Toxicity of Alternatives to Chlorofluorocarbons HFC-134a and HCFC-123 (1996) / Chapter Skim
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APPENDIX A: SUPPORTING DOCUMENTATION FOR THE EXPOSURE GUIDANCE LEVELS FOR HYDROCHLOROFLUOROCARBON-123
APPENDIX A: SUPPORTING DOCUMENTATION FOR THE EXPOSURE GUIDANCE LEVELS FOR HYDROCHLOROFLUOROCARBON-123
Pages 43-112
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Williams Armstrong Laboratory Toxicology Division anti Toxic Hazards Research Unit Wright Patterson Air Force Base
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Personnel with potential military occupational exposure to Sallied Signal Inc., Material Safety Data Sheet (Attachment I)
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Vickers (Tynciall Air Force Base, Fla., personal common., 1994) , there are about three aircraft fires per Air Force wing per year.
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Both operative and reductive pathways participate in the metab olism of HCFC 123. The reductive pathway occurs only under conditions of very low oxygen tension and wouIcI not be expected to be a common route in man (Dodd et al., 1993~.
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compared the metabolism of HCFC 123 and halothane in rat and human liver microsomes. For rat liver microsomes, the rate of for mation of TFA from HCFC 123 was 3.1 nmoVmg per 20 min and the formation of TFA from halothane was 2.1 nmol/mg per 20 min.
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Potential toxicity slur ing acute exposure to HCFC 123 includes severe central nervous system (CNS3 depression and cardiac sensitization. The liver might be a target organ of concern following acute exposure to HCFC 123.
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the pharmacological actions, including cardiac arrhythmias ant! cardiac sensitization, of bromochiorodifluoromethane (BCF)
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50 Toxicity of CFC Alternatives Concentration Marked Test Compound (% vol/vol) Responses Percent Fluorocarbon 11 0.13 0/12 0 0.61 1/12 8.3 0.96 5/12 41.7 Fluorocarbon 12 2.5 0/12 0 5.0 5/12 41.7 Fluorocarbon 22 2.5 0/12 0 5.0 2/12 16 Fluorocarbon 114 2.5 1/12 8.3 5.0 7/12 58.3 Fluorocarbon 1301 5.0 0/62 0 7.5 1/18 5.5 15 8/69 11.6 20 2/7 28.6 8/13 61.5 Fluorocarbon 142b 2.5 0/6 0 5.0 5/12 41.7 10.0 12/12 100.0 Fluorocarbon 152a 5.0 0/12 0 15.0 3/12 25.0 Propane 5.0 0/6 0 10.0 2/12 16.7 20.0 7/12 58.3 Isobutane 2.5 0/12 0 5.0 4/12 33.3 10.020.0 6/6 100.0 Vinyl chloride 2.5 0/12 0 5.0 6/12 50.0 10.0 6/6 100.0 Dimethyl ether 10.0 0/6 0 20.0 2/12 16.7 30.0 2/6 33.3 Source: Adapted from Reinhardt et al.
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has re ceivec3 considerable attention, because the spectrum of liver injury observed in guinea pigs exposed to anesthetic concentrations (1%) of halothane resembles that observed in nonfatal halothane hepati tis in humans (Lunam et al., 19891.
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The tumor incidences of concern were increases in benign hepatocellular adenomas or he patic cholangiofibromas or both, increases in benign pancreatic acinar cell adenomas, and increases in interstitial cell adenoma in
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effects of the Halon replacement chemical and jet fuel combustion products. To accomplish this directive, a cle tailed air monitoring survey of representative training exercise test burns was conductecI by using Halon replacement cancliclates, in clucling HCFC 123, and by burning jet fuel.
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Recently, the U.S. Environmental Protection Agency contracted with Meridian Research, Inc., to assess occupational exposures to Halon substitutes used for fire protection Meridian Research Inc., 1992~.
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Meridian Research used a gas volume equivalent value of 1.97 for the mocleling of HCFC 123 concentrations; thus, the concentration of HCFC 123 catcu fated to be neecled to fight a fire was twice as much as that of Halon 1211. In the single person office scenario where 1 Ib of HCFC 123 was discharged in 10 sec in a 960 *
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effects, malignant hyperthermia, and hepatotoxicity. Cardiac sensitization was chosen as the most sensitive end point because of the potent sensitizing effect of this chemical and similar chemicals in the epinephrine challenged dog model.
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1 3 4 Exposure Concentration, % 5 FIGURE 1 Extrapolation from the measured blood concentration at the NOEL The l min line connects blood concentrations measured after a l min exposure to 1% and 5% HCFC 123.
