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`39718
`
`Exhibit 18
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`39719
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION
`SUBJECT TO PROTECTIVE ORDER
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`UNITED STATES INTERNATIONAL TRADE COMMISSION
`
`WASHINGTON, DC
`
`Before the Honorable Clarlc S. Cheney
`Administrative Law Judge
`
`In the Matter of
`
`CERTAIN TOBACCO HEATING ARTICLES
`AND COMPONENTS THEREOF
`
`Investigation No. 337-TA-1199
`
`REBUTTAL EXPERT REPORT OF DR. STACEY M. BENSON
`
`RELATING TO THE PUBLIC INTEREST
`
`Stacey M. Benson
`
`October 23, 2020
`
`

`

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`ranged from 13.7 to 14.8 ng/mL with each having a comparable Tmax value of just over 37 minutes. These
`products deliver consistent nicotine, but not as efficiently has combustible tobacco because the uptake
`of the tobacco for these products is much slower than that which is observed with combustible cigarettes.
`
`
`There are a number of nicotine products available on the market with varied maximum plasma nicotine
`concentrations and time to maximum plasma nicotine concentrations. As shown above, PRRP oral nicotine
`products have lower maximum nicotine concentrations and it takes longer for that peak concentration to
`be experienced. This finding indicates that, in general, the nicotine delivery efficiency of these products
`is much lower than IQOS®. In my opinion, due to the differences experienced with the physical act of using
`these products (e.g. aesthetics of spitting or chewing gum), their lower nicotine delivery efficiency, and
`the increased risks of cancer some of them are associated with, it is inappropriate to consider them
`equivalent alternatives to IQOS®.
`
`
`C.
`
`ENDS Products Are Not Substitutes for IQOS®
`
`
`ENDS is a diverse category of non-combustible nicotine-containing inhalation product and is used for
`describing nicotine-containing e-liquid delivery systems. According to Dr. James Figlar, Executive Vice
`President of Research & Development and Scientific & Regulatory Affairs at RJ Reynolds Tobacco, “e-
`cigarettes don’t work the same way as heat-not-burn product[s],” and “[e-cigarettes are] a different
`animal all together.”47 For several reasons, ENDS products are not IQOS® substitutes.
`
`
`1.
`
`No ENDS Product Has Received the Same FDA Authorizations that IQOS® Has
`
`
`As discussed elsewhere in this report and by other of Respondents’ experts, IQOS® has been granted both
`PMTA and MRTP authorization by FDA. As of October 22, 2020, there are no other inhalable non-
`combustible tobacco/nicotine containing products with such authorizations or that have MRTPAs
`pending. This includes the category of ENDS products.
`
`
`2.
`
`ENDS Products Have Highly Variable Characteristics
`
`
`ENDS are highly variable, where the power settings, nicotine concentration, type of nicotine, puffing
`topography, and humectant can greatly affect the chemical composition of the aerosol and overall user
`aerosol exposure. It is my opinion that ENDS user exposure and corresponding experience is entirely
`dependent on the aerosol produced by the device, as well as other device characteristics such as the
`mouthpiece, size, and shape that make each device unique.
`
`
`a)
`
`ENDS Product Components Affect Aerosol
`
`
`The National Academies of Sciences, Engineering, and Medicine (NASEM) highlights in their report on the
`Public Health Consequences of E-Cigarettes how vastly different types of ENDS product characteristics can
`be. ENDS, some of which are modifiable, vary in their component parts. NASEM stated “the design and
`composition of e-cigarette devices (including e-liquid composition, device battery power, activation
`voltage, and coil resistance) vary considerably, and these variations influence the e-cigarette aerosol
`
`
`47 Figlar Dep. 113: 5-7
`
`
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`produced.”48 There is a large amount of variability amongst the three main components (battery,
`atomizer, and fluid reservoir) of ENDS. The design of ENDS have changed over time, with the first
`generation (e.g., cig-a-like), second generation (clearomizer), third generation (modifiable “mod”), and
`fourth generation (“pod” style). As suggested by Dr. Murrelle in his Table 1 list of ENDS products, there
`are 100s of device, component, and/or e-liquid brands, many of which are available to U.S. consumers.49
`
`
`Pods
`
`AlomIzmg unJts based on a newer
`technology; appealing design
`
`Various Styled
`Replaceable Atomizers
`....
