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Suggested Citation:"5 Fluorine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

5
Fluorine1
Acute Exposure Guideline Levels

PREFACE

Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances (NAC/AEGL Committee) has been established to identify, review and interpret relevant toxicologic and other scientific data and develop AEGLs for high priority, acutely toxic chemicals.

AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 mins (min) to 8 hours (h). Three levels—AEGL-1, AEGL-2 and AEGL-3—are developed for each of five exposure periods (10 and 30 min, 1 h, 4 h, and 8 h) and are distinguished by varying degrees of severity of toxic effects. The three AEGLs are defined as follows:


AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic, non-sensory

1

This document was prepared by the AEGL Development Team composed of Sylvia Talmage (Oak Ridge National Laboratory) and Chemical Manager Ernest V. Falke (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Subcommittee on Acute Exposure Guideline Levels. The NRC subcommittee concludes that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993; NRC 2001).

Suggested Citation:"5 Fluorine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure.

AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including susceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects or an impaired ability to escape.

AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including susceptible individuals, could experience life-threatening health effects or death.


Airborne concentrations below the AEGL-1 represent exposure levels that could produce mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic, non-sensory effects. With increasing airborne concentrations above each AEGL, there is a progressive increase in the likelihood of occurrence and the severity of effects described for each corresponding AEGL. Although the AEGL values represent threshold levels for the general public, including susceptible subpopulations, such as infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to idiosyncratic responses, could experience the effects described at concentrations below the corresponding AEGL.

SUMMARY

Fluorine is a reactive, highly irritating and corrosive gas used in the nuclear energy industry, as an oxidizer of liquid rocket fuels, and in the manufacture of various fluorides and fluorocarbons. Fluorine is a severe irritant to the eyes, mucous membranes, lungs, and skin; the eyes and the respiratory tract are the target organ and tissues of an acute inhalation exposure. Death is due to pulmonary edema. Data on irritant effects in humans and lethal and sublethal effects in five species of mammals (dog, rat, mouse, guinea pig, and rabbit) were available for development of AEGL values.

Regression analyses of the concentration-exposure durations (for the fixed end point of mortality) for all of the animal species reported in the key study (Keplinger and Suissa 1968) determined that the relationship between concentration and time is Cn × t = k, where n = approximately 2 (actual value of n for the most sensitive species in irritation and lethality studies, the mouse, is 1.77). This concentration exposure duration relationship was applied to both the AEGL-2 and AEGL-3 levels because the irritant and corrosive action of fluorine on the respiratory tissues differs by only a matter of degree for these AEGL levels: (1) respiratory irritation with edema resulting in mild, reversible lung congestion, and (2) severe respiratory irritation resulting in severe lung congestion. Death results from acute pulmonary edema and consequent respiratory failure. Although the data base for fluorine is small, the data from the key study, aug-

Suggested Citation:"5 Fluorine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

mented with data from several other studies, were considered adequate for derivation of the three AEGL classifications for five time periods.

The AEGL-1 was based on the observation that adult volunteers could tolerate exposure to 10 ppm for 15 min without irritant effects (Keplinger and Suissa 1968). Although this value is below the definition of an AEGL-1 (slight irritation), it provides the longest controlled exposure duration for which no irritation in humans was reported. An intraspecies uncertainty factor of 3 was applied because fluorine is highly corrosive to the tissues of the respiratory tract and effects are not expected to vary greatly among individuals, including susceptible individuals (NRC 2001). Although no data on asthmatics were found, the uncertainty factor of 3 was considered adequate to protect this sensitive subpopulation because the value was a NOAEL and because shorter-term, repeated exposures produced no substantially greater effects in healthy individuals. The value is supported by a second study in which volunteers “tolerated” exposure to 10 ppm for an undefined period of time (Belles 1965). A modifying factor of 2 was applied based on a limited data base and short exposure durations. The resulting value of 1.7 ppm was used across all AEGL-1 exposure durations because, at mildly irritating concentrations, adaptation to slight sensory irritation occurs. As noted, this value is supported by limited workplace monitoring data: workers exposed to fluorine at average yearly concentrations up to 1.2 ppm (range, 0.0-17 ppm) over a four-year period reported fewer incidences of respiratory complaints or diseases than a similar group of nonexposed workers (Lyon 1962). The workers are assumed to encompass a small range of sensitivity; the additional intraspecies uncertainty factor of 3 was considered sufficient to protect sensitive individuals.

Mild lung congestion was selected as the threshold for irreversible, long-lasting effects as defined by the AEGL-2. The AEGL-2 was based on an animal study in which mild lung congestion was observed in mice at 67 ppm for 30 min and 30 ppm for 60 min (Keplinger and Suissa 1968). Effects were slightly less serious in three other species. Although concentrations causing irritant effects or lethality in three other species for the same time periods suggested similar species sensitivity, the mouse data, because of slightly lower values, were chosen as the basis for developing the AEGL-2 and AEGL-3. Similar sensitivity was observed among all species in the key study; therefore, an interspecies uncertainty factor of 1 was applied to address interspecies variability. Fluorine is a highly corrosive gas that reacts directly with the tissues of the respiratory tract, with no pharmacokinetic component involved in the toxicity; therefore, there is likely to be little difference among individuals in response to fluorine at concentrations that define the AEGL-2. The 30- and 60-min values for the mouse were divided by an intraspecies uncertainty factor of 3 to protect sensitive individuals, since effects are not likely to differ greatly among individuals, and by a modifying factor of 2, based on a limited data base. The 30-min value was time scaled to the 10-min AEGL-2, and the 60-min value was time scaled to the 4-h AEGL-2 value. Time scaling was based on the C1.77 × t = k relationship. The value of n was derived from regression analysis of the mouse lethality data in the key

Suggested Citation:"5 Fluorine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

study. The 8-h-AEGL-2 value was set equal to the 4-h value because at low concentrations the hygroscopic fluorine would react with and/or be scrubbed by the nasal passages, and because at mildly irritating concentrations, adaptation to sensory irritation occurs. The 10- and 30-min AEGL-2 values are supported by studies in which human volunteers found short-term exposures to 15-25 ppm irritating to the eyes, nose, and throat (Rickey 1959; Keplinger and Suissa 1968).

The AEGL-3 values were derived from the highest exposures that resulted in no deaths in five species over 4 exposure durations (13 tests) for up to 45 days post exposure, but did produce severe lung congestion in the mouse (Keplinger and Suissa 1968). Severe lung congestion in the sensitive mouse was considered the threshold for lethality as defined by the AEGL-3. For the mouse, the 60-min highest non-lethal value was 75 ppm. This value is one-half of the 60-min LC50 value for the mouse. Because of the similar species sensitivity in the key study, based on both irritant effects and lethality, an interspecies uncertainty factor of 1 was considered sufficient to account for interspecies variability. The values were divided by an uncertainty factor of 3 to protect sensitive individuals (fluorine is a highly reactive, corrosive gas whose effect on respiratory tract tissues is not expected to differ greatly among individuals) and by a modifying factor of 2, based on a limited data base. Using the 60-min value of 75 ppm, AEGL-3 values for the other exposure times were calculated based on the C1.77 × t = k relationship. The value of n was derived from regression analysis of the mouse lethality data in the key study. The 8-h value was set equal to the 4-h value because fluorine would react with or be scrubbed by the nasal passages at these fairly low time-scaled concentrations. The safety of setting the 8-h value equal to the 4-h value is supported by another study in which a 7-h experimental exposure concentration of 100 ppm that resulted in an overall 60% mortality for four species (Eriksen 1945; Stokinger 1949) is higher than the extrapolated 7-h LC50 values for the mouse (50 ppm) and rat (65 ppm) based on the Keplinger and Suissa (1968) study. The calculated values are listed in Table 5-1.

1.
INTRODUCTION

Fluorine belongs to the halogen group of elements; these elements do not occur in the elemental state in nature. When formed experimentally, fluorine is a pale yellow, diatomic gas (F2) with a choking, irritating odor. Fluorine is used in the nuclear energy industry to produce gaseous uranium hexafluoride, as an oxidizer of liquid rocket fuels, and in the manufacture of various fluorides and fluorocarbons (Teitelbaum 2001).

Chemically, fluorine is the most electronegative of the halogens and is the most powerful oxidizing agent known (Teitelbaum 2001). It reacts vigorously with most oxidizable substances at room temperature, frequently with ignition. It also combines with most other elements to form fluorides. Reaction with water results in decomposition of the water and formation of hydrofluoric acid, oxygen

Suggested Citation:"5 Fluorine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

(di)fluoride, hydrogen peroxide, oxygen, and ozone (O’Neil et al. 2001). Other relevant chemical and physical properties are listed in Table 5-2.

Fluorine is produced in an enclosed system of fluorine-generating cells. Anhydrous hydrogen fluoride, the basic starting material is mixed with potassium fluoride-hydrogen fluoride to form potassium bifluoride (KHF2) which contains various concentrations of free hydrogen fluoride. Fluorine is produced by the electrolysis of anhydrous potassium bifluoride. Commercial fluorine plants operate in the United States, Canada, France, Germany, Italy, Japan, the United Kingdom, and South Africa. In 2003, the total commercial production capacity of fluorine in these countries was estimated at approximately 20,000 tons/year. Production data were unavailable for Russia and China. At most sites, elemental fluorine is used captively for the production of inorganic fluorides. The primary use of elemental fluorine is in the manufacture of uranium hexafluoride (Shia 2003).

In the U.S., fluorine is packaged and shipped under pressure (415 psi) in steel cylinders conforming to Department of Transportation specifications. The size of cylinders containing pure fluorine is limited to 2.7 kg; cylinders containing mixtures of 10-20% fluorine in nitrogen can contain up to 500 kg fluorine (Shia 2003).

2.
HUMAN TOXICITY DATA

2.1.
Acute Lethality

No reports of lethal effects from acute inhalation exposure to fluorine were identified. At low concentrations, fluorine is extremely irritating to the nose and eyes.

TABLE 5-1 Summary of AEGL Values for Fluorine

Classification

10-min

30-min

1-h

4-h

8-h

End Point (Reference)

AEGL-1a,b (Nondisabling)

1.7 ppm (2.6 mg/m3)

1.7 ppm (2.6 mg/m3)

1.7 ppm (2.6 mg/m3)

1.7 ppm (2.6 mg/m3)

1.7 ppm (2.6 mg/m3)

No irritant effects -humans (Keplinger and Suissa 1968)

AEGL-2c (Disabling)

20 ppm (31 mg/m3)

11 ppm (17 mg/m3)

5.0 ppm (7.8 mg/m3)

2.3 ppm (3.6 mg/m3)

2.3 ppm (3.6 mg/m3)

Mild lung congestion -mice (Keplinger and Suissa 1968)

AEGL-3 (Lethal)

36 ppm (56 mg/m3)

19 ppm (29 mg/m3)

13 ppm (20 mg/m3)

5.7 ppm (8.8 mg/m3)

5.7 ppm (8.8 mg/m3)

Severe lung congestion - mice (Keplinger and Suissa 1968)

aThe characteristic, pungent odor of fluorine will be noticeable at this concentration.

bThe same value was used across all time periods because, at mildly irritating concentrations, adaptation to sensory irritation occurs.

c30-min and 1-h values are based on separate data points.

