TITANIUM DIOXIDE EU Tobacco Directive 2014/40/EU, Article 6, Priority Additive

REPORT

Priority Additives Tobacco Consortium

KT&G Corporation 71, Beotkkot-gil, Daedeok-gu, Daejeon, Republic of Korea [email protected]

Priority Additive Tobacco Consortium 1 Report for Priority Additive: Titanium Dioxide

Table of Contents Table of Appendices ...... 2 Executive Summary ...... 3 1. Rationale for the Report ...... 5 2. Study Organization ...... 6 A. Priority Additives Tobacco Consortium ...... 6 B. Test and Reference Cigarette Production ...... 7 C. Laboratories ...... 7 D. Literature Review ...... 7 3. Comprehensive Literature Overview ...... 8 A. Systematic Literature Searches ...... 8 i. Searches and Selection of Studies ...... 8 ii. Study Characteristics ...... 10 iii. List of Titanium Dioxide References Included by KSR in this Systematic Review: ...... 10 B. Literature review ...... 11 4. Description and Use of the Additive ...... 12 A. Background ...... 12 B. Chemical Identity and other Characteristics ...... 12 5. Cigarette Manufacturing ...... 13 6. Study Concept ...... 14 A. Experimental setup ...... 14 B. Presentation of Results ...... 14 7. Study Results for Particle Transfer ...... 15 8. Summary and Overall Conclusion ...... 16 9. Abbreviations and Glossary ...... 18 10. References ...... 21

Priority Additive Tobacco Consortium 2 Report for Priority Additive: Titanium Dioxide

Table of Appendices

1 Systematic Literature Search Report

2 Test and Reference Cigarette Manufacturing Report

3 Inclusion rate of titanium dioxide in the cigarette filter

4 Study Report on quantification and identification of particles released from filter

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Executive Summary Under Article 6(2) of the Tobacco Products Directive, Directive 2014/40/EU, Member States shall require manufacturers and importers of cigarettes and roll-your-own tobacco containing an additive that is included in the priority list established by Commission Implementing Decision (EU) 2016/787 to carry out comprehensive studies. These studies shall examine as specified in Article 6(2) Tobacco Products Directive for each additive whether it:

“(a) contributes to the toxicity or addictiveness of the products concerned, and whether this has the effect of increasing the toxicity or addictiveness of any of the products concerned to a significant or measurable degree;

(b) results in a characterising flavour;

(d) leads to the formation of substances that have CMR properties, the quantities thereof, and whether this has the effect of increasing the CMR properties in any of the products concerned to a significant or measurable degree.”

Titanium dioxide is one of these priority additives as laid down in the Commission Implementing Decision (EU) 2016/787.

Titanium dioxide is not added to the tobacco and, therefore, is not burnt during cigarette consumption.

Titanium dioxide is applied to the cigarette filter material as a whitening agent. The titanium dioxide is bound to the cigarette filter material in a manner that the titanium dioxide should not be mechanically released. Any thermal release of titanium dioxide from the filter into mainstream smoke during cigarette consumption is prevented due to the high temperatures at which titanium dioxide evaporates (roughly 3’000°C).

Titanium dioxide has been registered under the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) Regulation 1907/2006. Currently, titanium dioxide does not have a European harmonised classification according to Classification, Labelling and Packaging Regulation EC 1272/2008 and is, therefore, considered non-carcinogenic, non-mutagenic/genotoxic and not toxic to reproduction. However, recently the classification for titanium dioxide was reviewed by the European Chemistry Agency´s (ECHA) committee for Risk Assessment (RAC) and it was concluded that titanium dioxide meets the criteria in the CLP Regulation to be classified as a category 2 carcinogen with the hazard statement H351 (inhalation) (ECHA RAC, 2017). However, the decision for reclassification of titanium dioxide is not yet in force.

In its first and second opinion SCENIHR and SCHEER (SCENIHR 2015, SCHEER 2016), respectively, addressed that “it is necessary to know the exposure level of titanium dioxide through cigarette smoking” to perform a risk evaluation. Based on this the Priority Additives Tobacco Consortium performed a transfer study to determine whether titanium dioxide is released resulting in consumer exposure. The results of this study together with the relevant literature suggests that titanium dioxide does not contribute to the “CMR properties of a tobacco products at the stage of consumption to a significant and measurable degree” (Tobacco Products Directive, Directive 2014/40/EU, Article 7.9).

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The following results were found:

 The release of titanium dioxide particles from the cigarette filters during sham smoking (not lit) ranged from 2 - 4 particles per replicate of 2000 puffs drawn through 200 cigarettes (10 puffs per cigarette x 200 cigarettes x 35ml = 70 liters). Out of these 2- 4 particles per replicate of 2000 puffs drawn through 200 cigarettes only one titanium dioxide particle was in the respirable range of 2-5 µm. In the air blank sample no titanium dioxide particles were found.

 Furthermore, in literature, epidemiological data (NIOSH, 2011; Thompson et al., 2016) and non-rat animal studies indicate that titanium dioxide is not a carcinogen and that any effects observed in rat studies are related to secondary mechanisms due to lung overload in the rat (Nikula et al., 2001; Morrow, 1988). The rat is known for its particular pulmonary sensitivity as compared to humans and other animals (rodent and non-rodent species).

Based on the literature and on the results of the transfer study, no increase in the “CMR properties [. . .] at the stage of consumption to a significant and measurable degree” (Tobacco Products Directive, Directive 2014/40/EU, Article 7.9) can be expected when 0.5 mg titanium dioxide is applied per cigarette filters.

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1. Rationale for the Report

Under Article 6(2) of the Tobacco Products Directive, Directive 2014/40/EU, Member States shall require manufacturers and importers of cigarettes and roll-your-own tobacco containing an additive that is included in the priority list established by Commission Implementing Decision (EU) 2016/787 to carry out comprehensive studies. These studies shall examine as specified in Article 6(2) Tobacco Products Directive for each additive whether it:

(b) results in a characterising flavour;

Titanium dioxide is one of these priority additives as laid down in the Commission Implementing Decision (EU) 2016/787.

Titanium dioxide is not added to the tobacco and, therefore, is not burnt during cigarette consumption.

In its second opinion SCHEER (SCHEER 2006) addressed that “it is necessary to know the exposure level of titanium dioxide through cigarette smoking” to perform a risk evaluation. Based on this the Priority Additives Tobacco Consortium performed a transfer study to determine whether titanium dioxide is released resulting in consumer exposure. The results of this study together with the relevant literature suggests that titanium dioxide does not contribute to the “CMR properties of a tobacco products at the stage of consumption to a significant and measurable degree” (Tobacco Products Directive, Directive 2014/40/EU, Article 7.9).

This report contains the result of a literature search and the transfer study.

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2. Study Organization

A. Priority Additives Tobacco Consortium Members of the Priority Additives Tobacco Consortium are: - BRITISH AMERICAN TOBACCO (INVESTMENTS) LIMITED, a company incorporated in England (company number 00074974) whose registered office is at Globe House, 1 Water Street, London, WC2R 3LA (BAT);

- IMPERIAL TOBACCO LIMITED, a company incorporated in England (company number 01860181) whose registered office is at 121 Winterstoke Road, Bristol, England, BS3 2LL (IT);

- JT INTERNATIONAL SA, a company incorporated in Switzerland (company number CHE- 105.274.060) whose registered office is at 8, rue Kazem Radjavi, 1202 Geneva, Switzerland (JTI);

- PHILIP MORRIS PRODUCTS SA, a company incorporated in Switzerland (company number IDE CHE-105.950.151) whose registered office is at Quai Jeanrenaud 3, 2000 Neuchâtel, Switzerland (PMI);

- KT&G CORPORATION, a company incorporated in the Republic of Korea (company number 3068130866) whose registered office is at 71, Beotkkot-gil, Daedeok-gu, Daejeon 306-712 (Pyeongchon-dong), Republic of Korea (KT&G);

- JOH. WILH. VON EICKEN GMBH, a company incorporated in Germany (company number HRB 12093 HL) whose registered office is at Drechslerstr. 1 – 3, 23556 Lübeck, Germany (VE);

- KARELIA TOBACCO COMPANY INC., a company incorporated in Greece (company number 15082945000) whose registered office is at Athinon Str, 241 00 Kalamata Greece (KTC);

- LANDEWYCK TOBACCO S.A., a company incorporated in Luxembourg (company number LU25912143) whose registered office is at 31, Rue de Hollerich, L-1741 Luxembourg (LT);

- MAC BAREN TOBACCO COMPANY A/S, a company incorporated in Denmark (company number CVR 88 21 22 15) whose registered office is at Porthusvej 100, DK- 5700 Svendborg, Denmark (MBT); Priority Additive Tobacco Consortium 7 Report for Priority Additive: Titanium Dioxide

- PÖSCHL TABAK GMBH & CO. KG, a company incorporated in Germany (company number HRA 6553) whose registered office is at Dieselstrasse 1, 84144 Geisenhausen, Germany (PT);

- SCANDINAVIAN TOBACCO GROUP A/S, a company incorporated in Denmark (company number 31 08 01 85) whose registered office is at Sydmarken 42, 2860 Søborg, Denmark (STG);

- CONTINENTAL TOBACCO, a company incorporated in Hungary (company number 05 10 000070) whose registered office is at Dohany u. 1-3, Satoraljaujhely, 3980, Hungary (CT).

B. Test and Reference Cigarette Production Cigarettes were manufactured by - British American Tobacco, Germany GmbH, Alsterufer 4, 20354 Hamburg, Germany

C. Laboratories Experiments were performed by:

 Particle collection: Reemtsma Cigarettenfabriken GmbH, Group Physical Analytics, Albert-Einstein-Ring 7, 22761 Hamburg, Germany

 Particle characterization was performed by the independent Contract Research Organization:Rap.ID Particle Systems GmbH, Köpenicker Str. 325, Haus 11, 12555 Berlin, Germany

D. Literature Review The Literature review was performed by a specialized expert group:

- Kleijnen Systematic Reviews Ltd, Riccall Road, Escrick, York, YO19 6FD, UK

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3. Comprehensive Literature Overview

Article 6.4 of EU Tobacco Product Directive 2014/40/EU requires a “. . . comprehensive overview compiling the available scientific literature . . .”. Two literature searches were conducted. One restricted to toxicity studies on the respective additive when employed as a tobacco additive. In addition, a literature search and review were conducted providing an overview of the additive in particular adding information on toxicological properties of the neat additive.

A. Systematic Literature Searches

Systematic literature searches were conducted by Kleijnen Systematic Reviews Ltd, York, UK, following the highest standards to meet best practice requirements (Centre for Reviews and Dissemination 2009, Higgins and Green 2011) to assess toxicity studies on the additive when employed as a tobacco additive.

The search was performed by information specialists in the relevant databases, e.g., Embase (Ovid) and MEDLINE (Ovid) (MEDLINE is the primary component of PubMed; what sets MEDLINE apart from the rest of PubMed is the added value of using the National Library of Medicine controlled vocabulary), using search terms and strategies developed specifically for each database (Kleijnen und Knipschild 1992). In addition, REACH and EFSA documents were identified at the agencies’ websites. The search strategies were independently peer reviewed by an information specialist using the Evidence Based Checklist for the Peer Review of Electronic Search Strategies, PRESS EBC (Canadian Agency for Drugs and Technologies in Health 2016). All references in identified studies were checked for information of further evidence. Clearly defined acceptance/inclusion criteria determined inclusion into the final compilation of references. i. Searches and Selection of Studies As a result of the electronic database searching for all 14 tobacco additives, a total of 10,863 records were identified. A breakdown of the search results per additive (including titanium dioxide) is provided in the Appendix 2 of the Kleijnen Systematic Review (KSR) Literature Search report. Manual searches and other sources provided a number of additional records, as described in Figure 1. After deduplication of the library, 6,097 records remained; these were screened at the title and abstract stage to identify publications that were potentially relevant to any of the 14 additives.

From these, 287 records were selected to be re-screened at the full paper stage. On completion of full paper screening, 286 records were excluded. In total, one publication was finally included for the systematic review of titanium dioxide toxicology. The results of the screening process are shown in Figure 1.

Studies excluded at the full paper stage are listed in the Appendix 3 of the Kleijnen Systematic Review (KSR) Literature Search report along with the main reason for exclusion.

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Priority Additive Tobacco Consortium 10 Report for Priority Additive: Titanium Dioxide

ii. Study Characteristics One record was included for the toxicological assessment of titanium dioxide as a tobacco additive. This paper was a literature review that cited two studies in the context of titanium dioxide: Dontenwill 19729and Eicher 1985.10 After title and abstract screening, these two papers were excluded for the following reasons: not the additive of interest, and outcome (not toxicity), respectively. Table 1: Title and publication year of included studies by study type Article Study ID Title Review Paschke 200211 Effects of ingredients on cigarette smoke composition and biological activity: a literature overview

Table 2: Aims and conclusions of original studies Study ID Aim and Author’s Text Overall Conclusion Paschke 200211 Aim To present a literature review of published scientific studies of the effects of tobacco product ingredients and various experimental additives on cigarette smoke composition and its biological activity Overall This review may provide public health officials as well as Conclusion scientists in government agencies and in the tobacco industry with a helpful overview of published information on tobacco product ingredients, their transfer into mainstream cigarette smoke, pyrolysis products, and influence on the biological activity of mainstream cigarette smoke

iii. List of Titanium Dioxide References Included by KSR in this Systematic Review: Paschke T, Scherer G, Heller W. Effects of ingredients on cigarette smoke composition and biological activity: a literature overview. Beitr Tabakforsch Int 2002;20(3):107-247.

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B. Literature review

No carcinogenic concern has been identified after oral exposure to TiO2 (NCI, 1979; Bernhard et al.

1990) and after dermal exposure to TiO2 (Furukawa et al., 2011; Sagawa et al., 2012; Xu et al., 2011).

Human data on the carcinogenicity hazard of inhaled titanium dioxide were available from case reports, case-control studies and cohort studies. Available literature data did not suggest an association between occupational exposure to TiO2 and risk for cancer. In 2011, NIOSH (National Institute for Occupational Safety and Health, April 2011) highlighted that “[I]n general, the five epidemiologic studies of TiO2-exposed workers represent a range of environments, from industry to population based, and appear to be reasonably representative of worker exposures over several decade”, and then concluded that “[O]verall, these studies provide no clear evidence of elevated risks of lung cancer mortality or morbidity among those workers exposed to TiO2 dust”. In addition, a recent peer reviewed publication by Thompson and collaborators (Thompson et al., 2016) analysed epidemiological data that quantitatively characterize carcinogenic endpoints in humans, and concluded that “[C]onsidered collectively, this body of evidence in humans consistently reported a lack of significantly elevated risk of lung cancer in association with TiO2 exposure”.

Several studies in experimental animals were performed to investigate the carcinogenic potential of titanium dioxide after inhalation. Lung tumours were observed in rats following chronic inhalation of TiO2 in two publications (Lee et al, 1985 and Heinrich et al., 1995) out of 4 studies (Lee et al., 1985; Heinrich et al., 1995; Muhle et al., 1989; Thyssen et al., 1978). In this case, the relevance of the findings in animals to humans must be considered. The anatomy of the lungs of rats and humans are fundamentally different and as such the location of the particulate matter accumulation in the lungs of rats is essentially different to that of humans, with the majority of similar sized non-soluble diesel particles in rats (up to 85%) being located in the alveolar and alveolar duct lumens and up to 91% of particulate matter in coal miners being located in the interstitium of the lungs, leading to different cells or particle-containing macrophages coming into in contact with particulate matter (Nikula et al., 2001). It was noted that “volumetric loading of macrophages and their subsequent inability to move and release of pro-inflammatory cytokines are key to the overload response” as seen in rats (Morrow, 1988). In contrast humans have macrophages 4-times the volume of those found in rats (Krombach et al., 1997). This implies that rat macrophages are more sensitive to lung overload than human macrophages (Nikula et al., 2001). Hence, this could account for differences in responses to non-soluble particles seen in rats and humans. There is also a lack of response in humans for polymorphic neutrophils (PMNs) in high dust exposed workers e.g. coal miners. PMNs are a critical part of the inflammatory response in the rat. The BALF biomarkers in human coal dust exposed workers corroborates the lack of carcinogenic response in the epidemiological data seen in humans (Morfeld et al., 2015).

In conclusion, epidemiological data (NIOSH, 2011; Thompson et al., 2016) and non-rat animal studies indicate that titanium dioxide is not a carcinogen and that any effects observed in rat studies are related to secondary mechanisms due to lung overload in the rat (Nikula et al., 2001; Morrow, 1988), which is known for its particular pulmonary sensitivity when compared to humans and other animals (rodent and non-rodent species).

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4. Description and Use of the Additive A. Background Titanium dioxide is the most widely used white pigment because of its brightness and very high refractive index. It is used in paints, sun creams, toothpaste, papers, plastics, etc. Worldwide more than five million tons are produced per year. The cigarette industry uses titanium dioxide as a whitening agent for the filter material. Titanium dioxide is bound to the cellulose acetate material of cigarette filters.

B. Chemical Identity and other Characteristics

Primary names: Titanium dioxide, Titania Chemical names: Titanium (IV) oxide Trade names and abbreviations: n.a. CAS number: 13463-67-7 Structural formula: -

Empirical formula: TiO2 Molecular weight: 79.87 g/mol Specific gravity: 4.23 kg/(m2·s2) rutile 3.78 kg/(m2·s2) anatase Solubility: insoluble in water

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5. Cigarette Manufacturing Information regarding full details regarding the manufacturing of the cigarettes can be found in the Cigarette Manufacturing Report (British American Tobacco 2017). Reference cigarettes (R365) without additives in the tobacco were supplied by BAT Bayreuth. The reference cigarette included a standard cellulose acetate filter which contained 0.5mg titanium dioxide per cigarette filter (300mg for 600 cigarettes). The cigarette filter was manufactured on site using cellulose acetate supplied by Celanese. The reference cigarette (R365) was based on a commercially available king size cigarette (length 83 mm, circumference 24.6 mm) with a single segment cellulose acetate filter and tobacco blend recipe without ingredients.. The calculated titanium dioxide content of the cigarette filters was 0.5 mg per cigarette filter (300mg for 600 cigarettes). The cigarettes were manufactured to be representative for those sold in the EU.

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6. Study Concept A. Experimental setup As titanium dioxide is used only in the cigarette filter, which is unburnt, and as its boiling point (about 3000°C) prevents a release into mainstream smoke during cigarette consumption, a transfer study in which cigarettes were sham smoked (not lit) was performed. No analysis of titanium dioxide in cigarette smoke was performed as this is technically not possible. An Imperial Tobacco in-house method (see Appendices 4) was developed to count and characterise particles released from cigarette filters during sham-smoking (cigarettes were not lit during the procedure). The additive-free reference cigarette R365 (three replicates) manufactured for the Priority Additive Tobacco Consortium was sham smoked in a vertical position under ISO smoking conditions (puff volume: 35ml, puff duration: 2s, puff interval: 60s). Each sham smoking run was performed with 200 cigarettes (10 puffs per cigarette; 70 litres of air in total drawn through the gold membrane). The results of the R365 cigarette was compared to an air blank sample (a single replicate), in which the equipment was used without cigarettes in the holders applying the same experimental set up. Sham smoking took place in a laboratory with filtered ambient air. Samples were collected directly on to gold membranes (pore size 0.8 µm). Image analysis was performed using optical microscopy to count and analyse the size and shape of the particles. All steps were performed automatically by a Single Particle Explorer® (rap.ID Particle Systems GmbH, Berlin, Germany). Counting and identification of particles was performed in six specific size ranges: particles were classified as being in the size ranges ≥2 to <5; ≥5 to<8; ≥8 to<11; ≥11 to<15; ≥15-to 30; and ≥ 30 µm. Particles were identified where possible using Raman Spectroscopy. Details on the methodology is given in Appendices 4. The focus of the report was to measure the release of titanium dioxide particles from the cellulose acetate (CA) filters. Between 12 - 18 “respirable shaped fibre-shaped particulates” (RFP) were detected in the R365 reference cigarette sample and 15 RFP were detected in the air blank control. The particles released from R365 cigarette samples were mainly identified as typical cigarette and filter constituents. The number of particles released from the cellulose acetate (CA) filter from R365, was not significantly higher than those found in the air blank sample. The release of titanium dioxide particles from the CA filters of the R365 reference sample ranged from 2 - 4 particles from 2000 puffs drawn through 200 cigarettes [10 puffs per cig, (70 litres of air in total drawn through the gold membrane)]. No particles of titanium dioxide were found in the air blank sample.

B. Presentation of Results As predefined in the study protocol, the results were presented particles/sample.

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7. Study Results for Particle Transfer

The observations of this study are be summarised as follows:

Four gold membranes were analysed:  One gold membrane of the collection of the air blank sample.  Three gold membranes of the collection of the sham smoking (not lit) with the reference cigarette.

The following results were obtained:  The total number of particles found per gold membranes ranged from 234 to 436 particles for the collection of 70 liters (35ml x 2000 puffs).

 The total number of particles both in terms of number and types of particles detected in the blank test were comparable to the values of the sham smoking with the reference cigarette.

 The total number of respiratory fibre particles (RFP) were comparable for both the air blank sample (15 particles) and sham smoking of the reference cigarette (12-18 particles).

 Raman spectroscopy identified the particles as most likely to be carbon. The other particles released from cigarette samples were mainly identified as typical cigarette and filter constituents. Limited numbers of particles could not be clearly identified due to fluorescence.

 The release of titanium dioxide particles from the cigarette filters during sham smoking ranged from 2 - 4 particles per replicate of 2000 puffs drawn through 200 cigarettes (10 puffs per cigarette x 200 cigarettes x 35ml = 70 liters). Out of these 2- 4 particles per replicate of 2000 puffs drawn through 200 cigarettes only one titanium dioxide particle was in the respirable range of 2-5 µm. In the air blank sample no titanium dioxide particles were found.

