Aerosol chemistry of pMRTP vs. 3R4F

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Harmful or Potentially Harmful Constituents

The FDA has determined that the phrase “harmful and potentially harmful constituents” (HPHCs) includes any chemical or chemical compound in a tobacco product or in tobacco smoke that i) is or potentially is inhaled, ingested, or absorbed into the body; and ii) causes or has the potential to cause direct or indirect harm to users or non-users of tobacco products1.

A list of HPHCs has been published in the Federal Register based on five broad criteria:

  • carcinogen (CA);
  • respiratory toxicant (RT);
  • cardiovascular toxicant (CT);
  • reproductive or developmental toxicant (RDT); or
  • addictive (AD).

The FDA has published the final list of 93 HPHCs in “Table 1—established list of the chemicals and chemical compounds identified as harmful and potentially harmful constituents in tobacco products and tobacco smoke” (2012). Among these, an abbreviated list of 18 constituents should be measured systematically when assessing HPHCs in cigarette smoke2.

In 2010, PMI established a list of 58 HPHCs (PMI-58 List) focusing on assessing candidate Modified Risk Tobacco Products (MRTPs) aerosols. This list was based on the following criteria:

  1. Smoke constituents determined by International Organization for Standardization (ISO) methods;
  2. Priority toxicants in tobacco smoke as listed by regulatory bodies, or proposed by cognizant authorities;
  3. Smoke constituents with established biomarkers of exposure;
  4. (Potentially) harmful aerosol constituents which are predominantly formed below 400°C, and which are NOT included in Criterion 2;
  5. (Potentially) harmful aerosol constituents which are predominantly formed above 400°C, and which are NOT included in Criterion 2;
  6. Aerosol characterization to identify aerosol constituents which have the potential to introduce novel hazards compared to lit-end cigarettes, and semi-quantitative analysis of ‘potentially harmful/harmful’ aerosol constituents;
  7. Product-specific analytes, such as menthol (when used as a tobacco additive) or glycerin (added as an aerosol former in some candidate MRTPs).

Products

Prototype Modified Risk Tobacco Product (pMRTP)

The pMRTP uses an extruded carbon heat source with CuO. Once ignited, the heat source heats the tobacco without burning it. A proprietary design thermally connects the tobacco to the carbon heat source and provides an effective and controlled temperature transfer to generate a nicotine-containing aerosol1,2. Additional constituents of the aerosol are water, glycerin, and tobacco flavors, together with reduced concentrations of tobacco by-products relative to cigarette smoke.

Reference Cigarette (3R4F)

3R4F cigarettes are standard reference cigarettes, used throughout the tobacco industry and academic laboratories as a consistent and uniform test item for inhalation toxicology research. They have been in use since 2006. 3R4F cigarettes were purchased from the University of Kentucky (for specifications, see http://www.ca.uky.edu/refcig).

HPHC Concentrations within Aerosols

Focusing on the product level, the candidate MRTP aerosol was generated using the Health Canada Intense (HCI) machine-smoking regimen3, and the concentration of the 58 HPHCs were determined and compared to the concentrations measured under the same conditions for a representative 3R4F cigarette batch.

References

  1. U.S. Department of Health and Human Services. Food and Drug Administration. Center for Tobacco Products. Modified Risk Tobacco Product Applications. Guidance for Industry. (2012)
  2. U.S. Food and Drug Administration.Reporting Harmful and Potentially Harmful Constituents in Tobacco Products and Tobacco Smoke Under Section 904(a)(3) of the Federal Food, Drug, and Cosmetic Act (2012)
  3. Health Canada. Health Canada Test Method T-115, Determination of "Tar" and Nicotine in Sidestream Tobacco Smoke. (1999)

Aerosol characterization of pMRTP (vs. 3R4F) Results

Harmful and potentially harmful constituents in pMRTP aerosol vs. 3R4F smoke

Focusing on the product level, both prototype MRTP aerosols and cigarette smoke were generated using the Health Canada Intense (HCI) machine-smoking regimen, and the concentration of the 58 HPHCs were determined.

The figure below provides a comparative analysis of HPHC yields of the prototype MRTP vs. the 3R4F reference cigarette on an equal nicotine delivery basis. For the values below the limit of quantification (LOQ), LOQ values are given.

Fig 1: Relative HPHC concentration in pMRTP smoke compared with 3R4F smoke, at equal nicotine concentrations.


