1 NAC Proposed 1: June 2009 

2 

3 

4 ACUTE EXPOSURE GUIDELINE LEVELS (AEGLs) 

5 FOR 

6 PERCHLORYL FLUORIDE 

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

8 

9 

10 

11 PROPOSED 

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

1 

2 PREFACE 

3 

4 Under the authority of the Federal Advisory Committee Act (FACA) P. L. 92-463 of 

5 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous 

6 Substances (NAC/AEGL Committee) has been established to identify, review and interpret 

7 relevant toxicologic and other scientific data and develop AEGLs for high priority, acutely toxic 

8 chemicals. 

9 

10 AEGLs represent threshold exposure limits for the general public and are applicable to 

11 emergency exposure periods ranging from 10 minutes to 8 hours. Three levels C AEGL-1, 

12 AEGL-2 and AEGL-3 C are developed for each of five exposure periods (10 and 30 minutes, 1 

13 hour, 4 hours, and 8 hours) and are distinguished by varying degrees of severity of toxic effects. 

14 The three AEGLs are defined as follows: 

15 

16 AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per 

cubic meter [ppm or mg/m3 17 ]) of a substance above which it is predicted that the general 

18 population, including susceptible individuals, could experience notable discomfort, irritation, or 

19 certain asymptomatic, non-sensory effects. However, the effects are not disabling and are 

20 transient and reversible upon cessation of exposure. 

21 

AEGL-2 is the airborne concentration (expressed as ppm or mg/m3 22 ) of a substance above 

23 which it is predicted that the general population, including susceptible individuals, could 

24 experience irreversible or other serious, long-lasting adverse health effects or an impaired ability 

25 to escape. 

26 

AEGL-3 is the airborne concentration (expressed as ppm or mg/m3 27 ) of a substance above 

28 which it is predicted that the general population, including susceptible individuals, could 

29 experience life-threatening health effects or death. 

30 

31 Airborne concentrations below the AEGL-1 represent exposure levels that could produce 

32 mild and progressively increasing but transient and nondisabling odor, taste, and sensory 

33 irritation or certain asymptomatic, non-sensory effects. With increasing airborne concentrations 

34 above each AEGL, there is a progressive increase in the likelihood of occurrence and the severity 

35 of effects described for each corresponding AEGL. Although the AEGL values represent 

36 threshold levels for the general public, including susceptible subpopulations, such as infants, 

37 children, the elderly, persons with asthma, and those with other illnesses, it is recognized that 

38 individuals, subject to unique or idiosyncratic responses, could experience the effects described 

39 at concentrations below the corresponding AEGL. 

40 

41 

42 
PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 3 of 28 

1 TABLE OF CONTENTS 

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

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

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

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

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

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

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

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

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

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

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

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

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

15 3.1. Acute Lethality ............................................................................................................................9 

16 3.1.1. Dogs ........................................................................................................................................9 

17 3.1.2. Rats..........................................................................................................................................9 

18 3.1.3. Mice ......................................................................................................................................10 

19 3.1.4. Guinea Pigs ..............................................................................................................................10 

20 3.2. Repeat Exposure........................................................................................................................10 

21 3.2.1. Dogs ......................................................................................................................................10 

22 3.2.2. Rats........................................................................................................................................11 

23 3.2.3. Mice.........................................................................................................................................12 

24 3.2.4. Guinea Pigs ...........................................................................................................................12 

25 3.3. Developmental/Reproductive Toxicity......................................................................................12 

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

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

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

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

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

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

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

33 4.4. Other Relevant Information.......................................................................................................14 

34 4.4.1. Species Variability ................................................................................................................14 

35 4.4.2. Susceptible Populations ........................................................................................................15 

36 4.4.3. Concentration-Exposure Duration Relationship ...................................................................15 
PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 4 of 28 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

16 8.3. Data Adequacy and Research ....................................................................................................20 

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

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

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

20 APPENDIX C: Category Plot of Toxicity Data and AEGL Values for Perchloryl Fluoride ..................255
PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 5 of 28 

1 LIST OF TABLES 

2 

3 TABLE 1. Summary of AEGL Values for Perchloryl Fluoride...................................................................................7 

4 TABLE 2. Chemical and Physical Properties ..............................................................................................................8 

5 TABLE 3. Summary of Inhalation Data in Laboratory Animals ...............................................................................13 

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

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

8 TABLE 6. AEGL-3 Values for Perchloryl Fluoride ..................................................................................................17 

9 TABLE 7. Summary of AEGL Values.......................................................................................................................18 

TABLE 8. Extant Standards and Guidelines for Perchloryl fluoride in ppm (mg/m3 10 )...............................................19
PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 6 of 28 

1 EXECUTIVE SUMMARY 

2 

3 Perchloryl Fluoride (CAS No. 7616-94-6) is a colorless, stable gas. Perchloryl fluoride is 

4 used as a fluorinating agent, an oxidant in rocket fuels and a gaseous dielectric for transformers. 

5 It is prepared by electrolysis of a saturated solution of sodium perchlorate in anhydrous 

6 hydrofluoric acid. It is a strong oxidizer and acts as a strong irritant of the eyes, mucus 

7 membranes and lungs. Systemic effects can occur upon inhalation including the induction of 

8 methemoglobinemia. 

9 

10 Human data were not available for developing AEGL values. Animal data were limited 

11 to two studies. During 4-hour studies, Greene et al. (1960) exposed dogs to concentrations 

12 ranging from 224 to 622 ppm. Only 4-hour LC50 values were reported for rats and mice. 

13 Repeat-exposure data were presented for dogs, rats, mice, and guinea pigs. In a second study, 

14 Dost et al. (1974), mortality values were presented for rats at several time points, but details of 

15 the exposures were not included. No information relevant to time-scaling AEGL was found. 

16 

17 The AEGL-1 values were derived from the concentration, 24 ppm, at which dogs and rats 

18 were exposed for 6 hours/day, 5 days/week for 26 weeks. At this concentration, all animals 

19 survived, exhibited no clinical signs, no signs of irritation and the only long-term effect observed 

20 was increased fluoride deposition in the bone and urine over the course of the 26 weeks. 

21 Therefore, this may be considered a no-effect level over an eight hour period. The POD, 24 ppm, 

22 was divided by interspecies and intraspecies uncertainty factors of 3 and 10, respectively, for a 

23 total of 30. An interspecies uncertainty factor of 3 was appropriate as lethality values among 

24 dogs, rats, and mice differed by less than a factor of 3. An intraspecies uncertainty factor of 10 

25 was considered appropriate because infants are considerably more susceptible to 

26 methemoglobinemia than healthy adults. In the absence of time-scaling information, the 6-hour 

value was time-scaled to the shorter and longer exposure durations (Cn 27 x t = k) using the default 

28 values of 3 and 1, respectively. Because of uncertainty in time-scaling from an 6-hour exposure 

29 duration to 10 minutes, the 10-minute value was set equal to the 30-minute value. 

