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Product Design

Menthol

Date: 25 Nov 1981
Length: 3 pages
504331475-504331477
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Abstract

Discusses the usage of the term menthol, its sources, usage in cigarettes as a cooling agent and the biological data available on menthol's effects on humans and laboratory rats and rabbits. Diffentiates between d-menthol, l-menthol and racemic menthol. Discusses carcinogenicity and menthol and its regulatory status. Notes menthol's inclusion on the Generally Recognizes As Safe ingredients list. Includes references.

Fields

Hypothesis
Use of additives
Modification of tobacco products through use of additives and measuring effects on dependence, behavior, and toxicity.
Keyword
Acceptable Daily Intake (ADI)
Animal testing
Carcinogenic (Cancer-causing)
Generally_Recognized_As_Safe
Human testing
Irritation (Attribute measure)
Lung tumors
Maximum Tolerated Dose (MTD)
Pyrolysis
Vapor phase
Volatility
Additive
Isomenthol
Mentha Arvensis (Mentha Arvensis Oil)
Menthol
Neoisomenthol
Neomenthol
Racemic menthol
Smoke Constituent
Benzo(a)pyrene
Phenol
Named Organization
FEMA (Flavors and Extracts Manufacturers Association) (Trade association of flavor ingredient manufacturers)
National Cancer Institute NCI
Division of Cancer Prevention and Control, National Cancer Institute located in Rockville, MD
United States Food and Drug Administration
World Health Organization (Concerned with global public health)
International organization concered with public health worldwide
Brand
SPUD
Subject
Menthol (Additives)