`More customizable
`-
`atomizers than
`clearomizers and fiuid
`reservoirs may be larger
`
`Replaceable Dripping
`Atomizers (RDAs )
`-- Coils bUJlt by user and fiUJd '(cid:173)
`Is dnpped directly on the
`filamen Can come in tank
`form
`
`I
`
`Clearomizers
`
`Removable atomIzmg urnt and
`larger transparent nuid
`reservoir than previous models
`
`Sub-ohm Atomizers
`
`Low resistance atom1zmg
`units and larger tanks than
`original clearomizers
`
`I
`
`2-Piece EC - Cartomizer
`
`Alom,zing unit and Rwd
`reservoir combined, separate
`battery
`
`LJ 1-Piece EC - Disposable
`
`Battery, atomlZlng um and
`fiuid reservoir combined into
`a single urnt
`
`3-Piece EC - Cartridge
`
`.. Classic style EC, first on the market 1-
`separate battery, atomizer, and Ruid
`reservoir
`
`Fourth Generation
`Pod; various shaped
`fixed voltage
`batteries
`
`Third Generation
`Mod; variable
`voltage, wattage,
`power batteries
`
`u
`
`Second Generation
`Clearomizers; larger,
`variable voltage
`wattage, power
`battenes
`
`D
`
`First Generation
`Cig-a-like; fixed, low
`voltage batteries
`
`D
`
`First Generation
`Cig-a-like; fixed, low
`voltage batteries
`
`
`
`Figure 1. Characteristics of the four generations of ENDS. Reprinted from Williams and Talbot 2019.
`
`
`b)
`
`Modifiable Physical Components of ENDS Products Affect Aerosol
`
`
`Heating coils and atomizers in ENDS influence the aerosol properties, therefore affecting the taste and
`potential health effects of the product. If, for instance, the heating power is too high, the user experiences
`a negative sensation called a “dry hit” because of the thermal decomposition of components such as
`
`
`48 NASEM (2018). Public Health Consequences of E-Cigarettes. Washington (DC), National Academy of Sciences,
`Engineering and Medicine., p. 75
`49 Murrelle, E. L. (2020). Expert Report of Edward L. Murrelle. Dated October 5th, 2020., p. 15-16
`
`
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`propylene glycol and glycerol.50,51 The amount of power applied to the atomizer is variable, and can affect
`the mass of aerosol produced: more power creates a denser aerosol per puff.52 First- and second-
`generation devices are known to produce lower power, ranging from 3.0-12.6 W, whereas newer devices
`produce between 10.0 and 162.4 W.53, 54, 55 Power, in combination with higher voltage, can also increase
`nicotine delivery. 56 Talih et al.57 found that increasing the wattage of the device from 3.0 to 7.5 resulted
`in a 4- to 5-fold increase in nicotine yield. Similarly, Farsalianos et al.58 conducted an experimental study
`to investigate the relationship between ENDS power settings and puff topography. Study investigators
`provided a third generation electronic cigarette battery and rebuildable tank atomizer, which subjects
`filled with their own choice of e-liquid. Participants vaped ad libitum in two blinded sessions, using a
`different power setting in each (6 W and 10 W). Generally, participants on the 6W power setting took
`statistically significantly more puffs of longer duration compared to the 10 W setting (57 vs. 46 puffs, p =
`0.001; 4.6 s/puff vs. 3.8 s/puff, p = 0.001). NASEM also concluded based on aerosol exposure studies that
`e-cigarettes have the potential to contain and emit toxic substances, but that the quantity and
`characteristics of those substances were highly variable based on the device and liquid characteristics.
`
` review by Fearon et al.59 summarized the differences in pharmacokinetics of ENDS devices reporting
`both ad libitum and regimented puffing scenarios. To minimize the variability in the pharmacokinetic
`response associated with ad libitum puffing, I only compared Cmax for the regimented puffing conditions
`of 5 minutes to 7.5 minutes. For cig-a-like and first generation ENDS, the Cmax ranged from 2 ng/mL for a
`V2 cig, to 9.1 ng/mL for a V2 cigs blu. For newer generation devices the range of Cmax values under
`regimented conditions were broad with a minimum of 2.7 ng/mL after use of an eVIC (open tank) for five
`minutes and up to 20 ng/mL for subjects who used their own first or second generation devices.
`
`
`50 Farsalinos, K. E., V. Voudris and K. Poulas (2015). "E-cigarettes generate high levels of aldehydes only in 'dry puff'
`conditions." Addiction 110(8): 1352-1356.
