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Suggested Citation:"REFERENCES." National Research Council. 2000. Submarine Exposure Guidance Levels for Selected Hydrofluorocarbons: HFC-236fa, HFC-23,and HFC-404a. Washington, DC: The National Academies Press. doi: 10.17226/9815.
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Suggested Citation:"REFERENCES." National Research Council. 2000. Submarine Exposure Guidance Levels for Selected Hydrofluorocarbons: HFC-236fa, HFC-23,and HFC-404a. Washington, DC: The National Academies Press. doi: 10.17226/9815.
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Suggested Citation:"REFERENCES." National Research Council. 2000. Submarine Exposure Guidance Levels for Selected Hydrofluorocarbons: HFC-236fa, HFC-23,and HFC-404a. Washington, DC: The National Academies Press. doi: 10.17226/9815.
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Suggested Citation:"REFERENCES." National Research Council. 2000. Submarine Exposure Guidance Levels for Selected Hydrofluorocarbons: HFC-236fa, HFC-23,and HFC-404a. Washington, DC: The National Academies Press. doi: 10.17226/9815.
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Suggested Citation:"REFERENCES." National Research Council. 2000. Submarine Exposure Guidance Levels for Selected Hydrofluorocarbons: HFC-236fa, HFC-23,and HFC-404a. Washington, DC: The National Academies Press. doi: 10.17226/9815.
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Suggested Citation:"REFERENCES." National Research Council. 2000. Submarine Exposure Guidance Levels for Selected Hydrofluorocarbons: HFC-236fa, HFC-23,and HFC-404a. Washington, DC: The National Academies Press. doi: 10.17226/9815.
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Suggested Citation:"REFERENCES." National Research Council. 2000. Submarine Exposure Guidance Levels for Selected Hydrofluorocarbons: HFC-236fa, HFC-23,and HFC-404a. Washington, DC: The National Academies Press. doi: 10.17226/9815.
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HYDROFLUOROCARBON-404A 76 These values can be converted to parts per million as follows: HFC-143a: 9,017 mg/m3× 0.29 = 2,615 ppm HFC-125: 7,630 mg/m3 × 0.20 = 1,526 ppm HFC-134a: 694 mg/m3 × 0.24 = 167 ppm. 24-hr EEGL of HFC-404a = 2,615 + 1,526 + 167 ≈ 4,300 ppm. 90-day CEGL: Of the mixture, 52% or 3,064 mg/m3 × 0.52 = 1,593 mg/m3 is HFC-143a 44% or 3,064 mg/m3 × 0.44 = 1,348 mg/m3 is HFC-125 4% or 3,064 mg/m3 × 0.04 = 123 mg/m3 is HFC-134a. These values can be converted to parts per million as follows: HFC-143a: 1,593 mg/m3 × 0.29 = 462 ppm HFC-125: 1,348 mg/m3 × 0.20 = 270 ppm HFC-134a: 123 mg/m3× 0.24 = 30 ppm. 90-day CEGL of HFC-404a = 462 + 270 + 30 = 800 ppm. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 1999. TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents. Biological Exposure Indices. Cincinnati, OH.: American Conference of Governmental Industrial Hygienists. AIHA (American Industrial Hygiene Association). 1991. Workplace Environmental Exposure Level Guide: 1,1,1,2-Tetrafluoroethane. Akron, OH.: American Industrial Hygiene Association. AIHA (American Industrial Hygiene Association). 1996. Workplace Environmental Exposure Level: 1,1,1-Trifluoroethane. Fairfax, Va.: American Industrial Hygiene Association.