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PRIVILEGED AND CONFIDENTIAL: ATTORNEY WORK PRODUCT MENTHOL Terminology - In terms of tobacco industry usage the term menthol is generally used in reference to the specific compcund_ 1-menthol, as distinguished from the isomer d-menthol. The latter plus other related menthols bearing prefixes such as iso, neo and neoiso are usually very minor constituents of commercial 1 - menthol. Sources - Both natural and synthetic menthol are available. Natural is obtained from the plant mentha arvensis by extraction of the essential oil followed by low temperature crystallization.. Brazil, Japan and China are the main sources of natural menthol. In the past ten years synthetic menthol has become commercially available. Minor constituents vary depending on the type of menthol used and can have some effect on the ultimate flavor. Usage - Menthol has been applied to cigare~tes as a cooling agent since 1926 with the introduction of "Spud" However, it has only been a major market factor since the mid - 1910's when the first filtered menthol cigarettes were introduced. Currently, it is usually applied in the range of 0.3 to 1.3% by weight to cigarettes. Mentholated brands account for approximately 28% of the market.2 Biological Data- The acute oral LD of menthol in rats (strain unspecified) has been reported in s4arate studies as 3.18 g/kg and 2.9 g/kg, while the intraperitoneal (i.p.) LD., was 750 mg/kg (3). Both the orai and i.p. LD50s in cats hava"been reported as 1.5 - 1.6 .g/kg. The subcutanez5us LD 0 in mice (strain unspecified) was 1.4 - 1.6 g/kg. In rabbits (s~rain unspecified), the i.p. LD 0 was approximately 2 g/kg while the dermal LD50 was greater th~n 5 g/kgi Racemic menthol (a mixture of d and 1 isomers) was mildly irritating when applied undiluted to intact or abraded rabbit skin for 24 hours under occlusion. At a concentration of 8% in petrolatum, it produced no irritation (48-hour closed-patch test) or sensitization reactions in human subjects. The effect of subcutaneously administered menthol on pentobarbital sleep-times in female Sprague-Dawle_v rats has been investigated.4 Rats were pretreated with 500 mg/kg menthol either 18 or 36 hours before receiving a 25 mg/kg intraperitoneal injection of phenobarbital. Sleep-time, i.e., the time elapsed between loss and regaining of the righting reflex, was then
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measured. Menthol pre-treatment had no effect on the sleep duration of phenobarbital-treated rats. 5 In a study by Stoner, et.a1., menthol was administered intraperitoneally in a tricaprylin vehicle (containing unspeci- fied impurities) to female A/He mice (30/group). Animals were injected 3 times weekly with the maximum tolerated dose (MTD) or 0.2 MTD for 7 weeks. In this study, the MTD is defined as the maximum single dose that 5/5 mice tolerated after receivi_zg 6 intraperitioneal injections over a 2-week period. The total doses given were 2 g/kg and 0.5 g/kg for the MTD and 0.2 MTD, respectively. Under the conditions of this study, menthol did not produce an increase in primary lung tumors when compared with controls. The carcinogenicity of dl-menthol has been evaluated in Fischer 344 rats and B6C3F1 gice as part of the National Cancer Institutes' Bioassay Program. Rats (50/sex/group) were administered dietary levels of 3750 or 7500 ppm for 103 weeks .while mice (50/sex/group) were given 2,000 or 4,000 ppm menthol in their diet,for 103 weeks. Results indicated that mean body weights of treated rats and mice were slightly lower than controls. No other clinical signs were noted. A dose-related trend in mortality, i.e., decreased survival, was observed in treated female mice. An adeauate number of animals (at least 6.2%/group) were alive at study end and were at risk for development of late-appearing tumors. There were no increased incidences of tumors observed in either rats or mice after menthol treatment. Under the conditions of this study, dl-menthol was not carcinogenic for either Fischer 344 rats or B6C3F1 mice. Pyrol_ytic Data - Due to it's volatility menthol is not pyrolyzed in the burning cigarette. Sublimation to the vapor phase occurs before contact with the burning ~oie9and thus mg$thol is transferred intact to the smoke. '' A study of the pyrolysis of menthol alone reports generation of phenol and benzo [a] pyrene, but this does not appear to be related to the smoke chemistry. Regulatory Status - iĀ•Ienthol was given GRAS status by FEMA in 1965 and is approved by the FDA for food use (21 CFR 121.1164) The Council of Europe 11 (1974) listed menthol, giving an Acceptable Daily Intake (ADI) of 2mj12kg. The Joint FAD/WHO Expert Comittee on Food Additives (1968) gave an unconditional ADI of 0-0.2 mg/kg. Menthol has been place13on the Hunter List as an accepted cigarette additive in Britain. These are no OSHA standards existing concerning limits of exposure to menthol in the workplace. 2
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References 1. R. K. Heimann, Tobacco and Americans, McGraw-Hill, N.Y., 1960. 2. Maxwell Report, Lehman Brothers Kuhn Loeb Res., N.Y., Oct. 25, 1981. 3. Opdyke, D. L., 1976. "Fragrance Raw Materials Monographs. Menthol Racemic." Fd. Cosmet. Toxicol. 14: 473-474. - '; 4. Jori, A., Bianchetti, A., and Prestini, P. E., 1969. `' "Effect of Essential Oils on Drug Metabolism." Biochem. Pharm. 18: 2081-2085. i - , 5. Stoner, G. D., Shimkin, M. B., Kniazeff, A. J., Weisburger, J. H., Weisburger, E. K., and Gori, G. B., 1973. "Test for Carcinogenicity of Food Additives and Chemotherapeutic Agents by the Pulmonary Tumor Response in Strain A Mice." Cancer Research 33: 3069-3085. 6. National Cancer Institute 1978, "Bioassay of dl-Menthol for 'F Possible Carcinogenicity." NCI-CG-TR-98. ~ 7. J. G. Curran, Delivery of Menthol from Cigarettes, Tob. 4 Sci., XVI (1972) 40. ~ 8. R. F. Dawson, R. D. Carpenter, Coresta Bulletin, Special, Abstract B001, 1970. 9. R. W. Jenkins, R. H. Newman, Cigarette Smoke Formation Studies, Beitr. Tabak-forschung, 5 (1970) 299. 10. I. Schmeltz, W. S. Schlotzhawer, Nature, 219 (1968) 370. 11. Council of Europe (1974). List (1), No. 63, p. 137. Strasbourg. 12. Joint FAD/WHO Expert Committee on Food Additives (1968). WHO/Food'Add./68.33; F.A.O. Nutr. Mtg. Rep. Ser. no. 44A, Rome, p. 58. 13. British Department of Health and Social Security, List of Permitted Additives to Tobacco Products, London Gazette, Jan. 13, 1978, p. 484. 3

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