# Protection of Stratospheric Ozone: Listing of Substitutes for Ozone-Depleting Substances-n-Propyl Bromide in Adhesives, Coatings, and Aerosols > Briefs, arguments, decisions, and more. URL: https://www.frixlaw.com/law-library/documents/fr%3AE7-9706 ## Record - **Collection:** Federal Register - **Document type:** Proposed Rule - **Published:** May 30, 2007 - **Citation:** 72 FR 30168 ## Text ENVIRONMENTAL PROTECTION AGENCY 40 CFR Part 82 [EPA-HQ-OAR-2002-0064; FRL-8316-7] RIN 2060-AK26 Protection of Stratospheric Ozone: Listing of Substitutes for Ozone-Depleting Substances—n-Propyl Bromide in Adhesives, Coatings, and Aerosols AGENCY: Environmental Protection Agency. ACTION: Notice of Proposed Rulemaking. SUMMARY: Pursuant to the U.S. Environmental Protection Agency's (EPA or “we”) Significant New Alternatives Policy (SNAP) program, this action proposes to list n-propyl bromide (nPB) as an unacceptable substitute for methyl chloroform, chlorofluorocarbon (CFC)-113, and hydrochlorofluorocarbon (HCFC)-141b when used in adhesives or in aerosol solvents because nPB in these end uses poses unacceptable risks to human health when compared with other substitutes that are available. In addition, EPA takes comment on alternate options that would find nPB acceptable subject to use conditions in adhesives or in aerosol solvents. This action also proposes to list nPB as acceptable, subject to use conditions, as a substitute for methyl chloroform, CFC-113, and hydrochlorofluorocarbon (HCFC)-141b in the coatings end use. This proposal supersedes EPA's proposal of June 3, 2003 on the acceptability of nPB as a substitute for ozone-depleting substances for aerosols and adhesives. DATES: Comments must be received in writing by July 30, 2007. Under the Paperwork Reduction Act, comments on the information collection provisions must be received by the Office of Management and Budget (OMB) on or before June 29, 2007. Any person interested in requesting a public hearing, must submit such request on or before June 29, 2007. If a public hearing is requested, a separate notice will be published announcing the date and time of the public hearing and the comment period will be extended until 30 days after the public hearing to allow rebuttal and supplementary information regarding any material presented at the public hearing. Inquiries regarding a public hearing should be directed to the contact person listed below. ADDRESSES: Submit your comments, identified by Docket ID No. EPA-HQ-OAR-2002-0064, by one of the following methods: • http://www.regulations.gov. Follow the on-line instructions for submitting comments. • E-mail: A-And-R-Docket@epa.gov. • Mail: Air and Radiation Docket, Environmental Protection Agency, Mailcode 6102T, 1200 Pennsylvania Ave., NW., Washington DC 20460, Attention Docket ID No. EPA-HQ-OAR-2002-0064. In addition, please mail a copy of your comments on the information collection provisions to the Office of Information and Regulatory Affairs, Office of Management and Budget (OMB), Attn: Desk Officer for EPA, 725 17th St., NW., Washington, DC 20503. • Hand Delivery: EPA Docket Center, (EPA/DC) EPA West, Room 3334, 1301 Constitution Ave., NW., Washington, DC, Attention Docket ID No. EPA-HQ-OAR-2002-0064. Such deliveries are only accepted during the Docket's normal hours of operation, and special arrangements should be made for deliveries of boxed information. Instructions: Direct your comments to Docket ID No. EPA-HQ-OAR-2002-0064. EPA's policy is that all comments received will be included in the public docket without change and may be made available online at http://www.regulations.gov , including any personal information provided, unless the comment includes information claimed to be Confidential Business Information (CBI) or other information whose disclosure is restricted by statute. Do not submit information that you consider to be CBI or otherwise protected through www.regulations.gov or e-mail. The http://www.regulations.gov Web site is an “anonymous access” system, which means EPA will not know your identity or contact information unless you provide it in the body of your comment. If you send an e-mail comment directly to EPA without going through http://www.regulations.gov , your e-mail address will be automatically captured and included as part of the comment that is placed in the public docket and made available on the Internet. If you submit an electronic comment, EPA recommends that you include your name and other contact information in the body of your comment and with any disk or CD-ROM you submit. If EPA cannot read your comment due to technical difficulties and cannot contact you for clarification, EPA may not be able to consider your comment. Electronic files should avoid the use of special characters, any form of encryption, and be free of any defects or viruses. For additional instructions on submitting comments, go to Section I.B. of the SUPPLEMENTARY INFORMATION section of this document. Docket: All documents in the docket are listed in the http://www.regulations.gov index. Although listed in the index, some information is not publicly available, i.e., CBI or other information whose disclosure is restricted by statute. Certain other material, such as copyrighted material, is not placed on the Internet and will be publicly available only in hard copy form. Publicly available docket materials are available either electronically in http://www.regulations.gov or in hard copy at the Air and Radiation Docket, EPA/DC, EPA West, Room 3334, 1301 Constitution Ave., NW., Washington, DC. The Public Reading Room is open from 8:30 a.m. to 4:30 p.m., Monday through Friday, excluding legal holidays. The telephone number for the Public Reading Room is (202) 566-1744, and the telephone number for the Air and Radiation Docket is (202) 566-1742. FOR FURTHER INFORMATION CONTACT: Margaret Sheppard, Stratospheric Protection Division, Office of Atmospheric Programs, Mail Code 6205J, Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460; telephone number (202) 343-9163; fax number (202) 343-2362 e-mail address: sheppard.margaret@epa.gov. Notices and rulemakings under the SNAP program are available on EPA's Stratospheric Ozone World Wide Web site at http://www.epa.gov/ozone/snap/regs. SUPPLEMENTARY INFORMATION: Table of Contents I. General Information A. Does this action apply to me? B. What should I consider as I prepare my comments for EPA? C. What acronyms and abbreviations are used in the preamble? II. How does the Significant New Alternatives Policy (SNAP) program work? A. What are the statutory requirements and authority for the SNAP program? B. How do the regulations for the SNAP program work? C. Where can I get additional information about the SNAP program? III. What is EPA proposing today? A. What is n-propyl bromide? B. What industrial end uses are included in our proposed decision? C. What is the proposed text for EPA's listing decisions? D. What does an unacceptability determination on adhesives and aerosols mean? E. What is the scope of the proposed determination for coatings? IV. What criteria did EPA consider in preparing this proposal? A. Availability of Alternatives to Ozone-Depleting Substances B. Impacts on the Atmosphere and Local Air Quality C. Ecosystem and Other Environmental Impacts D. Flammability and Fire Safety E. Health impacts and exposure V. How did EPA assess impacts on human health? A. Newly Available Exposure Data B. Newly Available Data on Health Effects C. Evaluation of Acceptable Exposure Levels for the Workplace D. Other Analyses of nPB Toxicity E. Community Exposure Guideline VI. What listing is EPA proposing for each end use, and why? A. Aerosol Solvents B. Adhesives C. Coatings VII. What other regulatory options did EPA consider? A. Alternative Option for Comment: Acceptable With Use Conditions Requiring Exposure Limit and Monitoring B. Regulatory Options Where nPB Would Be Acceptable With Use Conditions Requiring Specific Equipment VIII. What are the anticipated costs of this regulation to the regulated community? IX. How do the decisions for EPA's June 2003 proposal compare to those for this proposal? X. How can I use nPB as safely as possible? XI. Statutory and Executive Order Reviews A. Executive Order 12866: Regulatory Planning and Review B. Paperwork Reduction Act C. Regulatory Flexibility Act D. Unfunded Mandates Reform Act E. Executive Order 13132: Federalism F. Executive Order 13175: Consultation and Coordination With Indian Tribal Governments G. Executive Order 13045: Protection of Children From Environmental Health and Safety Risks H. Executive Order 13211: Actions That Significantly Affect Energy Supply, Distribution, or Use I. National Technology Transfer and Advancement Act XII. References I. General Information A. Does this action apply to me? This proposed rule would regulate the use of n-propyl bromide as an aerosol solvent and as a carrier solvent in adhesives and coatings. Businesses in these end uses that currently might be using nPB, or might want to use it in the future, include: • Businesses that manufacture electronics or computer equipment. • Businesses that require a high level of cleanliness in removing oil, grease, or wax, such as for aerospace applications or for manufacture of optical equipment. • Foam fabricators that glue pieces of polyurethane foam together or foam cushion manufacturers that glue fabric around a cushion. • Furniture manufacturers that use adhesive to attach wood parts to floors, tables and counter tops. • A company that manufactures ammunition for the U.S. Department of Defense. Regulated entities may include: Table 1.—Potentially Regulated Entities, by North American Industrial Classification System (NAICS) Code or Subsector Category NAICS code or subsector Description of regulated entities Industry 331 Primary Metal Manufacturing. Industry 332 Fabricated Metal Product Manufacturing. Industry/Military 332992 Small Arms Ammunition Manufacturing. Industry 333 Machinery Manufacturing. Industry 334 Computer and Electronic Product Manufacturing. Industry 335 Equipment Appliance, and Component Manufacturing. Industry 336 Transportation Equipment Manufacturing. Industry 337 Furniture and Related Product Manufacturing. Industry 339 Miscellaneous Manufacturing. Industry 326150 Urethane and Other Foam Product (except Polystyrene) Manufacturing. This table is not intended to be exhaustive, but rather a guide regarding entities likely to be regulated by this action. If you have any questions about whether this action applies to a particular entity, consult the person listed in the preceding section, FOR FURTHER INFORMATION CONTACT . B. What should I consider as I prepare my comments for EPA? 1. Submitting Confidential Business Information (CBI). Do not submit this information to EPA through www.regulations.gov or e-mail. Clearly mark the part or all of the information that you claim to be CBI. For CBI information in a disk or CD ROM that you mail to EPA, mark the outside of the disk or CD ROM as CBI and then identify electronically within the disk or CD ROM the specific information that is claimed as CBI. In addition to one complete version of the comment that includes information claimed as CBI, a copy of the comment that does not contain the information claimed as CBI must be submitted for inclusion in the public docket. Information so marked will not be disclosed except in accordance with procedures set forth in 40 CFR part 2. 2. Tips for Preparing Your Comments. When submitting comments, remember to: • Identify the rulemaking by docket number and other identifying information (subject heading, Federal Register (FR) date and page number). • Follow directions—The agency may ask you to respond to specific questions or organize comments by referencing a Code of Federal Regulations (CFR) part or section number. • Explain why you agree or disagree; suggest alternatives and substitute language for your requested changes. • Describe any assumptions and provide any technical information and/or data that you used. • If you estimate potential costs or burdens, explain how you arrived at your estimate in sufficient detail to allow for it to be reproduced. • Provide specific examples to illustrate your concerns, and suggest alternatives. • Explain your views as clearly as possible, avoiding the use of profanity or personal threats. • Make sure to submit your comments by the comment period deadline identified. C. What acronyms and abbreviations are used in the preamble? Below is a list of acronyms and abbreviations used in this document. 8-hr—eight hour ACGIH—American Conference of Governmental Industrial Hygienists AEL—acceptable exposure limit ASTM—American Society for Testing and Materials BMD—benchmark dose BMDL—benchmark dose lowerbound, the lower 95%-confidence level bound on the dose/exposure associated with the benchmark response BSOC—Brominated Solvents Consortium CAA—Clean Air Act CAS Reg. No—Chemical Abstracts Service Registry Identification Number CBI—Confidential Business Information CEG—community exposure guideline CERHR—Center for the Evaluation of Risks to Human Reproduction CFC-113—the ozone-depleting chemical 1,1,2-trifluoro-1,2,2-trichloroethane, C 2 Cl 3 F 3 , CAS Reg. No. 76-13-1 CFC—chlorofluorocarbon cfm—cubic feet per minute CFR—Code of Federal Regulations CNS—central nervous system DNA—deoxyribonucleic acid EDSTAC—The Endocrine Disruptor Screening and Testing Advisory Committee EPA—the United States Environmental Protection Agency FR—Federal Register GWP—global warming potential HCFC-141b—the ozone-depleting chemical 1,1-dichloro-1-fluoroethane, CAS Reg. No. 1717-00-6 HCFC-225ca/cb—the commercial mixture of the two ozone-depleting chemicals 3,3-dichloro-1,1,1,2,2-pentafluoropropane, CAS Reg. No. 422-56-0 and 1,3-dichloro-1,1,2,2,3-pentafluoropropane, CAS Reg. No. 507-55-1 HCFC—hydrochlorofluorocarbon HEC—human equivalent concentration HFC-245fa—the chemical 1,1,3,3,3-pentafluoropropane, CAS Reg. No. 460-73-1 HFC-365mfc—the chemical 1,1,1,3,3-pentafluorobutane, CAS Reg. No. 405-58-6 HFC-4310mee—the chemical 1,1,1,2,3,4,4,5,5,5-decafluoropentane, CAS Reg. No. 138495-42-8 HFC—hydrofluorocarbon HFE—hydrofluoroether HHE—health hazard evaluation ICF—ICF Consulting ICR—Information Collection Request iPB—isopropyl bromide, C 3 H 7 Br, CAS Reg. No. 75-26-3, an isomer of n-propyl bromide; also called 2-bromopropane or 2-BP K oc —organic carbon partition coefficient, for determining the tendency of a chemical to bind to organic carbon in soil LC 50 —the concentration at which 50% of test animals die LOAEL—Lowest Observed Adverse Effect Level Log K ow —logarithm of the octanol-water partition coefficient, for determining the tendency of a chemical to accumulate in lipids or fats instead of remaining dissolved in water mg/l—milligrams per liter MSDS—Material Safety Data Sheet NAICS—North American Industrial Classification System NIOSH—National Institute for Occupational Safety and Health NOAEL—No Observed Adverse Effect Level NOEL—No Observed Effect Level nPB—ln-propyl bromide, C 3 H 7 Br, CAS Reg. No. 106-94-5; also called 1-bromopropane or 1-BP NPRM—Notice of Proposed Rulemaking NTP—National Toxicology Program NTTAA—National Technology Transfer and Advancement Act ODP—ozone depletion potential ODS—ozone-depleting substance OEHHA—Office of Environmental Health Hazard Assessment of the California Environmental Protection Agency OMB—U.S. Office of Management and Budget OSHA—the United States Occupational Safety and Health Administration PCBTF—parachlorobenzotrifluoride, CAS Reg. No. 98-56-6 PEL—Permissible Exposure Limit ppm-parts per million RCRA—Resource Conservation and Recovery Act RFA—Regulatory Flexibility Act RfC—reference concentration SIP—state implementation plan SNAP—Significant New Alternatives Policy TCA—the ozone-depleting chemical 1,1,1-trichloroethane, CAS Reg. No. 71-55-6; also called methyl chloroform, MCF, or 1,1,1 TCE—the chemical 1,1,2-trichloroethene, CAS Reg. No. 79-01-6, C2Cl3H; also call trichloroethylene TERA—Toxicological Excellence for Risk Assessment TLV—Threshold Limit Value(tm) TSCA—Toxic Substances Control Act TWA—time-weighted average UMRA—Unfunded Mandates Reform Act U.S.C.