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HFE-7100: Methyl Nonafluorobutyl Ether (40%) (CAS Reg. No. 163702-07-6) plus Methyl Nonafluoroisobutyl Ether (60%) (CAS Reg. No. 163702-08-7)1 Acute Exposure Guideline Levels

SUMMARY

Hydrofluoroether-7100 (HFE-7100) is a mixture of methyl nonafluorobutyl and nonafluoroisobutyl ethers in ratios of 30-50 and 50-70%, respectively. This mixture has been developed as a replacement for presently used chlorofluorocarbons and other ozone-depleting chemicals. It is used in industrial situations as a cleaning agent, lubricant carrier, drying

1

This document was prepared by the AEGL Development Team composed of Sylvia Talmage (Oak Ridge National Laboratory) and the National Advisory Committee (NAC) on Acute Exposure Guideline Levels for Hazardous Substances member George Rusch (Chemical Manager). 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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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 5 HFE-7100: Methyl Nonafluorobutyl Ether (40%) (CAS Reg. No. 163702-07-6) plus Methyl Nonafluoroisobutyl Ether (60%) (CAS Reg. No. 163702-08-7)1 Acute Exposure Guideline Levels SUMMARY Hydrofluoroether-7100 (HFE-7100) is a mixture of methyl nonafluorobutyl and nonafluoroisobutyl ethers in ratios of 30-50 and 50-70%, respectively. This mixture has been developed as a replacement for presently used chlorofluorocarbons and other ozone-depleting chemicals. It is used in industrial situations as a cleaning agent, lubricant carrier, drying 1 This document was prepared by the AEGL Development Team composed of Sylvia Talmage (Oak Ridge National Laboratory) and the National Advisory Committee (NAC) on Acute Exposure Guideline Levels for Hazardous Substances member George Rusch (Chemical Manager). 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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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 agent, specialty solvent, and heat transfer medium. It is a volatile liquid with a slight ethereal odor. No information on production was located. Except for a single monitoring study conducted by 3M Company and reported by AIHA (1999) in which exposures were noted to be below 50 ppm, no information was located on human exposure. Animal data using the rat as the model addressed anesthetic properties, acute oral, dermal, and inhalation toxicity; neurotoxicity, and genotoxicity. A study with the beagle dog addressed cardiac sensitization. HFE-7100 is of low acute oral and inhalation toxicity. It does not have anesthetic properties, is not neurotoxic or genotoxic, and is not a cardiac sensitizer. In developmental studies with the rat, the fetal effect of an increase in supernumerary ribs was observed only in conjunction with slight maternal toxicity. No information useful for time scaling across the AEGL exposure durations was available. The AEGL-1 value is based on a subchronic study with the rat (Coombs et al. 1996a). In this study, groups of 20 male and female rats were exposed to concentrations up to 15,159 ppm for 6 h/day, 5 days/week for 13 weeks. This concentration was not neurotoxic. Reversible increases in weight of the liver, kidney, and spleen were observed, and these were considered a natural adaptation to chemical treatment. An interspecies uncertainty factor of 1 was applied because the concentration was basically a NOAEL, the exposures were repeated, and uptake is greater in the rodent than in primates (based on the higher respiratory rate and cardiac output of rodents compared with primates). Studies addressing neurotoxicity and cardiac sensitization and studies with pregnant rats failed to identify significant toxicological end points. Therefore, an intraspecies uncertainty factor of 3 was applied. A modifying factor of 2 was applied because human data are very limited and because some of the key studies used limited numbers of animals. The resultant value is 2,500 ppm. Time scaling may not be relevant for halogenated hydrocarbons as blood concentrations of these chemicals rapidly reach equilibrium and do not greatly increase as exposure duration is increased. The presence of the perfluoro group of HFE-7100 limits its solubility in biological fluids. Furthermore, the repeated number of the exposures in the key study supports the use of the same value across all time points. Therefore, the 2,500 ppm concentration is applicable for all AEGL-1 time points. The AEGL-2 value is based on a 5-min no-adverse-effect exposure prior to a cardiac sensitization test with beagles (Kenny et al. 1996) and is supported by a 4-week repeat exposure study with the rat (Coombs et

