period and at the end of 2 the recovery. All dogs survived the 26 weeks of exposure. Clini cal signs of toxicity were not 3 observed. Urinary fluoride levels increased four fold over a 6 month period, but were comparable 4 to controls at the end of the exposure and re mained normal during the recovery period. Bone 5 fluoride levels in treated dogs we re increased 46% when compared to the control dogs at the end 6 of the study. However, the author stated that the amount of fluoride in the bone did not reach the 7 4000 ppm level that is thought to be the concentration causing hist opathological changes. In 8 treated dogs killed after the final exposure (130 th ), there was spleen congestion containing some 9 iron-bearing pigments; however, this was not pr esent in the treated dogs after the 6 week 10 recovery. No effects were observed in the lungs of any of the dogs. 11
12
3.2.2. Rats 13
14 Twenty white adult male rats (derived Wistar CF-1 strain)/group were exposed by 15 inhalation to 0 (controls), 104 ppm or 185 ppm of perchloryl fluoride, 6 hours/day, and 5 16 days/week for 5 weeks (104 ppm) or 7 weeks (185 ppm) (Greene et al. 1960). Rats in groups of 17 three were killed immediately and 18 hours afte r the first and fourth exposure period of each 18 week. Blood was taken by cardiac puncture and the following hematology parameters were 19 measured: red blood cell count, white blood cell c ount (with differential) , reticulocyte count, 20 methemoglobin levels, hemoglobin, fragility, sediment ation rate, and hematocrit. Select tissues 21 were prepared for histological examination. Fl uoride deposition in the femur and urinary and 22
blood fluoride were determined in the rats at sacrifice. 23
24 Mortality for the rats was 18/20 (90%) in the 185 ppm group after 35 days of exposure 25 and 1/20 (5%) in the 104 ppm group after 25 days of exposure. Cyanosis was observed at both 26 concentrations with dyspnea also observed at the high concentration. After one week, rats 27 inhaling 185 ppm had a 23% increase in methem oglobin levels and 25% decrease in total 28 hemoglobin when compared to controls. The meth emoglobin levels recovered to normal after an 29 overnight recovery period. Both of these measurem ents were comparable to those of controls in 30
all rats after the second week. Grossly, rats exposed to 185 ppm had darkened organs and 31 splenic weight was increased to 4-5 times that of the controls. Histopathological lesions 32 included splenic, hepatic and renal hemosidero sis and pulmonary lesions, including alveolar 33 edema that developed into bronchopneumonia. Rats also exhibited stained incisors from 34 fluorosis. At 104 ppm, similar blood and tissue changes were observed, but were less severe. 35 The only raw data provided for this study were gr aphs showing the findings for the rats exposed 36 to 104 ppm. 37
38 Ten white adult male rats (derived Wistar CF-1 strain)/group were also exposed to 0 39 (controls) or 24 ppm perchloryl fluoride 6 hours/day, 5 days/week for 26 weeks (Greene et al. 40 1960). All rats survived to the end of exposure. Urinary fluoride levels for the rats were not 41 reported; however, the bone (femur) fluoride leve ls were three times greater than those of the 42
controls at the end of 6 months. As with th e dogs, rats had splenic congestion that was not 43 observed after a recovery period; no e ffects were observed in the lungs. 44
45PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 12 of 28

3.2.3. Mice 1
2 Twenty white adult female mice (Carworth Fa rms CF-1 strain)/group were exposed to 0 3 (controls) or 185 ppm of perchl oryl fluoride by inhalation, 6 h ours/day, and 5 days/week for 7 4 weeks (Greene et al. 1960). Animals were observe d for any toxic effects and sacrificed at the 5 end of the study. Mortality was 20/39 (51%) in the mice after 35 days of exposure with dyspnea 6 and cyanosis observed. 7
8 3.2.4. Guinea Pigs 9
10 Ten adult male guinea pigs (strain not provide d)/group were exposed to 0 (controls), 104 11 or 185 ppm of perchloryl fluoride by inhalati on, 6 hours/day, 5 days/week for 5 weeks (104 ppm) 12 or 7 weeks (185 ppm). Mortality was 100% (10/10) in guinea pigs afte r inhaling 185 ppm for 3 13 days and 100% (10/10) in guinea pigs inhali ng 104 ppm for 25 days. Dyspnea and cyanosis 14 were observed in the high-dose animals with only cyanosis observed at the low-dose. 15
16 Thirty adult male guinea pigs (strain not pr ovided)/group were exposed by Greene et al. 17 (1960) to 0 or 24 ppm of perc hloryl fluoride for 6 hours/day, 5 days/week for 26 weeks. 18 Animals were monitored for any toxic effects and ten guinea pigs/gr oup were sacrificed 19 periodically for blood and tissue samples. Mort ality occurred in 1/30 of the controls and 14/30 20 (47%) of the exposed animals, although the times of deaths were not provided. Clinical signs of 21 toxicity were not observed and while total hemo globin was consistently lower in treated guinea 22 pigs, the differences were not stat istically significant. Blood fluorid e levels were slightly higher 23 (raw data not provided) in the treated guinea pi gs but blood volumes obtained were small making 24 the data unreliable. Urinary fluoride levels in creased fivefold over a 6-month period but were 25 comparable to those of controls at the end of the exposure an d remained normal during the post26 exposure period. Bone (femur) fluoride levels in tr eated guinea pigs increase d to 4 times that of 27 controls at the end of the study. During the reco very period, the amount of fluoride deposited in 28 the femur did not diminish. Marked changes in the lungs were observed in both the control and 29 treated guinea pigs. Localized damage s uggesting a chronic condition was observed in 30 approximately 80-85% of the guinea pigs in bo th the control and treated groups, indicating 31 another possible entity was involve d. In some of the guinea pigs, Bordetella bronchoseptica was 32 isolated thus making all of the results of this study questionable. In treated guinea pigs, there 33 was spleen congestion and a corres ponding increase in splenic wei ght but these changes reversed 34 after the exposure stopped. 35
36 3.3. Developmental/Reproductive Toxicity 37
38
There are no data available. 39
40 3.4. Genotoxicity 41
42
There are no data available. 43
44PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 13 of 28