These breakthrough rates correspond well with historical tests conducted in the past at Imperial Tobacco.

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8. Summary and Overall Conclusion

(b) results in a characterising flavour;

Titanium dioxide is one of these priority additives as laid down in the Commission Implementing Decision (EU) 2016/787.

Titanium dioxide is not added to the tobacco and, therefore, is not burnt during cigarette consumption.

The following results were found:

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9. Abbreviations and Glossary

CAS Chemical Abstract Service (division of the American Chemical Society)

Cast Sheet Specific type of reconstituted tobacco

CHO Chinese Hamster Ovary

CMR Carcinogenic, Mutagenic, Reprotoxic (Classification according to EU CLP Regulation 1272/2008)

CLP Classification, Labelling and Packaging

CRL Charles River Laboratories

CRO independent Contract Research Organization

CSC Cigarette Smoke Condensate

DCCC Direct Conditioning & Casing Cylinder; equipment where the tobacco is warmed up, damped and mixed with most of the additives

EBC Evidence Based Checklist

EC European Community

ECHA European Chemicals Agency

ECVAM European Centre for the Validation of Alternative Methods

EFSA European Food Safety Authority

EU European Union

EURL European Union Reference Laboratory

Expanded Tobacco Tobacco where the cellular structure of the lamina has been expanded, puffed-up, in a process similar to that used to make puffed rice.

FDA Food and Drug Agency of the USA fMRI functional Magnetic Resonance Imaging

GCP Good Clinical Practices

GLP Good Laboratory Practices

GVP Gas Vapor Phase

HPLC/MS-MS High Pressure Liquid Chromatography with tandem Mass Spectrometry

IC50 Half maximal Inhibitory Concentration, a quantitative measure that indicates how much of a substance is needed to inhibit a given biological process, e.g., the concentration of TPM that reduces the number of viable cells due to cell Priority Additive Tobacco Consortium 19 Report for Priority Additive: Titanium Dioxide

death and decreased proliferation to half of that found in the control without TPM exposure.

ICR Institute of Cancer Research, USA

ISO International Organization for Standardization ivMN in vitro Micronucleus test; a genotoxicity test recommended in nearly all regulatory test batteries monitor cigarette Experimental cigarette produced in large quantities with minimal production variation; provided to interested researchers as a utility to compare their results of analyses on this cigarette type with those of other laboratories (in several scientific publications also referred to as Standard Reference Cigarette). In the studies conducted for the purpose of this report, the 3R4F Kentucky Reference cigarette served as the monitor item.

INCI International Nomenclature Cosmetic Ingredient

NCI National Cancer Institute (USA)

NFDPM Nicotine Free Dry Particulate Matter (TPM where the amount of nicotine and water has been subtracted mathematically)

NRU Neutral Red Uptake assay

PET Positron Emission Tomography

PK Pharmaco Kinetics

PMN polymorphic neutrophils

REACH Registration, Evaluation, Authorization and Restriction of Chemicals

Reconstituted Tobacco, Recon Tobacco product that makes use of, e.g., stems and broken bits (fines) where, as in a paper-mill, the tobacco after grinding and mixing with water and a binder (e.g. guar gum) is converted into a paper-like material, that can be processed like normal tobacco lamina reference cigarette The comparative study approach compares two types of cigarettes that differ only in one aspect: a cigarette with and a cigarette without the addition of the additive. The Reference Cigarette is the additive-free cigarette with identical tobacco blend and cigarette construction.

SCHEER Scientific Committee on Health, Environmental and Emerging Risks

SCENIHR Scientific Committee on Emerging and Newly Identified Health Risks

SPECT Single-Photon Emission Computed Tomography

Standard Reference Cigarette Priority Additive Tobacco Consortium 20 Report for Priority Additive: Titanium Dioxide

See Monitor Cigarette

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10. References British American Tobacco. 2017. Manufacturing Report, Project "Testpiece" (Part of the Appendices).

Bernard BK, Osheroff MR, Hofmann A, Mennear JH. Toxicology and carcinogenesis studies of dietary titanium dioxide-coated mica in male and female Fischer 344 rats. J Toxicol Environ Health. 1990; 29(4):417-29. Canadian Agency for Drugs and Technologies in Health 2017. 18.10.17. PRESS Peer Review of Electronic Search Strategies: 2015 guideline explanation and elaboration https://www.cadth.ca/press-2015-guideline-explanation-and-elaboration.

Centre for Reviews and Dissemination 2017. CRD's guidance for undertaking reviews in health care https://www.york.ac.uk/crd/SysRev/!SSL!/WebHelp/SysRev3.htm.

ECHA, European Chemical Agency, Committee for Risk Assessment (RAC), Opinion proposing harmonised classification and labeling at EU Level of titanium dioxide, 2017.

European Union. 2016. Priority list of additives contained in cigarettes and roll-your-own tobacco subject to enhanced reporting obligations

Furukawa F, Doi Y, Suguro M, Morita O , Kuwahara H, Masunaga T, Hatakeyama Y, Mori F. Lack of skin carcinogenicity of topically applied titanium dioxide nanoparticles in the mouse. Food and Chemical Toxicology. 2011 Apr; 49(4):744–9. Heinrich U, Fuhst R, Rittinghausen S, Creutzenberg O, Bellmann B, Koch W, Levsen K (1995). Chronic inhalation exposure of Wistar rats and two different strains of mice to diesel engine exhaust, carbon black, and titanium dioxide. Inhalation Toxicology 7(4): 533-556. Higgins JPT, Green S 2017. Cochrane handbook for systematic reviews of interventions, [4] Higgins JPT, Green S, eds. Cochrane handbook for systematic reviews of interventionserion 5.1.0 http://handbook.cochrane.org/. Imperial Tobacco. 2018. Quantification and identification of particles released from cellulose acetate filters from an additive-free reference cigarette R365 and an air blank. A focus on titanium dioxide release, using an Imperial Tobacco in-house derived method. Reemtsma Cigarettenfabriken GmbH, Group Physical Analytics. Kleijnen J, Knipschild P. 1992. The comprehensiveness of Medline and Embase computer searches. Searches for controlled trials of homoeopathy, ascorbic acid for common cold and ginkgo biloba for cerebral insufficiency and intermittent claudication. Pharm Weekbl Sci, 14 (5):316- 320. Krombach F (1997). Cell size of alveolar macrophages: an interspecies comparison. EHP 105(5) 1261- 1263. Lee KP, Trochimowicz HJ, Reinhardt CF (1985). Pulmonary response of rats exposed to titanium dioxide (TiO2) by inhalation for two years. Toxicology and Applied Pharmacology 79(2): 179- 192. Morrow, P.E. 1988. Possible mechanisms to explain dust overloading of the lungs. Fundam. Appl.Toxicol. 10:369–384 . Priority Additive Tobacco Consortium 22 Report for Priority Additive: Titanium Dioxide

Morfeld P et al., (2015) Translational toxicology in setting occupational exposure limits for dusts and hazard classification – a critical evaluation of a recent approach to translate dust overload findingsfrom rats to humans. Part Fibre Toxicol DOI:10.1186/s12989-015-0079-3. Muhle H, Mermelstein R, Dasenbrock C, Takenaka S, Mohr U, Kilpper R, MacKenzie J, Morrow P. Lung response to test toner upon 2-year inhalation exposure in rats. Exp Pathol. 1989; 37(1-4):239-42 NCI. Bioassay of titanium dioxide for possible carcinogenicity. Natl Cancer Inst Carcinog Tech Rep Ser. 1979; 97: 1-123. Nikula K et al., (2001). Influence of exposure concentration or dose on the distribution of particulate material in rat and human lungs. EHP 109, 4: 311-3148 NIOSH (2011). National Institute for Occupational Safety and Health. Current Intelligence Bulletin 63: Occupational Exposure to Titanium Dioxide, April 2011. Sagawa Y, Futakuchi M, Xu J, Fukamachi K, Sakai Y, Ikarashi Y, Nishimura T, Suzui M, Tsuda H, Morita A. Lack of promoting effect of titanium dioxide particles on chemically-induced skin carcinogenesis in rats and mice. J Toxicol Sci. 2012; 37(2):317-27. SCENIHR, Final Opinion on Additives used in tobacco products, Tobacco Additives Opinion 1, 25 January 2016. SCHEER, Final Opinion on Additives used in tobacco products, Tobacco Additives Opinion 1, 16 December 2016. Thompson CM, Suh M, Mittal L, Wikoff DS, Welsh B, Proctor DM (2016). Development of linear and threshold no significant risk levels for inhalation exposure to titanium dioxide using systematic review and mode of action considerations. Regulatory Toxicology and Pharmacology 80: 60-70 Thyssen J, Kimmerle G. Inhalation studies with polyurethane foam dust in relation to respiratory tract carcinogenesis. J Environ Pathol Toxicol. 1978 Mar-Apr; 1(4):501-8. Xu J, Sagawa Y, Futakuchi M, Fukamachi K, Alexander DB, Furukawa F, Ikarashi Y, Uchino T, Nishimura T, Morita A, Suzui M, Tsuda H. Lack of promoting effect of titanium dioxide particles on ultraviolet B-initiated skin carcinogenesis in rats. Food Chem Toxicol. 2011 Jun; 49(6):1298-302.

Appendix 1: Systematic Literature Search Report Systematic literature searches for the EU Tobacco Product Directive 2014/40/EU Art 6 in which manufacturers are requested to perform comprehensive studies for priority additives

Titanium Dioxide

Final Report by Kleijnen Systematic Reviews Ltd

Prepared for Priority Additives Tobacco Consortium

08 June 2018

Kleijnen Systematic Reviews Ltd Unit 6, Escrick Business Park Riccall Road Escrick York YO19 6FD

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Kleijnen Systematic Reviews Ltd 2 TABLE OF CONTENTS

TABLE OF CONTENTS ...... 3 TABLE OF TABLES ...... 4 1. EXECUTIVE SUMMARY ...... 5 2. BACKGROUND ...... 6 2.1 INTRODUCTION ...... 6 2.2 FOCUS OF THE REPORT...... 6 3. OBJECTIVES ...... 6 4. RESEARCH QUESTION ...... 6 5. METHODS ...... 6 5.1 LITERATURE SEARCHES ...... 6 5.2 STUDY SELECTION ...... 8 5.3 PROTOCOL AMENDMENTS ...... 9 6. RESULTS ...... 10 6.1 SEARCHES AND SELECTION OF STUDIES ...... 10 6.2 STUDY CHARACTERISTICS ...... 12 6.3 LIST OF TITANIUM DIOXIDE REFERENCES INCLUDED BY KSR IN THIS SYSTEMATIC REVIEW: ...... 12 6.4 LIST OF TITANIUM DIOXIDE REFERENCES PROVIDED BY PRIORITY ADDITIVE TOBACCO CONSORTIUM FOR CONSIDERATION: ...... 12 7. CONCLUSIONS ...... 13 8. REFERENCES ...... 14 APPENDIX 1: SEARCH STRATEGIES – TITANIUM DIOXIDE ...... 16 APPENDIX 2: DATABASE SEARCH RESULTS PER ADDITIVE ...... 23 APPENDIX 3: LIST OF PUBLICATIONS EXCLUDED AT FULL PAPER SCREENING ...... 24

Kleijnen Systematic Reviews Ltd 3 TABLE OF TABLES

Table 1: Title and publication year of included studies by study type ...... 12

Table 2: Aims and conclusions of original studies ...... 12

Kleijnen Systematic Reviews Ltd 4 1. EXECUTIVE SUMMARY This document constitutes part of a series of reviews for a specified list of 14 priority tobacco additives identified by the EU commission for toxicological analysis related to Article 6 of EU Tobacco Product Directive 2014/40/EU.1 The objective of this systematic review is to identify the available evidence on the toxicity of titanium dioxide as a tobacco additive. Electronic searches and hand searches of grey literature and reviews were carried out with no restriction by date, language or publication status. This review included toxicology studies of titanium dioxide as a tobacco additive including pyrolysis, smoke chemistry, in vitro, in vivo and human studies. It excluded studies pertaining to cigars, water pipes, electronic cigarettes or vaping. Studies that reported addictiveness or flavour were also excluded. A single publication – a review article - was included in this systematic review. Since this article failed to describe any studies that were of relevance to the inclusion criteria of this review, no further analyses could be performed.

Kleijnen Systematic Reviews Ltd 5 2. BACKGROUND

2.1 INTRODUCTION Article 6 (2) of the Tobacco Products Directive (Directive 2014/40/EU) requires manufacturers and importers of cigarettes and roll-your-own tobacco to carry out comprehensive studies on each additive included in the priority list established by the Commission Implementing Decision (EU) 2016/787. These studies shall examine certain aspects of these additives as specified in Article 6(2) of the Tobacco Products Directive.

2.2 FOCUS OF THE REPORT This report will be used to support the submission of toxicological data pertaining to titanium dioxide as a tobacco additive to the EU commission. This report is one of a series covering 14 priority additives of interest: carob bean extract, cocoa powder, fenugreek extract, fig juice extract, geraniol, glycerol, guaiacol, guar gum, liquorice extract powder, maltol, menthol, propylene glycol, sorbitol and titanium dioxide.

3. OBJECTIVES To conduct literature searches to identify studies examining tobacco additives, including human, animal, in vitro and smoke chemistry studies. This approach was informed by Article 6 of EU Tobacco Product Directive 2014/40/EU,1 and due to time constraints focussed on toxicity studies that utilised the additive in the context of tobacco. The tobacco additives of interest were defined in the Commission Implementing Decision (EU) 2016/787 of 18 May 2016.2 We aimed to identify all relevant studies in the specified range and perform a data extraction of key study characteristics and the main conclusions for each study.

4. RESEARCH QUESTION What toxicology data are available concerning titanium dioxide as a tobacco additive? This review includes studies on titanium dioxide toxicity when employed as a tobacco additive, including human, animal, in vitro and chemistry studies. This review excludes studies pertaining to cigars, water pipes, electronic cigarettes or vaping.

5. METHODS

5.1 LITERATURE SEARCHES The literature searches described here were conducted to retrieve studies on the toxicity of titanium dioxide as a tobacco additive. All searching was undertaken to the highest standard

Kleijnen Systematic Reviews Ltd 6 to meet best practice requirements recommended by the Centre for Reviews and Dissemination,3 and Cochrane.4 The search strategies combined relevant search terms for titanium dioxide and tobacco comprising of indexed keywords (e.g. Medical Subject Headings, MeSH and EMTREE) and free text terms appearing in the title and/or abstract of database records. Search terms were identified through discussion between the review team, by scanning background literature and ‘key articles’ already known to the review team, and by browsing database thesauri. Search strategies were developed specifically for each database and the keywords adapted according to the configuration of each database. Searches were not limited by language or date; nor were they limited to human studies only. Searches were initially conducted in November 2017. Update searches were conducted in January 2018, February 2018, March 2018 and May 2018. For the latest update search all databases and resources were searched from inception to May 2018. The results of the May 2018 update searches were then de-duplicated against the previous search results from November 2017, January 2018, February 2018 and March 2018. The following databases were searched for relevant studies from inception to May 2018: • Embase (Ovid): 1974-2018/week 19 • MEDLINE (Ovid): 1946-2018/May week 1 • MEDLINE In-Process Citations, MEDLINE Daily Update, and MEDLINE Epub Ahead of Print (Ovid): May 8, 2018 • Science Citation Index Expanded (Web of Knowledge): 1988-2018/05/08 • Toxicology Literature Online (TOXLINE) (NLM) (Internet): up to 8 May 2018 (https://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?TOXLINE) • Developmental and Reproductive Toxicology (DART) (NLM) (Internet): up to 8 May 2018 (https://toxnet.nlm.nih.gov/newtoxnet/dart.htm) • European Chemicals Agency (ECHA) (Internet): up to 8 May 2018 (https://echa.europa.eu/home) • European Food Safety Authority (EFSA) (Internet): up to 8 May 2018 (https://www.efsa.europa.eu/) Limited searches for ‘tobacco additive’ grey literature were conducted in the following resources: • OAIster (www.oaister.org/): up to 8 May 2018 • COPAC (http://copac.ac.uk/): up to 8 May 2018 • OpenGrey (http://www.opengrey.eu/): up to 8 May 2018 • Google (http://www.google.co.uk): up to 8 May 2018

Kleijnen Systematic Reviews Ltd 7 • Library of Congress (https://catalog.loc.gov): up to 8 May 2018 An eTOC (electronic Table of Contents) alert was set up in the following journal: • Beiträge zur Tabakforschung International/Contributions to Tobacco Research - Journal of BTFI GmbH. https://www.degruyter.com/view/j/cttr Citations searches for all additives Citation searches of key included studies across all fourteen additives were conducted. These key studies were identified in the initial November 2017 searches. The following key studies were used for citation searching: • Vanscheeuwijck PM, Teredesai A, Terpstra PM, Verbeeck J, Kuhl P, Gerstenberg B, et al. Evaluation of the potential effects of ingredients added to cigarettes. Part 4: subchronic inhalation toxicity. Food Chem Toxicol 2002;40(1):113-31. • Roemer E, Tewes FJ, Meisgen TJ, Veltel DJ, Carmines EL. Evaluation of the potential effects of ingredients added to cigarettes. Part 3: in vitro genotoxicity and cytotoxicity. Food Chem Toxicol 2002;40(1):105-11. • Rustemeier K, Stabbert R, Haussmann H, Roemer E, Carmines EL. Evaluation of the potential effects of ingredients added to cigarettes. Part 2: chemical composition of mainstream smoke. Food Chem Toxicol 2002;40(1):93-104. The full search strategies are reported in Appendix 1. 5.1.1 Handling of citations Each set of search results for each individual additive, including titanium dioxide, were downloaded into 14 separate EndNote bibliographic libraries, and the duplicate records removed from each library. The remaining references across all 14 additives were then downloaded into a single EndNote library for further de-duplication. Individual records within the EndNote reference libraries were tagged with searching information, such as searcher, date searched, database host, database searched, strategy name and iteration, theme or search question. This enabled the information specialist to track the origin of each individual database record, and its progress through the screening and review process. 5.1.2 Quality assurance within the search process For all searches undertaken by Kleijnen Systematic Reviews Information team, the main Embase search strategies for each set of searches were independently peer reviewed by a second Information Specialist, using the Canadian Agency for Drugs and Technologies in Health (CADTH) PRESS checklist.5, 6

5.2 STUDY SELECTION Title and abstracts of the identified records were screened against the eligibility criteria. For records that were thought to meet the eligibility criteria, the full paper was retrieved and assessed in full to decide on its inclusion or exclusion. The process was carried out

Kleijnen Systematic Reviews Ltd 8 independently by two reviewers. Any discrepancies were discussed, and if necessary, disagreements were resolved by the intervention of a third reviewer.

5.3 PROTOCOL AMENDMENTS At the request of the sponsor, the following amendments to the protocol were made: (1) The production of an individual report per additive; (2) The inclusion of pyrolysis studies that report data for relevant additives assayed in isolation (i.e. not in the context of tobacco); (3) The inclusion of in vivo and clinical studies in which cigarette smoke generated from cigarettes containing the additive of interest was applied via additional routes beyond inhalation (e.g. dermal exposure); (4) The extraction of the inclusion levels of the additive in the cigarette; (5) The extraction of statistically significant results; and (6) The removal of risk of bias scores and designations. These were originally generated for each study using the ToxRTool7 (for in vitro and in vivo outcomes) or a customised tool based on the Cochrane risk of bias tool8 (for human studies). These changes were approved after the full paper screening of the studies had taken place, and were not retrospectively applied to database records that had already undergone screening.

Kleijnen Systematic Reviews Ltd 9 6. RESULTS

6.1 SEARCHES AND SELECTION OF STUDIES As a result of the electronic database searching for all 14 tobacco additives, a total of 10,863 records were identified. A breakdown of the search results per additive (including titanium dioxide) is provided in Appendix 2. Manual searches and other sources provided a number of additional records, as described in Figure 1. After de-duplication of the library, 6,097 records remained; these were screened at the title and abstract stage to identify publications that were potentially relevant to any of the 14 additives. From these, 287 records were selected to be re-screened at the full paper stage. On completion of full paper screening, 286 records were excluded. In total, one publication was finally included for the systematic review of titanium dioxide toxicology. The results of the screening process are shown in Figure 1. Studies excluded at the full paper stage are listed in Appendix 3 along with the main reason for exclusion.

Kleijnen Systematic Reviews Ltd 10 Figure 1: PRISMA flow diagram

Records identified through other sources (n = 1,262) • Grey literature (n=91) Records identified through • Provided by industry (n=760) database searching • Citation searches (n=339) (n= 10,863) • Secondary references (n=72)

Records after duplicates removed (n = 6,097)

Records excluded by title and abstract Records screened (n =5,810) (n = 6,097)

Full-text articles excluded, with reasons (n =286) Full-text articles assessed • Additive not contained in for eligibility cigarettes or RYO tobacco (n = 287) (n = 15) • No additive reported (n = 3) • No relevant comparator (n = 5) • Tobacco system (n = 8) • Not an additive of interest (n = 30) Final included records • Outcome (n = 51) (n =1) • Unobtainable (n = 27) • No appropriate analysis (n = 4) • Included for other additives but not relevant for titanium dioxide (n = 143 )

6.2 STUDY CHARACTERISTICS One record was included for the toxicological assessment of titanium dioxide as a tobacco additive. This paper was a literature review that cited two studies in the context of titanium dioxide: Dontenwill 19729and Eicher 1985.10 After title and abstract screening, these two papers were excluded for the following reasons: not the additive of interest, and outcome (not toxicity), respectively. Table 1: Title and publication year of included studies by study type

Article Study ID Title

Review Paschke 200211 Effects of ingredients on cigarette smoke composition and biological activity: a literature overview

Table 2: Aims and conclusions of original studies

Study ID Aim and Author’s Text Overall Conclusion To present a literature review of published scientific Paschke 200211 Aim studies of the effects of tobacco product ingredients and various experimental additives on cigarette smoke composition and its biological activity This review may provide public health officials as well as Overall scientists in government agencies and in the tobacco Conclusion industry with a helpful overview of published information on tobacco product ingredients, their transfer into mainstream cigarette smoke, pyrolysis products, and influence on the biological activity of mainstream cigarette smoke

6.3 LIST OF TITANIUM DIOXIDE REFERENCES INCLUDED BY KSR IN THIS SYSTEMATIC REVIEW: Paschke T, Scherer G, Heller W. Effects of ingredients on cigarette smoke composition and biological activity: a literature overview. Beitr Tabakforsch Int 2002;20(3):107-247.

