& Research, 2017, 1–6 doi:10.1093/ntr/ntx054 Brief report Received November 15, 2016; Editorial Decision February 21, 2017; Accepted March 1, 2017

Brief report Nicotine Content and Physical Properties of Large and in the United States Bartosz Koszowski PhD, PharmD1, Meridith Hill Thanner PhD1, Wallace B. Pickworth PhD1, Kenneth M. Taylor PhD2, Lynn C. Hull PhD2, Megan J. Schroeder PhD2

1Battelle Public Health Center for Tobacco Research, Baltimore, MD; 2Office of Science, Center for Tobacco Products, US Food and Drug Administration, Silver Spring, MD

Corresponding Author: Megan J. Schroeder, PhD, United States Food and Drug Administration, Center for Tobacco Products/ Office of Science, 10903 New Hampshire Ave., Silver Spring, MD 20993, USA. Telephone: 301-796-2043; Fax: 301-595-1138; E-mail: [email protected]

Abstract Introduction: Cigars are combusted tobacco products consisting of filler, binder, and wrapper, which are derived from tobacco. Despite the abundance of literature on the composition of tradi- tional combusted , research is limited on the physical and chemical properties of cigars. Therefore, research on properties may be useful to better understand their health impact. Methods: In this study, twenty large cigar and products were characterized for physical properties (ie, weight, length, and diameter), filler nicotine content, and tobacco pH. Tobacco pH was used to calculate free nicotine content, free nicotine concentration, and percent free nicotine for all cigars using the Henderson–Hasselbach equation. An additional analysis was performed on a second batch of two large cigar and two cigarillo brands to determine within-brand consistency. All analyses were performed in triplicate. Results: The initial analysis of the twenty cigars showed that cigars exhibited wide variation in product size and nicotine content, although tobacco pH was similar across cigars. Furthermore, in the two large cigar and cigarillo brands analyzed a second time, there was considerable within- brand variance in nicotine content and concentration between the first and second analyses. Conclusions: While only a small sample of commercially-available cigars was analyzed, our data sug- gest there is wide variability in nicotine content and some physical properties in the domestic cigar market. The data may help to inform potential future regulatory decisions related to these products. Implications: This study reveals some of the challenges to experimental cigar research and illus- trates the need to characterize cigar products (eg, nicotine and tobacco content) before use in clinical studies. Additional studies and characterization of the physical and chemical properties of cigars may be useful to further understand these products’ toxicity, abuse potential, and public health impact.

Introduction extended to all tobacco products, including cigars.2 This authority The 2009 Family Prevention and Act1 over cigar products is particularly important due to documented granted FDA authority to regulate all tobacco products, with imme- changes in cigar use patterns over the past decade. While diate jurisdiction over cigarettes, cigarette tobacco, roll your own smoking rates declined substantially from 2000 to 2011, cigar con- tobacco, and smokeless tobacco. In May 2016, this jurisdiction was sumption than doubled during the same period.3,4 A wide

Published by Oxford University Press on behalf of Society for Research on Nicotine and Tobacco 2017. This work is written by 1 (a) US Government employee(s) and is in the public domain in the US.

