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).



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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 Guide- line Levels for Hazardous Substances (NAC/AEGL Committee) has been estab- lished 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 distin- guished 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 (Na- tional Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances). The NAC reviewed and revised the document and AEGLs as deemed neces- sary. Both the document and the AEGL values were then reviewed by the National Re- search 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). 230

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231 Fluorine 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 sus- ceptible 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 sus- ceptible 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 progres- sive 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 in- fants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to idiosyncratic responses, could experi- ence the effects described at concentrations below the corresponding AEGL. SUMMARY Fluorine is a reactive, highly irritating and corrosive gas used in the nu- clear energy industry, as an oxidizer of liquid rocket fuels, and in the manufac- ture 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 concen- tration 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 lev- els: (1) respiratory irritation with edema resulting in mild, reversible lung con- gestion, 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-

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232 Acute Exposure Guideline Levels mented with data from several other studies, were considered adequate for deri- vation of the three AEGL classifications for five time periods. The AEGL-1 was based on the observation that adult volunteers could tol- erate 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 irri- tation in humans was reported. An intraspecies uncertainty factor of 3 was ap- plied because fluorine is highly corrosive to the tissues of the respiratory tract and effects are not expected to vary greatly among individuals, including sus- ceptible individuals (NRC 2001). Although no data on asthmatics were found, the uncertainty factor of 3 was considered adequate to protect this sensitive sub- population 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 re- sulting value of 1.7 ppm was used across all AEGL-1 exposure durations be- cause, 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 respi- ratory 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 pro- tect 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 spe- cies 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 ob- served 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

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233 Fluorine 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 relation- ship. 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 fluo- rine 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 con- centration 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 oxi- dizer 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

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234 Acute Exposure Guideline Levels (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 potas- sium 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 contain- ing 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 1.7 ppm 1.7 ppm 1.7 ppm 1.7 ppm 1.7 ppm No irritant effects - (Nondisabling) (2.6 (2.6 (2.6 (2.6 (2.6 humans (Keplinger mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) and Suissa 1968) AEGL-2c 20 ppm 11 ppm 5.0 ppm 2.3 ppm 2.3 ppm Mild lung congestion - (Disabling) (31 (17 (7.8 (3.6 (3.6 mice (Keplinger and mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) Suissa 1968) AEGL-3 36 ppm 19 ppm 13 ppm 5.7 ppm 5.7 ppm Severe lung (Lethal) (56 (29 (20 (8.8 (8.8 congestion - mice mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) (Keplinger and Suissa 1968) a The characteristic, pungent odor of fluorine will be noticeable at this concentration. b The same value was used across all time periods because, at mildly irritating concentrations, adaptation to sensory irritation occurs. c 30-min and 1-h values are based on separate data points.

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235 Fluorine TABLE 5-2 Chemical and Physical Data for Fluorine Parameter Data Reference Chemical Name Fluorine ATSDR 2003 Synonyms Bifluoriden, fluor, fluorine-19, HSDB 2005 fluoro 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 3 Density 1.695 g/cm (air = 1.29) Lewis 1993 Solubility No data; reacts with water O’Neil et al. 2001 Vapor pressure 1 mm Hg at -223°C HSDB 2005 >10 atm at 20°C Teitelbaum 2001 Flammability Nonflammable; AAR 1987 powerful oxidizing agent 1 ppm = 0.64 mg/m3 Conversion factors ATSDR 2003 1 mg/m3 = 1.554 ppm 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 devel- oped 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.

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TABLE 5-3 Summary of Irritant Effects in Humans 236 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 slight irritation to the eyes and skin; no Keplinger and Suissa 1968 for 2-3 h respiratory difficulty 15-25 Three breaths Eye and nasal irritation Belles 1965 25 Not stated Tolerated; sore throats and chest pains of 6 h Rickey 1959 duration 25 5 min Slight irritation to eyes, inhaled intermittently Keplinger and Suissa 1968 without difficulty 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 Keplinger and Suissa 1968 when inhaled 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 Keplinger and Suissa 1968 inhale); slightly irritating to the skin 100-200 Not stated Reaction with skin and body hair Belles 1965

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237 Fluorine Belles (1965) reported a series of tests involving nine male volunteers. All tolerated repeated short-term exposure to 10 ppm without “intolerable” discom- fort. 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 re- ported 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 ciga- rette 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 au- thors, the eyes were the most sensitive indicator of irritation in humans. Keplin- ger and Suissa (1968) also reported that a few repeated exposures at a concentra- tion 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 pe- riod, 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 work- ers 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 fluo- rine determination in urine of unexposed workers and the inability of the meas- urement 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 in- creased asthmatic attack frequency over that in the non-exposed population. There is potential for individuals to become sensitized to halogens follow- ing 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).