6.4 LIST OF TITANIUM DIOXIDE REFERENCES PROVIDED BY PRIORITY ADDITIVE TOBACCO CONSORTIUM FOR CONSIDERATION: Several studies have been provided for consideration of inclusion for titanium dioxide by different members of the tobacco consortia, which may include British American Tobacco (BAT), Japan Tobacco International (JTI), Philip Morris International (PMI) and Imperial

Kleijnen Systematic Reviews Ltd 12 Tobacco Limited (ITL). These studies are listed below. Each study was subject to our screening and inclusion criteria; the studies that have been included in this systematic review from this source have been highlighted in our study selection flow chart under the origin, “provided by industry”. European Chemicals Agency (ECHA). Committee for Risk Assessment. RAC. Opinion proposing harmonised classification and labelling at EU level of Titanium dioxide. EC Number: 236-675-5. CAS Number: 13463-67-7. CLH-O-0000001412-86-163/F [Internet]. Helsinki, Finland: ECHA, 2017 [accessed 15.11.17] Available from: https://echa.europa.eu/documents/10162/682fac9f-5b01-86d3-2f70-3d40277a53c2

EFSA ANS Panel (EFSA Panel on Food Additives and Nutrient Sources added to Food). Scientific Opinion on the re-evaluation of titanium dioxide (E 171) as a food additive. EFSA Journal 2016;14(9):4545.

IARC. IARC Monographs, Volume 93. Carbon Black, Titanium Dioxide, and Talc, 2010

Warheit DB, Kreiling R, Levy LS. Relevance of the rat lung tumor response to particle overload for human risk assessment-Update and interpretation of new data since ILSI 2000. Toxicology 2016;374:42-59.

7. CONCLUSIONS A single review article was identified that described titanium dioxide as a cigarette additive in the context of smoke composition and biological activity. This article did not describe any original studies that fit the inclusion criteria of this systematic review.

Kleijnen Systematic Reviews Ltd 13 8. REFERENCES [1] European Commission. Directive 2014/40/EU of the European Parliament and of the Council of 3 April 2014 on the approximation of the laws, regulations and administrative provisions of the Member States concerning the manufacture, presentation and sale of tobacco and related products and repealing Directive 2001/37/EC [Internet]: European Commission, 2014 [accessed 18.10.17]. Available from: https://ec.europa.eu/health//sites/health/files/tobacco/docs/dir_201440_en.pdf

[2] European Commission. Commission Implementing Decision (EU) 2016/787 of 18 May 2016 laying down a priority list of additives contained in cigarettes and roll-your-own tobacco subject to enhanced reporting obligations (notified under document C(2016) 2923). Official Journal of the European Union 2016;L 131/88.

[3] Centre for Reviews and Dissemination. Systematic Reviews: CRD’s guidance for undertaking reviews in health care [Internet]. York: University of York, 2009 [accessed 18.10.17] Available from: http://www.york.ac.uk/inst/crd/SysRev/!SSL!/WebHelp/SysRev3.htm

[4] Higgins JPT, Green S, eds. Cochrane handbook for systematic reviews of interventions [Internet]. Version 5.1.0 [updated March 2011]: The Cochrane Collaboration, 2011 [accessed 18.10.17]. Available from: http://handbook.cochrane.org/

[5] Canadian Agency for Drugs and Technologies in Health. PRESS Peer Review of Electronic Search Strategies: 2015 guideline explanation and elaboration [Internet]. Ottawa: CADTH, 2016 [accessed 18.10.17] Available from: https://www.cadth.ca/press-2015-guideline-explanation-and-elaboration

[6] McGowan J, Sampson M, Salzwedel DM, Cogo E, Foerster V, Lefebvre C. PRESS Peer Review of Electronic Search Strategies: 2015 guideline statement. J Clin Epidemiol 2016;75:40-6.

[7] Joint Research Centre, European Union Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM), European Commission. ToxRTool - Toxicological data Reliability Assessment Tool [Internet]. European Commission, [accessed 20.10.17]. Available from: https://eurl- ecvam.jrc.ec.europa.eu/about-ecvam/archive-publications/toxrtool

[8] Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ 2011;343:d5928.

[9] Dontenwill W, Chevalier HJ, Harke HP, Klimischi HJ, Lafrenz U, Reckzeh G, et al. [Experimental studies on tumorigenic activity of cigarette smoke condensate on mouse skin. IV. Comparative studies of condensates from different reconstituted tobacco sheets, the effect of NaNO3 as additive to tobacco or reconstituted tobacco sheets, the effect of volatile constituents of smoke, the effect of initial treatment with DMBA]. Z Krebsforsch Klin Onkol Cancer Res Clin Oncol 1972;78(3):236-64.

[10] Eicher T, Müller F. Rauchbare Produkte; German Patent No. 2729759 (May 1985). 1985.

Kleijnen Systematic Reviews Ltd 14

[11] Paschke T, Scherer G, Heller W. Effects of ingredients on cigarette smoke composition and biological activity: a literature overview. Beitr Tabakforsch Int 2002;20(3):107-247.

Kleijnen Systematic Reviews Ltd 15 APPENDIX 1: SEARCH STRATEGIES – TITANIUM DIOXIDE Overall results: November 2017 Additive Number of Database Number of Final Number of Records Retrieved Duplicates Records Removed

Titanium dioxide 510 190 320

Update search results: January 2018

New records retrieved 4

Update search results: February 2018

New records retrieved 7

Update search results: March 2018

New records retrieved 4

Update search results: May 2018

New records retrieved 5

Search strategies

Embase (Ovid): 1974-2018/week 19 Searched: 8.5.18

1 tobacco/ (42729) 2 exp "tobacco use"/ (304327) 3 exp "smoking and smoking related phenomena"/ (315387) 4 (cigaret$ or smok$ or tobacco or handroll$ or hand-roll$ or selfroll$ or self-roll$ or make-your-own or myo or roll-your-own or ryo or rollie$ or rolly$ or fine cut).ti,ab,ot. (418975) 5 or/1-4 (496716) 6 titanium dioxide/ (19331) 7 ((titanium adj2 dioxide$) or 13463-67-7 or 1317-80-2 or 1317-70-0 or (titanium adj2 oxide$) or titanium, dioxo$ or titania$ or titanium white$ or pigment white 6 or PW6 or TiO2 or anatase$ or bayertitan rc k 20 or rutile$ or titanic dioxide$ or titanox or brookite$ or dioxotitan$ or titandioxid or UNII-15FIX9V2JP or NSC-200C or NSC200C).ti,ab,rn. (26333) 8 6 or 7 (26339) 9 5 and 8 (93)

MEDLINE (Ovid): 1946-2018/May week 1

Kleijnen Systematic Reviews Ltd 16 Searched: 10.5.18

1 Tobacco/ (28378) 2 exp "Tobacco Use"/ (1536) 3 Tobacco Products/ (2657) 4 Tobacco Industry/ (4198) 5 (cigaret$ or smok$ or tobacco or handroll$ or hand-roll$ or selfroll$ or self-roll$ or make-your-own or myo or roll-your-own or ryo or rollie$ or rolly$ or fine cut).ti,ab,ot. (271287) 6 or/1-5 (279149) 7 ((titanium adj2 dioxide$) or 13463-67-7 or 1317-80-2 or 1317-70-0 or (titanium adj2 oxide$) or titanium, dioxo$ or titania$ or titanium white$ or pigment white 6 or PW6 or TiO2 or anatase$ or bayertitan rc k 20 or rutile$ or titanic dioxide$ or titanox or brookite$ or dioxotitan$ or titandioxid$ or UNII-15FIX9V2JP or NSC-200C or NSC200C).ti,ab,rn. (13228) 8 6 and 7 (41)

MEDLINE In-Process & Other Non-Indexed Citations (Ovid): May 8, 2018; MEDLINE Daily Update (Ovid): May 8, 2018; MEDLINE Epub Ahead of Print (Ovid): May 8, 2018. Searched: 10.5.18

1 Tobacco/ (22) 2 exp "Tobacco Use"/ (44) 3 Tobacco Products/ (15) 4 Tobacco Industry/ (5) 5 (cigaret$ or smok$ or tobacco or handroll$ or hand-roll$ or selfroll$ or self-roll$ or make-your-own or myo or roll-your-own or ryo or rollie$ or rolly$ or fine cut).ti,ab,ot. (34441) 6 or/1-5 (34450) 7 ((titanium adj2 dioxide$) or 13463-67-7 or 1317-80-2 or 1317-70-0 or (titanium adj2 oxide$) or titanium, dioxo$ or titania$ or titanium white$ or pigment white 6 or PW6 or TiO2 or anatase$ or bayertitan rc k 20 or rutile$ or titanic dioxide$ or titanox or brookite$ or dioxotitan$ or titandioxid$ or UNII-15FIX9V2JP or NSC-200C or NSC200C).ti,ab,rn. (12807) 8 6 and 7 (8)

Science Citation Index (Web of Knowledge): 1988-2018/05/08 Searched: 8.5.18

# 5 262 #3 and #4 # 4 317,871 TS=(cigaret* or smok* or tobacco or handroll* or hand-roll* or selfroll* or self-roll* or make-your-own or myo or roll-your-own or ryo or rollie* or rolly* or fine cut) # 3 174,617 #1 or #2 # 2 161,422 TS=(13463-67-7 or 1317-80-2 or 1317-70-0 or titanium dioxo* or titania* or titanium white* or pigment white 6 or PW6 or TiO2 or anatase* or bayertitan rc k 20 or rutile* or titanic dioxide* or titanox or brookite* or dioxotitan* or titandioxid or UNII-15FIX9V2JP or NSC-200C or NSC200C)

Kleijnen Systematic Reviews Ltd 17 # 1 52,947 TS=(titanium NEAR/2 dioxide*) or TS=(titanium NEAR/2 oxide*)

TOXLINE (NLM): up to 8 May 2018 https://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?TOXLINE Searched: 8.5.18

("titanium dioxide" OR 13463-67-7[rn] OR 1317-80-2[rn] OR 1317-70-0[rn] OR "titanium oxide")(cigar* OR smok* OR tobacco) 75

DART (Developmental and Reproductive Toxicology Database): up to 8 May 2018 https://toxnet.nlm.nih.gov/newtoxnet/dart.htm Searched: 8.5.18

("titanium dioxide" OR 13463-67-7[rn] OR 1317-80-2[rn] OR 1317-70-0[rn] OR "titanium oxide")(cigar* OR smok* OR tobacco) 1

European Chemicals Agency (ECHA): up to 8 May 2018 https://echa.europa.eu/home Searched 8.5.18

Searched the ECHA Website Search terms November January February March May 2017 2018 2018 2018 2018 titanium dioxide" 13 0 0 4 0 tobacco [should match all keywords"] "titanium dioxide" 20 0 3 6 2 smoking [should match all keywords] Total 33 0 3 10 2

European Food Safety Authority (EFSA): up to 8 May 2018 https://www.efsa.europa.eu/ Searched 8.5.18

Search the EFSA Website: Publications Search terms November January February March May 2017 2018 2018 2018 2018 "titanium dioxide" 4 0 0 0 0

Beiträge zur Tabakforschung International/Contributions to Tobacco Research. The Journal of BTFI GmbH: up to Volume 28, Issue 1 (2018) https://www.degruyter.com/view/j/cttr Searched 8.5.18

Latest issue searched in the May 2018 update

Kleijnen Systematic Reviews Ltd 18 Search terms November 2017 January 2018 May 2018 carob OR ceratonia 1 0 0

Limited grey literature searches: up to 8 May 2018 Searched 8.5.18

OAIster (http://oaister.worldcat.org/) Advanced Search November January February March March 2017 2018 2018 2018 2018 > "2017" > "2018" > "2018" > "2018" kw:"tobacco additiv*" 67 0 0 0 0 ti:"tobacco additiv*" 14 0 0 0 0 kw:"tobacco 24 0 0 0 0 ingredient*" ti:"tobacco 2 0 0 0 0 ingredient*" kw:"cigarette* 8 0 0 0 0 additiv*" ti:"cigarette* 3 0 0 0 0 additiv*" kw:"cigarette* 9 0 0 0 0 ingredient*" ti:"cigarette* 2 0 0 0 0 ingredient*" Total 129 0 0 0 0 Total after removal of 39 - - - - duplicates

COPAC (http://copac.ac.uk/) Main Search November January February March May 2017 2018 2018 2018 2018 Year Year Year Year published: published: published: published: 2017- 2018 2018 2018 Title words: tobacco 12 0 0 0 0 additive* Subject: tobacco 8 0 0 0 0 additive* Title words: tobacco 1 0 0 0 0 ingredient* Subject: tobacco 0 0 0 0 0 ingredient* Title words: cigarette* 3 0 0 0 0 additiv* Subject: cigarette* 0 0 0 0 0 additiv*

Kleijnen Systematic Reviews Ltd 19 Title words: cigarette* 3 0 0 0 0 ingredient* Subject: cigarette* 0 0 0 0 0 ingredient* Total 27 0 0 0 0 Total after removal of 18 - - - - duplicates

OpenGrey (http://www.opengrey.eu/) Search November January February March May 2017 2018 2018 2018 2018 year>2017 year>2018 year>2018 year>2018 tobacco additiv* 3 0 0 0 0 tobacco 0 0 0 0 0 ingredient* cigarette* 1 0 0 0 0 additiv* cigarette* 0 0 0 0 0 ingredient* Total 4 0 0 0 0 Total after 3 - - - - removal of duplicates

Google (https://www.google.co.uk) Advanced Search: this exact word or phrase; last update: past month Search terms November January February March May 2017 2018 2018 2018 2018 past year past past past month month month allinurl: tobacco 10 0 0 0 0 additives filetype:pdf allintitle: tobacco 12 1 0 0 0 additive filetype:pdf allinurl: tobacco 15 1 0 0 0 ingredients filetype:pdf allinurl: tobacco 3 0 0 0 0 ingredient filetype:pdf allinurl: cigarette 9 0 0 0 0 additives filetype:pdf allinurl: cigarette 5 0 0 0 0 additive filetype:pdf allinurl: cigarette 11 0 0 0 0 ingredients

Kleijnen Systematic Reviews Ltd 20 filetype:pdf allintitle: cigarette 9 0 0 0 1 ingredient filetype:pdf Total 74 2 0 0 1 Total after removal 21 2 - - 1 of duplicates

Library of Congress: Online Catalog (https://catalog.loc.gov/) Advanced Search November January February March May 2017 2018 2018 2018 2018 Year Year Year Year Published/ Published/ Published/ Published/ Created: Created: Created: Created: Past Year Past Year Past Year Past Year Subject: 7 0 0 0 0 Authorized (SKEY): Tobacco Additives

Citation Searches: Key studies Science Citation Index (WoS): 1988-2018/01/18 PubMed (NLM): up to 19 January 2018 Google Scholar (https://scholar.google.co.uk/): up to 19 January 2018 Searched: 19.1.18

Vanscheeuwijck PM, Teredesai A, Terpstra PM, Verbeeck J, Kuhl P, Gerstenberg B, et al. Evaluation of the potential effects of ingredients added to cigarettes. Part 4: subchronic inhalation toxicity. Food Chem Toxicol 2002;40(1):113-31.

Roemer E, Tewes FJ, Meisgen TJ, Veltel DJ, Carmines EL. Evaluation of the potential effects of ingredients added to cigarettes. Part 3: in vitro genotoxicity and cytotoxicity. Food Chem Toxicol 2002;40(1):105-11.

Rustemeier K, Stabbert R, Haussmann H, Roemer E, Carmines EL. Evaluation of the potential effects of ingredients added to cigarettes. Part 2: chemical composition of mainstream smoke. Food Chem Toxicol 2002;40(1):93-104.

Database Vanscheeuwijck Roemer Rustemeier Science Citation Index 77 76 150 PubMed 6 5 30 Google Scholar 100 115 229 Total 788 Total after deduplication 309

Citation Searches: Key studies. February update

Kleijnen Systematic Reviews Ltd 21 Science Citation Index (WoS): 1988-2018/02/16; Cited Year(s) 2018 PubMed (NLM): up to 19 February 2018; Publication date from 2018/01/01 to 2018/12/31 Google Scholar (https://scholar.google.co.uk/): up to 19 February 2018; Since 2018 Searched: 19.2.18

Database Vanscheeuwijck Roemer Rustemeier Science Citation Index 0 0 2 PubMed 0 0 1 Google Scholar 0 2 3 Total 8 Total after deduplication 5

Citation Searches: Key studies. March update Science Citation Index (WoS): 1988-2018/03/16; Cited Year(s) 2018 PubMed (NLM): up to 19 March 2018; Publication date from 2018/02/01 to 2018/12/31 Google Scholar (https://scholar.google.co.uk/): up to 19 March 2018; Since 2018 Searched: 19.3.18

Database Vanscheeuwijck Roemer Rustemeier Science Citation Index 0 2 7 PubMed 0 0 0 Google Scholar 1 2 4 Total 16 Total after deduplication 10

Citation Searches: Key studies. May update Science Citation Index (WoS): 1988-2018/05/08; Cited Year(s) 2018 PubMed (NLM): up to 8 May 2018; Publication date from 2018/03/01 to 2018/12/31 Google Scholar (https://scholar.google.co.uk/): up to 8 May 2018; Since 2018 Searched: 8.5.18

Database Vanscheeuwijck Roemer Rustemeier Science Citation Index 0 1 1 PubMed 0 0 1 Google Scholar 0 2 1 Total 6 Total after deduplication 3

Kleijnen Systematic Reviews Ltd 22 APPENDIX 2: DATABASE SEARCH RESULTS PER ADDITIVE

Additive Carob Cocoa Fenugreek Fig juice Geraniol Glycerol Guaiacol bean extract extract # Records 221 549 82 27 191 2441 968 Found Nov 2017 # 56 240 13 1 72 1095 287 Duplicates Removed # Update 1 78 0 3 12 16 4 Jan 2018 # Update 2 4 2 0 1 9 7 Feb 2018 # Update 0 0 0 1 3 12 1 Mar 2018 # Update 3 1 0 0 2 23 8 May 2018 Final # 171 323 71 30 137 1406 701 Records Additive Guar Liquorice Maltol Menthol Propylene Sorbitol Titanium gum extract glycol dioxide # Records 54 531 55 2165 1053 1557 510 Found # 12 206 23 1255 498 728 190 Duplicates Removed # Update 0 30 1 16 21 7 4 Jan 2018 # Update 1 0 1 11 13 6 7 Feb 2018 # Update 1 2 0 16 62 4 4 Mar 2018 # Update 1 3 2 16 18 4 5 May 2018 Final # 45 360 36 969 669 850 340 Records

Kleijnen Systematic Reviews Ltd 23 APPENDIX 3: LIST OF PUBLICATIONS EXCLUDED AT FULL PAPER SCREENING Publication Reason for Exclusion Abobo CV, Ma J, Liang D. Effect of menthol on nicotine Not an outcome of pharmacokinetics in rats after cigarette smoke inhalation. interest (not toxicity, Nicotine Tob Res 2012;14(7):801-8. smoke chemistry or pyrolysis) Alakayak J, Knall C. Mentholated and non-mentholated cigarettes Not an outcome of alter transepithelial electrical resistance of calu-3 human interest (not toxicity, bronchial epithelial cells. Ethn Dis 2008;18(2 Suppl 1):S145-S146. smoke chemistry or pyrolysis) Alsharari SD, King JR, Nordman JC, Muldoon PP, Jackson A, Zhu Not an outcome of AZ, et al. Effects of menthol on nicotine pharmacokinetic, interest (not toxicity, pharmacology and dependence in mice. PLoS One smoke chemistry or 2015;10(9):e0137070. pyrolysis) Anonymous. Women who smoke menthol cigarettes have greater Not an outcome of nicotine exposure. Oncology (Williston) 1999;13(7):915. interest (not toxicity, smoke chemistry or pyrolysis) Antonio AM, Lagua IJ, Hamamura FD, Liu J, Park DJ, Pokhrel P, et Not an outcome of al. Menthol cigarette smoking and obesity: is there a link? Asia interest (not toxicity, Pac J Clin Oncol 2014;10(Suppl 9):52. smoke chemistry or pyrolysis) Antonio AM, Fagan P, Hamamura FD, Lagua IJ, Liu J, Park DJ, et al. Not an outcome of Menthol cigarette smoking and obesity in young adult daily interest (not toxicity, smokers in Hawaii. Prev Med Rep 2015;2:946-52. smoke chemistry or pyrolysis) Arnarp J, Bielawski J, Dahlin BM, Dahlman O, Enzell CR, Pettersson No additive reported T. Tobacco smoke chemistry. 2. Alkyl and alkenyl substituted guaiacols found in cigarette smoke condensate. Acta Chem Scand 1989;43(1):44-50. Aulbach P. Menthol A.D.I. Brown & Williamson. Bates No. 570 312 Unobtainable 954–570 312 955, 1975 Available from: http://tobaccodocuments.org/product_design/952496.html Baker RR, Massey ED, Smith G. An overview of the effects of Included for other tobacco ingredients on smoke chemistry and toxicity. Food Chem additives but not Toxicol 2004;42 Suppl:S53-83. relevant for titanium dioxide Baker RR, Pereira da Silva JR, Smith G. The effect of tobacco Included for other ingredients on smoke chemistry. Part II: casing ingredients. Food additives but not Chem Toxicol 2004;42 Suppl:S39-52. relevant for titanium dioxide Baker RR, Bishop LJ. The pyrolysis of tobacco ingredients. J Anal Included for other Appl Pyrolysis 2004;71(1):223-311. additives but not relevant for titanium dioxide

