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FLUORINE

BACKGROUND INFORMATION

PHYSICAL AND CHEMICAL PROPERTIES

Structural formula:

F2

Molecular weight:

37.996

CAS number:

7782–41–4

Melting point:

−220°C

Boiling point:

−188°C

Density:

1.5127

Physical state:

A pale yellow, diatomic gas, it is the most reactive nonmetal.

General characteristics:

It has a higher oxidation potential than ozone and reacts vigorously with almost all oxidizable substances at room temperature, frequently with ignition. It reacts violently with most organic compounds, usually causing extensive fragmentation of the molecule (O’Donnell, 1973; Windholz et al., 1976).

Other properties:

Fluorine decomposes in water, yielding hydrogen fluoride (HF), oxygen difluoride (OF2), hydrogen peroxide (H2O2), oxygen, and ozone. However, F2 persists in saturated water vapor for up to 1 h (Slabbey and Fletcher, 1958).

Conversion factors:

ppm=0.64 (mg/m3)

mg/m3=1.56 (ppm)

OCCURRENCE AND USE

Elemental fluorine does not occur in nature. Because it is the most electronegative element, it is extremely difficult to prepare; electrolysis of a KF=HF mixture, a procedure introduced in 1886, is still in use.

Although numerous fluorocarbon compounds are used as lubricants, coolants, refrigerants, etc., many of these are prepared from HF, rather than F2, because the reactions of the latter are difficult to control. Fluorine gas is used to manufacture uranium hexafluoride (UF6) for the separation of uranium isotopes. The elemental gas is also used to manufacture sulfur hexafluoride (SF6), a stable gas with high dielectric and insulating capacities for high-voltage systems. Fluorine is also used as an oxidant in rocket-fuel mixtures (ACGIH, 1980).

SUMMARY OF TOXICITY INFORMATION

EFFECTS ON HUMANS

Uncontrolled Exposure

Women and children living in a village in the vicinity of an aluminum factory in northern Italy suffered blemishes that were thought to have resulted from stack effluents, among which might have been fluorine or fluorides (Cavagna et al., 1969). Examination of those affected



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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Volume 1 FLUORINE BACKGROUND INFORMATION PHYSICAL AND CHEMICAL PROPERTIES Structural formula: F2 Molecular weight: 37.996 CAS number: 7782–41–4 Melting point: −220°C Boiling point: −188°C Density: 1.5127 Physical state: A pale yellow, diatomic gas, it is the most reactive nonmetal. General characteristics: It has a higher oxidation potential than ozone and reacts vigorously with almost all oxidizable substances at room temperature, frequently with ignition. It reacts violently with most organic compounds, usually causing extensive fragmentation of the molecule (O’Donnell, 1973; Windholz et al., 1976). Other properties: Fluorine decomposes in water, yielding hydrogen fluoride (HF), oxygen difluoride (OF2), hydrogen peroxide (H2O2), oxygen, and ozone. However, F2 persists in saturated water vapor for up to 1 h (Slabbey and Fletcher, 1958). Conversion factors: ppm=0.64 (mg/m3) mg/m3=1.56 (ppm) OCCURRENCE AND USE Elemental fluorine does not occur in nature. Because it is the most electronegative element, it is extremely difficult to prepare; electrolysis of a KF=HF mixture, a procedure introduced in 1886, is still in use. Although numerous fluorocarbon compounds are used as lubricants, coolants, refrigerants, etc., many of these are prepared from HF, rather than F2, because the reactions of the latter are difficult to control. Fluorine gas is used to manufacture uranium hexafluoride (UF6) for the separation of uranium isotopes. The elemental gas is also used to manufacture sulfur hexafluoride (SF6), a stable gas with high dielectric and insulating capacities for high-voltage systems. Fluorine is also used as an oxidant in rocket-fuel mixtures (ACGIH, 1980). SUMMARY OF TOXICITY INFORMATION EFFECTS ON HUMANS Uncontrolled Exposure Women and children living in a village in the vicinity of an aluminum factory in northern Italy suffered blemishes that were thought to have resulted from stack effluents, among which might have been fluorine or fluorides (Cavagna et al., 1969). Examination of those affected