—United States Code VMSs—volatile methyl siloxanes VOC—volatile organic compound II. How does the Significant New Alternatives Policy (SNAP) program work? A. What are the statutory requirements and authority for the SNAP program? Section 612 of the Clean Air Act (CAA) authorizes EPA to develop a program for evaluating alternatives to ozone-depleting substances, referred to as the Significant New Alternatives Policy (SNAP) program. The major provisions of section 612 are: • Rulemaking —Section 612(c) requires EPA to promulgate rules making it unlawful to replace any class I (chlorofluorocarbon, halon, carbon tetrachloride, methyl chloroform, and hydrobromofluorocarbon) or class II (hydrochlorofluorocarbon) substance with any substitute that the 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. • Listing of Unacceptable/Acceptable Substitutes —Section 612(c) also requires EPA to publish a list of the substitutes unacceptable for specific uses. We must publish a corresponding list of acceptable alternatives for specific uses. • Petition Process —Section 612(d) grants the right to any person to petition EPA to add a substitute to or delete a substitute from the lists published in accordance with section 612(c). EPA has 90 days to grant or deny a petition. Where the Agency grants the petition, we must publish the revised lists within an additional six months. • 90-day Notification —Section 612(e) requires EPA to require any person who produces a chemical substitute for a class I substance to notify the Agency not less than 90 days before new or existing chemicals are introduced into interstate commerce for significant new uses as substitutes for a class I substance. The producer must also provide the Agency with the producer's health and safety studies on such substitutes. • Outreach —Section 612(b)(1) states that the Administrator shall seek to maximize the use of federal research facilities and resources to assist users of class I and II substances in identifying and developing alternatives to the use of such substances in key commercial applications. • Clearinghouse —Section 612(b)(4) requires the Agency to set up a public clearinghouse of alternative chemicals, product substitutes, and alternative manufacturing processes that are available for products and manufacturing processes which use class I and II substances. B. How do the regulations for the SNAP program work? On March 18, 1994, EPA published the original rulemaking (59 FR 13044) that described the process for administering the SNAP program and issued the first acceptability lists for substitutes in the major industrial use sectors. These sectors include: Refrigeration and air conditioning; foam blowing; solvents cleaning; fire suppression and explosion protection; sterilants; aerosols; adhesives, coatings and inks; and tobacco expansion. These sectors comprise the principal industrial sectors that historically consumed large volumes of ozone-depleting substances. Anyone who plans to market or produce a substitute for an ozone-depleting substance (ODS) in one of the eight major industrial use sectors must provide the Agency with health and safety studies on the substitute at least 90 days before introducing it into interstate commerce for significant new use as an alternative. This requirement applies to the person planning to introduce the substitute into interstate commerce, typically chemical manufacturers, but may also include importers, formulators or end-users when they are responsible for introducing a substitute into commerce. The Agency has identified four possible decision categories for substitutes: Acceptable; acceptable subject to use conditions; acceptable subject to narrowed use limits; and unacceptable. Use conditions and narrowed use limits are both considered “use restrictions” and are explained below. Substitutes that are deemed acceptable with no use restrictions (no use conditions or narrowed use limits) can be used for all applications within the relevant sector end-use. Substitutes that are acceptable subject to use restrictions may be used only in accordance with those restrictions. It is illegal to replace an ODS with a substitute listed as unacceptable. After reviewing a substitute, the Agency may make a determination that a substitute is acceptable only if certain conditions of use are met to minimize risks to human health and the environment. We describe such substitutes as “acceptable subject to use conditions.” If you use these substitutes without meeting the associated use conditions, you use these substitutes in an unacceptable manner and you could be subject to enforcement for violation of section 612 of the Clean Air Act. For some substitutes, the Agency may permit a narrowed range of use within a sector. For example, we may limit the use of a substitute to certain end-uses or specific applications within an industry sector or may require a user to demonstrate that no other acceptable end uses are available for their specific application. We describe these substitutes as “acceptable subject to narrowed use limits.” If you use a substitute that is acceptable subject to narrowed use limits, but use it in applications and end-uses which are not consistent with the narrowed use limit, you are using these substitutes in an unacceptable manner and you could be subject to enforcement for violation of section 612 of the Clean Air Act. The Agency publishes its SNAP program decisions in the Federal Register . For those substitutes that are deemed acceptable subject to use restrictions (use conditions and/or narrowed use limits), or for substitutes deemed unacceptable, we first publish these decisions as proposals to allow the public opportunity to comment, and we publish final decisions as final rulemakings. In contrast, we publish substitutes that are deemed acceptable with no restrictions in “notices of acceptability,” rather than as proposed and final rules. As described in the rule implementing the SNAP program (59 FR 13044), we do not believe that rulemaking procedures are necessary to list alternatives that are acceptable without restrictions because such listings neither impose any sanction nor prevent anyone from using a substitute. Many SNAP listings include “comments” or “further information.” These statements provide additional information on substitutes that we determine are unacceptable, acceptable subject to narrowed use limits, or acceptable subject to use conditions. Since this additional information is not part of the regulatory decision, these statements are not binding for use of the substitute under the SNAP program. However, regulatory requirements listed in this column are binding under other programs. The further information does not necessarily include all other legal obligations pertaining to the use of the substitute. However, we encourage users of substitutes to apply all statements in the “Further Information” column in their use of these substitutes. In many instances, the information simply refers to sound operating practices that have already been identified in existing industry and/or building-code standards. Thus, many of the comments, if adopted, would not require the affected industry to make significant changes in existing operating practices. C. Where can I get additional information about the SNAP program? For copies of the comprehensive SNAP lists of substitutes or additional information on SNAP, look at EPA's Ozone Depletion World Wide Web site at http://www.epa.gov/ozone/snap/lists/index.html. For more information on the Agency's process for administering the SNAP program or criteria for evaluation of substitutes, refer to the SNAP final rulemaking published in the Federal Register on March 18, 1994 (59 FR 13044), codified at Code of Federal Regulations at 40 CFR part 82, subpart G. You can find a complete chronology of SNAP decisions and the appropriate Federal Register citations at http://www.epa.gov/ozone/snap/chron.html. III. What is EPA proposing today? In this action, EPA proposes to list n-propyl bromide (nPB) as (1) unacceptable for use as a substitute for CFC-113, 1 methyl chloroform 2 and HCFC-141b 3 in the adhesive and aerosol solvent end uses; and (2) acceptable subject to use conditions (limited to coatings at facilities that, as of May 30, 2007, have provided EPA with information demonstrating their ability to maintain acceptable workplace exposures) as a substitute for methyl chloroform, CFC-113, and HCFC-141b in the coatings end use. This Notice of Proposed Rulemaking (NPRM) supersedes the NPRM published on June 3, 2003 (68 FR 33284) for aerosol solvents and adhesives. 1 CFC-113 is also referred to as Freon-113, or 1,1,2-trifluoro-1,2,2-trichloroethane. Its CAS Reg. No. is 76-13-1. 2 Methyl chloroform is also referred to as 1,1,1-trichloroethane, TCA, MCF, or 1,1,1. Its CAS Reg. No. is 71-55-6. 3 HCFC-141b is also referred to as 1,1-dichloro-1-fluoroethane. Its CAS Reg. No. is 1717-00-6. A. What is n-propyl bromide? n-propyl bromide (nPB), also called 1-bromopropane, is a non-flammable organic solvent with a strong odor. Its chemical formula is C 3 H 7 Br. Its identification number in Chemical Abstracts Service's registry (CAS Reg. No.) is 106-94-5. nPB is used to remove wax, oil, and grease from electronics, metal, and other materials. It also is used as a carrier solvent in adhesives. Some brand names of products using nPB are: Abzol®, EnSolv®, and Solvon® cleaners; Pow-R-Wash® NR Contact Cleaner, Superkleen Flux Remover 2311 and LPS NoFlash NU Electro Contact Cleaner aerosols; and Whisper Spray and Fire Retardant Soft Seam 6460 adhesives. B. What industrial end uses are included in our proposed decision? This proposal addresses the use of n-propyl bromide in the aerosol solvent end use of the aerosol sector and the adhesives and coatings end uses in the adhesives, coatings, and inks sector as discussed below. EPA is issuing a decision on the use of nPB in metals, electronics, and precision cleaning in a separate final rule. EPA has insufficient information for ruling on other end uses or sectors where nPB might be used (e.g., inks, foam blowing, fire suppression). 1. Aerosol Solvents We understand that nPB is being used as an aerosol solvent in: • Lubricants, coatings, or cleaning fluids for electrical or electronic equipment; Lubricants, coatings, or cleaning fluids for aircraft maintenance; or • Spinnerrette lubricants and cleaning sprays used in the production of synthetic fibers. 2. Adhesives Types of adhesives covered under the SNAP program are those that formerly used methyl chloroform, specifically, adhesives for laminates, flexible foam, hardwood floors, tire patches, and metal to rubber adhesives. Of these applications, nPB-based adhesives have been used most widely in spray adhesives used in manufacture of foam cushions, and to a lesser degree in laminate adhesives. 3. Coatings The SNAP program regulates the use of carrier solvents in durable coatings, including paints, varnishes, and aerospace coatings (59 FR 13118). The SNAP program currently does not regulate carrier solvents in lubricant coatings, such as silicone coatings used on medical equipment (59 FR 13119). Methyl chloroform has been used as a carrier solvent in coatings, and to a much lesser degree, HCFC-141b also has been a carrier solvent. This rule responds to a submission from a facility that is substituting methyl chloroform with nPB as an ammunition coating (sealant). C. What is the proposed text for EPA's listing decisions? In the proposed regulatory text at the end of this document, you will find our proposed decisions for those end uses for which we have proposed nPB as unacceptable or acceptable subject to use conditions. The proposed conditions listed in the “Use Conditions” column would be enforceable while information contained in the “Further Information” column of those tables provides additional recommendations on the safe use of nPB. Our proposed decisions for each end use are summarized below in tables 2 through 4. Proposed Listings Table 2.—Aerosols Proposed Unacceptable Substitutes End Use Substitute Decision Further information Aerosol solvents n-propyl bromide (nPB) as a substitute for CFC-113, HCFC-141b, and methyl chloroform Unacceptable EPA finds unacceptable risks to human health in this end use compared to other available alternatives. nPB, also known as 1-bromopropane, is Number 106-94-5 in the CAS Registry. Table 3.—Adhesives, Coatings, and Inks Proposed Unacceptable Substitutes Enduse Substitute Decision Further information Adhesives n-propyl bromide (nPB) as a substitute for CFC-113, HCFC-141b, and methyl chloroform Unacceptable EPA finds unacceptable risks to human health in this end use compared to other available alternatives. nPB, also known as 1-bromopropane, is Number 106-94-5 in the CAS Registry. Table 4.