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variety and number of cigar products are sold in the US market- Inc. (, VA). All analytical methods used to characterize the place, including large cigars, cigarillos, and little cigars, which differ cigars have been validated and are accredited to ISO 17025:2005. in size, fller, favor, and design features.5 Although no universal def- To allow for comparisons, 24 hours prior to analysis, all cigars were nition or legal and regulatory distinctions for the different subcat- conditioned by placement in a drying oven to regulate temperature egories currently exist, large cigars and cigarillos differ from little to 22°C (+/− 1 degree) and humidity to 65% (+/− 5%) which is con- cigars predominantly in that they contain more tobacco fller and sistent with ISO 3401. have binders and wrappers that are prepared from reconstituted tobacco and tobacco leaf. Little cigars are manufactured similarly Physical Properties to cigarettes, typically do not contain a binder, and use a ciga- To determine length, each cigar was measured from the butt side of rette paper-based wrapper that contains air-cured tobacco pieces, the cigar to the end. Cigar diameter was measured 15 mm from the extracts, or remnants. Although there is no accepted approach to mouth end to avoid measurement at the cigar’s tapered end. Both defne cigars based on design features, the US Department of the measures were taken using a certifed ruler and recorded in millim- Treasury and the US Federal Trade Commission categorize cigars eters to the nearest 0.5 mm. based on weight.6 Cigars were weighed on a certifed and calibrated analytical The currently available studies on cigar product characteristics balance and recorded in grams to the nearest 0.0001 g, with both were published more than a decade ago and may not represent individual and average weights reported. Where applicable, cigars the cigar products that are presently marketed. While previous were weighed with and without flters; the flter was removed work has documented that nicotine content, tobacco weight, and prior to nicotine and pH analyses. To remove the flter, cigars were tobacco pH varies among and within cigar product categories,7 no pinched at the tobacco-flter joint to separate the flter. If the wrap- studies to date characterize current cigar products for both physi- per tore or any of the tobacco components remained adhered to cal and nicotine properties. Differences in physical characteristics the flter component, the cigar was discarded and not used for and tobacco pH, for example, may affect user smoking topography, testing. and thus the amount of nicotine to which cigar smokers are exposed. Furthermore, because unprotonated (“free”) nicotine is more readily Nicotine and Tobacco pH absorbed into biologic tissues than the protonated form,8 tobacco Following the length, diameter, and weight measurements, the cigar pH may be an important factor in the rate of nicotine absorption tobacco was ground, at room temperature, in preparation for the and, therefore, a product’s addiction potential.9 While several studies nicotine and pH analyses. The tobacco fller, binder, and wrapper have reported that cigar tobacco pH10,7 is more alkaline than ciga- components of the cigars and cigarillos were processed as a single rette tobacco, no recent reports have been published on large cigars composite sample using a ball mill grinder. or cigarillos. A better understanding of these relationships is impor- Alkaloids were extracted from a sample of 250 mg of tobacco tant for further clinical research and interpretations. with 4 mL aqueous 5N NaOH and 40 mL CH3OH containing qui- In the current study, nicotine content (total and free), tobacco noline as the internal standard. After shaking for 30 minutes, the pH, and physical characteristics were determined for ten commercial sample was centrifuged, and then directly analyzed by gas chroma- large cigars and ten cigarillos. The study’s aim was to understand the tography–mass spectrometry (GC–MS) using electron-impact ioni- variability of cigar characteristics, a critical aspect in conducting and zation (Agilent GC-MSD, SIM; selected ions: nicotine m/z 84 and interpreting clinical study results. 162, and quinoline m/z 129 were monitored). The alkaloids present in tobacco samples were quantifed using an internal standard. The linear range was 4–360 μg/mL. The limit of detection and limit Methods of quantifcation for nicotine were 1.2 and 4 μg/mL respectively. Nicotine concentration was calculated based on product weight. Cigars The pH of tobacco fller was determined by taking a 2 g sample Ten domestic large cigars and ten domestic cigarillos were selected of the ground tobacco of the entire cigar product (wrapper and fller) and purchased in August 2015 based on national 2014 Nielsen and combining it with 20 mL of degassed high performance liquid Market Share ratings indicating products with the greatest mar- chromatography grade water. This sample was placed on an orbital ket share, and subsequent regional availability in the Baltimore, shaker for 30 minutes and then incubated in the dark for 60 minutes. Maryland area. Cigar classifcation as large cigar or cigarillo was pH was measured using an electronic pH meter equipped with a based on product labeling. Secondary analyses on two large cigar glass electrode and then evaluated at specifed time intervals until a and two cigarillo products were subsequently conducted in January stable reading (≤10% variance) was obtained. 2016 on a different batch of products, purchased at a later date, to determine within-brand, between-batch variability. All products were stored in their original packaging at ambient temperature after Quality Control and Statistical Analyses purchase until analysis. For each cigar product, nicotine analyses were run in triplicate with Free nicotine content, free nicotine concentration, and percent individual data values reported as well as the average, standard free nicotine were calculated for each cigar based on nicotine con- deviation, and relative standard deviation for the three observations. tent/concentration and tobacco pH according to the Henderson– For this study, the nicotine analysis was monitored with KY 3R4F tobacco analyzed “as is” and spiked at a known concentration to Hasselbach equation with a pKa of 8.02 for nicotine. establish the percent recovery. Recovery values had an acceptance range of ±20%. The pH analysis was also verifed using the KY Physical and Nicotine Measurements 3R4F tobacco. All cigar characterization analyses (ie, physical properties, nicotine For each analytical run, a calibration curve was analyzed for each content, and tobacco pH) were performed by Enthalpy Analytical, batch of samples and an independently prepared quality control