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Volume 1 revealed no signs of fluorosis, and their urinary fluoride concentrations were normal. Animal experiments with extracts of stack effluents revealed no adverse effects at the concentrations used. The authors concluded that there was no evidence of an association of fluorine or fluorides with the observed skin conditions (Cavagna et al., 1969). Lyon (1962) reported that 61 workers exposed to fluorine who excreted fluoride at an average of 1.1 mg/L for 7 yr (2,535 determinations) had better health records than the 2,000 employees used as controls and had fewer respiratory complaints. The average F2 exposure was not known, but the author speculated that it was “greatly in excess of 0.1 ppm.” The same author observed that intermittent industrial exposures to F2 at up to 30 ppm for 5–30 min had no ill effects. No other reports of uncontrolled F2 exposures, accidental or occupational, are known to the Committee. Controlled Exposure Outdoor “spill” tests conducted by the U.S. Air Force revealed that single “short-term” F2 exposures at 25 ppm (duration not reported) were “intolerably irritating,” and exposure at 50 ppm made breathing impossible (Rickey, 1959). The number of subjects involved in this study was not reported. Belles (1965) observed nine male volunteers exposed to F2 under controlled conditions. Most of the subjects found that 15–25 ppm caused some nasal and eye irritation after two or three breaths. All subjects tolerated repeated short-term (duration unspecified) exposures at up to 10 ppm without discomfort. Additional details of this study were not available to the Committee. Keplinger and Suissa (1968) exposed 5 volunteers (aged 19–50) to F2 under a variety of conditions that permitted accurate measurement of F2 concentrations. Exposure took place under a mask that covered the eyes and nose, but not the mouth. Thus, the effects of F2 on respiration were not routinely measured (some subjects did inhale and some data on respiratory effects were obtained). The results of this study are summarized in Table 19. The authors also noted that, when exposure was repeated weekly, the subjects did not perceive as much irritation as they had on first exposure. The apparent development of tolerance is consistent with that seen in experimental animals. Finally, the authors studied the effects of exposure at 10 ppm for 3–5 min every 15 min for 2 or 3 h. All subjects tolerated such repeated exposures with only slight irritation of the eyes and skin. EFFECTS ON ANIMALS Acute exposure Almost all animal studies of F2 toxicity known to the Committee were acute (single exposures). The most comprehensive of such studies, and the only ones involving actual measurement of the concentrations of F2 at which the animals were exposed, were reported by Keplinger and Suissa (1968). The only known earlier studies were conducted during World War II; they involved only lethal concentrations (the

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Volume 1 concentrations were not monitored) and provide no information useful for present purposes (Ricca, 1970). Data obtained by Keplinger and Suissa from exposures at sublethal concentrations are summarized in Tables 20–23. These data were collected after determination of LC50s in the five species studied; the concentrations used were then fixed at 50%, 25%, 12.5%, and 6% of the LC50 values. The most pronounced effects of the F2 exposures observed were irritation of the eyes and respiratory tract. Dyspnea was also observed frequently. Although kidney and liver effects were observed, they occurred only at exposures greater than those producing diffuse congestion of the lung. Thus, only lung pathology data are reported in Tables 20–23. In rats, mice, guinea pigs, and rabbits, effects observed after exposures at approximately 50% and 25% of the LC50 values were not observed at approximately 12.5% of the LC50 values (see Tables 20–23). The lack of data on the LC50 value for dogs prevents determination of whether the same pattern holds for this species. The ranges of maximal no-observed-effect concentration for the five species were as follows: Duration, min No-observed-effect concentration, ppm ppm-min 5 51–88 260–440 15 49–70 740–1,100 30 32–35 960–1,100 60 28–38a 1,500–2,300 aIncludes dog data. For both dogs and rats, complete blood counts (hemoglobin, hematocrit, erythrocyte count, and total and differential leukocyte counts) were measured before exposure and on the second, seventh, fourteenth, and twenty-first days after exposure. No measurable changes were noted in these counts after any of the exposures. Short-Term Exposure Keplinger (1969) studied the effects of intermittent exposure to F2 by exposing mice, rats, and rabbits four times at weekly intervals. Two magnitudes of exposure were used: one that caused slight effects after a single exposure and one that produced marked effects after such an exposure. The animals were sacrificed 7, 14, 21, or 45 d after the last exposure. The results of these studies are summarized in Table 24. The author concluded that four weekly exposures to F2 caused no more, and in some cases less, damage than a single exposure at the same concentration. The data suggest the development of a tolerance to F2. It was also shown that the LC50 value for mice was increased by pre-exposing the test animals to F2. This provides additional evidence of the development of tolerance. PHARMACOKINETICS The extent to which fluoride (F−) toxicity data may provide insight

