Altria Group, Inc. · NYSE:MO

Altria — Technical Presentation (September 2018)

10 slides from Altria's technical presentation, Sep 12, 2018

1. Slide 1: Applying a Threshold of Toxicological Concern (TTC) in Risk Assessments to Address the Complex Chemical Mixtures of Tobacco Products

   Applying a Threshold of Toxicological Concern (TTC) in Risk Assessments to Address the Complex Chemical Mixtures of Tobacco Products Kimberly Ehman, PhD, DABT September 12, 2018 Altria Client Services l Regulatory Sciences l September 12, 2018 l Final l 1

2. Slide 2: FDA's Predictive Toxicology Roadmap

   FDA’s Predictive Toxicology Roadmap  Toxicology Issues that Need Addressing for FDA-Regulated Products: - “Determining comparative toxicity of tobacco products, which are inherently toxic”  Evaluation of new or increased ingredients in the Substantial Equivalence (SE) pathway  Promising New Techn

3. Slide 3: Risk Characterization

   Risk Characterization  Integration of hazard assessment, dose-response data and exposure assessment to determine likelihood that an identified chemical is going to introduce risk into the exposed population  Identification of acceptable daily exposures - Literature search (e.g., IRIS, NTP, ECHA, O

4. Slide 4: TTC Overview: Two Categories

   TTC Overview: Two Categories  Non-genotoxic chemicals - TTCs based on frequency distributions (5th percentile) of NOEL or NOAEL divided by an uncertainty factor of 100 (Kroes et al., 2000, 2004) - Cramer Classes:  Class I: 1800 µg/day (low toxicity)  Class II: 540 µg/day (medium toxicity)  Class

5. Slide 5: Risk Characterization – Application of an Inhalation TTC

   Risk Characterization – Application of an Inhalation TTC  TTC is a risk assessment tool based on the principle of establishing a human exposure threshold below which there is a very low probability of appreciable risk to human health (Kroes et al., 2000 and 2004)  1.5 µg/day is used across regulat

6. Slide 6: Application in SE Pathway (Cigarettes)

   Application in SE Pathway (Cigarettes)  Product-specific question related to ingredient added to the New Product  Applied conservative exposure assumptions (i.e., 40 cigarettes/day) to several ingredients that were present in the New Product and would result in potential exposure at levels below 1

7. Slide 7: Application in PMTA Pathway

   Application in PMTA Pathway  Draft guidance for Electronic Nicotine Delivery Systems (ENDS) products: - Provide adequate information in the PMTA to characterize the constituents in the e-liquid and identify characteristics of the e-liquid that may impact the constituents in the aerosol - Provide st

8. Slide 8: Summary

   Summary  In the absence of tobacco-specific risk assessment guidance, acceptable approaches from other FDA Centers should be considered for tobacco products  A TTC of 1.5 µg/day is acceptable for mutagenic drug impurities - all routes of exposure (ICH M7, 2014) and for evaluation of extractable/le

9. Slide 9: Thank You

   Thank You Altria Client Services l Regulatory Sciences l September 12, 2018 l Final l 9

10. Slide 10: Applying a Threshold of Toxicological Concern (TTC) in Risk Assessments to Address the Complex Chemical Mixtures of Tobacco Products

    Applying a Threshold of Toxicological Concern (TTC) in Risk Assessments to Address the Complex Chemical Mixtures of Tobacco Products September 12, 2018 Kimberly Ehman, PhD, DABT Altria Client Services l Regulatory Sciences l September 12, 2018 l Final l 10

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