—Adhesives, Coatings, and Inks Substitutes That Are Proposed Acceptable Subject to Use Conditions End Use Substitute Decision Use conditions Further information Coatings n-propyl bromide (nPB) as a substitute for methyl chloroform, CFC-113, and HCFC-141b Acceptable subject to use conditions Use is limited to coatings facilities that, as of May 30, 2007, have provided EPA information demonstrating their ability to maintain acceptable workplace exposures EPA recommends the use of personal protective equipment, including chemical goggles, flexible laminate protective gloves and chemical-resistant clothing. EPA expects that all users of nPB would comply with any final Permissible Exposure Limit that the Occupational Safety and Health Administration issues in the future under 42 U.S.C. 7610(a). nPB, also known as 1-bromopropane, is Number 106-94-5 in the CAS Registry. Note: As of May 30, 2007, the Lake City Army Ammunition Plant is the only facility using nPB in coatings that has provided information to EPA that meets this condition. D. What does an unacceptability determination on adhesives and aerosols mean? In this action, EPA is proposing to find nPB unacceptable as a substitute for methyl chloroform, CFC-113, and HCFC-141b for use as a carrier solvent in adhesives and as an aerosol solvent. If this proposal were to become final, it would be illegal to use nPB or blends of nPB and other solvents in adhesives or in aerosol solvent formulations as a substitute for ozone-depleting substances. E. What is the scope of the proposed determination for coatings? We propose to list nPB as an acceptable substitute, subject to use conditions, for methyl chloroform, CFC-113, and HCFC-141b in coatings for facilities that, as of May 30, 2007, have provided EPA information demonstrating their ability to maintain acceptable workplace exposures. EPA has received a petition to allow use of nPB for the ammunition coating application at Lake City Army Ammunition Plant. This is the only coatings application or facility for which EPA has exposure and usage data demonstrating an ability to maintain workplace exposure levels below even the minimum level of the range of exposures that EPA is considering to be potentially acceptable (i.e., 17 to 30 ppm) (see section IV.E for an evaluation of the health risks associated with nPB). If other facilities are interested in using nPB as a substitute for methyl chloroform, CFC-113, or HCFC-141b in their coatings application, or if a person wishes to market nPB for such use, then the interested party would need to make a submission under the SNAP program. IV. What criteria did EPA consider in preparing this proposal? In the original rule implementing the SNAP program (March 18, 1994; 59 FR 13044, at 40 CFR 82.180(a)(7)), the Agency identified the criteria we use in determining whether a substitute is acceptable or unacceptable as a replacement for class I or II compounds: (i) Atmospheric effects and related health and environmental impacts; [e.g., ozone depletion potential] (ii) General population risks from ambient exposure to compounds with direct toxicity and to increased ground-level ozone; (iii) Ecosystem risks [e.g., bioaccumulation, impacts on surface and groundwater]; (iv) Occupational risks; (v) Consumer risks; (vi) Flammability; and (vii) Cost and availability of the substitute. In this review, EPA considered all the criteria above. However, n-propyl bromide is used in industrial applications such as electronics cleaning or spray adhesives used in foam fabrication. In those consumer products made using nPB, such as a piece of furniture or a computer, the nPB would have evaporated long before a consumer would purchase the item. Therefore, we believe there is no consumer exposure risk to evaluate in the end uses we evaluated for this rule. Section 612(c) of the Clean Air Act directs EPA to publish a list of replacement substances (“substitutes”) for class I and class II ozone depleting substances based on whether the Administrator determines they are safe (when compared with other currently or potentially available substitutes) for specific uses or are to be prohibited for specific uses. EPA must compare the risks to human health and the environment of a substitute to the risks associated with other substitutes that are currently or potentially available. In addition, EPA also considers whether the substitute for class I and class II ODSs “reduces the overall risk to human health and the environment” compared to the ODSs being replaced. Our evaluation is based on the end use; for example, we compared nPB as a carrier solvent in adhesives to other available or potentially available adhesive alternatives. Although EPA does not judge the effectiveness of an alternative for purposes of determining whether it is acceptable, we consider effectiveness when determining whether alternatives that pose less risk are available in a particular application within an end use. There are a wide variety of acceptable alternatives listed for aerosol solvents, but not all may be appropriate for a specific application because of differences in materials compatibility, flammability, degree of cleanliness required, local environmental requirements, and other factors. EPA evaluated each of the criteria separately and then considered overall risk to human health and the environment in comparison to other available or potentially available alternatives. We concluded that overall, environmental risks were not sufficient to find nPB unacceptable in any of the evaluated end uses. However, the overall risks to human health, and particularly the risks to worker health, are sufficiently high in the adhesive and aerosol solvent end uses to warrant our proposal to find nPB unacceptable. A. Availability of Alternatives to Ozone-Depleting Substances Other alternatives are available in each end use considered in this proposal. Examples of other available alternatives for aerosol solvents that have already been found acceptable or acceptable subject to use conditions under the SNAP program include water-based formulations, alcohols, ketones, esters, ethers, terpenes, HCFC-141b, HCFC-225ca/cb, hydrofluoroethers (HFEs), hydrofluorocarbon (HFC)-4310mee, HFC-365mfc, HFC-245fa, hydrocarbons, trans-1,2-dichloroethylene, methylene chloride, trichloroethylene 4 (TCE), perchloroethylene 5 , and parachlorobenzotrifluoride (PCBTF). Of these, hydrocarbons, alcohols, blends of trans-1,2-dichloroethylene and HFEs or HFCs, and HCFC-225ca/cb are most likely to be used in the same applications as nPB. nPB is already commercially available in aerosols. Its use is primarily for electrical contact cleaning, with some use for benchtop cleaning applications (Williams, 2005). 4 Also called trichlorethene or TCE, C 2 Cl 3 H, CAS Reg. No. 79-01-6. 5 Also called PERC, tetrachloroethylene, or tetrachloroethene, C 2 Cl 4 , CAS Reg. No. 127-18-4. Many alternatives are also available for use in adhesives, coatings, and inks: Water-based formulations, high solid formulations, alcohols, ketones, esters, ethers, terpenes, HFEs, hydrocarbons, trans-1,2-dichloroethylene, chlorinated solvents, PCBTF, and a number of alternative technologies (e.g., powder, hot melt, thermoplastic plasma spray, radiation-cured, moisture-cured, chemical-cured, and reactive liquid). Of these, the alternative adhesives most likely to be used in the same applications as nPB are water-based formulations, adhesives with methylene chloride, and flammable adhesives with acetone (IRTA, 2000). nPB is already used in adhesives, and particularly in foam fabrication and in constructing seating for aircraft (IRTA, 2000; Seilheimer, 2001). To our knowledge, nPB is potentially available as a carrier solvent in coatings, but has not yet been commercialized, except for use by one facility, the Lake City Army Ammunition Plant. The Lake City Army Ammunition Plant evaluated twenty-nine carrier solvent alternatives to methyl chloroform and determined that nPB is the only satisfactory alternative for their application given the current process at that facility (Harper, 2005). B. Impacts on the Atmosphere and Local Air Quality As discussed in the June, 2003 proposal, nPB emissions from the continental United States are estimated to have an ozone depletion potential (ODP) of approximately 0.013-0.018, (Wuebbles, 2002), lower than that of the ozone depletion potential of the substances that nPB would replace—CFC-113 (ODP = 1.0), and methyl chloroform and HCFC-141b (ODPs = 0.12) (WMO, 2002). Some other acceptable alternatives for these ODSs also have low ODPs. For example, HCFC-225ca/cb has an ODP of 0.02-0.03 (WMO, 2002) and is acceptable as an aerosol solvent. There are other acceptable solvents for aerosols, adhesives, and coatings that essentially have no ODP—aqueous cleaners, HFEs, HFC-4310mee, HFC-365mfc, HFC-245fa, hydrocarbons, volatile methyl siloxanes (VMSs), methylene chloride, TCE, perchloroethylene, and PCBTF. Based on this information, we do not believe the use of nPB within the U.S., and within the end-uses reviewed in this rulemaking, poses a significantly greater risk to the ozone layer than other available substitutes. Comments on the June 2003 NPRM expressed concern that other countries, particularly those in equatorial regions, might assume that nPB does not pose a danger to the stratospheric ozone layer if the U.S. EPA's SNAP program finds nPB acceptable (Linnell, 2003; Steminiski, 2003). Because the ODP for nPB is higher when used in the tropics, 6 we recognize the concerns raised by these commenters. However, EPA is regulating use in the U.S. and cannot dictate actions taken by other countries. We believe the more appropriate forum to address this concern is through the Parties to the Montreal Protocol. At the most recent Meeting of the Parties, the Parties made the following decision with regard to n-propyl bromide, in order to “allow Parties to consider further steps regarding n-propyl bromide, in the light of available alternatives” (Decision XVIII/11): 6 nPB emissions in the tropics have an ODP of 0.071 to 0.100; the portions of the U.S. outside the continental U.S., such as Alaska, Hawaii, Guam, and the U.S. Virgin Islands, contain less than 1 percent of the U.S.'s businesses in industries that could use nPB. Thus, their potential impact on the ozone layer must be significantly less than that of the already low impact from nPB emissions in the continental U.S. (U.S. Economic Census, 2002a through f). 1. To request the Scientific Assessment Panel to update existing information on the ozone depletion potential of n-propyl bromide, including ozone depleting potential depending on the location of the emissions and the season in the hemisphere at that location; 2. To request the Technology and Economic Assessment Panel to continue its assessment of global emissions of n-propyl bromide, * * * paying particular attention to: (a) Obtaining more complete data on production and uses of n-propyl bromide as well as emissions of n-propyl bromide from those sources; (b) Providing further information on the technological and economical availability of alternatives for the different use categories of n-propyl bromide and information on the toxicity of and regulations on the substitutes for n-propyl bromide; (c) Presenting information on the ozone depletion potential of the substances for which n-propyl bromide is used as a replacement; 3. To request that the Technology and Economic Assessment Panel prepare a report on the assessment referred to in paragraph 1 in time for the twenty-seventh meeting of the Open-ended Working Group for the consideration of the Nineteenth Meeting of the Parties. (MOP 18, 2006) The global warming potential (GWP) index is a means of quantifying the potential integrated climate forcing of various greenhouse gases relative to carbon dioxide. Earlier data found a direct 100-year integrated GWP (100yr GWP) for nPB of 0.31 (Atmospheric and Environmental Research, Inc., 1995). More recent analysis that considers both the direct and the indirect GWP of nPB found a 100-yr GWP of 1.57 (ICF, 2003a; ICF, 2006a). In either case, the GWP for nPB is comparable to or below that of previously approved substitutes in these end uses. Use of nPB may be controlled as a volatile organic compound (VOC) under state implementation plans (SIPs) developed to attain the National Ambient Air Quality Standards for ground-level ozone, which is a respiratory irritant. Users located in ozone nonattainment areas may need to consider using a substitute for cleaning that is not a VOC or if they choose to use a substitute that is a VOC, they may need to control emissions in accordance with the SIP. Companies have petitioned EPA, requesting that we exempt nPB from regulation as a VOC. However, unless and until EPA issues a final rulemaking exempting a compound from the definition of VOC and states change their SIPs to exclude such a compound from regulation, that compound is still regulated as a VOC. Other acceptable ODS-substitute solvents that are VOCs for state air quality planning purposes include most oxygenated solvents such as alcohols, ketones, esters, and ethers; hydrocarbons and terpenes; trichloroethylene; trans-1,2-dichloroethylene; monochlorotoluenes; and benzotrifluoride. Some VOC-exempt solvents that are acceptable ODS substitutes include HFC-245fa, HCFC-225ca/cb, HFC-365mfc and HFC-4310mee for aerosol solvents, and methylene chloride, perchloroethylene, HFE-7100, HFE-7200, PCBTF, acetone, and methyl acetate for aerosol solvents, adhesives, and coatings. C. Ecosystem and Other Environmental Impacts EPA considered the possible impacts of nPB if it were to pollute soil or water as a waste and compared these impacts to screening criteria developed by the Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC, 1998) (see Table 5). Available data on the organic carbon partition coefficient (K oc ), the breakdown processes in water and hydrolysis half-life, and the volatilization half-life indicate that nPB is less persistent in the environment than many solvents and would be of low to moderate concern for movement in soil. Based on the LC 50 , the acute concentration at which 50% of tested animals die, nPB's toxicity to aquatic life is moderate, being less than that for some acceptable cleaners (for example, trichloroethylene, hexane, d-limonene, and possibly some aqueous cleaners) and greater than that for some others (methylene chloride, acetone, isopropyl alcohol, and some other aqueous cleaners). The LC 50 for nPB is 67 milligrams per liter (mg/l), which is greater and thus less toxic than an LC 50 of 10 mg/l, one of EPA's criteria for listing under the Toxics Release Inventory (US EPA, 1992; ICF, 2004a). Based on its relatively low bioconcentration factor and log K ow value (logarithm of the octanol-water partition coefficient), nPB is not prone to bioaccumulation. Table 5 summarizes information on environmental impacts of nPB; trans-1,2-dichloroethylene, a commonly-used solvent in blends for aerosol solvents, precision cleaning, and electronics cleaning; acetone, a commonly-used carrier solvent in adhesives; trichloroethylene, a solvent used for metals, electronics, and precision cleaning that could potentially be used in aerosol or adhesive end-uses; and methyl chloroform, an ODS that nPB would replace. Table 5.