3.5. Chronic Toxicity/Carcinogenicity 1
2
There are no data available. 3
4 3.6. Summary 5
6 Greene et al. (1960) conducted both acute and repeat-exposure studies. Dogs exposed to 7 224 or 425 ppm of perchloryl fluoride for 4 hours survived, whereas 4-hour exposures to 451 and 8 622 ppm were partially lethal. Four-hour LC 50 values for rats and mice were 385 and 630 ppm, 9 respectively. In repeat expos ures, dogs and rats survived a 26-week exposure to 24 ppm 10 perchloryl fluoride (6 hours/day, 5 days/week). Similar effects of contact irritation (dyspnea, 11 labored breathing) and some effects of systemic absorption leading to methemoglobinemia 12 (cyanosis) and fluoride deposition we re observed in all species. Do st et al (1974) reported that 13 2000 ppm for 25 minutes and 1000 pp m for 60 minutes were not le thal to rats. Data are 14
summarized in Table 3. 15
16
TABLE 3. Summary of Inhalation Data in Laboratory Animals Acute Lethality Studies

Species Concentration (ppm) Exposure
Duration Effect Reference
Dog a 224 4 hrs Moderate cyanosis, hyperpnea Greene et al. 1960 Dog 425 4 hrs Severe cyanosis, hyperpnea, emesis Greene et al. 1960 Dog 451 4 hrs Severe cyanosis, hyperpnea, motor instability, convulsions; one dog moribund in chamber, other dog treated with methylene blue and survived Greene et al. 1960

Dog 622 2.5 hrs Severe cyanosis, hyperpnea, salivation, motor instability; convulsions; one dog died, other dog treated with methylene
blue and survived Greene et al. 1960

Rat 384 4 hrs LC 50 Greene et al. 1960 Rat 5000 15 min 100% mortality Dost et al. 1974
Rat 2000 25 min
40 min No mortality 100% mortality Dost et al. 1974

Rat 1000 60 min No mortality Dost et al. 1974
Mouse 630 4 hrs LC 50 Greene et al. 1960 Repeat-Exposure Studies b
Species Concentration (ppm) Exposure
Duration Effect Reference

Dog 0, 24 6 hrs/d, 5 d/wk
for 26 wks All survived; no clinical signs; ↑ fluoride
in femur after 6 months Greene et al. 1960

Rat 0, 104, 185 6 hrs/d, 5 d/wk for 5 wks (104 ppm) or 7 wks (185 ppm) 104 ppm: 1/20 died (> 25 exposure days) cyanosis, ↑ methemoglobin, ↓ hemoglobin, histopathological changes (liver, spleen, kidney) 185 ppm: 18/20 died (> 35 exposure days), dyspnea, same effects as 104 ppm
but more severe Greene et al. 1960

Rat 0, 24 6 hrs/d, 5 d/wk
for 26 wks All survived no clinical signs; ↑ fluoride
in femur after 6 months Greene et al. 1960

Mouse 0, 185 6 hrs/d, 5 d/wk 185 ppm: 20/39 died (after 35 exposure Greene et al. 1960PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 14 of 28

for 7 wks days); dyspnea and cyanosis
Guinea pig 0, 104, 185 6 hrs/d, 5 d/wk for 5 wks (104 ppm) or 7 wks (185) ppm 104 ppm: 10/10 died (> 25 exposure days); cyanosis 185 ppm: 10/10 died (> 3 exposure days) dyspnea and cyanosis Greene et al. 1960

Guinea pig 0, 24 6 hrs/d, 5d/wk
for 26 wks 1/30 control and 14/30 treated died c ↑ fluoride in bone, lung lesions c Greene et al. 1960

a Two dogs/group. 1

b In all repeat exposure studies, there were no eff ects observed in the contro ls unless otherwise stated. 2