`51 Geiss, O., I. Bianchi and J. Barrero-Moreno (2016). "Correlation of volatile carbonyl yields emitted by e-cigarettes
`with the temperature of the heating coil and the perceived sensorial quality of the generated vapours." Int J Hyg
`Environ Health 219(3): 268-277.
`52 Gillman, I. G., K. A. Kistler, E. W. Stewart and A. R. Paolantonio (2016). "Effect of variable power levels on the yield
`of total aerosol mass and formation of aldehydes in e-cigarette aerosols." Regul Toxicol Pharmacol 75: 58-65.
`53 Alexander (2015). "Electronic cigarettes: the new face of nicotine delivery and addiction." Journal of Thoracic
`Disease 7(8): E248-E251.
`54 Voos, N., L. Kaiser, M. C. Mahoney, C. M. Bradizza, L. T. Kozlowski, N. L. Benowitz, R. J. O'Connor and M. L.
`Goniewicz (2019). "Randomized within-subject trial to evaluate smokers' initial perceptions, subjective effects and
`nicotine delivery across six vaporized nicotine products." Addiction 114(7): 1236-1248.
`55 Wagener, T. L., E. L. Floyd, I. Stepanov, L. M. Driskill, S. G. Frank, E. Meier, E. L. Leavens, A. P. Tackett, N. Molina
`and L. Queimado (2017). "Have combustible cigarettes met their match? The nicotine delivery profiles and harmful
`constituent exposures of second-generation and third-generation electronic cigarette users." Tob Control 26(e1):
`e23-e28.
`56 Alexander (2015). "Electronic cigarettes: the new face of nicotine delivery and addiction." Journal of Thoracic
`Disease 7(8): E248-E251.
`57 Talih, S., Z. Balhas, T. Eissenberg, R. Salman, N. Karaoghlanian, A. El Hellani, R. Baalbaki, N. Saliba and A. Shihadeh
`(2015). "Effects of user puff topography, device voltage, and liquid nicotine concentration on electronic cigarette
`nicotine yield: measurements and model predictions." Nicotine Tob Res 17(2): 150-157.
`58 Farsalinos, K., K. Poulas and V. Voudris (2018). "Changes in Puffing Topography and Nicotine Consumption
`Depending on the Power Setting of Electronic Cigarettes." Nicotine Tob Res 20(8): 993-997.
`59 Fearon, I. M., A. C. Eldridge, N. Gale, M. McEwan, M. F. Stiles and E. K. Round (2018). "Nicotine pharmacokinetics
`of electronic cigarettes: A review of the literature." Regul Toxicol Pharmacol 100: 25-34.
`
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`Aside from device generational differences, there has been significant variation in the user experience of
`ENDS of different designs. For example, Voos et al. 60 demonstrated that modifiable (mod) devices had the
`highest nicotine yield [9.11 milligrams (mg)] of all tested designs, while disposable products had the
`lowest nicotine yield (0.64 mg). Similarly, Aldermann et al.61 compared the pharmacokinetics of two
`rechargeable devices and one disposable device. The disposable model had a lower puff mass (1.95
`mg/puff) compared to the rechargeable device puff masses (2.16 mg/puff and 3.07 mg/puff). In Melstrom
`et al.,62 a group of six non-users were recruited for an experimental study regarding cotinine levels
`following secondhand exposure to ENDS. For the disposable ENDS exposure session, mean [standard
`deviation (SD)] post-exposure Cmax was 0.117 (0.089) ng/mL in serum, 0.124 (0.107) ng/mL in saliva, and
`1.415 (1.484) ng/mg creatinine in urine. Cmax was higher following exposure to tank-style ENDS devices,
`with a mean (SD) of 0.326 (0.346) ng/mL in serum, 0.395 (0.415) ng/mL in saliva, and 4.242 (4.225) ng/mg
`creatinine in urine. The differences in cotinine levels following secondhand exposure emphasize the
`differences in the aerosol and the user experience.