Suggested Citation:"5 Fluorine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

TABLE 5-2 Chemical and Physical Data for Fluorine

Parameter

Data

Reference

Chemical Name

Fluorine

ATSDR 2003

Synonyms

Bifluoriden, fluor, fluorine-19, fluoro

HSDB 2005

CAS Registry No.

7782-41-4

HSDB 2005

Chemical formula

F2

O’Neil et al. 2001

Molecular weight

37.99

O’Neil et al. 2001

Physical state

Pale, yellowish green gas

O’Neil et al. 2001

Melting/boiling point

−219.61°C /−188.13°C

O’Neil et al. 2001

Density

1.695 g/cm3 (air = 1.29)

Lewis 1993

Solubility

No data; reacts with water

O’Neil et al. 2001

Vapor pressure

1 mm Hg at −223°C

>10 atm at 20°C

HSDB 2005

Teitelbaum 2001

Flammability

Nonflammable; powerful oxidizing agent

AAR 1987

Conversion factors

1 ppm = 0.64 mg/m3

1 mg/m3 = 1.554 ppm

ATSDR 2003

2.2.
Nonlethal Toxicity

No human studies documenting specific fluorine exposure levels and time of exposure were found for acute, irreversible effects. Limited data are available on reversible, non-disabling effects of fluorine gas to humans. In many of the studies, details of the exposures, particularly the exposure times, were not given. Fluorine has a characteristic, pungent odor (O’Neil et al. 2001). The odor threshold for fluorine is 0.10-0.20 ppm (Rickey 1959; Amoore and Hautala 1983). Available human data are summarized in Table 5-3 and discussed below.

Rickey (1959) reported on an outdoor spill test conducted by the U.S. Air Force. Two volunteers walked into the dispersed cloud downwind of a test spill. The measured concentration was 25 ppm which the men were able to tolerate; a specific exposure time was not stated. Following the exposure, both men developed sore throats and chest pains that lasted 6 h. The author stated that 20-50 ppm cannot be tolerated by humans but did not give additional data to support the statement.

Suggested Citation:"5 Fluorine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

TABLE 5-3 Summary of Irritant Effects in Humans

Concentration (ppm)

Exposure Time

Effects

Reference

10

Not stated

“Tolerated”

Belles 1965

10

15 min

No irritation of eyes, nose, or respiratory tract

Keplinger and Suissa 1968

10

3-5 min every 15 min for 2-3 h

slight irritation to the eyes and skin; no respiratory difficulty

Keplinger and Suissa 1968

15-25

Three breaths

Eye and nasal irritation

Belles 1965

25

Not stated

Tolerated; sore throats and chest pains of 6 h duration

Rickey 1959

25

5 min

Slight irritation to eyes, inhaled intermittently without difficulty

Keplinger and Suissa 1968

50

3 min

Irritating to eyes and slightly irritating to nose

Keplinger and Suissa 1968

67

1 min

Irritating to eyes and nose but not unbearable

Keplinger and Suissa 1968

78

1 min

Irritating to eyes and nose; caused coughing when inhaled

Keplinger and Suissa 1968

100

0.5 min

Very irritating to eyes and nose; no “after effects”

Keplinger and Suissa 1968

100

1 min

Very irritating to eyes and nose (subjects did not inhale); slightly irritating to the skin

Keplinger and Suissa 1968

100-200

Not stated

Reaction with skin and body hair

Belles 1965

Suggested Citation:"5 Fluorine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

Belles (1965) reported a series of tests involving nine male volunteers. All tolerated repeated short-term exposure to 10 ppm without “intolerable” discomfort. Concentrations of 15 to 25 ppm caused some eye and nasal irritation to the majority of subjects after just three breaths. Skin exposure tests indicated that reaction with body hair and dermal irritation may be expected between 100 and 200 ppm.

Keplinger and Suissa (1968) exposed five adult volunteers (19-50 years of age) to concentrations up to 100 ppm via a face mask. These tests were designed to test for irritation only. A concentration of 10 ppm for up to 15 min was reported to be nonirritating to the eyes and nose. A concentration of 25 ppm for 5 min caused slight irritation to the eyes but could be inhaled without respiratory difficulty. A concentration of 50 ppm for 3 min was irritating to the eyes and slightly irritating to the nose. Concentrations of 67 to 100 ppm for 1 min were irritating to the eyes and nose and became uncomfortable after a few seconds. The subjects reported the 67 ppm concentration as being less irritating than cigarette smoke in the eye. The subjects did not inhale at the 100 ppm concentration; inhalation exposure to 78 ppm caused coughing. The 100 ppm concentration caused slight irritation of the skin and a “sticky” feeling. According to the authors, the eyes were the most sensitive indicator of irritation in humans. Keplinger and Suissa (1968) also reported that a few repeated exposures at a concentration of 10 ppm for 3 to 5 min every 15 min over a 2- to 3-h time period caused only slight irritation to the eyes and skin. No respiratory difficulty was reported.

Lyon (1962) reported a lack of significant medical findings in 61 workers exposed to fluorine concentrations in excess of 0.1 ppm. Over a nine-year period, yearly average air concentrations ranged from 0.3 to 1.4 ppm (range <0.1 to 24.7 ppm). Workers were exposed either for 50-60% of their work time for periods of 7-9 months or 10% of their work time at the highest concentrations. Average daily urine fluorine excretion was 1.1 mg/L. Medical records of workers exposed to average yearly concentrations up to 1.2 ppm (range, 0.0-17 ppm) were evaluated for the last four years of exposure. These workers reported fewer incidences of respiratory complaints or diseases than a similar group of 2000-3000 nonexposed workers. Usefulness of the study is limited by the lack of fluorine determination in urine of unexposed workers and the inability of the measurement technique to differentiate between fluorine and hydrogen fluoride. However, the author noted that samples were taken only when the characteristic odor of fluorine was present and the characteristic odor of hydrogen fluoride was absent. In contrast, Machle and Evans (1940) reviewed several monitoring studies in which undefined exposures to fluorine in industry resulted in increased asthmatic attack frequency over that in the non-exposed population.

There is potential for individuals to become sensitized to halogens following acute exposure. A review of studies on drinking water fluoridation and a study with rabbits treated with sodium fluoride did not indicate that immune reactions occurred (ATSDR 2003).

Suggested Citation:"5 Fluorine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
2.3.
Developmental/Reproductive Toxicity

No studies were located regarding reproductive or developmental effects in humans after inhalation exposure to fluorine. Fluoride is rapidly absorbed following oral ingestion, crosses the placenta in limited amounts, and is found in placental and fetal tissue (ATSDR 2003). Studies on the incidence of reproductive or developmental effects in areas using fluoridated water have found no correlation between fluoridation levels and birth defects (ATSDR 2003).

2.4.
Genotoxicity

No data concerning the genotoxicity of fluorine in humans were identified in the available literature.

2.5.
Carcinogenicity

Although several studies indicated an increase in respiratory cancers among workers engaged in several industries where they could be exposed to hydrogen fluoride or fluoride dusts, the concomitant exposure to other chemicals and smoking status of the workers, along with the lack of clear exposure concentration make the studies of questionable relevance (ATSDR 2003). There is no carcinogenicity data for fluoride gas.

2.6.
Summary

No human data involving acute lethal exposures were located. Limited data are available on reversible, non-disabling effects of fluorine gas to humans. In many of the studies, details of the exposures, particularly the duration of exposure, were not given. In a fairly well reported study with human volunteers, 10 ppm for 15 min caused no irritation of the eyes, nose, or respiratory tract and 10 ppm for 3 to 5 min every 15 min for 2 to 3 h caused slight irritation to the eyes and skin but no respiratory difficulty.

3.
ANIMAL TOXICITY DATA

3.1.
Acute Lethality

Data on acute lethal concentrations of fluorine for exposure durations of 5 min to 7 h are available for the rat, mouse, guinea pig, and rabbit. A study with the dog involved repeated exposure. Data on single acute exposures are summarized in Table 5-4.

Suggested Citation:"5 Fluorine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

TABLE 5-4 Summary of Acute Lethal Inhalation Data in Laboratory Animals

Species

Concentration (ppm)

Exposure Time

Effecta

Reference

Rat

10,000

5 min

100% mortality

Eriksen 1945; Stokinger 1949

1000

30 min

100% mortality

500

1 h

100% mortality

200

3 h

100% mortality

100

7 h

54% mortality

Rat

700

5 min

LC50

Keplinger and Suissa 1968

390

15 min

LC50

270

30 min

LC50

185

1 h

LC50

Mouse

10,000

5 min

100% mortality

Eriksen 1945; Stokinger 1949

1000

30 min

100% mortality

500

1 h

100% mortality

200

3 h

100% mortality

100

7 h

96% mortality

Mouse

600

5 min

LC50

Keplinger and Suissa 1968

375

15 min

LC50

225

30 min

LC50

150

1 h

LC50

Guinea pig

10,000

5 min

100% mortality

Eriksen 1945; Stokinger 1949

1000

30 min

100% mortality

500

1 h

100% mortality

200

3 h

90% mortality

100

7 h

no mortality

Guinea pig

395

15 min

LC50

Keplinger and Suissa 1968

170

1 h

LC50

Rabbit

10,000

5 min

100% mortality

Eriksen 1945; Stokinger 1949

1000

30 min

100% mortality

500

1 h

100% mortality

200

3 h

100% mortality

100

7 h

88% mortality

Rabbit

820

5 min

LC50

Keplinger and Suissa 1968

270

30 min

LC50

aLC50 and 100% mortality values were obtained at 14 days post exposure.

3.1.1.
Dogs

No studies on single exposures were located. In short-term, repeated exposures, groups of five dogs (sex and strain unspecified) were administered fluorine at concentrations of 0.5, 2, 5, and 16 ppm for up to 35 days (Stokinger 1949). The exposure regime (not stated) was apparently 5-6 h/day, 5 days/week for a total exposure of 170 h. Concentrations were estimated by metering; no analyses were made. At the two higher concentrations, dogs exhibited seizures followed by death. At the 16 ppm exposure, mortality was 100% by the 60th h of exposure. No toxic symptoms and no deaths were observed at the two lower

Suggested Citation:"5 Fluorine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

concentrations. Histological changes included moderate to moderately severe hemorrhage and liver congestion in 4 of 4 animals at 16 ppm, red discoloration of the lungs, mild bronchitis, and bronchiectasis in 4 of 5 dogs at 5 ppm, pulmonary hemorrhage and edema in 2 of 5 dogs at 2 ppm, and no consistent significant damage at 0.5 ppm.

3.1.2.
Rats

Eriksen (1945) and Stokinger (1949) reported the same study in which a fluorine concentration of 10,000 ppm for an exposure time of 5 min was fatal to rats (sex and strain unspecified) within 24 h, with the majority of deaths occurring by the end of the exposure period. Thirty minutes of exposure to 1000 ppm caused 87% mortality and mortality reached 100% by 14 days post exposure. A concentration of 500 ppm for 1 h caused 90% mortality by the end of the exposure period. Percent mortality increased at 24 h post exposure, and at 14 days, all animals were dead. By 4 days post exposure, mortality was 100% for rats exposed to 200 ppm for 3 h. At 14 days after exposure to 100 ppm for 7 h, 54% of the animals were dead.