Kleijnen Systematic Reviews Ltd 24 Publication Reason for Exclusion Baker RR, Pereira da Silva JR, Smith G. The effect of tobacco Included for other ingredients on smoke chemistry. Part I: flavourings and additives. additives but not Food Chem Toxicol 2004;42 Suppl:S3-S37. relevant for titanium dioxide Baker RR, Bishop LJ. The pyrolysis of non-volatile tobacco Included for other ingredients using a system that simulates cigarette combustion additives but not conditions. J Anal Appl Pyrolysis 2005;74(1-2):145-70. relevant for titanium dioxide Baker RR. The generation of formaldehyde in cigarettes - Not an additive of Overview and recent experiments. Food Chem Toxicol interest 2006;44(11):1799-822. Baker RR. Letter to the editor - Carbonyl compounds in cigarette Not an additive of smoke. Environ Toxicol 2006;21(6):621-2. interest Baker RR. Sugars, carbonyls and smoke. Food Chem Toxicol Not an additive of 2007;45(9):1783-6. interest Benowitz NL, Samet JM. The threat of menthol cigarettes to U.S. Included for other public health. N Engl J Med 2011;364(23):2179-81. additives but not relevant for titanium dioxide Bergner KG, Sperlich H. [Application of paper chromatography in Unobtainable the study of food products. III. Paper-chromatographic detection of glycerin and glycols in tobacco]. Mitt Geb Lebensmittelunters Hyg Trav Chim Aliment Hyg 1953;44(4):388-95. Bernson VS, Pettersson B. The toxicity of menthol in short-term Additive not contained bioassays. Chem Biol Interact 1983;46(2):233-46. in cigarettes or RYO tobacco Bethea TN, Rosenberg L, Boggs DA, Palmer JR. Menthol cigarettes Included for other in relation to breast cancer incidence in African American women. additives but not Cancer Res 2012;72(8 Suppl 1):664. relevant for titanium dioxide Blot WJ, Cohen SS, Aldrich M, McLaughlin JK, Hargreaves MK, Included for other Signorello LB. Lung cancer risk among smokers of menthol additives but not cigarettes. J Natl Cancer Inst 2011;103(10):810-6. relevant for titanium dioxide Bombick BR, Avalos JT, Putnam KP. Comparative studies on the Unobtainable genotoxic and cytotoxic potential of mainstream smoke condensate from menthol and non-menthol cigarettes which burn or primarily heat tobacco. 55th Tobacco Science Research Conference, 2001: 25. Borgerding MF, Milhous Jr LA, Hicks RD, Giles JA. Cigarette smoke Not a tobacco system composition. Part 2. Method for determining major components of interest in smoke of cigarettes that heat instead of burn tobacco. J Assoc Off Anal Chem 1990;73(4):610-5. Brinkman MC, Chuang JC, Gordon SM, Kim H, Kroeger RR, Polzin Included for other GM, et al. Exposure to and deposition of fine and ultrafine additives but not

Kleijnen Systematic Reviews Ltd 25 Publication Reason for Exclusion particles in smokers of menthol and nonmenthol cigarettes. Inhal relevant for titanium Toxicol 2012;24(5):255-69. dioxide Brooks DR, Palmer JR, Strom BL, Rosenberg L. Menthol cigarettes Included for other and risk of lung cancer. Am J Epidemiol 2003;158(7):609-16; additives but not discussion 617-20. relevant for titanium dioxide Brown B, Kolesar J, Lindberg K, Meckley D, Mosberg A, Doolittle D. No additive reported Comparative studies of DNA adduct formation in mice following dermal application of smoke condensates from cigarettes that burn or primarily heat tobacco. Mutat Res 1998;414(1-3):21-30. Brown J, DeAtley T, Welding K, Schwartz R, Chaiton M, Lawrence Not an outcome of Kittner D, et al. Tobacco industry response to menthol cigarette interest (not toxicity, bans in Alberta and Nova Scotia, Canada. Tob Control smoke chemistry or 2017;26(e1):e71-e74. pyrolysis) Brozinski M, Dölberg U, Lipp G. The determination of menthol in Not an outcome of tobacco, in filters and in the smoke of mentholated cigarettes. interest (not toxicity, Beitr Tabakforsch Int 1972;6(3):124-30. smoke chemistry or pyrolysis) Camarasa G, Alomar A. Menthol dermatitis from cigarettes. Included for other Contact Dermatitis 1978;4(3):169-70. additives but not relevant for titanium dioxide Carew B, Muir J. Cigarette allergy an ethical challenge for Not an additive of dermatologists. Australas J Dermatol 2012;53:29. interest Carmines EL. Evaluation of the potential effects of ingredients Included for other added to cigarettes. Part 1: cigarette design, testing approach, additives but not and review of results. Food Chem Toxicol 2002;40(1):77-91. relevant for titanium dioxide Carmines EL, Lemus R, Gaworski CL, Meisgen T, Rustemeier K, Van Included for other Miert E, et al. Effects of the addition of licorice extract to tobacco additives but not on the chemical composition and biological activity of cigarette relevant for titanium smoke. Paper presented at 42nd Annual Meeting of the Society of dioxide Toxicology; 9-13 Mar 2003; Salt Lake City: United States. Toxicol Sci 2003;72:387. Carmines EL, Gaworski CL, Philip Morris USA. Toxicologic Included for other evaluation of glycerin for use as a cigarette ingredient. First draft: additives but not Philip Morris USA, 2004 Available from: http://tobacco- relevant for titanium information.hpa.gov.tw/common/Download.ashx?t=CLI8001&f=8 dioxide 9400818_603/89400818_603_A0055.PDF Carmines EL, Gaworski CL. Toxicological evaluation of glycerin as a Included for other cigarette ingredient. Food Chem Toxicol 2005;43(10):1521-39. additives but not relevant for titanium dioxide Carmines EL, Lemus R, Gaworski CL. Toxicologic evaluation of Included for other licorice extract as a cigarette ingredient. Food Chem Toxicol additives but not

Kleijnen Systematic Reviews Ltd 26 Publication Reason for Exclusion 2005;43(9):1303-22. relevant for titanium dioxide Carpenter CL, Jarvik ME, Morgenstern H, McCarthy WJ, London SJ. Included for other Mentholated cigarette smoking and lung-cancer risk. Ann additives but not Epidemiol 1999;9(2):114-20. relevant for titanium dioxide Ciftci O, Topcu S, Caliskan M, Gullu H, Erdogan D, Yildirim E, et al. Unobtainable Smoking mentholated cigarettes impairs coronary microvascular function as severely as does smoking regular cigarettes. Acta Cardiol 2008;63(2):135-40. Ciftci O, Caliskan M, Gullu H, Yildirir A, Muderrisoglu H. Included for other Mentholated cigarette smoking induced alterations in left and additives but not right ventricular functions in chronic smokers. Anadolu Kardiyol relevant for titanium Derg 2008;8(2):116-22. dioxide Ciftci O, Gullu H, Caliskan M, Topcu S, Erdogan D, Yildirir A, et al. Included for other Mentholated cigarette smoking and brachial artery, carotid additives but not artery, and aortic vascular function. Turk Kardiyol Dern Ars relevant for titanium 2009;37(4):234-40. dioxide Clark PI, Gautam S, Gerson LW. Effect of menthol cigarettes on Not an outcome of biochemical markers of smoke exposure among black and white interest (not toxicity, smokers. Chest 1996;110(5):1194-8. smoke chemistry or pyrolysis) Clark TJ, Bunch JE. Qualitative and quantitative analysis of flavor Included for other additives on tobacco products using SPME-GC mass spectroscopy. additives but not J Agric Food Chem 1997;45(3):844-9. relevant for titanium dioxide Clark PI, Gardiner P. Menthol should not be given a free pass Included for other based on studies of biomarkers of toxicity. Cancer Epidemiol additives but not Biomarkers Prev 2011;20(7):1269-71. relevant for titanium dioxide Coggins CR, Ayres PH, Mosberg AT, Sagartz JW, Burger GT, Hayes Not a tobacco system AW. Ninety-day inhalation study in rats, comparing smoke from of interest cigarettes that heat tobacco with those that burn tobacco. Fundam Appl Toxicol 1989;13(3):460-83. Coggins CRE, Jerome AM, Edmiston JS, Oldham MJ. A Included for other comprehensive evaluation of the toxicology of cigarette additives but not ingredients: aliphatic carbonyl compounds. Inhal Toxicol relevant for titanium 2011;23(Suppl 1):102-18. dioxide Coggins CR, Fisher MT, Smith DC, Oldham MJ. A comprehensive Included for other evaluation of the toxicology of cigarette ingredients: cocoa- additives but not derived ingredients. Inhal Toxicol 2011;23 Suppl 1:70-83. relevant for titanium dioxide Coggins CR, Wagner KA, Werley MS, Oldham MJ. A Included for other comprehensive evaluation of the toxicology of cigarette additives but not ingredients: carbohydrates and natural products. Inhal Toxicol relevant for titanium

Kleijnen Systematic Reviews Ltd 27 Publication Reason for Exclusion 2011;23 Suppl 1:13-40. dioxide Coggins CR, Liu J, Merski JA, Werley MS, Oldham MJ. A Not an additive of comprehensive evaluation of the toxicology of cigarette interest ingredients: aliphatic and aromatic carboxylic acids. Inhal Toxicol 2011;23 Suppl 1:119-40. Coggins CR, Sena EJ, Langston TB, Oldham MJ. A comprehensive Not an additive of evaluation of the toxicology of cigarette ingredients: aromatic interest carbonyl compounds. Inhal Toxicol 2011;23 Suppl 1:90-101. Coggins CR, Edmiston JS, Jerome AM, Langston TB, Sena EJ, Smith Included for other DC, et al. A comprehensive evaluation of the toxicology of additives but not cigarette ingredients: essential oils and resins. Inhal Toxicol relevant for titanium 2011;23 Suppl 1:41-69. dioxide Coggins CR, Merski JA, Oldham MJ. A comprehensive evaluation Not an additive of of the toxicology of cigarette ingredients: heterocyclic nitrogen interest compounds. Inhal Toxicol 2011;23(Suppl 1):84-9. Coggins CR, Sena EJ, Oldham MJ. A comprehensive evaluation of Not an additive of the toxicology of cigarette ingredients: inorganic compounds. interest Inhal Toxicol 2011;23(Suppl 1):157-71. Coggins CR, Merski JA, Oldham MJ. A comprehensive evaluation Included for other of the toxicology of the "Deli" cast sheet process used in additives but not experimental cigarettes. Inhal Toxicol 2013;25 Suppl 2:64-8. relevant for titanium dioxide Cohn AM, Johnson AL, Hair E, Rath JM, Villanti AC. Menthol Not an outcome of tobacco use is correlated with mental health symptoms in a interest (not toxicity, national sample of young adults: implications for future health smoke chemistry or risks and policy recommendations. Tob Induc Dis 2016;14:1. pyrolysis) Combes R, Scott K, Crooks I, Dillon D, Meredith C, McAdam K, et Included for other al. The in vitro cytotoxicity and genotoxicity of cigarette smoke additives but not particulate matter with reduced toxicant yields. Toxicol In Vitro relevant for titanium 2013;27(5):1533-41. dioxide Curvall M, Jansson T, Pettersson B, Hedin A, Enzell CR. In vitro Not an additive of studies of biological effects of cigarette smoke condensate. I. interest Genotoxic and cytotoxic effects of neutral, semivolatile constituents. Mutat Res 1985;157(2-3):169-80. Czegeny Z, Bozi J, Sebestyen Z, Blazso M, Jakab E, Barta-Rajnai E, Included for other et al. Thermal behaviour of selected flavour ingredients and additives but not additives under simulated cigarette combustion and tobacco relevant for titanium heating conditions. J Anal Appl Pyrolysis 2016;121:190-204. dioxide Dalhamn T, Rylander R. Reduction of cigarette smoke ciliotoxicity Unobtainable by certain tobacco additives. Am Rev Respir Dis 1971;103(6):855- 7. De Souza JE, Scherbak M. The effect of glycerol added to tobacco Unobtainable on the constituents of cigarette smoke. Analyst 1964;89(1064):735-9. Department of Health and Human Services, Food and Drug Not an outcome of

Kleijnen Systematic Reviews Ltd 28 Publication Reason for Exclusion Administration. TAB B 2014-850 Deeming Final Rule Redline interest (not toxicity, Changes. Deeming Tobacco Products To Be Subject to the Federal smoke chemistry or Food, Drug, and Cosmetic Act, as Amended by the Family Smoking pyrolysis) Prevention and Tobacco Control Act; Restrictions on the Sale and Distribution of Tobacco Products and Required Warning Statements for Tobacco Products. 21 CFR Parts 1100, 1140, and 1143 [Docket No. FDA-2014-N-0189], 2016 Available from: https://www.regulations.gov/#!documentDetail;D=FDA-2014-N- 0189-83193 Department of Health and Social Security, Baron Hunter of Unobtainable Newington. First report of the independent Scientific Committee on Smoking and Health: tobacco substitutes and additives in tobacco products, their testing and marketing in the United Kingdom. London: Stationery Office, 1975. DIN. Toxicological assessment of additives for tobacco products - Unobtainable A guidance. English translation of DIN SPEC 10133:2014-09. Berlin: DIN, 2014 Dolka C, Piad‚ JJ, Jaccard G. Menthol addition to cigarettes using Included for other breakable capsules in the filter. Impact on the mainstream smoke additives but not yields of the health Canada list constituents. Chem Res Toxicol relevant for titanium 2013;26(10):1430-43. dioxide Doolittle DJ, Lee CK, Burger GT, Hayes AW. Comparative studies No relevant analysis on the genotoxic potential of sidestream smoke from cigarettes which burn or only heat tobacco. Paper presented at Fifth International Conference on Environmental Mutagens; 10-15 Jul 1989; Cleveland: United States. Environ Mol Mutagen 1989;14(Suppl 15):52. Doolittle DJ, Lee CK, Ivett JL, Mirsalis JC, Riccio E, Rudd CJ, et al. No relevant analysis Comparative studies on the genotoxic activity of mainstream smoke condensate from cigarettes which burn or only heat tobacco. Environ Mol Mutagen 1990;15(2):93-105. Doolittle DJ, Lee CK, Ivett JL, Mirsalis JC, Riccio E, Rudd CJ, et al. No relevant analysis Genetic toxicology studies comparing the activity of sidestream smoke from cigarettes which burn or only heat tobacco. Mutat Res 1990;240(2):59-72. Elmenhorst H. The identification of maltol in cigarette smoke. Not an outcome of Beitr Tabakforsch Int 1971;6(2):70-3. interest (not toxicity, smoke chemistry or pyrolysis) Ertel A, Eng R, Smith SM. The differential effect of cigarette smoke Included for other on the growth of bacteria found in humans. Chest additives but not 1991;100(3):628-30. relevant for titanium dioxide European Chemicals Agency (ECHA). CLH report. Proposal for Additive not contained Harmonised Classification and Labelling Based on Regulation (EC) in cigarettes or RYO

Kleijnen Systematic Reviews Ltd 29 Publication Reason for Exclusion No 1272/2008 (CLP Regulation), Annex VI, Part 2. International tobacco Chemical Identification: Geraniol; (2E)-3,7-dimethylocta-2,6-dien- 1-ol. EC Number: 203-377-1. CAS Number: 106-24-1, 2017 Available from: https://echa.europa.eu/documents/10162/13626/clh_rep_gerani ol_en.pdf/784d6935-cbc4-ea48-1df7-90423713b953 European Chemicals Agency (ECHA). COMMENTS AND RESPONSE Additive not contained TO COMMENTS ON CLH: PROPOSAL AND JUSTIFICATION. in cigarettes or RYO Substance name: geraniol; (2E)-3,7-dimethylocta-2,6-dien-1-ol. tobacco CAS number: 106-24-1. EC number: 203-377-1. Dossier submitter: Denmark [Internet]: European Chemicals Agency (ECHA), 2017 [accessed 19.1.18] Available from: https://echa.europa.eu/documents/10162/13626/clh_comment_ geraniol_en.pdf/66032ib0b-8c8d-029e-6498-040706373171 European Chemicals Agency (ECHA). Comments of BASF SE on the Additive not contained CLH report - Proposal for Harmonised Classification and Labelling in cigarettes or RYO of Geraniol; (2E)-3,7-dimethylocta-2,6-dien-1-ol provided by the tobacco Danish Environmental Protection Agency on 30 August 2017 [Internet]: European Chemicals Agency (ECHA), 2017 [accessed 19.1.18] Available from: https://echa.europa.eu/documents/10162/13626/clh_comment_ geraniol_attachments_en.zip/b08eb4d2-7385-f046-6935- 58a64fefcef7 Fagan P, Pokhrel P, Herzog TA, Pagano IS, Franke AA, Clanton MS, Not an outcome of et al. Nicotine metabolism in young adult daily menthol and interest (not toxicity, nonmenthol smokers. Nicotine Tob Res 2016;18(4):437-46. smoke chemistry or pyrolysis) Farsalinos KE, Romagna G, Allifranchini E, Ripamonti E, Bocchietto Not an additive of E, Todeschi S, et al. Comparison of the cytotoxic potential of interest cigarette smoke and electronic cigarette vapour extract on cultured myocardial cells. Int J Environ Res Public Health 2013;10(10):5146-62. Ferris Wayne G, Connolly GN. Application, function, and effects of Included for other menthol in cigarettes: a survey of tobacco industry documents. additives but not Nicotine Tob Res 2004;6 Suppl 1:S43-54. relevant for titanium dioxide Florin I, Rutberg L, Curvall M, Enzell CR. Screening of tobacco Not an additive of smoke constituents for mutagenicity using the Ames' test. interest Toxicology 1980;15(3):219-32. Freeman C. Avicel RCN-15. Skin sensitisation study in guinea pigs. Unobtainable Unpublished Report I91- 1216 from FMC Corporation, USA submitted to WHO (cited in JECFA, 1998), 1991 Friedman GD, Sadler M, Tekawa IS, Sidney S. Mentholated Included for other cigarettes and non-lung smoking related cancers in California, additives but not USA. J Epidemiol Community Health 1998;52(3):202. relevant for titanium

Kleijnen Systematic Reviews Ltd 30 Publication Reason for Exclusion dioxide Fujimoto H, Tsuji H, Okubo C, Fukuda I, Nishino T, Lee KM, et al. Not an additive of Biological responses in rats exposed to mainstream smoke from a interest heated cigarette compared to a conventional reference cigarette. Inhal Toxicol 2015;27(4):224-36. Gan W, Echiverri K, Smith JH. Association between overall and Included for other mentholated cigarette smoking with headache: results from the additives but not National Health and Nutrition Examination Survey 1999-2004. relevant for titanium Paper presented at 57th Annual Scientific Meeting of the dioxide American Headache Society; 18-21 Jun 2015; Washington, DC: United States. Headache 2015;55(Suppl 3):157. Gan WQ, Estus S, Smith JH. Association between overall and Included for other mentholated cigarette smoking with headache in a nationally additives but not representative sample. Headache 2016;56(3):511-8. relevant for titanium dioxide Garten S, Falkner RV. Continual smoking of mentholated Included for other cigarettes may mask the early warning symptoms of respiratory additives but not disease. Prev Med 2003;37(4):291-6. relevant for titanium dioxide Gaworski CL, Dozier MM, Gerhart JM, Rajendran N, Brennecke LH, Included for other Aranyi C, et al. 13-week inhalation toxicity study of menthol additives but not cigarette smoke. Food Chem Toxicol 1997;35(7):683-92. relevant for titanium dioxide Gaworski CL, Dozier MM, Heck JD, Gerhart JM, Rajendran N, David Included for other RM, et al. Toxicologic evaluation of flavor ingredients added to additives but not cigarette tobacco: 13-week inhalation exposures in rats. Inhal relevant for titanium Toxicol 1998;10(4):357-81. dioxide Gaworski CL, Heck JD, Bennett MB, Wenk ML. Toxicologic Included for other evaluation of flavor ingredients added to cigarette tobacco: skin additives but not painting bioassay of cigarette smoke condensate in SENCAR mice. relevant for titanium Toxicology 1999;139(1-2):1-17. dioxide Gaworski CL, Oldham MJ, Coggins CR. Toxicological considerations Included for other on the use of propylene glycol as a humectant in cigarettes. additives but not Toxicology 2010;269(1):54-66. relevant for titanium dioxide Gaworski CL, Oldham MJ, Wagner KA, Coggins CRE, Patskan GJ. An Included for other evaluation of the toxicity of 95 ingredients added individually to additives but not experimental cigarettes: approach and methods. Inhal Toxicol relevant for titanium 2011;23(Suppl 1):1-12. dioxide Gaworski CL, Wagner KA, Morton MJ, Oldham MJ. Insights from a Included for other multi-year program designed to test the impact of ingredients on additives but not mainstream cigarette smoke toxicity. Inhal Toxicol 2011;23(Suppl relevant for titanium 1):172-83. dioxide Gerharz J, Bendels MHK, Braun M, Klingelhofer D, Groneberg DA, Included for other Mueller R. Particulate matter emissions of different brands of additives but not

