B6
Perfluoropropane and Other Aliphatic Perfluoroalkanes
Chiu-Wing Lam, Ph.D., D.A.B.T.
Johnson Space Center Toxicology Group
Medical Operations Branch
Houston, Texas
PHYSICAL AND CHEMICAL PROPERTIES
Perfluoropropane (PFA3, octafluoropropane) is gaseous at room temperature. It is colorless and odorless. Some physical characteristics are as follows:
Formula: |
CF3CF2CF3 |
CAS no.: |
76-19-7 |
Synonyms: |
Freon 218, FC-218, PF 5030 3M Performance Fluid |
Molecular weight: |
188.08 |
Boiling point: |
–37°C |
Vapor pressure: |
114.8 psia at 21°C (3M 1995a) |
Solubility in water: |
Extremely low |
Conversion factors: |
1 ppm = 7.68 mg/m3 |
|
1 mg/m3 = 0.13 ppm (at 25°C) |
OCCURRENCE AND USE
When compressed, gaseous PFA3 is easily condensed into liquid. PFA3 is currently used as a secondary coolant in refrigerators aboard the Russian space-station Mir. According to Russian toxicologists, if all the PFA3 were to escape from the cooling system into the Mir cabin, the cabin concentration could reach 5000 mg/m3 (G.I.Solomina and L.N.Mouakhamedieva, Institute of Biomedical Problems, Moscow, personal commun., 1996). PFA3 is not used in the U.S. space program, and to our knowledge, astronauts have not been exposed to
PFA3 in U.S. spacecraft. However, NASA has joined the Russian Space Agency in using the Mir space station. Mir-18 was the first mission that involved a U.S. astronaut living onboard the Russian spacecraft. For this mission, the cabin air samples showed that PFA3 was the trace contaminant present in the highest concentration; its concentrations in Mir ranged from 20 to 48 mg/m3 (Limero 1995).
TOXICOKINETICS AND METABOLISM
Toxicokinetics
PFA3 is practically insoluble in water (3M 1995a). The air/blood/liver/fat partition coefficients (PCs) of PFA3 were 1/0.25/0.07/0.04 (Creech et al. 1995), as determined by the vial equilibration method of Gargas et al. (1986). For solubility comparison, the corresponding PCs of chloroform, determined by the same method, were 1/20.8/21.1/203 (Gargas et al. 1989). Those data suggest that at the same airbrone exposure concentration, the blood, liver, and fat would take up, respectively, 83, 300, and 5000 times more chloroform than PFA3 when the equilibrium is reached. Theoretical predictions showed that concentrations of very low water-soluble, volatile compounds in body water would approach steady state within 1 hof exposure (Goldstein 1974).
Metabolism
Perfluoroalkanes (PFAs) are very stable. They are not oxidized even by ozone to any appreciable extent; their atmospheric half-life greater than 5000 y (R.G. Perkins, 3M Company, personal commun., 1995). Creech et al. (1995) detected no increases in fluoride in urine of rats exposed to 1% PFA3 for 4 h.
TOXICITY SUMMARY
PFA3 is a low-molecular-weight PFA. PFAs are chemically inert; included in this family is Teflon (a polymeric, high-molecular-weight PFA). The major concern from exposure to high concentrations of gaseous PFAs is their potential for cardiac toxicity. Cardiac effects are known to occur when humans or animals are exposed to high concentrations of other fluorinated hydrocarbons (FCs), including Freons (Table 6-1). FCs, such as chlorofluorocarbons, could induce cardiac arrhythmias by sensitizing the heart to epinephrine (Aviado and
Micozzi 1981; Hanig and Herman 1991). The inertness of PFAs has attracted few attempts to investigate the toxic properties of these compounds. Only a few unpublished toxicological studies on PFA3 and other PFAs were found; none of them were conducted with human subjects. These studies revealed that PFAs are very low in toxicity (McHale 1972; 3M 1993a,b, 1995a,b,c) (Table 6-2). At very high concentrations, PFA3 could indeed induce cardiac effects (3M 1993a). However, the concentrations of PFA3 that produce cardiac effects are substantially higher than those of other halogenated compounds that are not fully fluorinated. A survey of the literature on fluorine-containing alkanes reveals that substituting fluorine for chlorine or hydrogen atoms in an FC decreases the compound's toxicity, including cardiac toxicity (Table 6-1).
