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SUMMARY OF DATA FOR CHEMICAL SELECTION
-CITRONELLOL
CAS NO. 106-22-9
BASIS OF NOMINATION TO THE CSWG
The nomination of citronellol to the CSWG is based on high production volume,
widespread human exposure, and an unknown potential for adverse health effects from
long-term administration. Citronellol came to the attention of the CSPG because of
information supplied by the Food and Drug Administration (FDA) from a review of
“GRAS” substances used as spices and food additives. According to the FDA data,
citronellol is found in 17 different spices. It is also a common flavoring in beverages
and foods and is one of the most widely used fragrance materials, having the sweet
aroma of rose. Occupational exposure to citronellol in the United States is significant,
estimated to be over 160,000 workers in 62 industries. Citronellol is present in high
concentrations in citronella, geranium, and rose oils, accounting for additional human
exposure. It is also closely related to citronellal and seven esters also having “GRAS”
status.
SELECTION STATUS
ACTION BY CSWG: 7/16/97
Studies requested:
- Metabolism studies
-
-
-
Mechanistic studies to include examination of the role of
Carcinogenicity
In vitro cytogenetic analysis
α2u -globulin in transport
- In vivo micronucleus assay
Priority: Moderate
Rationale/Remarks:
- High production levels
- Widespread exposure as an ingredient in natural products
- Lack of chronic toxicity data
- Test in parallel with linalool
INPUT FROM GOVERNMENT AGENCIES/INDUSTRY
Dr. Dan Benz, Center for Food Safety and Applied Nutrition (CFSAN), Food and Drug
Administration (FDA) and Dr. Ed Matthews (formerly with CFSAN) provided
information on citronellol from FDA’s Priority-Based Assessment of Food Additives
(PAFA) database. Ms. Joellen Putnam, Scientific Project Manager, Flavor and Extract
Manufacturers’ Association (FEMA) provided a copy of the FEMA monograph on
citronellol.
CHEMICAL IDENTIFICATION
CAS Registry Number:
H3 C H
106-22-9
Chemical Abstracts Service
(8CI,9CI) CH2 OH
Name: 6-Octen-1-ol, 3,7-dimethylSynonyms and Trade
dlcitronellol;
H3 C CH3
Names: Cephrol; citronellol; β-citronellol;
−-citronellol; Rhodinol; Rodinol
Structural Class: Acyclic, unsaturated, monoterpenoid tertiary,
allylic alcohol
Structure, Molecular Formula and Molecular Weight:
O Mol. wt.: 156.27C10H20
Chemical and Physical Properties:
Natural citronellol consists solely of the β form although α-citronellol has been prepared
(Bedoukian, 1985).
Description: Colorless, oily liquid with a rose-like odor (FEMA, 1997)
Boiling Point: 224%C (Lide, 1995)
Vapor pressure: ~0.009 mm Hg at 20%C (FEMA, 1997)
Refractive index: 1.4543 at 20%C (Lide, 1995)
Flash Point: >93%C (CC) (FEMA, 1997)
Density: 0.8560 g/cm3 at 20%C (Lide, 1995)
Solubility: Very slightly soluble in water; miscible with alcohol,
ether (Budavari, 1996)
Technical Products and Impurities: Citronellol is available in several grades (purity): Citronellol
Terpenes (2.0-20.0%), Citronellol Select (20.0-25.0%), Citronellol 80 (80.0-85.0%),
Citronellol Prime (85.0-87.0%), and Citronellol AJ, FCC (94.0-96.0%) (Millenium Specialty
Chemicals, 1995a,b,c,d,e).
EXPOSURE INFORMATION
Production and Producers: Citronellol is listed in the EPA’s TSCA Inventory (NLM, 1997a).