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238 Acute Exposure Guideline Levels 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 reproduc- tive 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 concen- tration 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 ex- posure, 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 summa- rized in Table 5-4.

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239 Fluorine TABLE 5-4 Summary of Acute Lethal Inhalation Data in Laboratory Animals Effecta Species Concentration (ppm) Exposure Time Reference 100% mortality Eriksen 1945; Rat 10,000 5 min 100% mortality Stokinger 1949 1000 30 min 1h 100% mortality 500 3h 100% mortality 200 7h 54% mortality 100 Rat 700 5 min LC50 Keplinger and 390 15 min LC50 Suissa 1968 270 30 min LC50 185 1h LC50 Eriksen 1945; Mouse 10,000 5 min 100% mortality 1000 30 min 100% mortality Stokinger 1949 500 1h 100% mortality 100% mortality 200 3h 96% mortality 100 7h LC50 Mouse 600 5 min Keplinger and 375 15 min LC50 Suissa 1968 225 30 min LC50 150 1h LC50 Guinea pig 10,000 5 min 100% mortality Eriksen 1945; Stokinger 1949 1000 30 min 100% mortality 500 1h 100% mortality 200 3h 90% mortality 100 7h no mortality Guinea pig 395 15 min LC50 Keplinger and 170 1h LC50 Suissa 1968 100% mortality Eriksen 1945; Rabbit 10,000 5 min Stokinger 1949 1000 30 min 100% mortality 500 1h 100% mortality 200 3h 100% mortality 88% mortality 100 7h Rabbit 820 5 min LC50 Keplinger and 270 30 min LC50 Suissa 1968 a LC50 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 expo- sures, groups of five dogs (sex and strain unspecified) were administered fluo- rine 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

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240 Acute Exposure Guideline Levels 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, pulmo- nary hemorrhage and edema in 2 of 5 dogs at 2 ppm, and no consistent signifi- cant 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 occur- ring 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 expo- sure 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 attrib- uted 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 re- vealed that lung damage was either slight or had undergone substantial repair. Kidney abnormalities including general engorgement, slight edema, slight swell- ing 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. Tech- nical problems in monitoring fluorine gas levels make the quantitative exposure level data unreliable in this study; however, qualitative results from these ex- periments 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 irrita- tion of the eyes and nose. Death occurred approximately 12 to 18 h after expo- sure. 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 concentra- tions of 0.5, 2, 5, and 16 ppm were conducted over a period of 21-35 days (Stok- inger 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

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263 Fluorine The EEGL is the concentration of contaminants that can cause discomfort or other evi- dence of irritation or intoxication in or around the workplace, but avoids death, other severe acute effects and long-term or chronic injury. c IDLH (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 irre- versible health effects. d REL-TWA (Recommended Exposure Limits - Time Weighted Average, National Insti- tute of Occupational Safety and Health) (NIOSH 2005) is defined analogous to the ACGIH-TLV-TWA. e PEL-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. f TLV-TWA (Threshold Limit Value - Time Weighted Average, American Conference of Governmental Industrial Hygienists) (ACGIH 2004) is the time-weighted average con- centration 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. g TLV-STEL (Threshold Limit Value - Short Term Exposure Limit, American Conference of Governmental Industrial Hygienists) (ACGIH 2004) is defined as a 15-min TWA ex- posure 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. h MAK (Maximale Arbeitsplatzkonzentration [Maximum Workplace Concentration- German Research Association] (DFG 2002) is defined analogous to the ACGIH-TLV- TWA. i MAK 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. j MAC (Maximaal Aanvaarde Concentratie [Maximal Accepted Concentration] Dutch Expert Committee for Occupational Standards, The Netherlands)) (MSZW 2004) is de- fined analogous to the ACGIH-TLV-TWA. k OELV -LLV(Occupational Exposure Limit Value-Level Limit Value). j OELV -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 con- sisting 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 long- est 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