CNS toxicity that could impair cognitive performance is another concern associated with exposures to high concentrations of relatively biologically inert FCs (e.g., bromotrifluoromethane (NRC 1984a)). The extremely low solubility of PFA3 in water, blood, and tissues would imply that the PFA3 concentration in the brain would be low. Any CNS toxicity in humans due to PFA3, if it occurs, would likely manifest at only very high concentrations. That is likely to be true for other PFAs also. These speculations are indeed supported by the findings that rats exposed to 80% PFA1, PFA2, or PFA3 experienced only minimal effects (initial hyperactivity followed by hypoactivity (see Table 6-2)).
TABLE 6-1 Acute Inhalation Toxicity of Selected Fluorinated Alkanes
Compound |
Namea |
Exposure, ppm × time |
Toxicity in Rats |
Epinephrineb + Exposure (ppm) |
Cardiac Toxicity in Dogs |
References |
CFCl3 |
FC 11 |
26,220 × 4 h |
LC |
5000 |
Lowest concentration that elicited a marked response |
NRC 1984b |
CFCl2H |
FC 21 |
50,000 × 4 h |
LC |
10,000 |
Affected 2/12 dogs |
NRC 1984c |
CF2ClH |
FC 22 |
300,000 × 2 h |
LC |
50,000 |
Effects observed |
ACGIH 1991a |
CF2Cl2 |
FC 12 |
620,000 × 3 h |
LC |
80,000 |
EC50 |
NRC 1984d |
CF3Br |
FC1301 |
560,000 × 1 h |
Mild-to-moderate CNS effects |
200,000 |
EC50 |
McHale 1972 |
CF4 |
FC 14 (PFA1) |
780,000 × 1 h |
Mild effects |
600,000 |
Very mild effect |
McHale 1972 |
CF3CCl3 |
FC 113 |
50,000 × 4 h |
LC |
5000 |
EC:20-35% |
NRC 1984e |
CF3CFCl2 |
FC 114 |
600,000 × 2 h |
LC |
45,000 |
EC50 |
NRC 1984f |
CF3CF2Cl |
FC 115 |
800,000 × 4 h |
No clinic signs |
150,000 |
Affected 1/13 dog |
ACGIH 1991b |
CF3CF3 |
FC 116 (PFA2) |
800,000 × 1 h |
Very mild CNS effects, no deaths |
— |
— |
McHale 1972 |
CF3CF2CF3 |
FC 218 (PFA3) |
800,000 × 1 h |
Very mild CNS effects, no deaths |
400,000 |
1/8 dog: definite positive response; 1/8 dog: weak response |
McHale 1972 3M 1993a |
CF3(CF2)2CF3 |
(PFA4) |
800,000 × 1 h |
No toxic signs, no deaths |
400,000 |
No effects |
3M 1995a |
CF3(CF2)3CF3 |
(PFA5) |
280,000 × 4 h |
No effects, no deaths |
— |
— |
3M 1993a |
CF3(CF2)4CF3 |
(PFA6) |
381,000 × 1 h |
No clinical signs, no pathological changes or deaths |
170,000 |
No or very mild effects |
3M 1995b |
a PFAs are abbreviations for perfluoroalkanes used in this document. b Pretreated with epinephrine before inhalation exposure to the compound. LC, lethal concentration; EC, effect concentration; EC50 = concentration that produces an effect on 50% of exposed animals. |
TABLE 6-2 Toxicity Summary of Perfluoroalkanes
PFAs |
Exposure Concentration |
Exposure Length |
Animals |
Effects |
Reference |
PFA1 |
80% |
1 h |
10 rats |
Initial hyperactivity followed by hypoactivity, hyperemia |
McHale 1972 |
|
22.6% |
10 d (24 h/d) |
20 rats, 20 guinea pigs |
No clinical signs, no macroscopic or microscopic lesions |
McHale 1972 |
|
20% or 60% |
— |
6 dogs/group (epinephrine-sensitized) |
Occasional preventricular contractions in three of the six dogs exposed to 60% |
McHale 1972 |
PFA2 |
80% |
1 h |
10 rats |
Initial hyperactivity followed by hypoactivity, hyperemia |
McHale 1972 |
|
12.1% |
10 d (24 h/d) |
20 rats, 20 guinea pigs |
No clinical signs, no macroscopic or microscopic lesions |
McHale 1972 |
PFA3 |
80% |
1 h |
10 rats |
Initial hyperactivity followed by hypoactivity, hyperemia |
McHale 1972 |
|
11% |
4 h |
10 rats |
No clinical signs, no macroscopic and microscopic lesions |
3M 1993a |
|
11.3% |
10 d (24 h/d) |
20 rats, 20 guinea pigs |
No clinic signs, no microscopic lesions |
McHale 1972 |
|
5%, 10%, 20%, 30%, and 40% |
— |
6 dogs/group (epinephrine-sensitized) |
1 positive cardiac response (multiple and multifocal ectopic beats), 1 weak positive response in the eight 40%-exposed dogs; no effects at ≤ 30% |
3M 1993a |
PFA4 |
9.8% and 79% |
4 h |
10 rats/group |
No clinical signs, no macroscopic or microscopic lesions |
3M 1993b |
|
5%, 10%, 20%, 30%, or 40% |
— |
6-8 dogs/group (epinephrine-sensitized) |
No cardiac effects |
3M 1993b |
PFA6 |