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sample was analyzed with each group of approximately ten samples. For example, a 32.6% and 36.7% change in nicotine content was Acceptance criteria for quality control runs were ±10% of expected found for the Palma and White Owl New Yorker values. products, respectively. Tobacco pH remained similar across batches For each variable, an arithmetic mean with standard deviation (Figure 1D). Due to changes in nicotine content and concentration, was calculated for each cigar product tested. To compare differences percent free nicotine differed by 16%–45% (data not shown); the between the 2015 and 2016 product batches, absolute percent differ- largest differences were observed in the large cigar products. ences were calculated. Due to the small sample size, statistical com- parisons between products were not performed. Discussion Results In the present study, 10 large cigars and 10 cigarillos (based on US market share) were surveyed to assess their physical characteris- The physical properties and nicotine content of the 10 large cigars tics, nicotine content, and tobacco pH. Wide variations in product and 10 cigarillos are presented in Table 1. size and nicotine content were found, although the pH was similar across all cigars. When secondary analyses of four products were Physical Characteristics conducted to assess the consistency of measured variables across Large Cigars product batches, there was considerable variation in the nicotine The weights of sampled large cigars ranged from 2.68 g ( Ville content and concentration. Natural Deluxe) to 17.6 g ( 1875 Churchill); length As seen here and in a previous study by Henningfeld et al.,7 ranged from 106 mm (Backwoods Original) to 177 mm (Romeo Y domestic cigars vary widely in their size and nicotine content. Unlike Julieta 1875 Churchill). Large cigar diameters ranged from 9.05 mm cigarettes, which have a great deal of between-brand uniformity, (Backwoods Original) to 19 mm (Romeo Y Julieta 1875 Churchill). the large cigars and cigarillos in our study have widely variable weights (1.6–17.6 g), lengths (94–177 mm), and nicotine content Cigarillos (14–99 mg). The variability of tobacco and nicotine content in cigars The weights of sampled cigarillos ranged from 1.64 g (Garcia complicates comparisons of use behavior (eg, products used per Y Vega Whiffs Natural) to 4.24 g (Middleton’s Black & Mild); day), nicotine addiction, and toxicant exposure among cigar smok- 11 length ranged from 93.5 mm (Garcia Y Vega Whiffs Natural) to ers. Furthermore, cigars vary in favor, style, type of tobacco in 12 128 mm (Middleton’s Black & Mild). Cigarillo diameters ranged the fller and wrapper, and ability to be adulterated. Consequently, from 8.70 mm (Garcia Y Vega Whiffs Natural) to 11.5 mm (Swisher simple descriptions of “cigars” or “cigar smokers” are ambiguous Diamonds). and may lead to confusion and/or inaccurate conclusions. In our study, the nicotine concentration for cigar products varied widely (~5–29 mg/g tobacco), but was similar to the nicotine con- Nicotine Content centrations of major US cigarette brands (13–26 mg/g tobacco).13 Large Cigars However, because cigarettes contain less tobacco (<1 g) than cigars, The nicotine content in large