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 al. 1996b). Six male beagles exposed to 48,900 ppm for 5 min prior to a cardiac sensitization test showed no response to exposure. Although the beagles did exhibit clinical signs following a challenge dose of epinephrine, there was no cardiac sensitization. The beagles fully recovered and were used in subsequent tests. One of two beagles exposed to the next highest concentration, 89,300 ppm for 5 min (prior to the cardiac sensitization test), became slightly agitated and exhibited tremors and stiff limbs. This response might impair the ability to escape. Therefore, according to the definition of the AEGL-2 in the Standing Operating Procedures for developing AEGLs (NRC 2001), the 48,900 ppm was considered a NOAEL. In a second study, groups of 10 male and female rats were exposed to concentrations up to 30,000 ppm for 6 h/day, 5 days/week for 4 weeks (Coombs et al. 1996b). At 30,000 ppm, the majority of rats exhibited reversible centrilobular hepatocyte hypertrophy which is a normal adaptive response to chemical treatment. Although of short duration, the 5-min study with beagles, supported by the 4-week repeat study with rats, was used to derive the AEGL-2. Beagles were considerably more sensitive to the effects of HFE-7100 than rats. Both beagles and rats have higher respiratory rates and cardiac output than humans, resulting in greater chemical uptake. Therefore, an interspecies uncertainty factor of 1 was applied. Studies with rats, including neurotoxicity and developmental studies, failed to identify significant toxicological end points. HFE-7100 was not a cardiac sensitizer; therefore, heart patients should not be at added risk. An intraspecies uncertainty factor of 3 was considered sufficient to protect potentially susceptible individuals. Because human data are very limited and because some of the key studies used limited numbers of animals, a modifying factor of 2 was applied. The resulting value is 8,200 ppm. Time scaling may not be relevant for halogenated hydrocarbons as blood concentrations of these chemicals rapidly reach equilibrium and do not greatly increase as exposure duration is increased. Furthermore, the presence of the perfluoro group of HFE-7100 limits its solubility in biological fluids. The repeat nature of the rat study also supports the use of a single value across the AEGL exposure durations. Therefore, the 8,200 ppm concentration is applicable for all AEGL-2 time points. The AEGL-3 value is based on the same study with beagles (Kenny et al. 1996) and is supported by an acute inhalation study with the rat (3M Company 1995). One of two beagles inhaling 89,300 ppm for 5 min became slightly agitated, and showed clinical signs of tremors and stiffness of the limbs. The second beagle, administered a challenge dose

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 of adrenaline during a second 5-min exposure exhibited severe clinical signs including whole-body tremors. Although the 89,300 ppm exposure for 5 min was a clear NOAEL for death, the challenge dose of epinephrine to the second dog (during continuing exposure) with the resulting severe clinical signs is applicable to an emergency situation and can be considered life-threatening in susceptible individuals. However, in a 4-h study with rats inhaling 100,000 ppm, clinical signs were slight, consisting of slightly lowered respiration and sluggishness in one of three rats (3M Company 1995). Convulsions leading to death occurred only in rats inhaling 214,000 ppm for 40 min or more (Eger 1998). The more conservative NOAEL for lethality in the study with beagles was used to develop AEGL-3 values. Beagles were considerably more sensitive to the effects of HFE-7100 than rats. Both beagles and rats have higher respiratory rates and cardiac output than humans, resulting in greater chemical uptake. Therefore, an interspecies uncertainty factor of 1 was applied. Studies with rats, including neurotoxicity and developmental studies, failed to identify significant toxicological end points. HFE-7100 was not a cardiac sensitizer; therefore, heart patients should not be at added risk. An intraspecies uncertainty factor of 3 was considered sufficient to protect potentially susceptible individuals. Because human data are very limited and because some of the key studies used limited numbers of animals, a modifying factor of 2 was applied. Time scaling may not be relevant for anesthetics and halogenated hydrocarbons as blood concentrations of these chemicals rapidly reach equilibrium and do not greatly increase as exposure duration is increased. Therefore, the resulting 15,000 ppm concentration is applicable for all AEGL-3 time points. The 89,300 ppm concentration may be a conservative estimate of the threshold for lethality as rats survived a 4-h exposure to 100,000 ppm (3M Company 1995) and the dose-response curve for convulsions and death (ED50 of 214,000 ppm) is predicted to be steep (Eger 1998). The calculated values are listed in the Table 5-1. 1. INTRODUCTION HFE-7100 is composed of a combination of methyl nonafluorobutyl and nonafluoroisobutyl ethers in ratios of 30-50 and 50-70%, respectively. Animal toxicity tests were generally performed using a 40:60