30 

31 No acute studies addressed effects consistent with the definition of an AEGL-2. In the 

32 absence of appropriate chemical-specific data, AEGL 2 values were set at one-third of the 

33 AEGL-3 values (NRC 2001). This approach is supported by the steep-concentration-response 

34 curve. In a 4-hour study, two of two dogs survived at 425 ppm; whereas, one of two dogs was 

35 found moribund at 451 ppm (Green et al. 1960). 

36 

37 The AEGL-3 values were based on a concentration of 224 ppm which induced moderate 

38 cyanosis and hyperpnea in dogs during a 4-hour exposure. No dogs died at the next highest 

39 concentration of 451 ppm, but this value is above the rat 4-hour LC50 of 385 ppm in the same 

40 study. The 4-hour 224 ppm concentration was divided by interspecies and intraspecies 

41 uncertainty factors of 3 and 10, respectively, for a total of 30. Lethality values among dogs, rats, 

42 and mice differed by less than a factor of 3, and lethal values for the rat were considered in 

43 setting the point of departure. An intraspecies uncertainty factor of 10 was considered 

44 appropriate because infants are considerably more susceptible to methemoglobinemia than 

45 healthy adults. In the absence of time-scaling information, the 4-hour value was time-scaled to 

the shorter and longer exposure durations (Cn 46 x t = k) using the default values of 3 and 1, 
PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 7 of 28 

1 respectively. Because of uncertainty in time-scaling from a 4-hour exposure duration to 10 

2 minutes, the 10-minute value was set equal to the 30-minute value. 

3 

4 Values are summarized in the table below. 

5 

TABLE 1. Summary of AEGL Values for Perchloryl Fluoride 

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

AEGLB1 

(Nondisabling) 

1.8 ppm 

(7.6 mg/m3

) 

1.8 ppm 

(7.6 mg/m3) 

1.5 ppm 

(6.3 mg/m3) 

0.92 ppm 

(3.9 mg/m3) 

0.60 ppm 

(2.5 mg/m3) 

No effects in dog/rats 

after 26 week exposure 

(Greene et al. 1960) 

AEGLB2 

(Disabling) 

5.0 ppm 

(21 mg/m3

) 

5.0 ppm 

(21 mg/m3) 

4.0 ppm 

(17 mg/m3) 

2.5 ppm 

(11 mg/m3) 

1.2 ppm 

(5.0 mg/m3) 

One third of the AEGL-3 

values (NRC 2001) 

AEGLB3 

(Lethal) 

15 ppm 

(63 mg/m3

) 

15 ppm 

(63 mg/m3) 

12 ppm 

(50 mg/m3) 

7.5 ppm 

(32 mg/m3) 

3.7 ppm 

(16 mg/m3) 

Highest concentration 

causing no deaths in 

mice, rats and dogs after 

4 hrs. 

 (Greene et al. 1960) 

6 

7 

8 1. INTRODUCTION 

9 

10 Perchloryl fluoride is a colorless gas with a characteristic sweet odor. Chemically, it is 

11 the acyl fluoride of perchloric acid and is prepared by electrolysis of a saturated solution of 

12 sodium perchlorate in anhydrous hydrofluoric acid. It is a very stable compound. Perchloryl 

13 fluoride is used as a fluorinating agent, an oxidant in rocket fuels and a gaseous dielectric for 

14 transformers (Mendiratta et al. 2005). It is a strong oxidizer, and acts as a strong irritant of the 

15 eyes, mucous membranes and lungs. Absorption results in methemoglobinemia. Dermal contact 

16 with the liquid form of perchloryl fluoride can also produce burns. 

17 

18 Production data were not identified for perchloryl fluoride. Perchloryl fluoride does not 

19 burn and is not flammable, but it can support combustion. Chemical and physical properties are 

20 provided in Table 2. 

21 
PERCHLORYL 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-O3 HSDB 2008 

Molecular weight 102.45 HSDB 2008 

CAS Reg. No. 7616-94-6 HSDB 2008 

Physical state Colorless 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/m3 

1 mg/m3 = 0.24 ppm ACGIH 1991 

1 

2 

3 2. HUMAN TOXICITY DATA 

4 2.1. Acute Lethality 

5 

6 There are no data available. 

7 

8 2.2. Nonlethal Toxicity 

9 

10 There are no data available that address the nonlethal toxicity of perchloryl fluoride in 

11 humans. Anecdotal information about human exposure to perchloryl fluoride vapor describes 

12 symptoms of upper respiratory irritation, as well as headaches and dizziness (HSDB 2008). 

13 

14 Perchloryl fluoride has a characteristic sweet odor. Greene et al. (1960) used human 

15 volunteers (number and gender of participants not provided) to estimate the median detectable 

16 concentration of perchloryl fluoride gas. The gas, mixed with room air was metered into an 

17 inhalation chamber using a Fair-Wells Osmoscope (no further study details provided). At 41 

18 ppm, 50% of the volunteers detected the odor and described it as sweet, musty or nitric acid-like. 

19 

20 2.3. Neurotoxicity 

21 

22 There are no data available. 

23 

24 2.4. Developmental/Reproductive Toxicity 

25 

26 There are no data available. 

27 
PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 9 of 28 

1 2.5. Genotoxicity 

2 

3 There are no data available. 

4 

5 2.6. Carcinogenicity 

6 

7 There are no data available. 

8 

9 2.7. Summary 

10 

11 Data on perchloryl fluoride exposure in humans either by occupational exposure or 

12 experimental exposure are not available. Greene et al. (1960) conducted an odor threshold 

13 clinical study with human volunteers and reported that 50% of participants could detect 

14 perchloryl fluoride at 41 ppm, although study details were minimal. 

15 

16 3. ANIMAL TOXICITY DATA 

17 3.1. Acute Lethality 

18 3.1.1. Dogs 

19 

20 Two adult male beagle dogs/group were exposed for 4 hours to concentrations of 224, 

21 425, or 451 ppm. Two additional dogs inhaled 622 ppm for 2.5 hours (Greene et al. 1960) 

22 (Table 3). The gas was metered through a calibrated flow meter and was diluted with room air 

23 prior to entering the exposure chamber. Atmospheric concentration of the chemical in the 

24 chamber was estimated from the weight of the compound used. Blood was collected before and 

25 after exposure for hemoglobin and methemoglobin levels; gross and histopathological 

26 examinations were performed. Out of the eight study dogs, there were two deaths; one exposed 

27 to 451 ppm for 4 hours was moribund upon removal from the chamber and one exposed to 622 

28 ppm for 2.5 hours died, although the time of death was not provided. The remaining dogs 

29 exposed to 451 or 622 ppm were injected with methylene blue to counteract increased 

30 methemoglobin. All dogs experienced concentration-related cyanosis and hyperpnea. Dogs also 

31 exhibited convulsions and motor instability when exposed to 451 or 622 ppm. At 425 ppm, 

32 methemoglobin levels increased to 15.5 % immediately after exposure, decreasing to 4.8% after 

33 an 18-hour recovery period. Methemoglobin levels reached 28.7 and 70.9% in dogs exposed to 

34 451 and 622 ppm, respectively, prior to methylene blue therapy. After methylene blue therapy (2 

35 mg/kg) was initiated as a treatment, the methemoglobin levels dropped to 3.8 and 0.0% in the 

36 dogs exposed to 451 ppm and 622 ppm, respectively. No further study details were provided. 