38% (saturated vapor) |
1 h |
Rats |
No clinical signs, no deaths; necropsy showed no gross pathological changes |
3M 1995b |
PFAs |
Exposure Concentration |
Exposure Length |
Animals |
Effects |
Reference |
PFA6 |
30.5% |
30 exposures, 7 h/d, 5 d/w |
26 rats |
Some clinical chemistry and hematological variables differed slightly from those of control rats, but were within biologically acceptable ranges; no macroscopic or microscopic lesions |
3M 1995a |
|
5% |
2 w (6 h/d, 5 d/w) |
20 rats |
No clinical signs; no macroscopic lesions |
3M 1995a |
|
0.5%, 1.5%, or 5% |
90 d (6 h/d, 5 d/w) |
10 rats/group |
No clinical signs; some clinical chemistry and hematological variables differed slightly from those of control rats, but were within biologically acceptable ranges; no macroscopic or microscopic lesions |
3M 1995a |
|
5%, 10%, or 17.5% |
— |
6 dogs/group (epinephrine-sensitized) |
No cardiac toxicity |
3M 1995a |
Acute Exposures
General Toxicity
McHale (1972) evaluated the acute toxicity of inhaled perfluoromethane (PFA1), perfluoroethane (PFA2), and PFA3. Three groups of male rats (10 per group) were exposed for 1 h to 80% (target concentration) of these PFAs (with 20% oxygen) (Table 6-2). Two additional groups of rats were exposed to either air (control) or 56% bromotrifluoromethane (also with 20% oxygen). Bromotrifluoromethane, a compound of known toxicity, was used for comparison. During the exposures, all animals exposed to the PFAs exhibited initial hyperactivity and subsequent hypoactivity, hyperemia (redness of skin), and closed eyes. Rats exposed to bromotrifluoromethane also exhibited initial hyperactivity and subsequent hypoactivity, but also showed increases in respiration rate, abdominal breathing, slight-to-moderate ataxia (incoordination), and a slight bluish tint to the skin. All animals seemed normal during the 14-d post-exposure observation period, and none died. A study by the 3M Company (3M 1993a) on 10 rats (5 males, 5 females) exposed to 11% PFA3 for 4 h showed neither deaths nor clinical signs. Necropsy of these animals after a 15-d observation period revealed some lung congestion in one rat. Microscopic pathological examination of lungs, liver, and kidneys showed no abnormalities in any of the PFA-exposed rats.
The higher molecular-weight PFAs also showed little or no biological activity even at high exposure concentrations. Groups of 10 rats (5 males, 5 females) were exposed to 9.8% or 79% perfluorobutane (PFA4) for 4 h or to 38.1% perfluorohexane (PFA6) for 1 h; neither deaths nor pharmacotoxic signs were observed during the exposure or during the 14-d post-exposure period. Necropsy revealed no gross pathological changes (3M 1993a, 1995c). Microscopic findings on animals exposed to PFA4 showed no abnormalities. No information was provided regarding whether tissues of rats exposed to PFA6 were examined microscopically.
Cardiac Effects
Cardiac sensitization was assessed in a study in which dogs (six to eight per group) were pretreated with epinephrine and exposed either to 5%, 10%, 20%, 30%, or 40% PFA3. One definite positive cardiac response (multiple and multifocal ectopic beats) and one questionable (weak) response were observed among the eight dogs exposed to 40% PFA3 (3M 1993a). However, exposures to PFA4 at the same concentrations produced no cardiac abnormalities (3M
1993b). No cardiac effects were observed in any of the dogs exposed to 5%, 10%, or 17.5% PFA6 after being injected with epinephrine (3M 1995c). Trichlorofluoromethane at 2%, used as a positive control, elicited 100% cardiac response in the dogs in all three 3M cardiac-sensitization studies. McHale (1972) also assessed cardiac sensitization in beagles injected intravenously with epinephrine (8 µg/kg) and exposed to 20% PFA1 (80% air) or 60% PFA1 (40% O2). No cardiac arrhythmias were observed; the only responses were occasional preventricular contractions in three of the six dogs exposed to 60% PFA1. These results showed that PFAs have very low cardiac-sensitizing activity.