Autopsy results indicated that fluorine gas was severely corrosive to the respiratory tract as shown by bronchial and alveolar necrosis. Death was attributed to respiratory failure resulting from acute pulmonary damage involving edema, emphysema, and hemorrhage. Gross observations of animals surviving the 100 and 200 ppm concentrations and sacrificed 14 days post exposure revealed that lung damage was either slight or had undergone substantial repair. Kidney abnormalities including general engorgement, slight edema, slight swelling of the cortex and inflammation of the medulla were observed (frequency not stated) at 14 days post exposure but not at the end of the exposure period. Technical problems in monitoring fluorine gas levels make the quantitative exposure level data unreliable in this study; however, qualitative results from these experiments are useful.

Keplinger and Suissa (1968) exposed groups of 10 Osborne-Mendel rats (sex unspecified) to measured concentrations of fluorine for periods of 5, 15, 30, or 60 min. The LC50 values were 700, 390, 270, and 185 ppm, respectively. Few signs of intoxication were observed immediately after exposure except for irritation of the eyes and nose. Death occurred approximately 12 to 18 h after exposure. A few deaths were recorded after 24 h. Animals that lived for 48 h post exposure generally survived the 14-day observation period. Animals exposed to high concentrations died of respiratory failure with the lungs showing diffuse congestion and hemorrhage; no damage occurred in other organs. No deaths were reported in rats tested at 50% of the LC50 for each of the time periods.

Repeated daily exposures of rats (sex and strain unspecified) to concentrations of 0.5, 2, 5, and 16 ppm were conducted over a period of 21-35 days (Stokinger 1949). The exposure regime (not stated) was apparently 5-6 h/day, 5 days/week. Rats exposed at the two highest concentrations had symptoms of

Suggested Citation:"5 Fluorine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

coarsening and stiffening of the fur and irritation of the eyes and nose; these symptoms were mild at the two lower concentrations. Mortalities at the end of the exposure period were 0, 8, 27, and 50% at 0.5, 2, 5, and 16 ppm, respectively. A 10% weight loss occurred at the 16 ppm exposure concentration, but weight gains occurred at the lower exposure concentrations. Blood and hematology parameters were unchanged at all concentrations. Severe pulmonary irritation, oral lesions, and testicular degeneration occurred at 16 ppm; no grossly observable lung changes occurred at the two lower concentrations.

3.1.3.
Mice

Eriksen (1945) and Stokinger (1949) exposed mice (sex and strain unspecified) to fluorine concentrations ranging from 100 to 10,000 ppm for 7 h to 5 min, respectively. Concentrations of 10,000 ppm for 5 min, 1000 ppm for 30 min, 500 ppm for 1 h, and 200 ppm for 3 h were 100% fatal by the end of a 14-day post-exposure period. A concentration of 100 ppm for 7 h resulted in 96% mortality. The majority of animals that died did so by the end of the exposure period. Autopsies indicated that fluorine gas was severely corrosive to the respiratory tract as shown by edema, emphysema, and hemorrhage. Death was attributed to respiratory failure resulting from acute pulmonary damage. As noted in Section 3.1.2., technical problems in monitoring fluorine gas levels make the quantitative exposure level data unreliable; however, qualitative results from these experiments are useful.

Keplinger and Suissa (1968) exposed groups of 10 Swiss-Webster mice (sex unspecified) to measured concentrations of fluorine for periods of 5, 15, 30, or 60 min. The LC50 values for the mice for the four respective time intervals were 600, 375, 225, and 150 ppm. Few signs of intoxication were observed immediately after exposure except for irritation of the eyes and nose. Death occurred approximately 12 to 18 h after exposure. A few deaths were recorded after 24 h. Animals that lived for 48 h post exposure generally survived the 14-day observation period. No deaths were reported in mice tested at 50% of the LC50 for each of the time periods. Animals exposed to high concentrations died of respiratory failure with the lungs showing diffuse congestion and hemorrhage; no damage occurred in other organs.

3.1.4.
Guinea Pigs

Eriksen (1945) and Stokinger (1949) exposed guinea pigs (sex and strain unspecified) to fluorine concentrations ranging from 100 to 10,000 ppm for exposure times of 7 h to 5 min, respectively. Concentrations of 10,000 ppm for 5 min, 1000 ppm for 30 min, and 500 ppm for 1 h were 100% fatal by the end of a 14-day post exposure period. A concentration of 200 ppm for 3 h resulted in 90% mortality, and a concentration of 100 ppm for 7 h resulted in no mortality. The majority of animals that died did so by the end of the exposure period. Au-

Suggested Citation:"5 Fluorine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

topsies indicated that fluorine gas was severely corrosive to the respiratory tract as shown by edema, emphysema, and hemorrhage. Death was attributed to respiratory failure resulting from acute pulmonary damage. Sublethal concentrations produced gross changes in the liver and kidneys (not further described). As noted in Section 3.1.2., technical problems in monitoring fluorine gas levels make the quantitative exposure level data unreliable; however, qualitative results from these experiments are useful.

Keplinger and Suissa (1968) exposed groups of five New England guinea pigs (sex unspecified) to measured concentrations of fluorine for periods of 15 or 60 min. LC50 values were 395 ppm at 15 min and 170 ppm at 60 min. Few signs of intoxication were observed immediately after exposure except for irritation of the eyes and nose. Cause of death and organ pathology were the same as discussed for the rat and mouse above.

3.1.5.
Rabbits

Eriksen (1945) and Stokinger (1949) exposed rabbits (sex and strain unspecified) to fluorine concentrations ranging from 100 to 10,000 ppm for 7 h to 5 min, respectively. Concentrations of 10,000 ppm for 5 min, 1000 ppm for 30 min, 500 ppm for 1 h, and 200 ppm for 3 h were 100% fatal by the end of a 14-day post exposure period. A concentration of 100 ppm for 7 h resulted in 88% mortality. The majority of animals that died did so by the end of the exposure period. Autopsies indicated that fluorine gas was severely corrosive to the respiratory tract as shown by edema, emphysema, and hemorrhage. In rabbits, pulmonary hemorrhage was a more important component of lung damage than in other species. Death was attributed to respiratory failure resulting from acute pulmonary damage. “Infectious processes” were present in the lungs of some survivors. As noted in Section 3.1.2., technical problems in monitoring fluorine gas levels make the quantitative exposure level data unreliable; however, qualitative results from these experiments are useful.

Keplinger and Suissa (1968) exposed groups of 5 New England rabbits (sex unspecified) to measured concentrations of fluorine for two time periods. LC50 values for exposures of 5 and 30 min were 820 and 270 ppm, respectively. Clinical signs and organ pathology were the same as for the rat and mouse discussed above.

In short-term, repeated exposures, rabbits (sex and strain unspecified) were administered fluorine at concentrations of 0.5, 2, 5, and 16 ppm for up to 35 days (Stokinger 1949). The exposure regime was not stated, but was presumably 5 h/day for a total exposure of 170 h. At the two higher concentrations, mortality was 100%; at 2 ppm, 2 of 10 rabbits died; and at 0.5 ppm, 1 of 18 rabbits died. Histological changes included liver congestion and moderate to moderately severe lung hemorrhage in 4 of 4 animals at 16 ppm and moderate pulmonary irritation and slight liver damage in 4 of 5 animals at 5 ppm. At 2 ppm

Suggested Citation:"5 Fluorine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

there was mild bronchial inflammation in 3 of 4 animals, and at 0.5 ppm there was little or no pulmonary damage.

3.2.
Nonlethal Toxicity

Studies conducted at concentrations that were less than lethal are summarized in Table 5-5. Data are presented for the dog, rat, mouse, guinea pig, and rabbit. The latter four species were exposed to concentrations approximating 50, 25, and 12.5% of their respective LC50 values for exposure durations of 5, 15, 30, and 60 min.

3.2.1.
Dogs

Dogs (sex and strain unspecified) exposed to 93 ppm for 60 min had symptoms of irritation, cough, slight labored breathing, and vomiting (Keplinger and Suissa 1968). Examinations at 7 to 14 days post exposure revealed small areas of hemorrhage in the lungs. Dogs exhibited only eye irritation at an exposure of 68 ppm for 1 h. No irritation or gross pathologic changes in the lung were evident following exposure to 38 ppm for 1 h. In short-term, repeated exposures, dogs treated with fluorine at a concentration of 0.5 ppm for up to 35 days (presumably 5 h/day) showed no significant lung damage (Stokinger 1949).

3.2.2.
Rats

Sublethal effects of inhalation exposure to fluorine were assessed in Osborne-Mendel rats (sex unspecified) exposed to concentrations of 500 ppm and 350 ppm (71% and 50% of the 5-min LC50 values) for 5 min, 195 ppm (50% of the 15-min LC50) for 15 min, and 140 ppm (50% of the 30-min LC50) for 30 min (Keplinger and Suissa 1968). Very few signs of intoxication were observed immediately after exposure. Rats exposed to these concentrations experienced marked irritation of the eyes and respiratory tract immediately after exposure, and labored breathing and lethargy were observed several hours later. At sacrifice (up to 45 days post exposure), there was moderate to severe diffuse congestion of the lungs.

Sublethal exposures produced kidney and liver damage (Keplinger and Suissa 1968). Kidney damage was characterized by focal areas of coagulation necrosis in the cortex and focal areas of lymphocytic infiltration throughout the cortex and medulla. Liver damage included coagulation necrosis, periportal hemorrhages, and diffuse cloudy swelling. Kidney damage occurred at the same concentrations as lung involvement. Liver involvement occurred only at the highest sublethal concentrations. No-effect concentrations for organ pathology were 79 ppm for 5 min, 65 ppm for 15 min, 51 ppm for 30 min, and 30 ppm for 60 min.