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 TABLE 5-1 Summary of AEGL Values for HFE-7100 Classification 10 min 30 min 1 h 4 h 8 h End point (Reference) AEGL–1 (Nondisabling) 2,500 ppm (25,550 mg/m3) 2,500 ppm (25,550 mg/m3) 2,500 ppm (25,550 mg/m3) 2,500 ppm (25,550 mg/m3) 2,500 ppm (25,550 mg/m3) Reversible organ weight changes, repeated exposures, rat (Coombs et al. 1996a) AEGL–2 (Disabling) 8,200 ppm (84,000 mg/m3) 8,200 ppm (84,000 mg/m3) 8,200 ppm (84,000 mg/m3) 8,200 ppm (84,000 mg/m3) 8,200 ppm (84,000 mg/m3) NOAEL for clinical signs, dog (Kenny et al. 1996); NOAEL for clinical signs-repeat exposures, rat (Coombs et al. 1996b) AEGL–3 (Lethal) 15,000 ppm (150,000 mg/m3) 15,000 ppm (150,000 mg/m3) 15,000 ppm (150,000 mg/m3) 15,000 ppm (150,000 mg/m3) 15,000 ppm (150,000 mg/m3) Severe clinical signs, dog (Kenney et al. 1996); no deaths, rat (3M Company 1995) mixture of the n-butyl and isobutyl isomers (AIHA 1999). HFE-7100 has been developed as a replacement for chlorofluorocarbons, hydrochlorofluorocarbons, hydrofluorocarbons and perfluorocarbons for use as a cleaning and rinsing agent, lubricant carrier, drying agent, specialty solvent, and heat transfer medium (AIHA 1999). The Environmental Environmental Protection (EPA) has listed 3M HFE-7100 as an acceptable substitute for ozone depleting substances in specific solvent cleaning and aerosol industry applications under its Significant New Alternatives Program. No information on the manufacturing process or production was located.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 HFE-7100 is a highly volatile liquid with a slight ethereal odor. No information on the odor threshold was located. Chemical and physical data are listed in Table 5-2. 2. HUMAN TOXICITY DATA 2.1. General Toxicity No data on human toxicity were located. Air monitoring conducted by the 3M Company (1997) and reported by AIHA (1999) indicates that concentrations are generally less than 50 ppm near vapor degreasers where HFE-7100 was being used as a solvent. No adverse health effects were reported from workers engaged in this process. 2.2. Neurotoxicity No information was located on neurotoxicity of HFE-7100 to humans. 2.3. Developmental/Reproductive Toxicity No information was located on the developmental or reproductive toxicity of HFE-7100 to humans. 2.4. Genotoxicity No information was located on the genotoxicity of HFE-7100 to humans. 2.5. Carcinogenicity No information was located on the carcinogenicity of HFE-7100 to humans.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 TABLE 5-2 Chemical and Physical Data Parameter Value Reference Synonyms Methyl nonafluorobutyl ether: 1-methoxy-1,1,2,2,3,3,4,4,4-nonafluorobutane; 1-methoxyperfluorobutane; 1,1,1,2,2,3,3,4,4-nonafluoro-4-methoxybutane Methyl nonafluoroisobutyl ether: 1-methoxy-2-trifluoromethyl-1,1,2,3,3,3- hexafluoropropane; 1-methoxyperfluoroisobutane; 2-(difluoromethoxymethyl)-1,1,1,2,3,3,3- heptafluoropropane 3M Company 2000 Chemical formula C5H3F9O Methyl nonafluorobutyl ether: CF3-CF2-CF2-CF2-O-CH3 (31.0%) Methyl nonafluoroisobutyl ether: (CF3)2-CF-CF2-O-CH3 (68.7%) AIHA 1999; Coombs et al. 1996b Molecular weight 250 AIHA 1999 CAS Reg. No. Methyl nonafluorobutyl ether: 163702-07-6 Methyl nonafluoroisobutyl ether: 163702-08-7 3M Company

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 Parameter Value Reference Physical state Clear, colorless liquid 3M Company 2000 Solubility in water <12 ppm 3M Company 2000 Oil/gas partition coefficient 9.66 Eger et al. 1999 Saline/gas partition coefficient 0.0050 Eger et al. 1999 Vapor pressure 202 mm Hg at 25°C 3M Company 2000   0.26 atmospheres Eger et al. 1999 Saturated vapor pressure 2.24 × 105 ppm at 20°C 3M Company 2000 Vapor density (air = 1) 8.6 3M Company 2000 Flammable Limits   3M Company 2000 LEL None   UEL None   Specific gravity 1.5 g/mL 3M Company 2000 Melting point –135°C 3M Company 2000 Boiling point 61°C 3M Company 2000 Conversion factors 1 ppm = 10.22 mg/m3 AIHA 1999   1 mg/m3 = 0.0978 ppm  

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 2.6. Summary HFE-7100 is a newly developed ether with a slight ethereal odor that is intended for use as a cleaning agent and speciality solvent. No information was located on toxicity, developmental or reproductive effects, genotoxicity, or carcinogenicity in humans. The only monitoring report indicates that workplace exposures were less than 50 ppm. 3. ANIMAL TOXICITY DATA Orally, HFE-7100 is practically non-toxic. A dose of 5 g to 5 male and 5 female adult Sprague-Dawley rats produced no clinical signs (one animal exhibited soft stool on the day of treatment) and had no effect on mortality, morbidity, body weight, or gross pathology after 14 days (Hazleton Wisconsin, Inc. 1995a). Repeated (28-day) oral doses of 0, 8, 40, 200, or 1,000 mg/kg to male and female Sprague-Dawley rats produced irregular respiration and salivation at the high dose, but no deaths (Mitsubishi Chemical Safety Institute 1996a). Increased liver and thymus weights accompanied by cellular hypertrophy and increased blood albumin were observed, primarily in the 1,000 mg/kg/group. These effects were reversible during a 14-day recovery period. When tested on the skin or eyes of New Zealand white rabbits, HFE-7100 was minimally irritating to the skin (score of 0.7 out of 8 at the 4-h observation) and practically non-irritating to the eye (score or 2.0 out of 110 at the 1-h observation and 0 out of 110 at the 24-h observation) (Hazleton Wisconsin, Inc. 1995b; 1995c). HFE-7100 was not a dermal sensitizer when tested on the skin of guinea pigs (Hazleton Wisconsin, Inc. 1996a). When applied to the skin of rabbits for 5 days, absorption was minimal (Corning Hazleton 1996a). 3.1. Acute Lethality The convulsive and anesthetic properties of HFE-7100 were studied using four adult male Sprague-Dawley rats (Eger 1998). The rats were placed in individual tubes within a larger flow-through chamber. Chamber atmospheres were monitored by gas chromatography. Chamber atmospheres were increased in steps beginning with 25-50% of the predicted minimum alveolar anesthetic concentration (MAC; calculated by