Kleijnen Systematic Reviews Ltd 31 Publication Reason for Exclusion mentholated cigarettes. J Air Waste Manag Assoc 2018;09:09. relevant for titanium dioxide German Cancer Research Center (DKFZ). Additives in tobacco Included for other products: contribution of carob bean extract, cellulose fibre, guar additives but not gum, liquorice, menthol, prune juice concentrate and vanillin to relevant for titanium attractiveness, addictiveness and toxicity of tobacco smoking dioxide [Internet]. Heidelberg: German Cancer Research Center (DKFZ), 2012 [accessed 17.11.17] Available from: https://www.dkfz.de/de/tabakkontrolle/download/PITOC/PITOC_ Additives_in_Tobacco_Products_Report.pdf Ghosh A, Nethery RC, Herring AH, Tarran R. Flavored little cigar Not an additive of smoke induces cytotoxicity and apoptosis in airway epithelia. Cell interest Death Discov 2017;3:17019. Glick ZR, Saedi N, Ehrlich A. Allergic contact dermatitis from Included for other cigarettes. Dermatitis 2009;20(1):6-13. additives but not relevant for titanium dioxide Gomez-Siurana A, Marcilla A, Beltran M, Martinez I, Berenguer D, Included for other Garcia-Martinez R, et al. Thermogravimetric study of the pyrolysis additives but not of tobacco and several ingredients used in the fabrication of relevant for titanium commercial cigarettes: effect of the presence of MCM-41. dioxide Thermochim Acta 2011;523(1-2):161-9. Gomez-Siurana A, Marcilla A, Beltran M, Martinez I, Berenguer D, Included for other Garcia-Martinez R, et al. Study of the oxidative pyrolysis of additives but not tobacco-sorbitol-saccharose mixtures in the presence of MCM-41. relevant for titanium Thermochim Acta 2012;530:87-94. dioxide Gomez-Siurana A, Marcilla A, Beltran M, Berenguer D, Martinez- Included for other Castellanos I, Menargues S. TGA/FTIR study of tobacco and additives but not glycerol-tobacco mixtures. Thermochim Acta 2013;573:146-57. relevant for titanium dioxide Gomez-Siurana A, Marcilla A, Beltran M, Berenguer D, Martinez- Included for other Castellanos I, Catala L, et al. TGA/FTIR study of the MCM-41- additives but not catalytic pyrolysis of tobacco and tobacco-glycerol mixtures. relevant for titanium Thermochim Acta 2014;587:24-32. dioxide Gordon SM, Brinkman MC, Meng RQ, Anderson GM, Chuang JC, Included for other Kroeger RR, et al. Effect of cigarette menthol content on additives but not mainstream smoke emissions. Chem Res Toxicol relevant for titanium 2011;24(10):1744-53. dioxide Gordon SM. Real-time measurement and uptake of carcinogens Not an outcome of by menthol cigarette smokers. Project Number: 5R01CA162085- interest (not toxicity, 02 [Internet]. RePORTER Database National Institutes of Health, smoke chemistry or 2012 [accessed 14.11.17]. Available from: pyrolysis) https://projectreporter.nih.gov/project_info_description.cfm?aid =8338913&icde=14178220 Green J, Chalmers J, Kinnard P. The transfer of tobacco additives Not an additive of

Kleijnen Systematic Reviews Ltd 32 Publication Reason for Exclusion to cigarette smoke: examination of the possible contribution of interest pyrolysis products to mainstream smoke composition. Beitr Tabakforsch Int 1989;14(5):283-8. Gullotta V, Hayes C, Martin B. The effects of nicotine and menthol Unobtainable on electrophysiology and subjective responses. June 27, 1991. Philip Morris. Bates no. 2028817734/7740, 1991 Available from: http://legacy.iibrary.uesf.edu/tid/rip12e00 Ha MA, Smith GJ, Cichocki JA, Fan L, Liu YS, Caceres AI, et al. Included for other Menthol attenuates respiratory irritation and elevates blood additives but not cotinine in cigarette smoke exposed mice. PLoS One relevant for titanium 2015;10(2):e0117128. dioxide Hahn J, Schaub J. Influence of tobacco additives on the chemical Included for other composition of mainstream smoke. Beitr Tabakforsch Int additives but not 2010;24(3):100-16. relevant for titanium dioxide Harllee GC, Leffingwell JC. Casing materials – cocoa (Part 1). Not an outcome of Tobacco International 1979;181(5):40-52. interest (not toxicity, smoke chemistry or pyrolysis) Harrison E, Biswas L, Avusula R, Zhang M, Gong Y, Liu X. Effects of Not an outcome of menthol and its interaction with nicotine-conditioned cue on interest (not toxicity, nicotine-seeking behavior in rats. Psychopharmacology (Berl) smoke chemistry or 2017;234(23-24):3443-53. pyrolysis) Hebert JR, Kabat GC. Menthol cigarettes and esophageal cancer. Included for other Am J Public Health 1988;78(8):986-7. additives but not relevant for titanium dioxide Hebert JR, Kabat GC. Menthol cigarette smoking and oesophageal Included for other cancer. Int J Epidemiol 1989;18(1):37-44. additives but not relevant for titanium dioxide Hebert JR. Invited commentary: menthol cigarettes and risk of Included for other lung cancer. Am J Epidemiol 2003;158(7):617-20. additives but not relevant for titanium dioxide Heck JD, Gaworski CL, Rajendran N, Morrissey RL. Toxicologic Included for other evaluation of humectants added to cigarette tobacco: 13-week additives but not smoke inhalation study of glycerin and propylene glycol in Fischer relevant for titanium 344 rats. Inhal Toxicol 2002;14(11):1135-52. dioxide Heck JD. Smokers of menthol and nonmenthol cigarettes exhibit Included for other similar levels of biomarkers of smoke exposure.[Erratum appears additives but not in Cancer Epidemiol Biomarkers Prev. 2009 Jul;18(7):2155]. relevant for titanium Cancer Epidemiol Biomarkers Prev 2009;18(2):622-9. dioxide Heck JD. A review and assessment of menthol employed as a Included for other cigarette flavoring ingredient. Food Chem Toxicol 2010;48 Suppl additives but not

Kleijnen Systematic Reviews Ltd 33 Publication Reason for Exclusion 2:S1-38. relevant for titanium dioxide Heck JD, Hamm J, L.A., Lauterbach JH, Non-Voting Industry Included for other Representatives of the Tobacco Products Scientific Advisory additives but not Committee. Industry menthol report. Menthol cigarettes: no relevant for titanium disproportionate impact on public health: US Food and Drug dioxide Administration 2011 Henderson BJ, Wall TR, Henley BM, Kim CH, Nichols WA, Moaddel Additive not contained R, et al. Menthol alone upregulates midbrain nAChRs, alters in cigarettes or RYO nAChR subtype stoichiometry, alters dopamine neuron firing tobacco frequency, and prevents nicotine reward. J Neurosci 2016;36(10):2957-74. Highstein B, Zeligman I. Nonthrombocytopenic purpura caused by Included for other mentholated cigarettes. JAMA 1951;146(9):816. additives but not relevant for titanium dioxide Hoffman AC. The health effects of menthol cigarettes as Included for other compared to non-menthol cigarettes. Tob Induc Dis 2011;9 Suppl additives but not 1:S7. relevant for titanium dioxide Hooper MW, Zhao W, Byrne MM, Davila E, Caban-Martinez A, Not an outcome of Dietz NA, et al. Menthol cigarette smoking and health, Florida interest (not toxicity, 2007 BRFSS. Am J Health Behav 2011;35(1):3-14. smoke chemistry or pyrolysis) Hu B, Wang S, Xie F, Liu H. [Application of high performance liquid Not an outcome of chromatography-evaporative light scattering detection in interest (not toxicity, determination of water-soluble sugars and sorbitol in tobacco smoke chemistry or flavourings and casings]. Se Pu 2012;30(3):298-303. pyrolysis) Hughes MH, Lott KF, Heck JD. Estimation of the retention of Not an outcome of menthol in the respiratory tract of menthol cigarette smokers: a interest (not toxicity, pilot study. Beitr Tabakforsch Int 2014;26(1):26-33. smoke chemistry or pyrolysis) Illinois Institute of Technology Research Institute (IITRI). 90-day Unobtainable rat inhalation toxicity study of the mainstream smoke from cigarettes containing target levels of 0, 10,000, 20,000 or 40,000 ppm of cocoa. Volumes I to III. Final Report, IITRI Project Number 8739-117-001. Chicago: IITRI, 2006 Inaba Y, Uchiyama S, Kunugita N. Spectrophotometric No relevant determination of ammonia levels in tobacco fillers of and comparator sidestream smoke from different cigarette brands in Japan. Environ Health Prev Med 2018;23(1):15. Intorp M, Pani J, Blumenstock M. Influence of tobacco additives Included for other on the chemical composition of mainstream smoke: additional additives but not analysis of three tobacco industry based laboratories. Beitr relevant for titanium Tabakforsch Int 2010;24(3):139-44. dioxide

Kleijnen Systematic Reviews Ltd 34 Publication Reason for Exclusion Iqbal D, Khan A, Ansari IA, Khan MS. Investigating the role of novel Not an additive of bioactive compound from ficus virens ait on cigarette smoke interest induced oxidative stress and hyperlipidemia in rats. Iran J Pharm Res 2017;16(3):1089-1103. Ishiguro S, Sugawara S. Gas chromatographic analysis of cigarette Not an additive of smoke by trimethylsilylation method. Beitr Tabakforsch Int interest 1978;9(4):218-21. IUCLID. IUCLID Dataset. Carob gum (9000-40-2). 2000. Unobtainable IUCLID. IUCLID Dataset. Geraniol (106-24-1). 2000. Unobtainable IUCLID. IUCLID Dataset. Glycerol (56-81-5). 2000. Unobtainable IUCLID. IUCLID Dataset. Guaiacol (90-05-1). 2000. Unobtainable Jansson T, Curvall M, Hedin A, Enzell CR. In vitro studies of Included for other biological effects of cigarette smoke condensate. II. Induction of additives but not sister-chromatid exchanges in human lymphocytes by weakly relevant for titanium acidic, semivolatile constituents. Mutat Res 1986;169(3):129-39. dioxide Jansson T, Curvall M, Hedin A, Enzell CR. In vitro studies of the Not an additive of biological effects of cigarette smoke condensate. III. Induction of interest SCE by some phenolic and related constituents derived from cigarette smoke. A study of structure-activity relationships. Mutat Res 1988;206(1):17-24. Jarvik ME, Tashkin DP, Caskey NH, McCarthy WJ, Rosenblatt MR. Included for other Mentholated cigarettes decrease puff volume of smoke and additives but not increase carbon monoxide absorption. Physiol Behav relevant for titanium 1994;56(3):563-70. dioxide Jenkins RWJ, Newman RH, Chavis MK. Cigarette smoke formation Included for other studies: II. Smoke distribution and mainstream pyrolytic additives but not composition of added 14C-menthol (U). Beitr Tabakforsch Int relevant for titanium 1970;5(6):299-301. dioxide Jöckel K-H, Pohlabeln H, Jahn I. S15.2: use of menthol cigarettes Included for other and risk of lung cancer. Paper presented at the Joint Meeting of additives but not the IBS-DR and the DAE; 16-19 Mar 2004; Heidelberg: Germany. relevant for titanium Biom J 2004;46(Suppl 1):33. dioxide Jones MR, Apelberg BJ, Navas-Acien A. Smoking, menthol Included for other cigarettes and peripheral arterial disease in the 1999- 2004 additives but not national health and nutrition examination survey (NHANES). relevant for titanium Circulation 2012;125(10 Suppl 1):AP144. dioxide Jones MR, Tellez-Plaza M, Navas-Acien A. Smoking, menthol Included for other cigarettes and all-cause, cancer and cardiovascular mortality: additives but not evidence from the National Health and Nutrition Examination relevant for titanium Survey (NHANES) and a meta-analysis. PLoS One dioxide 2013;8(10):e77941. Jones MR, Apelberg BJ, Samet JM, Navas-Acien A. Smoking, Included for other menthol cigarettes, and peripheral artery disease in U.S. adults. additives but not Nicotine Tob Res 2013;15(7):1183-9. relevant for titanium dioxide

Kleijnen Systematic Reviews Ltd 35 Publication Reason for Exclusion Jordt SE, Willis DN, Liu B, Morris JB. Menthol attenuates Not an outcome of respiratory irritation responses to multiple cigarette smoke interest (not toxicity, irritants. Am J Respir Crit Care Med 2012;185. smoke chemistry or pyrolysis) Jordt SE, Ha MA, Smith GJ, Cichocki JA, Balakrishna S, Fan L, et al. Not an outcome of Menthol attenuates chemosensory irritation and elevates blood interest (not toxicity, cotinine in cigarette smoke exposed mice. Chem Senses smoke chemistry or 2015;40(7):596. pyrolysis) Kabat GC, Hebert JR. Use of mentholated cigarettes and lung Included for other cancer risk. Cancer Res 1991;51(24):6510-3. additives but not relevant for titanium dioxide Kabat GC, Hebert JR. Use of mentholated cigarettes and Included for other oropharyngeal cancer. Epidemiology 1994;5(2):183-8. additives but not relevant for titanium dioxide Kabat GC, Shivappa N, Hebert JR. Mentholated cigarettes and Not an outcome of smoking-related cancers revisited: an ecologic examination. Regul interest (not toxicity, Toxicol Pharmacol 2012;63(1):132-9. smoke chemistry or pyrolysis) Kabbani N. Not so Cool? Menthol's discovered actions on the Not an outcome of nicotinic receptor and its implications for nicotine addiction. Front interest (not toxicity, Pharmacol 2013;4:95. smoke chemistry or pyrolysis) Kahnert S, Nair U, Mons U, Potschke-Langer M. [Effects of Included for other menthol as an additive in tobacco products and the need for additives but not regulation]. Bundesgesundheitsblatt Gesundheitsforschung relevant for titanium Gesundheitsschutz 2012;55(3):409-15. dioxide Kaur G, Muthumalage T, Rahman I. Mechanisms of toxicity and Not a tobacco system biomarkers of flavoring and flavor enhancing chemicals in of interest emerging tobacco and non-tobacco products. Toxicol Lett 2018;288:143-55. Kienhuis AS, Staal YCM, Soeteman-Hernández LG, van de Nobelen Not an additive of S, Talhout R. A test strategy for the assessment of additive interest attributed toxicity of tobacco products. Food Chem Toxicol 2016;94:93-102. Kim HS, Pack EC, Koo YJ, Lee YJ, Sung DK, Lee SH, et al. Not an outcome of Quantitative analysis of menthol and identification of other interest (not toxicity, flavoring ingredients in capsule cigarettes marketed in Korea. smoke chemistry or Regul Toxicol Pharmacol 2018;92:420-8. pyrolysis) Klus H, Scherer G, Müller L. Influence of additives on cigarette Included for other related health risks. Beitr Tabakforsch Int 2012;25(3):411-93. additives but not relevant for titanium dioxide Klus H, Scherer G, Müller L. Executive summary - influence of Included for other

Kleijnen Systematic Reviews Ltd 36 Publication Reason for Exclusion additives on cigarette related health risks. Beitr Tabakforsch Int additives but not 2012;25(3):492-3. relevant for titanium dioxide Kogel U, Titz B, Schlage WK, Nury C, Martin F, Oviedo A, et al. Not a tobacco system Evaluation of the Tobacco Heating System 2.2. Part 7: systems of interest toxicological assessment of a mentholated version revealed reduced cellular and molecular exposure effects compared with mentholated and non-mentholated cigarette smoke. Regul Toxicol Pharmacol 2016;81 Suppl 2:S123-S138. Kogel U, Titz B, Schlage WK, Nury C, Martin F, Oviedo A, et al. No relevant Systems toxicological assessment of the mentholated Tobacco comparator Heating System 2.2 aerosol revealed reduced cellular and molecular exposure effects compared with cigarette smoke. Toxicol Lett 2016;259:S228. Kostygina G, Glantz SA, Ling PM. Tobacco industry use of flavours Not an outcome of to recruit new users of little cigars and cigarillos. Tob Control interest (not toxicity, 2016;25(1):66-74. smoke chemistry or pyrolysis) Kröller E. Ergebnisse von schwelversuchen an zusatzstoffenzu Unobtainable tabakwaren. 3. Mitteilung (pflanzlicheschleim- und gummiarten). Dtsch. Lebensm.-Rundsch. 1965;61:150-5. Laurene AH, Cundiff RH, Greene GH. Determination of glycerol Unobtainable and propylene glycol in cigarette smoke. Tob Sci 1965;9:1-4. Lebrun S, Oviedo A, Ho J, Wei Teck T, Kogel U, Patrice L, et al. No relevant Toxicological assessment of the mentholated heat-not-burn comparator product THS2.2 in a 90-day inhalation study complemented with systems toxicology. Naunyn Schmiedebergs Arch Pharmacol 2017;390:S72. Lee CK, Doolittle DJ, Burger GT, Hayes AW. Comparative No relevant analysis genotoxicity testing of mainstream whole smoke from cigarettes which burn or only heat tobacco. Paper presented at Fifth International Conference on Environmental Mutagens; 10-15 Jul 1989; Cleveland: United States. Environ Mol Mutagen 1989;14(Suppl 15):112. Lee CK, Doolittle DJ, Burger GT, Hayes AW. Comparative Not a tobacco system genotoxicity testing of mainstream whole smoke from cigarettes of interest which burn or heat tobacco. Mutat Res 1990;242(1):37-45. Lee PN. Systematic review of the epidemiological evidence Included for other comparing lung cancer risk in smokers of mentholated and additives but not unmentholated cigarettes. BMC Pulm Med 2011;11:18. relevant for titanium dioxide Lempert LK, Yerger V, Glantz SA. Letter by Lempert et al regarding Included for other article, "Menthol and nonmenthol cigarette smoking: all-cause additives but not deaths, cardiovascular disease deaths, and other causes of death relevant for titanium among blacks and whites". Circulation 2016;134(9):e119-20. dioxide

Kleijnen Systematic Reviews Ltd 37 Publication Reason for Exclusion Leverette RD. Comparison of the bacterial mutagenicity of Included for other mainstream whole smoke from cigarettes with different levels of additives but not menthol. Paper presented at 50th Annual Meeting of the Society relevant for titanium of Toxicology; 6-10 Mar 2011; Washington DC: United States. dioxide 2011. Li F, Dong X, Yan G, Xie Q. Effects of licorice flavonoids and Included for other liquiritin apioside on cigarette smoke extract induced cell toxicity, additives but not IL-8 and MUC5AC MRNA expression in the human small airway relevant for titanium epithelial cell NCI-H292. Am J Respir Crit Care Med 2010;181(1 dioxide MeetingAbstracts). Li X, Luo Y, Jiang X, Zhang H, Zhu F, Hu S, et al. Chemical analysis Not an additive of and simulated pyrolysis of tobacco heating system 2.2 compared interest to conventional cigarettes. Nicotine Tob Res 2018;08:08. Lin AH, Liu MH, Ko HB, Perng DW, Lee TS, Kou YR. Inflammatory Not an outcome of effects of menthol vs. non-menthol cigarette smoke extract on interest (not toxicity, human lung epithelial cells: a double-hit on TRPM8 by reactive smoke chemistry or oxygen species and menthol. Front Physiol 2017;8:263. pyrolysis) Liu C. Glycerol transfer in cigarette mainstream smoke. Beitr Included for other Tabakforsch Int 2004;21(2):111-6. additives but not relevant for titanium dioxide Liu BY, Lin YJ, Lee HF, Ho CY, Ruan T, Kou YR. Menthol suppresses Additive not contained laryngeal C-fiber hypersensitivity to cigarette smoke in a rat in cigarettes or RYO model of gastroesophageal reflux disease: the role of TRPM8. J tobacco Appl Physiol 2015;118(5):635-45. Ludicke F, Baker G, Magnette J, Picavet P, Weitkunat R. Reduced Not an additive of exposure to harmful and potentially harmful smoke constituents interest with the tobacco heating system 2.1. Nicotine Tob Res 2017;19(2):168-75. Ludicke F, Picavet P, Baker G, Haziza C, Poux V, Lama N, et al. Not a tobacco system Effects of switching to the menthol tobacco heating system 2.2, of interest smoking abstinence, or continued cigarette smoking on clinically relevant risk markers: a randomized, controlled, open-label, multicenter study in sequential confinement and ambulatory settings (Part 2). Nicotine Tob Res 2018;20(2):173-82. MacDougall JM, Fandrick K, Zhang X, Serafin SV, Cashman JR. Additive not contained Inhibition of human liver microsomal (S)-nicotine oxidation by (-)- in cigarettes or RYO menthol and analogues. Chem Res Toxicol 2003;16(8):988-93. tobacco Malberg K. [Do menthol cigarettes additionally increase the risk of Included for other stroke? Commentary]. MMW-Fortschritte der Medizin additives but not 2012;154(8):36. relevant for titanium dioxide Manek RA, Sheth NR, Chavda JR, Vaghasiya JD, Modi KP, Patel DV. Additive not contained Liquorice exaggerates protective action of Solanum in cigarettes or RYO xanthocarpum against cigarette smoke induced pulmonary tobacco