`
`
`
`NASEM reports that nicotine exposure is dependent on device and e-liquid characteristics. They stated
`that while cigarettes are relatively consistent in their nicotine delivery, the “efficiency, speed, and
`magnitude of nicotine delivery to the user varies widely across different e-cigarette products and user
`characteristics.63 Different devices are compatible with different types of e-liquid. As of 2014,64 there were
`hundreds of e-liquid brands and thousands of unique e-liquid flavors available to U.S. consumers. The
`composition of the e-liquid can vary by nicotine type, nicotine concentration, humectant ratio, and
`flavoring chemical additives. The flavorants and additives in e-liquids can vary widely across products,
`obscuring comparisons of aerosol composition that may arise from not only one ingredient, but a
`collective mixture of all ingredients. Recently, Omaiye et al.65 identified 155 different flavor chemicals
`across 277 e-liquids.
`
`The form of nicotine in the e-liquid can vary: nicotine salts or freebase. Due to the lower pH, nicotine salt
`e-liquids release an aerosol that is less harsh and unpleasant tasting than those with freebase nicotine,
`
`c)
`
`E-liquid Formulation and nicotine yield are extremely variable in ENDS
`
`
`60 Voos, N., L. Kaiser, M. C. Mahoney, C. M. Bradizza, L. T. Kozlowski, N. L. Benowitz, R. J. O'Connor and M. L.
`Goniewicz (2019). "Randomized within-subject trial to evaluate smokers' initial perceptions, subjective effects and
`nicotine delivery across six vaporized nicotine products." Addiction 114(7): 1236-1248.
`61 Alderman, S. L., C. Song, S. C. Moldoveanu and S. K. Cole (2015). "Particle Size Distribution of E-Cigarette Aerosols
`and the Relationship to Cambridge Filter Pad Collection Efficiency." Beiträge zur Tabakforschung / Contributions to
`Tobacco Research 26(4).
`62 Melstrom, P., B. Koszowski, M. H. Thanner, E. Hoh, B. King, R. Bunnell and T. McAfee (2017). "Measuring PM2.5,
`Ultrafine Particles, Nicotine Air and Wipe Samples Following the Use of Electronic Cigarettes." Nicotine Tob Res
`19(9): 1055-1061.
`63 NASEM (2018). Public Health Consequences of E-Cigarettes. Washington (DC), National Academy of Sciences,
`Engineering and Medicine., p. 257
`64 Omaiye, E. E., K. J. McWhirter, W. Luo, P. A. Tierney, J. F. Pankow and P. Talbot (2019). "High concentrations of
`flavor chemicals are present in electronic cigarette refill fluids." Sci Rep 9(1): 2468.
`65 Omaiye, E. E., K. J. McWhirter, W. Luo, P. A. Tierney, J. F. Pankow and P. Talbot (2019). "High concentrations of
`flavor chemicals are present in electronic cigarette refill fluids." Sci Rep 9(1): 2468.
`
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`allowing users to inhale more deeply, which results in a higher nicotine absorption in the lungs.66, 67, 68 This
`variability in nicotine exposure dependent upon type of nicotine and product type is evident in a recent
`study using various myblu and blu products.69 Coincidentally, the purported representative product of the
`ENDS category in Dr. Murelle’s report was the myblu by Fontem Ventures.70 O’Connell et al.71 compared
`the subjective effects and pharmacokinetic properties of three myblu and one blu PRO nicotine salt and
`one myblu freebase e-liquid devices. There were statistically significant differences on the user experience
`of dizziness, nausea, urge to smoke, and nicotine content. The Cmax of the freebase liquid (5.048 ng/mL)
`was also much lower than the majority of the nicotine salt liquid products (6.51-10.27 ng/mL). This study
`underscores the variability of nicotine delivery amongst a single manufacturer (Fontem Ventures) of two
`ENDS (myblu and blu PRO), with different nicotine types and concentrations, and its effects on aerosol.
`
`3.
`
`ENDS Product Variability Affects Aerosol and Thus User HPHC Exposure
`
`
`Dr. Murrelle asserted, “there are many non-combustible tobacco/nicotine product categories available to
`U.S. consumers that are in the interest of public health. The potential absence of IQOS® from the market
`would not negatively impact combustible cigarette smokers in the U.S.”72 To reinforce his position, Dr.