HYDROFLUOROCARBON-404A 77 Alexander, D.J., and S.E. Libretto. 1995. An overview of the toxicology of HFA-134a (1,1,1,2- tetrafuloeoethane). Human Exper. Toxicol. 14:715-720. Alexander, D.J., E. Mortimer, G.D. Dines, S.E. Libretto, and D.N. Mallett. 1995. One-year study in dogs of the toxicity of HFA-134a by inhalation. Inhalation Toxicol. 7:1153-1162. Alexander, D.J., S.E. Libretto, M.J. Adams, E.W. Hughes, and M. Bannerman. 1996. HFA-134a (1,1,1,2-tetrafluoroethane): effects of inhalation exposure upon reproductive performance, development and maturation of rats. Human Exp. Toxicol. 15:508-517. Anderson, D., and C.R. Richardson. 1979. Arcton 134a: A Cytogenetic Study in the Rat. Study Number SR0002, Report Number CTL/P/444, Central Toxicology Laboratoy, ICI, England. Araki, A. 1991. Report on Reverse Mutation Assay in Bacteria on Tetrafluoroethane. Japan Bioassay Laboratory, Study Nos. 5292 & 5312. Japan Industrial Safety and Health Association. Asakura, M. 1991. Report on a Chromosomal Aberration Test of 1,1,1,2-Tetrafluoroethane in Cultured Mammalian Cells. Japan Bioassay Laboratory, Study Number 5879. Japan Industrial Safety and Health Association. Azar, A., H.J. Trochimowicz, J.B. Terrill, and L.S. Mullin. 1973. Blood levels of fluorocarbon related to cardiac sensitization. Am. Ind. Hyg. Assoc. J. 34:102-109. Barton, S.J., P. McDonald, and J. Sandow. 1994. HFA-134a Study of the Effects on Testicular Endocrine Function After Inhalation Exposure (6 h per day). IRI Project No. 490704. Study prepared by Inveresk Research International, Tranent, Scotland, for International Pharmaceutical Aerosol Consortium for Toxicology Testing, Washington, D.C. Brock, W.J., H.J. Trochimowicz, C.H. Farr, R.J. Millischer, and G.M. Rusch. 1996. Acute, subchronic, and developmental toxicity and genotoxicity of 1,1,1-trifluoroethane (HFC-143a). Fundam. Appl. Toxicol. 31:200-209. Brooker, A.J., P.J. Brown, D.M. John, and D.W. Coombs. 1992. The Effect of HFC 125 on Pregnancy of the Rabbit. Report No. ALS 10/920856. Huntingdon Research Centre, Cambridgeshire, England. Brusick, D.J. 1976. Mutagenicity data of Genetron 134a. Final Report, LBI Report No. 2683, (unpublished data), Litton Bionetics. Callander, R.D., and K.P. Priestley. 1990. HFC 134a. An Evaluation Using the Salmonella Mutagenicity Assay. Report No. CTL/P/2422, Central Toxicology Laboratory, (unpublished data), ICI, England. Collins, M.A. 1984. HFC 134a: Acute Toxicity in Rats to Tetrafluoroethane. Unpublished data from Central Toxicology Laboratory, ICI, England. Collins, M.A., G.M. Rusch, F. Sato, P.M. Hext, and R.J. Millischer. 1995. 1,1,1,2- Tetrafluoroethane: repeat exposure inhalation toxicity in the rat, developmental toxicity in the rabbit, and genotoxicity in vitro and in vivo. Fundam Appl. Toxicol. 25:271-280. Dance, C.A., and G. Hodson-Walker. 1992. In Vitro Assessment of the Clastogenic