For citronellol, the method of production is closely related to usage. Premium quality
citronellol used in expensive perfumes is organoleptically controlled (Millenium
Speciality Chemicals, 1995b). (-)-Citronellol is still obtained mainly from geranium oil
by saponification followed by fractional distillation. Much larger quantities of (+)- and
(Å)-citronellol are used and are prepared by partial or total synthesis. The following
methods have been reported for the production of citronellol: (1) synthesis of (+)- and
(Å)-citronellol from the citronellal fraction of essential oils; (2) synthesis of (Å)citronellol from geraniol fractions of essential oils; (3) synthesis of (Å)-citronellol from
synthetic geraniol-nerol or citral; and (4) preparation of (-)-citronellol from optically
active pinenes (Bauer et al., 1988).
In the first method, (+)-citronellal is obtained by distillation of Java citronella oil and is
hydrogenated to (+)-citronellol in the presence of a catalyst (e.g., Raney nickel).
Similarly, (Å)-citronellol is prepared from the (Å)-citronellal fraction of Eucalyptus
citriodora oil. In the second method, citronellol is produced by catalytic hydrogenation
of saponified geraniol fractions obtained from Java citronella oil, followed by fractional
distillation. Selective hydrogenation of the double bond in the 2-position of geraniol in
geraniol-citronellol mixtures isolated from essential oils can be achieved by using Raney
cobalt as a catalyst. In the third method, a considerable amount of commercial synthetic
(Å)-citronellol is produced by partial hydrogenation of synthetic geraniol and/or nerol.
Another starting material is citral, which can be hydrogenated, e.g., in the presence of a
catalyst system consisting of palladium, ruthenium, and trimethylamine. In the fourth
method, (+)-cis-pinane obtained from pinene is pyrolyzed to give (+)-3,7-dimethyl-1,6octadiene; this is converted into (-)-citronellol (97% purity) by reaction with
triisobutylaluminum or diisobutylaluminum hydride, followed by air oxidation and
hydrolysis of the resulting aluminum alcoholate (Bedoukian, 1985; Bauer et al., 1988).
Recent import data indicate that 202,000 and 109,000 kg of citronellol were imported
into the U.S. from the UK, France, Germany, Switzerland, China, and Japan in 1995
and 1996, respectively (Anon., 1997).
Use Pattern: Citronellol is one of the most widely used fragrance materials, particularly
for rose notes (aroma) and for floral compositions in general. As a flavor material,
citronellol is added for bouquetting purposes to citrus compositions. It is the starting
material for numerous citronellyl esters and for hydroxydihydocitronellol, an
intermediate in the production of hydroxydihydrocitronellal, and it may be added directly
to soaps and detergents (Bauer et al., 1988; Millenium Speciality Chemicals, 1995b).
The bulk of citronellol used in industry is derived from pinene, however, considerable
quantities of natural citronellol isolated from essential oils are used by perfumers.
Because of the varying quantities of geraniol and trace impurities present, the natural
citronellol possesses a distinctive olfactory characteristic. Reduction of citronellal also
yields a type of citronellol preferred by some perfumers. The annual consumption of
citronellol by perfumers in the U.S. was estimated to be around 200,000 lbs. in the
1980s (Bedoukian, 1985).
Numerous natural and artificial flavorings in alcoholic and nonalcoholic beverages (1-4
ppm), hard and soft candies (2-18 ppm), chewing gum (8-9 ppm), ice creams (1-40
ppm), gelatin puddings (2-6 ppm), and baked goods (6-20 ppm) contain various
amounts of citronellol. The GRAS list of flavoring ingredients published in 1965
includes citronellol and seven of its common esters (Bedoukian, 1985; FEMA, 1997).
Citronellol has been detected as a volatile component of orange juice (0.015-0.08 ppm),
lemon peel oil, bilberry (0.001 ppm), guava (0.06-0.82 ppm), nutmeg (trace), beer
(0.01 ppm), white wine (trace), red wine (0.02-0.04 ppm), black tea (2-10 ppm), green
tea (1 ppm), mango, star anise (500-800 ppm), and plum brandy (0-16 mg/l) (De
Vincenzi et al., 1987; FEMA, 1997).