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Volume 1 into F2 toxicity cannot be ascertained. Presumably, if F2 were metabolized only to F−, then data on the latter would be of some value. There is, however, no evidence on the chemical fate of F2 in animal systems. Indeed, it is expected that F2 will cause extensive chemical changes in biomolecules. Ricca (1970) reported that F2 can oxidize proteins and fats, and it is likely that numerous degradation products of biomolecules are produced after F2 exposures. Therefore, it does not seem reasonable to assume that fluoride toxicity is importantly related to that expected for F2. COMMITTEE RECOMMENDATIONS EXPOSURE LIMITS In 1968 (NRC, 1968), the Committee recommended the following EELs for F2: 10-min EEL: 15 ppm 30-min EEL: 10 ppm 60-min EEL: 5 ppm The 15-ppm EEL proposed for exposures up to 10 min was based on the human data described above. It assumes that minor, nonincapacitating eye irritation (a most useful early warning of F2 exposure) may occur and will not result in degradation in performance during an emergency exposure. The previously cited data support such a conclusion, and no recent data are available to suggest changes in the 10-min EEL. EELs for 30 and 60 min cannot be derived by consideration of the human exposure data, because exposures did not exceed 15 min. Animal toxicity data are available for 30- and 60-min exposures and can be used to establish such EELs. The 10-min EEL of 15 ppm (Ct=150 ppm-min) is approximately 30% of the Ct of the most sensitive test animal and reflects a no-observed-effect exposure (500 ppm-min, calculated by interpolation of the 5-min and 15-min data). The Ct values for 30- and 60-min exposures of the most sensitive test animal are 960 and 1,500 ppm-min, respectively. If the same safety factor as that based on the 10-min exposure data (0.3) is applied, then acceptable Ct values for humans for 30- and 60-min exposures are 290 and 450 ppm-min, respectively. Thus, for a 30-min exposure, an EEL of (290 ppm-min)/(30 min)=9.7 ppm, or 10 ppm, is appropriate. Similarly, for a 60-min exposure, an EEL of (450 ppm-min)/(60 min)=7.5 ppm is acceptable. Thus, recommended EELs for F2 are as follows: 10-min EEL: 15 ppm 30-min EEL: 10 ppm 60-min EEL: 7.5 ppm

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Volume 1 TABLE 19 Irritation Caused by Fluorine in Volunteer Human Subjectsa Concentration, ppm Time, min Effects 10 3 No irritation of eyes and nose 10 5 No irritation of eyes and nose; not uncomfortable 10 15 No irritation of eyes and nose, inhaled without irritation of respiratory tract 23 5 Slight irritation to eyes; could inhale without respiratory difficulty (inhaled intermittently over the 5-min period) 50 3 Irritation of the eyes; slight irritation of the nose 67 1 Irritation of eyes and nose; although exposure was quite irritating, concentration not unbearable 78 1 Irritation of the eyes and nose; (less irritating to eyes than cigarette smoke); face slightly irritated after exposure; inhalation caused coughing 100 1 Very irritating to eyes and nose; eyes burned after exposure; felt like “film” over the eyes after exposure; skin felt sticky and slightly irritated after exposure; subjects did not inhale 100 0.5 Very irritating to eyes and nose; no after-effect aKeplinger and Suissa, 1968.

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Volume 1 TABLE 20 Sublethal Effects of Fluorine in Animals Exposed for 5 Minutesa Species (Strain)b Concentration, ppmc Toxic Signs Gross Lung Pathology Rat (Osborne Mendel) 500 Marked irritation of eyes and respiratory tract; dyspnea Severe diffuse congestion 350 Irritation; dyspnea Moderate diffuse congestion 175 Eye irritation; slight dyspnea Mild diffuse congestion 88 None No change 44 None No change Mouse (Swiss Webster) 467 Marked irritation of eyes and respiratory tract; dyspnea Severe diffuse congestion 300 Irritation; dyspnea Moderate diffuse congestion 174 Slight dyspnea; irritation Very mild diffuse congestion 79 None No change 38 None No change Rabbit (New Zealand) 410 Irritation; dyspnea Moderate diffuse congestion 134 Slight dyspnea No change 51 None No change 26 None No change aKeplinger and Suissa, 1968. bThe text of the report is unclear in the matter of the sex and number of animals used. LC50 determinations were made with 10 animals per group. It appears that 5 animals per group were used for the sublethal studies, but this is not certain. cPurity of F2 not specified, but contamination highly unlikely. Each concentration determined by measurement of samples from exposure chamber. Lowest four concentrations used for each species are approximately 50%, 25%, 12.5% and 6% of LC50 values, except for unexplained deviation in studies in rabbits.