Kleijnen Systematic Reviews Ltd 38 Publication Reason for Exclusion inflammation. Planta Med 2014;80(10):839. Marcilla A, Gómez-Siurana A, Beltrán MI, Martínez Castellanos I, Included for other Berenguer Muñoz D, García Martínez R, et al. Catalytic effect of additives but not MCM-41 in the pyrolysis of tobacco and several substances used relevant for titanium as additives in the preparation of commercial cigarettes. dioxide Comunicación presentada en forma de póster en el "12th Mediterranean Congress of Chemical Engineering", Barcelona (Spain), November 15-18, 2011. Ingeniería Química 2011. Marcilla A, Gómez-Siurana A, Beltrán MI, Martínez Castellanos I, Included for other Berenguer Muñoz D, García Martínez R, et al. Thermogravimetric additives but not analysis of the pyrolysis of several materials used in the relevant for titanium preparation of commercial cigarettes. Comunicación presentada dioxide en forma de póster en el "12th Mediterranean Congress of Chemical Engineering", Barcelona (Spain), November 15-18, 2011. Ingeniería Química 2011. Martínez Castellanos I. Estudio del efecto de la presencia de Not an additive of diferentes catalizadores sobre la composición del humo del interest tabaco: síntesis y modificación de catalizadores: Universidad de Alicante; 2011. Martins SDdS. Caracterização de fumo inalável de cigarro quanto Not an additive of a alguns compostos orgânicos voláteis e muito voláteis: interest Universidade do Porto; 2008. McGrath TE, Brown AP, Meruva NK, Chan WG. Phenolic Not an additive of compound formation from the low temperature pyrolysis of interest tobacco. J Anal Appl Pyrolysis 2009;84(2):170-8. Merckel C, Pragst F, Ratzinger A, Aebi B, Bernhard W, Sporkert F. Not an outcome of Application of headspace solid phase microextraction to interest (not toxicity, qualitative and quantitative analysis of tobacco additives in smoke chemistry or cigarettes. J Chromatogr A 2006;1116(1-2):10-9. pyrolysis) Merckel C, Pragst F. Tobacco additives in cigarettes - Intended Included for other purpose and potential of danger. J Verbrauch Lebensm additives but not 2007;2(3):287-301. relevant for titanium dioxide Meruva N, Smith M, Plunkett S. Quantitative determination of Included for other menthol in a single puff of mainstream cigarette smoke. Beitr additives but not Tabakforsch Int 2013;25(5):528-34. relevant for titanium dioxide Miguez-Burbano MJ, Rosenberg R, Malow R, Burbano X, Devieux Not an outcome of J, Madhavan N. The effect of mentholated cigarette use on interest (not toxicity, interleukin-6 responses across different HIV positive race/ethnic smoke chemistry or subgroups. Int J Interferon Cytokine Mediat Res 2010;2(1):157-64. pyrolysis) Miguez-Burbano MJ, Vargas M, Quiros C, Lewis JE, Espinoza L, Included for other Deshratan A. Menthol cigarettes and the cardiovascular risks of additives but not people living with HIV. J Assoc Nurses AIDS Care 2014;25(5):427- relevant for titanium 35. dioxide

Kleijnen Systematic Reviews Ltd 39 Publication Reason for Exclusion Miki K, Miki M, Nakamura Y, Suzuki Y, Okano Y, Ogushi F, et al. Not an outcome of Early-phase neutrophilia in cigarette smoke-induced acute interest (not toxicity, eosinophilic pneumonia. Intern Med 2003;42(9):839-45. smoke chemistry or pyrolysis) Miller GE, Jarvik ME, Caskey NH, Segerstrom SC, Rosenblatt MR, Not an outcome of McCarthy WJ. Cigarette mentholation increases smokers' exhaled interest (not toxicity, carbon monoxide levels. Exp Clin Psychopharmacol 1994;2(2):154- smoke chemistry or 60. pyrolysis) Moldoveanu S, Coleman WI. The influence of a humectant on the Not an outcome of retention by humans of solanesol from cigarette smoke (part 1, interest (not toxicity, propylene glycol). Beitr Tabakforsch Int 2008;23(3):153-9. smoke chemistry or pyrolysis) Moldoveanu S, Coleman WI. The influence of a humectant on the Not an outcome of retention by humans of solanesol from cigarette smoke (part 2, interest (not toxicity, glycerin). Beitr Tabakforsch Int 2009;23(6):378-83. smoke chemistry or pyrolysis) Montoya A, March C, Mocholi A, Abad A, Manclus JJ, Ferrero JM. Not an outcome of Electrochemical assays based on enzyme-electrode systems to interest (not toxicity, determine glycerol and propylene-glycol in tobacco casing. Sens smoke chemistry or Actuator B-Chem 1993;16(1-3):429-34. pyrolysis) Moolchan ET, Hudson DL, Schroeder JR, Sehnert SS. Heart rate No relevant and blood pressure responses to tobacco smoking among African- comparator American adolescents. J Natl Med Assoc 2004;96(6):767-71. Müller L, Röper W. Commentary: it ain’t necessarily so. Beitr Not an outcome of Tabakforsch Int 2000;19(2):51-4. interest (not toxicity, smoke chemistry or pyrolysis) Munafo M. Understanding the role of additives in tobacco Not an outcome of products. Nicotine Tob Res 2016;18(7):1545. interest (not toxicity, smoke chemistry or pyrolysis) Munro HM, Tarone RE, Wang TJ, Blot WJ. Menthol and Included for other nonmenthol cigarette smoking: all-cause deaths, cardiovascular additives but not disease deaths, and other causes of death among blacks and relevant for titanium whites. Circulation 2016;133(19):1861-6. dioxide Murray RP, Connett JE, Skeans MA, Tashkin DP. Menthol Included for other cigarettes and health risks in Lung Health Study data. Nicotine Tob additives but not Res 2007;9(1):101-7. relevant for titanium dioxide Muscat JE. Menthol cigarettes and lung cancer mortality. Nicotine Included for other Tob Res 2012;14(10):1246-7; author reply 1248. additives but not relevant for titanium dioxide National Institute for Public Health and the Environment (RIVM). Included for other Tobacco additives: information for professionals [Internet]. additives but not

Kleijnen Systematic Reviews Ltd 40 Publication Reason for Exclusion Bilthoven, The Netherlands: National Institute for Public Health relevant for titanium and the Environment (RIVM), 2012 [accessed 22.01.18] Available dioxide from: https://www.rivm.nl/Documenten_en_publicaties/Algemeen_Act ueel/Brochures/Leefstijl_Voeding/Tobacco_additives_information _for_professionals Nesemann E, Seehofer F. The determination of tobacco additives Not an outcome of 2nd report: a method for series analyses of menthol in tobacco interest (not toxicity, and tobacco products. Beitr Tabakforsch Int 1972;6(3):131-3. smoke chemistry or pyrolysis) Noriyasu A, Konishi T, Mochizuki S, Sakurai K, Tanaike Y, Included for other Matsuyama K, et al. Menthol-enhanced cytotoxicity of cigarette additives but not smoke demonstrated in two bioassay models. Tob Induc Dis relevant for titanium 2013;11(1):18. dioxide Ogura N, Kono Y, To M, Mikami S, Soeda S, Hara H, et al. Menthol- Included for other flavored cigarettes: potentially a strong trigger of acute additives but not eosinophilic pneumonia. Am J Med 2017;130(2):e63-e64. relevant for titanium dioxide Okuyemi KS, Lawrence D, Hammons G, Alexander LA. Use of Included for other mentholated cigarettes: what can we learn from national data additives but not sets? Addiction 2010;105 Suppl 1:1-4. relevant for titanium dioxide Oviedo A, Lebrun S, Kogel U, Ho J, Tan WT, Titz B, et al. Evaluation Not an outcome of of the Tobacco Heating System 2.2. Part 6: 90-day OECD 413 rat interest (not toxicity, inhalation study with systems toxicology endpoints demonstrates smoke chemistry or reduced exposure effects of a mentholated version compared pyrolysis) with mentholated and non-mentholated cigarette smoke. Regul Toxicol Pharmacol 2016;81 Suppl 2:S93-S122. Oviedo A, Lebrun S, Ho J, Tan WT, Kogel U, Leroy P, et al. Not an outcome of Toxicological assessment of the mentholated Tobacco Heating interest (not toxicity, System 2.2 - A modified risk tobacco product - In a 90-day smoke chemistry or inhalation study complemented with systems toxicology. Toxicol pyrolysis) Lett 2016;259:S227. Pacheco Y. [Cigarette smoking]. Rev Med (Paris) 1980;21(19- Not an additive of 20):1017-20. interest Pappas RS, Gray N, Gonzalez-Jimenez N, Fresquez M, Watson CH. No relevant Triple Quad-ICP-MS measurement of toxic metals in mainstream comparator cigarette smoke from spectrum research cigarettes. J Anal Toxicol 2016;40(1):43-8. Park SJ, Foreman MG, Demeo DL, Bhatt SP, Hansel NN, Wise RA, Included for other et al. Menthol cigarette smoking in the COPDGene cohort: additives but not relationship with COPD, comorbidities and CT metrics. relevant for titanium Respirology 2015;20(1):108-14. dioxide Park S, Suh Y, Lee Y, Lee H, Kim S, Choe Y, et al. Relationship of Included for other menthol cigarett smoking with COPD, comorbidities, and CT additives but not

Kleijnen Systematic Reviews Ltd 41 Publication Reason for Exclusion metrics. Am J Respir Crit Care Med 2015;191:A2856. relevant for titanium dioxide Parrish ME, Lyons-Hart JL, Shafer KH. Puff-by-puff and intrapuff Not an outcome of analysis of cigarette smoke using infrared spectroscopy. Vib interest (not toxicity, Spectrosc 2001;27(1):29-42. smoke chemistry or pyrolysis) Paschke M, Hutzler C, Henkler F, Luch A. Oxidative and inert Included for other pyrolysis on-line coupled to gas chromatography with mass additives but not spectrometric detection: on the pyrolysis products of tobacco relevant for titanium additives. Int J Hyg Environ Health 2016;219(8):780-91. dioxide Paumgartten FJR, Gomes-Carneiro MR, de Oliveira A. The impact Included for other of tobacco additives on cigarette smoke toxicity: a critical additives but not appraisal of tobacco industry studies. Cad Saude Publica relevant for titanium 2017;33:21. dioxide Perreault D. [Menthol cigarettes]. Perspect Infirm 2015;12(5):12. Not an outcome of interest (not toxicity, smoke chemistry or pyrolysis) Philip Morris USA. Guar gum summary of evaluation for use as a Included for other cigarette ingredient [Internet]: Philip Morris, 2002 [accessed additives but not 31.1.18] Available from: relevant for titanium https://www.industrydocumentslibrary.ucsf.edu/tobacco/docs/sq dioxide vn0021 Picavet P, Haziza C, Lama N, Donelli A, Baker G, Ancerewicz J, et Not an outcome of al. Reduced exposure to harmful and potentially harmful interest (not toxicity, constituents after 90 days of use of tobacco heating system 2.2 in smoke chemistry or Japan: a comparison with continued combustible cigarette use or pyrolysis) smoking abstinence. Toxicol Lett 2016;258:S89. Pickworth WB, Moolchan ET, Berlin I, Murty R. Sensory and Included for other physiologic effects of menthol and non-menthol cigarettes with additives but not differing nicotine delivery. Pharmacol Biochem Behav 2002;71(1- relevant for titanium 2):55-61. dioxide Pletcher MJ, Hulley BJ, Houston T, Kiefe CI, Sidney S. Are Included for other mentholated cigarettes more addictive or more harmful than additives but not non-mentholated cigarettes? Results from CARDIA. Circulation relevant for titanium 2005;111(14):E239-40. dioxide Pletcher MJ, Hulley BJ, Houston T, Kiefe CI, Benowitz N, Sidney S. Included for other Menthol cigarettes, smoking cessation, atherosclerosis, and additives but not pulmonary function: the Coronary Artery Risk Development in relevant for titanium Young Adults (CARDIA) Study. Arch Intern Med dioxide 2006;166(17):1915-22. Potts RJ, Meckley DR, Shreve WK, Pence DH, Ayres PH, Doolittle D, Included for other et al. Comparative 13-week inhalation study of cigarette smoke additives but not from cigarettes containing cast sheet tobacco. Inhal Toxicol relevant for titanium 2007;19(8):701-24. dioxide

Kleijnen Systematic Reviews Ltd 42 Publication Reason for Exclusion Potts RJ, Bombick BR, Meckley DR, Ayres PH, Pence DH. A Included for other summary of toxicological and chemical data relevant to the additives but not evaluation of cast sheet tobacco. Exp Toxicol Pathol relevant for titanium 2010;62(2):117-26. dioxide Pritchard WS, Houlihan ME, Guy TD, Robinson JH. Little evidence Included for other that "denicotinized" menthol cigarettes have pharmacological additives but not effects: an EEG/heart-rate/subjective-response study. relevant for titanium Psychopharmacology (Berl) 1999;143(3):273-9. dioxide Product Integrity Philip Morris USA. Evaluation of glycerol for use Included for other as a cigarette ingredient. Prepared by Product Integrity Philip additives but not Morris USA: Product Integrity Philip Morris USA, 2001 Available relevant for titanium from: http://tobacco- dioxide information.hpa.gov.tw/common/Download.ashx?t=CLI8001&f=2 4562233/24562233_A0004.PDF Purkis SW, Müller C, Introp M. The fate of ingredients in and Included for other impact on cigarette smoke. Food Chem Toxicol 2011;49(12):3238- additives but not 48. relevant for titanium dioxide Putnam KP, Bombick DW, Doolittle DJ. Use of the neutral red Unobtainable cytotoxicity assay to determine the cytotoxic potential of cigarette smoke condensate from menthol and non-menthol eclipse and tobacco-burning cigarettes; R.J. Reynolds Tobacco Company, Research and Development Report, 2000, Document No. EMT2000 0223, 2000 Available from: http://legacy.library.ucsf.edu/tid/ehh07h00 R. J. Reynolds Tobacco Company. Chemical and biological analyses Unobtainable of the smoke of menthol and non-menthol cigarettes. Winston- Salem, North Carolina: R.J. Reynolds Tobacco Company, 2000 Rabinoff M, Caskey N, Rissling A, Park C. Pharmacological and Included for other chemical effects of cigarette additives. Am J Public Health additives but not 2007;97(11):1981-91. relevant for titanium dioxide Rakieten N, Rakieten ML, Feldman D, Boykin MJ, Jr. Mammalian Included for other ciliated respiratory epithelium; studies with particular reference additives but not to effects of menthol, nicotine, and smoke of mentholated and relevant for titanium nonmentholated cigarettes. AMA Arch Otolaryngol dioxide 1952;56(5):494-503. Renne RA, Yoshimura H, Yoshino K, Lulham G, Minamisawa S, Included for other Tribukait A, et al. Effects of flavoring and casing ingredients on the additives but not toxicity of mainstream cigarette smoke in rats. Inhal Toxicol relevant for titanium 2006;18(9):685-706. dioxide Richardson TL. African-American smokers and cancers of the lung Included for other and of the upper respiratory and digestive tracts. Is menthol part additives but not of the puzzle? West J Med 1997;166(3):189-94. relevant for titanium dioxide

Kleijnen Systematic Reviews Ltd 43 Publication Reason for Exclusion RJ Reynolds. Summary of gums [Internet]: RJ Reynolds, 1993 Included for other [accessed 31.1.18] Available from: additives but not https://www.industrydocumentslibrary.ucsf.edu/tobacco/docs/m relevant for titanium xxj0092 dioxide Rodgman A. Some studies of the effects of additives on cigarette Included for other mainstream smoke properties. II. Casing materials and additives but not humectants. Beitr Tabakforsch Int 2002;20(4):279-99. relevant for titanium dioxide Rodgman A. Some studies of the effects of additives on cigarette Included for other mainstream smoke properties. I. Flavorants. Beitr Tabakforsch Int additives but not 2002;20(2):83-103. relevant for titanium dioxide Rodgman A. Some studies of the effects of additives on cigarette Included for other mainstream smoke properties. III. Ingredients reportedly used in additives but not various commercial cigarette products in the USA and elsewhere. relevant for titanium Beitr Tabakforsch Int 2004;21(2):47-104. dioxide Roemer E, Hackenberg U. Mouse skin bioassay of smoke Included for other condensates from cigarettes containing different levels of cocoa. additives but not Food Addit Contam 1990;7(4):563-9. relevant for titanium dioxide Roemer E, Rustenmeier K, Vanscheeuwijck PM, Meisgen TJ, Veltel Unobtainable DJ, Haussmann H, et al. Effects of the addition of flavor ingredients to tobacco on the chemical composition and biological activity of cigarette smoke (abstract #77). Paper presented at 39th Annual Meeting of the Society of Toxicology; 19-23 Mar 2000; Philadelphia: United States. The Toxicologist 2000;54(1):16. Roemer E, Tewes FJ, Meisgen TJ, Veltel DJ, Carmines EL. Included for other Evaluation of the potential effects of ingredients added to additives but not cigarettes. Part 3: in vitro genotoxicity and cytotoxicity. Food relevant for titanium Chem Toxicol 2002;40(1):105-11. dioxide Roemer E, Wittke S, TrellesSticken E, Piade JJ, Bonk T, Schorp MK. Included for other The addition of cocoa, glycerol, and saccharose to the tobacco of additives but not cigarettes: implications for smoke chemistry, in vitro cytotoxicity, relevant for titanium mutagenicity and further endpoints. Beitr Tabakforsch Int dioxide 2010;24(3):117-38. Roemer E, Schorp MK, Piadé JJ, Seeman JI, Leyden DE, Haussmann Not an additive of HJ. Scientific assessment of the use of sugars as cigarette tobacco interest ingredients: a review of published and other publicly available studies. Crit Rev Toxicol 2012;42(3):244-78. Roemer E, Dempsey R, Hirter J, Deger Evans A, Weber S, Ode A, et Included for other al. Toxicological assessment of kretek cigarettes. Part 6: the additives but not impact of ingredients added to kretek cigarettes on smoke relevant for titanium chemistry and in vitro toxicity. Regul Toxicol Pharmacol 2014;70 dioxide Suppl 1:S66-80. Rostron B. Response to "menthol cigarettes and lung cancer Included for other

Kleijnen Systematic Reviews Ltd 44 Publication Reason for Exclusion mortality". Nicotine Tob Res 2012;14(10):1248. additives but not relevant for titanium dioxide Rostron B. Lung cancer mortality risk for U.S. menthol cigarette Included for other smokers. Nicotine Tob Res 2012;14(10):1140-4. additives but not relevant for titanium dioxide Rostron B. Methodology, menthol, and mortality. Nicotine Tob Included for other Res 2013;15(2):619. additives but not relevant for titanium dioxide Rostron B. Menthol cigarette use and stroke risk among US Included for other smokers: a critical reappraisal. JAMA Intern Med 2014;174(5):808- additives but not 9. relevant for titanium dioxide Rustemeier K, Stabbert R, Haussmann H, Roemer E, Carmines EL. Included for other Evaluation of the potential effects of ingredients added to additives but not cigarettes. Part 2: chemical composition of mainstream smoke. relevant for titanium Food Chem Toxicol 2002;40(1):93-104. dioxide Sakagami H. Studies on the components of licorice root used for Unobtainable tobacco flavouring. III. The behavior of glycyrrhizic acid and glycyrrhetinic acid added to tobacco smoke. Nippon Nogeikagaku Kaishi 1973;47:623-6. Samet JM, Pentz MA, Unger JB. Flavoured tobacco products and Not an outcome of the public's health: lessons from the TPSAC menthol report. Tob interest (not toxicity, Control 2016;25(Suppl 2):ii103-ii105. smoke chemistry or pyrolysis) SCENIHR (Scientific Committee on Emerging and Newly Identified Not an outcome of Health Risks), European Commission. Addictiveness and interest (not toxicity, attractiveness of tobacco additives [Internet]: European smoke chemistry or Commission, 2010 [accessed 17.11.17] Available from: pyrolysis) http://ec.europa.eu/health/scientific_committees/emerging/docs /scenihr_o_031.pdf Schlotzhauer WS, Chortyk OT. Effects of varied smoking machine No additive reported parameters on deliveries of total particulate matter and selected smoke constituents from an ultra low-tar cigarette. J Anal Toxicol 1983;7(2):92-5. Schmeltz I, Schlotzhauer WS. Benzo(a)pyrene, phenols and other Included for other products from pyrolysis of the cigarette additive, (d,1)-menthol. additives but not Nature 1968;219(5152):370-1. relevant for titanium dioxide Schorp MK, Tricker AR, Dempsey R. Reduced exposure evaluation Not a tobacco system of an electrically heated cigarette smoking system. Part 1: non- of interest clinical and clinical insights. Regul Toxicol Pharmacol 2012;64(2 Suppl):S1-10.

