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Iodotrifluoromethane: Toxicity Review 1 Introduction Several halocarbons—chlorofluorocarbons (CFCs), halons (chlorofluorobromines), carbon tetrachloride, and methyl chloroform—have been found to deplete the stratospheric ozone layer and thus to allow greater than normal amounts of harmful ultraviolet radiation to reach the earth. Such an increase in ultraviolet radiation could have devastating health consequences. The U.S. Environmental Protection Agency (EPA) estimated that by 2075 there could be over 150 million new cases of skin cancer in the United States alone that could be attributed to increased ultraviolet radiation (52 Fed. Reg. 47492 ). In addition, an increase in ultraviolet radiation can increase the incidence of eye cataracts and cause a general weakening of the immune system. Concerns about ozone-depleting substances led to the adoption of the Montreal Protocol on Substances That Deplete the Ozone Layer,1 and this internationally accepted agreement (signed by the United States on September 16, 1987) has led to bans on the production and use of halons and CFCs. The U.S. Army has used Halon 1301 as a fire extinguishant in a number of rotary-aircraft engines (for example, Apache, Kiowa, Comanche, Chinook, Black Hawk, and Cobra) and in ground-vehicle engines and personnel compartments (including armored personnel carriers, interim armored vehicles, Crusader, medium tactical vehicles, Abrams, and Bradley) (Vitali 2003). Halon 1301 is a colorless, odorless, inert gas that is low in toxicity, and it has been particularly effective in protecting 1 Information on the Montreal Protocol may be found at http://www.unep.org/ozone/pdfs/Montreal-Protocol2000.pdf.
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Iodotrifluoromethane: Toxicity Review essential electronic equipment, crew compartments in combat vehicles, machinery spaces in military ships, and high bay rooms for flight simulators (Wickham 2002). The Army has begun a search to identify Halon 1301 replacements, such as hydrofluorocarbons (HFCs) and hydrochlorofluorocarbons (HCFCs). In 1994, the United States under the Clean Air Act (CAA) banned the production and import of ozone-depleting substances, including halons (Halon 1211, 1301, and 2402). Those halons are being replaced with HFCs, HCFCs, and other chemicals. Before the use of these halon replacements by the Army, they must be reviewed to ascertain their ozone-depleting potential, as well as their efficacy, toxicity, flammability, and exposure potential. Iodotrifluoromethane (trifluoroiodomethane, trifluoromethyl iodide, trifluoroiodide, FIC-1311, CF3I; Chemical Abstract, Service number 2314-97-8) is one of several candidate compounds under consideration by the Army (and others) as a replacement for Halon 1301. CFCs and halon substitutes have been the subjects of scientific inquiry and scrutiny by numerous organizations, such as EPA, the National Fire Protection Association (NFPA), and the U.S. Occupational Safety and Health Administration (OSHA). EPA, under Section 612 of the CAA, is required to “evaluate substitutes for ozone-depleting substances in an effort to reduce risk to human health and the environment.” The EPA Significant New Alternatives Policy (SNAP) was established to conduct the evaluations of these substitutes and to generate a list of acceptable substitutes for major industrial use sectors. The SNAP-use sectors include refrigeration and air conditioning; foam blowing; solvent cleaning; fire suppression and explosion protection; sterilants; aerosols; adhesives, coatings, and inks; and tobacco-fluffing agents. EPA defines “substitute” as “any chemical, product substitute, or alternative manufacturing process, existing or new, intended for use as a replacement for a Class I or Class II substance.”2 In 1995, EPA published a final rule under the SNAP program to accept CF3I as a substitute for Halon 1301 in “normally unoccupied areas only” (60 Fed. Reg. 31092 ). The rule stated that any employee who could possibly be in the area must be able to escape within 30 seconds (sec), 2 Class I substances include CFCs, halons, carbon tetrachloride, methyl chloroform, methyl bromide, and hydrobromofluorocarbon. Class II (hydrochlorofluorocarbon) substances are those with any substitute that the EPA administrator determines may present adverse effects to human health or the environment where the administrator has identified an alternative that (1) reduces the overall risk to human health and the environment, and (2) is currently or potentially available (40 Code of Federal Regulations 82.172).