HYDROFLUOROCARBON-404A 78 Activity of HFC 125 in Cultured Chinese Hamster Ovary (CHO) Cells. LSR Report No. 91/PAR006/1015a. Life Science Research Ltd., Eye, Suffolk, England. Dance, C.A., K.E. Beach, and G. Hodson-Walker. 1992. In Vitro Assessment of the Clastogenic Activity of HFC 125 in Cultured Human Lymphocytes. LSR Report No. 91/ PAR005/1014a. Life Science Research Ltd., Eye, Suffolk, England. DuPont Company. 1994. Metabolism of HFC-143a in the Rat. Haskell Laboratory Report No. 3-94. (Unpublished data.) Haskell Laboratory, E.I. du Pont de Nemours & Co., Newark, DE. ECETOC (European Centre for Ecotoxicology and Toxicology of Chemicals). 1994. Joint Assessment of Commodity Chemicals No. 24, Pentafluoroethane (HFC-125), May, 1994. [ISSN-0773-6339-24]. ECETOC (European Centre for Ecotoxicology and Toxicology of Chemicals). 1995. Joint Assessment of Commodity Chemicals No. 31, 1,1,1,2-Tetrafluoroethane (HFC-134a), February, 1995. [ISSN-0773-6339-31]. Edwards, C.N., G. Hodson-Walker, and S. Cracknell. 1992. HFC 125: Assessment of Clastogenic Action on Bone Marrow Erythrocytes in the Micronucleus Test. LSR Report No. 92/ PAR004/0148. Life Science Research Ltd., Eye, Suffolk, England. Ellis, M.K., L.A. Gowans, T. Green, and R.J.N. Tanner. 1993. Metabolic fate and disposition of 1,1,1,2-tetrafluoroethane (HFC134a) in rat following a single exposure by inhalation. Xenobiotica 23:719-729. Emmen, H.H., and E.M.G. Hoogendijk. 1999. Report on an Ascending Dose Safety Study Comparing HFA-134a with CFC-12 and Air, Administered by Whole-Body Exposure to Healthy Volunteers. TNO Report V98.754 – Vol. 1 and 2, Zeist, The Netherlands: TNO Nutrition and Food Research Institute. EPA ( U.S. Environmental Protection Agency). 1986. Guidelines for Health Risk Assessment of Chemical Mixtures. 51 FR 34014. Sept, 24. Finch, J.R., E.J. Dadey, S.L. Smith, L.I. Harrison, and G.A. Digenis. 1995a. Dynamic monitoring of total-body absorption by 19F NMR spectroscopy: one hour ventilation of HFA-134a in male and female rats. Magn. Reson. Med. 33:409-413. Finch, J.R., W.R. Banks, D.R. Hwang, M.R. Satter, B. Ezzidene, J.C. Mantil, and G.A. Digenis. 1995b. Synthesis and in vivo disposition studies of 18F-labeled HFA-134a. Appl. Radiat. Isot. 46:241-248. Groten J.P., E.D. Schoen, P.J. van Bladeren, C.F. Kuper, J.A. van Zorge, and V.J. Feron. 1996. Subacute toxicity of a mixture of nine chemicals in rats: detecting interactive effects with a fractionated two-level factorial design. Fundam. Appl. Toxicol. 36:15-29. Hardy, C.J. 1992. Assessment of Cardiac Sensitization Potential in Dogs: Comparison of HFC-125 and Halon 13B1 Report No. ALS11/920116. Huntingdon Research Centre Ltd., Cambridgeshire, England. Hardy, C.J., I.J. Sharman, and G.C. Clark. 1991. Assessment of Cardiac Sensitization Potential in Dogs. Rep. No. CTL/C/2521. Huntingdon Research Centre, Cambridgeshire, U.K. Harris, J.W., J.P. Jones, J.L. Martin, A.C. La Rosa, M.J. Olson, L.R. Pohl, and M.W. An