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Hepatoto~city due to HCFC 123 was observed in guinea pigs exposed once for 4 hr to HCFC 123 concentrations of 3%, 2%, I%, or 0.~%. However, the selection of cardiac sensitization as the most sensitive end point for a ~ min EEGL is still consiclerec!
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· No information is available on the potential for HCFC 123 to produce liver toxicity in guinea pigs at short (~30 mini exposure times. The impact of a ~ min exposure would!
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1982. Acute inhalation toxicity of some halogenated and non halogenated hydrocarbons.
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1989. The patho~ogy of halothane hepatotoxicity in a guinea pig moclel: A comparison with human halothane hepatitis.
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1991. Aer obic dehalogenation of halothane showing different substrate depend ency from anaerobic dehalogenation in liver microsomes of guinea pigs.
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1973. Cardiac Sensitization Po tential (EC50)
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. Material Safety Data Sheet
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Attachment 2 Halothane BACKGROUND INFORMATION Physical and Chemical Properties Chemical formula: Molecular weight: Chemical names: C2HBrCIF3 197.39 2 Bromo 2 chloro 1,1,1 trifluoroeth ane, bromochlorotrifluoroethane, 1,1,1 trifluoro 2,2 chlorobromoethane, Fluothane CAS number: 151 67 7 Physical state: Highly volatile liquid Density at 20: 1.871 Boiling point: 50.2°C Vapor pressure: Solubility: General characteristics: 243 mm Hg (it? 20°C Soluble in water 0.345%; miscible in petroleum ether, other fat solvents Inflammable, sensitive to light, may be stabilized with 0.01% thymol 79
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with cardiac sensitization, malignant hyperthermia, or hepatotox icily. Each of these manifestations of toxicity wtI!
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In one group of 17 dogs exposed to 1.36% halothane, the mean fatal close of epinephrine was 5.1 + 5.1 ~g/kg. The extreme variability in the epinephrine dose neces sary to produce fatal ventricular fibrillation in 13 of 17 dogs sug gested that other factors may have altered inclividual susceptibility.
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However, confounding factors, such as inexact exposure concentra lions, premectications, ventilation rates, and disease state, combine to add uncertainly to the analysis. Two examples demonstrate typi cat ciata: Incidence, % End Point, Cases (no.)
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Malignant Hyperthermia In humans, inhalation anesthetics, primarily halothane, can in cluce skeletal muscle rigidity, hypermetabolism, and high fever, which can cause irreversible tissue damage and death. These ef fects, caller!
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in such diseases as halothane incluced hepatitis in humans and inhalant induced cardiac sensitization in dogs (Trochimow~cz ant! Mullin, 19731.
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(19841. The following table summarizes halo thane test procedures used by other investigators using the MH positive end point of muscle rigidity: Test time, men 20~3;thenl7)
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evaluate the mechanisms of acute liver injury proclucecI by halothane, a laboratory animal model was developed by using the guinea pig (l~unam et al., 1985; Lind et al., 19871. The spectrum of liver injury observed in guinea pigs exposer} to halo thane resembles that observed in nonfatal halothane hepatitis in humans (Lunam et al., 1989~.
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Of lLO guinea pigs exposed to I% halothane ant! evaluated 2 days following exposure, four hac!
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to either 0.~% or I% HCFC 123 had minimal to milc3 liver lesions that were similar to those observed in guinea pigs exposed to 0.~% halo thane (Link et al., 1992~. These preliminary (unpublished results of the guinea pig study with HCFC 123 indicate that halo thane is more potent than HCFC 123 in producing hepatotoxicity in the guinea pig model.
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1987. Halo thane hepatotoxicity in guinea pigs.
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1991. Evidence for intraluminal C a++ regulatory site defect in sarcoplasmic reticulum from malignant hyperthermia pig muscle.
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Pp. 113 140 in Malignant Hyperthermia, I.A.
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Attachment 3 Summary of Toxicity Studies of HCFC- ~ 23 I
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94 Toxicity of CFC Alternatives Source: Raventos and Lemon, 1965 Mouse micronucleus genotoxicity test: 2,000, 6,000, 18,000 ppm x 6 hr Toxicity in all groups, but no micronuclei in bone' marrow erythrocytes Source: Muller and Hoftnann, 1988 Rat LCso: 32,000 ppm (4 hr) 4 hr dose, ppm 55,000 52,500 42,100 33,700 32,000 20,700 Mortality 6/6 6/6 4/6 3/6 3/6 0/6 CNS depression observed at all closes Source: Hall and Moore, 1975 I~C50: 52,575 ppm (6 hr)
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- Attachment 3: HCFC-123 Summary 95 Source Coate, 1976 L~Cso 35,000 ppm (4 hr) Source: Waritz and Clayton, 1966 L~D~o Ravage in corn oil; 20 50% solutions)
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ANIMAL STUDIES: REPEAT EXPOSURE A General Toxicity 1.