Suggested Citation:"5 Fluorine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

TABLE 5-5 Summary of Sublethal Effects in Laboratory Animals

Species

Concentration (ppm)

Exposure Time

Effecta

Reference

Dog

93

1 h

irritation, cough, slight labored breathing, vomiting, small areas of hemorrhage in lungs

Keplinger and Suissa 1968

93

15 min

slight lung congestion

68

1 h

eye irritation

38

1 h

no effect

Rat

500

5 min

marked signs of intoxication, severe changes in lungs

Keplinger and Suissa 1968; Keplinger 1969

350

5 min

moderate lung congestion

325

5 min

moderate lung congestion

175

5 min

labored breathing; mild lung congestion

150

5 min

very mild lung congestion

88

5 min

no effect

Rat

195

15 min

irritation, labored breathing, moderate diffuse congestion

Keplinger and Suissa 1968

98

15 min

very mild lung congestion

49

15 min

no effect

Rat

140

30 min

irritation of eyes and nose, slight labored breathing, moderate diffuse lung congestion

Keplinger and Suissa 1968; Keplinger 1969

68, 70

30 min

very mild lung congestion

35

30 min

no effect

Rat

140

1 h

severe diffuse lung congestion, kidney and liver changes

Keplinger and Suissa 1968; Keplinger 1969

Rat

93

1 h

eye irritation and labored breathing; mild diffuse lung congestion

Keplinger and Suissa 1968; Keplinger 1969

75

1 h

mild diffuse lung congestion

47

1 h

very mild diffuse lung congestion

28

1 h

no effect

Suggested Citation:"5 Fluorine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

Mouse

467

5 min

marked irritation of eyes and respiratory tract, labored breathing, severe diffuse lung congestion

Keplinger and Suissa 1968; Keplinger 1969

321

5 min

moderate diffuse lung congestion

300

5 min

eye irritation and labored breathing; moderate diffuse lung congestion

174

5 min

slightly labored breathing; very mild diffuse lung congestion

130

5 min

very mild lung congestion

79

5 min

no effect

Mouse

350, 359

15 min

severe diffuse lung congestion to congestion with hemorrhages

Keplinger and Suissa 1968; Keplinger 1969

265, 285

15 min

moderate diffuse lung congestion

188

15 min

eye irritation and labored breathing; moderate diffuse lung congestion

87

15 min

very mild diffuse lung congestion

65

15 min

no effect

Mouse

113

30 min

eye irritation and labored breathing; mild diffuse lung congestion

Keplinger and Suissa 1968; Keplinger 1969

64, 67

30 min

very mild lung congestion

32

30 min

no effect

Mouse

75

1 h

eye irritation and labored breathing, severe diffuse lung congestion

Keplinger and Suissa 1968; Keplinger 1969

55

1 h

very mild lung congestion

50

1 h

labored breathing; mild diffuse lung congestion

30

1 h

very mild diffuse lung congestion

15

1 h

no effect

Guinea pig

198

15 min

eye irritation and labored breathing; mild diffuse lung congestion

Keplinger and Suissa 1968

70

15 min

no effect

Suggested Citation:"5 Fluorine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

Species

Concentration (ppm)

Exposure Time

Effecta

Reference

Guinea pig

135

1 h

eye irritation and labored breathing; mild diffuse lung congestion

Keplinger and Suissa 1968

73

1 h

no effect

Guinea pig

100

7 h

severe damage to the respiratory system

Eriksen 1945; Stokinger 1949

Rabbit

410

5 min

eye irritation and labored breathing; moderate diffuse lung congestion

Keplinger and Suissa 1968

134

5 min

slightly labored breathing

51

5 min

no effect

Rabbit

135

30 min

eye irritation, very mild diffuse congestion

Keplinger and Suissa 1968

71

30 min

no irritation, very mild diffuse congestion

32

30 min

no effect

aMeasured up to 45 days post exposure; serial sacrifice revealed that effects did not become worse with time and, in some cases, lung changes showed some regression starting 7 days post-exposure.

Suggested Citation:"5 Fluorine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

Mild effects of inhalation exposure to fluorine were assessed in rats exposed to concentrations equal to 25% of the LC50 values for exposure times of 5, 15, 30, and 60 min (175, 98, 70, and 47 ppm, respectively) (Keplinger and Suissa 1968). Rats exposed to these concentrations experienced eye irritation, slightly labored breathing and very mild to mild diffuse congestion of the lungs. No-effect levels and exposure times were 88 ppm for 5 min, 49 ppm for 15 min, 35 ppm for 30-min, and 28 ppm for 60 min.

Groups of 10 Osborne-Mendel rats were treated with single and repeated exposures of fluorine (Keplinger 1969). Single exposures occurred for 5 min at concentrations of 85-150 ppm and 256-450 ppm, for 30 min at 46-68 ppm, and for 60 min at 45-75 ppm and 88-170 ppm. The animals were sacrificed immediately after exposure or at 7, 14, 21, or 45 days after the last exposure; however, the day of sacrifice for each test was not reported. Gross pathology results were not well described, and results of each individual test were not reported; those results that were reported are summarized in Table 5-5. Single exposures for 5 min at 85-150 ppm induced very mild lung congestion and some kidney changes, but no liver lesions. At the higher concentrations, 256-450 ppm, moderate diffuse congestion of the lungs and gross damage (primarily discoloration) of the liver and kidneys occurred. Following exposure to 46-68 ppm for 30 min, the livers were grossly normal while the lungs and kidneys showed slight gross pathologic changes. Exposure for 60 min at the lower concentration range resulted in lung and kidney changes but no effect on the liver. At the higher concentration range, severe diffuse congestion and hemorrhages of the lungs were observed. Both the kidneys and livers showed gross changes.

Keplinger (1969) also reported on repeated exposure. Lung, kidney and liver effects in rats exposed four times at daily to weekly intervals to various concentrations were compared with effects following a single treatment at the same concentration. Effects on the lungs (congestion, hemorrhage), kidneys, and liver were greater following the single exposure than following the repeated weekly exposures. For example, four repeated exposures to 30 ppm for 60 min every other day produced lesser effects than a single exposure to 30 ppm for 60 min; sacrifice occurred immediately after the last or single exposure (Keplinger 1969).

3.2.3.
Mice

Sublethal effects of inhalation exposure to fluorine were assessed in Swiss-Webster mice exposed to concentrations equal to 78% of the 5-min LC50 (467 ppm) and 50% of the 5-min, 15-min, 30-min, and 1-h LC50 values (300, 188, 113, and 75 ppm, respectively) (Keplinger and Suissa 1968). A few additional tests were carried out at concentrations between the LC50 and 50% of the LC50 (Keplinger 1969). Very few signs of intoxication were observed immediately after exposure. Mice exposed to 467 ppm for 5 min experienced marked irritation of the eyes and respiratory tract immediately after exposure and la-

Suggested Citation:"5 Fluorine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

bored breathing and lethargy were observed several hours later. At sacrifice there was severe diffuse congestion of the lungs. At concentrations equal to 50% of the 5-min, 15-min, and 60-min LC50 values, mice showed moderate to severe diffuse congestion of the lungs.

In mice exposed to sublethal concentrations (specific concentrations not stated) there was some evidence of gross damage to the lungs, liver, and kidneys (Keplinger and Suissa 1968). Histological examination of the lungs revealed massive hemorrhages into the alveolar spaces and coagulation necrosis of alveoli with peribronchial lymphocytic proliferation. After 7 days there was proliferation of septal cells, macrophages and lymphocytes. Beginning at 7 days post exposure, livers showed coagulation necrosis, periportal hemorrhages and diffuse cloudy swelling. Focal areas of coagulation necrosis appeared in the cortex of the kidney and focal areas of lymphocytic infiltration appeared throughout the cortex and medulla. Concentrations that caused no effects in the lungs did not cause effects in the liver or kidneys. Damage occurred in both the lung and kidney at the same concentration; liver changes occurred at higher concentrations. Although not specifically stated for each species, some or all of these same effects occurred in other species to the same or a lesser degree.

Mild effects were observed in mice at 174 ppm (5 min), 87 ppm (15 min), 67 ppm (30 min), and 50 ppm (60 min) (Keplinger and Suissa 1968). No-effect concentrations for organ pathology were 79 ppm for 5 min, 65 ppm for 15 min, 51 ppm for 30 min, and 30 ppm for 60 min. Four repeated exposures such as 30 ppm for 60 min every other day produced lesser effects than a single exposure of the same magnitude; sacrifice occurred immediately after the last or single exposure (Keplinger 1969).

3.2.4.
Guinea pigs

Disabling, irreversible effects were not observed in New England guinea pigs exposed to concentrations lower than the LC50 values (Keplinger and Suissa 1968). In guinea pigs exposed to 50% of the 15-min LC50 (198 ppm), signs of eye and respiratory irritation and labored breathing and gross lung changes of mild diffuse congestion were present. At exposures to concentrations of 100 and 70 ppm for 5 min, mild effects were occasionally observed. For the 60-min exposures, eye and respiratory irritation and mild diffuse congestion of the lung were observed at 135 ppm (79% of the 60-min LC50) and no effects were observed at 73 ppm (43% of the 60-min LC50).

3.2.5.
Rabbits

Eye and respiratory irritation and moderate diffuse congestion of the lungs were observed in New Zealand rabbits exposed to 410 ppm for 5 min (50% of the 5-min LC50) (Keplinger and Suissa 1968). Effects in rabbits at 16% of the

Suggested Citation:"5 Fluorine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

5-min LC50 (134 ppm) and 50% of the 30-min LC50 (135 ppm) were slight to mild (Keplinger and Suissa 1968). In short-term, repeated exposures, rabbits administered fluorine at a concentration of 0.5 ppm for up to 35 days (presumably 5 h/day) showed little or no lung damage (Stokinger 1949).

3.3.
Developmental and Reproductive Toxicity

No studies addressing developmental or reproductive effects following acute inhalation exposure to fluorine were located.

3.4.
Genotoxicity

No data on inhalation exposures were located in the available literature. Genotoxicity studies were conducted with sodium fluoride or potassium fluoride. Negative results were found for Salmonella typhimurium TA100, TA1535, TA1537, and TA98 with or without metabolic activation, and positive results were found in the mouse lymphoma (with and without activation), sister chromatid exchange (with and without activation), and chromosome aberration tests (without activation) (NTP 1990), but generally at doses that produced cellular toxicity (ATSDR 2003).

3.5.
Chronic Toxicity and Carcinogenicity

No carcinogenicity studies using acute or longer-term inhalation exposure were located. Because inhaled fluorine would exert its systemic effects as fluoride ion, oral studies of fluoride administration may be relevant. A chronic oral carcinogenicity study in which sodium fluoride was administered to male and female rats and mice in the drinking water resulted in equivocal evidence of bone cancer in male rats, but not in female rats or mice of either gender (NTP 1990). The cancer was a rare bone osteosarcoma. Another chronic oral study, with sodium fluoride administered in the feed found no evidence of cancer in male or female rats (Maurer et al. 1990).

3.6.
Summary

LC50 concentrations for the mouse, rat, guinea pig, and rabbit from the study of Keplinger and Suissa (1968) are summarized in Table 5-6 and graphed in Figure 5-1. With the exception of the 5-min LC50 for the rabbit, the LC50 values for all four species at the different exposure times were not statistically significantly different. Additionally, a 7-h LC54 value of 100 ppm for the rat was available (Eriksen 1945; Stokinger 1949).

Suggested Citation:"5 Fluorine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

TABLE 5-6 Summary of LC50 Data in Animals (ppm)

Exposure Time

Rat

Mouse

Guinea Pig

Rabbit

5 min

700

600

820

15 min

390

375

395

30 min

270

225

270

60 min

185

150

170

Abbreviation: A dash (—) indicates no data.

Source: Keplinger and Suissa 1968. Reprinted with permission; copyright 1968, Journal of Industrial Hygiene and Toxicology.

No data on acute inhalation and developmental toxicity were located. Genotoxicity was observed only at concentrations that were toxic to cells (ATSDR 2003). Chronic and carcinogenicity studies with oral. administration of sodium fluoride resulted in equivocal evidence of cancer in one study (NTP 1990) and no evidence of cancer in a second study (Maurer et al. 1990).

The only experimental data available for longer-term exposures was the 7-h exposure of rats, mice, guinea pigs and rabbits to 100 ppm which resulted in an over-all mortality of 60% (Eriksen 1945; Stokinger 1949). At this exposure concentration and duration, the mouse and rabbit were the most sensitive species as indicated by high mortality, the rat was intermediate in sensitivity, and the guinea pig was the least sensitive species with no mortality.

Lowest values for disabling, irreversible effects; nondisabling, reversible effects; and no-effect concentrations for various exposure periods for each species are summarized in Table 5-7. In many cases, the listed concentration is the only tested concentration.