`Murrelle presents a second table73 in his expert report that compares the aerosol chemical profile of
`IQOS® and other nicotine containing products. The purpose was to evaluate the concentration of a subset
`of harmful and potentially harmful constituents (HPHC)s across product categories. The HPHCs included
`in Dr. Murrelle’s table is the FDA abbreviated HPHC list for combustible cigarettes.74 Dr. Murrelle chose a
`“representative” product for each category with preference for those “with applications that have been
`submitted to and reviewed by FDA.” 75 This table, however, does not paint the full picture on the high
`variability of HPHCs in inhalable non-combustible tobacco or nicotine-containing products on the market,
`nor does he transparently provide the basis for these data (e.g. the basis of one unit or the references on
`which he relied to present this data). Also, of the ENDS products listed from his own Table 1,76 I found
`that 150 of the products' companies stated they submitted or intended to submit a PMTA. Therefore, the
`representative product chosen for ENDS cannot possibly represent all of these extremely different
`products. Alternatively, I prepared a table of the two heat-not-burn (HNB) products that have been
`
`66 NASEM (2018). Public Health Consequences of E-Cigarettes. Washington (DC), National Academy of Sciences,
`Engineering and Medicine., p. 257
`67 O'Connell, G., J. D. Pritchard, C. Prue, J. Thompson, T. Verron, D. Graff and T. Walele (2019). "A randomised, open-
`label, cross-over clinical study to evaluate the pharmacokinetic profiles of cigarettes and e-cigarettes with nicotine
`salt formulations in US adult smokers." Intern Emerg Med 14(6): 853-861.
`68 Voos, N., M. L. Goniewicz and T. Eissenberg (2019). "What is the nicotine delivery profile of electronic cigarettes?"
`Expert Opin Drug Deliv 16(11): 1193-1203.
`69 O'Connell, G., J. D. Pritchard, C. Prue, J. Thompson, T. Verron, D. Graff and T. Walele (2019). "A randomised, open-
`label, cross-over clinical study to evaluate the pharmacokinetic profiles of cigarettes and e-cigarettes with nicotine
`salt formulations in US adult smokers." Intern Emerg Med 14(6): 853-861.
`70 Murrelle, E. L. (2020). Expert Report of Edward L. Murrelle. Dated October 5th, 2020., p. 28
`71 O'Connell, G., J. D. Pritchard, C. Prue, J. Thompson, T. Verron, D. Graff and T. Walele (2019). "A randomised, open-
`label, cross-over clinical study to evaluate the pharmacokinetic profiles of cigarettes and e-cigarettes with nicotine
`salt formulations in US adult smokers." Intern Emerg Med 14(6): 853-861.
`72 Murrelle, E. L. (2020). Expert Report of Edward L. Murrelle. Dated October 5th, 2020., p. 6
`73 Murrelle, E. L. (2020). Expert Report of Edward L. Murrelle. Dated October 5th, 2020., p. 25
`74 FDA (2012). Reporting Harmful and Potentially Harmful Constituents in Tobacco Products and Tobacco Smoke
`Under Section 904(a)(3) of the Federal Food, Drug, and Cosmetic Act. Draft Guidance. March, 2012. Silver Spring,
`MD, U.S. Dept. of Health and Human Service, Food and Drug Administration, Center for Tobacco Products.
`75 Murrelle, E. L. (2020). Expert Report of Edward L. Murrelle. Dated October 5th, 2020., p. 6
`76 Murrelle, E. L. (2020). Expert Report of Edward L. Murrelle. Dated October 5th, 2020., p. 15-16
`
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`authorized for marketing by the FDA (IQOS® via PMTA and MRTP, and Eclipse/Neocore via Substantial
`Equivalence), and also included a few ENDS products that have been characterized in the publically
`available literature (e.g., blu, myblu, JUUL) to demonstrate the high variability in HPHC concentration
`----
`across products (Table 1).
`
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`Table 1. Comparison of HPHC in smoke or aerosol of HNB, ENDS, and combustible cigarettes
`
`Combustible
`cigarettes
`
`50 combustible
`cigarettes (ISO,
`unit/puff)1
`4.17
`1.95
`
`HNB
`IQOS®/THS2.2
`(unit/puff)
`ISO/non-
`intense2
`0.039
`0.012
`
`ENDS
`
`Eclipse
`(unit/puff)
`-
`-
`
`blu (per
`puff)
`<0.0005
`<0.01
`
`myblu
`(per puff)
`<0.47
`<3.33
`
`JUUL (per
`puff)
`
`-
`-
`
`Vype
`ePen (per
`puff)
`
`-
`-
`
`Vuse (per
`mL e-
`liquid)3
`
`-
`-
`
`II.