cigars ranged from 18.1 mg/cigar total nicotine exposure may be higher from cigars. (Blunt Ville Natural Deluxe) to 505 mg/cigar (Romeo Y Julieta 1875 Nicotine is a weak base and, as such, its ionization in aqueous Churchill); nicotine concentration ranged from 6.76 mg/g (Blunt media depends on the concentration of hydrogen ions (ie, pH).14 In Ville Natural Deluxe) to 28.6 mg/g tobacco (Romeo Y Julieta 1875 this study, the aqueous pH of large cigars ranged from 6.17 to 7.43; Churchill). The tobacco pH for large cigars ranged from 5.88 (Hav- cigarillo pH ranged from 5.34 to 7.23. This range in pH is similar a-Tampa Jewels Original) to 7.43 (Blunt Ville Natural Deluxe). to that reported by Henningfeld et al.7 and the 1998 NCI Cigar Monograph.12 Furthermore, since nicotine is a weak base, the aque- Cigarillos ous pH affects the amount of nicotine in the unionized free base The nicotine content in sampled cigarillos ranged from 14.0 mg/ form. The free base form of nicotine crosses biological membranes cigar (Zig Zag Straight Up) to 36.4 mg/cigar (Good Times Straight more easily than the ionized form.14 Our study suggests that the rela- Natural); nicotine concentration ranged from 4.84 mg/g (Zig Zag tively alkaline cigar tobacco may support nicotine dermal absorption Straight Up) to 12.0 mg/g tobacco (Good Times Straight Natural). through the lips and fngers, and potentially augment pulmonary and The tobacco pH for cigarillos ranged from 5.34 (Middleton’s Black buccal absorption from smoke. Even though the aqueous pH of sus- & Mild) to 7.23 (Zig Zag Straight Up). pended ground tobacco product does not necessarily refect main- stream smoke pH15 (the main vehicle of pulmonary nicotine delivery Secondary Product Sampling and Analysis from combustible tobacco products), the relative alkalinity of cigar Two large cigars (Dutch Masters Palma and White Owl New Yorker) tobacco and/or smoke may explain why some cigar smokers are less and two cigarillos (Middleton’s Black & Mild and Royal Comfort likely to inhale mainstream smoke than cigarette smokers.12 Black) were purchased again in 2016 and analyzed as previously Currently, there are no regulatory criteria that defne terminology described to assess possible differences between product batches. for specifc cigar types. To illustrate, some products in our study are Across two production batches, all cigar physical characteris- labelled as cigarillos but are larger than some products labeled as tics differed by less than 10%, except for the Dutch Masters Palma large cigars, and some large cigars have the physical characteristics product, which exhibited a 12.7% change in weight (Figure 1A) of cigarillos (eg, Middleton’s Black & Mild [4.24 g; categorized as and the Middleton Black & Mild product, which exhibited a 10% a cigarillo] vs. Blunt Ville Natural Deluxe [2.68 g; categorized as a change in diameter (data not shown). Despite consistency in physical large cigar]). In addition, cigar size does not necessarily correlate properties, there were substantial differences in nicotine content and with nicotine or free nicotine content. For example, two cigarillo concentration, particularly for the large cigars (Figure 1B and C). products, Zig Zag Straight Up and Royal Comfort Black, have less