c The high mortality and lung data are questionable as both the control and treated guinea pigs had Bordetella 3 bronchoseptica infections. 4
5 6 4. SPECIAL CONSIDERATION S 7 4.1. Metabolism and Disposition 8
9
There were no studies available on the metabolis m and disposition of perchloryl fluoride. 10 In the longer-term repeat studies by Greene et al. (1960), rats, guinea pi gs and dogs had fluoride 11 deposition in the bone (femur) and in the urin e of dogs and guinea pigs, indicating that the 12
molecule is broken down with the release of fluoride. Fluorosis was also observed on the teeth 13
of rats. 14
15 4.2. Mechanism of Toxicity 16
17
No studies or data were identified describi ng the mechanism of toxicity for perchloryl 18 fluoride. Two mechanisms of action may be pres ent. The oxidative properties of perchloryl 19 fluoride may lead to direct-contact lung damage. Formation of methemoglobin in all species 20 studied indicates that following absorption, perchloryl fluoride or its metabolites oxidize the 21 ferrous (Fe +2 ) iron in hemoglobin to th e oxidized ferric form (Fe +3 ). Methemoglobin is unable to 22 transport oxygen to the organs and tissues, resu lting in cyanosis. Methemoglobin concentrations 23
of ≥ 70% are considered the threshold for lethality (Kiese 1974; Seger 1992). Normal 24 methemoglobin levels in humans are <1%. 25
26 4.3. Structure Activity Relationships 27
28 Greene et al. (1960) provided a table compari ng fluoride deposition in the femurs of rats 29 exposed to 104 ppm perchloryl fluoride and similar exposures to fluorine (F 2 ) and hydrogen 30 fluoride (HF). Based on the findings, the amount of fluoride deposited from perchloryl fluoride 31 exposure was about one-fourth and one-hal f that following exposure to HF and F 2 , respectively. 32 One possible explanation for the lo wer absorption of perchloryl fluoride is that it has a more 33 stable structure compared to the other fluorides. 34
35
4.4. Other Relevant Information 36 4.4.1. Species Variability 37
38 Data suggest limited interspeci es variability. Greene et al. (1960) exposed rats, mice, 39 guinea pigs and dogs to similar c oncentrations of perchloryl fluor ide and observed similar effects 40
in all animals. All exhibite d labored breathing, cyanosis, co nvulsions and changes in the 41PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 15 of 28

hemoglobin and methemoglobin levels in the blood. The 4-hr concentration at which one of two 1 dogs was moribund (451 ppm) and the LC 50 concentrations for rats (385 ppm) and mice (630 2 ppm) are within 3-fold of each other. 3
4 4.4.2. Susceptible Populations 5
6 As with other lung irritants, humans with compromised lung function would be more 7 susceptible to the toxic effects of perchloryl fluoride. Also, young children and the elderly are 8 naturally more susceptible to methemoglobinemia and could develop this condition more readily 9 when exposed to perchloryl fluoride as th ey both have increa sed fetal hemoglobin 10 concentrations. The elderly may also be on mu ltiple oxidant medications that can lower their 11 threshold for developing methemoglobinemia (Wilburn-Goo and Lloyd 1999) . A rare, genetic 12 defect which causes a deficiency of nicotinami de adenine dinucleotide-cytochrome b5 reductase 13 enzyme (NADH-cytochrome b5 reductase) has been documented. This enzyme co-factor 14 reduces methemoglobin in normal erythrocytes. Fetal hemoglobin is more susceptible to 15 oxidation than adult hemoglobin; this co-factor lacks full activity until in fants are 4 months of 16 age (Seger 1992). Humans can either be carriers in which they show no clinical signs but have a 17 lower threshold for developing acquired meth emoglobinemia ,or if autosomal recessive 18 transmission occurs, they exhibi t cyanosis at birth and must be treated, as it can cause death 19 within a few years (Da-Silva et al. 2003). 20
21 4.4.3. Concentration-Exposure Duration Relationship 22
23 The concentration-exposure time relationship for many irritant and systemically-acting 24 vapors and gases can be descri bed by the relationship C n x t = k, where the exponent, n, ranges 25 from 0.8 to 3.5 (ten Berge et al. 1986). Data were unavailable for an empirical derivation of n in 26 the equation, C n x t = k. In the absence of chemical spec ific data, an n of 3 will be applied to 27 extrapolate to shorter time periods, and an n of 1 will be applied to extrapolate to longer time 28 periods, to provide AEGL values that woul d be protective of hu man health (NRC 2001). 29
30
5. DATA ANALYSIS FOR AEGL-1 31 5.1. Summary of Human Data Relevant to AEGL-1 32
33 No applicable human data are available for deriving AEGL-1 valued. 34
35 5.2. Summary of Animal Data Relevant to AEGL-1 36
37 There were two studies with laboratory animal s (Greene et al. 1960; Dost et al. 1974) that 38 addressed lethality. A longer term study (Greene et al 1960) in which dogs and rats were 39 exposed to 24 ppm of perchloryl fluoride 6 hours/day, 5 days/week for 26 weeks indicated no 40
acute effects at this concentration. 41
42
5.3. Derivation of AEGL-1 43
44 The 26-week term study (Greene et al 1960) wi ll be used to derive AEGL values. The 45
AEGL-1 values were derived from the concen tration, 24 ppm, at which dogs and rats were 46PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 16 of 28

exposed for 6 hours/day, 5 days/week. At this co ncentration, all animals survived, exhibited no 1 clinical signs, no signs of irri tation and the only long-term effect observed was increased fluoride 2 deposition in the bone and urine over the course of the 26 weeks. Therefore, this may be 3
considered a no-effect level ove r an eight hour period. The 24 pp m concentration was divided by 4 interspecies and intraspecies uncertainty of 3 and 10 for a total of 30. An interspecies 5 uncertainty factor of 3 was considered appropria te as lethality values among dogs, rats, and mice 6 differed by less than a factor of 3. An intraspe cies uncertainty factor of 10 was considered 7 appropriate because infants are considerably more susceptible to methemoglobinemia than 8 healthy adults. Time-scaling followed the relationship C n x t = k where n equals 1 or 3 for longer 9 and shorter exposure durations , respectively (NRC 2001). The 30-minute AEGL-3 value was 10 adopted as the 10-minute value due to uncertainties in extrapolat ing from the 6-hour value (NRC 11 2001). AEGL-1 values are provided (Table 4). 12
13
TABLE 4. AEGL-1 Values for Perchloryl Fluoride