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Iodotrifluoromethane: Toxicity Review and the employer must ensure that no unprotected employees enter the area during agent discharge. In 1997, EPA published a final rule accepting CF3I as a substitute for another halocarbon, Halon 1211, used for fire suppression in nonresidential applications only (61 Fed. Reg. 25585 ). EPA prohibits consumer residential applications of CF3I. The SNAP program now recommends that use of CF3I be in accordance with the safety guidelines in the latest edition of the NFPA 2001 Standard on Clean Agent Fire Extinguishing Systems (67 Fed. Reg. 4185 ). The 2001 Standard (NFPA 2000) is a guidance document that contains minimal requirements for total-flooding clean fire-extinguishing systems. It states that a human may be exposed to concentrations of CF3I above the no-observed-adverse-effect level (NOAEL) of 2,000 parts per million (ppm) up to 3,000 ppm for as long as 5 minutes (min). At concentrations above 3,000 ppm, exposure to the chemical is permissible in both occupied and unoccupied spaces, but the time of “safe” exposure decreases. In determining the time for human exposure to various chemicals, NFPA has required that an agent “must first have been evaluated in a manner equivalent to the process used by the U.S. Environmental Protection Agency’s SNAP Program” (NFPA 2000). NFPA evaluated data derived from EPA-approved and peer-reviewed physiologically based pharmacokinetic (PBPK) models. In the case of CF3I, EPA and NFPA based their reviews on a NOAEL of 2,000 ppm and a lowest-observed-adverse-effect level (LOAEL) of 4,000 ppm in dogs. OSHA has also set general guidelines for the use of halocarbon substitutes. These state that “where egress from a normally occupied area takes longer than 30 seconds but less than one minute, the employer shall not use the agent in a concentration greater than its cardiotoxic LOAEL” (29 CFR 1910 Subpart L). The Army does not have a stated policy regarding ozone-depleting substances. Army Regulation 40-5: Preventive Medicine (1990) addresses the health and safety issues related to the use of the substances. The U.S. Army Center for Health Promotion and Preventive Medicine at Aberdeen Proving Ground, Maryland, reviewed the toxicity of CF3I, in May 1999 (McCain and Macko 1999) and updated the review in 2002 (Chaney 2002) and proposed an exposure limit of 2,000 ppm for CF3I. THE SUBCOMMITTEE’S CHARGE The Office of the Surgeon General of the U.S. Army requested that the National Research Council Committee on Toxicology (COT) form a sub-
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Iodotrifluoromethane: Toxicity Review committee to review the toxicologic, toxicokinetic, and related data on CF3I and to evaluate the scientific basis of the Army’s proposed CF3I exposure limit of 2,000 ppm. At the Army’s request, the Research Council convened the Subcommittee on Iodotrifluoromethane under COT. Members of the subcommittee were selected for their expertise in toxicology, pharmacology, occupational health, chemistry, biostatistics, PBPK modeling, and risk assessment. In addition to evaluating the Army’s toxicity review, the subcommittee was asked to identify relevant database deficiencies and to make recommendations for future research. ORGANIZATION OF REPORT The body of this report is organized in five chapters. Chapter 2 presents an overview of the physical and chemical properties and efficacy section of the Army’s toxicity review of CF3I. Chapter 3 comments on the health-effects data on acute, subacute, subchronic, reproductive and developmental toxicity, carcinogenicity, and genotoxicity of CF3I. Chapter 4 reviews available data on cardiac sensitization. Chapter 5 presents an overview of the use of a PBPK model in understanding the modes of action of CF3I. Finally, Chapter 6 critiques the available human exposure information, including those in the Army’s toxicity review.
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