37 

38 3.1.2. Rats 

39 

40 Greene et al. (1960) exposed rats to perchloryl fluoride in a manner similar to that 

41 described above for dogs. Groups of 10 adult male rats (derived Wistar CF-1 strain) were 

42 exposed to perchloryl fluoride at concentrations of 220 to 885 ppm for 4 hours (individual 

43 concentrations not reported). The gas was metered through a calibrated flow meter and was 

44 diluted with room air prior to entering the chamber. Atmospheric concentration of the chemical 

45 in the chamber was analyzed by collecting samples of the chamber air using quantitative 

46 hydrolysis of perchloryl fluoride with 10% alcoholic potassium hydroxide in a series of bubblers. 
PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 10 of 28 

1 Rats that died showed labored breathing, cyanosis, pronounced gasping and convulsions. Most 

2 deaths occurred during the exposure or within 2 days post-exposure. Surviving rats were kept 

3 for 7 days post-exposure. The 4-hour LC50 for rats was 385 ppm (95% confidence limits of 367-

4 404 ppm). Rats that died had moderate discoloration of the blood with accompanying 

5 discoloration of the viscera, especially the lungs. Microscopic examination showed marked 

6 congestion in the pulmonary vasculature with some areas of hemorrhage in the alveoli. No raw 

7 data to confirm the results were included in the study report. 

8 

9 Dost et al. (1974) exposed male Sprague-Dawley rats to 5000 ppm perchloryl fluoride for 

10 15 minutes; 2000 ppm for 25 or 40 minutes; or 1000 ppm for 60 minutes (number of rats/group 

11 not provided). Exposures were whole body in a 3.6-L chamber that accommodated two rats at a 

12 time. Exposure to 5000 ppm for 15 minutes and 2000 ppm for 40 minutes was lethal to all rats. 

13 All rats survived exposure to 2000 ppm for 25 minutes and 1000 ppm for 60 minutes. 

14 Methemoglobin was observed at all exposure concentrations, and in lethal exposures exceeded 

15 60% of total hemoglobin. No further details were available. 

16 

17 3.1.3. Mice 

18 

19 In the mouse lethality study, Greene et al. (1960) exposed 20 female Carworth Farms CF20 1 strain mice/group to perchloryl fluoride at concentrations of 220 to 885 ppm for 4 hours. The 

21 delivery system and concentration analysis were as described for the rat, above. Mice that died 

22 showed labored breathing, cyanosis, pronounced gasping and convulsions; most deaths occurred 

23 during or within 2 days post-exposure. Surviving mice were kept for 14 days post-exposure. The 

24 4-hour LC50 for mice was 630 ppm (95% confidence limits of 569-697 ppm) with the mice that 

25 died having the same discoloration of the internal organs as observed in the rats, but to a lesser 

26 degree. No raw data to confirm the results were included in the study report. 

27 

28 3.1.4. Guinea Pigs 

29 

Kushneva (1999) provided an LC50 of 220 mg/m3 30 (52 ppm) for guinea pigs. An exposure 

31 duration was not provided. 

32 

33 3.2. Repeat Exposure 

34 

35 All repeat exposure studies were performed by the same laboratory (Greene et al. 1960). 

36 In these studies, dogs, rats, mice, and guinea pigs were exposed in various scenarios ranging 

37 from 5 weeks up to 26 weeks. Chamber concentrations were determined analytically with 

38 samples collected by quantitative hydrolysis of perchloryl fluoride with 10% alcoholic potassium 

39 hydroxide in a series of three bubblers. Collections of samples were 0.125 L/min to 0.150 

40 L/min. In all of the studies, data were reported in graphic format without actual values listed. 

41 

42 3.2.1. Dogs 

43 

44 Three beagles/group were exposed to 0 (controls) or 24 ppm perchloryl fluoride by 

45 inhalation for 6 hours/day, 5 days/week for 26 weeks (Greene et al. 1960). Dogs were either 

46 sacrificed at the end of the exposure period or allowed a 6-7 week recovery period (number of 
PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 11 of 28 

1 dogs allowed to recover not provided). Fluoride levels were measured in the blood and urine 

2 throughout the study and in the bone (femur) at the end of the exposure period and at the end of 

3 the recovery. All dogs survived the 26 weeks of exposure. Clinical signs of toxicity were not 

4 observed. Urinary fluoride levels increased fourfold over a 6 month period, but were comparable 

5 to controls at the end of the exposure and remained normal during the recovery period. Bone 

6 fluoride levels in treated dogs were increased 46% when compared to the control dogs at the end 

7 of the study. However, the author stated that the amount of fluoride in the bone did not reach the 

8 4000 ppm level that is thought to be the concentration causing histopathological changes. In 

treated dogs killed after the final exposure (130th 9 ), there was spleen congestion containing some 

10 iron-bearing pigments; however, this was not present in the treated dogs after the 6 week 

11 recovery. No effects were observed in the lungs of any of the dogs. 

12 

13 3.2.2. Rats 

14 

15 Twenty white adult male rats (derived Wistar CF-1 strain)/group were exposed by 

16 inhalation to 0 (controls), 104 ppm or 185 ppm of perchloryl fluoride, 6 hours/day, and 5 

17 days/week for 5 weeks (104 ppm) or 7 weeks (185 ppm) (Greene et al. 1960). Rats in groups of 

18 three were killed immediately and 18 hours after the first and fourth exposure period of each 

19 week. Blood was taken by cardiac puncture and the following hematology parameters were 

20 measured: red blood cell count, white blood cell count (with differential), reticulocyte count, 

21 methemoglobin levels, hemoglobin, fragility, sedimentation rate, and hematocrit. Select tissues 

22 were prepared for histological examination. Fluoride deposition in the femur and urinary and 

23 blood fluoride were determined in the rats at sacrifice. 