4.
SPECIAL CONSIDERATIONS

4.1.
Metabolism and Disposition

Pharmacokinetic data from acute exposures were not available. Metabolic/kinetic considerations are not relevant regarding the determination of AEGL values as animals die of acute respiratory failure. Fluorine is hygroscopic and will react with the moist mucus membranes of the respiratory passages.

Following inhalation, fluorine may be absorbed by the lungs, particularly following the formation of hydrofluoric acid by reaction with moisture in the lungs. Fluoride from the circulating blood is deposited in the bone where it substitutes for the hydroxyl group of hydroxyapatite, the principal mineral component of bone. Renal excretion of fluoride is rapid; accumulation in the kidney occurs as fluoride is concentrated in the urine for elimination (Teitelbaum 2001).

Suggested Citation:"5 Fluorine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
FIGURE 5-1 LC50 values for four species of animals. The continuous lines represent values for the mouse and rat. Source: Keplinger and Suissa 1968. Reprinted with permission; copyright 1968, Journal of Industrial Hygiene and Toxicology.

FIGURE 5-1 LC50 values for four species of animals. The continuous lines represent values for the mouse and rat. Source: Keplinger and Suissa 1968. Reprinted with permission; copyright 1968, Journal of Industrial Hygiene and Toxicology.

Suggested Citation:"5 Fluorine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

TABLE 5-7 Summary of Nonlethal Effects in Animalsa

Species

Exposure Time

Disabling Effects (ppm)

Nondisabling Effects (ppm)

No Effect (ppm)

Dog

5 min

15 min

93

30 min

60 min

93

68

38

Rat

5 min

325

150

88

15 min

195

98

49

30 min

140

70

35

60 min

140

47

28

Mouse

5 min

300

130

79

15 min

188

87

65

30 min

64, 67

32

60 min

75

30

15

Guinea pig

5 min

15 min

198

70

30 min

60 min

135

73

Rabbit

5 min

410

134

51

15 min

30 min

135

32

60 min

aEffects include both irritation and organ lesions.

A dash (—) indicates no data.

Source: Keplinger and Suissa 1968. Reprinted with permission; copyright 1968, Journal of Industrial Hygiene and Toxicology.

4.2.
Mechanism of Toxicity

Although fluorine reacts with water vapor in the moist respiratory passages, some fluorine persists in saturated water vapor for periods up to 1 h (Slabbey and Fletcher 1958). Therefore, it is likely that some of the inhaled fluorine will persist in the elemental form in the saturated air of the respiratory tract and will be carried into the lungs. The available studies show that damage to the respiratory tract, particularly the lung (edema, emphysema, and hemorrhage), is the major pathology associated with acute exposure to fluorine (Eriksen 1945; Stokinger 1949; Keplinger and Suissa 1968; Keplinger 1969). Fluorine is characterized as a severe irritant to the eyes, mucous membranes, skin, and lungs (NRC 1984; ACGIH 2004). Serious systemic effects are unlikely to occur from an acute exposure. In the studies summarized in Table 5-5, the eye and tissues of the respiratory tract sustain the impact of an acute exposure. Therefore, the concentration of fluorine in the inhaled air and not the absorbed dose is the primary determinant of effects.

Suggested Citation:"5 Fluorine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
4.3.
Structure-Activity Relationships

The combined human and animal data on fluorine are sufficient for derivation of inhalation exposure guidelines and the use of structure-activity comparisons is not necessary. Like hydrogen chloride (HCl) and chlorine (Cl2), fluorine is an irritant to the eyes, skin, and respiratory tract. When compared with mortality data for HCl and chlorine (Cl2), fluorine is more toxic than HCl and slightly more toxic than Cl2 to laboratory rodents. Mortality data indicate that HF is more toxic than HCl but less toxic than F2 to laboratory rodents (Wohlslagel et al. 1976; Teitelbaum 2001; ATSDR 2003; NRC 2004). Kusewitt et al. (1989) exposed Fischer 344 rats to hydrogen halides at concentrations of 100 to 1000 ppm for 30 min. Tissue injury was confined to the nasal region with relative toxicities of HF>HCl≥HBr.

Penetration of any chemical to the lungs depends on water solubility. The more water soluble halides are scrubbed in the upper respiratory passages, and there is less penetration to the bronchioles and lungs. Fluorine decomposes water, forming HF, OF2, hydrogen peroxide, oxygen, and ozone (O’Neil et al. 2001). The same reaction is predicted to occur in the moist respiratory passages. However, some unreacted fluorine will penetrate to the lungs. The water solubility of chlorine is 0.092 mol/L (25°C), and the water solubility of bromine is 0.214 mol/L (20°C). For the end point of lethality, the order of water solubility is also the order of toxicity, i.e., fluorine is poorly scrubbed and therefore more easily penetrates to the lungs, resulting in lower LC50 values than for the other halogens. For example, the 1-h LC50 values for chlorine in the rat range from 293-455 ppm (NRC 2004), whereas, the value for fluorine in the Keplinger and Suissa 1968 study is 185 ppm. Both chlorine and bromine are more readily scrubbed in the upper respiratory tract than is fluorine.

4.4.
Concentration-Exposure Duration Relationship

When data are lacking for desired exposure times, scaling across time may be based on the relationship between acute toxicity (concentration) and exposure duration (ten Berge et al. 1986). The only available data for scaling across time are LC50 data for the rat, mouse, and guinea pig for 5, 15, 30, and 60-min exposure durations. These data show that the association between concentration and exposure duration is a logarithmic one and the equations derived from the empirical data by regression analysis are expressed as Cn × t = k (where C = concentration, t = time in minutes, and k is a constant). For the three species the equations derived from the LC50 data are

Suggested Citation:"5 Fluorine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

Therefore, the relationship between concentration and time in approximately C2 × t = k. Appendix A contains a graph of this relationship for the mouse data.

4.5.
Other Relevant Information
4.5.1.
Susceptible Populations

No data on susceptible populations were located. Fluorine is highly irritating and corrosive to the tissues of the respiratory tract. The direct action of fluorine on the respiratory tract is not expected to vary greatly among most individuals. Although no data on fluorine exposures and asthmatics were located, studies with chlorine indicate that, compared with the general population, the respiratory tract of some asthmatics may be very reactive to the presence of irritant gases (NRC 2004). Machle and Evans (1940) reviewed several monitoring studies in which undefined exposures to fluorine in industry resulted in increased asthmatic attack frequency compared to that in the non-exposed population.

4.5.2.
Species Variability

A comparison of the animal and human data indicates that humans may be more sensitive to the irritant effects of fluorine than animals in that experimental animals suffered no gross effects at concentrations that humans found intolerable. For example, a concentration of 73 ppm for 1 h was a no-effect concentration for the guinea pig, but humans could not inhale 78 ppm for a short time without coughing.

Rats and rabbits exposed to 10,000 ppm of fluorine exhibited similar pulmonary damage; however, pulmonary hemorrhage was extensive in the rabbit whereas it was absent or extremely slight in the rat (Eriksen 1945; Stokinger 1949). At concentrations of 200 ppm and above, mortality rates were similar for rats, mice, rabbits, and guinea pigs for the different time periods. Guinea pigs succumbed more rapidly than the other three species at the three highest exposure levels (10,000, 1000, and 500 ppm), but showed less mortality at the 200 ppm level and no mortality at the 100 ppm level. These data, although slightly conflicting at times, do not indicate great species variability in response to fluorine exposures.

In another study, the 5-, 15-, 30-, and 60-min LC50 values for the rat, mouse, rabbit, and guinea pig were remarkably similar with only slightly lower values for the mouse compared to the other species (Keplinger and Suissa 1968). In all cases, death resulted from acute pulmonary edema and consequent respiratory failure. The similarity in LC50 values for each time period suggests similar species sensitivity.

Suggested Citation:"5 Fluorine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

5.
DATA ANALYSIS FOR AEGL-1

5.1.
Summary of Human Data Relevant to AEGL-1

A number of authors report 10 ppm as a concentration that caused either no discomfort or sensory irritation (Belles 1965; Keplinger and Suissa 1968). A higher level of 25 ppm caused eye irritation during a 5-min exposure (Keplinger and Suissa 1968), sore throat and chest pains that lasted for 6 h (duration of exposure not specified but presumed short) (Rickey 1959), and eye and nasal irritation after three breaths (Belles 1965). Humans were also exposed to 10 ppm for 3 to 5 min every 15 min over a 2- to 3-h period with only slight irritation to the eyes and skin (Keplinger and Suissa 1968).

5.2.
Summary of Animal Data Relevant to AEGL-1

The animal data indicated that at 25% of the LC50, there were mild signs of intoxication characterized by slight labored breathing and closed eyes (Keplinger and Suissa 1968). Below 25% of the LC50 there were no gross signs of lung pathology. Using the data of Keplinger and Suissa (1968) and Keplinger (1969), Ricca (1970) estimated the no-effect concentration with respect to lung, liver, and kidney pathology (based on C × t values) at 15% of the rat LC50 concentration. For the 1-h exposure, this concentration would be 28 ppm.

However, absence of apparent effects and gross signs of intoxication does not ensure that slight irritation or discomfort did not take place. No-effect concentrations are listed in Table 5-7. No-effect concentrations for the rat are 35 ppm for 30 min and 28 ppm for 60 min. For the mouse, the 30- and 60-min no-effect concentrations are 32 ppm and 15 ppm, respectively; the 60-min no-effect concentrations for the dog and guinea pig are 39 and 73 ppm, respectively. For all species, the 30-min no-effect concentrations range from 32 to 35 ppm and the 60-min no-effect concentrations range from 15 to 73 ppm. These values do not necessarily indicate the relative sensitivity of the species but, rather, reflect the experimental concentrations selected by the researchers.

5.3.
Derivation of AEGL-1

Because human data for irritant effects are available, they should be used to derive the AEGL-1. The data of Keplinger and Suissa (1968) are the most comprehensive for humans exposed to 10 ppm. The 10 ppm concentration for 15 min was reported as a no-effect level for eye and nasal irritation but can be considered the threshold for notable discomfort as the next highest concentration tested, 25 ppm, produced slight to moderate discomfort. The 15-min time was the longest exposure duration for which no irritation was reported. An intraspecies uncertainty factor of 3 was applied to this NOAEL value because the con-

Suggested Citation:"5 Fluorine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

tact irritation from the highly corrosive fluorine is not expected to vary greatly among individuals, including susceptible individuals (NRC 2001). Although no data on asthmatics were found, the uncertainty factor of 3 is considered adequate to protect this sensitive subpopulation because the value is a NOAEL and because shorter-term, repeated exposures produced only slight irritation in healthy individuals. The value is supported by a second study in which volunteers “tolerated” exposure to 10 ppm for an undefined period of time (Belles 1965).

The clinical and experimental data base for human and animal exposures is limited to a single study (Keplinger and Suissa 1968). Other than the review of fluorine industrial exposures by Machle and Evans (1940) in which asthma attacks occurred more frequently in the industry than in non-exposed populations, no data on sensitive populations were found. A modifying factor of 2 was applied based on this limited database. The resulting value of 1.7 ppm (10 ppm/6) was used across all AEGL-1 exposure durations (Table 5-8 and Appendix B) because at mildly irritating concentrations there is accommodation to irritating gases. This value is supported by limited workplace monitoring data: workers exposed to fluorine at average yearly concentrations up to 1.2 ppm (range, 0.0-17 ppm) over a four-year period reported fewer incidences of respiratory complaints or diseases than a similar group of nonexposed workers (Lyon 1962). The workers are assumed to encompass a small range of sensitivity; the additional intraspecies uncertainty factor of 3 was considered sufficient to protect sensitive individuals.

