SETTING THE QUALITY AND SAFETY STANDARDS FOR NOVEL TOBACCO PRODUCTS SRNT-E Satellite Symposium: Comparing Regulations on Tobacco and Nicotine Products Maciej L. Goniewicz maciej.goniewicz@roswellpark.org

DISCLOSURE INFORMATION Maciej L. Goniewicz I have the following financial relationships to disclose: In 2011, I was awarded the Global Research Award for Nicotine Dependence (GRAND). This is an independently-reviewed competitive grants program supported by Pfizer, manufacturer of smoking cessation medications. That award was paid to my former employer, Queen Mary University of London, UK. The research project supported by GRAND award was completed in 2013. I have no financial relationships with manufacturers, distributors, or retailers of e-cigarettes and tobacco industry. I will not discuss off label use and investigational use in my presentation.

INGREDIENTS

SOURCE OF TOXICANTS IN E-CIGARETTES PRESENT IN THE PRODUCT Impurities in solvents technical vs. pharmaceutical grade (USP) Impurities in nicotine Flavors and additives Impurities in flavor extracts or additives Contaminants from manufacturing process Contaminants from storage containers Degradation byproducts Substances introduced by retailers GENERATED DURING USE Byproducts of thermal degradation Degradation byproducts generated during storage Impurities from storage Substances introduced by users

IMPURITIES IN SOLVENTS US Food and Drug Administration Study (2009) Diethylene glycol is highly toxic and affects renal and neurological functions. FDA conducted a preliminary analysis on 18 samples of e-cigarettes and components from two US leading brands. Out of those 18 samples, one product was tested positive for about 1% diethylene glycol. Hutzler et al. Arch Toxicol 2014 Ethylene glycol TOXIC Diethylene glycol HIGHLY TOXIC Poliethylene glycol (PEG) SAFE German Federal Institute For Risk Assessment Study Ethylene glycol affects the central nervous system (CNS), heart, and the kidneys. Ethylene glycol was detected in 13 out of 28 liquid samples. Ethylene glycol occasionally is used to replace glycerol and propylene glycol in e-liquids.

Tobacco Specific Nitrosamines (TSNAs) IMPURITIES IN NICOTINE Tobacco Specific Nitrosamines (TSNAs) Product NNN NNK NAT NAB Total Nicorette gum (ng/gum) 2.00 ND Nicoderm patch (ng/patch) 8.00 E-cigarettes (ng/g) 3.87 1.46 2.16 0.69 8.18 Swedish Snus (ng/g) 980 180 790 60 2010 Marlboro (Ultra-light) (ng/g) 2900 750 1100 58 4808 Marlboro (Red) (ng/g) 960 2300 100 6260 Cahn et al. J Pub Health Pol 2010

FLAVORS AND ADDITIVES IN LIQUIDS DIACETYL (2,3-BUTANEDIONE) ACETYL PROPIONYL (2,3-PENTANEDIONE) Approved and safe when ingested (GRAS) but inhalation of DA has been associated with decline in respiratory function, development of bronchiolitis obliterans (“popcorn lung disease”). DA and AP were measured in 159 nicotine solutions, including 81 products purchased in the United States, and in aerosol produced by an e-cigarette. DA and AP were found in 74.2% of the samples, mostly in sweet-flavored liquids. Similar concentrations were found in liquid and aerosol for both chemicals. Farsalinos et al. Nicotine Tob Res 2014

CARBONYLS IN E-CIGARETTE AEROSOL E-cigarette aerosol contains toxic and carcinogenic carbonyl compounds. Formaldehyde is classified by IARC as a human carcinogen (Group 1), and acetaldehyde as possibly carcinogenic to humans (Group 2B) Both solvent and battery output voltage significantly affect levels of carbonyl compounds in e-cigarette aerosol. High-power e-cigarettes may expose users to high levels of carbonyl compounds. Kosmider et al. Nicotine Tob Res 2014

STRATEGIES TO REDUCE TOXICANT LEVELS IN E-CIGARETTES Source Potential Approach Impurities in solvents Use of USP grade solvents (standards) Impurities in nicotine Use of pure nicotine (standards) Flavors and additives Testing for inhalation toxicity (standards) Disclosing chemical constituents Approval process Contaminants from manufacturing process Good Manufacturing Process (GMP) Contaminants from storage containers Inert, airtight and light-resistant containers (standards) Degradation byproducts Proper labelling (storage indications) Safe packaging (standards) Substances introduced by retailers Sealed packages and bottles Byproducts of thermal degradation Threshold for vaporization temperature/battery power/voltage (product standards) Substances introduced by users Tightly-closed containers and bottles (standards)

PRODUCT TESTING

ANALYTICAL METHODS USED IN E-CIGARETTE TESTING Famele et al. Nicotine Tob Res 2014

INHALATION TOXICITY TESTING CASE OF ACETALDEHYDE INGESTION Acetaldehyde is a potent volatile flavoring compound found in many beverages and foods Health effects: Only acute symptoms: dizziness, nausea, vomiting, diarrhea GRAS Classification Acetaldehyde is listed by the FDA as a synthetic flavoring substance that is generally recognized as safe (GRAS) for its intended use (21 CFR 182.60) INHALATION Acetaldehyde at low levels gives a pleasant fruity aroma, but at high concentrations it possesses a pungent irritating odor Health Effects: Irritation of eyes, nose, throat, skin; narcosis; pulmonary edema Carcinogenic Classification: EPA: Group B2, probable human carcinogen IARC: Group 2B, possibly carcinogenic to humans NTP: Reasonably Anticipated to be Human Carcinogen

PACKAGING

IMPORTANCE OF PACKAGING The quality of the packaging of e-cigarettes and nicotine products plays a very important role in the quality and safety of such products. The kind of packaging and the materials used must be chosen in such a way that: the packaging itself does not have an adverse effect on the product (e.g. through chemical reactions, leaching of packaging materials or absorption); the product does not have an adverse effect on the packaging, changing its properties or affecting its protective function. Proper packaging should: protect against all adverse external influences that can alter the properties of the product, e.g. moisture, light, oxygen and temperature variations; protect against biological contamination; protect against physical damage; carry the correct information and identification of the product.

LABELING

PRODUCT LABELING

Source: http://www.collegept.org/Physiotherapists/pc/RiskContinuum