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 dividing two atm by the oil/gas partition coefficient) and continuing until the animals exhibited clonic convulsions. Animals were observed for 20 min at each concentration. HFE-7100 was not anesthetic, as defined by movement in response to a painful stimulus, at any partial pressure applied, up to 0.24-0.26 atm, the vapor pressure, nor did it decrease the requirement for anesthesia for a known anesthetic when given concurrently with that anesthetic. With increasing partial pressures, the rats became increasingly excited and at slightly more than 0.2 atm, 3 of 4 exhibited convulsions. The convulsive ED50 was 0.214 atm (214,000±1,000 ppm). Convulsions were associated with an increase in body temperature. The three rats that exhibited convulsions subsequently died. No exposure durations were provided, but the stepwise increments in concentration leading up to the convulsive concentration would indicate an exposure of at least 40 min. 3.2. Nonlethal Toxicity 3.2.1. Dogs During cardiac sensitization studies, six beagles were exposed to 0, 10,000, 18,800, or 48,900 ppm for 5 min before administration of exogenous epinephrine. Two beagles were successfully exposed to 89,300 ppm for 5 min. No clinical signs were described at the lower concentrations. During the 5-min exposure to 89,300 ppm, one beagle became slightly agitated and exhibited signs of tremors and stiff limbs. Signs were not described in the second dog prior to administration of a challenge dose of epinephrine. 3.2.2. Rats The remaining studies used the rat as the test species. Only one study with acute exposure was located. Additional studies with repeated and subchronic exposures are included in the following discussion. Three male Sprague-Dawley rats were exposed in a 40 L flow-through chamber at a nominal concentration of 100,000 ppm which was regularly monitored (3M Company 1995). Oxygen concentration was maintained near 20%. The exposure period was 4 h. The animals were active near the start of exposure, although one animal appeared slightly

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 sluggish approximately 30 min into the exposure. At 3 h into the exposure, respirations ranged from 60-80/min which was described as slightly depressed. All animals survived the exposure and recovery period (undefined). Therefore, the 4-h LC50 is greater than 100,000 ppm. No further details were provided in this unpublished memo. Groups of 5 male and 5 female Crl:CD BR Sprague-Dawley rats were exposed to 0 (air) or targeted concentrations of 1,500, 3,000, 9,500, or 30,000 ppm for 6 h/day, 5 days/week, for 4 weeks (Coombs et al. 1996b). Measured concentrations, analyzed by gas chromatography, were 1,489, 2,935, 9,283, and 28,881 ppm, respectively. The study generally followed EPA guidelines for subchronic studies in that body weight was monitored, blood was collected to monitor effects on hematology and clinical chemistry, and urine was collected for urinalysis. Following exposure, major organs were weighed and tissues were examined microscopically. There were no treatment-related clinical signs during the exposures and there were no toxicologically significant effects on body weight, food consumption, hematology parameters, or gross pathology. A liver weight increase in male rats in the 28,881 ppm group was accompanied by centrilobular hepatocyte hypertrophy in 3 of 5 males. Hepatocyte hypertrophy was observed in 4 of 5 females in the 28,881 group although liver weight was not affected. Hepatocyte hypertrophy was also observed in 1 of 5 males and 2 of 5 females in the 9,283 ppm group. Hepatocyte hypertrophy was generally scored as minimal. Focal necrosis was not observed. Changes in clinical chemistry parameters involved increased serum glucose and decreased serum cholesterol in males in the 28,881 ppm group. Palmitoyl CoA oxidase activity was non-significantly increased in male rats in the 28,881 ppm group. Urinary protein was increased in males in the 9,283 and 28,881 ppm groups, and urinary fluoride was increased in rats of both sexes in all but the 1,489 ppm group. Groups of 10 young male and 10 young female Sprague-Dawley rats were exposed to target concentrations of 1,500, 4,500, 7,500, or 15,000 ppm for 6 h/day, 5 days/week for 13 weeks (Coombs et al. 1996a). Mean analyzed concentrations were 1,502, 4,550, 7,533, and 15,159 ppm, respectively. Isomer ratios by weight were stated as being 68.7% methyl nonafluoroisobutyl ether and 31.0% methyl nonafluorobutyl ether. The study generally followed EPA guidelines for subchronic studies in that clinical signs and body weight were monitored, blood was collected for hematology and clinical chemistry measurements, and urine was collected for urinalysis. Following exposure, a necropsy was per-