24 

25 Mortality for the rats was 18/20 (90%) in the 185 ppm group after 35 days of exposure 

26 and 1/20 (5%) in the 104 ppm group after 25 days of exposure. Cyanosis was observed at both 

27 concentrations with dyspnea also observed at the high concentration. After one week, rats 

28 inhaling 185 ppm had a 23% increase in methemoglobin levels and 25% decrease in total 

29 hemoglobin when compared to controls. The methemoglobin levels recovered to normal after an 

30 overnight recovery period. Both of these measurements were comparable to those of controls in 

31 all rats after the second week. Grossly, rats exposed to 185 ppm had darkened organs and 

32 splenic weight was increased to 4-5 times that of the controls. Histopathological lesions 

33 included splenic, hepatic and renal hemosiderosis and pulmonary lesions, including alveolar 

34 edema that developed into bronchopneumonia. Rats also exhibited stained incisors from 

35 fluorosis. At 104 ppm, similar blood and tissue changes were observed, but were less severe. 

36 The only raw data provided for this study were graphs showing the findings for the rats exposed 

37 to 104 ppm. 

38 

39 Ten white adult male rats (derived Wistar CF-1 strain)/group were also exposed to 0 

40 (controls) or 24 ppm perchloryl fluoride 6 hours/day, 5 days/week for 26 weeks (Greene et al. 

41 1960). All rats survived to the end of exposure. Urinary fluoride levels for the rats were not 

42 reported; however, the bone (femur) fluoride levels were three times greater than those of the 

43 controls at the end of 6 months. As with the dogs, rats had splenic congestion that was not 

44 observed after a recovery period; no effects were observed in the lungs. 

45 
PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 12 of 28 

1 3.2.3. Mice 

2 

3 Twenty white adult female mice (Carworth Farms CF-1 strain)/group were exposed to 0 

4 (controls) or 185 ppm of perchloryl fluoride by inhalation, 6 hours/day, and 5 days/week for 7 

5 weeks (Greene et al. 1960). Animals were observed for any toxic effects and sacrificed at the 

6 end of the study. Mortality was 20/39 (51%) in the mice after 35 days of exposure with dyspnea 

7 and cyanosis observed. 

8 

9 3.2.4. Guinea Pigs 

10 

11 Ten adult male guinea pigs (strain not provided)/group were exposed to 0 (controls), 104 

12 or 185 ppm of perchloryl fluoride by inhalation, 6 hours/day, 5 days/week for 5 weeks (104 ppm) 

13 or 7 weeks (185 ppm). Mortality was 100% (10/10) in guinea pigs after inhaling 185 ppm for 3 

14 days and 100% (10/10) in guinea pigs inhaling 104 ppm for 25 days. Dyspnea and cyanosis 

15 were observed in the high-dose animals with only cyanosis observed at the low-dose. 

16 

17 Thirty adult male guinea pigs (strain not provided)/group were exposed by Greene et al. 

18 (1960) to 0 or 24 ppm of perchloryl fluoride for 6 hours/day, 5 days/week for 26 weeks. 

19 Animals were monitored for any toxic effects and ten guinea pigs/group were sacrificed 

20 periodically for blood and tissue samples. Mortality occurred in 1/30 of the controls and 14/30 

21 (47%) of the exposed animals, although the times of deaths were not provided. Clinical signs of 

22 toxicity were not observed and while total hemoglobin was consistently lower in treated guinea 

23 pigs, the differences were not statistically significant. Blood fluoride levels were slightly higher 

24 (raw data not provided) in the treated guinea pigs but blood volumes obtained were small making 

25 the data unreliable. Urinary fluoride levels increased fivefold over a 6-month period but were 

26 comparable to those of controls at the end of the exposure and remained normal during the post27 exposure period. Bone (femur) fluoride levels in treated guinea pigs increased to 4 times that of 

28 controls at the end of the study. During the recovery period, the amount of fluoride deposited in 

29 the femur did not diminish. Marked changes in the lungs were observed in both the control and 

30 treated guinea pigs. Localized damage suggesting a chronic condition was observed in 

31 approximately 80-85% of the guinea pigs in both the control and treated groups, indicating 

32 another possible entity was involved. In some of the guinea pigs, Bordetella bronchoseptica was 

33 isolated thus making all of the results of this study questionable. In treated guinea pigs, there 

34 was spleen congestion and a corresponding increase in splenic weight but these changes reversed 

35 after the exposure stopped. 

36 

37 3.3. Developmental/Reproductive Toxicity 

38 

39 There are no data available. 

40 

41 3.4. Genotoxicity 

42 

43 There are no data available. 

44 
PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 13 of 28 

1 3.5. Chronic Toxicity/Carcinogenicity 

2 

3 There are no data available. 

4 

5 3.6. Summary 

6 

7 Greene et al. (1960) conducted both acute and repeat-exposure studies. Dogs exposed to 

8 224 or 425 ppm of perchloryl fluoride for 4 hours survived, whereas 4-hour exposures to 451 and 

9 622 ppm were partially lethal. Four-hour LC50 values for rats and mice were 385 and 630 ppm, 

10 respectively. In repeat exposures, dogs and rats survived a 26-week exposure to 24 ppm 

11 perchloryl fluoride (6 hours/day, 5 days/week). Similar effects of contact irritation (dyspnea, 

12 labored breathing) and some effects of systemic absorption leading to methemoglobinemia 

13 (cyanosis) and fluoride deposition were observed in all species. Dost et al (1974) reported that 

14 2000 ppm for 25 minutes and 1000 ppm for 60 minutes were not lethal to rats. Data are 

15 summarized in Table 3. 

16 

TABLE 3. Summary of Inhalation Data in Laboratory Animals 

Acute Lethality Studies 

Species 

Concentration 

(ppm) 

Exposure 

Duration Effect Reference 

Doga 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 LC50 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 LC50 Greene et al. 1960 

Repeat-Exposure Studiesb

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. 1960 
PERCHLORYL 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 diedc

↑ fluoride in bone, lung lesionsc

Greene et al. 1960 

a 1 Two dogs/group. 

b 2 In all repeat exposure studies, there were no effects observed in the controls unless otherwise stated. c 3 The high mortality and lung data are questionable as both the control and treated guinea pigs had Bordetella

4 bronchoseptica infections. 

5 

6 

7 4. SPECIAL CONSIDERATIONS 

8 4.1. Metabolism and Disposition 

9 

10 There were no studies available on the metabolism and disposition of perchloryl fluoride. 

11 In the longer-term repeat studies by Greene et al. (1960), rats, guinea pigs and dogs had fluoride 

12 deposition in the bone (femur) and in the urine of dogs and guinea pigs, indicating that the 

13 molecule is broken down with the release of fluoride. Fluorosis was also observed on the teeth 

14 of rats. 

