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MAY 0 51993 TOXICITY TESTING PLAN FOR LOW IGNITION-POTENTIAL CIGARETTES I U.S. Consumer Product Safety Commission and its Expert Panel, in consultation with the U.S. Department of Health and Human Services ' "ECE'1 ~71FD N1A Y ~ 4 r993 J• I i I I I March 18, 1993 I

CONTRIBUTORS Expert Panel David M. Burns, MD, (University of California at San Diego Medical Center), Professor of Medicine C. Gary Gairola, PhD (Tobacco and Health Research Institute, University of Kentucky at Lexington), Associate Professor of Pharmacology and Experimental Therapeutics Jeffrey E. Harris, MD, PhD (Internal Medicine Associates, Massachusetts General Hospital) DietrichlHoffmann, PhD (American Health Foundation), Associate Director and Chief, Environmental Carcinogenesis Harold~C. Pillsbury, Jr., Cigarette Testing Consultant Federal Government .Brian C. Lee, PhD, DABT (US Consumer Product Safety Commission), Toxicologist, Manager, Expert Panel Donald Shopland, MD, (US Department of Health and Human Services, National Institutes of Health, National Cancer Institute), Coordinator, Smoke and Tobacco Program 1 I I

I I TOXICITY TESTING PLAN FOR LOW IGNITION-POTENTIAL CIGARETTES Table of Contents Health Effects Assessment Plan Brian C. Lee, PhD, DABT I I I j I I I Chapter A overview and Major Considerations in the Toxicity Testing of Low Ignition-Potential Cigarettes Jeffrey E. Harris, MD, PhD B Smoking Machine Parameters for Collection of Total Particulate Matter and Gases from Low Ignition- Potential Cigarettes Harold C. Pillsbury, Jr. C Assessing Changes in Topography (Inhalation Profile) and Biological Effects of Tobacco Smoke in Humans David M. Burns, MD D Analysis of Toxic Smoke Constituents Dietrich Hoffmann, PhD E Short-Term Tests for the Evaluation of Cigarette Smoke Toxicity C. Gary Gairola, PhD F In Vivo Bioassays for Carcinogenicity Dietrich Hoffmann, PhD

I I I I I I I I HEALTH EFFECTS ASSESSMENT PLAN Brian C. Lee, PhD, DABT U.S. Consumer Product Safety Commission March 18, 1993 I

Table 1 Health Effects Assessment Plan Outline of Tiers Tier I - Analyses of chemicals Whole smoke acidity (pH) Gas reduction/oxidation potential phase gases carbon monoxide hydrogen cyanide ~. nitric oxide aldehydes j, ~ ~ acetaldehyde ~ G4~j:(.e~`(' acrolein proprionaldehyde volatile hydrocarbons benzene toluene 1,3-butadiene isoprene volatile nitrosamines N-nitrosodiethylamine N-nitrosodimethylamine N-nitrosopyrrolidine Particulate phase catechol nicotine phenols, as phenol. polyaromatic hydrocarbon benzo(a)'pyrene tar-FTC tobacco specific nitrosamines N'-nitrosonornicotine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone Tier II- In Vitro Tests Salmonella mutagenicity (Ames' assay), mouse embryo fibroblast cell transformation assay Tier III - Human Smoking Behavior cotinine carbon monoxide topography Tier IV - Animal Tests mouse inflammatory lung response hamster upper respiratory tract carcinogenicity mouse skin painting carcinogenicity ~

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I I Table 1 Health Effects Assessment Plan Outline of Tiers Tier I - Analyses of chemicals Whole smoke acidity (pH) reduction/oxidation potential Gas phase gases carbon monoxide hydrogen cyanide nitric oxide aldehydes acetaldehyde acrolein . proprionaldehyde vQlatile hydrocarbons benzene toluene 1,3-butadiene isoprene volatile nitrosamines N-nitrosodiethylamine N-nitrosodimethylamine N-nitrosopyrrolidine Particulate phase catechol nicotine phenols, as phenol. polyaromatic hydrocarbon benzo(a)pyrene tar-FTC tobacco specific nitrosamines N'-nitrosonornicotine 4-(methylnitrosamino)1-1-(3-pyridyl)-1-butanone Tier II- In Vitro Tests Salmonella mutagenicity (Ames' assay) mouse embryo fibroblast cell transformation assay Tier III - Human Smoking Behavior cotinine carbon monoxide topography Tier IV - Animal Tests mouse inflammatory lung response hamster upper respiratory tract carcinogenicity mouse skin painting carcinogenicity