—Ecosystem and Other Environmental Properties of n PB and Other Solvents Property Description of environmental property Value for nPB Value for trans-1,2-dichloro-ethylene Value for acetone Value for trichloroethylene Value for methyl chloroform K oc , organic-carbon partition coefficient Degree to which a substance tends to stick to soil or move in soil. Lower values (< 300) * indicate great soil mobility; values of 300 to 500 indicate moderate mobility in soil 330 (Source: ICF, 2004a) 32 to 49 (Source: ATSDR, 1996) 5.4 (Source: ATSDR, 1994) 106 to 460 (Source: ATSDR, 1997) 152 (Source: U.S. EPA, 1994a). Break down in water Mechanism and speed with which a compound breaks down in the environment. (Hydrolysis half-life values > 25 weeks * are of concern.) Hydrolysis is significant. Hydrolysis half-life of 26 days (Source: ICF, 2004a) Photolytic decomposition, dechlorination and biodegradation are significant; hydrolysis not significant (Source: ATSDR, 1996) Biodegradation is most significant form of breakdown (Source: ATSDR, 1994) Volatilization and biodegradation most significant, with hydrolysis relatively insignificant. Hydrolysis half-life of 10.7 to 30 months (Source: ATSDR, 1997) Volatilization most significant; biodegradation and hydrolysis also occur (Source: ATSDR, 2004). Volatilization half-life from surface waters Tendency to volatilize and pass from water into the air 3.4 hours-4.4 days (Source: ICF, 2004a) 3 to 6.2 hours (Source: ATSDR, 1996) 7.8 to 18 hours (Source: ATSDR, 1994) 3.4 hours to 18 days (Source: ATSDR, 1997) Hours to weeks (Source: U.S. EPA, 1994a). LC 50 (96 hours) for fathead minnows Concentration at which 50% of animals die from toxicity after exposure for 4 days 67 mg/L (Source: Geiger, 1988) 108 mg/L (Source: U.S. EPA, 1980) 7280 to 8120 mg/L (Source: Fisher Scientific, 2001) 40.7 to 66.8 mg/L (Source: NPS, 1997) 52.8 to 105 mg/L (Source: U.S. EPA, 1994a). log K ow Logarithm of the octanol/water partition coefficient, a measure of tendency to accumulate in fat. Log K ow values >3 ;* indicate high tendency to accumulate 2.10 (Source: ICF, 2004a) −0.48 (Source: LaGrega et al. , 2001, p. 1119) −0.24 (Source: LaGrega et al. , 2001, p. 1117) 2.38 (Source: LaGrega et al. , 2001, p. 1127) 2.50 (Source: LaGrega et al. , 2001, p. 1127). Bioconcentration factor High factors (>1000) * indicate strong tendency for fish to absorb the chemical from water into body tissues 23 (Source: HSDB, 2004) 5 to 23 (Source: ATSDR, 1996) <1 (Source: ATSDR, 1994) 10 to 100 (Source: ATSDR, 1997) <9 (Source: U.S. EPA, 1994a). * Criteria from EDSTAC, 1998. nPB is not currently regulated as a hazardous air pollutant and is not listed as a hazardous waste under the Resource Conservation and Recovery Act (RCRA). nPB is not required to be reported as part of the Toxic Release Inventory under Title III of the Superfund Amendments and Reauthorization Act. Despite this, large amounts of nPB might be harmful if disposed of in water. We recommend that users dispose of nPB as they would dispose of any spent halogenated solvent (F001 waste under RCRA). Users should not dump nPB into water, and should dispose of it by incineration. We conclude that nPB does not pose a significantly greater risk to the environment than other available alternatives, and that the use of nPB within the U.S. should not be prohibited under the SNAP program on the basis of its environmental impacts. D. Flammability and Fire Safety A number of commenters on the June 2003 proposal provided additional information on the flammability of nPB using standard test methods for determining flash point, such as the American Society for Testing and Materials (ASTM) D 92 open cup, ASTM D56 Tag closed cup, and ASTM D93 Pensky-Martens closed cup methods (BSOC, 2000; Miller, 2003; Morford, 2003a, 2003b, and 2003c; Shubkin, 2003; Weiss Cohen, 2003). We agree with the commenters that by these standard test methods, nPB displayed no flash point. Thus under standard test conditions, nPB is not flammable, and it should not be flammable under normal use conditions. With its low potential for flammability, nPB is comparable to chlorinated solvents, HCFCs, HFEs, HFC-245fa, HFC-4310mee, and aqueous cleaners, and is less flammable than many acceptable substitutes, such as ketones, alcohols, terpenes, and hydrocarbons. nPB exhibits lower and upper flammability limits of approximately 3% to 8% (BSOC, 2000). A number of other solvents that are typically considered to be non-flammable also have flammability limits (for example, methylene chloride, HCFC-141b, and methyl chloroform). If the concentration of vapor of such a solvent falls between the upper and lower flammability limits, it could catch fire in presence of a flame. Such a situation is unusual, but users should take appropriate precautions in cases where the concentration of vapor could fall between the flammability limits. E. Health Impacts and Exposure In evaluating potential human health impacts of nPB used as a substitute for ozone-depleting substances, EPA considered impacts on both exposed workers and on the general population. Using the same approach finalized in the original SNAP rulemaking, EPA evaluated the available toxicity data using EPA guidelines to develop health-based criteria to characterize human health risks (US EPA, 1994b. Inhalation Reference Concentration Guidelines; U.S. EPA, 1991. Guidelines for Developmental Toxicity Risk Assessment; U.S. EPA, 1995a. Benchmark Dose guidelines; U.S. EPA, 1996. Guidelines for Reproductive Toxicity Risk Assessment). To assess human health risks, EPA followed the four basic steps of risk assessment outlined by the National Academy of Sciences: hazard identification, dose-response relationship, exposure assessment, and risk characterization (NAS, 1983). First, EPA examined available studies on nPB's effects. Second, EPA considered the acceptable exposure levels for evaluating worker exposure and a community exposure guideline (CEG) for evaluating exposure to the general population based upon inhalation exposure. Third, EPA compared the acceptable exposure levels and CEG to available exposure data and projections of exposure levels to assess exposure, including new exposure data available since publication of the June 2003 NPRM. Finally, EPA decided whether there was sufficient evidence indicating that nPB could be used as safely as other alternatives available in a particular end use. Authority To Set an Acceptable Exposure Limit Two commenters on the June 2003 NPRM said that EPA has no jurisdiction to develop any acceptable exposure limit (AEL) designed to be applicable to a workplace environment and that only the Occupational Safety and Health Administration (OSHA) has that authority (Stelljes, 2003; Morford, 2003d). In contrast, another commenter said that EPA has the authority to set an AEL for nPB under section 612 of the Clean Air Act, has done so in the past for other chemicals (e.g., HFC-4310mee, HCFC-225ca/cb), and should require the AEL as a use condition (Risotto, 2003). EPA believes it has the authority to calculate exposure limits for the workplace under section 612. Section 612(c) specifically states that The Administrator shall issue regulations: providing that it shall be unlawful to replace any class I or class II substance with any substitute substance which the Administrator determines may present adverse effects to human health or the environment, where the Administrator has identified an alternative to such replacement that— (1) reduces the overall risk to human health and the environment; and (2) is currently or potentially available. Thus, we must compare the risks to human health and the environment of a substitute to the risks associated with other substitutes that are currently or potentially available, as required by the Clean Air Act. In order to compare risks to human health, EPA performs quantitative risk assessments on different chemicals comparing exposure data and exposure limits, following the process described above by the National Academies of Science (NAS, 1983) and as described in the preamble to the original final SNAP rule (March 18, 1994; 59 FR 13066). Because most humans who are exposed to nPB are exposed in the workplace, the appropriate exposure data and exposure limits to protect human health must include workplace exposure data and acceptable exposure limits for the workplace. Because there is wide disparity in acceptable exposure limits for nPB developed by industry, ranging from 5 ppm to 100 ppm (Albemarle, 2003; Chemtura, 2006; Docket A-2001-07, item II-D-19; Enviro Tech International, 2006; Farr, 2003; Great Lakes Chemical Company, 2001), and because there is not a Permissible Exposure Limit for nPB set by the Occupational Safety and Health Administration, EPA believes it is appropriate to independently evaluate the human health risks associated with use of nPB in the workplace. Similarly, EPA has developed a community exposure guideline to assess the human health effects of nPB exposure to the general public. Skin Notation Several commenters on the June 2003 proposal stated that a skin notation for nPB is appropriate, while another commenter agreed with EPA's proposal that no skin notation was necessary (Smith, 2003; HESIS, 2003; Werner, 2003, Weiss Cohen, 2003). Rat studies indicate that dermal exposure to nPB results in neither appreciable absorption through the skin (RTI, 2005) nor systemic toxicity (Elf Atochem, 1995). Unlike methyl chloride and dichlorvos, which are absorbed through the skin and could contribute to systemic toxicity (ACGIH, 1991), EPA is not proposing to include a skin notation for nPB in the information provided to users associated with this rulemaking because of the relatively low level of absorption. The American Conference of Governmental Industrial Hygienists (ACGIH) provides no skin notation in its documentation for threshold limit values (TLVs) for several solvents, including nPB (ACGIH, 2005), methylene chloride, and perchloroethylene, and there is no evidence that absorption through the skin is greater for nPB than for the other halogenated compounds. Further, including a statement giving advice about how to reduce skin exposure in the “Further Information” column of listings is likely to be more informative to workers than a skin notation. Given the possibility that some nPB can be absorbed through the skin in humans, and that the solvent can irritate the skin, EPA encourages users to wear protective clothing and flexible laminate gloves when using nPB and encourages vendors to include such precautions in their Material Safety Data Sheets (MSDSs). EPA requests comment on whether it would be useful, in lieu of a skin notation to add the following statement in the “further information” column of each end use where we find nPB acceptable with restrictions: “EPA recommends the use of personal protective equipment, including chemical goggles, flexible laminate protective gloves and chemical-resistant clothing, when using nPB.” EPA also considered the potential health effects of contamination of nPB formulations with isopropyl bromide (iPB). 7 In the June 2003 proposed rule, we proposed as a use condition that nPB formulations contain no more than 0.05% iPB by weight. One commenter opposed the proposed use condition, stating that it places an undue legal burden on end users, rather than the manufacturers of raw materials, that it would not benefit worker safety, and that the nPB industry has worked to reduce iPB content below 0.05% (Morford, 2003e). We agree that industry has met this contamination limit for several years without regulation. Furthermore, EPA agrees that if users are exposed to nPB concentrations no higher than the highest potentially acceptable concentration (30 ppm), a worker's exposure to iPB will be sufficiently low to avoid adverse effects. Therefore, this proposed rule does not include a use condition limiting iPB content in nPB formulations. 7 iPB is also referred to as 2-bromopropane, 2-propyl bromide, or 2-BP. Its CAS registry number is 75-26-3. 1. Workplace Risks In the June 2003 NPRM, EPA proposed that an exposure limit of 25 ppm would be protective of a range of effects observed in animal and human studies, including reproductive and developmental toxicity, neurotoxicity, and hepatotoxicity. Reduction of sperm motility in rats, noted across multiple studies at relatively low exposures, was determined to be the most sensitive effect. The Agency derived an exposure limit of 18 ppm from a dose response relationship in male rat offspring (“F1 generation”) whose parents were exposed to nPB from prior to mating through birth and weaning of the litters (WIL, 2001). We then proposed to adjust this value upwards to 25 ppm based on principles of risk management, consistent with one of the original “Guiding Principles” of the SNAP program (59 FR 13046, March 18, 1994). As we discussed in the June 2003 NPRM, EPA noted that adhesives users should be able to achieve an AEL of 25 ppm and that 25 ppm was between the level based on the most sensitive endpoint (sperm motility in the F1 offspring generation at 18 ppm) and the second most sensitive endpoint (sperm motility in the F0 parental generation at 30 ppm). Following SNAP program principles, we noted that “a slight adjustment of the AEL may be warranted after applying judgment based on the available data and after considering alternative derivations” (69 FR 33295). Because the animals were exposed to nPB for some time periods that would not occur during actual occupational exposure, we stated further that “18 ppm is a reasonable but possibly conservative starting point, and that exposure to 25 ppm would not pose substantially greater risks, while still falling below an upper bound on the occupation[al] exposure limit.” Since the 2003 proposal, the Agency has reviewed both information available at the time of the 2003 NPRM related to the health risks associated with nPB use, as well as more recent case studies of nPB exposures and effects in the workplace, newly published toxicological studies, comments to the June 2003 NPRM, including new risk assessments on nPB, and a new threshold limit value (TLV) issued by ACGIH. OSHA has not developed a permissible exposure limit (PEL) for nPB that EPA could use to evaluate toxicity risks from workplace exposure. The ACGIH, an independent organization with expertise in industrial hygiene and toxicology, has developed a final workplace exposure limit of 10 ppm (ACGIH, 2005); however, as discussed below, EPA has concerns about the documentation and basis of ACGIH's derivation. The Agency reconsidered which exposure levels are likely to protect against various health effects, based on review of all available information. We summarize benchmark dose data for a number of endpoints found in these analyses in Table 6 below. We examined these data to assess the acceptability of nPB use in the aerosol solvent, adhesive and coatings end uses reviewed in this proposed rule. These data indicate that, once uncertainty factors are applied consistent with EPA guidelines, the lowest levels for acceptable exposures would be derived for reproductive effects. 