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 ppm for 10 min. No clinical signs were described during the 5-min exposure prior to the second challenge dose of epinephrine. Clinical signs were observed during the second 5 min (of the 10-min exposure) following a challenge dose of epinephrine (Kenny et al. 1996). Therefore, 48,900 ppm for 5 min was a NOAEL for clinical signs in the absence of exogenous epinephrine. HFE-7100 was not a cardiac sensitizer at this concentration or at the higher concentration of 89,300 ppm. A study with the rat used repeated exposures (Coombs et al. 1996b). Exposure to the highest concentration, 30,000 ppm for 4 weeks, resulted in only hepatocyte hypertrophy, a reversible effect when exposure is discontinued. This concentration was not neurotoxic as functional observational battery observations were negative. In a developmental study, exposure of pregnant rats to 30,000 ppm did not result in severe adverse effects to either the dams or fetuses. 6.3. Derivation of AEGL-2 The exposure of beagles to 48,900 ppm was chosen as the basis for the AEGL-2. No clinical signs were described during the 5-min exposure prior to the challenge dose of epinephrine. The NOAEL of 48,900 ppm was chosen as the basis for the AEGL-2 because at the next highest exposure, 89,300 ppm, the severe clinical signs of agitation, tremors, and stiff limbs might impair the ability to escape. An interspecies uncertainty factor of 1 was applied to the 48,900 ppm for several reasons: when considering clinical signs, the dog was shown to be more sensitive than the rat, and the respiration rate of dogs and rodents is greater than that of humans, resulting in greater uptake. Although exposures were at a lower concentration, the no-effect concentrations of 30,000 ppm in well-conducted repeat exposure and developmental studies support the interspecies uncertainty factor of 1. Studies addressing neurotoxicity and cardiac sensitization and studies with pregnant rats failed to identify significant toxicological end points. Furthermore, the chemical is poorly soluble in biological fluids. Therefore, an intraspecies uncertainty factor of 3 was applied to protect potentially susceptible individuals. Because human data are very limited and because some of the key studies used limited numbers of animals, a modifying factor of 2 was applied. The resulting value is 8,200 ppm. Time scaling may not be relevant for halogenated hydrocarbons as blood concentrations of these chemicals rapidly reach equilibrium and do

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 not greatly increase as exposure duration is increased (NRC 1996). Furthermore, the presence of the perfluoro group of HFE-7100 limits its solubility in biological fluids. Therefore, the 8,200 ppm concentration is applicable for all AEGL-2 time points. The use of the same value across all exposure durations is supported by the study in which rats were exposed to concentrations up to 30,000 ppm for 6 h/day, 5 days/week for four weeks. These rats exhibited reversible liver hypertrophy which is attributed to the repeated nature of the exposures (Coombs et al. 1996b). The use of repeated exposures in this study supports using a single value across the AEGL-2 timepoints. Values appear in Table 5-6. 7. DATA ANALYSIS FOR AEGL-3 7.1. Summary of Human Data Relevant to AEGL-3 No human data relevant to development of AEGL-3 values were located. 7.2. Summary of Animal Data Relevant to AEGL-3 In a study with rats, the EC50 for convulsions was 214,000 ppm and 3 of 4 rats died following the exposure (Eger 1998). However, no rats died following a 4-h exposure to 100,000 ppm (3M Company 1995). Prior to the second challenge dose of epinephrine during a cardiac sensitization test, one of two dogs exposed to 89,300 ppm exhibited severe clinical signs including agitation, tremors, and stiff limbs (Kenny et al. 1996). The second dog survived the second challenge dose of epinephrine but exhibited extremely severe clinical signs. TABLE 5-6 AEGL-2 Values for HFE-7100 10 min 30 min 1 h 4 h 8 h 8,200 ppm (84,000 mg/m3) 8,200 ppm (84,000 mg/m3) 8,200 ppm (84,000 mg/m3) 8,200 ppm (84,000 mg/m3) 8,200 ppm (84,000 mg/m3)

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 7.3. Derivation of AEGL-3 Taken together, the animal data indicate that the threshold for lethality in both the rat and dog lies above 89,300 ppm. Because the data are insufficient for calculating the exact threshold for lethality in either species, the 5-min exposure of the dog to 89,000 ppm was used as the basis for the AEGL-2 values. Although the tremors in dogs are rapidly reversible and do not cause lasting effects, they may have a severe effect on populations such as patients with heart disease. An interspecies uncertainty factor of 1 was applied to the 48,900 ppm for several reasons: when considering clinical signs, the dog was shown to be more sensitive than the rat, and the respiration rate of dogs and rodents is greater than that of humans, resulting in greater uptake. Studies addressing neurotoxicity and cardiac sensitization and studies with pregnant rats failed to identify significant toxicological end points. Therefore, an intraspecies uncertainty factor of 3 was applied to protect potentially susceptible individuals. Because human data are very limited and because some of the key studies used limited numbers of animals, a modifying factor of 2 was applied. Time scaling may not be relevant for halogenated hydrocarbons as blood concentrations of these chemicals rapidly reach equilibrium and do not greatly increase as exposure duration is increased. Therefore, the resulting 15,000 ppm concentration is applicable for all AEGL-3 time points. The 89,300 ppm concentration may be a conservative estimate of the threshold for lethality as rats survived a 4-h exposure to 100,000 ppm (3M Company 1995). Application of the same uncertainty and modifying factors to the 100,000 ppm concentration results in a slightly higher value, 17,000 ppm. Values appear in Table 5-7. The 15,000 ppm concentration is supported by the repeated exposure of pregnant rats to 30,000 ppm (Huntingdon Life Sciences 1998). No adverse effects other than a transient lower weight gain were observed in dams exposed from days 6 through 19 of gestation. Pregnant rats represent a susceptible animal population. Furthermore, humans have a much lower respiratory rate and cardiac output than rodents. TABLE 5-7 AEGL-3 Values for HFE-7100 10 min 30 min 1 h 4 h 8 h 15,000 ppm (150,000 mg/m3) 15,000 ppm (150,000 mg/m3) 15,000 ppm (150,000 mg/m3) 15,000 ppm (150,000 mg/m3) 15,000 ppm (150,000 mg/m3)