15 

16 4.2. Mechanism of Toxicity 

17 

18 No studies or data were identified describing the mechanism of toxicity for perchloryl 

19 fluoride. Two mechanisms of action may be present. The oxidative properties of perchloryl 

20 fluoride may lead to direct-contact lung damage. Formation of methemoglobin in all species 

21 studied indicates that following absorption, perchloryl fluoride or its metabolites oxidize the 

ferrous (Fe+2) iron in hemoglobin to the oxidized ferric form (Fe+3 22 ). Methemoglobin is unable to 

23 transport oxygen to the organs and tissues, resulting in cyanosis. Methemoglobin concentrations 

24 of ≥70% are considered the threshold for lethality (Kiese 1974; Seger 1992). Normal 

25 methemoglobin levels in humans are <1%. 

26 

27 4.3. Structure Activity Relationships 

28 

29 Greene et al. (1960) provided a table comparing fluoride deposition in the femurs of rats 

30 exposed to 104 ppm perchloryl fluoride and similar exposures to fluorine (F2) and hydrogen 

31 fluoride (HF). Based on the findings, the amount of fluoride deposited from perchloryl fluoride 

32 exposure was about one-fourth and one-half that following exposure to HF and F2, respectively. 

33 One possible explanation for the lower absorption of perchloryl fluoride is that it has a more 

34 stable structure compared to the other fluorides. 

35 

36 4.4. Other Relevant Information 

37 4.4.1. Species Variability 

38 

39 Data suggest limited interspecies variability. Greene et al. (1960) exposed rats, mice, 

40 guinea pigs and dogs to similar concentrations of perchloryl fluoride and observed similar effects 

41 in all animals. All exhibited labored breathing, cyanosis, convulsions and changes in the 
PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 15 of 28 

1 hemoglobin and methemoglobin levels in the blood. The 4-hr concentration at which one of two 

2 dogs was moribund (451 ppm) and the LC50 concentrations for rats (385 ppm) and mice (630 

3 ppm) are within 3-fold of each other. 

4 

5 4.4.2. Susceptible Populations 

6 

7 As with other lung irritants, humans with compromised lung function would be more 

8 susceptible to the toxic effects of perchloryl fluoride. Also, young children and the elderly are 

9 naturally more susceptible to methemoglobinemia and could develop this condition more readily 

10 when exposed to perchloryl fluoride as they both have increased fetal hemoglobin 

11 concentrations. The elderly may also be on multiple oxidant medications that can lower their 

12 threshold for developing methemoglobinemia (Wilburn-Goo and Lloyd 1999). A rare, genetic 

13 defect which causes a deficiency of nicotinamide adenine dinucleotide-cytochrome b5 reductase 

14 enzyme (NADH-cytochrome b5 reductase) has been documented. This enzyme co-factor 

15 reduces methemoglobin in normal erythrocytes. Fetal hemoglobin is more susceptible to 

16 oxidation than adult hemoglobin; this co-factor lacks full activity until infants are 4 months of 

17 age (Seger 1992). Humans can either be carriers in which they show no clinical signs but have a 

18 lower threshold for developing acquired methemoglobinemia ,or if autosomal recessive 

19 transmission occurs, they exhibit cyanosis at birth and must be treated, as it can cause death 

20 within a few years (Da-Silva et al. 2003). 

21 

22 4.4.3. Concentration-Exposure Duration Relationship 

23 

24 The concentration-exposure time relationship for many irritant and systemically-acting 

vapors and gases can be described by the relationship Cn 25 x t = k, where the exponent, n, ranges 

26 from 0.8 to 3.5 (ten Berge et al. 1986). Data were unavailable for an empirical derivation of n in 

the equation, Cn 27 x t = k. In the absence of chemical specific data, an n of 3 will be applied to 

28 extrapolate to shorter time periods, and an n of 1 will be applied to extrapolate to longer time 

29 periods, to provide AEGL values that would be protective of human health (NRC 2001).

30 

31 5. DATA ANALYSIS FOR AEGL-1 

32 5.1. Summary of Human Data Relevant to AEGL-1 

33 

34 No applicable human data are available for deriving AEGL-1 valued. 

35 

36 5.2. Summary of Animal Data Relevant to AEGL-1 

37 

38 There were two studies with laboratory animals (Greene et al. 1960; Dost et al. 1974) that 

39 addressed lethality. A longer term study (Greene et al 1960) in which dogs and rats were 

40 exposed to 24 ppm of perchloryl fluoride 6 hours/day, 5 days/week for 26 weeks indicated no 

41 acute effects at this concentration. 

42 

43 5.3. Derivation of AEGL-1 

44 

45 The 26-week term study (Greene et al 1960) will be used to derive AEGL values. The 

46 AEGL-1 values were derived from the concentration, 24 ppm, at which dogs and rats were 
PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 16 of 28 

1 exposed for 6 hours/day, 5 days/week. At this concentration, all animals survived, exhibited no 

2 clinical signs, no signs of irritation and the only long-term effect observed was increased fluoride 

3 deposition in the bone and urine over the course of the 26 weeks. Therefore, this may be 

4 considered a no-effect level over an eight hour period. The 24 ppm concentration was divided by 

5 interspecies and intraspecies uncertainty of 3 and 10 for a total of 30. An interspecies 

6 uncertainty factor of 3 was considered appropriate as lethality values among dogs, rats, and mice 

7 differed by less than a factor of 3. An intraspecies uncertainty factor of 10 was considered 

8 appropriate because infants are considerably more susceptible to methemoglobinemia than 

healthy adults. Time-scaling followed the relationship Cn 9 x t = k where n equals 1 or 3 for longer 

10 and shorter exposure durations, respectively (NRC 2001). The 30-minute AEGL-3 value was 

11 adopted as the 10-minute value due to uncertainties in extrapolating from the 6-hour value (NRC 

12 2001). AEGL-1 values are provided (Table 4). 

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/m3) 

1.8 ppm 

(7.6 mg/m3) 

1.5 ppm 

(6.3 mg/m3) 

0.92 ppm 

(3.9 mg/m3) 

0.60 ppm 

(2.5 mg/m3) 

14 

15 

16 6. DATA ANALYSIS FOR AEGL-2 

17 6.1. Summary of Human Data Relevant to AEGL-2 

18 

19 No human data are available for use in deriving AEGL-2 values. 

20 

21 6.2. Summary of Animal Data Relevant to AEGL-2 

22 

23 No animal data are available that defined effects consistent with the definition of an 

24 AEGL-2. 

25 

26 6.3. Derivation of AEGL-2 

27 

28 In the absence of appropriate chemical-specific data, AEGL 2 values were derived as a 3-

29 fold reduction of the AEGL-3 values (NRC 2001). This approach is supported by the steep 

30 concentration-response curve. In a 4-hour study, two of two dogs survived at 425 ppm; whereas, 

31 one of two dogs was found moribund at 451 ppm (Green et al., 1960). AEGL-2 values are 

32 provided in Table 5. 