10-min 30-min 1-hr 4-hr 8-hr

1.8 ppm (7.6 mg/m 3 ) 1.8 ppm (7.6 mg/m 3 ) 1.5 ppm (6.3 mg/m 3 ) 0.92 ppm (3.9 mg/m 3 ) 0.60 ppm (2.5 mg/m 3 )

14
15
6. DATA ANALYSIS FOR AEGL-2 16 6.1. Summary of Human Data Relevant to AEGL-2 17
18
No human data are available for use in deriving AEGL-2 values. 19
20 6.2. Summary of Animal Data Relevant to AEGL-2 21
22
No animal data are available that defined e ffects consistent with the definition of an 23
AEGL-2. 24
25
6.3. Derivation of AEGL-2 26
27 In the absence of appropriate chemical-specifi c data, AEGL 2 values were derived as a 3- 28 fold reduction of the AEGL-3 values (NRC 2001) . This approach is supported by the steep 29 concentration-response curve. In a 4-hour study, two of two dogs survived at 425 ppm; whereas, 30 one of two dogs was found moribund at 451 ppm (G reen et al., 1960). AEGL-2 values are 31 provided in Table 5. 32
33
TABLE 5. AEGL-2 Values for Perchloryl Fluoride

10-min 30-min 1-hr 4-hr 8-hr 5.0 ppm (21 mg/m 3 ) 5.0 ppm (21 mg/m 3 ) 4.0 ppm (17 mg/m 3 ) 2.5 ppm (11 mg/m 3 ) 1.2 ppm (5.0 mg/m 3 )

34
35PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 17 of 28

7. DATA ANALYSIS FOR AEGL-3 1 7.1. Summary of Human Data Relevant to AEGL-3 2
3
No human data are available for use in deriving AEGL-3 values. 4
5 7.2. Summary of Animal Data Relevant to AEGL-3 6
7 Greene et al. (1960) exposed two dogs, ten ra ts and twenty mice per group to varying 8
concentrations in 4-hour acute i nhalation studies. Dogs exhibite d clinical signs (cyanosis and 9 hyperpnea) at 224 ppm, but no mortality occurred. Cyanosis worsened at 425 ppm and one of 10 the dogs exposed at 451 ppm was found moribund in the chamber. The LC 50 values for rats and 11 mice were 385 and 630 ppm, respectively. No mort ality occurred in rats exposed to 2000 ppm 12 for 25 minutes or to 1000 ppm for 60 minutes (Dost et al. 1974). Details of this latter study were 13 not provided. 14
15
7.3. Derivation of AEGL-3 16
17 The study of Greene et al. (1960) in wh ich groups of two dogs inhaled several 18
concentrations for 4 hours was chosen as the ke y study. Dogs survived concentrations of 224 19 and 451 ppm for 4 hours. The concentration of 224 ppm was chosen as th e point of departure 20
because it is below the LC 50 value of 384 ppm for rats in the same study. The 4-hour 224 ppm 21 concentration was divided by inters pecies and intraspecies uncerta inty factors of 3 and 10 for a 22 total of 30. An interspecies uncertainty factor of 3 was considered appropri ate as lethality values 23 among dogs, rats, and mice differed by less than a fact or of 3, and lethal values for the rat were 24 considered in addressing the point of departure. An intraspecies uncer tainty factor of 10 was 25 considered appropriate because in fants are considerably more su sceptible to methemoglobinemia 26 than healthy adults. Time-scaling followed the relationship C n x t = k where n equals 1 or 3 for 27 longer and shorter exposure durations, respec tively (NRC 2001). The 30-minute AEGL-3 value 28 was adopted as the 10-minute value due to uncerta inties in extrapolating from the 4-hour value 29 (NRC 2001). AEGL-3 values are provided in Table 6. 30
31
TABLE 6. AEGL-3 Values for Perchloryl Fluoride

10-min 30-min 1-hr 4-hr 8-hr 15 ppm (63 mg/m 3 ) 15 ppm (63 mg/ m 3 ) 12 ppm (50 mg/m 3 ) 7.5 ppm (32 mg/ m 3 ) 3.7 ppm (16 mg/ m 3 )

32 The AEGL-3 values appear low in light of the short exposure of human volunteers to 33 several concentrations including 41 ppm (Greene et al. 1960). Ho wever, the sparse data base 34 justifies the low numbers. 35
36
37
8. SUMMARY OF AEGLS 38 8.1. AEGL Values and Toxicity Endpoints 39
40
Because of a lack of acute studies with anim als exhibiting AEGL-1 effects, a longer term 41 study at a concentration in which dogs and rats exhibited no acute effects was used for the 42PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 18 of 28

derivation. No studies that addre ssed effects consistent with the definition of an AEGL-2 were 1 found. The concentration-response cu rve for lethality is steep. Th erefore, AEGL-2 values were 2 derived by dividing the AEGL-3 values by 3. The point of departure for AEGL-3 values was the 3 4-hour concentration of 224 ppm that caused no deaths in dogs, but was below the 4-hour LC 50 4 value of 384 ppm for rats. For AEGL-1 and - 3, the POD was divided by interspecies and 5 intraspecies uncertainty factors of 3 and 10, resp ectively, for a total of 30. In the absence of 6 time-scaling information, the 4-hour or 6-hour value was time scaled to the other AEGL 7 exposure durations using the default values of 3 and 1 for shorter and longer exposure durations, 8 respectively. All AEGL valu es are provided in Table 7. 9
10
TABLE 7. Summary of AEGL Values Exposure Duration Classification 10-min 30-min 1-hr 4-hr 8-hr