HYDROFLUOROCARBON-404A 79 ders. 1992. Pentahaloethane-based chlorofluorocarbon substitutes and halothane: correlation of in vivo hepatic protein-trifluoroacetylation and urinary trifluoroacetic acid excretion with calculated enthalpies of activation. Chem. Res. Toxicol. 5:720-725. Harrison, L.I., D. Donnell, J.L. Simmons, B.P. Ekholm, K.M. Cooper, and P.J. Wyld. 1996. Twenty- eight-day double-blind safety study of an HFA-134a inhalation aerosol system in healthy subjects. J. Pharm. Pharmacol. 48:596-600. Hext, P.M. 1989. HFC-134a: 90-Day Inhalation Toxicity Study in the Rat. ICI Rep. No. CTL/ P/2466. Central Toxicology Laboratory, Imperial Chemical Industries, Alderley Park, Macclesfield, Cheshire, U.K. Hext, P.M., and R.J. Parr-Dobrzanski. 1993. HFC-134a: A 2-Year Inhalation Toxicity Study in the Rat. ICI Rep. No. CTL/P/3841. Central Toxicology Laboratory, Imperial Chemical Industries, Alderley Park, Macclesfield, Cheshire, U.K. Hodge, M.C.E., M. Kilmartin, R.A. Riley, T.M. Weight, and J. Wilson. 1979a. Arcton 134a: Teratogenicity Study in the Rat. ICI Rep. No. CTL/P/417. Central Toxicology Laboratory, Imperial Chemical Industries, Alderley Park, Macclesfield, Cheshire, U.K. Hodge, M.C.E., D. Anderson, I.P. Bennett, and T.M. Weight. 1979b. Arcton 134a: Dominant Lethal Study in the Mouse. ICI Rep. No. CTL/P/437, Central Toxicology Laboratory, Imperial Chemical Industries, Alderley Park, Macclesfield, Cheshire, U.K. ICI Chemicals & Polymers. 1991. Cardiac Sensitization Study in Dogs. [Personal communication]. I.C.I. Chemicals & Polymers, Attn: Dr. David Farrar. P.O. Box 14, The Heath, Runcorn, Cheshire WA7 4QG, England. Kawano, T., H.J. Trochimowicz, G. Malinverno, and G.M. Rusch. 1995. Toxicological evaluation of 1,1,1,2,2-pentafluororethane (HFC-125). Fundam. Appl. Toxicol. 28:223-231. Krishnan, K., and J. Brodeur. 1991. Toxicological consequences of combined exposures to environmental pollutants. Arch. Complex Environ. Studies 3:1-106. Longstaff, E., M. Robinson, C. Bradbrook, J.A. Styles, and I.F.H. Purchase. 1984. Genotoxicity and carcinogenicity of fluorocarbons: assessment by short-term in vitro tests and chronic exposure in rats. Toxicol. Appl. Pharmacol. 72:15-31. Lu, M., and R. Staples. 1981. 1,1,1,2-Tetrafluoroethane (FC-134a): Embryo-Fetal Toxicity and Teratogenicity Study by Inhalation in the Rat. Report No. 317-81. Haskell Laboratory, Wilmington, DE. Mackay, J.M. 1990. HFC 134a. An Evaluation in the in Vitro Cytogenetic Assay in Human Lymphocytes. Report Number CTL/P/2977, Central Toxicology Laboratory, ICI, England. Master, R.E., R.J. Brown, D.M. John, and D.W. Coombs. 1992. A Study of the Effect of HFC 125 on Pregnancy of the Rat (Inhalation Exposure). Report No. ALS 9/920434. Huntingdon Research Centre Ltd., Cambridgeshire, England. May, K., D. Watson, and G. Hodson-Walker. 1992. HFC 125 in Gaseous Phase: Assessment of Mutagenic Potential in Amino Acid Auxotrophs of Salmonella