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1.62 1.05 3.70 1.86 2.40 0.33 2.41 7.03 1.84 2.89 0.50 0.26 1.02 0.05 0.60 1.22 0.49 0.50 0.63 1.95 [mg/cigar] 2.51 (1.84) 0.72 (0.55) Free nicotine

a 0.25 0.36 1.38 0.20 0.32 0.15 0.35 0.40 0.26 0.38 0.17 0.16 0.34 0.02 0.19 0.43 0.19 0.19 0.25 0.68 Calculated 0.41 (0.35) 0.26 (0.18) Free nicotine [mg/g tobacco]

2.19 3.66 1.87 2.93 0.72 4.67 1.39 3.58 4.77 2.19 1.33 2.80 0.21 2.62 4.67 1.71 1.96 2.29 [%] Free 20.45 13.95 Ncotine 4.63 (5.70) 3.37 (3.89)

pH Tobacco Tobacco 6.37 (0.02) 6.60 (0.01) 7.43 (0.01) 6.30 (0.01) 6.50 (0.03) 5.88 (0.01) 6.71 (0.01) 6.17 (0.02) 6.59 (0.03) 6.72 (0.02) 6.53 (0.41) 6.37 (0.01) 6.15 (0.01) 6.48 (0.03) 5.34 (0.02) 6.45 (0.02) 6.71 (0.02) 6.26 (0.01) 6.32 (0.03) 6.39 (0.01) 7.23 (0.03) 6.39 (0.49)

Nicotine characterization

Nicotine 11.6 (0.30) 9.96 (0.28) 6.76 (0.07) 7.42 (0.07) 7.37 (0.10) 7.95 (0.17) 7.66 (0.02) 7.89 (0.26) 7.33 (0.12) 9.22 (0.34) 9.59 (0.18) 4.84 (0.17) 9.19 (2.44) 10.90 (0.40) 10.90 (0.20) 20.40 (0.50) 28.60 (0.40) 12.19 (6.98) 11.80 (0.10) 12.00 (0.50) 11.20 (0.00) 10.80 (0.10) concentration [mg/g tobacco]

[mg/cigar] 74.00 (1.80) 28.80 (0.80) 18.10 (0.20) 99.30 (4.00) 82.00 (1.30) 46.10 (1.10) 51.60 (0.50) 51.30 (0.70) 60.60 (1.30) 22.90 (0.10) 19.40 (0.20) 36.40 (1.50) 25.50 (0.80) 22.90 (0.40) 26.20 (1.00) 28.70 (0.00) 25.50 (0.50) 27.40 (0.20) 14.00 (0.50) 24.89 (5.89) 505.00 (8.00) 101.68 (143.74) Nicotine content

[mm] Mean (Standard deviation) Diameter 9.05 (1.28) 9.40 (0.50) 8.70 (0.47) 9.65 (0.49) 12.70 (0.50) 16.60 (0.70) 15.10 (0.60) 10.20 (0.40) 14.80 (0.60) 19.00 (1.70) 15.00 (0.70) 15.20 (0.40) 13.71 (3.27) 11.10 (1.00) 10.80 (0.40) 10.50 (0.50) 10.60 (0.50) 11.50 (0.50) 10.50 (0.60) 10.20 (0.40) 10.90 (0.60) 10.45 (0.79)

[mm] Length 157 (2) 106 (6) 144 (2) 144 (1) 153 (1) 122 (1) 125 (1) 177 (1) 128 (1) 144 (1) 140 (20) 112 (1) 107 (1) 128 (1) 113 (0) 107 (1) 109 (1) 110 (1) 111 (1) 113 (1) 110 (8) 93.50 (0.50)

Physical characterization 6.39 (0.74) 2.89 (0.16) 2.68 (0.31) 9.14 (0.44) 7.53 (0.54) 3.83 (0.32) 6.96 (0.36) 6.97 (0.37) 7.63 (0.61) 7.16 (4.26) 2.99 (0.28) 1.64 (0.10) 3.04 (0.34) 4.24 (0.19) 3.13 (0.28) 2.84 (0.22) 2.57 (0.10) 2.66 (0.08) 2.54 (0.15) 2.90 (0.16) 2.86 (0.64) wrapper) [g] 17.60 (0.10) Weight (with Weight

1.27 0.82 1.00 2.25 1.12 0.66 1.64 5.25 0.68 0.90 1.25 1.44 0.35 1.28 0.86 0.70 0.50 0.75 0.75 0.70 cigar [$] Price per 1.66 (1.35) 0.86 (0.35) lter) f lter) f Cigar name Antonio Y Cleopatra Dark Natural Antonio Backwoods Original Natural Deluxe Ville Blunt Dutch Masters Palma Presidente Vega Y Garcia Jewels Original (with Hav-a-Tampa Blunt Y Julieta 1875 Churchill Romeo Swisher Sweets Perfecto Yorker White Owl New Mean (Standard Deviation) Green Dutch Master’s Whiffs Natural Vega Y Garcia Straight Natural Times Good & Mild (with Black Middleton’s Phillies Natural Brown Black Comfort Royal Swisher Diamonds Swisher Sweets Original White Owl Silver Zig Zag Straight Up Mean (Standard Deviation) Physical and Nicotine Characterization of Large Cigars Cigarillos Physical 1.