AEGL-1 (Nondisabling) 1.8 ppm (7.6 mg/m 3 ) 1.8 ppm (7.6 mg/m 3 ) 1.5 ppm (6.3 mg/m 3 ) 0.92 ppm (3.9 mg/m 3 ) 0.60 ppm (2.5 mg/m 3 )

AEGL-2 (Disabling) 5.0 ppm (21 mg/m 3 ) 5.0 ppm (21 mg/m 3 ) 4.0 ppm (17 mg/m 3 ) 2.5 ppm (11 mg/m 3 ) 1.2 ppm (5.0 mg/m 3 )

AEGL-3 (Lethal) 15 ppm (63 mg/m 3 ) 15 ppm (63 mg/m 3 ) 12 ppm (50 mg/m 3 ) 7.5 ppm (32 mg/ m 3 ) 3.7 ppm (16 mg/ m 3 )

11
12 8.2. Comparison with Other St andards and Guidelines 13
14
The ACGIH TLV-TWA and OSHA PEL-TWA were both established from the Greene et 15 al. (1960) study; the recommende d 3 ppm was approximately 1/10 th of the 24 ppm concentration 16 that caused fluorosis and hematological alte ration in experimental animals over repeated 17 exposures (26 weeks). The 8-hour AEGL-2 and AE GL-3 values appear low in comparison to the 18 TWA value, but the standards are for healthy adults , whereas, the AEGL valu es are protective of 19 sensitive infant and elderly populations. The ID LH of 100 ppm was based on the Greene et al. 20 (1960) LC 50 for rats of 385 ppm in a 4-hour acute i nhalation toxicity st udy. Standards and 21 guidelines are provided in Table 8. 22
23PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 19 of 28

TABLE 8. Extant Standards and Guidelines for Perchloryl fluoride in ppm (mg/m 3 ) Exposure Duration Guideline 10 min 30 min 1 hr 4 hr 8 hr

AEGL-1 1.8 ppm (7.6 mg/m 3 ) 1.8 ppm (7.6 mg/m 3 ) 1.5 ppm (6.3 mg/m 3 ) 0.92 ppm (3.9 mg/m 3 ) 0.60 ppm (2.5 mg/m 3 )

AEGL-2 5.0 ppm (21 mg/m 3 ) 5.0 ppm (21 mg/m 3 ) 4.0 ppm (17 mg/m 3 ) 2.5 ppm (11 mg/m 3 ) 1.2 ppm (5.0 mg/m 3 )

AEGL-3 15 ppm (63 mg/m 3 ) 15 ppm (63 mg/m 3 ) 12 ppm (50 mg/m 3 ) 7.5 ppm (32 mg/m 3 ) 3.7 ppm (16 mg/m 3 )

PEL-TWA (OSHA) a 3 ppm (14 mg/m 3 )

IDLH (NIOSH) b 100 ppm (420 mg/m 3 )

REL-TWA (NIOSH) c 3 ppm (14 mg/m 3 )

REL-STEL (NIOSH) d 6 ppm (25 mg/m 3 )

(15 min)

TLV-TWA (ACGIH) e 3 ppm (14 mg/m 3 )

TLV-STEL (ACGIH) f 6 ppm (25 mg/m 3 )

(15 min) MAC (SDU Uitgevers) g 3 ppm (14 mg/m 3 )

1

a OSHA PEL-TWA (Occupational Safety and Health Administra tion, Permissible Exposure Limits - Time Weighted 2 Average) (OSHA 2005) is defined analogous to the ACGIH-TLV-TWA, but is for exposures of no more than 10 3 hours/day, 40 hours/week. 4 5

b IDLH (Immediately Dangerous to Life and Health, National Institute of Occupational Safety and Health) (NIOSH 6 1996) represents the maximum concentration from which one could escape within 30 minutes without any escape7 impairing symptoms, or any irreversible health effects. 8 9

c NIOSH REL-TWA (National Institute of Occupational Safety and Health, Recommended Exposure Limits - Time 10 Weighted Average) (NIOSH 2005) is defined analogous to the ACGIH-TLV-TWA. 11 12

d NIOSH REL-STEL (Recommended Exposure Limits - Shor t Term Exposure Limit) (NIOSH 2005) is defined 13 analogous to the ACGIH TLV-STEL. 14 15

e ACGIH TLV-TWA (American Conference of Governmental Industrial Hygienists, Threshold Limit Value - Time 16 Weighted Average) (ACGIH 2008 and 1991) is the ti me-weighted average concen tration for a normal 8-hour 17 workday and a 40-hour workweek, to which nearly all workers may be repeatedly exposed, day after day, without 18