A category plot of the animal and human data in relation to the AEGL values can be found in Appendix C.

6.
DATA ANALYSIS FOR AEGL-2

6.1.
Summary of Human Data Relevant to AEGL-2

Irritant effects were noted in human volunteers at concentrations of 25 ppm for 5 min and 50 ppm for 3 min. Irritant effects at these concentrations were described as slight and are below the discomfort described by the AEGL-2 definition. The concentration of 67 ppm for 1 min was described as irritating to the eyes and nose but not unbearable. This description is similar to that of the AEGL-2, but the exposure period is extremely short.

6.2.
Summary of Animal Data Relevant to AEGL-2

In the animal studies, Keplinger and Suissa (1968) characterized the symptoms of exposure equivalent to approximately 25% of the LC50 as mild with slightly labored breathing, closed eyes, and mild to very mild lung congestion. For the respective species, 30-min concentrations corresponding to 20-25%

Suggested Citation:"5 Fluorine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

of the LC50 were 70 ppm (rat), 67 ppm (mouse), and 71 ppm (rabbit). One-hour concentrations corresponding to 20-43% of the LC50 were 47 ppm (rat), 30 ppm (mouse), and 73 ppm (no-effect concentration for guinea pig); these data are summarized in Table 5-7.

6.3.
Derivation of AEGL-2

Mild lung congestion was chosen as the threshold for irreversible or other serious, long-lasting effects as defined by the AEGL-2. The mouse was chosen as the most sensitive species although the experimental results for respective exposure periods for the tested species are very similar. The single data set (Keplinger and Suissa 1968) was extensive, being based on five species and four exposure durations. The mildest effects noted in the Keplinger and Suissa (1968) study were very mild or mild diffuse congestion which were observed at approximately 25% (20-43%) of the LC50 values. The rapid change in effects as the LC50 is successively halved indicates the steepness of the dose-response curve for fluorine.

The mouse 30-min and 1-h values which caused very mild lung congestion were chosen for calculation of the AEGL-2 values. These concentrations are 67 ppm (30% of the 30-min LC50) and 30 ppm (20% of the 60-min LC50), respectively. An interspecies uncertainty factor of 1, an intraspecies uncertainty factor of 3, and a modifying factor of 2 were then applied to these numbers to derive the AEGL-2 (see discussion of uncertainty factors for AEGL-3). Extrapolation across time was based on the equation for the mouse, C1.77 × t = k. The 4-and 8- h values were scaled from the 1-h value (see Appendix B for calculations). The values are listed in Table 5-9. The 8-h-AEGL-2 value was set equal to the 4-h value because at low concentrations the hygroscopic fluorine would react with and/or be scrubbed by the nasal passages, and because at mildly irritating concentrations, adaptation to sensory irritation occurs.

Although human exposure for durations longer than 1 min were to concentrations below the definition of the AEGL-2, a comparison of the human data with the derived values can be made. Extrapolating the 3-min exposure to 50 ppm from the data of Keplinger and Suissa (1968) to a 30-min time period results in a value of 13.6 ppm. The effects during this exposure, eye irritation (not otherwise specified) and slight nose irritation, are below the definition of the AEGL-2.

TABLE 5-8 AEGL-1 Values for Fluorine

10-min

30-min

1-h

4-h

8-h

1.7 ppm (2.6 mg/m3)

1.7 ppm (2.6 mg/m3)

1.7 ppm (2.6 mg/m3)

1.7 ppm (2.6 mg/m3)

1.7 ppm (2.6 mg/m3)

Suggested Citation:"5 Fluorine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

TABLE 5-9 AEGL-2 Values for Fluorine

10-min

30-min

1-h

4-h

8-h

20 ppm (31 mg/m3)

11 ppm (17 mg/m3)

5.0 ppm (7.8 mg/m3)

2.3 ppm (3.6 mg/m3)

2.3 ppm (3.6 mg/m3)

7.
DATA ANALYSIS FOR AEGL-3

7.1.
Summary of Human Data Relevant to AEGL-3

No information on irreversible or life-threatening effects caused by fluorine in humans was located. A concentration of 50 ppm was characterized as irritating and concentrations of 67-100 ppm were “very irritating and became uncomfortable after a few seconds.”

7.2.
Summary of Animal Data Relevant to AEGL-3

In the animal studies, Keplinger and Suissa (1968) characterized the symptoms of exposure equivalent to 50% of the LC50 values as “dyspnea, lethargy, red nose, and swollen eyes.” No deaths occurred in any species (dog, rat, mouse, guinea pig, rabbit) at approximately 50% of the respective LC50 values. All species tested at 50% of the LC50 survived for up to 45 days post exposure. Effects ranged from disabling, characterized by respiratory irritation and labored breathing with severe diffuse lung congestion (mouse, 50% of the 1-h LC50), to practically non-disabling, characterized by no eye or nose irritation and very mild diffuse lung congestion (guinea pig, 43% of the 1-h LC50). At 50% of the 15-min LC50, guinea pigs showed signs of respiratory irritation and labored breathing and gross changes in the lungs of mild diffuse congestion. Mice were tested at 50, 34, 20, and 10% of the LC50 for a 60-min exposure period. At a concentration equal to 50% of the 60-min LC50, the mouse showed signs of irritation and labored breathing and severe diffuse congestion of the lungs. At concentrations equal to 34 and 20% of the 60-min LC50, effects in the mouse were mild and very mild diffuse congestion, respectively, whereas the guinea pig, tested at 43% of its 60-min LC50 suffered no effects. The dog was tested at a concentration closer to one-third (93 ppm) rather than one-half of the 1-h LC50 concentration for the other species; at this concentration effects on the lungs were slight and would be more likely defined as an AEGL-2 level of effect. From the data involving effects at concentrations lower than the LC50 values for the various time periods, the guinea pig appears to be the least sensitive species and the mouse is the most sensitive species. The only experimental data available for longer term exposures was the 7-h exposure of rats, mice, guinea pigs and rabbits to 100 ppm which resulted in an over-all mortality of 60% (Eriksen 1945; Stokinger 1949). The extrapolated data of Keplinger and Suissa (1968), 7-h LC50 values of 65 and 50 ppm for the rat and mouse, respectively, yield more conservative concentrations.

Suggested Citation:"5 Fluorine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
7.3.
Derivation of AEGL-3

The LC50 values for the rat and mouse are very close for the 15, 30, and 60 min time periods (Keplinger and Suissa 1968). At 15 and 60 min, the mouse, rat, and guinea pig LC50 values are almost identical (Table 5-6). At 30 min the mouse, rat, and rabbit LC50 values are very close. The strong concordance of the LC50 values between four animal species at three time points presents a strong case for the conclusion that lethality is a function of the concentration of fluorine in the air. Therefore, the exposure concentration equals the dose for fluorine and there is no need for scaling factors among species. Keplinger and Suissa (1968) demonstrated that at 50% of the LC50 there were no deaths in five tested species in a total of 13 tests conducted over a 5- to 60-min exposure duration. Therefore, 50% of the LC50 concentration was chosen as the NOEL for “life threatening effects.” The mouse was chosen as the most sensitive species although all of the LC50 values were very similar. The 60-min value of 75 ppm was used as the basis for the AEGL-3.

Fluorine is a contact-site, direct-acting toxicant; there is no metabolic or pharmacokinetic component to fluorine-induced effects and there is likely to be little difference between species or among individuals in the response of biological tissues to fluorine exposure. The fact that the LC50 values for four species were essentially identical, and the mechanism of action is direct chemical (corrosive) destruction of lung tissue would argue for the use of an uncertainty factor of 1 when extrapolating from animals to man. However, the data used to develop the AEGL-3 were obtained primarily from one laboratory and not confirmed elsewhere. Therefore, a modifying factor of 2 is used for this uncertainty. A factor of 3 is added to account for variability in human susceptibility (fluorine is a highly reactive, corrosive gas whose effect on the respiratory tissues is not expected to differ greatly among individuals). The combined uncertainty/modifying factor is 6. Concentrations were scaled across time using the C1.77 × t = k relationship. Scaling from the 1-h experimental value to the 8-h exposure duration was considered realistic based on the similarity of extrapolated LC50 values from the Keplinger and Suissa (1968) study and the 7-h experimental values from the Eriksen (1945) and Stokinger (1949) study. The 8-h value was set equal to the 4-h value as was done for the AEGL-2. Values are summarized in Table 5-10 and calculations are in Appendix B.

8.
SUMMARY OF AEGLS

8.1.
AEGL Values and Toxicity End Points

In summary, the AEGL values for various levels of effects and various time periods were derived using the following methods. The AEGL-1 was based on a study with human volunteers in which a concentration of 10 ppm administered for 15 min produced no irritation of the eyes, nose, or respiratory tract.

Suggested Citation:"5 Fluorine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

TABLE 5-10 AEGL-3 Values for Fluorine

10-min

30-min

1-h

4-h

8-h

36 ppm (56 mg/m3)

19 ppm (29 mg/m3)

13 ppm (20 mg/m3)

5.7 ppm (8.8 mg/m3)

5.7 ppm (8.8 mg/m3)

This value was divided by 3 to account for differences in human sensitivity. Although no data on asthmatics, potentially susceptible populations were found, the fact that healthy humans have “tolerated” short-term exposures to 17 ppm indicates that the uncertainty factor of 3 is sufficient. A modifying factor of 2 was applied based on a limited data base. Because accommodation to the irritant effects of irritant gases occurs at mildly irritating concentrations, the derived value of 1.7 ppm was applied across all AEGL-1 time intervals.

In the absence of relevant human data, animal data were used to derive the AEGL-2 and AEGL-3 values. AEGL-2 values were derived based on concentrations equal to 25% of the LC50 values from a study with the most sensitive species, the mouse. These concentrations, 67 and 30 ppm for 30- and 60 min exposures, respectively, produced only very mild lung congestion. An uncertainty factor of 3 for differences in human sensitivity and a modifying factor of 2 for the use of a single data set were then applied to these numbers. Extrapolation across time was based on the regression equation for LC50 values and exposure times in the mouse, C1.77 × t = k.

The AEGL-3 values were based on data using the laboratory mouse in which severe effects but no deaths were noted at 50% of the 30- and 60-min LC50 values (113 and 75 ppm, respectively). A concentration equal to 50% of the 60-min LC50 was selected from the mouse studies and scaled to other exposure times using the equation C1.77 × t = k. An uncertainty factor of 3 for differences in human sensitivity and a modifying factor of 2 for the fact that the data set came from one laboratory and was not confirmed elsewhere were applied.

The AEGLs are summarized in Table 5-11. A summary of the derivations is contained in Appendix D.