Kleijnen Systematic Reviews Ltd 45 Publication Reason for Exclusion Schramke H, Roemer E, Dempsey R, Hirter J, Meurrens K, Berges Included for other A, et al. Toxicological assessment of kretek cigarettes. Part 7: the additives but not impact of ingredients added to kretek cigarettes on inhalation relevant for titanium toxicity. Regul Toxicol Pharmacol 2014;70(S1):S81-9. dioxide Schwartz R, Chaiton M, Borland T, Diemert L. Tobacco industry Not an outcome of tactics in preparing for menthol ban. Tob Control 2017:pii: interest (not toxicity, tobaccocontrol-2017-053910. [Epub ahead of print]. smoke chemistry or pyrolysis) Shi X, He Z, Dou A, Zhang F, Lian W, Xu G. [Effect of menthol Not an outcome of cigarette on rats for metabonomics by liquid chromatography- interest (not toxicity, mass spectrometry]. Chinese Journal of Chromatography smoke chemistry or 2010;28(8):765-8. pyrolysis) Sidney S, Tekawa IS, Friedman GD, Sadler MC, Tashkin DP. Included for other Mentholated cigarette use and lung cancer. Arch Intern Med additives but not 1995;155(7):727-32. relevant for titanium dioxide Sidney S, Sorel ME, Quesenberry CP. Does menthol cigarette use Included for other increase the risk of cardiovascular disease (CVD) hospitalization additives but not and mortality in black smokers? Paper presented at 46th Annual relevant for titanium Conference on Cardiovascular Disease Epidemiology and dioxide Prevention; 2-5 Mar 2006; Phoenix: United States. Circulation 2006;113(8):E378-9. Siegel M. A lost opportunity for public health--the FDA advisory Included for other committee report on menthol. N Engl J Med 2011;364(23):2177-9. additives but not relevant for titanium dioxide Sjöberg AM, Pyysalo H. Identification of food thickeners by Included for other monitoring of their pyrolytic products. J Chromatogr additives but not 1985;319(1):90-8. relevant for titanium dioxide Squier CA, Mantz MJ, Wertz PW. Effect of menthol on the Additive not contained penetration of tobacco carcinogens and nicotine across porcine in cigarettes or RYO oral mucosa ex vivo. Nicotine Tob Res 2010;12(7):763-7. tobacco Stanford Research Institute. Study of the mutagenic effects of Unobtainable guar gum (FDA-71-16). Maxwell WA, Newell GW, Stanford Research Institute, PB-221 815, 1972 Stanford Research Institute. Study of mutagenic effects of sorbitol Additive not contained (71- 31). Compound report No. 10. Prepared under DHEW in cigarettes or RYO Contract No. FDA 71-267. Menlo Park, CA: Stanford Research tobacco Institute, 1972 Stein YS, Antal MJ, Jones M. A study of gas phase pyrolysis of Included for other glycerol. J Anal Appl Pyrolysis 1983;4(4):283-96. additives but not relevant for titanium dioxide Stellman SD, Chen Y, Muscat JE, Djordjevic MV, Richie JP, Jr., Included for other

Kleijnen Systematic Reviews Ltd 46 Publication Reason for Exclusion Lazarus P, et al. Lung cancer risk in white and black Americans. additives but not Ann Epidemiol 2003;13(4):294-302. relevant for titanium dioxide Stellman SD. Tobacco-related cancer risks and menthol cigarettes: Included for other a case-control study. Am J Epidemiol 2011;173:S86. additives but not relevant for titanium dioxide Stotesbury S, Digard H, Willoughby L, Couch A. The pyrolysis of Not an additive of tobacco additives as a means of predicting their behaviour in a interest burning cigarette. Beitr Tabakforsch Int 1999;18(4):147-63. Styles JA. DNA content of cultured mammalian cells exposed to Not an additive of smoke and smoke fractions from cigarettes containing tobacco or interest NSM, a tobacco substitute. Br J Exp Pathol 1976;57(3):286-95. Sutherland G, Russell MAH, Stapleton JA, Feyerabend C. Glycerol Not an outcome of particle cigarettes: a less harmful option for chronic smokers. interest (not toxicity, Thorax 1993;48(4):385-7. smoke chemistry or pyrolysis) Talhout R, Opperhuizen A, van Amsterdam JG. Sugars as tobacco Not an additive of ingredient: effects on mainstream smoke composition. Food interest Chem Toxicol 2006;44(11):1789-98. The British Industrial Biological Research Association (Bibra). Unobtainable Toxicity profile. Menthol. Bibra, 1986: 7. Thielen A. Conference report: Experimental assessment of the Not an additive of toxicological effects of inhaled complex mixtures on the interest respiratory system - feasability and limitations, 23-25 April 2005, Barcelona, Spain. Beitr Tabakforsch Int 2005;21(7):419-22. Thompson MF, Poirier GL, Davila-Garcia MI, Huang W, Tam K, Not an outcome of Robidoux M, et al. Menthol enhances nicotine-induced locomotor interest (not toxicity, sensitization and in vivo functional connectivity in adolescence. J smoke chemistry or Psychopharmacol 2017:269881117719265. pyrolysis) Thorne D, Larard S, Baxter A, Meredith C, Gaҫa M. The Not a tobacco system comparative in vitro assessment of e-cigarette and cigarette of interest smoke aerosols using the γH2AX assay and applied dose measurements. Toxicol Lett 2017;265:170-8. Titz B, Kogel U, Martin F, Schlage WK, Xiang Y, Nury C, et al. A 90- Not an additive of day OECD TG 413 rat inhalation study with systems toxicology interest endpoints demonstrates reduced exposure effects of the aerosol from the carbon heated tobacco product version 1.2 (CHTP1.2) compared with cigarette smoke. II. Systems toxicology assessment. Food Chem Toxicol 2018;115:284-301. Tobacco Products Scientific Advisory Committee (TPSAC). Included for other Menthol cigarettes and public health: review of the scientific additives but not evidence and recommendations. Rockville, MD: Food and Drug relevant for titanium Administration, 2011 dioxide US Food and Drug Administration. Preliminary scientific Included for other

Kleijnen Systematic Reviews Ltd 47 Publication Reason for Exclusion evaluation of the possible public health effects of menthol versus additives but not nonmenthol cigarettes [Internet]: US Food and Drug relevant for titanium Administration, 2013 [accessed 17.11.17] Available from: dioxide https://www.fda.gov/downloads/ucm361598.pdf van Andel I, Wolterink G, van de Werken G, Stevenson H, van Included for other Aerts LAGJM, Vleeming W. The health and addiction risk of the additives but not glycyrrhizic acid component of liquorice root used in tobacco relevant for titanium products. RIVM report 340630001/2003 [Internet]. Bilthoven, The dioxide Netherlands: National Institute for Public Health and the Environment (RIVM), 2003 [accessed 22.01.18] Available from: http://www.rivm.nl/en/Documents_and_publications/Scientific/R eports/2003/oktober/The_health_and_addiction_risk_of_the_gly cyrrhizic_acid_component_of_liquorice_root_used_in_tobacco_p roducts Van Landingham C, Fuller W, Mariano G, Marano K, Curtin G, Included for other Sulsky SI. Data on cardiovascular and pulmonary diseases among additives but not smokers of menthol and non-menthol cigarettes compiled from relevant for titanium the National Health and Nutrition Examination Survey (NHANES), dioxide 1999-2012. Data Brief 2017;12:386-99. Van Velzen A, Vermeeren Y, Van Riel A, Meulenbelt J, De Vries I. Additive not contained Ingestion of smoke fluid: be aware of diethylene glycol. Clin in cigarettes or RYO Toxicol 2013;51(9):907. tobacco Vanscheeuwijck PM, Teredesai A, Terpstra PM, Verbeeck J, Kuhl P, Included for other Gerstenberg B, et al. Evaluation of the potential effects of additives but not ingredients added to cigarettes. Part 4: subchronic inhalation relevant for titanium toxicity. Food Chem Toxicol 2002;40(1):113-31. dioxide Villanti AC, Giovino GA, Burns DM, Abrams DB. Menthol cigarettes Included for other and mortality: keeping focus on the public health standard. additives but not Nicotine Tob Res 2013;15(2):617-8. relevant for titanium dioxide Villanti AC, Collins LK, Niaura RS, Gagosian SY, Abrams DB. Not an outcome of Menthol cigarettes and the public health standard: a systematic interest (not toxicity, review. BMC Public Health 2017;17(1):983. smoke chemistry or pyrolysis) Vozoris NT. Mentholated cigarettes and cardiovascular and Included for other pulmonary diseases: a population-based study. Arch Intern Med additives but not 2012;172(7):590-1. relevant for titanium dioxide Vozoris NT. The association between mentholated cigarettes and Included for other cardiovascular and pulmonary diseases in the United States additives but not population. Am J Respir Crit Care Med 2012;185:A6047. relevant for titanium dioxide Walk RA. Draft “White Paper” on Guar Gum. Bates: 2061999543- Unobtainable 2061999567: Philip Morris, 1994 [accessed 31.1.18] Available from: http://tobaccodocuments.org/pm/2061999543-9567.html

Kleijnen Systematic Reviews Ltd 48 Publication Reason for Exclusion Weeks SM. Licorice and tobacco. J Am Dent Assoc Additive not contained 1988;116(6):612. in cigarettes or RYO tobacco Werley MS, Coggins CR, Lee PN. Possible effects on smokers of Included for other cigarette mentholation: a review of the evidence relating to key additives but not research questions. Regul Toxicol Pharmacol 2007;47(2):189-203. relevant for titanium dioxide White WB. Menthol cigarette use and subclinical cardiovascular Included for other disease in African Americans in the Jackson Heart Study. Paper additives but not presented at the American Heart Association's Epidemiology and relevant for titanium Prevention/Lifestyle and Cardiometabolic Health 2018 Scientific dioxide Sessions; 20-23 Mar 2018; New Orleans: United States. Circulation 2018;137(Suppl 1):AP102. WHO Framework Convention on Tobacco Control (FCTC). Partial Not an outcome of guidelines for implementation of Articles 9 and 10 of the WHO interest (not toxicity, Framework Convention on Tobacco Control (Regulation of the smoke chemistry or contents of tobacco products and regulation of tobacco product pyrolysis) disclosures). FCTC/COP4(10): WHO Framework Convention on Tobacco Control (FCTC), 2010 Available from: http://www.who.int/fctc/guidelines/Decisions9and10.pdf Williams JM, Gandhi KK, Steinberg ML, Foulds J, Ziedonis DM, Not an outcome of Benowitz NL. Higher nicotine and carbon monoxide levels in interest (not toxicity, menthol cigarette smokers with and without schizophrenia. smoke chemistry or Nicotine Tob Res 2007;9(8):873-81. pyrolysis) Willis DN, Liu B, Ha MA, Jordt SE, Morris JB. Menthol attenuates Additive not contained respiratory irritation responses to multiple cigarette smoke in cigarettes or RYO irritants. FASEB J 2011;25(12):4434-44. tobacco Wilson J, Clapp MJL, Conning DM. Effect of glycerol on local and Additive not contained systemic carcinogenicity of topically applied tobacco condensate. in cigarettes or RYO Br J Cancer 1978;38(2):250-7. tobacco Wise PM, Wysocki CJ. The effect of menthol vapor on sensitivity Additive not contained to chemical irritation. Chem Senses 2011;36(9):A41. in cigarettes or RYO tobacco Wu Y, Yang H, Liu H, Yang Z, Zhu M, Pan X, et al. [Research of herb Included for other components on scavenging harmful components and reducing additives but not cytotoxicity of cigarette smoke]. Zhongguo Zhong Yao Za Zhi relevant for titanium 2011;36(22):3184-8. dioxide Xia JF, Wang Y, Tang FD, Xu QP, Zhao XJ, Liu JB, et al. [Effect of Unobtainable spearmint oil on airway inflammation, interleukin-8 and CCR2 expression in lung tissue of COPD rats]. Zhongguo Yao Xue Za Zhi 2010;45(6):423-8. Yermakoff J. Sensory irritation study for menthol. R. J. Reynolds. Unobtainable Bates No. 505 347 068–505 347 070, 1987 Available from: http://tobaccodocuments.org/product_design/505347068– 7070.html

Kleijnen Systematic Reviews Ltd 49 Publication Reason for Exclusion Yip S, Taylor L, Ashraf-Khorassani M, Yu J, Borgerding M, Coleman Included for other W, et al. HPLC-MS determination of acrolein and acetone additives but not generated from 13C3 -labeled glycerol added to cigarette tobacco relevant for titanium using two machine-smoking regimes. Beitr Tabakforsch Int dioxide 2010;24(2):48-57. Young-Wolff KC, Hickman NJ, 3rd, Kim R, Gali K, Prochaska JJ. Not an outcome of Correlates and prevalence of menthol cigarette use among adults interest (not toxicity, with serious mental illness. Nicotine Tob Res 2015;17(3):285-91. smoke chemistry or pyrolysis) Zeiger E, Anderson B, Haworth S, Lawlor T, Mortelmans K. Unobtainable Salmonella mutagenicity tests: V. Results from the testing of 311 chemicals. Environ Mol Mutagen 1992;19 Suppl 21:2-141. Zhao Y, Ding L, Liu JY, Yang HW, Yin XQ, Tuo SX, et al. Pyrolysis Included for other characteristics of different humectant at high temperature. Asian additives but not J Chem 2014;26(15):4893-6. relevant for titanium dioxide

Kleijnen Systematic Reviews Ltd 50

Appendix 2: Test and Reference Cigarette Manufacturing Report CONFIDENTIAL

This report is shared under the collaboration agreement between the parties* dated 21 March 2017.

This report contains some supplier-related information and is subject to the Information Sharing Protocol (at Annex 4 to the Collaboration Agreement), and must not be shared more widely by any party within its internal organisation or externally [except as required to be sent to the European Commission under confidentiality]. Unauthorised use or disclosure of the content of this report may result in legal action.

The test articles and their specifications have been designed solely for the purposes of the parties’ collaboration and should not be considered as representative of the commercial manufacturing practices of any of the parties.

*Parties to the agreement: • British American Tobacco (Investments) Limited • Japan Tobacco International SA • Philip Morris Products SA • Imperial Tobacco Limited • KT&G Corporation • Joh. Wilh. Von Eicken GmbH • Karelia Tobacco Company Inc • Landewyck Tobacco S.A. • Mac Baren Tobacco Company A/S • Pӧschl Tabak GmbH & Co. KG • Scandinavian Tobacco Group A/S •

CONFIDENTIAL – NOT FORContinental FURTHER DISTRIBUTION Tobacco 24.11.2017 Group 1 Project Name / Ref: “Testpiece” (x95.10.152 PCE)

Scope of Project: Manufacturing of Cigarette Prototypes with defined ingredients and flavourings with agreed concentrations listed by EU as “priority ingredients”

 Total number of Cigarette Prototypes to be manufactured: 43 (14 ingredients x 3 concentration levels + 1 Reference/Control cigarette without any Casing / flavor applied)  Target smoke yields: 8 mg/cig NFDPM (“tar”); 0.7 mg/cig Nicotine and 9mg/cig Carbon Monoxide  The ingredient concentrations are described in this Report as “Low” / “Max” / “Max Plus”.

Ingredient Levels were defined to cover a broader range of concentrations even exceeding the Max or Quantity Not Exceeded (QNE) levels used by the participating companies:

LOW MAX MAX Plus “Max level” or QNE conc “Max level” or QNE conc “Max level” or QNE conc - 50% + 50%

Cigarette Production Machine: Molins Mark 9 / Hauni Max S

 Maker Speed (typical) : 1200-1500 Cigarettes / minute  Cigarette Format : 83 mm total Cig length / 27 mm Filter length  Tipping length on Cigarette : 32 mm  Target Cigarette Circumference : 24.60 mm  Ventilation type : 1 Laser line at 13 mm distance from cig mouth end  Ventilation Target : 37% (actuals: 36% - 40% to meet delivery targets)*  Target tobacco weight: 620 mg to achieve a firmness of min 70%  Filter Type : Standard Mono acetate  Filter Format : 108 mm x 24.30 mm used on all samples  Time Period : Cigarette manufacture: Jan 2017 to June 2017

*In case of Tar yields exceeding ISO tolerance, ventilation adjustments were made.

CONFIDENTIAL – NOT FOR FURTHER DISTRIBUTION 24.11.2017 2 Table of contents

1) Bill of Materials used on all manufactured Cigarette Prototypes ...... 4 2a) Cigarette Smoke Analytical Results ...... 6 2b) Cigarette Smoke Analytical Results (continued) ...... 7 3) Cigarette Dimension measurements ...... 8 4a) Cigarette Weights, Ventilation, Open Cig Pressure drop ...... 9 4b) Cigarette Weights, Ventilation, Open Cig Pressure drop (continued) ...... 10 5a) Cigarette Quality parameters ...... 11 5b) Cigarette Quality parameters (continued)...... 12 6) Special Ingredient analysis ...... 13 6a) Special Ingredient analysis “LOW” sample results ...... 14 6b) Special Ingredient analysis “MAX” sample results ...... 15 6c) Special Ingredient analysis “MAX PLUS” sample results ...... 16 6d) Casing Mix samples ...... 17 7) “MARSENA” Base blend recipe ...... 18 8) Packaging ...... 19 9) Eurofins Lab analysis for Guar Gum Recon as made by PMI and Cigarettes manufactured by PCE....21 10) Listing of ingredients used on Cigarettes ...... 21 11) PMI cross reference list of Samples ...... 22 12) Appendices...... 27

CONFIDENTIAL – NOT FOR FURTHER DISTRIBUTION 29.11.2017 3

11) PMI cross reference list of Samples

Targeted Achieved Cigarette Levels Test/Reference Manufacturing Amount of Amount of CAS Tobacco No. Additive of Item Type codes Tobacco Tobacco Number Weight Additive Additive Additive [mg/cig]

Reference Cigarette item (without 1 Reference R365 - - - - 622 tobacco Item additives)

Cigarette Test Carob bean 84961- 2 M562 Low 0.2000% * 594 Item extract 45-5

Cigarette Test Carob bean 84961- 3 N427 Max 0.4000% * 623 Item extract 45-5

Cigarette Test Carob bean Max 84961- 4 Q328 0.6000% * 604 Item extract Plus 45-5

Cigarette Test Cocoa 95009- 5 E835 Low 0.5000% 0.6046% 610 Item Powder 22-6

Cigarette Test Cocoa 95009- 6 G736 Max 1.0000% 1.0141% 619 Item Powder 22-6

Cigarette Test Cocoa Max 95009- 7 I754 1.5000% 1.4400% 608 Item Powder Plus 22-6

Cigarette Test Fenugreek 84625- 8 K645 Low 0.0100% * 641 Item extract 40-1

Cigarette Test Fenugreek 84625- 9 L528 Max 0.0200% * 660 Item extract 40-1

Cigarette Test Fenugreek Max 84625- 10 M537 0.0300% * 649 Item extract Plus 40-1

Cigarette Test Fig Juice 90028- 11 D827 Low 0.0250% * 613 Item concentrate 74-3

Cigarette Test Fig Juice 90028- 12 F854 Max 0.1500% * 634 Item concentrate 74-3

CONFIDENTIAL – NOT FOR FURTHER DISTRIBUTION 29.11.2017 22 Targeted Achieved Cigarette Levels Test/Reference Manufacturing Amount of Amount of CAS Tobacco No. Additive of Item Type codes Tobacco Tobacco Number Weight Additive Additive Additive [mg/cig]

Cigarette Test Fig Juice Max 90028- 13 G728 0.3000% * 607 Item concentrate Plus 74-3

Cigarette Test 106-24- 14 Geraniol J625 Low 0.0150% 0.0161% 621 Item 1

Cigarette Test 106-24- 15 Geraniol H742 Max 0.0300% 0.0251% 598 Item 1

Cigarette Test Max 106-24- 16 Geraniol K652 0.0450% 0.0529% 614 Item Plus 1

Cigarette Test 17 Glycerol R346 Low 2.5000% 2.303% 56-81-5 627 Item

Cigarette Test 18 Glycerol T238 Max 5.0000% 4.326% 56-81-5 636 Item

Cigarette Test Max 19 Glycerol W265 6+% 5.974% 56-81-5 645 Item Plus

Cigarette Test 20 Guaiacol F852 Low 0.0005% 0.000559% 90-05-1 612 Item

Cigarette Test 21 Guaiacol H753 Max 0.0010% 0.000877% 90-05-1 600 Item

Cigarette Test Max 22 Guaiacol J627 0.0015% 0.001555% 90-05-1 600 Item Plus

Estimated* Cigarette Test 9000- 23 Guar gum J635 Low 0.5000% between 610 Item 30-0 0.33 to 0.55%

Estimated* Cigarette Test 9000- 24 Guar gum K653 Max 1.0000% between 601 Item 30-0 1.03 to 1.18%

Estimated* Cigarette Test Max 9000- 25 Guar gum L527 1.5000% between 639 Item Plus 30-0 1.44 to 1.57%

CONFIDENTIAL – NOT FOR FURTHER DISTRIBUTION 29.11.2017 23 Targeted Achieved Cigarette Levels Test/Reference Manufacturing Amount of Amount of CAS Tobacco No. Additive of Item Type codes Tobacco Tobacco Number Weight Additive Additive Additive [mg/cig]

Liquorice Cigarette Test 68916- 26 extract M547 Low 0.6000% 0.420% 624 Item 91-6 powder

Liquorice Cigarette Test 68916- 27 extract N583 Max 1.2000% 1.050% 621 Item 91-6 powder

Liquorice Cigarette Test Max 68916- 28 extract P457 1.8000% 1.782% 603 Item Plus 91-6 powder

Cigarette Test 118-71- 29 Maltol E842 Low 0.0050% 0.0045% 617 Item 8

Cigarette Test 118-71- 30 Maltol D824 Max 0.0100% 0.0079% 621 Item 8

Cigarette Test Max 118-71- 31 Maltol G725 0.0150% 0.0111% 618 Item Plus 8

Cigarette Test l- Menthol, 2216- 32 L674 Low 0.6000% 0.552% 606 Item synthetic 51-5

Cigarette Test l- Menthol, 2216- 33 P458 Max 1.2000% 1.142% 650 Item synthetic 51-5

Cigarette Test l- Menthol, Max 2216- 34 Q476 1.8000% 1.730% 625 Item synthetic Plus 51-5

Cigarette Test Propylene 35 N428 Low 2.5000% 2.05% 57-55-6 616 Item glycol

Cigarette Test Propylene 36 Q473 Max 5.0000% 4.53% 57-55-6 571 Item glycol

Cigarette Test Propylene Max 37 R347 6+% 4.80% 57-55-6 617 Item glycol Plus

Cigarette Test 38 Sorbitol P438 Low 0.6000% 0.65% 50-70-4 604 Item

Cigarette Test 39 Sorbitol R357 Max 1.2000% 1.10% 50-70-4 620 Item

CONFIDENTIAL – NOT FOR FURTHER DISTRIBUTION 29.11.2017 24 Targeted Achieved Cigarette Levels Test/Reference Manufacturing Amount of Amount of CAS Tobacco No. Additive of Item Type codes Tobacco Tobacco Number Weight Additive Additive Additive [mg/cig]

Cigarette Test Max 40 Sorbitol S384 1.8000% 1.60% 50-70-4 614 Item Plus

PG 1%, PG 1.1%, PG 1%, Glycerol 1%, Glycerol Glycerol 1%, 57-55-6 Plus addition 0.57%, Plus Plus addition & 56-81- of top flavors: addition of top of top flavors: 5 & Fenugreek flavors: Fenugreek 84625- extract Only Fenugreek Cigarette Test extract 40-1 & 41 0.02%, S374 one extract*, 596 Item 0.02%, 106-24- Geraniol level Geraniol Geraniol 1 & 90- 0.03%, 0.024%, 0.03%, 05-1 & Guaiacol Guaiacol Guaiacol 118-71- 0.001%, 0.00047%, 0.001%, 8 Maltol 0.01% Maltol Maltol 0.01% (Mix 1) 0.0042%

PG 2%, PG 2%, PG 1.57%, Glycerol Glycerol Glycerol 1.5%, Sorbitol 57-55-6 1.5%, 0.97%, Sorbitol 2%, Plus & 56-81- Sorbitol 2%, 1.54%, Plus addition of 5 & 50- Plus addition addition of top top flavors: 70-4 & of top flavors: flavors: Fenugreek Only 84625- Cigarette Test Fenugreek Fenugreek 42 extract T257 one 40-1 & 599 Item extract extract*, 0.02%, level 106-24- 0.02%, Geraniol Geraniol 1 & 90- Geraniol 0.027%, 0.03%, 05-1 & 0.03%, Guaiacol Guaiacol 118-71- Guaiacol 0.00061%, 0.001%, 8 0.001%, Maltol Maltol 0.01% Maltol 0.01% 0.0061% (Mix 2)

PG 1%, PG 1%, PG 1.13%, 57-55-6 Glycerol Glycerol Glycerol & 56-81- 1.5%, 1.5%, 0.93%, 5 & Only Cigarette Test Liquorice Liquorice Liquorice 68916- 43 W275 one 615 Item 0.8%, Cocoa 0.8%, Cocoa 0.44%, Cocoa 91-6 & 0.4 %, Carob level 0.4%, Carob 0.24 %, Carob 95009- bean ext. bean ext. bean ext.*, Fig 22-6 & 0.4%, Fig 0.4%, Fig juice 84961- juice juice concentrate*, 45-5 &

CONFIDENTIAL – NOT FOR FURTHER DISTRIBUTION 29.11.2017 25 Targeted Achieved Cigarette Levels Test/Reference Manufacturing Amount of Amount of CAS Tobacco No. Additive of Item Type codes Tobacco Tobacco Number Weight Additive Additive Additive [mg/cig]

concentrate concentrate Guar Gum*, 90028- 0.025%, Guar 0.025%, Guar Plus addition 74-3 & Gum 1%, Plus Gum 1%, Plus of top flavors: 9000- addition of addition of Fenugreek 30-0 & top flavors: top flavors: extract*, 84625- Fenugreek Fenugreek Geraniol 40-1 & extract extract 0.026%, 106-24- 0.02%, 0.02%, Guaiacol 1 & 90- Geraniol Geraniol 0.00051%, 05-1 & 0.03%, 0.03%, Maltol 118-71- Guaiacol Guaiacol 0.0046% 8 0.001%, 0.001%, Maltol 0.01% Maltol 0.01% (Mix 3)

*Technically not possible to detect Achieved Amount of Tobacco Additive(s).