adverse effect. 19 20

f ACGIH TLV-STEL (Threshold Limit Value - Short Term Exposure Limit) (ACGIH 2008) is defined as a 15- 21 minute TWA exposure which should not be exceeded at an y time during the workday ev en if the 8-hour TWA is 22 within the TLV-TWA. Exposures above the TLV-TWA up to the STEL should not be longer than 15 minutes and 23 should not occur more than 4 times per day. There should be at least 60 minutes between successive exposures in 24 this range. 25 26PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 20 of 28

g MAC (Maximaal Aanvaarde Concentratie [Maximal Accepted Concentration]) (SDU Uitgevers 2 000) [under the 1 auspices of the Ministry of Social Affairs and Employment], The Hague, The Netherlands. Is defined analogous to 2

the ACGIH-TLV-TWA. 3 4 5 8.3. Data Adequacy and Research 6
7 Human data are lacking for perchloryl fluorid e. Animal data are also very limited and 8 although many species (dogs, rats, guinea pigs and mice) were exposed by inhalation to 9 perchloryl fluoride, most of the studies were conducted by the same laboratory and details were 10 not reported. 11
12
13
9. REFERENCES 14
15 ACGIH (American Conference of Government and Industr ial Hygienists). 2008. Documentation of the 16 Threshold Limit Values and Biological Exposure Indices: Perchloryl Fluoride, p. 47. ACGIH, 17 Cincinnati, OH. 18
19 ACGIH (American Conference of Government and Industr ial Hygienists). 1991. Documentation of the 20 Threshold Limit Values and Biological Exposure Indices: Perchloryl Fluoride. Sixth Ed., ACGIH, 21 Cincinnati, OH. 22 23 Da-Silva, S., I. Sajan, and J. Underwood, III. 2 003. Congenital methemoglobinemia: a rare cause of 24 cyanosis in the newborn- a case report. Pediatrics 112: 158-161. 25 26 Dost, F.N., D.J. Reed, V.N. Smith, and C.H. Wang. 1974. Toxic properties of chlorine trifluoride. 27 Toxicol. Appl. Pharmacol. 27:527-536. 28 29 Greene, E.A., J.L. Colbourn, E. Donati and M.H. Weeks. 1960. The inhalation toxicity of perchloryl 30 fluoride. U.S. Army Chemical Research and Development Laboratories Technical Report: CRDLR 31 3010, Army Chemical Center, Maryland. 32 33 HSDB (Hazardous Substances Data Bank). 2008. Perchloryl Fluoride. HSDB, Natl. Library of 34 Medicine, TOXNET system. October 31, 2008. 35 36 Kiese, M. 1974. Methemoglobinemia: A Comprehensive Treatise. Cleveland, OH: CBC Press. 37 38 Kushneva. 1999. Handbook of Toxicological and H ygienic Standards (PDK) of Potentially Hazardous 39 Substances. Developed by the Institute of Biophysics and its (associated) branches. 40
41 Mendiratta, S.K., R.L. Dotson and R.T. Brooker. 2005 . Perchloric acid and perchlorates. Kirk-Othmer 42 Encyclopedia of Chemical Technology, John Wiley and Sons, Inc. 43
44 NIOSH (National Institute for Occupational Safety and Health). 2005. NIOSH Pocket Guide to 45 Chemical Hazards-Perchloryl Fluoride. NIOSH, Cincinnati, OH. On-line (Feb. 2009) at 46 http://www.cdc.gov/niosh/ 47 48PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 21 of 28

NIOSH (National Institute for Occupational Safety an d Health). 1996. Documentation of Immediately 1 Dangerous to Life and Health Concentra tions (IDLH). Found on-line (Feb. 2009) at 2 http://www.cdc.gov/niosh/idlh/7616946.html

. 3 4 NRC (National Research Council). 2001. Standard operating procedures for developing acute exposure 5 guideline levels for hazardous chemicals. Washington, D.C.: National Academy Press. 6
7 OSHA (Occupational Safety and Health Administration) . 2005. Code of Federal Regulations, CFR 29, 8 Part1910, Table Z-1. 9 10 SDU Uitgevers. 2000. MAC Ministry of Social Affairs and Employment. Nationale MAC (Maximum 11 Allowable Concentration) List, The Hague, The Netherlands. 12 13 Seger,D.L. 1992. Methemoglobin-Forming Chemical s. Hazardous Materials Toxicology: Clinical 14 Principles of Environmental Health, J.B. Sullivan a nd G.R. Krieger, eds. Baltimore, MD: Williams & 15 Wilkins, pp. 800-806 16 17 ten Berge, W.F., Zwart, A., Appelman, L.M. 1986. Concentration-time mortality response relationship 18 of irritant and systemically acting vapours and gases. J. Hazard. Materials: 13: 301-309. 19 20 Wilburn-Goo, Dawn and Larry Lloyd. 1999. W hen patients become cyanotic: acquired 21 methemoglobinemia. JADA 130: 826-831. 22 23
24PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 22 of 28