`
`
`
`Abbreviated77
`HPHC list for
`combustible
`cigarettes
`
`
`
`Chemicals
`1,3-Butadiene (µg)
`1-Aminonapthalene
`(ng)
`2-Aminonapthalene
`(ng)
`4-Aminobiphenyl (ng)
`Acetaldehyde (µg)
`
`Acrolein (µg)
`
`BaP (ng)
`Carbon monoxide (mg)
`Formaldehyde (µg)
`
`Nicotine (mg)
`
`<0.02
`
`<3.33
`
`-
`
`1.22
`
`0.23
`47.72
`
`4.25
`
`0.94
`1.05
`2.83
`
`0.08
`
`0.006
`
`0.009
`18.125
`
`0.815
`
`0.167
`0.040
`0.308
`
`0.082
`
`0.09
`
`0.05
`5-5.6
`
`0.77-2.2
`
`0.04-0.08
`0.50
`0.05
`
`0.01
`
`<0.01
`<0.074;
`0.015-0.057*
`<0.033-0.19;
`0.002-0.024*
`<0.02
`<0.001
`<0.354;
`0.018-0.062*
`0.008-0.033
`
`<0.67
`<10.1 -
`<17.5
`<0.37 -
`<4.38
`<3.33
`<0.01
`<2.63
`
`0.0854
`
`-
`
`-
`0.106
`
`0.070
`
`-
`0.057
`0.122
`
`0.032
`
`-
`
`-
`-
`
`-
`
`-
`-
`-
`
`18.9-38.8
`
`BDL/NQ
`0.054
`-
`-
`
`-
`-
`-
`-
`
`-
`0.403
`
`ND
`
`-
`-
`0.373; 0.12-
`0.26*
`0.138;
`0.154-
`0.188*
`-
`-
`-
`-
`
`6.76
`10.63
`0.82
`1.65
`
`0.683
`1.083
`0.019
`0.683
`
`1.53-2.13
`1.33-1.73
`0.08
`0.36
`
`<0.02
`<0.02
`<0.0002
`-
`
`<6.7
`<6.7
`<0.28
`<15.5
`
`NNK (ng)6
`NNN (ng)7
`Acrylonitrile (µg)
`Ammonia (µg)
`
`77 FDA (2012). Reporting Harmful and Potentially Harmful Constituents in Tobacco Products and Tobacco Smoke Under Section 904(a)(3) of the Federal Food,
`Drug, and Cosmetic Act. Draft Guidance. March, 2012. Silver Spring, MD, U.S. Dept. of Health and Human Service, Food and Drug Administration, Center for
`Tobacco Products.
`
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`Arsenic (ng)
`Benzene
`Cadmium (ng)
`Crotonaldehyde (µg)
`
`Isoprene (µg)
`Toluene (µg)
`
`Acetyl Propionyl
`Anabasine
`Chromium (ng)
`Diacetyl
`Diethylene glycol
`Ethylene glycol
`Glycerol (mg)
`Lead (ng)
`Menthol (µg)
`Nickel (ng)
`Propylene glycol
`Citation(s)
`
`0.59
`3.71
`-
`1.50
`
`36.17
`5.48
`
`-
`-
`-
`-
`-
`-
`0.195*
`-
`-
`-
`0.00292*
`Counts 2005;
`*Margham
`2016
`
`<1.13
`0.037
`<0.350
`0.313
`
`0.171
`0.162
`
`-
`-
`<0.55
`-
`-
`-
`0.318
`-
`-
`-
`-
`Schaller 2016
`
`Smoking/vape method4
`
`ISO
`
`ISO or SR-12
`
`Cigarette or E-liquid
`nicotine type5
`
`Counts 2005: 48
`commercially
`available
`cigarettes, 1R4F
`reference
`
`PMI Regular
`Tobacco stick
`(IQOS®/THS2.2)
`
`Additional
`HPHC from
`2016 PMTA
`guidance**
`
`
`
`
`
`
`
`
`
`-
`0.33
`-
`-
`
`0.93
`0.39
`
`<4
`<0.0005
`<4
`<0.003-
`<0.031
`<0.0021
`<0.0003-
`<0.003
`-
`-
`<4
`-
`-
`-
`-
`<4
`-
`<4
`-
`Tayyarah
`2014;
`*Ogunwale
`2017
`
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`Slade
`2002;
`Labstat
`report;
`ECLIPSE
`2000
`All ISO/FTC Tayyarah
`2014: Health
`Canada;
`Ogunwale
`2017:
`custom
`Nic salt: 16-
`24 mg
`No PG,
`VG=75-82
`
`Eclipse I
`(1996) and
`II (2000)
`
`-
`<0.21
`-
`<4.38
`
`<0.33
`-
`
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`Rudd
`2020
`
`-
`-
`-
`0.567
`
`-
`-
`
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`Talih 2019;
`*Reilly 2019
`
`-
`-
`-
`-
`
`-
`0.020
`
`-
`-
`0.399
`<0.087
`-
`-
`1.570
`-
`-
`0.5*
`0.709
`Margham
`2016;
`*Williams
`2017
`
`CORESTA
`
`1.6% w/w
`nicotine
`
`Talih 2019:
`15x 4 s
`puffs
`Reilly 2019:
`mCORESTA
`
`Talih 2019:
`68 mg/mL,
`33/67
`PG/VG
`Reilly 2019:
`
`Margham