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; relative liver weight increase (in the high exposure level males and in all three HCFC 123 exposure level females; these increases were dose related- reversible) ; initial diagnosis of liver lesions (reversible)
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; body weight gain and food consump lion decreases (males at 5,000 ppm; females at 1,000 and 5,000 ppm) ; serum glucose and triglyceride de creases (males and females at all doses)
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; increased incicler~ce of neoplas tic ant} non neoplastic morphological changes and hepatic peroxi somal beta oxidation increases (at all doses) ; increased tumor inciclences of concern benign hepatocellular adenomas anchor hepatic cholangiofibromas, benign pancreatic acinar cell adenomas, and infers titiai cell adenoma in the testes
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CNS depression cluring exposure, equivocal fetal toxicity, and no terata Source: Culik and Kelly, 1976 5,000 ppm x 6 hr/day x 10 gestation clays (gestation days 6 15) Maternal body weight gain decrease, no fetal toxicity Source: IBT, 1977 2.
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1981. An acute inhalation toxicity study of fluoro carbon 123 in the Chinese hamster.
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1973. Cardiac sensitization potential (EC50)
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Technical Report No. AL/OE'TR 1995 0025,, Armstrong Laboratory, Wright Patterson Air Force Base, Ohio.
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, I, 2, 3, 4, 5, 7.5, 10, 15, 30, 45, and 60 min during expo sure and I, 3, 6, 16, and 31 min after exposure and analyzed for HCFC 123. At the end of the exposure periods, animals were euthanizecI and samples from selected tissues (heart, liver, fat, ant!
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105 ,/ i 111 11 ~ o of: ~ Q -Al o -Al o o U]
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He catheter was attached to a three way valve so that heparinized saline could be used to flush the catheter. A 3 mL glass syringe was used to draw blood samples.
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Figures 4 and 5 are graphs of the triplicate blood concentrations at the early time points for all animals exposed to I% and 5% HCFC 123, respectively. The experimental design allowed for the sampling of eight animals at LO min cluring the I% exposure con centrations.
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108 .= ¢ ID 3 V o Is 5~ o o .e o ·4-, ~ ~ o o o CS~ ~ Cat Cal ~ ~ Cal ~ Go Lit ~ ~ ·e e e U1 00 ee e e [A ~ ~ ~ e e e e ~ ~ t- _d e e e e O ~ ~ ~ 1 1 1 1 O ~ ` ~·e ~ e eO C~ I I I I · e· 00 U~ _1 e ~ co e ~ ~ 00 ~ _1 C~ ~I I I e ~l l CX)
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Exposure Concentration and Exposure Time Heart Muscle Liver Fat Animal I.D. 1% for 1 min 14.7 13.8 12.9 2.1 1999 6.7 7 5.1 0.6 1974 1% for 5 min 15.8 5.5 14.6 15.9 1975 18.6 7.2 19.5 13.9 1986 1% for 60 min 39.4 34.7 51.1 199.1 1992 37.9 66.6 46 182.2 1995 1% for 30 min after 2.5 5.3 2.2 118.5 1993 60 min exposure 2.6 10.2 3.6 195.3 1994 5% for 1 min 107.4 24.9 75.8 3.9 1979 94.8 29.1 48.2 9.7 1990 5%for5 min 141 39.5 81.8 78.3 1997 179.8 36.4 174.9 46.2 1983 70 60 50 40 30 20 10 O o + ...
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$ ....= ...~.... $ , .- , ~T ~ I r 1 ~ 1 0 1 2 3 4 Minutes 5 6 7 FIGURE 4 1% HCFC 123 dog blood levels for all exposed ani mars.
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DISCUSSION Analysis of the pharmacokinetics from this study facilitates ex trapolating the 5 min cardiac sensitization level to the l min level. As expected, both blood and tissue concentrations increased with exposure time and increasing concentration.
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TABLE 4 Blood and Tissue Concentrationsa in Dogs Exposed by Inhalation to 1% or 5% HCFC 123 1% HCFC 123 5% HCFC 123 Sample 1 min 5 mitt 1 mitt 5 min Blood 5.2 9.0 21.4 114.9 (4.1 7.6)
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