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 These are the two primary determinants of systemic uptake of volatile chemicals. Therefore, at similar concentrations, rodents will absorb substantially more of a chemical than primates. The use of the 5-min value for all time periods is supported by fact that the exposures were repeated in the study with the rat above, a conservative approach to developing AEGL values was used, and there were no deaths in rats exposed to 100,000 ppm for 4 h (3M Company 1995). The only observed adverse effect in the latter study was mild—a slightly lower respiratory rate. 8. SUMMARY OF AEGLS 8.1. AEGL Values and Toxicity End Points The AEGL values and their relationship to each other are summarized in Table 5-8. 8.2. Comparison with Other Standards and Guidelines HFE-7100 is a newly developed chemical and only a Workplace Environmental Exposure Level (WEEL) has been developed. The WEEL for an 8-h workday is 750 ppm (AIHA 1999). The WEEL was based on the NOEL of 7,500 ppm in the 90-day toxicity study with rats (Coombs et al. 1996a). 8.3. Data Adequacy and Research Needs Human data are lacking. Recent animal studies were well conducted and addressed multiple end points; however several of the key studies used limited numbers of animals. TABLE 5-8 Summary of AEGL Values (ppm) Classification Exposure Duration 10 min 30 min 1 h 4 h 8 h AEGL-1 (Nondisabling) 2,500 2,500 2,500 2,500 2,500