Short-Term and Subchronic Exposures
McHale (1972) conducted a 10-d continuous (24 h/d) exposure study with PFA1, PFA2, PFA3, or bromotrifluoromethane. Each exposure group consisted of 10 male and 10 female rats, and 10 male and 10 female guinea pigs. The average analytical concentrations were 20.6% (PFA1), 12.1% (PFA2), 11.3% (PFA3), and 5.1% (bromotrifluoromethane). Parameters studied included toxicity signs, clinical chemistry, hematology, gross pathology of all organs, microscopic histopathology of selected organs (lungs, liver, heart, kidneys, and spleen), organ weights, and organ-to-body-weight ratios of these organs and adrenals.
No overt signs of toxicity were present during the exposures. Clinical chemistry data were unremarkable. Hematological examinations of rats and guinea pigs revealed elevation of total leukocyte counts in some PFA-exposed groups (Table 6-3). However, all groups had pneumonitis and associated inflammation that could easily account for the mild elevation in leukocyte counts. Moreover, the elevation of leukocyte counts was not statistically significant for all three PFAs, and not considered an adverse effect of these compounds. Gross pathology showed no lesions associated with any particular group. Histopathological findings also revealed no differences between the FC-exposed animals and the controls.
Another inhalation study was conducted with two groups of rats (10 males and 10 females per group) exposed to either air or 10% PFA4 for 2 w (6 h/d; 5 d/w) (3M 1993b). A similar study was also conducted with 5% PFA6 (3M 1995c). Clinical observations, body and organ weight measurements, and gross pathological examination were conducted. No deaths or exposure-related effects were observed for either compound except for a small increase in liver weight of the female rats and in kidney weight of the male rats in the PFA6-exposed group. Microscopic examination showed no difference between the exposed and control groups. 3M also conducted an inhalation study with 26 rats (16 males, 10 females) given 30 exposures (7h/d, 5 d/w) to ''near-satu-
rated" (30.5%) PFA6 vapor (3M 1995c). Mortality, abnormal weight patterns, and gross pathological changes were not observed. Microscopic examination of the lung and liver showed no significant histopathological changes. Blood chemistry revealed that some of the parameters in exposed animals were different from those of control animals. However, according to 3M, all of these blood results were within biologically acceptable ranges. A 90-d inhalation study (6 h/d, 5 d/w) conducted with groups of 10 rats (5 males, 5 females) exposed to 0, 5000, 15,000, or 50,000 ppm PFA6 produced no exposure-related deaths. Clinical signs were normal. Minor differences in several hematological and clinical-chemistry variables were observed, but according to 3M (1995b), the values from the exposed animals were within normal limits and were not considered toxicologically significant. Histopathological examination showed no exposure-related histological changes.
Genotoxicity
Vapors of PFA3, PFA4, PFA5, or PFA6 were tested for their potential mutagenic activity on Salmonella typhimurium (strains TA1535, TA1537, TA1538, TA98, and TA100) in the presence or absence of liver enzymes. The concentrations tested were 80% for PFA3 and PF4 and near-saturated vapors (> 10%) for PFA5 and PFA6. No mutagenic activity was observed (3M 1993a, b, 1995b, c). These results are not surprising given the extremely low water solubility and chemical inertness of these compounds.
EXPOSURE LIMITS
Exposure Limits Set by Other Organizations
No exposure limits have been established for any PFAs by any organization in the United States, including 3M, the manufacturer of the products. The Russian Space Agency has set a maximum allowable concentration for PFA3 of 150 mg/m3 (G. I. Solomina and L. N. Mouakhamedieva, Institute of Biomedical Problems, Moscow, personal commun., 1996).
Nasa Spacecraft Maximum Allowable Concentrations (SMACs)
SMACs are derived in accordance with guidelines developed by the SMACs subcommittee of the Committee on Toxicology (NRC 1992). The SMACs (Table 6-3) are set by choosing the lowest values among the ACs (see Table 6-4).