Fig 2: Relative HPHC concentrations in 3R4F and pMRTP smoke, at equal nicotine concentrations (red circle). The size of the bubble is proportional to the concentration of the HPHC. For the HPHCs whose measurement was below LOQ, the value is replaced by LOQ.


Table 1: Yields per cigarette of selected 3R4F and pMRTP mainstream smoke constituents normalized for nicotine levels (mean+/-SD)

FDA (2012)8
3R4F
Modified risk tobacco product (MRTP)

HPHC Category

HPHC in ACToR6

(CAS registry #)7

Abbreviated FDA List4
Carcinogen
Cardiovascular toxicant
Reproductive or Developmental Toxicant
Respiratory toxicant
Addictive
Health Canada (2012)9
Hoffmann List
(199310,199711)
IARC12
Surgeon general (1981)13
Talhout et al. (2011)14
WHO TobReg (2008)15
Concentration unit
(per mg nicotine)
Mean
Sd
Mean
Sd
ISO parameters Tar 0 mg 14.3 0.7 6.9 1.6
Total particulate matter (TPM) 0 mg 22.2 1.2 35.6 1.3
Nicotine
(54-11-5)
0 mg 1 0.05 1 0.1
Carbon monoxide
(630-08-0)
0 mg 14.8 0.7 2.6 0.5
Water
(7732-18-5)
0 mg 7 0.7 27.8 1.4
Aldehydes Acetaldehyde
(75-07-0)
2B µg 323 11.9 70.8 10.1
Acetone
(67-64-1)
0 µg 77 5.5 11.7 2.4
Acrolein
(107-02-8)
3 µg 719 50.1 8.4 1.4
Butyraldehyde
(123-72-8)
0 µg 41.7 3.6 6.8 1.1
Crotonaldehyde
(4170-30-3)
3 µg 40.5 4.3 <LOQ
Formaldehyde
(50-00-0)
1 µg 28.3 3.5 17.1 2.8
Methyl ethyl ketone
(78-93-3)
0 µg 91.9 5.8 <LOQ
Propionaldehyde
(123-38-6)
3 µg 58.1 2.68 4.7 0.9
Aliphatic hydrocarbons, volatiles, semi-volatiles 1,3-Butadiene
(106-99-0)
1 µg 36.7 3.6 <LOQ
Isoprene
(78-79-5)
2B µg 427 36.4 1.5 0.3
Aliphatic nitrogen compounds Acetamide
(60-35-5)
2B µg 7.2 0.4 2.2 0.3
Acrylamide
(79-06-1)
2A µg 2.03 0.157 1.11 0.131
Acrylonitrile
(107-13-1)
2B µg 14.4 0.894 <LOQ
Aromatic amines 1-Aminonaphthalene
(134-32-7)
3 ng 9.95 0.6 <LOQ
2-Aminonaphthalene
(91-59-8)
1 ng 5.1 0.2 0.07 0.01
3-Aminobiphenyl
(2243-47-2)
0 ng 1.6 0.2 <LOQ
4-Aminobiphenyl
(92-67-1)
1 ng 1.3 0.1 <LOQ
o-Toluidine
(95-53-4)
1 ng 43.5 1.5 1.1 0.2
Elements Arsenic
(7440-38-2)
1 ng 3.3 0.2 4.9 0.4
Cadmium
(7440-43-9)
1 ng 63.7 3.3 <LOQ
Chromium
(7440-47-3)
1 ng <LOQ <LOQ
Lead
(7439-92-1)
2B ng 14.8 0.8 <LOQ
Mercury
(7439-97-6)
3 ng 1.9 0.1 0.8 0.1
Nickel
(7440-02-0)
1 ng <LOQ <LOQ
Selenium
(7782-49-2)
3 ng 0.7 0.1 <LOQ
Halogen compounds Vinyl chloride
(75-01-4)
1 ng 50.2 2.8 2.2 0.5
Inorganic compounds Ammonia
(7664-41-7)
0 µg 19.4 0.8 17.9 0.9
Hydrogen cyanide
(74-90-8)
0 µg 215 17.2 <LOQ
Nitric oxide (NO)
(10102-43-9)
0 µg 218 10.3 31.2 1.7
Nitrogen oxides
(11104-93-1)
0 µg 240 12.3 31.7 1.6
Monocyclic aromatic hydrocarbons Benzene
(71-43-2)
1 µg 46.8 1.7 1.1 0.06
Styrene
(100-42-5)
2B µg 11.9 0.5 0.1 0.01
Toluene
(108-88-3)
3 µg 97.8 3.8 0.5 0.06
N-nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)
(64091-91-4)
1 ng 117 5.6 13.5 1.8
N'-nitrosoanabasine (NAB)
(1133-64-8)
3 ng 18 1.2 3.1 0.4
N-nitrosoanatabine (NAT)
(71267-22-6)
3 ng 173 10.1 26 2.7
N'-nitrosonornicotine (NNN)
(16543-55-8)
1 ng 155 4.3 16.9 2
Others Benzidine
(92-87-5)
1 ng N.D. N.D.
Ethylene oxide
(75-21-8)
1 µg 12.9 1 0.09 0.01
Nitrobenzene
(98-95-3)
2B N.D. N.D.
Propylene oxide
(75-56-9)
2B µg 0.7 0.02 0.04 0.003
Pyridine
(110-86-1)
3 µg 18 0.8 0.7 0.1
Quinoline
(91-22-5)
0 µg 0.27 0.03 <LOQ
Phenols Catechol
(120-80-9)
2B µg 43.8 2.2 8.6 0.9
Hydroquinone
(123-31-9)
3 µg 40.2 1.9 3.2 0.3
m+p cresol
(108-39-4,106-44-5)
0 µg 6 0.5 0.04 0.02
o-Cresol
(95-48-7)
0 µg 2.1 0.2 0.03 0.01
Phenol
(108-95-2)
3 µg 6.6 0.5 0.5 0.2
Resorcinol
(108-46-3)
3 µg 0.9 0.04 0.01 0.001
Polycyclic aromatic hydrocarbons Benz[a]anthracene
(56-55-3)
2B ng 9.2 3.2 9.6 0.5
Benzo[a]pyrene
(50-32-8)
1 ng 4.7 1.9 4.0 0.3
Dibenz[a,h]anthracene
(53-70-3)
2A ng <LOQ 0.4 0.05
Pyrene
(129-00-0)
3 ng 25.5 15.2 37.4 1.8
<LOQ: below lower limit of quantification; N.D.: not determined.
Carcinogenic substances classification from the International Agency for Research on Cancer (IARC)
  • 0: no data
  • Group 1: Carcinogenic to humans
  • Group 2A: Probably carcinogenic to humans
  • Group 2B: Possibly carcinogenic to humans
  • Group 3: Not classifiable as to its carcinogenicity to humans
  • Group 4: Probably not carcinogenic to humans