8.2.
Comparison with Other Standards and Guidelines

Standards and guidance levels for workplace and community exposures are listed in Table 5-12. The AEGL values are very close to other guidelines for emergency exposures. The NIOSH IDLH 30-min value refers to respirator use, but is slightly higher (25 ppm) than the 30-min AEGL-3 of 19 ppm. The NIOSH IDLH is based on the observation of Rickey (1959) that two men were able to tolerate 25 ppm very briefly but both developed sore throats and chest pains that lasted 6 h; 50 ppm could not be tolerated. The definitions of the preliminary ERPGs correspond to the three AEGLs. The ERPG 1-h values were recently changed from 2, 7.5, and 10 ppm to 0.5, 5, and 20 ppm, reasonably close to the AEGL values. Documentation for the values was not given in this source. The

Suggested Citation:"5 Fluorine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

NRC Emergency Exposure Guidance Levels (EEGLs) are for occupational exposures and not the general public. The 30- and 60-min EEGLs are 10 and 7.5 ppm whereas the 30- and 60-min AEGL-2 values are 11 and 5 ppm. The EEGL guidelines are based on the human and animal data of Keplinger and Suissa (1968).

Although the populations are not comparable, the ACGIH TLV-TWA and STEL of 1 and 2 ppm, respectively, are similar to the AEGL-1 value of 1.7 ppm. The ACGIH TLV-TWA guideline is based on the lack of significant medical findings in workers exposed to fluorine for 7 years (Lyon 1962) coupled with evidence of tolerance development in animals (Keplinger 1969). The ACGIH TLV-STEL is based on the human study in which exposures to 10 ppm, repeated for 3 to 5 min every 15 min for 2-3 h, produced only slight irritation to the eyes and skin (Keplinger and Suissa 1968). The OSHA PEL-TWA is also based on the Lyon (1962) study; however, OSHA and NIOSH believed that the Lyon study did not involve 61 workers continually exposed but instead was a compilation of data on workers who may have had some short-term exposure to fluorine. Thus, their TWA is 10 times lower than that of ACGIH. Neither NIOSH nor OSHA have promulgated short-term exposure limits (STELs). The German MAK and Dutch MAC peak limits are both 0.2 ppm.

8.3.
Data Adequacy and Research Needs

Data from human studies are sparse and used healthy human subjects; exposures were usually short-term, with some exposure durations not stated. The study by Keplinger and Suissa (1968) used several short exposure durations and concentrations were measured. Data from animal studies used five species and encompassed a wide range of exposure concentrations and exposure durations, but none of the durations was for longer than 1 h for less than lethal effects. The animal studies were undertaken 27-47 years ago and analytical techniques have improved since then. The data base for human studies is inadequate (except for the AEGL-1) and the data base for animal studies is adequate, at least for 30-and 60-min exposures.

TABLE 5-11 Summary of AEGL Values

Classification

Exposure Duration

10-min

30-min

1-h

4-h

8-h

AEGL-1a (Nondisabling)

1.7 ppm (2.6 mg/m3)

1.7 ppm (2.6 mg/m3)

1.7 ppm (2.6 mg/m3)

1.7 ppm (2.6 mg/m3)

1.7 ppm 2.6 mg/m3)

AEGL-2b (Disabling)

20 ppm (31 mg/m3)

11 ppm (17 mg/m3)

5.0 ppm (7.8 mg/m3)

2.3 ppm (3.6 mg/m3)

2.3 ppm (3.6 mg/m3)

AEGL-3 (Lethal)

36 ppm (56 mg/m3)

19 ppm (29 mg/m3)

13 ppm (20 mg/m3)

5.7 ppm (8.8 mg/m3)

5.7 ppm (8.8 mg/m3)

aAEGL-1 values held constant across time because of accommodation to mildly irritating concentrations of irritant gases.

b30-min and 1-h AEGL-2 values are based on separate data points.

Suggested Citation:"5 Fluorine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

TABLE 5-12 Extant Standards and Guidelines for Fluorine

Guideline

Exposure Duration

10 min

30 min

1 h

4 h

8 h

AEGL-1

1.7 ppm

1.7 ppm

1.7 ppm

1.7 ppm

1.7 ppm

AEGL-2

20 ppm

11 ppm

5.0 ppm

2.3 ppm

2.3 ppm

AEGL-3

36 ppm

19 ppm

13 ppm

5.7 ppm

5.7 ppm

ERPG-1 (AIHA)a

 

 

0.5 ppm

 

 

ERPG-2 (AIHA)

 

 

5 ppm

 

 

ERPG-3 (AIHA)

 

 

20 ppm

 

 

EEGL (NRC)b

15 ppm

10 ppm

7.5 ppm

 

 

IDLH (NIOSH)c

 

25 ppm

 

 

 

REL-TWA (NIOSH)d

 

 

 

 

0.1 ppm

PEL-TWA (OSHA)e

 

 

 

 

0.1 ppm

TLV-TWA (ACGIH)f

 

 

 

 

1 ppm

TLV-STEL (ACGIH)g

 

 

 

 

2 ppm

MAK (Germany)h

 

 

 

 

0.1 ppm

MAK Peak Limit (Germany)i

 

 

 

 

0.2 ppm

MAC Peak Limit (The Netherlands)j

 

 

 

 

0.2 ppm? (0.5mg/m3)

OELV-LLV (Sweden)

 

 

 

 

0.1 ppm

OELV-STV (Sweden)

0.3 ppm (15 min.)

 

 

 

 

aERPG (Emergency Response Planning Guidelines, American Industrial Hygiene Asso-(15 min.) ciation (AIHA 2004).

The ERPG-1 is the maximum airborne concentration below which it is believed nearly all individuals could be exposed for up to 1 h without experiencing other than mild, transient adverse health effects or without perceiving a clearly defined objectionable odor.

The ERPG-2 is the maximum airborne concentration below which it is believed nearly all individuals could be exposed for up to 1 h without experiencing or developing irreversible or other serious health effects or symptoms that could impair an individual’s ability to take protective action.

The ERPG-3 is the maximum airborne concentration below which it is believed nearly all individuals could be exposed for up to 1 h without experiencing or developing life-threatening health effects.

bEEGL (Emergency Exposure Guidance Levels, National Research Council (NRC 1984).

Suggested Citation:"5 Fluorine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

The EEGL is the concentration of contaminants that can cause discomfort or other evidence of irritation or intoxication in or around the workplace, but avoids death, other severe acute effects and long-term or chronic injury.

cIDLH (Immediately Dangerous to Life and Health, National Institute of Occupational Safety and Health) (NIOSH 1996) represents the maximum concentration from which one could escape within 30 min without any escape-impairing symptoms, or any irreversible health effects.

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

ePEL-TWA (Permissible Exposure Limits - Time Weighted Average, Occupational Health and Safety Administration) (NIOSH 2005) is defined analogous to the ACGIH-TLV-TWA, but is for exposures of no more than 10 h/day, 40 h/week.

fTLV-TWA (Threshold Limit Value - Time Weighted Average, American Conference of Governmental Industrial Hygienists) (ACGIH 2004) is the time-weighted average concentration for a normal 8-h workday and a 40-h workweek, to which nearly all workers may be repeatedly exposed, day after day, without adverse effect.

gTLV-STEL (Threshold Limit Value - Short Term Exposure Limit, American Conference of Governmental Industrial Hygienists) (ACGIH 2004) is defined as a 15-min TWA exposure which should not be exceeded at any time during the workday even if the 8-h TWA is within the TLV-TWA. Exposures above the TLV-TWA up to the STEL should not be longer than 15 min and should not occur more than 4 times per day. There should be at least 60 min between successive exposures in this range.

hMAK (Maximale Arbeitsplatzkonzentration [Maximum Workplace Concentration-German Research Association] (DFG 2002) is defined analogous to the ACGIH-TLV-TWA.

iMAK Spitzenbegrenzung (Peak Limit [give category]) (German Research Association 2002) (DFG 2002) constitutes the maximum average concentration to which workers can be exposed for a period up to 30 min with no more than 2 exposure periods per work shift; total exposure may not exceed 8-h MAK.

jMAC (Maximaal Aanvaarde Concentratie [Maximal Accepted Concentration] Dutch Expert Committee for Occupational Standards, The Netherlands)) (MSZW 2004) is defined analogous to the ACGIH-TLV-TWA.

kOELV -LLV(Occupational Exposure Limit Value-Level Limit Value).

jOELV -CLV(Occupational Exposure Limit Value-Ceiling Limit Value) (Swedish Work Environment Authority 2005) is the maximum acceptable average concentration (time-weighted average) of an air contaminant in respiratory air. An occupational exposure limit value is either a level limit value (one working day) or a ceiling limit value (15 min or some other reference time period), and short time value (A recommended value consisting of a time-weighted average for exposure during a reference period of 15 min).

Although data from one study could be used to estimate the concentration-exposure duration relationships for several animal species (Cn × t = k), the longest exposure duration was only 1 h. The study of Eriksen (1945) and Stokinger (1949), although flawed due to difficulty in monitoring the test concentrations, tend to support the extrapolation to longer exposure times. Their single data

Suggested Citation:"5 Fluorine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

point for the rat, 54% mortality at a concentration of 100 ppm for 7 h, when extrapolated to a 1-h exposure gives an approximate LC50 of 300 ppm (the actual concentration is probably lower due to chamber losses [Ricca 1970]). This value is within a factor of 2 of the 1-h LC50 for the rat of 187 ppm in the Keplinger and Suissa study.

The total body of data on the sublethal and lethal effects of fluorine is reasonably consistent. The mechanism of action is understood. Although most of the experimental exposures were of short duration, at least one additional experimental value is consistent with the derived time-scaling relationship. Application of an intraspecies uncertainty factor of 3 to the human data, an interspecies uncertainty factor of 1 to the animal data, and a modifying factor of 2 to reasonably consistent but limited human and animal data is appropriate to insure the safety of the values.

9.
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Suggested Citation:"5 Fluorine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

Keplinger, M.L., and L.W. Suissa. 1968. Toxicity of fluorine short-term inhalation. Am. Ind. Hyg. Assoc. J. 29(1):10-18.

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×

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Suggested Citation:"5 Fluorine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

APPENDIX A
Time-Scaling Graph for Fluorine

FIGURE A-1 LC50 values for the mouse. Source: Keplinger and Suissa 1968. Reprinted with permission; copyright 1968, Journal of Industrial Hygiene and Toxicology.

FIGURE A-1 LC50 values for the mouse. Source: Keplinger and Suissa 1968. Reprinted with permission; copyright 1968, Journal of Industrial Hygiene and Toxicology.

Time (minutes)

Concentration (ppm)

Log time

Log concentration

5

600

0.6990

2.7782

15

375

1.1761

2.5740

30

225

1.4771

1.3522

60

150

1.7782

2.1761

Regression Output:

Intercept

3.1958

Slope

−0.5658

R Squared

0.9872

Correlation

−0.9936

Degrees of Freedom

2

Observations

4

n = 1.77

k = 444989

Suggested Citation:"5 Fluorine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

APPENDIX B
Derivation of AEGL Values for Fluorine

Derivation of AEGL-1

Key Study:

Keplinger and Suissa 1968

Toxicity end point:

No irritant effects in humans exposed to 10 ppm for 15 min

Scaling:

Not used; because accommodation to low concentrations of fluorine, the values were not time-scaled

Uncertainty factor:

3 for differences in human sensitivity (an uncertainty factor of 3 rather than 10 was used because 10 ppm for 15 min is a no-effect level; in addition, fluorine reacts chemically with the tissues of the respiratory tract and effects are unlikely to differ among individuals).