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264 Acute Exposure Guideline Levels point for the rat, 54% mortality at a concentration of 100 ppm for 7 h, when ex- trapolated 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 rea- sonably consistent. The mechanism of action is understood. Although most of the experimental exposures were of short duration, at least one additional ex- perimental value is consistent with the derived time-scaling relationship. Appli- cation of an intraspecies uncertainty factor of 3 to the human data, an interspe- cies 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. REFERENCES AAR (Association of American Railroads). 1987. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, DC: Association of American Railroads. ACGIH (American Conference of Governmental Industrial Hygienists). 2004. Documen- tation of the Threshold Limit Values and Biological Exposure Indices: Fluorine. American Conference of Governmental Industrial Hygienists, Cincinnati, OH. AIHA (American Industrial Hygiene Association). 2004. Emergency Response Planning Guidelines. Fairfax, VA: AIHA Press. Amoore, J.E., and E. Hautala. 1983. Odor as an aid to chemical safety: Odor thresholds compared with threshold limit values and volatilities for 214 industrial chemicals in air and water dilution. J. Appl. Toxicol. 3(6):272-290. ATSDR (Agency for Toxic Substances and Disease Registry. 2003. Toxicological Profile for Fluorides, Hydrogen Fluoride, and Fluorine. U.S. Department of Health and Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry, Atlanta, GA [online]. Available: http://www.atsdr.cdc.gov/toxprofiles/ tp11.pdf [accessed Nov. 4, 2008]. Belles, F., ed. 1965. Fluoride Handbook. Cleveland, TN: National Aeronautics and Space Administration, Lewis Research Center. DFG (Deutsche Forschungsgemeinschaft). 2002. List of MAK and BAT Values 2002. Maximum Concentrations and Biological Tolerance Values at the Workplace Re- port No. 38. Weinheim, Federal Republic of Germany: Wiley VCH. Eriksen, N. 1945. A Study of the Lethal Effect of the Inhalation of Gaseous Fluorine (F2) at Concentrations from 100 ppm to 10,000 ppm. DOE/EV/03490-T3. NTIS DE85- 010190. U.S. Atomic Energy Commission Pharmacology Report 435. University of Rochester, Rochester, NY. HSDB (Hazardous Substances Data Bank). 2005. Fluorine (CASRN 7782-41-4). TOXNET, Specialized Information Services, U.S. National Library of Medicine, Bethesda, MD [online]. Available: http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen? HSDB [accessed Nov. 4, 2008]. Keplinger, M.L. 1969. Effects from repeated short-term inhalation of fluorine. Toxicol. Appl. Pharmacol. 14(1):192-200.

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265 Fluorine Keplinger, M.L., and L.W. Suissa. 1968. Toxicity of fluorine short-term inhalation. Am. Ind. Hyg. Assoc. J. 29(1):10-18. Kusewitt, D.F., D.M. Stavert, G. Ripple, T. Mundie, and B.E. Lehnert. 1989. Relative acute toxicities in the respiratory tract of inhaled hydrogen fluoride, hydrogen bromide, and hydrogen chloride. Toxicologist 9:36. Lewis, R.J. 1993. Hawley’s Condensed Chemical Dictionary, 12th Ed. New York: Van Nostrand Reinhold. Lyon, J.S. 1962. Observations on personnel working with fluorine at a gaseous diffusion plant. J. Occup. Med. 4:199-201. Machle, W. and E.E. Evans. 1940. Exposure to fluorine in industry. J. Ind. Hyg. Toxicol. 22(6):213-217. Maurer, J.K., M.C. Chang, B.G. Boysen, and R.L. Anderson. 1990. 2-Year carcinogenic- ity study of sodium fluoride in rats. J. Natl. Cancer Inst. 82(13):118-126. MSZW (Ministerie van Sociale Zaken en Werkgelegenheid). 2004. Nationale MAC-lijst 2004: Fluor. Den Haag: SDU Uitgevers [online]. Available: http://www.lasrook. net/lasrookNL/maclijst2004.htm [accessed Oct. 24, 2008]. NIOSH (National Institute of Occupational Safety and Health). 1996. Documentation for Immediately Dangerous to Life or Health Concentrations (IDLH): NIOSH Chemical Listing and Documentation of Revised IDLH Values (as of 3/1/95)- Fluorine. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute of Occupational Safety and Health [online]. Available: http://www.cdc.gov/niosh/idlh/7782414.html [accessed Oct. 30, 2008]. NIOSH (National Institute of Occupational Safety and Health). 2005. NIOSH Pocket Guide to Chemical Hazards: Fluorine. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute of Occu- pational Safety and Health, Cincinnati, OH. September 2005 [online]. Available: http://www.cdc.gov/niosh/npg/npgd0289.html [accessed Oct. 16, 2008]. NRC (National Research Council). 1984. Fluorine. Pp. 77-88 in Emergency and Con- tinuous Exposure Limits for Selected Airborne Contaminants, Vol. 1. Washington, DC: National Academy Press. NRC (National Research Council). 1993. Guidelines for Developing Community Emer- gency Exposure Levels for Hazardous Substances. Washington, DC: National Academy Press. NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: Na- tional Academy Press. NRC (National Research Council). 2004. Acute Exposure Guideline Levels for Selected Airborne Chemicals, Vol. 4. Washington, DC: National Academies Press. NTP (National Toxicology Program). 1990. Toxicology and Carcinogenesis Studies of Sodium Fluoride (CAS No. 7861-49-4) in F344/N Rats and B6C3F1 Mice (Drink- ing Water Studies). Technical Report Series No. 393. NIH Publication No. 91- 2848. National Toxicology Program, Research Triangle Park, NC. O’Neil, M.J., A. Smith, P.E. Heckelman, J.R. Obenchain, Jr., J. Gallipeau, and M.A. D’Arecca. 2001. Fluorine. P. 737 in The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals, 13th Ed. Whitehouse Station, NJ: Merck. Ricca, P.M. 1970. A survey of the acute toxicity of elemental fluorine. Am. Ind. Hyg. Assoc. J. 31(1):22-29. Rickey, R.P. 1959. Decontamination of Large Liquid Fluorine Spills. AFFTC-TR-59-31. U.S. Air Force, Air Research and Development Command, Air Force Flight Test