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 AEGL-2 (Disabling) 8,200 8,200 8,200 8,200 8,200 AEGL-3 (Lethal) 15,000 15,000 15,000 15,000 15,000 9. REFERENCES 3M Company. 1995. Acute inhalation toxicity for HFE-7100 in the rat. Unpublished memo, 3M Company, Toxicology Services, 3M Center, St. Paul, MN. 3M Company. 1997. Final results of HFE-7100 air samples. Unpublished memo, 3M Company, Toxicology Services, 3M Center, St. Paul, MN, August 18, 1997. (Cited in AIHA 1999). 3M Company. 2000. Material Safety Data Sheet. Minnesota Mining and Manufacturing Company, St. Paul, MN. ACGIH (American Conference of Governmental Industrial Hygienists). 2002. Documentation of the Threshold Limit Values and Biological Exposure Indices. Cincinnati, OH: ACGIH. AIHA. 1999. Workplace Environmental Exposure Levels: HFE-7100. American Industrial Hygiene Association, Fairfax, VA. Bakshi, K.S. 1998. Toxicity of alternatives to chlorofluorocarbons: HFC-134a and HCFC-123. Inhal. Toxicol. 10:963-967. Charles River Laboratories. 1996. Historical control data (1992-1994) for developmental and reproductive toxicity studies using the Crl:CD®(SD)BR rat. Charles River Laboratories, March, 1996. Coombs, D.W., C.K. Shepherd, M. Bannerman, C.J., Hardy, D. Crook, M. Hall, and G.F. Healey. 1996a. T-6334: 13-Week repeat dose inhalation toxicity study in rats. MIN 196/961181, Huntingdon Life Sciences, Huntingdon, Cambridgeshire, England. Coombs, D.W., C.K. Shepherd, M. Bannerman, C.J., Hardy, D. Crook, M. Hall, E.W. Hughes, and C. Gopinath. 1996b. T-6334: 28-Day repeat dose inhalation toxicity study in rats. MIN 181/952688, Huntingdon Life Sciences, Huntingdon, Cambridgeshire, England. Corning Hazleton, Inc. 1996a. 5-Daily dose dermal absorption/toxicity study of T-6334 in rabbits. CHW 6329-184, September 23, 1996. Corning Hazleton, Inc., Madison, WI. Corning Hazleton, Inc. 1996b. Single-dose intravenous pharmacokinetic study of T-6334 in rabbits. CHW 6329-170, September 27, 1996. Corning Hazleton, Inc., Madison, WI.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 Eger, E.I., II. 1998. Nonimmobilizers and transitional compounds may produce convulsions by two mechanisms. Unpublished paper with accompanying memo. Department of Anesthesia, University of California, San Francisco, CA. Eger, E.I., II. 2002. Memo from Dr. Edmond I. Eger, Department of Anesthesia, University of California, San Francisco, to Sylvia S. Talmage, Oak Ridge National Laboratory, August 19, 2002. Eger, E.I., II, D.D. Koblin, J. Sonner, D. Gong, M.J. Laster, P. Ionescu, M.J. Halsey, and T. Hudlicky. 1999. Nonimmobilizers and transitional compounds may produce convulsions by two mechanisms. Anesth. Analg. 88:884-892. Hazleton Wisconsin, Inc. 1995a. Acute oral toxicity study of T-6334 in rats (OECD Guidelines). HWI 50904618, December 8, 1995, Hazleton Wisconsin, Inc., Madison, WI. Hazleton Wisconsin, Inc. 1995b. Primary dermal irritation/corrosion study of T-6334 in rabbits (OECD Guidelines). HWI 50904619, November 9, 1995, Hazleton, Wisconsin, Inc., Madison, WI. Hazleton Wisconsin, Inc. 1995c. Primary eye irritation/corrosion study of T-6334 in rabbits (OECD Guidelines). HWI 50904620, November 9, 1995, Hazleton Wisconsin, Inc., Madison, WI. Hazleton Wisconsin, Inc. 1996. Dermal sensitization study of T-6334 in guinea pigs - closed patch technique (EPA Guidelines). HWI 50904621, January 25 1996, Hazleton, Wisconsin, Inc., Madison, WI. Huntingdon Life Sciences Limited. 1996a. T-6334 - A preliminary study of the effect on pregnancy of the rat (inhalation administration). MIN 180/952539, February 20, 1996. Huntingdon Life Sciences Ltd., Huntingdon, Cambridgeshire, England. Huntingdon Life Sciences Limited. 1996b. T-6334 - A study for effects on embryofoetal development of the rat (inhalation administration. MIN 197/961467, November 29, 1996. Huntingdon Life Sciences Ltd., Huntingdon, Cambridgeshire, England. Huntingdon Life Sciences Limited. 1996c. T-6334 - Mouse micronucleus test. MIN 195/960755, July 1, 1996. Huntingdon Life Sciences Ltd., Huntingdon, Cambridgeshire, England. Huntingdon Life Sciences Limited. 1998. T-6334 - A study for effects on embryofetal development of the rat (inhalation administration). MIN 236/971252, March 10, 1998. Huntingdon Life Sciences Ltd., Huntingdon, Cambridgeshire, England.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 Kenny, T.J., C.K. Shepherd, M. Bannerman, C.J. Hardy, and I.S. Gilkison. 1996. T-6334: Assessment of cardiac sensitization potential in dogs. MIN 182/953117, Huntingdon Life Sciences, Limited. Koblin, D.D., B.S. Chortkoff, M.J. Laster, E.I. Eger, II, M.J. Halsey, and P. Ionescu. 1994. Polyhalogenated and perfluorinated compounds that disobey the Meyer-Overton hypothesis. Anesth. Analg. 79:1043-1048. Mitsubishi Chemical Safety Institute. 1996a. Toxicity study of T-6334 by oral administration to rats for 28 days. Study No. 5L587, May 15, 1996. Mitsubishi Chemical Safety Institute Ltd., Ibaraki, Japan. Mitsubishi Chemical Safety Institute. 1996b. Bacterial reverse mutation study of T-6334. Study No. 5L585, February 28, 1996. Mitsubishi Chemical Safety Institute Ltd., Ibaraki, Japan. Mitsubishi Chemical Safety Institute. 1996c. Chromosomal aberration test of the mixture of 2-(difluoromethoxymethyl)-1,1,1,2,3,3,3-heptafluoropropane and 1,1,1,2,2,3,3,4,4-nonafluoro-4-methoxybutane in cultured mammalian cells. Study No. 5979. Mitsubishi Chemical Safety Institute Ltd., Ibaraki, Japan. NRC (National Research Council). 1993. Guidelines for Developing Community Emergency Exposure Levels for Hazardous Substances. Washington, DC: National Academy Press. NRC (National Research Council). 1996. Toxicity of Alternatives to Chlorocarbons: HFC-134a and HCFC-123. National Academy Press, Washington, DC. NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: National Academy Press. NRC (National Research Council). 2002. Acute Exposure Guideline Levels for Selected Airborne Chemicals, Vol. 2. Washington, DC: National Academy Press. Reinhardt, C.F., A. Azar, M.E. Maxfield, P.E. Smith, and L.S. Mullin. 1971. Cardiac arrhythmias and aerosol "sniffing." Arch. Environ. Health 22:265-279.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 APPENDIX A ACUTE EXPOSURE GUIDELINE LEVELS FOR HFE-7100 (CAS Reg. No. 163702-07-6 and 163702-08-7) DERIVATION SUMMARY AEGL-1 VALUES 10 min 30 min 1 h 4 h 8 h 2,500 ppm 2,500 ppm 2,500 ppm 2,500 ppm 2,500 ppm Key Reference: Coombs, D.W., C.K. Shepherd, M. Bannerman, C.J. Hardy, D. Cook, M. Hall and G.F. Healy. 1996a. T-6334: 13 Week repeat dose inhalation toxicity study in rats. MIN 196/961181, Huntingdon Life Sciences, Huntingdon, Cambridgeshire, England. Test Species/Strain/Number: Rats/Sprague-Dawley/20 males and 20 females. Exposure Route/Concentrations/Durations: Inhalation: 1,502, 4,550, 7,533, 15,159 ppm, 6 h/day, 5 days/week for 13 weeks. Effects: 1,502, 4,550, 7,533 ppm - no effects 15,159 ppm - reversible liver weight increase, minimal organ weight changes. End point/Concentration/Rationale: Reversible organ weight changes/15,159 ppm/no adverse effect with repeated exposures (changes attributed to repeat exposures). Uncertainty Factors/Rationale: Total uncertainty factor: 3 Interspecies: 1, uptake would be similar in primates and rodents, although based on higher respiratory rates and cardiac output, equilibrium would be reached more rapidly in rodents than primates. Intraspecies: 3, no significant toxicological end points identified; poor solubility in biological fluids. Modifying Factor: 2, limited data on humans; limited number of animals in several studies. Animal to Human Dosimetric Adjustment: Not applied. Time Scaling: Repeated nature of the exposures allows use of a single value across all timepoints.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 Data Adequacy: Well conducted repeat dose, subchronic, developmental/reproductive, neurotoxicity, and cardiac sensitization studies, but minimal human data and limited number of animals in several studies. AEGL-2 VALUES 10 min 30 min 1 h 4 h 8 h 8,200 ppm 8,200 ppm 8,200 ppm 8,200 ppm 8,200 ppm Key Reference: Kenny, T.J., C.K. Shepherd, M. Bannerman, C.J. Hardy, and I.S. Gilkison. 1996. T-6334: Assessment of cardiac sensitization potential in dogs. MIN 182/953117, Huntingdon Life Sciences, Limited, Huntingdon, Cambridgeshire, England. Support: Coombs, D.W., C.K. Shepherd, M. Bannerman, C.J., Hardy, D. Crook, M. Hall, E.W. Hughes, and C. Gopinath. 1996b. T-6334: 28-Day repeat dose inhalation toxicity study in rats. MIN 181/952688, Huntingdon Life Sciences, Huntingdon, Cambridgeshire, England. Test Species/Strain/Number: Dog/beagle/6 (Kenny et al. 1996). Rat/Sprague-Dawley/10 (Coombs et al. 1996b). Exposure Route/Concentrations/Durations: Inhalation/10,000, 18,000, 48,900, and 89,300 ppm/5 min prior to cardiac sensitization test (Kenny et al. 1996). Inhalation/0, 1,500, 3,000, 9,500, or 30,000 ppm for 6 h/d, 5 d/wk, for 4 wk (Coombs et al. 1996b). Effects: Kenny et al. 1996: 10,000 ppm: no effects 18,800 ppm: minimal effects 48,900 ppm: no clinical signs prior to administration of epinephrine; signs of stress following second dose of epinephrine (restlessness, trembling, limb rigidity). 89,300 ppm: severe signs of stress (salivation, tremors, limb rigidity) All dogs recovered; not a cardiac sensitizer when concurrently injected with epinephrine. Coombs et al. 1996b: No clinical signs at any concentration. End point/Concentration/Rationale: No signs of stress in dogs; not a cardiac sensitizer, 48,900 ppm