Human Exposure: There is potential for widespread, low level exposures to citronellol
in general and to consumer populations resulting from its presence as a flavoring agent
in foods and as a fragrance material. The National Occupational Exposure Survey
(NOES), which was conducted by the National Institute for Occupational Safety and
Health (NIOSH) between 1981 and 1983, estimated that 163,706 workers in 62
industries, including 87,309 female employees, were potentially exposed to citronellol in
the workplace. The NOES database does not contain information on the frequency,
level, or duration of exposure to workers of any chemical listed therein (NLM, 1997a).
Environmental Occurrence: In many natural products, citronellol occurs as a mixture of
its two enantiomers; the pure (+)-citronellol [1117-61-9] and (-)-citronellol [7540-51-4]
form are seldom found (Bauer et al., 1988). Citronellol has been reported in nearly a
hundred essential oils. It is interesting that rose oils yield the practically pure (-)-form
whereas geranium oils give a mixture of both with the (-)-form predominating
(Bedoukian, 1985).
Citronellol was identified in influent wastewater during a screening for non-regulated
organic compounds in municipal wastewater in Göteborg, Sweden (Paxéus & Schröder,
1996).
Citronellol has also been qualitatively identified in perfumes, shampoo, after-shave
lotion, nail enamel remover, and fabric softener (Wallace et al., 1991).
Regulatory Status: No standards or guidelines have been set by NIOSH or OSHA for
occupational exposure to or workplace maximum allowable levels of citronellol. The
American Conference of Governmental Industrial Hygienists (ACGIH) has not
recommended a threshold limit value (TLV) or biological exposure index (BEI) for
citronellol. Citronellol is a “generally recognized as safe” (GRAS) substance approved
by the FDA as a direct food additive (synthetic flavoring substance) for human
consumption (FDA, 1996).
EVIDENCE FOR POSSIBLE CARCINOGENIC ACTIVITY
Human Data: No epidemiological studies or case reports investigating the association of
exposure to citronellol and cancer risk in humans were identified in the available
literature.
Animal Data: No 2-year carcinogenicity studies of citronellol in animals were identified
in the available literature. Toxicity information identified was limited to acute and
subchronic studies. Acute toxicity values are shown in Table 1.
Table 1. Acute toxicity data for citronellol
Route Species LD50 (mg/kg) Reference
Moreno, 1973Oral Rat 3450
Intramuscular Mouse 4000 Northover & Verghese, 1962
Subcutaneous Mouse 880 Nozawa, 1952
Dermal Rabbit 1780-3520 Moreno, 1973
No adverse effects were reported when citronellol, as part of a 50:50 mixture with
linaloo1, was added to the diet of rats for 12 weeks at a level calculated to provide an
average daily intake of 50 mg/kg. A slight retardation of growth rate and decreased food
efficiency uptake in males were attributed to unpalatability of the test diet (Oser, 1967).
The ability of citronellol to inhibit azoxymethane (AOM) induced neoplasia has been
assessed. Male F344 rats (18-19 rats per group) were administered subcutaneous AOM
doses of 15 mg/kg bw twice a week for 3 weeks followed by 5 mg citronellol/g of diet
for 22 weeks. Citronellol administration resulted in a modest decrease in the number of
adenocarcinomas of the duodenum which was not statistically significant. Incidence in
the control and citronellol-treated rats was 50% and 26%, respectively; multiplicity was
0.6 and 0.4 tumors/rat, respectively. Citronellol had no effect on tumors of the large
bowel (Wattenberg, 1991).
Short-Term Tests: At concentrations of 8-16 ppm, citronellol was not mutagenic in
Salmonella typhimurium strains TA98 or TA100. Strain TA98 was tested with and
without S9 while TA100 was only tested without activation (Kono et al., 1995).
Rockwell and Raw (1979) also reported negative results in strains TA98 and TA100
when citronellol was tested at 0.05-100 &l with S9. Urine samples from rats
administered 0.5 ml of citronellol were also negative when assayed with strains TA98
and TA100 (Rockwell & Raw, 1979).
Citronellol (17 &g/disk) was negative in the rec-assay in Bacillus subtilis strains H17
and M45 (Oda et al., 1978).
Metabolism: Available information on the metabolism, retention, and excretion of
citronellol is extremely limited.