`2016: ISO
`Williams
`2017: 4.3
`s puff/5
`min
`Margham
`2016:
`1.86% nic,
`PG/VG
`25/48
`
`-
`-
`-
`-
`
`-
`-
`
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`Omaiye
`2019
`
`custom
`
`5% nic
`salt,
`PG/VG
`not
`provided
`
`18
`
`

`

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`39728
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION SUBJECT TO PROTECTIVE ORDER
`
`Margham 2016:
`3R4F reference
`
`*Nic salt: 16
`mg
`
`Williams
`2017: 12.5
`mg nic
`
`64-94 mg
`nic/g e-
`liquid, PG
`29-31, VG
`69-71
`
`* indicates data from the 2nd study listed
`**the 2016 Draft Guidance HPHC list was included since this was the PMTA guidance available when IQOS was submitted and ultimately authorized for PMT.
`FDA (2016). Premarket Tobacco Product Applications for Electronic Nicotine Delivery Systems. Draft Guidance. May, 2016. Silver Spring, MD, U.S. Dept. of Health
`and Human Service, Food and Drug Administration, Center for Tobacco Products.
`1. Counts et al. 2005 HPHC values are an average from 50 commercially available and research reference combustible cigarettes
`2. SR-1 non-intense puffing regime was used when ISO was not provided; SR-1 was 40 mL puff volume, 2.4s puff draw, 30 s puff interval
`3. Data for e-liquid only. Vuse is the Complainants' product
`4. Puffing topography/regime used: ISO (35 mL puff volume, 2 s puff draw, 60 s puff interval), HCI (55 mL puff volume, 2 s puff draw, 30 s puff interval), Health
`Canada (55 mL puff volume, 2 puffs/min), Ogunwale 2017 custom (91 mL puff volume, 4 s puff draw, 2 puffs/min), CORESTA (55 mL puff volume, 3 s puff draw,
`30 s puff interval), mCORESTA (75 mL puff volume, 2.5 s puff draw, 30 s puff interval), Omaiye 2019 custom (43-55 mL puff volume, 4.3 s puff draw, 60 s puff
`interval).
`5. PG = propylene glycol, VG = glycerin or vegetable glycerin, nic salt = nicotine salt
`6. NNK = Nicotine-derived nitrosamine ketone
`7. NNN = N-nitrosonornicotine
`Unit abbreviations: ng = nanograms, µg = micrograms, mg = milligrams
`
`
`
`
`19
`
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`

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`CONTAINS CONFIDENTIAL BUSINESS INFORMATION SUBJECT TO PROTECTIVE ORDER
`
`In preparing this table, one priority was to ensure that all data were presented in as consistent a manner
`as possible, and with transparent bases, including citations and consistent units. In order to compare
`HPHC levels across products as reported in the literature, data generated using the ISO puffing regime (35
`mL puff volume, 2 s puff draw, 60 s puff interval) were used when available to permit the most analogous
`comparison to the IQOS® data. However, publicly available HPHC data using the ISO method is only
`available for Eclipse, as a direct comparison to the IQOS® data.78, 79 Comparing the IQOS® HPHC data to
`that from the Eclipse product indicates that for some HPHCs, concentrations are higher per puff for IQOS®
`and for others, concentrations are higher per puff for Eclipse. In most HPHCs, concentrations are lower
`for both IQOS® and the Eclipse product, when compared to combustible cigarettes.