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Volume 1 TABLE 21 Sublethal Effects of Fluorine in Animals Exposed for 15 Minutesa Species (Strain)b Concentration, ppmc Toxic Signs Gross Lung Pathology Rats (Osborne Mendel) 195 Irritation; dyspnea Moderate diffuse congestion 98 None Very mild diffuse congestion 49 None No change Mouse (Swiss Webster) 188 Irritation; dyspnea Moderate diffuse congestion 87 None Very mild diffuse congestion 65 None No change Guinea pig (New England) 198 Irritation; dyspnea Mild diffuse congestion 100 None Very mild diffuse congestion 70 None No change Dog (unspecified) 93 Eye irritation Slight congestion 39 None No change aKeplinger and Suissa, 1968. bThe text of the report is unclear in the matter of the sex and number of animals used. LC50 determinations were made with 10 animals per group. It appears that 5 animals per group were used for the sublethal studies, but this is not certain. cPurity of F2 not specified, but contamination highly unlikely. Each concentration determined by measurement of samples from exposure chamber. Concentrations used for the rat were approximately 50%, 25%, and 12.5%, of LC50 values; concentrations corresponding to 12.5% of the LC50 were used in mice and guinea pigs. It is unclear how concentrations were selected for the dog.

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Volume 1 TABLE 22 Sublethal Effects of Fluorine in Animals Exposed for 30 Minutesa Species (Strain)b Concentration, ppmc Toxic Signs Gross Lung Pathology Rat (Osborne Mendel) 140 Irritation of eyes and nose; slight dyspnea Moderate diffuse congestion 70 None Very mild diffuse congestion 35 None No change 18 None No change Mouse (Swiss-Webster) 113 Irritation and dyspnea Mild diffuse congestion 67 None Very mild diffuse congestion 32 None No change 16 None No change Rabbit (New Zealand) 135 Irritation Mild diffuse congestion 71 None Very mild diffuse congestion 32 None No change 19 None No change aKeplinger and Suissa, 1968. bThe text of the report is unclear in the matter of the sex and number of animals used. LC50 determinations were made with 10 animals per group. It appears that 5 animals per group were used for the sublethal studies, but this is not certain. cPurity of F2 not specified, but contamination highly unlikely. Each concentration determined by measurement of samples from exposure chamber. Concentrations used for each species were approximately 50%, 25%, 12.5%, 6% of LC50 values.

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Volume 1 TABLE 23 Sublethal Effects of Fluorine in Animals Exposed for 60 Minutesa Species (Strain)b Concentration, ppmc Toxic Signs Gross Lung Pathology Rats (Osborne Mendel) 93 Irritation and dyspnea Mild diffuse congestion 47 None Very mild diffuse congestion 28 None No change 14 None No change Mouse (Swiss Webster) 150 Irritation, dyspnea Severe diffuse congestion 75 Dyspnea Mild diffuse congestion 50 None Very mild diffuse congestion 30 None No change Guinea pig (New England) 135 Irritation; dyspnea Mild diffuse congestion 75 None No change Dog (Unspecified) 93 Irritation; cough; slight dyspnea; vomiting Small areas of hemorrhage 68 Eye irritation No change 38 None No change 15 None No change aKeplinger and Suissa, 1968. bThe text of the report is unclear in the matter of the sex and number of animals used. LC50 determinations were made with 10 animals per group. It appears that 5 animals per group were used for the sublethal studies, but this is not certain. cPurity of F2 not specified, but contamination highly unlikely. Each concentration determined by measurement of samples from exposure chamber. Concentrations used for the rat were approximately 50%, 25%, 12.5%, and 6% of the LC50 values; 100%, 50%, 30%, and 20% of the LC50 value was used in mice; and 50% and 25% of the LC50 value was used in guinea pigs. It is unclear how concentrations were selected for the dog. Concentrations equal to 6% of LC50 were not used in of mice and guinea pigs.