8 The data indicate that levels sufficient to protect against male reproductive effects (e.g., reduced sperm motility) would be in a range from 18 to 30 ppm, 9 in the range of 17 to 22 ppm to protect against female reproductive effects (e.g., number and length of estrous cycles), and at approximately 20 ppm for effects related to reproductive success (live litter size). 8 By EPA guidelines, we would apply an uncertainty factor of −10, or approximately 3, for differences between species for all health effects. We would also apply an uncertainty factor of √10 (3) for variability within the working population for reproductive and developmental effects, because, among other reasons, these conditions would not necessarily screen out an individual from being able to work, unlike for liver or nervous system effects. Therefore, for reproductive and developmental effects, we use a composite uncertainty factor of 10. See further discussion of uncertainty factors in section V.C. below. 9 Based on WIL, 2001, as analyzed in ICF, 2002. The equivalent values based upon Stelljes and Wood's (2004) analysis of WIL, 2001 would be slightly lower, from 16 to 28 ppm. Table 6.—Summary of Endpoints Using Benchmark Response Modeling Endpoint a Study Benchmark dose lowerbound (BMDL) b (ppm) Human equivalent concentration (HEC) c (ppm) Liver Effects d Liver vacuolation in males (F 1 offspring generation) WIL, 2001 as analyzed in ICF, 2002 110 116 Liver vacuolation in males (F 0 parent generation) WIL, 2001 as analyzed in ICF, 2002 143 150 Liver vacuolation ClinTrials, 1997b as analyzed in ICF, 2002 and Stelljes & Wood, 2004 226 170 Reproductive Effects—Male Sperm motility (F 1 offspring generation) WIL, 2001 as analyzed in ICF, 2002 WIL, 2001 as analyzed in Stelljes & Wood, 2004 169 156 177 164 Sperm motility (F 0 parent generation) WIL, 2001 as analyzed in ICF, 2002 WIL, 2001 as analyzed in Stelljes & Wood, 2004 282 263 296 276 Prostate weight (F 0 parent generation) WIL, 2001 as analyzed in TERA, 2004 190 200 Sperm count Ichihara et al. , 2000b as analyzed in Stelljes & Wood, 2004 232 325 Sperm deformities (F 0 parent generation) WIL, 2001 as analyzed in Stelljes & Wood, 2004 296 311 Reproductive Effects—Female Number of estrus cycles during a 3 week period (F 0 parent generation) WIL, 2001 as analyzed in ICF, 2006 WIL, 2001 as analyzed in ICF, 2006 162 208 170 218 Estrous cycle length (F 1 offspring generation) d WIL, 2001 as analyzed in TERA, 2004 400 420 Estrous cycle length (F 0 parent generation) e WIL, 2001 as analyzed in TERA, 2004 210 220 No estrous cycle incidence (F 1 offspring generation) WIL, 2001 as analyzed in TERA, 2004 180 189 No estrous cycle incidence (F 0 parent generation) WIL, 2001 as analyzed in TERA, 2004 480 504 Reproductive Effects—Reproductive Success Decreased live litter size (F 1 offspring generation) WIL, 2001 as analyzed in TERA, 2004 190 200 Decreased live litter size (F 2 offspring generation) WIL, 2001 as analyzed in TERA, 2004 170 179 Pup weight gain, post-natal days 21 to 28 (F 1 offspring generation) WIL, 2001 as analyzed in TERA, 2004 180 189 Developmental Effects Fetal body weight WIL, 2001 as analyzed in TERA, 2004 310 326 Fetal body weight WIL, 2001 as analyzed in CERHR, 2002a 305 320 Nervous System Effects Hindlimb strength Ichihara et al , 2000a as analyzed in Stelljes and Wood, 2004 214 300 a Unless explicitly stated, data are from a parental generation. Of the studies analyzed, only the WIL, 2001 study has multiple generations to be analyzed. b The benchmark response value represents a specified level of excess risk above a control response. c When considering workplace exposures, the human equivalent concentration is the BMDL, adjusted to apply to a 40-hour work week in which workers are exposed for 8 hours a day for five days per week. Animals in the WIL, 2001 study were exposed for 6 hours a day, 7 days a week. Animals in the Ichihara, 2000a and 2000b studies were exposed for 8 hours a day, 7 days a week. Animals in the ClinTrials, 1997b study were exposed for 6 hours a day, 5 days a week. d After applying an uncertainty factor of 3 for animal to human extrapolation, acceptable levels of exposure to protect against liver effects would be in the range of 39 to 57 ppm. e Omits data from those animals that have stopped estrous cycling altogether (TERA, 2004). 2. General Population Risks EPA used a community exposure guideline of 1 ppm to assess potential risks to the general population living near a facility using nPB (see section V.E below). Of the end uses covered in this rule, use of nPB-based adhesives would result in the highest exposure levels, and so, we first examined general population exposure from adhesives. ICF Consulting modeled inhalation exposure to nPB to people living near a plant using nPB-based adhesives in several scenarios using the Agency's SCREEN3 model (US EPA, 1995b). Based on this modeling, EPA found that the exposure to individuals in the general population was below the community exposure guideline. The analysis indicates that nPB is no greater a hazard to the general population than other acceptable solvents under the SNAP program. For further discussion, see the risk screen for nPB (ICF, 2006a). Representatives from a state environmental agency and from a potential user of nPB have asked EPA whether we had developed a reference concentration (RfC). We clarify that the community exposure guideline is a value developed by the SNAP program for our risk assessment of nPB following EPA's RfC Guidelines. However, it is not a formal RfC developed by EPA's National Center for Environmental Assessment and is not in IRIS. At this time, EPA does not have plans to issue an official RfC for nPB. V. How did EPA assess impacts on human health? A. Newly Available Exposure Data Since publication of the June 2003 NPRM, EPA has received additional information on exposure levels in each end use discussed in this proposal. In the adhesives end use, we considered new exposure modeling based on information from site visits to facilities using spray adhesives (ICF, 2006a). These data predicted that: • At average rates of ventilation and adhesive application, average workplace exposures would be approximately 60 ppm. • Average adhesive application rates and poor ventilation rates resulted in average exposures of approximately 250 ppm. • High (90th percentile) adhesive application rates and average ventilation rates resulted in average exposures of approximately 600 ppm. • In the worst case scenario with high adhesive application rates and poor ventilation, average workplace exposures would be as high as 2530 ppm. We compared the modeled data in the four exposure scenarios to measured exposure data in three health hazard evaluations by the National Institute for Occupational Safety and Health (NIOSH) (NIOSH 2002a, 2002b, 2003a). Our understanding is that North Carolina OSHA received complaints from workers and requested that NIOSH evaluate health hazards at these three facilities. NIOSH found average exposure levels of 68 ppm, 116 ppm, 127 ppm, and 195 ppm for sprayers actively using the adhesive prior to installation of state-of-the-art ventilation systems (NIOSH 2002a, 2002b, 2003a). The plant with an average exposure level of 68 ppm for sprayers (9 samples) had an average exposure level comparable to the average concentration of 60 ppm in the modeling scenario with average adhesive rates and average ventilation levels. The other plants with average exposure levels of 116 to 127 ppm (20 samples), and of 195 ppm (36 samples) for sprayers had exposure levels between the average modeled exposure for a facility with average adhesive application rates and average ventilation (60 ppm) and the average modeled exposure for a facility with average adhesive application rates and poor ventilation (250 ppm). Based on this comparison, EPA believes the modeled exposure levels are a reasonable predictor of actual exposure based on current industry practice in the adhesive end use. In the aerosol solvent end use, we received a study on workplace exposure levels of nPB-based aerosols from a commenter (Linnell, 2003). This study was performed to simulate typical exposure levels in a number of situations where nPB might be used in the workplace while using different types of ventilation equipment, rather than using data from current industry users of nPB-based aerosols in their actual manufacturing or maintenance processes. As discussed below in section VI.A., we are concerned that the exposure data and ventilation levels in this study may not be representative of use of nPB-based aerosols in industry. Personal breathing zone samples taken from the collars of workers showed 8-hour time-weighted average (TWA) exposures of 5.5, 13, and 32 ppm for workers using 310 g of nPB from a spray can 10 (Linnell, 2003). The two higher exposure levels occurred in the absence of any local or regional ventilation; the use of both local and regional ventilation equipment with ventilation levels around 1900 ft 3 /min was associated with the lowest exposure level. Short-term exposures of 370, 1,100 and 2,100 ppm taken from a room with regional ventilation at 640 cubic feet per minute (cfm), when averaged over an 8-hour period, resulted in exposures of 12, 34, and 66 ppm (Linnell, 2003). EPA considers the highest of these 8-hour values, 66 ppm, not to be representative of worker exposure from inhalation because the measurement was taken from the worker's wrist, rather than from his breathing zone. Another short-term exposure value of 190 ppm, taken from a vented booth with local ventilation at 472 cfm, in addition to the regional ventilation of 640 cfm, resulted in an 8-hour exposure of 6 ppm. Similar measurements were made in another study we considered in developing the June 2003 NPRM: Eight hour (8-hr) TWA exposures of 11.3, 15.1, 17.0, and 30.2 ppm with regional ventilation of 300 cubic feet per minute from a fan for the entire room (Confidential submission, 1998). 10 Unlike samples measured directly in the breathing zone, area samples measured in the study are not considered representative of actual exposure and are not discussed here. Short-term measurements taken over 15 minutes from personal samplers, although in some cases extremely high, are not discussed in detail here because available toxicity information does not indicate need for a short-term exposure limit for nPB in addition to the 8-hr TWA limit (ACGIH, 2005; ERG, 2004). Additional information on these other samples is in the occupational exposure assessment for aerosols in the risk screen for nPB (ICF, 2006a). Another commenter submitted information on aerosol exposures for a number of other available alternative aerosols (Werner, 2003). While these data do not include nPB, based on the properties of aerosol solvents, we believe it is reasonable to compare concentrations of these different chemicals to potential nPB exposures. The study compared concentrations of eight different chemicals that are acceptable under the SNAP program in aerosol formulations: HFE-7100, HFE-7200, trans-1,2-dichloroethylene, HCFC-225ca and -225cb, acetone, pentane, and HFC-134a. In this study, with ventilation of only 48 cfm, 8-hr TWA exposure from the different chemicals varied from 35.5 ppm to 194.0 ppm, 11 below the recommended exposure levels for these particular chemicals (ICF, 2006a) but above the range of exposure levels that EPA would consider acceptable for nPB. 11 These measurements can be converted to estimates of nPB exposure by multiplying the measured concentration of the alternate chemical by the molecular weight of the same alternate chemical and dividing this by the molecular weight of nPB, 123. After performing this calculation, the equivalent exposure levels for nPB vary from 29.5 ppm to 394.4 ppm. In addition, we considered new information from modeling of nPB exposures (ICF, 2006a). The modeling examined exposure levels that would be expected at ventilation levels of 450 cfm, 625 cfm, and 1350 ppm, considering the molecular weight of the compound and the composition of different aerosol blends. EPA's SNAP program has previously used these same levels to calculate potential aerosol exposures, based upon exposure levels expected during benchtop cleaning. In a space with an air exchange rate of 450 ft 3 /minute or less, 12 EPA's modeling predicts 8-hour average exposure of approximately 16 to 17 ppm if a user sprays 450 g of nPB (approximately 1 lb), 13 and corresponding higher exposure values at higher spray rates (e.g., 33 ppm if the amount of nPB sprayed is 900 g) (ICF, 2006a). Exposure values were predicted to be lower at higher ventilation rates. 12 This corresponds roughly to a regional or room fan at low levels or natural air currents in an open area. Confined areas would have even lower air exchange rates with higher exposure levels. 13 We consider use of 1000 g/day to be the high end of typical use, based on the setup of one of the exposure studies (Confidential Submission, 1998). The typical aerosol solvent user in the electronics industry uses a can per day (Williams, 2005). This is comparable to or slightly less than the spray rate assumed in the modeling. Since the June 2003 NPRM, EPA received a new submission for nPB in coatings (Lake City Army Ammunition Plant, 2003). The Lake City Army Ammunition Plant provided data on workplace exposure to nPB (Lake City Army Ammunition Plant, 2004). The mean exposure at this facility was 3.7 ppm. Out of 31 samples taken, 25 (approximately 80%) were below 5 ppm. Only one of 31 samples had an exposure level above 10 ppm, and that exposure value was approximately 21 ppm. B. Newly Available Data on Health Effects Since publication of the June 2003 NPRM, EPA has examined additional occupational (Table 7) and animal (Table 8) studies that have become available: Table 7.