`
`When comparing to the ENDS products listed in Table 1, which represent a small snapshot of the wide
`variety of ENDS available (limited to cig-a-like disposable and pod style devices), similar findings emerge.
`While there is not a large amount of data on HPHCs in aerosol for ENDS, of the data available, there are
`overall substantial reductions in HPHCs when compared to combustible cigarettes, but the levels of HPHCs
`vary widely within the ENDS category. When comparing to the IQOS® product, some HPHC concentrations
`are higher per puff, where others are lower in the ENDS products.
`
`Notably, Dr. Murrelle omits additional chemicals that ENDS products release. The HPHCs included in Dr.
`Murrelle’s table is the FDA abbreviated HPHC list for combustible cigarettes.80 Dr. Murrelle’s analysis
`focuses primarily on analysis of the abbreviated HPHCs in comparing IQOS® to other products on the
`market, including combustible cigarettes and ENDS products. However, it is well known that there are
`additional HPHCs in ENDS, as evidenced by the FDA Draft Guidance 81 and Final Guidance82 , that must be
`quantified in ENDS aerosol to appropriately evaluate exposure potential of aerosol to the consumer.
`Therefore, I included additional HPHCs that are listed in the Draft Guidance 83 in Table 1. While most
`HPHCs on the abbreviated HPHC list for combustible cigarettes are generally lower in concentration in
`ENDS compared to cigarettes, additional factors (e.g., additional HPHCs, flavorant and additive chemicals)
`may also contribute to overall risk but were not considered in Dr. Murrelle’s analysis.
`
`
`
`78 Slade, J., G. N. Connolly and D. Lymperis (2002). "Eclipse: does it live up to its health claims?" Tob Control 11 Suppl
`2: ii64-70.
`79 Eclipse Expert Panel (2000). A Safer Cigarette? A Comparative Study. A Consensus Report. Inhal Toxicol 12 Suppl
`5:1-58.
`80 FDA (2012). Reporting Harmful and Potentially Harmful Constituents in Tobacco Products and Tobacco Smoke
`Under Section 904(a)(3) of the Federal Food, Drug, and Cosmetic Act. Draft Guidance. March, 2012. Silver Spring,
`MD, U.S. Dept. of Health and Human Service, Food and Drug Administration, Center for Tobacco Products.
`81 FDA (2016). Premarket Tobacco Product Applications for Electronic Nicotine Delivery Systems. Draft Guidance.
`May, 2016. Silver Spring, MD, U.S. Dept. of Health and Human Service, Food and Drug Administration, Center for
`Tobacco Products.
`82 FDA (2019). Premarket Tobacco Product Applications for Electronic Nicotine Delivery Systems: Guidance for
`Industry. June, 2019. Silver Spring, MD, U.S. Dept. of Health and Human Service, Food and Drug Administration,
`Center for Tobacco Products.
`83 FDA (2016). Premarket Tobacco Product Applications for Electronic Nicotine Delivery Systems. Draft Guidance.
`May, 2016. Silver Spring, MD, U.S. Dept. of Health and Human Service, Food and Drug Administration, Center for
`Tobacco Products.
`
`
`
`20
`
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`

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`CONTAINS CONFIDENTIAL BUSINESS INFORMATION SUBJECT TO PROTECTIVE ORDER
`
`Recently, studies have shown that inorganics, such as metals and silicon, potentially leaching from ENDS
`device components, may also be detected in ENDS aerosol. Specifically, Williams et al.84 found that the
`Vype (unknown model) had detectable levels of 12 of the screened elements detected (7.3 µg/10 puffs)
`and the Blu disposable ENDS had detectable levels of 11 of the screened elements (1.8 µg/10 puffs). In
`this study, over 75 % of the detectable elements screened in Vype and Blu aerosol was silicon. It is unclear
`to me at this time if these metals are present in HNB products.
`
`In addition to metals, Dr. Murrelle did not acknowledge other constituents potentially contributing to
`exposure risk associated with ENDS products, including flavorants and additives found in e-liquids. These
`flavorants and additives in e-liquids can vary widely across products, obscuring comparisons of risk that
`may arise from not only one ingredient, but a collective mixture of all ingredients. Recently, Omaiye et
`al.85 identified 155 flavor chemicals across 277 e-liquids. IQOS® are simple products by comparison,
`containing tobacco leaf, binders, and humectants, but generally lacking many of the additives or flavorants
`used in ENDS products (Schaller, et al 2016). Further the risks associated with the inhalat