HYDROFLUOROCARBON-404A 80 Typhimurium and Escherichia Coli (the Ames Test). LSR Report No. 91/PAR003/1152a. Life Science Research Ltd., Eye, Suffolk, England. Mehendale, H.M. 1994. Amplified interactive toxicity of chemicals at nontoxic levels: mechanistic considerations and implications to public health. Environ. Health Perspect. 102 (Suppl. 9):139-149. Mercier, O. 1989. HFA-134a: Test to Determine the Index of Primary Cutaneous Irritation in the Rabbit. Report No. 911422. Hazelton, France. Mercier, O. 1990a. HFA-134a: Test to Evaluate the Ocular Irritation in the Rabbit. Report No. 912349. Hazelton, France. Mercier, O. 1990b. HFA-134a: Test to Evaluate the Sensitising Potential by Topical Applications in the Guinea Pig. The Epicutaneous Maximisation Test. Report No. 001380. Hazelton, France. Monte, S.Y., I. Ismail, D.N. Mallett, C. Matthews, and R.J. Tanner. 1994. The minimal metabolism of inhaled 1,1,1,2-tetrafluoroethane to trifluoroacetic acid in man as determined by high sensitivity 19F nuclear magnetic resonance spectroscopy of urine samples. J. Pharm. Biomed. Anal. 12:1489-1493. Müller, W., and T. Hofmann. 1989. CFC 134a: Micronucleus Test in Male and Female NMRI Mice After Inhalation. Study Number 88.1244. Pharma Research Toxicology and Pathology, Hoechst AG, Federal Republic of Germany. Mullin, L.S., and R.W. Hartgrove. 1979. Cardiac Sensitization. Rep. No. 42-79. Haskell Laboratory, Wilimington, DE. Mullin, L.S., C.F. Reinhardt, and R.E. Hemingway. 1979. Cardiac arrhythmias and blood levels associated with inhalation of Halon 1301. Am. Ind. Hyg. Assoc. J. 40:653-658. Mumtaz, M.M., and P.R. Durkin. 1992. A weight-of-evidence approach for assessing interactions in chemical mixtures. Toxicol. Ind. Health 8:377-406. Mumtaz, M.M., C.T. DeRosa, and P.R. Durkin. 1994. Approaches and challenges in risk assessments of chemical mixtures. Pp. 565-597. In: Toxicology of Chemical Mixtures: Case Studies, Mechanisms, and Novel Approaches, R.S.H. Yang, ed., San Diego, CA.: Academic Press. Mumtaz, M.M., C.T. De Rosa, J. Groten, V.J. Feron, H. Hansen, and P.R. Durkin. 1998. Estimation of toxicity of chemical mixtures through modeling of chemical interactions. Environ Health Perspect. 106( suppl 6.): 1353-1360. NRC (National Research Council). 1996. Toxicity of Alternatives to Chlorofluorocarbons: HFC-134a and HCFC-123. Washington D.C.: National Academy Press. Nakayama, E., K. Nagano, M. Ohnishi, S. Katagiri, and O. Montegi. 1992a. Acute Inhalation Toxicity Study of 1,1,1,2,2-Pentafluoroethane in Rats. Study No. 0184. Japan Bioassay Laboratory, Hirasawa, Japan. Nakayama, E., K. Nagano, M. Ohnishi, and O. Montegi. 1992b. Four-week Inhalation Study of 1,1,1,2,2-Pentafluoroethane (HFC 125) in Rats. Study No. 0182. Japan Bioassay Laboratory, Hirasawa, Japan. Nakayama, E., K. Nagano, M. Ohnishi, and O. Montegi. 1993. Thirteen-week Inhalation Toxicity Study of 1,1,1,2,2-Pentafluoroethane (HFC 125) in Rats. Study No. 0197, Japan Bioassay Laboratory, Hirasawa, Japan.