33 

TABLE 5. AEGL-2 Values for Perchloryl Fluoride 

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

5.0 ppm 

(21 mg/m3

) 

5.0 ppm 

(21 mg/m3) 

4.0 ppm 

(17 mg/m3) 

2.5 ppm 

(11 mg/m3) 

1.2 ppm 

(5.0 mg/m3) 

34 

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

1 7. DATA ANALYSIS FOR AEGL-3 

2 7.1. Summary of Human Data Relevant to AEGL-3 

3 

4 No human data are available for use in deriving AEGL-3 values. 

5 

6 7.2. Summary of Animal Data Relevant to AEGL-3 

7 

8 Greene et al. (1960) exposed two dogs, ten rats and twenty mice per group to varying 

9 concentrations in 4-hour acute inhalation studies. Dogs exhibited clinical signs (cyanosis and 

10 hyperpnea) at 224 ppm, but no mortality occurred. Cyanosis worsened at 425 ppm and one of 

11 the dogs exposed at 451 ppm was found moribund in the chamber. The LC50 values for rats and 

12 mice were 385 and 630 ppm, respectively. No mortality occurred in rats exposed to 2000 ppm 

13 for 25 minutes or to 1000 ppm for 60 minutes (Dost et al. 1974). Details of this latter study were 

14 not provided. 

15 

16 7.3. Derivation of AEGL-3 

17 

18 The study of Greene et al. (1960) in which groups of two dogs inhaled several 

19 concentrations for 4 hours was chosen as the key study. Dogs survived concentrations of 224 

20 and 451 ppm for 4 hours. The concentration of 224 ppm was chosen as the point of departure 

21 because it is below the LC50 value of 384 ppm for rats in the same study. The 4-hour 224 ppm 

22 concentration was divided by interspecies and intraspecies uncertainty factors of 3 and 10 for a 

23 total of 30. An interspecies uncertainty factor of 3 was considered appropriate as lethality values 

24 among dogs, rats, and mice differed by less than a factor of 3, and lethal values for the rat were 

25 considered in addressing the point of departure. An intraspecies uncertainty factor of 10 was 

26 considered appropriate because infants are considerably more susceptible to methemoglobinemia 

than healthy adults. Time-scaling followed the relationship Cn 27 x t = k where n equals 1 or 3 for 

28 longer and shorter exposure durations, respectively (NRC 2001). The 30-minute AEGL-3 value 

29 was adopted as the 10-minute value due to uncertainties in extrapolating from the 4-hour value 

30 (NRC 2001). AEGL-3 values are provided in Table 6. 

31 

TABLE 6. AEGL-3 Values for Perchloryl Fluoride 

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

15 ppm 

(63 mg/m3

) 

15 ppm 

(63 mg/ m3) 

12 ppm 

(50 mg/m3) 

7.5 ppm 

(32 mg/ m3) 

3.7 ppm 

(16 mg/ m3) 

32 

33 The AEGL-3 values appear low in light of the short exposure of human volunteers to 

34 several concentrations including 41 ppm (Greene et al. 1960). However, the sparse data base 

35 justifies the low numbers. 

36 

37 

38 8. SUMMARY OF AEGLS 

39 8.1. AEGL Values and Toxicity Endpoints 

40 

41 Because of a lack of acute studies with animals exhibiting AEGL-1 effects, a longer term 

42 study at a concentration in which dogs and rats exhibited no acute effects was used for the 
PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 18 of 28 

1 derivation. No studies that addressed effects consistent with the definition of an AEGL-2 were 

2 found. The concentration-response curve for lethality is steep. Therefore, AEGL-2 values were 

3 derived by dividing the AEGL-3 values by 3. The point of departure for AEGL-3 values was the 

4 4-hour concentration of 224 ppm that caused no deaths in dogs, but was below the 4-hour LC50

5 value of 384 ppm for rats. For AEGL-1 and -3, the POD was divided by interspecies and 

6 intraspecies uncertainty factors of 3 and 10, respectively, for a total of 30. In the absence of 

7 time-scaling information, the 4-hour or 6-hour value was time scaled to the other AEGL 

8 exposure durations using the default values of 3 and 1 for shorter and longer exposure durations, 

9 respectively. All AEGL values are provided in Table 7. 

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/m3

) 

1.8 ppm 

(7.6 mg/m3) 

1.5 ppm 

(6.3 mg/m3) 

0.92 ppm 

(3.9 mg/m3) 

0.60 ppm 

(2.5 mg/m3) 

AEGL-2 

(Disabling) 

5.0 ppm 

(21 mg/m3) 

5.0 ppm 

(21 mg/m3) 

4.0 ppm 

(17 mg/m3) 

2.5 ppm 

(11 mg/m3) 

1.2 ppm 

(5.0 mg/m3) 

AEGL-3 

(Lethal) 

15 ppm 

(63 mg/m3) 

15 ppm 

(63 mg/m3) 

12 ppm 

(50 mg/m3) 

7.5 ppm 

(32 mg/ m3) 

3.7 ppm 

(16 mg/ m3) 

11 

12 

13 8.2. Comparison with Other Standards and Guidelines 

14 

15 The ACGIH TLV-TWA and OSHA PEL-TWA were both established from the Greene et 

al. (1960) study; the recommended 3 ppm was approximately 1/10th 16 of the 24 ppm concentration 

17 that caused fluorosis and hematological alteration in experimental animals over repeated 

18 exposures (26 weeks). The 8-hour AEGL-2 and AEGL-3 values appear low in comparison to the 

19 TWA value, but the standards are for healthy adults, whereas, the AEGL values are protective of 

20 sensitive infant and elderly populations. The IDLH of 100 ppm was based on the Greene et al. 

21 (1960) LC50 for rats of 385 ppm in a 4-hour acute inhalation toxicity study. Standards and 

22 guidelines are provided in Table 8. 

