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PRIVILEGED AND CONFIDENTIAL:
ATTORNEY WORK PRODUCT
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 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
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.
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,
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
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
Regulatory Status - iIenthol 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.
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1. R. K. Heimann, Tobacco and Americans, McGraw-Hill, N.Y.,
2. Maxwell Report, Lehman Brothers Kuhn Loeb Res., N.Y., Oct.
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.
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.
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.