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266 Acute Exposure Guideline Levels Center, Edwards Air Force Base, CA; AD-228-033. Ft Belvoir, VA: Defense Technical Information Center. Shia, G. 2003. Fluorine. Kirk-Othmer Encyclopedia of Chemical Technology. New York: John Wiley and Sons [online]. Available: http://www.mrw.interscience.wiley.com/ emrw/9780471238966/kirk/article/fluoshia.a01/current/abstract?hd=article-title,flu orine [accessed Nov. 5, 2008]. Slabbey, V.A., and E.A. Fletcher. 1958. Rate of Reaction of Gaseous Fluorine with Wa- ter Vapor at 35º C. Cleveland, TN: National Advisory Committee on Aeronautics, Lewis Research Center. Stokinger, H.E. 1949. Toxicity following inhalation of fluorine and hydrogen fluoride. Pp. 1021-1057 in Pharmacology and Toxicology of Uranium Compounds, C. Voegtlin, and H.C. Hodge, eds. New York: McGraw-Hill. Swedish Work Environment Authority. 2005. Occupational Exposure Limit Value and Measures Against Air Contaminants. AFS 2005:17 [online]. Available: http:// www.av.se/dokument/inenglish/legislations/eng0517.pdf [accessed Oct. 21, 2008]. Teitelbaum, D.T. 2001. The Halogens. Pp. 731-826 in: Patty’s Toxicology, 5th Ed., Vol. 3, E. Bingham, B. Cohrssen, and C.H. Powell, eds. New York: John Wiley & Sons. ten Berge, W.F., A. Zwart, and L.M. Appelman. 1986. Concentration-time mortality response relationship of irritant and systemically acting vapours and gases. J. Haz- ard. Mater. 13(3):301-309. Wohlslagel, J., L.C. DiPasquale, and E.H. Vernot. 1976. Toxicity of solid rocket motor exhaust: effects of HCl, HF, and alumina on rodents. J. Combust. Toxicol. 3:61- 69.

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267 Fluorine APPENDIX A Time-Scaling Graph for Fluorine Best Fit Concentration x Time Curve 2.9 2.8 2.7 Log Concentration (ppm) 2.6 2.5 2.4 2.3 2.2 2.1 0.6 0.8 1 1.2 1.4 1.6 1.8 Log Time (minutes) 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

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268 Acute Exposure Guideline Levels 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. C1.77 × t = k (ten Berge et al. 1986) Scaling: 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. (67 ppm/6)1.77 × 30 min = 2091 ppm1.77 Amin Calculations: (30 ppm/6)1.77 × 60 min = 1035.92 ppm1.77Amin C1.77 × 10 min = 2091 ppm1.77Amin 10-min AEGL-2 C = 20 ppm 30-min AEGL-2 67 ppm/6 = 11 ppm 1-h AEGL-2 30 ppm/6 = 5 ppm C1.77 × 240 min = 1035.92 ppm1.77Amin 4-h AEGL-2 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

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269 Fluorine 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. C1.77 × t = k (ten Berge et al. 1986) Scaling: 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. (75 ppm/6)1.77 × 60 min = 5244.23 ppm1.77Amin Calculations: C1.77 × 10 min = 5244.23 ppm1.77Amin 10-min AEGL-3 C = 36 ppm C1.77 × 30 min = 5244.23 ppm1.77Amin 30-min AEGL-3 C = 19 ppm 60-min AEGL-3 75 ppm/6 = 13 ppm C1.77 × 240 min = 5244.23 ppm1.77Amin 4-h AEGL-3 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

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APPENDIX C 270 Category Graph of Toxicity Data and AEGL Values for Fluorine FIGURE C-1 Category graph of toxicity data and AEGL values for fluorine.

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271 Fluorine 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.

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272 Acute Exposure Guideline Levels 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.

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273 Fluorine 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.