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Volume 1 TABLE 24 Pathology in Mice and Rats after Single and Repeated Exposures to Fluorinea       Repeated exposuresb Single exposureb Species (Strain)c Time, min Conc., ppmd Lung Kidney Liver Lung Kidney Liver Mouse/Swiss-Webster 5 130 1 N N 1 P N 5 321 1 P N 3 P P 30 64 1 N N 1 P N 30 55 1 N N 1 P N Rat (Osborne Mendel) 5 150 1 N N 1 P N 5 325 1–2 N N 3 P P 30 68 1 N N 1 P N 60 75 1–2 N N 1 P N 60 140 2–3 N N 4 P P Rabbits (New Zealand) 15 56–73 N N N N N N 30 49–55 N N N N N N aKeplinger, 1969. bFour exposures at weekly intervals. N=normal or no change; P=some pathology; 1,2,3,4=degree of gross lung pathologic change (1 mildest and 4 most severe). cSex unspecified; 10 mice or rats per group; number of rabbits per group unspecified. dConcentration determined by measurement.

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Volume 1 REFERENCES American Conference of Governmental Industrial Hygienists. 1980. Documentation of the Threshold Limit Values. 4th ed. Cincinnati, Ohio: American Conference of Governmental Industrial Hygienists. p. 197. Belles, F., ed. 1965. Fluorine Handbook. Cleveland, TN: National Aeronautics and Space Administration, Lewis Research Center. [Quoted by Ricca, P.M. 1970. A survey of the acute toxicity of elemental fluorine. Am. Ind. Hyg. Assoc. J. 31:22–29] Cavagna, G., Locati, G., and Ambrosi, L. 1969. Experimental studies in newborn rats and mice on the supposed capillary-damaging effects of fluorine and fluorine-containing industrial pollutants. Med. Lav. 60:267–273. [See also Cavagna, G., and Bobbio, G. 1970. Chemical-physical characteristics and biological effects of effluent from and aluminum factory. Med. Lavoro 61:69–101. Chem. Abs. 73:90976g, 1970] Keplinger, M.L. 1969. Effects from repeated short-term inhalation of fluorine. Toxicol. Appl. Pharmacol. 14:192–200. Keplinger, M.L., and Suissa, L.W. 1968. Toxicity of fluorine short-term inhalation. Am. Ind. Hyg. Assoc. J. 29:10–18. Lyon, J.S. 1962. Observations on personnel working with fluorine at a gaseous diffusion plant. J. Occup. Med. 4:199–201. National Research Council, Committee on Toxicology. 1968. Recommendations for Emergency Exposure Limits to Fluorine (F2). Washington, D.C.: National Academy of Sciences. [1 p.] O’Donnell, T.A. 1973. Fluorine. Pp. 1009–1106 in J.C.Bailar, Jr., H.J.Emeleus, and R.Nyholm, eds. and A.F.Trotman-Dickenson, Exec. Ed. Comprehensive Inorganic Chemistry. Vol. 2. Oxford: Pergamon Press Ltd. Ricca, P.M. 1970. A survey of the acute toxicity of elemental fluorine. Am. Ind. Hyg. Assoc. J. 31:22–29. Rickey, R.P. 1959. Decontamination of Large Liquid Fluorine Spills. U.S. Air Force Flight Training Command, TR-59–21. [Quoted by Ricca, P.M. 1970. A survey of the acute toxicity of elemental fluorine. Am. Ind. Hyg. Assoc. J. 31:22–29.] Slabbey, V.A., and Fletcher, E.A. 1958. Rate of Reaction of Gaseous Fluorine with Water Vapor at 35°C. Cleveland, TN: National Advisory Committee on Aeronautics, Lewis Research Center, [Quoted by Ricca, P.M. 1970. A survey of the acute toxicity of elemental fluorine. Am. Ind. Hyg. Assoc. J. 31:22–29.

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Volume 1 Windholz, M., Budavari, S., Stroumtsos, L.Y., and Fertig, M.N. 1976. The Merck Index: An Encyclopedia of Chemicals and Drugs. 9th ed. Rahway, N.J: Merck Co. p. 4043.