HYDROFLUOROCARBON-404A 81 Nikijenko, T.K., and M.S. Tolgskaya. 1965. On the toxico-pathomorphological changes in animals under the effect of Freons-141, 142, and 143, and the intermediate products of their production. [Russian]. Gig. Tr. Prof. Zabol. 9:37-44. Olson, M.J., and S.E. Surbrook, Jr. 1991. Defluorination of the CFC-substitute 1,1,1,2- tetrafluoroethane: comparison in human, rat and rabbit hepatic microsomes. Toxicol. Lett. 59:89-99. Olson, M.J., C.A. Reidy, and J.T. Johnson. 1990a. Defluorination of 1,1,1,2-tetrafluoroethane (R-134a) by rat hepatocytes. Biochem. Biophys. Res. Commun. 166:1390-1397. Olson, M.J., C.A. Reidy, J.T. Johnson, and T.C. Pederson. 1990b. Oxidative defluorination of 1,1,1,2-tetrafluoroethane (R-134a) by rat liver microsomes. Drug Metab. Dispos. 18:992-998. Olson, M.J., S.G. Kim, C.A. Reidy, J.T. Johnson, and R.F. Novak. 1991. Oxidation of 1,1,1,2- tetrafluoroethane in rat liver microsomes is catalyzed primarily by cytochrome P450IIE1. Drug Metab. Dispos. 19:298-303. PAFT (Programme for Alternative Toxicology Testing). 1989. Toxicology Forum, European Symposium, Toulouse, France. Panepinto, A.S. 1990. Four Hours Inhalation Approximate Lethal Concentrations (ALC) of HFC 125, Haskell Laboratory Report 582-90, Haskell Laboratory, DuPont. Pike, V.W., F.I. Aigbirhio, C.A.J. Freemantle, B.C. Page, C.G. Rhodes, S.L. Waters, T. Jones, P. Olsson, G.P. Ventresca, R.J.N. Tanner, M. Hayes, and J.M.B. Hughes. 1995. Disposition of inhaled 1,1,1,2-tetrafluoroethane (HFA134A) in healthy subjects and in patients with chronic airflow limitation. Measurement by 18F-labeling and whole-body γ-counting. Drug Metab. Dispos. 23:832-839. Riley, R.A., I.P. Bennet, I.S. Chart, C.W. Gore, M. Robinson, and T.M. Weight. 1979. Arcton 134a: Subacute Toxicity to the Rat by Inhalation. ICI Rep. No. CTL/P/463, Central Toxicology Laboratory, Imperial Chemical Industries, Alderley Park, Macclesfield, Cheshire, U.K. Rissolo, S.B., and J.A. Zapp. 1967. Acute Inhalation Toxicity. Rep. No. 190-67, Haskell Laboratory, Wilmington, DE. Silber, L.S., and G.L. Kennedy. 1979a. Acute Inhalation Toxicity of Tetrafluoroethane. Rep. No. 422-79. Haskell Laboratory, Wilmington, DE. Silber, L.S., and G.L. Kennedy. 1979b. Subacute Inhalation Toxicity of Tetrafluoroethane (FC-134a). Rep. No. 228-79. Haskell Laboratory, Wilmington, DE. Surbrook, S.E., Jr., and M.J. Olson. 1992. Dominant role of cytochrome P-450 2E1 in human hepatic microsomal oxidation of the CFC-substitute 1,1,1,2-tetrafluoroethane. Drug Metab. Dispos. 20:518-524. Teuschler, L.K., and R.C. Hertzberg. 1995. Current and future risk assessment guidelines, policy, and methods development for chemical mixtures. Toxicology 105:137-144. Trochimowicz, H.J., A. Azar, J.B. Terrill, and L.S. Mullin. 1974. Blood levels of fluorocarbon related to cardiac sensitization: Part II. Am. Ind. Hyg. Assoc. J. 35:632-639. Trueman, R.W. 1990. HFC 134a: Assessment for the Induction of Unscheduled DNA

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As part of the effort to phase out the use of stratospheric ozone-depleting substances, such as chlorofluorocarbons (CFCs), the U.S. Navy is considering hydrofluorocarbons (HFCs) as replacements for the CFC refrigerants used aboard its submarines. Before using the HFCs, the Navy plans to set emergency exposure guidance levels (EEGLs) and continuous exposure guidance levels (CEGLs) to protect submariners from health effects that could occur as a result of accidental releases or slow leaks.

In this report, the Subcommittee on Exposure Guidance Levels for Selected Hydrofluorocarbons of the National Research Council's (NRC 's) Committee on Toxicology independently reviews the scientific validity of the Navy's proposed 1-hr and 24-hr EEGLs and 90-day CEGLs for two of the candidate refrigerants-HFC-236fa and HFC-404a. In addition, the subcommittee reviews the the EEGLs and CEGL for HFC-23, one of the combustion products of HFC-236fa. This NRC report is intended to aid the Navy in using HFCs safely.

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