1
APPENDIX A: Derivation of AEGL Values 2
Derivation of AEGL-1 3
4 Key Study: Greene, E.A., J.L. Colbourn, E. Donati and M.H. Weeks. 1960. The inhalation 5 toxicity of perchloryl fluoride. U.S. Army Chemical Research and Development 6 Laboratories Technical Report: CRDLR 3010, Army Chemical Center, 7 Maryland. 8
9 Toxicity Endpoint: Study causing no tr eatment-related adverse effects 10
11 Scaling: C n x t = k 12 n = 3 for extrapolating to the 30-min, 1-hour and 4-hour time-points 13 (24 ppm) 3 x 6 hours = 8.3 x 10 4 ppm hr 14
15 n = 1 for extrapolating to the 8-hour time-point 16 (24 ppm) 1 x 6 hours = 144 ppm hr 17
18 Uncertainty factors: 3 for interspecies variability 19 10 for intraspecies variability 20
Total UF = 30 21
22 10-min.AEGL-1: 1.8 ppm (set equal to the 30-min value because of the long exposure 23 duration of the key study). 24
25
30-min. AEGL-1: C 3 x 0.5 hr. = 8.3 x 10 4 ppm hr 26
C 3 = 1.7 x 10 5 ppm 27 C = 55.4 ppm 28 30-min AEGL-3 = 55.4 ppm/30 = 1.8 ppm 29
30
1-hr. AEGL-1: C 3 x 1 hr = 8.3 x 10 4 ppm ·hr 31
C 3 = 8.3 x 10 4 ppm 32 C = 43.6 ppm 33 1 hr AEGL-3 = 43.6 ppm/30 = 1.5 ppm 34
35
4-hr. AEGL-1: C 3 x 4 hr = 8.3 x 10 4 ppm ·hr 36
C 3 = 20,750 ppm 37 C = 27.5 ppm 38 4 hr AEGL-3 = 27.5 ppm/30 = 0.92 ppm 39
40
8-hr. AEGL-1: C 1 x 8 hr = 144 ppm ·hr 41
C 1 = 18 ppm 42 8 hr AEGL-3 = 18 ppm/30 = 0.60 ppm 43
44
45
46
47PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 23 of 28

1
Derivation of AEGL-2 2
3 Key Study: Greene, E.A., J.L. Colbourn, E. Donati and M.H. Weeks. 1960. The inhalation 4 toxicity of perchloryl fluoride. U.S. Army Chemical Research and Development 5 Laboratories Technical Report: CRDLR 3010, Army Chemical Center, 6 Maryland. 7
8 Toxicity Endpoint: 1/3 rd of AEGL-3 values. For chemicals with a steep concentration9 response curve, AEGL-2 values may be calculated by dividing AEGL-3 10 values by 3 (NRC 2001). 11
12 Scaling: See derivation of AEGL-3 13
14 Uncertainty factors: S ee derivation of AEGL-3 15
16 10-min.AEGL-2: 15 ppm/3 = 5.0 ppm 17
18 30-min. AEGL-2: 15 ppm/3 = 5.0 ppm 19
20 1-hr. AEGL-2: 12 ppm/3 = 4.0 ppm 21
22 4-hr. AEGL-2: 7.5 ppm/3 = 2.5 ppm 23
24 8-hr. AEGL-2: 3.7 ppm/3 = 1.2 ppm 25
26PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 24 of 28

Derivation of AEGL-3 1
2 Key Study: Greene, E.A., J.L. Colbourn, E. Donati and M.H. Weeks. 1960. The inhalation 3 toxicity of perchloryl fluoride. U.S. Army Chemical Research and Development 4 Laboratories Technical Report: CRDLR 3010, Army Chemical Center, 5 Maryland. 6
7 Toxicity Endpoint: Highest 4-hour concentrati on causing no mortality in dogs, but below the 8
LC 50 value for rats in the same study. 9
10 Scaling: C n x t = k 11 n = 3 for extrapolating to the 30-min and 1-hour time-points 12 (224 ppm) 3 x 4 hours = 4.5 x 10 7 ppm hr 13
14 n = 1 for extrapolating to the 8-hour time-point 15 (224 ppm) 1 x 4 hours = 896 ppm hr 16
17 Uncertainty factors: 3 for interspecies variability 18 10 for intraspecies variability 19
Total UF = 30 20
21 10-min.AEGL-3: 15 ppm (set equal to the 30-min value because of the long exposure 22 duration of the key study). 23
24
30-min. AEGL-3: C 3 x 0.5 hr. = 4.50 x 10 7 ppm hr 25
C 3 = 9.0 x 10 7 ppm 26 C = 448 ppm 27 30-min AEGL-3 = 448 ppm/30 = 15 ppm 28
29
1-hr. AEGL-3: C 3 x 1 hr = 4.50 x 10 7 ppm ·hr 30
C 3 = 4.50 x 10 7 ppm 31 C = 356 ppm 32 1 hr AEGL-3 = 356 ppm/30 = 12 ppm 33
34 4-hr. AEGL-3 C = 224 ppm/30 35 C = 7.5 ppm 36
37
8-hr. AEGL-3: C 1 x 8 hr = 896 ppm ·hr 38
C 1 = 112 ppm 39 8 hr AEGL-3 = 112 ppm/30 = 3.7 ppm 40
41
42PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 25 of 28

1 APPENDIX B: Category Plot of Toxicity Data and AEGL Values for Perchloryl Fluoride 2
3
4

0 1 10 100 1000 10000ppm

0 60 120 180 240 300 360 420 480 Minutes No Effect

Discomfort

Disabling

Some Lethality

Lethal

AEGL Chemical Toxicity - TSD Animal Data Perchloryl Fluoride

AEGL-3

AEGL-2

AEGL-1

5PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 26 of 28

1
Data: 2
For Category 0 = No effect, 1 = Discomfort, 2 = Disabling, SL = Some Lethality, 3 = Lethal

Source Species ppm Minutes 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

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 (LC 50 ) mouse 630 240 SL (LC 50 )