—Recent Studies on n PB Occupational Exposure Case Study Sample size/population Exposure data Observations Remarks Beck and Caravati, 2003 6 foam cushion factory workers (gluers) Exposure during 30-40 hr/wk for a 3-month period. Exposure measured in one day was a mean of 130 ppm (range, 91-176 ppm) Lower leg weakness accompanied by pain and difficulty with standing and walking, numbness of legs and feet, hyperreflexia and hypertonicity of lower extremities, dizziness and shortness of breath, and peripheral neurotoxicity. Measured serum bromide levels were elevated, range 44-170 mg/dL Small sample size studied. Possible interference or synergistic effects from other adhesive ingredients (1,2-epoxybutane and styrene-butadiene). Majersik et al. , 2004; Majersik et al. , 2005 * 6 foam cushion factory workers (gluers) 5-8 hr/day for at least 2 years with mean air concentration of 130 ppm on last day of study. Measurements taken over 9 hours (equivalent to 92-127 ppm with mean of 108 ppm for an 8-hour TWA) Subacute onset of lower extremity pain, difficulty walking, and high serum bromide levels in blood. Neurotoxic symptoms persisted for at least 2 years after exposure ended Follow-up to Beck and Caravati (2003). Chronic nPB exposure associated with incapacitating neurotoxic syndrome. Initial report from Utah OSHA indicated erroneously that workers were not spraying while measurements were taken. In fact, adhesives were being sprayed and fans were being used only for portions of the day that measurements were taken, making measurements likely to be representative of conditions during the past several months at the plant. Ichihara et al. , 2004a 37 chemical plant workers (24 males and 13 females) 12 hour shifts over 2-day period, mean concentration of 82 ppm (range, 0-170 ppm) Mucosal irritation (nose, throat), headache, dizziness, constipation, intoxication, and feeling light-headed or heavy-headed. Four female workers complained of disruption or cessation of menstruation. No severe chronic symptoms of neurological damage at less than 170 ppm. Several workers had hemoglobin and hematocrit values outside of the normal range and were diagnosed with mild anemia; most of these cases also showed signs of iron deficiency Inadequate exposure characterization and exposure to other potential toxicants, small sample size, and no appropriate control group. Healthy worker effect possible, where more sensitive workers left the factory between 1996 and 1999. Ichihara et al. , 2004b 27 female chemical plant workers (23 age matched with 23 females from a beer factory control group) 1-day exposure period, range of exposure, 0.34-49 ppm Responses indicated anxiety, fatigue, confusion, tension, and depression. Changes in menstrual status but not statistically significant. Effects on peripheral and central nervous system—diminished vibration sensation of the foot; significantly longer distal latency in the tibial nerve; decreased values in sensory nerve conduction velocity in the sural nerve; and lower scores on memory and perceptual tests. No comparable effects seen in control group No long-term exposure measurements, small sample size; lack of controls for age, height, and body-weight. Low B vitamin levels in normal range in some workers but researchers concluded this did not cause observed neurological effects. Additionally, the study did not indicate any significant differences in the prevalence of menstrual cycle abnormalities. Nemhauser, 2005 * Foam cushion factory workers (gluers) in North Carolina In 1999 study, 16 workers exposed to mean air concentration of 116 ppm, and 12 sprayers exposed to mean concentration of 108 ppm with range of 58 to 254 ppm. In 2001 study, 13 workers exposed to nPB mean air concentration of 46 ppm and 12 sprayers were exposed to mean concentration of 101 ppm, with range of 38 to 281 ppm Higher exposure to nPB and dose-dependent relationship among those who reported anxiety, headache, and ataxia. No reproductive abnormalities reported in medical survey for men or women. Semen analysis found no differences between exposed and unexposed workers Small sample sizes studied with moderate worker participation. Healthy worker effect likely occurred: Those that had most significant health effects had already removed themselves from workplace by the time of the study. No arsenic found at the plant. Neurotoxic effects caused by nPB. See related Health Hazard Evaluation (HHE): NIOSH, 2003a. NIOSH, 2003a 16 workers in 1999 evaluation; 13 workers in 2001 follow-up evaluation 1999 Initial Site Visit: Geometric mean nPB concentration (from personal samples), 81.2 (range, 18-254 ppm); 2001 follow-up: Geometric mean, 81.2 ppm (range, 7-281 ppm) Most workers exposed to nPB levels > 25 ppm. Exposure concentrations lower in 2001 than 1999, but difference not statistically significant. Headache, anxiety, feeling drunk associated with nPB exposure. Hematological endpoints unaffected in exposed group. No correlation of nPB exposure with sperm or semen indices or with neurological abnormalities Arsenic was not attributed to occupational exposure. The National Institute for Occupational Safety and Health (NIOSH) stated that neurological symptoms may have been related to excess exposure to nPB, but that no other effects could conclusively be related to nPB exposure. Raymond and Ford, 2005 * 4 foam cushion factory workers (gluers) in North Carolina Exposure study conducted 9 months after index patient became ill indicated workers exposed to mean nPB air concentration of 116 ppm. 4 workers exposed for 2-3 weeks before initial symptoms detected Dizziness, numbness, ocular symptoms, lower extremity weakness and unsteady gait, weakness, hypesthesia, and ataxic gait in all four workers. Symptoms decreased over time but after six years, at least one worker re-exposed twice at other furniture plants; one or more still suffer from ataxia Small sample size, possible confounding effect from arsenic. Toraason et al. , 2006 41 and 22 foam cushion factory workers (gluers) at 2 facilities 1-3 days up to 8 hrs per day, with concentrations of 0.2-271 ppm at facility A, 4-27 ppm at facility B No statistically significant differences in DNA damage with worker's nPB exposure. In vitro results showed nPB increased DNA damage Authors find limited evidence that nPB poses a “small risk” for DNA damage. * Presentation at North American Congress of Clinical Toxicology on September 14, 2005. Table 8.—Recent Animal Studies of n PB Effects Citation Population/sample size Exposure Observations Comments Fueta et al. , 2002 24 male Wistar rats (12 control, 12 exposed) 6 hr/day, 5 day/wk for 8 weeks at 700 ppm No apparent morphological defects in the brain Only one exposure concentration was used (which is higher than the level already associated with other toxic effects in rodents [400 ppm]) and a shorter exposure duration (8 weeks) was used than the other subchronic studies that have shown effects (13 weeks). Fueta et al. , 2004 58 male Wistar rats (29 experimental and 29 in control group) 6 hr/day, 5 day/wk for 4 to 8 weeks, 700 ppm No apparent morphological defects in the brain. Chronic inhalation changes brain enzyme levels and electrical activity that is reversible after exposure Unclear how nPB and/or its metabolites directly act on receptors or channels in the brain. Furuhashi et al. , 2006 80 Wistar rats (pups and their dams) (1) 8 hr/day (4 hr, followed by 2.5-hr rest period, followed by 4 hr exposure), 7 day/wk during gestation and nursing at 0, 100, 400, 800 ppm in first experiment (2) Dams exposed (800 ppm) during gestation (Group A), offspring not exposed during nursing. Offspring of Group (B) of unexposed dams were nursed by exposed dams. Offspring in control groups C and D not exposed (1) At 800 ppm: most rat offspring died within 2 days of birth or in utero;. body weights of dams significantly lower, organ weights of offspring significantly lower after weaning at 800 ppm in males, and 800 and 400 ppm in females. Most sperm and estrous indicators did not differ among the groups, although the rate of sperm arrival to the cauda epididymis was significantly lower in the 400 ppm group. Inconsistent or no changes in biochemical indicators (2) Second experiment No difference in body weights and pregnancy endpoints between exposed (800 ppm) and unexposed dams. Live offspring at birth, survival rates, body weights, significantly decreased, number of dead offspring, significantly increased in 800-ppm groups Authors concluded that exposure to nPB during pregnancy and lactation adversely affects growth and survival of offspring. Low numbers of offspring in 400- and 800-ppm exposure groups prevent statistical testing EPA comments: Study design inconsistent with guidelines for developmental studies, so comparisons to previous studies are difficult. The mechanism for the adverse effects observed is not known (e.g., indirect exposure through milk, changes in nursing behavior, changes in milk production, exposure in utero, changes in the intrauterine environment) Honma et al. , 2003 Fisher 344 male rats 8 hr/day, 7day/wk for three weeks exposed to 0, 10, 50, 200 or 1000 ppm (5 rats/dosage and 5 different tests) 3 week exposure to greater than 50 ppm temporarily increased locomotor activity and ambulatory and rearing behaviors in male rats Neurological effects shown to be transient and reversible at ≥ 200 ppm (Ichihara et al. , 2000) or absent after 28 days of exposure at concentrations ≥ 400 ppm (ClinTrials, 1997a) or after 90 days of exposure at concentrations up to 600 ppm (ClinTrials, 1997b) in other studies. Human studies are limited by co-exposures and poor estimates of exposure concentrations. Thus, EPA is not using this endpoint as the basis of an AEL. Ishidao et al. , 2002 30 male Wistar rats 6 hr/day, 5 day/wk with test groups (10/dose) exposed to 700 ppm for 4 and 12 weeks and 1500 ppm for 3 and 4 weeks nPB is metabolized rapidly in the rat following exposures to nPB at concentrations ≥ 700 ppm for at least 3 weeks Exposure levels are higher than in some other studies and are much higher than concentrations seen in the workplace. nPB metabolism appears to be different following multiple exposures as compared to acute exposures (see RTI, 2005; ICF, 2006b). NTP, 2003 Female and male B6C3F1 mice and Fischer 344 rats 0, 62.5, 125, 250, 500 (rats and mice), 1000 (rats) ppm for 90 days Early mortality in mice at 500 ppm accompanied by liver and lung cell degeneration and cytoplasmic vacuolization. Cytoplasmic vacuolization also in rat liver cells ≥ 250 ppm (males) and ≥ 500 ppm (females), with increased severity at higher doses. No adverse central nervous system (CNS) effects or histopathology reported Unpublished study. Conclusions drawn from a review of raw data from the National Toxicology Program (NTP) Web site. In general, the severity of effects (in non-reproductive organs) is slightly higher at lower concentrations in male rats than in females. RTI, 2005/Garner et al. , 2006 Female and male B6C3F1mice and Fisher 344N rats, four to six animals in each test trial Exposure via several injection routes (intraperitoneal, intravenous, cannuliz-ation), inhalation, and dermal. Injection conducted via bolus dosing at 5, 20, or 100 mg/kg body weight. Inhalation concentrations of 70, 240, 800, and 2700 ppm administered in a single acute exposure. A dose of 96 mg/kg was applied to a shaved area on the backs of six male rats with a non-occlusive charcoal filter covering (that is, one that does not prevent evaporation) nPB cleared by mice after 48 hours as follows: 45% as volatiles in the breath, 28% as CO 2 in the breath, 26% in urine, <3% in feces, and 2% retained in the body. Distribution was similar in male rats, although amounts in urine and volatiles in breath were higher in mice. At higher doses, the amount of nPB excreted in urine and as CO 2 decreased, with a much greater change in rats compared to mice • After pretreatment with a cytochrome P450 inhibitor, a decrease in nPB cleared as CO 2 (80%) and urine (40%); pretreatment with a glutathione inhibitor reduced nPB cleared as CO 2 by 10% and urine by 4% • The Vmax, a measure of the maximum initial rate of an enzyme-catalysed reaction, is 0.227 for male rats, 0.143 for female rats, 0.329 for male mice and 0.234 for female mice. Half-lives were comparable between males and females at ≤ 800 ppm • For rats exposed to nPB through skin, 37% of the dose was excreted in volatiles, 1.2 % in urine, 1.7% as CO 2 , and 35.7% was on the applicators or in the skin washes. Only 0.32% remained in tissues. Airborne concentrations of nPB in the chamber were 4 to 10 ppm after dosing The study authors concluded that: • nPB administered via intraperitoneal injection or inhalation is eliminated mostly through the breath, with urine as a secondary path. • Metabolism of nPB appears to be primarily through cytochrome P450 enzymes (CYP2E1), particularly in mice; glutathione conjugation still plays an important role in rats. • At high concentrations, female rats may have a decreased capacity to metabolize nPB compared to male rats. • nPB decreases glutathione levels in the liver after a one-time exposure to nPB at concentrations as low as 70 ppm. • nPB is not appreciably absorbed (~3-27%) in rats following dermal application. EPA agrees with these points, except we found that gender differences were only apparent in rats at very high concentrations (2700 ppm and greater). We also note that: • Inhalation tests were only one-time exposures at very high concentrations (240 to 2700 ppm), and thus, are not comparable to long-term dosing at the lower levels expected in the workplace. • Results of dermal testing are not conclusive because of potential for inhalation exposure. Sohn et al. , 2002 40 male and 40 female Sprague-Dawley rats 6 hr/day, 5 day/wk for 13 weeks, test groups (10/sex/dose) were exposed to 0, 200, 500 or 1250 ppm No effects on mortality, activity, weight gain, food consumption, urinalysis, or histological effects in the brains and spinal cords The differences between the various studies may be due to variability in exposure methodology and achieved concentrations of nPB. Stump, 2005* 125 female/125 male rats in first generation and 100 female/100 male rats in offspring generation Both test groups of 25 male rats/ 25 female rats exposed to 0, 100, 200, 250, 500 and 750 ppm nPB for 10 weeks Decreased litter size at 250 and 500 ppm in both generations. Decreased fertility at 100 and 250 ppm in offspring generation Complete infertility at 750 ppm. Reproductive effects seen in both rat sexes which is a strong signal of reproductive toxicity potential in humans. The author considers 100 ppm to be a lowest observed adverse effect level (LOAEL). This is a presentation of data from WIL, 2001. Wang et al. , 2003 36 male Wistar rats 8 hr/day, 5 day/wk for 12 weeks, test groups ( 9 rats) were exposed to 0, 200, 400 or 800 ppm Decrease in creatine kinase in the spinal cord (17% at ≥ 200 ppm) and brain (15-28% at ≥ 400 ppm) at 200, 400, and 800 ppm. No physical or behavioral changes observed Small study size. No behavioral changes or physical symptoms were observed in the animals, so the toxicological relevance of the decrease in creatine kinase is questionable. Yamada et al. , 2003 40 female Wistar rats 8 hr/day, 7 day/wk with test groups (9/dose) exposed to 0, 200, 400, or 800 ppm for 12 weeks All rats at 800 ppm became seriously ill after 7 weeks of exposure. Significant decrease in antral follicles at ≥ 200 ppm, and a decrease in the number of female rats exhibiting regular estrous cycles in 400-ppm females during 7-9 weeks of exposure and at 2-3 weeks at the 800-ppm dose Data suggest that nPB is affecting the maturation of ovarian follicles. A no observed adverse effect level (NOAEL) of 200 ppm is identified with a LOAEL of 400 ppm for the changes in estrus cycles. * Presentation at North American Congress of Clinical Toxicology on September 14, 2005 • In