1 Transfer cannot be determined due to a high background level in the reference cigarette

CONFIDENTIAL – NOT FOR FURTHER DISTRIBUTION 29.11.2017 26

29 30 31 32 33 34

A2 Cocoa Powder (95009-22-6)

• Certificate of analysis • Product specification • Food Grade Statement

CONFIDENTIAL – NOT FOR FURTHER DISTRIBUTION 25.05.2018 1 36 37 38 39 40

Cocoa – Chocolate – Coatings & Fillings Products Statement

Date: Replaces: Doc. valid until: Reference: January 2018 January 2017 January 2019 N/A From: Company: Department/Location: Applicable to: Danielle Rump Cargill Cocoa & Chocolate FSQR Cocoa, Chocolate, Coating and Fillings

STATEMENT

At Cargill food safety is the top priority. All of the facilities around the world comply with the same high corporate standards for food safety and quality. Additionally, the Cargill food safety and quality teams work closely together with suppliers to ensure that the proper control measures and procedures are in place for all products supplied to Cargill Cocoa & Chocolate.

Cargill Cocoa & Chocolate assures that the products supplied meet all relevant EU regulatory requirements, more specifically: - Regulation (EC) N° 178/2002 on general principles and requirements of food law, - Regulation (EC) N° 852/2004 on the hygiene of foodstuffs, - Regulation (EC) N° 1881/2006, as amended, for certain contaminants in foodstuffs, - Regulation (EC) N° 396/2005, as amended, on MRLs of pesticides in or on food, - Directive 2000/36/EC relating to cocoa and chocolate products intended for human consumption., - Codex Alimentarius Stan 105-1981, for cocoa powder and dry mixtures of cocoa and sugars, - Codex Alimentarius Stan 86-1981, for cocoa butter, - Codex Alimentarius Stan 141-1983, for cocoa (cacao) mass (cocoa/chocolate liquor) and cocoa cake. - Codex Alimentarius: Stan 87-1981, for chocolate and chocolate products.

Conformity Cargill Cocoa & Chocolate confirms that the cocoa products, chocolates, coatings and fillings are manufactured in accordance to its norms and in conformity with its specifications.

Genetically Modified Organisms (GMO) Cargill Cocoa & Chocolate certifies that for all the cocoa products, chocolates, coatings and fillings manufactured within its EMEA and Asia group, the ingredients used are of non-GMO origin. When soya lecithin is being used as emulsifier in these recipes, this lecithin only comes from “Identity Preserved” sources. According to the European Regulations (EC) N° 1829/2003 and N° 1830/2003, cocoa products, chocolates, coatings and fillings do not require a specific labelling in respect to GMO.

Ionization/Irradiation Cargill Cocoa & Chocolate assures that the cocoa products, chocolates, coatings and fillings manufactured within its EMEA and Asia group, as well as their ingredients, are not submitted to any kind of ionization/irradiation.

Nanotechnology Cargill Cocoa & Chocolate assures that to the best of our knowledge the cocoa products, chocolates, coatings and fillings manufactured within its EMEA and Asia group, as well as their ingredients, are produced without using nanothechnology or intentionally engineered nanomaterials. Consequently, the above mentioned products do not have to be labelled as nano ingredient according to Regulation (EC) N°1169/2011.

If you have any questions, don’t hesitate to contact your Cargill Food Safety, Quality and Regulatory contact for further information and background. Email: [email protected]

FSQR Customer Relations Food Safety, Quality & Regulatory Cargill Cocoa & Chocolate

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A8 Guar Gum (9000-30-0)

• Certificate of analysis • Food Grade Statement • OPAC cast leaf production

CONFIDENTIAL – NOT FOR FURTHER DISTRIBUTION 25.05.2018 2 77

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Appendix 3: Inclusion Rate of Titanium Dioxide in the Cigarette Filter Composite List of Non-Tobacco Ingredients included in the Manufacture of Priority Additives Consortium Cigarettes

Appendix 4: Study Report on Quantification and Identification of Particles Released from Filter

Report Prepared for the Priority Additive Tobacco Consortium

Quantification and identification of particles released from cellulose acetate filters from an additive-free reference cigarette R365 and an air blank. A focus on titanium dioxide release, using an Imperial Tobacco in-house derived method.

Report prepared by:

Dr Liam Simms, Principal Toxicologist, Imperial Tobacco Limited.

Date: 9/05/2018

Page 1 of 21

ABSTRACT

An Imperial Tobacco in-house method was developed to count and characterise particles released from cigarette filters during sham-smoking (cigarettes were not lit during the procedure). The Additive-free reference cigarettes R365 (a-c, three replicates), as manufactured for the Priority Additive Tobacco Consortium testing platform (Add Manufacturing report reference) were compared to an air blank sample ( a single replicate), the equipment used with no cigarettes in the holders. Both cigarettes and air blank were sham smoked using a puff volume of 35 mls. Samples were collected directly on to gold membranes (pore size 0.8 µm). Image analysis was performed using optical microscopy to count and analyse the size and shape of the particles. All steps were performed automatically by a Single Particle Explorer® (rap.ID Particle Systems GmbH, Berlin, Germany). Counting and identification of particles was performed in six specific size ranges: particles were classified as being in the size ranges (≥2 to <5; ≥5 to<8; ≥8 to<11; ≥11 to<15; ≥15-to 30; ≥ 30 µM. Particles were identified where possible using Raman Spectroscopy.

The focus of the report was the release of titanium dioxide particles from the Cellulose Acetate filters as this is one of the priority additives. Between 12 - 18 “respirable shaped fibre-shaped particulates” (RFP) were detected in the reference cigarette sample (R365a-c) and 15 RFP were detected in the air blank control. The particles released from cigarette samples (R365 a-c) were mainly identified as typical cigarette and filter constituents. The number of particles released from the Cellulose Acetate (CA) filter from R365, was not significantly higher than those found in the air blank sample. The release of titanium dioxide particles from the CA filters of the R365 reference sample ranged from 2 - 4 particles from 2000 puffs drawn through 200 cigarettes (10 puffs per cig, 70 litres of air in total per gold membrane). No particles of titanium dioxide were found in the air blank sample.

INTRODUCTION

There is currently no standard methodology for characterising the incidence of particle release from filters. As described in the literature [2-4], procedures were developed based on current best practices within the tobacco industry. These covered ‘tap tests’ in which the filter end is placed on an agar gel surface to simulate mouth contact and ‘sham smoking’ tests. In the latter case, filters were subjected to a standard puffing cycle and any particles released into the air stream was collected. In all published cases, particles were counted and characterised using image analysis systems.

AIM OF STUDY

To quantify and identify particles released from a standard cigarette CA filter in the R365 reference sample. There was a focus on the release of titanium dioxide particles from the

Page 2 of 21 Additives Tobacco Consortium, as titanium dioxide was identified as one of the priority ingredients as laid down in the Comission Implementing Decision 2016-787 . For the tests performed in this study the additive-free reference cigarettes were used.

EXPERIMENTAL

Principle

Additive-free rreference cigarettes (R365) were supplied by BAT Bayreuth for analyses of particle release from the cellulose acetate filter (the cigarette filter was manufactured on site using cellulose acetate supplied by Celanese). The reference cigarette (R365) was based on a commercially available king size cigarette (length 83 mm, circumference 24.6 mm) with a single segment cellulose acetate filter and tobacco blend recipe without ingredients. (See Appendix 16.1.1 of the Manufacturing Report for the detailed product specification). Cigarette samples were delivered in polypropylene wrapped packs to Reemtsma Cigarettenfabriken, Physical Testing Laboratory, Hamburg, Germany. Cigarettes were removed directly from the cigarette packaging and tested in the particle sampler; there was no conditioning of the reference cigarettes prior to testing.

Unlit cigarettes were “sham smoked” in a vertical position on a sampling apparatus according to ISO conditions (35 ml puff). In the vertical position, particles released from the cigarettes fall directly onto the membrane without any obstruction. A sample of particles released from the mouth end of the cigarette filters were collected on a commercially produced gold-coated capillary pore membrane filter. The loaded filter was then analysed at an independent laboratory (RapID) directly using a Raman microprobe without any alteration of the particulate deposit. The individual particles were measured and counted in randomly selected areas of the filter according to defined particle counting rules, and classified to three different types of particles/fibres based on their length/width ratio. The chemical characterisation of particles collected was performed by Raman spectroscopy.

Sampling Apparatus: “Sham Smoking” of Cigarettes

A rotary sampling apparatus (“Particle Sampler Burghart”) was designed to allow “sham smoking” (defined as puffing unlit cigarettes) according to standard smoking regimes (Figure 1). Cigarettes were sham smoked in a vertical position according to ISO conditions: each sham smoking run was performed with 200 cigarettes using a 35 mL puff volume, a puff duration 2 seconds, puff frequency 60 seconds. Ten puffs were taken per cigarette. Ten sham smoking runs were performed with each membrane. Following this protocol, particles from 2000 puffs delivered by 200 cigarettes were collected and a total volume of 70 litres of filtered air was drawn through each membrane.

During sampling, the cigarettes were covered by a Plexiglas hood equipped with four air filters (pore size 0.2 µm). Prior to sampling, the hood was flushed with filtered air for 5 minutes to generate a defined environment within the hood and to maintain a constant

Page 3 of 21 “background noise” during sampling. A constant air flow was ensured during sampling. Each working day, the sampling system was checked for leak tightness and the puff volume was controlled.

Me mb ran e hol der Pu mp

Figure 1: Particle Sampler Burghart (raised and lowered hood)

Cigarette Holder, Particle Collecting System

The cigarette holder and membrane housing were constructed as follows: In the cigarette holders, labyrinth seals were used covered with metal plates to assure vertical positioning of the cigarettes. No washer supports were used in the cigarette holders but the cigarettes were retained in the holder by metal rings equipped with small pins. This assembly allowed a tight seal and an even hold of the cigarette with minimal pressure on the filter and minimal coverage of its mouth end cross section area.

The membrane housing (Figure 2) was made of stainless steel and designed in a way that the membrane was inserted between two components and sandwiched by two “O”-ring seals. The housing was firmly closed by pushing both elements together and interconnecting them using a bayonet connector. With this arrangement, the membrane was directly exposed to the mouth end of the cigarettes within a distance of 10 mm when mounted on the sampling apparatus. Particles released from the cigarettes would fall directly onto the membrane without any obstruction.

Particles were collected on Raman-inactive gold-coated polycarbonate membrane filters with a defined pore size (0.8 µm, Supplied by RapID) which are enclosed by an aluminium ring. The membrane was mounted into a membrane holder with an effective diameter of 2.2 cm (diameter of “O”-ring seals). In order to avoid contamination, the membrane holder was rinsed with isopropanol and dried under clean room conditions before the membrane was inserted and the holder was assembled and sealed with a cap in a clean room bench.

Page 4 of 21 Immediately after sampling, the membrane holder was recapped again for particle counting and characterisation.

Figure 2: Membrane holder (schematic diagram, dismantled and assembled)

Particle Counting and Characterisation

Image analysis was performed using optical microscopy to count and analyse the size and shape of the particles. All steps were performed automatically by a Single Particle Explorer® (rap.ID Particle Systems GmbH, Berlin, Germany) which randomly generates a specific number of microscopic images in 500 µm x 500 µm fields of the membrane surface. Counting and identification of particles was performed in six specific size ranges: particles were classified as being in the size ranges (≥2 to <5; ≥5 to<8; ≥8 to<11; ≥11 to<15; ≥15-to 30; ≥ 30 µM)

For automatic particle counting, the original image was transformed to a negative pattern as illustrated in Figure 3. Stripes on the membrane are unavoidable during their industrial production and result in “dotted lines” in the negative pattern (marked blue in Figure 3). These stripes were eliminated and were not considered for particle counting.

Figure 3: Example for original image (left) and negative pattern (right) used for particle counting.

Page 5 of 21 In combination with the image analysis, an automated Raman microprobe measurement was performed [5, 6]: Full characterisation was achieved by microscopic examination combined with a Raman spectroscopic system which allows the assignment of chemical compositions of organic or polymeric particles [7, 8]. The resulting Raman spectra were then compared with a database and the best match was automatically generated into a report. This document also stores the particle images and their associated original spectroscopic information. These tables are summarised later in the report.

The Raman microprobe allows the investigation of molecular vibrations associated with specific organic functional groups and yields structural information. It can provide limited information on non-metallic inorganics. A limitation of the Raman technique is the competitive fluorescence that can accompany Raman spectroscopy. If strong fluorescence occurs, no information on chemical constituent can be collected [7, 8]. Those particles detected but not clearly identified by Raman spectroscopy (the spectral trace did not correlate well with the trace for reference compounds in the database) were summarised in the table under unknown substance. Most of the unidentified particles on analyses of the spectral traces, most likely contain carbon.

The numerical concentration of the particles was determined by the particle count result, the examined filter area and the effective filter area. The detected particles were classified in to three categories [9, 10]:

 “Spherical particles” – particles without a specific orientation and elongated particles with a length/width ratio L:W < 3:1.  “Respirable fibre-shaped particulates” (RFP) – elongated particles with a length > 5µm, a width < 3 µm and a length/width ratio L:W > 3:1.  “Non-respirable fibre-shape particulates” (non-RFP) – elongated particles with a length/width ratio L:W > 3 : 1 which are not considered RFPs.

Particle number and size accuracy testing demonstrated a qualified performance of 15 %. The system for particle counting and characterisation is considered to be within specification when the counting accuracy determines a mean particle size with less than 15 % deviation from the true size of the spheres. Failure is usually attributed to generation of a poorly focused image [4, 11].

SAMPLES, BLANK TEST WITH FILTERED AIR

An air blank test was performed to describe the background particle “noise” of the particle collecting system. For the blank test, the system was operated in exactly the same way as during sampling from cigarettes – but without any cigarettes inserted in the holders. Thus, the blank test describes the number of particles detected in filtered ambient air. Three replicate measurements were performed for the reference cigarette samples (R365) and a single run of air blank (no cigarettes in the machine).

Page 6 of 21 RESULTS AND DISCUSSION

Reference Sample (R365) Containing a Cellulose Acetate Filter

Tables 1a-1c represent the three replicate measurements for the additive-free reference cellulose acetate filter samples (R365). The reported number of particles are collected among 2000 puffs (200 cigarettes x 10 puffs).

In the present study, the majority of the identified particles were organics such as carbon. Particles containing titanium dioxide and calcium carbonate were also observed. Due to fluorescence, some particles could not clearly identified (with certainty) and were summarised in the table as florescence.

Table 1a: Number of particles and size distribution for Reference (R365) CA filters (replicate 1) collected among 2000 puffs (200 cigarettes x 10 puffs)

Page 7 of 21 Table 1b: Number of particles and size distribution for Reference (R365) CA filters (replicate 2) collected among 2000 puffs (200 cigarettes x 10 puffs)

Page 8 of 21 Table 1c: Number of particles and size distribution for Reference (R365) CA filters (replicate 3) collected among 2000 puffs (200 cigarettes x 10 puffs)

For the reference (R365) CA control cigarettes, the particles found were mainly identified as typical cigarette and filter constituents. Possible contaminants observed polystyrene, polyethylene and polyethylene terephthalate. Some particles could only be counted, but not be identified unambiguously (Fluorescence, Manifold). Most particles had a spherical shape, only a few “non-respirable fibre-shape particulates” (non-RFP) could be detected.

Blank Test (Air Only No Cigarettes)

For the blank test, the system was operated without any cigarettes inserted in the holders and in exactly the same way as for sampling from cigarettes. Thus, the blank test (Table 2) describes the number of particles detected in the filtered ambient air inside the Plexiglas hood.

Page 9 of 21 Table 2: Number of particles and size distribution for air blank test.

No titanium dioxide particles were detected in the air blank

For the air blank test, most particles detected were characterised as carbon, fluorescence, diamond and pigment blue. The latter were considered a contaminant during sampling/sample handling. The total number of particles detected was comparable to that of the Reference (R365) samples.

Two fluorescent particles were classified as “respirable fibre-shaped particulates” (RFP). All the other particles had a spherical shape. Titanium dioxide particles were not detected in the air blank sample.

Summary

The observations of this study are be summarised as follows:

Four gold membranes were analysed, one air blank sample and three samples of the additive-free reference cigarette (R365), with the total number of particles found in 70 litres of air drawn through the membrane, ranging from between 234 and 436 particles per 2000 puffs (200 cigarettes x 10 puffs). The total number of particles both in terms of number and types of particles detected in the blank test was comparable to the values of the reference samples (R365). The total number of respiratory fibre particles (RFP) were comparable with in both the air and reference cigarette samples: 15 particles in the air blank identified and between 12-18 particles in the reference cigarette (R365) samples.

An analysis of the Raman spectra for the unknown substance (particles), identified the particles as most likely to be carbon. The other particles released from cigarette samples

Page 10 of 21 were mainly identified as typical cigarette and filter constituents. Limited numbers of particles could not be clearly identified due to florescence.

The release of titanium dioxide particles from the CA filters of the R365 reference cigarette sample ranged from 2 - 4 particles from 2000 puffs drawn through 200 cigarettes (10 puffs per cigarette, 70 litres of air drawn through the gold membrane) vs no titanium dioxide particles found in the air blank sample.

REFERENCES

[1] J.L. Pauly, S.J. Stegmeier, A.G. Mayer, J.D. Lesses, R.J. Streck: “Release of carbon granules from cigarettes with charcoal filters”, Tobacco Control 6, 33-40 (1997). [2] A.D. McCormack, M.J. Taylor: “Investigation of Fibre and Particle Release from Cigarette Filters”, Paper presented to CORESTA Smoke and Technology Group, Brighton (1998). [3] W. Röper, A. Murray: “Evidence of Cellulose Acetate Fibre Release from Cigarette Filters during Smoking”, Paper presented to CORESTA Smoke and Technology Group, Vienna (1995). [4] K. Agyei-Aye, S. Appleton, R.A. Rogers, C.R. Taylor: “Assessment of the Elution of Charcoal, Cellulose Acetate, and Other Particles from Cigarettes with Charcoal and Activated Charcoal/Resin Filters”, Inhalation Toxicology 16, 615-635 (2004). [5] M. Niemann, O.K. Valet: “Development of an integrated measurement system for foreign particulate matter testing in OINPD based on IPAC-RS recommendations”, Respiratory Drug Delivery Europe, 181-184 (2005). [6] O.K. Valet, M. Niemann: “Quantification of the particle explorer system for foreign particles counting and identification in a dry powder inhaler product based on IPAC- RS recommendations”, Respiratory Drug Delivery Europe, 1-4 (2006). [7] D.P. Strommen: “Raman Spectroscopy” in Handbook of Instrumental Techniques for Analytical Chemistry, Prentice Hall PTR, chapter 16, 285-307 (1997). [8] G. Gauglitz, T. Vo-Dinh: “Raman Spectroscopy” in Handbook of Spectroscopy, Vol. 1, Wiley-VCH, p. 44 (2003). [9] World Health Organization: “Determination of airborne fibre number concentrations – A recommended method, by phase-contrast optical microscopy (membrane filter method)”, Geneva (1997). [10] VDI 3492 Guideline “Indoor air measurement – Measurement of inorganic fibrous particles. Scanning electron microscopy method”, October 2004. [11] O.K. Valet, M. Lankers, personal communication, February 2007. [12] J Heyder “Deposition of inhaled particles in the human respiratory tract and consequences for regional targeting in respiratory drug delivery”. Proc Am Thor Soc 1: 315-320 (2004)

Page 11 of 21

Appendix 1 Report from rapid on particle counting and identification

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