Modifying factor:

2 to account for a single data set.

Calculation:

10 ppm/6 = 1.7 ppm

Derivation of AEGL-2

Key Study:

Keplinger and Suissa 1968

Toxicity end point:

Very mild diffuse lung congestion in mice exposed to 67 ppm for 30 min and 30 ppm for 1 h.

Scaling:

C1.77 × t = k (ten Berge et al. 1986)

Uncertainty factors:

1 for interspecies differences (four species had similar LC50 values)

3 to account for differences in human sensitivity (the toxicity end point is a mild effect level and the toxic effect is due to a chemical reaction with biological tissue of the respiratory tract which is unlikely to be different among individuals).

Modifying factor:

2 to account for a single data set.

Calculations:

(67 ppm/6)1.77 × 30 min = 2091 ppm1.77 ·min

(30 ppm/6)1.77 × 60 min = 1035.92 ppm1.77·min

10-min AEGL-2

C1.77 × 10 min = 2091 ppm1.77·min

C = 20 ppm

30-min AEGL-2

67 ppm/6 = 11 ppm

1-h AEGL-2

30 ppm/6 = 5 ppm

4-h AEGL-2

C1.77 × 240 min = 1035.92 ppm1.77·min

C = 2.3 ppm

8-h AEGL-2

Because of accommodation to low concentrations of irritant gases, the 8-h value was set equal to the 4-h value.

C = 2.3 ppm

Suggested Citation:"5 Fluorine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
Derivation of AEGL-3

Key Study:

Keplinger and Suissa 1968

Toxicity end point:

Severe diffuse lung congestion in mice exposed to 75 ppm for 1 h.

Scaling:

C1.77 × t = k (ten Berge et al. 1986)

Uncertainty factors:

1 for interspecies differences (four species had similar LC50 values)

3 to account for differences in human sensitivity (the toxic effect is due to a chemical reaction with biological tissue of the respiratory tract which is unlikely to be different among individuals).

Modifying factor:

2 to account for a single data set.

Calculations:

(75 ppm/6)1.77 × 60 min = 5244.23 ppm1.77·min

10-min AEGL-3

C1.77 × 10 min = 5244.23 ppm1.77·min

C = 36 ppm

30-min AEGL-3

C1.77 × 30 min = 5244.23 ppm1.77·min

C = 19 ppm

60-min AEGL-3

75 ppm/6 = 13 ppm

4-h AEGL-3

C1.77 × 240 min = 5244.23 ppm1.77·min

C = 5.7 ppm

8-h AEGL-3

Because of accommodation to low concentrations of irritant gases, the 8-h value was set equal to the 4-h value.

C = 5.7 ppm

Suggested Citation:"5 Fluorine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

APPENDIX C
Category Graph of Toxicity Data and AEGL Values for Fluorine

FIGURE C-1 Category graph of toxicity data and AEGL values for fluorine.

FIGURE C-1 Category graph of toxicity data and AEGL values for fluorine.

Suggested Citation:"5 Fluorine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

APPENDIX D
Derivation Summary for Fluorine AEGLs

AEGL-1 VALUES

10-min

30-min

1-h

4-h

8-h

1.7 ppm

1.7 ppm

1.7 ppm

1.7 ppm

1.7 ppm

Key Reference: Keplinger, M.L., and L.W. Suissa. 1968. Toxicity of fluorine short-term inhalation. Am. Ind. Hyg. Assoc. J. 29(1):10-18.

Test Species/Strain/Number: 5 human subjects

Exposure Route/Concentrations/Durations: Inhalation: 10-100 ppm for various exposure durations.

Effects:

10 ppm for 15 min: no eye, nose or respiratory irritation (basis for AEGL-1)

25 ppm for 5 min: eye irritation

50 ppm for 3 min: irritating to eyes, slightly irritating to nose

67 ppm for 1 min: irritating to eyes and nose

100 ppm for 1 min: very irritating to eyes and nose; subjects did not inhale

End Point/Concentration/Rationale: 10 ppm for 15 min resulted in no sensory irritation in healthy human subjects. Although this value is below the definition of an AEGL-1, it provides the longest exposure duration for which no irritation is reported. All studies indicated that fluorine is highly irritating and corrosive.

Uncertainty Factors/Rationale:

Total uncertainty factor: 3

Interspecies: Not applicable, human subjects were tested

Intraspecies: 3- The effect was a NOAEL for sensory irritation. Limited workplace monitoring data showed that workers exposed to fluorine at average yearly concentrations up to 1.2 ppm (range, 0.0-17 ppm) over a four-year period reported fewer incidences of respiratory complaints or diseases than a similar group of nonexposed workers (Lyon 1962). The workers are assumed to encompass a small range of sensitivity; the additional intraspecies uncertainty factor of 3 was considered sufficient to protect sensitive individuals.

Modifying Factor: 2 - to account for a limited data base.

Animal to Human Dosimetric Adjustment: Not applicable; human data used.

Time Scaling: Not applied; at mildly irritating concentrations, adaptation to sensory irritation occurs.

Data Adequacy: The key study was well conducted and documented; data in supporting studies were limited.

Suggested Citation:"5 Fluorine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

AEGL-2 VALUES

10-min

30-min

1-h

4-h

8-h

20 ppm

11 ppm

5.0 ppm

2.3 ppm

2.3 ppm

Key Reference: Keplinger, M.L., and L.W. Suissa. 1968. Toxicity of fluorine short-term inhalation. Am. Ind. Hyg. Assoc. J. 29(1):10-18.

Test Species/Strain/Number: Swiss-Webster mice (sex not stated), 10/exposure group

Exposure Route/Concentrations/Durations:

Inhalation: 38, 79, 174, 300, 467, 600 ppm for 5 min

32, 65, 87, 188, 375 ppm for 15 min

16, 32, 67, 113, 225 ppm for 30 min

15, 30, 50, 75, 150 ppm for 1 h

Effects (the 30-min and 1-h exposures were considered):

30-min exposures:

16 ppm: no toxic signs, no gross lung pathology

32 ppm: no toxic signs, no gross lung pathology

67 ppm: no toxic signs, very mild diffuse lung congestion (basis for AEGL-2)

13 ppm: irritation and labored breathing, mild diffuse lung congestion

225 ppm: LC50

1-h exposures:

15 ppm: no toxic signs, no gross lung pathology

30 ppm: no toxic signs, very mild diffuse lung congestion (basis for AEGL-2)

50 ppm: labored breathing, mild diffuse lung congestion

75 ppm: irritation and labored breathing, severe diffuse lung congestion

150 ppm: LC50

End Point/Concentration/Rationale: 67 ppm for 30 min and 30 ppm for 1 h resulted in very mild diffuse lung congestion. Very mild lung congestion was considered the threshold for serious long-lasting effects such as severe lung congestion, seen at the next highest level tested.

Uncertainty Factors/Rationale:

Total uncertainty factor: 3

Interspecies: 1 - The effect (lung congestion) as well as LC50 values reported in the study were very similar for the rat, rabbit, and guinea pig (indicating similar species sensitivity). With the exception of the 5-min LC50 value for the rabbit, the LC50 values for all four species at 15, 30, and 60 min were very similar.

Intraspecies: 3 - At the AEGL-2 concentrations, the effect of irritant gases is expected to be directly damaging to the tissues. The corrosive effect is not expected to differ greatly among individuals.

Modifying Factor: 2 - to account for a limited data base.

Animal to Human Dosimetric Adjustment: Not applied.

Time Scaling: Cn × t = k where n = 1.77; based on regression analysis of the mouse (the most sensitive species) LC50 data from the study conducted at 5, 15, 30, and 60 min (Keplinger and Suissa 1968). The 10-min value was time scaled from the 30-min value and the 4-h value was time scaled from the 1-h value. The 8-h value was set equal to the 4-h value because at low concentrations the hygroscopic fluorine would react with or be scrubbed by the nasal passages.

Data Adequacy: The key study was well conducted and documented; there were limited confirming data from other laboratories.

Suggested Citation:"5 Fluorine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×

AEGL-3 VALUES

10-min

30-min

1-h

4-h

8-h

36 ppm

19 ppm

13 ppm

5.7 ppm

5.7 ppm

Key Reference: Keplinger, M.L., and L.W. Suissa. 1968. Toxicity of fluorine short-term inhalation. Am. Ind. Hyg. Assoc. J. 29(1):10-18.

Test Species/Strain/Number: Swiss-Webster mice (sex not stated), 10/exposure group

Exposure Route/Concentrations/Durations:

Inhalation: 38, 79, 174, 300, 467, 600 ppm for 5 min

32, 65, 87, 188, 375 ppm for 15 min

16, 32, 67, 113, 225 ppm for 30 min

5, 30, 50, 75, 150 ppm for 1 h

Effects: The 1-h substudy using the mouse was considered

15 ppm: no toxic signs, no gross lung pathology

30 ppm: no toxic signs, very mild diffuse lung congestion (basis for AEGL-2)

50 ppm: labored breathing, mild diffuse lung congestion

75 ppm: irritation and labored breathing, severe diffuse lung congestion

150 ppm: LC50

End Point/Concentration/Rationale: 75 ppm for 1 h resulted in irritation and labored breathing and severe diffuse lung congestion in the mouse. No deaths occurred. Severe diffuse lung congestion was considered the threshold for lethality.

Uncertainty Factors/Rationale:

Total uncertainty factor: 3

Interspecies: 1 - The effects (lung congestion) as well as LC50 values reported in the study were very similar for the rat, rabbit, and guinea pig (indicating similar species sensitivity). With the exception of the 5-min LC50 for the rabbit, the LC50 values for all four species a t 15, 30, and 60 min were very similar. Thus, the concentration:end point did not differ greatly among species.

Intraspecies: 3 - Lung congestion at a specific concentration is not expected to differ greatly among individuals.

Modifying Factor: 2 - to account for a limited data base

Animal to Human Dosimetric Adjustment: Not applied.

Time Scaling: Cn × t = k where n = 1.77; based on regression analysis of the mouse (the most sensitive species) LC50 data from the study conducted at 5, 15, 30, and 60 min (Keplinger and Suissa 1968). The values were time scaled from the 1-h data. The 8-h value was set equal to the 4-h value as was done for the AEGL-2. The safety of setting the 8-h value equal to the 4-h value is supported by another study in which a 7-h exposure to 100 ppm resulted in an overall 60% mortality in four species (Eriksen 1945; Stockinger 1949). The time-scaled 7-h LC50 values from the key study for the mouse (50 ppm) and rat (65 ppm) are lower.

Data Adequacy: The key study was well conducted and documented, but there were limited confirming data from other laboratories.

Suggested Citation:"5 Fluorine." National Research Council. 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8. Washington, DC: The National Academies Press. doi: 10.17226/12770.
×
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This book is the eighth volume in the series Acute Exposure Guideline Levels for Selected Airborne Chemicals, and reviews AEGLs for acrolein, carbon monoxide, 1,2-dichloroethene, ethylenimine, fluorine, hydrazine, peracetic acid, propylenimine, and sulfur dioxide for scientific accuracy, completeness, and consistency with the NRC guideline reports.

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