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 Uncertainty Factors/Rationale: Total uncertainty factor: 3 Interspecies: 1, both beagles and rats have higher respiratory rates and cardiac output than humans. Intraspecies: 3, no significant toxicological end points identified in other studies; poor solubility in biological fluids for all species. Modifying Factor: 2, limited data on humans, limited number of animals in several studies. Animal to Human Dosimetric Adjustment: Not applied Time Scaling: Not applied; low solubility of test compound in blood, rapidly reaches equilibrium; cardiac response does not change when chemical is administered for hours. Data Adequacy: Well conducted repeat dose, subchronic, developmental/reproductive, neurotoxicity, and cardiac sensitization studies. Limited human data; limited number of animals in some key studies. AEGL-3 VALUES 10 min 30 min 1 h 4 h 8 h 15,000 ppm 15,000 ppm 15,000 ppm 15,000 ppm 15,000 ppm Key Reference: Kenny, T.J., C.K. Shepherd, M. Bannerman, C.J. Hardy, and I.S. Gilkison. 1996. T-6334: Assessment of cardiac sensitization potential in dogs. MIN 182/953117, Huntingdon Life Sciences, Limited, Huntingdon, Cambridgeshire, England. Support: 3M Company. 1995. Acute inhalation toxicity for HFE-7100 in the rat. Unpublished memo, 3M Company, Toxicology Services, 3M Center, St. Paul, MN. Test Species/Strain/Number: Dog/beagle/6 (only 1 of 2 dogs observed 89,300 ppm) (Kenny et al. 1996). Rat/Sprague-Dawley/3 (3M Company 1995). Exposure Route/Concentrations/Durations: Inhalation/10,000, 18,800, 48,900, and 89,300 ppm/5 min (Kenny et al. 1996). Inhalation/100,000 ppm/4 h (3M Company 1995). Effects: Kenny et al. 1996. 10,000 ppm: no clinical signs. 18,800 ppm: no clinical signs. 48,900 ppm: no clinical signs prior to administration of epinephrine 89,300 ppm: severe clinical signs.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 3M Company 1995. 100,000 ppm for 4 h: no deaths. End point/Concentration/Rationale: Severe clinical signs/89,300 ppm/considered lethal threshold due to severity of signs. Supported by no deaths in rats at 100,000 ppm (3M Company 1995). Uncertainty Factors/Rationale: Total uncertainty factor: 3 Interspecies: 1—respiratory rate and cardiac output higher in beagles and rats than in humans. Intraspecies: 3—no significant toxicological end points identified in other studies; poor solubility in biological fluids for all species. Modifying Factor: 2—limited data on humans; limited number of animals in several studies. Animal to Human Dosimetric Adjustment: Not applied. Time Scaling: Not applied; low solubility of test compound in blood, rapidly reaches equilibrium; cardiac response does not change when chemical is administered for hours. Data Adequacy: Well conducted repeat dose, subchronic, developmental/reproductive, neurotoxicity, and cardiac sensitization studies. Limited human studies; limited number of animals in this and several support studies. The 89,300 ppm may be a conservative estimate of a lethal concentration as no rats died after a 4-h exposure to 100,000 ppm.