23 
PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 19 of 28 

TABLE 8. Extant Standards and Guidelines for Perchloryl fluoride in ppm (mg/m3) 

Exposure Duration 

Guideline 10 min 30 min 1 hr 4 hr 8 hr 

AEGL-1 1.8 ppm 

(7.6 mg/m3

) 

1.8 ppm 

(7.6 mg/m3) 

1.5 ppm 

(6.3 mg/m3) 

0.92 ppm 

(3.9 mg/m3) 

0.60 ppm 

(2.5 mg/m3) 

AEGL-2 5.0 ppm 

(21 mg/m3

) 

5.0 ppm 

(21 mg/m3) 

4.0 ppm 

(17 mg/m3) 

2.5 ppm 

(11 mg/m3) 

1.2 ppm 

(5.0 mg/m3) 

AEGL-3 15 ppm 

(63 mg/m3

) 

15 ppm 

(63 mg/m3) 

12 ppm 

(50 mg/m3) 

7.5 ppm 

(32 mg/m3) 

3.7 ppm 

(16 mg/m3) 

PEL-TWA (OSHA)a 3 ppm 

 (14 mg/m3

) 

IDLH (NIOSH)b 100 ppm 

(420 mg/m3

) 

REL-TWA 

(NIOSH)c 3 ppm 

 (14 mg/m3

) 

REL-STEL 

(NIOSH)d

6 ppm 

 (25 mg/m3

) 

 (15 min) 

 

TLV-TWA 

(ACGIH)e 3 ppm 

(14 mg/m3

) 

TLV-STEL 

(ACGIH)f

6 ppm 

(25 mg/m3

) 

(15 min) 

 

MAC (SDU 

Uitgevers)g 3 ppm 

(14 mg/m3

) 

1 a 2 OSHA PEL-TWA (Occupational Safety and Health Administration, Permissible Exposure Limits - Time Weighted 

3 Average) (OSHA 2005) is defined analogous to the ACGIH-TLV-TWA, but is for exposures of no more than 10 

4 hours/day, 40 hours/week. 

5 b 6 IDLH (Immediately Dangerous to Life and Health, National Institute of Occupational Safety and Health) (NIOSH 

7 1996) represents the maximum concentration from which one could escape within 30 minutes without any escape8 impairing symptoms, or any irreversible health effects. 

9 c 10 NIOSH REL-TWA (National Institute of Occupational Safety and Health, Recommended Exposure Limits - Time 

11 Weighted Average) (NIOSH 2005) is defined analogous to the ACGIH-TLV-TWA. 

12 d 13 NIOSH REL-STEL (Recommended Exposure Limits - Short Term Exposure Limit) (NIOSH 2005) is defined 

14 analogous to the ACGIH TLV-STEL. 

15 e 16 ACGIH TLV-TWA (American Conference of Governmental Industrial Hygienists, Threshold Limit Value - Time 

17 Weighted Average) (ACGIH 2008 and 1991) is the time-weighted average concentration for a normal 8-hour 

18 workday and a 40-hour workweek, to which nearly all workers may be repeatedly exposed, day after day, without 

19 adverse effect. 

20 f 21 ACGIH TLV-STEL (Threshold Limit Value - Short Term Exposure Limit) (ACGIH 2008) is defined as a 15-

22 minute TWA exposure which should not be exceeded at any time during the workday even if the 8-hour TWA is 

23 within the TLV-TWA. Exposures above the TLV-TWA up to the STEL should not be longer than 15 minutes and 

24 should not occur more than 4 times per day. There should be at least 60 minutes between successive exposures in 

25 this range. 

26 
PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 20 of 28 

g 1 MAC (Maximaal Aanvaarde Concentratie [Maximal Accepted Concentration]) (SDU Uitgevers 2000) [under the 

2 auspices of the Ministry of Social Affairs and Employment], The Hague, The Netherlands. Is defined analogous to 

3 the ACGIH-TLV-TWA. 

4 

5 

6 8.3. Data Adequacy and Research 

7 

8 Human data are lacking for perchloryl fluoride. Animal data are also very limited and 

9 although many species (dogs, rats, guinea pigs and mice) were exposed by inhalation to 

10 perchloryl fluoride, most of the studies were conducted by the same laboratory and details were 

11 not reported. 

12 

13 

14 9. REFERENCES 

15 

16 ACGIH (American Conference of Government and Industrial Hygienists). 2008. Documentation of the 

17 Threshold Limit Values and Biological Exposure Indices: Perchloryl Fluoride, p. 47. ACGIH, 

18 Cincinnati, OH. 

19 

20 ACGIH (American Conference of Government and Industrial Hygienists). 1991. Documentation of the 

21 Threshold Limit Values and Biological Exposure Indices: Perchloryl Fluoride. Sixth Ed., ACGIH, 

22 Cincinnati, OH. 

23 

24 Da-Silva, S., I. Sajan, and J. Underwood, III. 2003. Congenital methemoglobinemia: a rare cause of 

25 cyanosis in the newborn- a case report. Pediatrics 112: 158-161. 

26 

27 Dost, F.N., D.J. Reed, V.N. Smith, and C.H. Wang. 1974. Toxic properties of chlorine trifluoride. 

28 Toxicol. Appl. Pharmacol. 27:527-536. 

29 

30 Greene, E.A., J.L. Colbourn, E. Donati and M.H. Weeks. 1960. The inhalation toxicity of perchloryl 

31 fluoride. U.S. Army Chemical Research and Development Laboratories Technical Report: CRDLR 

32 3010, Army Chemical Center, Maryland. 

33 

34 HSDB (Hazardous Substances Data Bank). 2008. Perchloryl Fluoride. HSDB, Natl. Library of 

35 Medicine, TOXNET system. October 31, 2008. 

36 

37 Kiese, M. 1974. Methemoglobinemia: A Comprehensive Treatise. Cleveland, OH: CBC Press. 

38 

39 Kushneva. 1999. Handbook of Toxicological and Hygienic Standards (PDK) of Potentially Hazardous 

40 Substances. Developed by the Institute of Biophysics and its (associated) branches. 

41 

42 Mendiratta, S.K., R.L. Dotson and R.T. Brooker. 2005. Perchloric acid and perchlorates. Kirk-Othmer 

43 Encyclopedia of Chemical Technology, John Wiley and Sons, Inc. 

44 

45 NIOSH (National Institute for Occupational Safety and Health). 2005. NIOSH Pocket Guide to 

46 Chemical Hazards-Perchloryl Fluoride. NIOSH, Cincinnati, OH. On-line (Feb. 2009) at 

47 http://www.cdc.gov/niosh/ 

48 
PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 21 of 28 

1 NIOSH (National Institute for Occupational Safety and Health). 1996. Documentation of Immediately 

2 Dangerous to Life and Health Concentrations (IDLH). Found on-line (Feb. 2009) at 

3 http://www.cdc.gov/niosh/idlh/7616946.html. 

4 

5 NRC (National Research Council). 2001. Standard operating procedures for developing acute exposure 

6 guideline levels for hazardous chemicals. Washington, D.C.: National Academy Press. 

7 

8 OSHA (Occupational Safety and Health Administration). 2005. Code of Federal Regulations, CFR 29, 

9 Part1910, Table Z-1. 

10 

11 SDU Uitgevers. 2000. MAC Ministry of Social Affairs and Employment. Nationale MAC (Maximum 

12 Allowable Concentration) List, The Hague, The Netherlands. 

13 

14 Seger,D.L. 1992. Methemoglobin-Forming Chemicals. Hazardous Materials Toxicology: Clinical 

15 Principles of Environmental Health, J.B. Sullivan and G.R. Krieger, eds. Baltimore, MD: Williams & 

16 Wilkins, pp. 800-806 

17 

18 ten Berge, W.F., Zwart, A., Appelman, L.M. 1986. Concentration-time mortality response relationship 

19 of irritant and systemically acting vapours and gases. J. Hazard. Materials: 13: 301-309. 