values calculated based on measured nicotine/pH in tobacco using the Henderson–Hasselbalch equation. Table Large Cigars Cigarillos August 2015; follow-up purchase for re-analysis in January 2016; Bolded rows indicate products that were re-analyzed. Initial cigar purchase in a

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Figure 1. Consistency within products (differences between first and second purchased batch of two large cigars and two cigarillos) for weight (Panel A), nicotine content and concentration (Panel B and C), and tobacco pH (Panel D).

tobacco weight than most of the tested large cigar products, but Declaration of Interests also have the greatest amount of free nicotine on a per mass of None declared. tobacco basis. These study results illustrate the wide variation in product size and nicotine content within the domestic cigar market. Because Acknowledgments cigar size and tobacco weight do not necessarily correspond to the Appreciation to Enver Holder-Hayes and Deborah Neveleff, The US Food and amount of free nicotine, a basic analysis of cigar products may be Drug Administration, Offce of Science, Center for Tobacco Products for their essential before cigar use in clinical studies. Additionally, consumers contributions to the manuscript. Appreciation to Carson Smith (Battelle) and smoking the same brand of cigar may unintentionally be exposed Jacek Domagala (intern to Battelle from Notre Dame of Maryland University) to varying doses of nicotine and potentially other smoke constitu- for editorial support. Disclaimer: This publication represents the views of the author(s) and does not represent FDA/CTP position or policy. LCH and MJS ents. Establishing criteria to differentiate large cigars, cigarillos, and contributed equally to this work. little cigars into mutually exclusive classes is complex, but may be benefcial for research and regulatory efforts as well as appropriate product labelling for consumers. References 1. United States Congress. Family Smoking Prevention and Tobacco Control Study Limitations Act. Public Law. 2009. 111–131. 2. Food and Drug Administration, Center for Tobacco Products (FDA CTP). These analyses were performed on a limited number of cigar prod- Deeming Tobacco Products To Be Subject to the Federal Food, Drug, and ucts, and therefore our results may not be representative of all cigars Cosmetic Act, as Amended by the Family Smoking Prevention and Tobacco available in the US market. Furthermore, free base nicotine calcula- Control Act. Food and Drug Administration. 2016. 21 CFR Parts 1100, 1140, tions based on tobacco pH measurements may fundamentally differ and 1143. www.federalregister.gov/documents/2016/05/10/2016-10685/ from the pH generated from these tobacco products. deeming-tobacco-products-to-be-subject-to-the-federal-food-drug-and- Thus, the free nicotine calculations should be interpreted with cau- cosmetic-act-as-amended-by-the. Accessed October 28, 2016. tion. Additionally, the reported within product variations may not 3. Chen J, Kettermann A, Rostron BL, Day HR. Biomarkers of exposure apply to all other cigar products. Moreover, small sample size limited among U.S. cigar smokers: an analysis of 1999-2012 National Health our ability to perform statistical comparisons within and between and Nutrition Examination Survey (NHANES) data. Cancer Epidemiol Biomarkers Prev. 2014;23(12):2906–2915. products. 4. Corey CG, King BA, Coleman BN, et al.; Centers for Disease Control and Prevention. Little fltered cigar, cigarillo, and premium cigar smok- ing among adults–United States, 2012-2013. MMWR Morb Mortal Wkly Funding Rep. 2014;63(30):650–654. Research supported by a contract awarded to Battelle by the Food 5. Pickworth W, Thanner MH. Symposium overview, cigar use: epidemiol- and Drug Administration (Center for Tobacco Products). IDIQ/TO#: ogy, toxicant exposure, health and policy implications. Tob Regul Sci. HHSF223201310/030I_HHSF22301004T. 2017;3(2 suppl 1):S3–S7.

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