References

  1. Gladden, T. et al. Combustible heat source for a smoking article. Patent WO2012/164077 A1 (2012).
  2. Maeder, S. et al. Distillation-based smoking article. Patent WO 2009/022232 A2 (2009).
  3. U.S. Department of Health and Human Services. Food and Drug Administration. Center for Tobacco Products.Modified Risk Tobacco Product Applications. Guidance for Industry (2012)
  4. U.S. Food and Drug Administration.Reporting Harmful and Potentially Harmful Constituents in Tobacco Products and Tobacco Smoke Under Section 904(a)(3) of the Federal Food, Drug, and Cosmetic Act (2012).
  5. Health Canada. Health Canada Test Method T-115,Determination of "Tar" and Nicotine in Sidestream Tobacco Smoke. (1999).
  6. ACToR: Link based on CAS number to the world largest toxicity metabase ACToR from EPA
  7. CAS: ID from the CAS registry
  8. FDA 2012: Classification from: Harmful and Potentially Harmful Constituents in Tobacco Products and Tobacco Smoke: Established List
  9. Health Canada 2012 List
  10. 1993: Hoffmann D. Analysis of Toxic Smoke Constituents. In: U.S.Consumer Product Safety Commission (CPSC) in Consultation with the U.S: Department of Health and Human Services. Vol. 5 Toxicity testing plan for low ignition-potential cigarettes, U.S. Consumer Product Safety Commission 1993.
  11. 1997: Hoffmann D and Hoffmann I. The Changing Cigarette. Journal of Toxicology and Environmental Health, 50:307-364, 1997.
  12. IARC: Groups as for IARC 2012
  13. Surgeon general (1981). The Health Consequences of Smoking. The Changing Cigarette, a Report of the Surgeon General. U.S. Department of Health and Human Services, 1981.
  14. Talhout et al., 2011: 1 Talhout, R. et al. Hazardous compounds in tobacco smoke. International journal of environmental research and public health 8, 613-628, doi:10.3390/ijerph8020613 (2011).
  15. WHO TobReg 2008: TobReg Recommendation

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