20 

21 Wilburn-Goo, Dawn and Larry Lloyd. 1999. W hen patients become cyanotic: acquired 

22 methemoglobinemia. JADA 130: 826-831. 

23 

24 
PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 22 of 28 

1 

2 APPENDIX A: Derivation of AEGL Values

3 Derivation of AEGL-1 

4 

5 Key Study: Greene, E.A., J.L. Colbourn, E. Donati and M.H. Weeks. 1960. The inhalation 

6 toxicity of perchloryl fluoride. U.S. Army Chemical Research and Development 

7 Laboratories Technical Report: CRDLR 3010, Army Chemical Center, 

8 Maryland. 

9 

10 Toxicity Endpoint: Study causing no treatment-related adverse effects 

11 

Scaling: Cn 12 x t = k 

13 n = 3 for extrapolating to the 30-min, 1-hour and 4-hour time-points 

 (24 ppm)3 x 6 hours = 8.3 x 104 14 ppm hr 

15 

16 n = 1 for extrapolating to the 8-hour time-point 

 (24 ppm)1 17 x 6 hours = 144 ppm hr 

18 

19 Uncertainty factors: 3 for interspecies variability 

20 10 for intraspecies variability 

21 Total UF = 30 

22 

23 10-min.AEGL-1: 1.8 ppm (set equal to the 30-min value because of the long exposure 

24 duration of the key study). 

25 

30-min. AEGL-1: C3 x 0.5 hr. = 8.3 x 104 26 ppm hr 

 C3= 1.7 x 105 27 ppm 

28 C = 55.4 ppm 

29 30-min AEGL-3 = 55.4 ppm/30 = 1.8 ppm 

30 

1-hr. AEGL-1: C3

 x 1 hr = 8.3 x 104 31 ppm ·hr 

 C3

 = 8.3 x 104 32 ppm 

33 C = 43.6 ppm 

34 1 hr AEGL-3 = 43.6 ppm/30 = 1.5 ppm 

35 

4-hr. AEGL-1: C3

 x 4 hr = 8.3 x 104 36 ppm ·hr 

 C3 37 = 20,750 ppm 

38 C = 27.5 ppm 

39 4 hr AEGL-3 = 27.5 ppm/30 = 0.92 ppm 

40 

8-hr. AEGL-1: C1 41 x 8 hr = 144 ppm ·hr 

 C1 42 = 18 ppm 

43 8 hr AEGL-3 = 18 ppm/30 = 0.60 ppm 

44 

45 

46 

47 
PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 23 of 28 

1 

2 Derivation of AEGL-2 

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 

Toxicity Endpoint: 1/3rd 9 of AEGL-3 values. For chemicals with a steep concentration10 response curve, AEGL-2 values may be calculated by dividing AEGL-3 

11 values by 3 (NRC 2001). 

12 

13 Scaling: See derivation of AEGL-3 

14 

15 Uncertainty factors: See derivation of AEGL-3 

16 

17 10-min.AEGL-2: 15 ppm/3 = 5.0 ppm 

18 

19 30-min. AEGL-2: 15 ppm/3 = 5.0 ppm 

20 

21 1-hr. AEGL-2: 12 ppm/3 = 4.0 ppm 

22 

23 4-hr. AEGL-2: 7.5 ppm/3 = 2.5 ppm 

24 

25 8-hr. AEGL-2: 3.7 ppm/3 = 1.2 ppm 

26 
PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 24 of 28 

1 Derivation of AEGL-3 

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: Highest 4-hour concentration causing no mortality in dogs, but below the 

9 LC50 value for rats in the same study. 

10 

Scaling: Cn 11 x t = k 

12 n = 3 for extrapolating to the 30-min and 1-hour time-points 

 (224 ppm)3

 x 4 hours = 4.5 x 107 13 ppm hr 

14 

15 n = 1 for extrapolating to the 8-hour time-point 

 (224 ppm)1 16 x 4 hours = 896 ppm hr 

17 

18 Uncertainty factors: 3 for interspecies variability 

19 10 for intraspecies variability 

20 Total UF = 30 

21 

22 10-min.AEGL-3: 15 ppm (set equal to the 30-min value because of the long exposure 

23 duration of the key study). 

24 

30-min. AEGL-3: C3

 x 0.5 hr. = 4.50 x 107 25 ppm hr 

 C3

= 9.0 x 107 26 ppm 

27 C = 448 ppm 

28 30-min AEGL-3 = 448 ppm/30 = 15 ppm 

29 

1-hr. AEGL-3: C3

 x 1 hr = 4.50 x 107 30 ppm ·hr 

 C3

 = 4.50 x 107 31 ppm 

32 C = 356 ppm 

33 1 hr AEGL-3 = 356 ppm/30 = 12 ppm 

34 

35 4-hr. AEGL-3 C = 224 ppm/30 

36 C = 7.5 ppm 

37 

8-hr. AEGL-3: C1 38 x 8 hr = 896 ppm ·hr 

 C1 39 = 112 ppm 

40 8 hr AEGL-3 = 112 ppm/30 = 3.7 ppm 

41 

42 
PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 25 of 28 

1 

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

3 

4 

0 

1 

10 

100 

1000 

10000 

ppm

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

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

1 

2 Data: 

 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 (LC50) 

 mouse 630 240 SL (LC50) 

 

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) 

3 
PERCHLORYL FLUORIDE NAC/Proposed 1: June 2009/ Page 27 of 28 

1 APPENDIX C: Derivation Summary for Perchloryl Fluoride AEGLs

2 (CAS Reg. No. 7616-94-6) 

3 

4 DERIVATION SUMMARY 

5 

6 

7 

8 AEGL-1 VALUES 

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. 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, 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 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, Perchloryl fluoride is systemically absorbed 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 Cn 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 

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

1 AEGL-2 VALUES 

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/Concentrations/Durations: Due to limited data and the steep 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 1/3rd 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 

3 AEGL-3 VALUES 

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 Chemical Research and Development Laboratories Technical Report: CRDLR 

3010, Army Chemical Center, Maryland. 

Test Species/Strain/Number: 2 male Beagle dogs per concentration 

Exposure Route/Concentrations/Durations: Inhalation/224, 425, 451 ppm/4-hours; 4-hour LC50 values for rats 

and mice 

Effects: Rat LC50 is 385 ppm; Mouse LC50 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 Factors/Rationale 

Total uncertainty factor: 30 

Interspecies: 3, the 4-hr 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, Perchloryl fluoride is systemically absorbed 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 Cn 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 

5