page 1 I. Introduction The Fire-Safe Cigarette Act of 1990 requires the U.S. Consumer Product Safety Commission (CPSC);, in consultation with the Secretary of the U.S. Department of Health and Human Services (DHHS), to develop information on changes in the toxicity of smoke and resultant health effects of cigarettes with a reduced ability to start fires. The Act stated that CPSC "shall not obligate more than $50,000 todevelop such information." The Technical Advisory Group (TAG) established by the Act agreed that this amount precluded any significant testing of prototypes. The Act succeeds the Cigarette Safety Act of 1984 which established a Technical Study Group to examine the feasibility of developing cigarettes with lowered ignition potential. The Technical Study Group concluded it is technically feasible and may be commercially feasible to develop cigarettes that will have a significantly reduced propensity to ignite upholstered furniture or mattresses. The Act expresses a consideration for the possible nationwide health implications of changes resulting from the market substitution/entrance of low-i2gnition cigarette types. There were about 50 million smokers in the U.S. in 1991, according to the National Cancer Institute. The primary concern is that a small increase in the risk of a serious health effect, due to new cigarette types, could result in a great increase in human mortality and morbidity and thus overbalance the benefits that would be achieved from the reduction of fires. CPSC staff, in consultation with DHHS and with the concurrence of the TAG, decided that in view of the statutory $50,000 limitation, a plan must be developed for the toxicological work needed. CPSC convened an expert panel to assist in the development of the plan. The panel was composed of knowledgeable scientists in the field of cigarette toxicity testing. These members were nominated by TAG members and selected by the CPSC staff. This report discusses significant issues and recommends testing necessary for the comprehensive assessment of health effects of low-ignition potential cigarette smoke. It is not intended to be a detailed manual of cigarette toxicity testing, although some necessary technical information is presented.

II. General Discussion page 2 Several adverse health effects of serious concern are the basis for considering the various existing toxicity tests. These effects include: lung and throat cancer, chronic obstructive lung disease, heart and vessel disease, male and female reproductive effects, fetal growth retardation, and psychophysiological addiction, as indicated.in Chapter A. Not all of these health effects can be addressed at this time due to the impracticality or non-existence of adequate tests, expenses, or time needed for testing. Therefore, only the tests believed to be practical are recommended. Estimates of costs and times needed for testing are included in Chapters B and D-F. Major issues surrounding the testing include sidestream smoke, bases of comparisons, analytical vs. in vitro vs. in vivo testing, machine reflection of human smoking behavior, design or performance-based testing, screening paradigms, and disclosure of new additives or increased levels of existing additives, as discussed!in Chapter A. Since low ignition-potential cigarettes might cause changes in smoking behaviors and therefore modify the toxicity, altered human behavior may become a significant factor in exposure, as discussed in Chapter C. Since the smoke is collected by mechanically smoking the cigarettes, the apparatus should be set to reflect smoking behavior as closely as technically feasible. Two methods presently exist for the mechanical smoking of cigarettes, as noted in Chapter B. The Federal Trade Commission (FTC) method, established in 1969, is used in the United States, and the CORESTA method (ISO 3308-1991) is mainly used in Europe. The FTC method is described in Chapter B and is very similar to' the CORESTA method. Both methods analyze for tar, nicotine, carbon monoxide, and moisture content. In light of present knowledge on the adverse health effects and toxic constituents of cigarette smoke, further testing beyond the Federally mandated requirements for tar, nicotine, and carbon monoxide levels is needed to evaluate the toxicity. Levels of key chemical constituents known to be associated with adverse health effects need to be measured, as described in Chapter D. Cigarette smoke is a complex mixture of more than 3,500 chemicals containing at least 35 known carcinogens, and analysis of a limited number of individual chemicals may not predict the net toxic effects of the smoke. In order to address certain conglomerative toxicities of the non-gaseous constituents, in vitro and animal testing are needed, as described in Chapters E and F. Limited whole-animal testing is necessary because of the complexity of the biological systems and a variety of toxic reactions caused by cigarette smoke. As an example, pulmonary inflammation testing requires intact immune, respiratory, and circulatory systems to be simultaneously present. E f I r I F

page 3 I I I I I I I I I I I I The CPSC staff recommends the following guidance plan`after reviewing the considerations of its expert panel.and DHHS.:. III. Assessment Plan This plan provides guidance for the development of data needed to evaluate the changes in toxicity associated with low ignition-potential cigarettes. Performance-based, rather than design-based, testing will be used to provide data specific to cigarette prototypes. A screening paradigm that requires , acceptable performance levels by a candidate cigarette type a- one tier of tests before proceeding with the next tier is recommended. This would allow early rejection of candidates evaluated as unacceptable. However, definition of acceptablez _ levels of performance is beyond the scope of this plan and th direction given by the Act. Therefore, the tests.are present in a sequence of tiers for screening without ascribing accept levels of performance at each tier. Results of the recommended testing will be used to asses the relative toxicity of low-ignition potential cigarettes. toxicity of a candidate low ignition cigarette should be comp to: 1) the specific marketed brand/type intended for replacement, or comparable marketed brands/types for a non- replacement candidate, and 2) standard reference cigarettes, such as the University of Kentucky standard cigarettes mentioned in Chapter E, for quality control. There are insufficient test methods and data on exposure to cigarette smoke and resultant effects for the direct translation of the results into absolute risks to humans. Since the overall health goal is to avoid the production of greater or perhaps new toxicities than that caused by existing cigarettes, a comparative approach of assessing toxicity is appropriate. Selection of the guidance plan tests assumes that no new additives would be present in the candidate cigarettes and that presently used additives would not exceed the levels in the current cigarettes. Since toxic effects not considered by this guidance plan could also occur, it is recommended that additives exceeding the current maximum levels of use on a per unit weight of tobacco basis must be disclosed to the U.S. Department of i, Health and Human Services. Confidential business information I status may be requested for the data disclosed. ~