general, the recent animal studies collectively show a range of effects associated with nPB exposure that are qualitatively consistent with previously published findings. (Exceptions to this are the negative results regarding central nervous system toxicity in the NTP (2003) study and the Sohn (2002) study on rats.) Some general conclusions we draw from the new studies include: • Case reports of nPB exposure in the workplace indicate that severe, possibly irreversible, neurological effects may occur at sustained concentrations of approximately 100 ppm or greater (Beck and Caravati, 2003; Majersik et al , 2004; Majersik et al. , 2005; Ichihara et al. , 2002a; Miller, 2005; Raymond and Ford, 2005). In other cases, similar or higher concentrations up to 170 ppm caused less severe nervous system effects (Nemhauser, 2005; NIOSH, 2003a; Ichihara, 2004a). Some neurological effects occurred in workers at levels of less than 50 ppm (Ichihara et al. , 2004b). Because of design and methodological limitations, such as small numbers of subjects and limited exposure information, these studies do not provide a sufficient quantitative basis to derive an acceptable exposure limit. • Data on female rats indicate that nPB affects the maturation of ovarian follicles and the ovarian cycle (Yamada et al. , 2003), consistent with previously reviewed data (WIL , 2001; Sekiguchi et al. , 2002). • Some data on occupation exposure suggest that workers exposed to nPB may have experienced menstrual disorders (Ichihara et al. , 2002; Ichihara et al. , 2004b). However, the data are not statistically significant and are not sufficient to conclude that nPB exposure caused these female reproductive effects. • Data on DNA damage in workers exposed to nPB was not statistically significant (Toraason et al. , 2006). • Metabolic data on mice and rats indicate some species differences. Metabolism of nPB appears to be primarily through cytochrome P450 enzymes, particularly in mice; glutathione conjugation also plays a role, and a bigger role for rats than for mice (RTI, 2005). • New data from toxicological studies on nervous system effects remain inconsistent and equivocal concerning the level at which nervous system effects occur (Fueta et al. , 2002; Fueta et al. , 2004; Honma et al. , 2003; Ishidao et al. , 2002, NTP, 2003; Sohn et al. 2002, Wang et al. , 2003). A number of commenters on the June 2003 NPRM suggested that EPA should consider neurotoxicity as the endpoint in deriving an AEL for nPB (Linnell, 2003; Werner, 2003; Rusch and Bernhardt, 2003, Rusch, 2003). In particular, they requested that EPA consider the study conducted by Wang (2003) and epidemiological data on neurotoxic effects of nPB. As discussed above, the data on neurotoxic effects of nPB on workers are limited and are not sufficient to determine acceptable levels of exposure. In the study on rats by Wang et. al. (2003), measurements found a decrease in enzymes in the spinal cord and brain at 200, 400, and 800 ppm, but the animals displayed no physical or behavioral changes. Because of the lack of physical symptoms or behavioral changes, EPA does not believe that the decrease in enzyme levels in the central nervous system are toxicologically relevant. Other studies examining neurological effects of nPB showed those effects to be transient and reversible at and above 200 ppm (Ichihara et al. , 2000a). Exposures of 200 ppm and above for three weeks had no effect on memory, learning function, or coordination of limbs (Honma, 2003); the effect of spontaneous locomotor activity seen in this study at 50 ppm and above was not considered adverse by the authors. In other studies, neurological effects were absent after extended periods of exposure-after 28 days of exposure at concentrations> 400 ppm (ClinTrials, 1997a) and after 90 days of exposure at concentrations up to 600 ppm (ClinTrials, 1997b). Thus, although neurological effects have been associated with nPB exposure, the data are currently insufficient to quantify and determine acceptable exposure levels based on this endpoint. One commenter on the June 2003 NPRM requested that EPA evaluate a study by Yamada et al. (2003), a study published just prior to the June 2003 NPRM. In response to the comment, EPA reexamined Yamada et al. , 2003 and re-evaluated the literature (Ichihara et al. , 1999, 2002, 2004a,b; Sekiguchi, 2002, Yamada et al. , 2003; WIL, 2001) to assess potential reproductive toxicity in females (ICF, 2006a, Att. A). A peer review of these effects is in the public docket (ICF, 2004b). Multiple benchmark analyses found a statistically significant decrease in the number of estrous cycles and increase in estrous cycle length associated with nPB exposure, consistent with other reproductive endpoints, namely reductions in sperm motility, decreased live litter size, and change in prostate weight (ICF, 2002a; ICF, 2006a; Stelljes and Wood, 2004; TERA, 2004). Reproductive effects are seen in males, females, and offspring, and in different generations of the two-generation study (WIL, 2000). They also are consistent with results seen in one-generation reproductive studies, such as Ichihara et al. (2000b) and Yamada (2003). See Table 6 above in section IV.E.1. for a more complete list of the different health effects. EPA believes that the preponderance of the data indicate that exposure levels sufficient to protect against male reproductive effects ( e.g. , reduced sperm motility) would be in a range from 18 to 30 ppm, in the range of 17 to 22 ppm to protect against female reproductive effects ( e.g. , number and length of estrous cycles), and at approximately 20 ppm for effects related to reproductive success (live litter size). We have not determined what specific level within those ranges (an overall range of 17 to 30 ppm) is most appropriate for evaluating whether a substitute may be used safely and consider these exposure levels to be potentially acceptable. Therefore, we assessed the acceptability of nPB by considering whether it could be used safely in the three end-uses. For end-uses with likelihood of exposures above the range we are considering, while following typical industry practices, we are proposing an unacceptability determination. For end-uses that as their normal practice meet exposure levels below the range we are considering, we are proposing an acceptability determination. It is not necessary for 100% of exposure data for an end use to be above or below the range of 17 to 30 ppm in order to make a determination on the acceptability of an end use because there may be occasional cases that are not following common industry practices. Unusual events would not indicate the industry's likelihood of keeping exposures at safe levels, and thus, should not be the determining factor in our decision. Rather, we consider the overall likelihood that typical industry use would consistently result in acceptably low or unacceptably high exposures. In the June 2003 NPRM, EPA used a BMDL of 169 ppm as a point of departure for developing an AEL. Some commenters stated that data from the F1 generation is inappropriate for calculating occupational exposure, citing statements from toxicologists, such as, “occupational exposure involves adults only.” They also stated that EPA has not required this for other chemicals and that the resulting value is more conservative than what is normal and appropriate for industrial toxicology (Morford, 2003f, Ruckriegel, 2003). Others stated that sperm motility effects on the F1 generation are appropriate to consider (Risotto, 2003; Farr, 2003), particularly because of the potential for in utero effects and because of the consistent presence of these reproductive effects in both generations and at multiple levels. EPA acknowledges that using data from the F1 offspring generation may be conservative because the pups in the F1 generation were exposed to nPB between weaning and sexual maturity (WIL, 2001). During occupational exposure, this period of exposure would not occur because children under age 16 are not allowed to work in industrial settings. However, EPA believes that because of the potential for in utero effects that would only be seen in the offspring generation, looking only at the F0 parental generation could underestimate the adverse health impacts of a chemical. Therefore, we believe it is appropriate to consider effects seen in both the F0 parental generation and the F1 offspring generation. Further, effects on sperm motility in the parental and offspring generations are seen at levels generally consistent with multiple reproductive effects seen in both generations and both sexes exposed to nPB, such as estrous cycle length, lack of estrous cycling, the number of estrous cycles in a given period of time, fertility indices, and the number of live pup births (TERA, 2004; ICF, 2006a; SLR International, 2001). Therefore, we believe that the available data indicate that in order to protect against adverse reproductive effects, an exposure level within the range of 17 to 30 ppm, would potentially be acceptable. We would reach the same proposed decisions of unacceptability based upon data from the F0 generation. C. Evaluation of Acceptable Exposure Levels for the Workplace To calculate acceptable exposure levels for nPB, EPA uses standard risk assessment methods delineated in Agency guidance (U.S. EPA, 1994b) in evaluating data, choosing a benchmark dose level or a NOAEL, and making the adjustments and uncertainty factors prescribed to account for differences in the duration of exposure and in sensitivity between and within species. Adjustment for Occupational Exposure Pattern To account for differences between the exposure pattern used in the WIL study (6 hours per day for 7 days per week) when compared to a typical workweek of 8 hours per day and 5 days a week, a “human equivalent concentration” (HEC) is first calculated by adjusting the benchmark dose level: (BMDL in ppm × 6 hours/8 hours) × 7 days/5 days = HEC (ppm) HECs for the major health endpoints are shown in Table 6 above in section IV.E.1. Uncertainty Factors According to EPA risk assessment guidance for reference concentrations (RfC) (EPA 1994a), uncertainty factors of up to 10 may be applied to the HEC for each of the following conditions: (1) Data from animal studies are used to estimate effects on humans; (2) Data on healthy people or animals are adjusted to account for variations in sensitivity among members of the human population (inter-individual variability); (3) Data from subchronic studies are used to provide estimates for chronic exposure; (4) Studies that only provide a LOAEL rather than a NOAEL or benchmark dose; or (5) An incomplete database of toxicity information exists for the chemical. EPA believes that two uncertainty factors are appropriate for this database to account for that: (1) Physiological differences between humans and rats; and (2) variability within the working population. The rationale for the use of these two uncertainty factors is described below. EPA RfC guidelines state that an uncertainty factor of 10 may be used for potential differences between study animals and humans. This factor of 10 consists in turn of two uncertainty factors of 3—the first to account for differences in pharmacodynamics 14 and the second to account for differences in pharmacokinetics 15 between the study of animal and humans. (The value of three is the square root of 10 rounded to one digit, with 10 representing an order of magnitude (EPA,1994a). In practice, EPA uses the square root of 10 when there are two or four uncertainty factors of 3, yielding a total uncertainty factor of 10 or 100, and we use a value of 3 when multiplying by an uncertainty factor of 10). By EPA RfC guidelines (U.S. EPA, 1994b), no adjustment for differences in pharmacokinetics is necessary in this instance because the blood/air partition coefficient 16 for nPB in the human (7.1) is less than in the rat (11.7), indicating that the delivered dose of nPB into the bloodstream in rats is slightly higher than in humans. Consistent with Appendix J of EPA's RfC guidelines for an inhaled compound that exerts its effects through the bloodstream, EPA applies an uncertainty factor of 1 for pharmacokinetics. 14 Pharmacodynamics refers to the biochemical and physiological effects of chemicals in the body and the mechanism of their actions. 15 Pharmacokinetics refers to the activity or fate of chemicals in the body, including the processes of absorption, distribution, localization in tissues, biotransformation, and excretion. 16 The blood/air partition coefficient is the ratio of a chemical's concentration between blood and air when at equilibrium. However, EPA recognizes that the lack of an uncertainty adjustment for pharmacokinetic differences between animals and humans rests on a default approach applied to category 3 gases described in Appendix J of its guidelines for deriving an inhalation RfC. This default approach assumes that nPB's toxicokinetics follow a model in which: (1) The toxicity is directly related to the inhaled parent compound in the arterial blood, and (2) the critical metabolic pathways scale across species, with respect to body weight, in the same way as the ventilation rate. Given the hypothesized metabolic pathways for nPB (ICF, 2002a; CERHR, 2002a), it is plausible that toxicity in rats may be related to a reactive metabolite in the target tissue rather than the blood level of the parent compound. EPA is not aware of any quantitative data on nPB metabolism in humans, or evidence implicating the biologically active agent or mode of action. Some commenters on the June 2003 NPRM stated that EPA should use an uncertainty factor of 1 or 2 to extrapolate from animals to humans (Weiss Cohen, 2003), while others suggested uncertainty factors of 2 or 3 for pharmacokinetics, or an overall uncertainty factor of 10 for rat to human extrapolation because of a lack of information on the metabolism and mode of action of nPB and because the rat is an insensitive model for effects on male reproduction in humans (Werner, 2003; Rusch and Bernhardt, 2003). Commenters provided no data to indicate that (1) the toxicity is not directly related to the inhaled parent compound in the arterial blood, or (2) the critical metabolic pathways do not scale across species, with respect to body weight, in the same way as the ventilation rate. Recent studies provide additional data regarding metabolism of nPB in rats and mice (RTI, 2005), but data on human metabolism are still lacking. One analysis of these metabolic data suggested that mice are less sensitive to the effects of nPB than rats and hypothesized that humans would also be less sensitive than rats (Stelljes, 2005). However, this analysis makes numerous assumptions about toxic nPB metabolites and metabolic activation pathways that have not been confirmed by experimental data. A review