TABLE 6-3 Spacecraft Maximum Allowable Concentrations (SMACs) of Perfluoropropane
Exposure Duration |
Concentration, ppm |
Concentration, mg/m3 |
Target Toxicity |
1 h |
11,000 |
85,000 |
CNS effects |
24 h |
11,000 |
85,000 |
CNS effects |
7 d |
11,000 |
85,000 |
CNS effects |
30 d |
11,000 |
85,000 |
CNS effects |
180 d |
11,000 |
85,000 |
CNS effects |
RATIONALE FOR ACCEPTABLE CONCENTRATIONS (ACS) FOR EXPOSURES
ACs Based on the CNS Effects of the Acute Exposure Studies
PFA3 is not metabolized. The brain is a richly and fast-perfused organ. Thus, the CNS effects of PFA3 would be due solely to PFA3 concentration in the brain. For a given exposure concentration, the blood concentration of PFA3 would likely approach a steady state within 60 min, and the concentration in the brain will follow the blood in a comparable time. Thus, the possible CNS effects induced by PFA3 would be independent of exposure length of ≤ 60 min. Thus, one AC value is set for all exposure durations.
McHale (1972) reported that a 1-h exposure of rats to 80% PFA3 resulted in only mild CNS responses. 3M reported that a 4-h exposure of rats to 11% PFA3 caused no clinical signs (3M 1993a). An AC of 1.1% is obtained by applying an animal-to-human extrapolation safety factor of 10 to the NOAEL of 11%.
ACs Based on Cardiac Effects
The heart, like the brain, is also a richly and fast-perfused organ. For the reasons presented above, one AC value could be set for all exposure durations. 3M (1993a) has reported that no cardiac effects were observed in epinephrine-treated dogs exposed to 30% PFA3. Therefore, using an uncertainty factor of 10 to account for interspecies variability, the AC is set at 3% (30% ÷ 10). The space factor of 5 is not used here because the epinephrine-treated dog model is a conservative test, and epinephrine is probably associated with cardiac arrhythmias observed in humans.
ACs Based on Subchronic Animal Exposure Data
McHale (1972) showed that continuous inhalation exposure of rats to 11.3% PFA3 for 10 d (24 h/d) produced neither clinical signs nor microscopic lesions. Using an uncertainty factor of 10 for interspecies variability, ACs for 7 d, 30 d, and 180 d of exposure are set at 1.1% (11.3% ÷ 10). The AC derived from various toxicity end points are summarized in Table 6-4. The SMACs are set by choosing the lowest values among these ACs.
TABLE 6-4 Acceptable Concentrations of PFA3
End Point, Exposure Data, Reference |
|
Uncertainty Factors |
Acceptable Concentrations, ppm |
||||||
Species |
Time |
Species |
Spaceflight |
1 h |
24 h |
7 d |
30 d |
180 d |
|
CNS effects |
Rat |
1 |
10 |
— |
11,000 |
11,000 |
11,000 |
11,000 |
11,000 |
NOAEL, 11% (3M 1993a) |
|
|
|
|
|
|
|
|
|
Cardiotoxicity |
Dog |
1 |
10 |
1a |
30,000 |
30,000 |
30,000 |
30,000 |
30,000 |
NOAEL, 30% (3M 1993a) |
|
|
|
|
|
|
|
|
|
Subchronic toxicity |
Rat |
1 |
10 |
— |
NS |
NS |
11,000 |
11,000 |
11,000 |
NOAEL, 11.3% (McHale 1972) |
|
|
|
|
|
|
|
|
|
SMACs |
|
|
|
|
11,000 |
11,000 |
11,000 |
11,000 |
11,000 |
—, not applicable. NS, not set. aSee text for explanation of not using the spaceflight factor 5. |
SMACs for Other Volatile Perfluoroalkanes
As discussed above, PFAs have extremely low solubility in water and are biologically inert and extremely low in toxicity. No evidence exists to suggest that increasing or decreasing the molecular weight of these compounds drastically changes their toxicity. Therefore, the SMACs for the other straight-chain PFAs are set at the same values as those of PFA3. A survey of perfluorocyclobutane toxicity indicates that this cyclic PFA is more cardiotoxic than the aliphatic PFAs discussed in this document. The generalization about the toxicity of aliphatic PFAs would not be applicable to the cyclic PFAs. Therefore, the SMACs set for PFAs in this document would not be applicable to cyclic PFAs.
ACKNOWLEDGMENTS
The author is grateful to Dr. Henry Trochimowicz of Haskell Laboratory (du Pont de Nemours & Co.), and Dr. Roger Perkins of 3M for kindly providing several unpublished reports.
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