Dost et al. 1974 rat 5000 15 3 (100% mortality) rat 2000 25 2 (no mortality) rat 2000 40 3 (100% mortality) rat 1000 60 2 (no mortality)
3PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 27 of 28

APPENDIX C: Derivation Summary for Perchloryl Fluoride AEGLs 1 (CAS Reg. No. 7616-94-6) 2
3
DERIVATION SUMMARY 4
5
6
7
AEGL-1 VALUES 8

inute 30-minute 1-hour 4-hour 8-hour 1.8 ppm 1.8 ppm 1.5 ppm 0.92 ppm 0.60 ppm Key Reference: Greene, E.A., J.L. Colbourn, E. Dona ti and M.H. Weeks. 1960. The inhalation toxicity of perchloryl fluoride. U.S. Army Chem ical Research and Development Labora tories Technical Report: CRDLR 3010, Army Chemical Center, Maryland. Test Species/Strain/Number: Two Beagle dogs/dose; Ten Sprague-Dawley rats/dose Exposure Route/Concentrations/Durations: Exposed to 24 ppm by inhalation 5 days/wk, 6 hrs/day 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 Endpoint/Concentration/Rationale: No effect except for increased fluoride deposition in bones after 26 weeks Uncertainty Factors/Rationale: Total uncertainty factor : 30 Interspecies : 3, the 4-hr concentration at which 1 of 2 dogs were moribund (451 ppm) and the LC 50 concentrations for rats (385 ppm) and mice (630 pp m) are within 3-fold of each other and all species developed similar symptoms (dyspnea and cyanosis). Intraspecies : 10, Perchloryl fluoride is systemically absorb ed and to account for the possible increased sensitivity of some humans, especially infants, for development of methemoglobinemia. Modifying Factor: Not applied Animal to Human Dosimetric Adjustment: Not applicable Time Scaling: Extrapolation to different exposure durations was performed using the equation C n x t = k (ten Berge et al. 1986), where n=3 for extrapolation to 30-min, 1 hour and 4 hours and n=1 for extrapolation to 8 hours. The 30-minute value is adopted as the 10-minute value since extrapolating from 4 hours to 10-minutes is not recommended (NRC 2001). Data Adequacy: Adequate

9PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 28 of 28

AEGL-2 VALUES 1

10-min 30-min 1-hr 4-hr 8-hr 5.0 ppm 5.0 ppm 4.0 ppm 2.5 ppm 1.2 ppm Key Reference : NRC 2001 Test Species/Strain/Number : Not applicable Exposure Route/Concen trations/Durations : Due to limited data and the st eep concentration-response curve, the AEGL-3 values were divided by 3 (NRC 2001)
Effects : Not applicable Endpoint/Concentration/Rationale: Data were limited and NRC (2001) recommends taking 1/3 rd of AEGL-3 values with limited data in the presence of steep concentration response curve. Uncertainty Factors/Rationale : Not applicable Total uncertainty factor : See derivation of AEGL-3 Interspecies : Not applicable Intraspecies : Not applicable Modifying Factor : Not applicable Animal to Human Dosimetric Adjustment : Not applicable Time Scaling : Not applicable Data Adequacy: Not adequate

2
AEGL-3 VALUES 3
4

10-min 30-min 1-hr 4-hr 8-hr 15 ppm 15 ppm 12 ppm 7.5 ppm 3.7 ppm Key Reference: Greene, E.A., J.L. Colbourn, E. Donati and M. H. Weeks. 1960. The inhalation toxicity of perchloryl fluoride. U.S. Army Ch emical Research and Development La boratories Technical Report: CRDLR 3010, Army Chemical Center, Maryland. Test Species/Strain/Number: 2 male Beagle dogs per concentration Exposure Route/Concen trations/Durations : Inhalation/224, 425, 451 ppm/4-hours; 4-hour LC 50 values for rats
and mice

Effects : Rat LC 50 is 385 ppm; Mouse LC 50 is 630 ppm Beagles : 224 ppm- both dogs had cyanosis and hyperpnea 425 ppm- both dogs had severe cyanosis, hyperpnea 451 ppm- 1 out of 2 dogs found moribund in chamber Endpoint/Concentration/Rationale : At 224 ppm, highest non-lethal concentration in dogs with no projected mortality in rats and mice Uncertainty Fact ors/Rationale Total uncertainty factor : 30 Interspecies : 3, the 4-hr concentration at which 1 of 2 dogs were moribund (451 ppm) and the LC 50 concentrations for rats (385 ppm) and mice (630 pp m) are within 3-fold of each other and all species developed similar symptoms (dyspnea and cyanosis). Intraspecies : 10, Perchloryl fluoride is systemically abso rbed and to account for the possible increased sensitivity of some humans, especially infants, for development of methemoglobinemia. Modifying Factor : Not applied Animal to Human Dosimetric Adjustment : Not applicable Time Scaling: Extrapolation to different exposure durations was performed using the equation C n x t = k (ten Berge et al. 1986), where n=3 for extrapolation to 30-min, 1 hour and 4 hours and n=1 for extrapolation to 8 hours. The 30-minute value is adopted as the 10-minute value since extrapolating from 4 hours to 10-minutes is not recommended (NRC 2001). Data Adequacy: Adequate

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