of this analysis is available in the public docket (ICF, 2006c). Despite the difference in metabolic pathways for nPB in mice and rats (RTI, 2005), EPA finds no significant species-specific differences in toxicity exist between rats and mice at inhaled concentrations <500 ppm for 13 weeks (NTP, 2003; ICF, 2006b). These metabolic and subchronic inhalation studies conducted under the National Toxicology Program did not specifically examine for reproductive toxicity or nPB metabolism in target organs that control reproductive function. In summary, there are little available data about the metabolic activation or reactive metabolites responsible for reproductive toxicity in rodents. Similarly, for nPB, there is little information available about differences and similarities between rodents and humans. Given this circumstance, EPA assumes, in the absence of evidence to the contrary, that nPB toxicity is directly related to the inhaled parent compound in the arterial blood and that the critical metabolic pathways scale across species in a manner similar to the ventilation rate. Therefore, the Agency is proposing to apply an uncertainty factor of 1 to account for interspecies differences in pharmacokinetics. EPA requests additional data and comment from the public on the pharmacokinetics, metabolism, and mode of action of nPB that will help determine whether an interspecies uncertainty factor greater than the default value of 1 is warranted to account for pharmacokinetics. If data become available indicating that nPB does not conform to the constraints assumed by the default pharmacokinetic model in the RfC guidelines, we would revise our risk assessment for nPB as necessary, and apply an uncertainty factor for pharmacokinetics consistent with the RfC guidelines in extrapolating from animal to humans. Depending on the resulting difference in the acceptable exposure levels, we would also revise our acceptability determinations accordingly. Given the available data on the blood/air partition coefficient and EPA RfC guidance in the absence of other information, EPA is applying the same rationale used for other compounds reviewed under EPA's SNAP program with a comparable amount of data where an uncertainty factor of 1 for pharmacokinetics was applied. To account for uncertainty in pharmacodynamics of nPB, EPA is applying the default uncertainty factor of 3. This follows the procedures in EPA's RfC guidelines for situations where there are no data to compare pharmacodynamics in rats versus humans (U.S. EPA, 1994b). Recently published data on humans and rodents do not decrease the uncertainty regarding the pharmacodynamics of nPB; therefore, modification of the uncertainty factor of 3 for differences between species is not justified. One commenter stated that EPA did not cite any data that describes the size, condition, or very existence of a subpopulation of men especially sensitive to the effects of nPB. In addition, this commenter asserted that sensitive populations are not traditionally considered when deriving an occupational exposure limit, and that EPA has never mentioned a concern with sensitive subpopulations in previous SNAP reviews. EPA disagrees with the comments. There are preexisting reproductive conditions as well as significant variability in fertility among otherwise healthy adults in the workplace. Women over age 35 and men over age 40 have fertility rates up to three times lower than those of people in their twenties, with effects on the ovarian cycle and on sperm motility as major factors changing with increasing age for women and men, respectively (Dunson et al. , 2002). Adding damage from other factors, such as smoking or occupation exposure to chemicals such as nPB, therefore, can potentially harm an individual's ability to reproduce further (Dunson, et al. 2002). In addition, we note that EPA has used uncertainty factors in the past to protect sensitive subpopulations on other chemicals reviewed under the SNAP program (e.g., trifluoroiodomethane at 69 FR 58907, October 1, 2004). For deriving AELs from health endpoints such as liver effects and neurotoxicity, the SNAP program typically has assigned an uncertainty factor of 1 for sensitive subpopulations because we assume that individuals who are especially susceptible to these effects will have greater difficulty working than most people. However, there is no connection between the ability to reproduce and the ability to work in the industrial sectors discussed in this rule. Thus, we find it appropriate to apply an uncertainty factor greater than 1 for reproductive effects. Some commenters on the June 2003 NPRM said that an uncertainty factor of 1 is appropriate for variability within the working population because sensitive subpopulations will not be present in the working population (Stelljes, 2003, Morford, 2003f). Other commenters stated that there will be very little difference in variability between the worker population and the general population and that it is unclear why EPA selected an uncertainty factor of 3 instead of 10 (Werner, 2003). Commenters suggested uncertainty factors for variability in the working population of 1, 2, and 5 (Stelljes, 2003; Weiss Cohen, 2003; Werner, 2003). EPA's RfC guidelines recommend an uncertainty factor of 10 to account for intraspecies variability within the general population. However, in deriving an acceptable exposure limit, EPA's focus is on worker exposure, which excludes some particularly vulnerable populations, such as children, most adolescents, and the elderly. Thus, we believe that a full uncertainty factor of 10, as for the general population, may be higher than necessary to protect workers. However, because of variability in reproductive function due to factors present among workers, such as aging, smoking, and sexually transmitted disease, and because there is no screening of workers that would make workers more likely to have healthy reproductive systems than non-workers of the same age, we believe than an uncertainty factor of 1 is not sufficiently protective. Under EPA guidelines, 3 is a default value for an uncertainty factor where there is indication that a value less than an order of magnitude (10) but greater than one is appropriate, and where the available data are not sufficiently quantified to select a specific value. Therefore, EPA is again proposing to assign an uncertainty factor of 3 to account for difference between individuals in the working population. The uncertainty factors of 3 for animal-human extrapolation and 3 for variability within the human working population (each representing the square root of ten, half an order of magnitude) yield a composite uncertainty factor of 10. This factor was applied to all HECs derived from reproductive studies summarized in Table 6 in section IV.E.1 above. The resultant values are higher than the value that would have been obtained had EPA used the TLV of 10 ppm developed by the ACGIH. EPA believes that the benchmark dose approach more accurately characterizes the observed effects and provides a more robust utilization of the data. D. Other Analyses of nPB Toxicity Analyses Reviewed During Preparation of June 2003 NPRM One commenter on the June 2003 NPRM stated that documents by Drs. Doull, Rozman, Stelljes, Murray, Rodricks, and the KS Crump Group were not acknowledged (Morford, 2003f, g, and h). EPA specifically mentioned and responded to the occupational exposure limit recommendations from Drs. Rozman, Doull, and Stelljes in the preamble to the June 2003 NPRM at 68 FR 33298-33299. In addition, EPA included more detailed written responses to these derivations and the evaluation by Dr. Rodricks in the online docket prior to proposal (EPA-HQ-OAR-2002-0064-0017, -0018, and -0019). We considered these documents in preparation of the June 2003 proposal as well as this proposal. In general, we disagree that the neurotoxicity endpoint selected by Drs. Rozman and Doull is the most appropriate endpoint for setting an AEL and we agree with Dr. Stelljes that sperm motility in the F1 offspring generation of the WIL, 2001 2-generation study is an appropriate endpoint. We agree with a number of these documents that data from the F1 generation may be conservative because workplace exposure would not include exposure to the F1 animals during the four-week period from weaning to sexual maturity. However, EPA believes that because of the potential for in utero effects that would only be seen in the offspring generation, looking only at the F0 parental generation could underestimate the adverse health impacts of a chemical. Therefore, it was appropriate for us to consider effects seen in both the F0 parental generation and the F1 offspring generation. Further, effects on sperm motility in the parental and offspring generations are seen at levels generally consistent with multiple reproductive effects seen in both generations and both sexes exposed to nPB, such as estrous cycle length, lack of estrous cycling, the number of estrous cycles in a 3-week period, and the number of live pup births (TERA, 2004; ICF, 2006a; SLR International, 2001; Stelljes and Wood, 2004). We believe that the document from the K. S. Crump group, a survey of the ratio of points of departure to TLVs set by the ACGIH, is not relevant now that the ACGIH has issued a TLV specifically for nPB. ACGIH appears to set an AEL for nPB that is a factor of 10 lower than the endpoint cited as lowest (100 ppm for effects on pup weight) (ACGIH, 2005). Thus, ACGIH has used an approach for nPB consistent with the total uncertainty factor of 10 assigned by EPA. In general, we find that these documents submitted by the commenter assigned uncertainty factors in a manner inconsistent with EPA guidance. This would result in a higher AEL than we would determine following the approach EPA has used on other chemicals, as well as an AEL that in our view would not sufficiently protect human health from nPB's effects because of multiple sources of uncertainty in available data ( e.g. , variability within the working population, differences between animals and humans in how nPB affects the reproductive system). Since the 2003 NPRM, a number of reviews of nPB toxicity have been issued, several of which include recommendations for occupational exposure limits. CERHR, 2003a and 2004a are similar to CERHR, 2002a, the expert panel report for nPB for the Center for the Evaluation of Risks to Human Reproduction (CERHR). CERHR, 2003b and 2004b are similar to CERHR, 2002b, the CERHR expert panel's report for iPB. These documents discuss the usefulness of data in available studies for assessing nPB's health impacts and establish No Observed Adverse Concentration levels of 100 ppm for both male and female reproductive effects in animals, but do not derive an AEL. Rozman and Doull, 2005 derived an AEL of 25 ppm for nPB based on neurotoxicity, using more recent information than Rozman and Doull, 2002. The Stelljes and Wood (2004) analysis is similar in its results to SLR International (2001), a study by the same authors. EPA previously reviewed SLR International, 2001 in developing the June 2003 NPRM. Both studies by Stelljes and Wood concluded with a recommended AEL of 156 ppm, based on male reproductive effects and uncertainty factors of 1 in driving the AEL. Stelljes (2005) reviews RTI's 2005 study on metabolism of nPB in mice and rats and other literature and speculates that humans should be less sensitive to nPB than either mice or rats based on differences in metabolite production. Stelljes (2005) recommends that no uncertainty factor is required to extrapolate from animals to humans and that an uncertainty factor of no more than 2 is appropriate to account for differences within the working population. All of these documents assigned uncertainty factors in a manner that is not sufficiently supported by the available data and that is inconsistent with EPA's guidance. For example, Stelljes (2005) discusses metabolic data in rats and mice from RTI, 2005 and concludes that on this basis, the uncertainty factor for extrapolation from animals to humans should be 1. However, the metabolic data relate to pharmacokinetics—the activity of chemicals in the body—and do not address EPA's proposed uncertainty factor of 3 related to pharmacodynamics (the biochemical and physiological effects of chemicals in the body and the mechanism of their actions). Using the AEL from one of these documents would result in a higher, less protective AEL than we would determine following the approach EPA has used for other chemicals under the SNAP program and would not consider multiple sources of uncertainty in health effects (i.e., variability within the working population and differences between animals and humans in how nPB affects the reproductive system). Thus, we are concerned that the AELs based on these documents would not be sufficiently protective and would result in an inappropriate acceptability decision. Detailed reviews of these documents are available in the public docket. Toxicological Excellence in Risk Assessment (TERA), 2004 reviews other AEL derivations for nPB, performs a benchmark dose (BMD) analysis, and recommends an AEL of 20 ppm based on live litter size. This analysis is consistent with EPA guidance for BMD modeling and for assigning uncertainty factors. A review of this document is available in the public docket (ICF, 2004c). ICF (2004b, 2006a) derived an AEL for nPB based upon female reproductive effects. ICF (2004b, 2006a) discussed the relevant literature (Ichihara et al., 1999, 2002, 2004a, 2004b; Sekiguchi, 2002; Yamada et al. , 2003; WIL, 2001) and calculated mean estrous cycle length and the mean number of estrous cycles occurring during a three-week period at different exposure levels in the WIL, 2001 2-generation study. ICF (2004b, 2006a) found statistically significant reductions in the number of estrous cycles in a three-week period, both including and excluding females that had stopped their estrous cycles, at 250, 500, and 750 ppm in the F0 parental generation and at 500 and 750 ppm in the F1 generation. ICF (2004b, 2006a) conducted BMD modeling and calculated BMDL values of the number of estrous cycles in a three-week period that varied from 102 to 208 ppm, depending upon the model used and the benchmark criteria selected. All data were calculated based on the mean reductions in estrous cycle number calculated from the WIL, 2001 study. Values were calculated for the F0 generation; the number of data for the F1 generation was too small for statistical analysis. The BMDLs that ICF calculated for the number of estrous cycles in a three-week period were 162 ppm and 208 ppm, depending on [Text truncated at 120,000 characters. The full text is on the page linked above.] --- Source: Frix Law Library, https://www.frixlaw.com/law-library/documents/fr%3AE7-9706. Public record. Not legal advice.