FEMA (1994) speculates that citronellol will be metabolized in humans principally by
alcohol oxidation and 4-oxidation to yield 2,6-dimethyl-6-octendioic acid. This acid
would be excreted primarily in the urine as an unspecified glucuronic acid conjugate.
FEMA bases these speculations on studies of citronellal and on branched-chain aliphatic
alcohols and related aldehydes, overall.
Citing studies by Parke (1974), Phillips and coworkers (1976), and Diliberto and
coworkers (1988), FEMA notes that branched-chain aliphatic alcohols are rapidly
absorbed from the gastrointestinal tract. Once absorbed, FEMA notes that metabolic
pathways available to form oxygenated polar metabolites include 4-oxidation, alcohol
oxidation, hydration, selective hydrogenation, and conjugation. Based on the work of
Chadha and Madyastha (1982, 1984) and Ishida and coworkers (1989), FEMA
speculates that 4-oxidation of citronellal to yield diols will compete favorably with
oxidation of citronellol to yield citronellal. This would lead to the formation of 2,6dimethyl-2-octendioic acid (reduced Hildebrandt’s acid). FEMA supports the
plausibility of this metabolic pathway by noting that 2,6-dimethyl-2-octendioic acid
(Asano & Yamakawa, 1950) and an alcohol precursor, 8-hydroxy-3,6-dimethyl-6octenoic acid (Fischer & Beilig, 1940) have been reported as urinary excretion products
of d-citronellol.
While the metabolic pathway described above is plausible, it is unlikely that it is the only
one. Ishida and coworkers (1989) found an acidic metabolite in the urine of rabbits
administered citronellal. They also found three neutral metabolites, (-)- and (+) pmenthane-3,8-diols and isopregol. The p-menthane diols were also formed when rabbit
gastric juice was mixed with citronellal. It also has been shown that rabbits can
metabolize citronellol to reduced Hildebrandt acid and a 7-hydroxymethyl precursor.
Together these two compounds accounted for only 10% of the administered dose (Lewis
et al., 1994).
Citronellal can be metabolized in rabbits by undergoing a proton-catalysed cyclization
and conjugation with glucuronic acid (Lewis et al., 1994). Citronellol, the
corresponding alcohol, does not undergo cyclization. How these differences influence
uptake, excretion, and metabolism is not known.
Certain other spice components are known to induce liver enzymes, an important
consideration in their metabolism and potential toxicity. Very little information was
found on citronellol. Chadha and Madyastha (1984), citing previous work, noted that
rat liver and lung microsomal preparations catalyze the hydroxylation of citronellol to
form 4- oxidation products.
Other Biological Effects: Citronellol was one of 19 acyclic terpenes evaluated for
potential toxicity/carcinogenicity by “Computer Optimized Molecular Parametric
Analysis of Chemical Toxicity” (COMPACT) which uses molecular orbital
determinations of a chemical’s spatial and electronic parameters for prediction of its
metabolic activation or detoxification by the cytochrome P-450 (CYP) super family of
mixed-function oxidase enzymes. Previous studies characterized the spatial dimensions
of the CYP1K1, 1A2, and 2E1 enzymes which are known to activate mutagens and
carcinogens. None of the terpenes was found to have shape or electronic parameters
appropriate for metabolic activation by CYP1A1 or 1A2. In addition, none of the
chemicals had spatial parameters critical for substrates of CYP2E, and are therefore
unlikely to induce formation of reactive oxygen species (ROS) or to initiate or promote
malignancy or toxicity by mechanisms involving ROS (Lewis et al., 1994).
Structure Activity Relationships: Citronellol was chosen as a representative of the
various impure oils (mixtures), spices, flavorings, fragrances, and household products
that contain some form of citronella. As structurally related compounds, food grade
geranyl acetate, which contains 29% citronellyl acetate, and the closely related citronellal
were obvious choices. Other compounds selected were citral and myrcene, two spice
components that like citronellol have an acyclic structure that can fold into an open ringlike configuration. Citral, a mixture of geraniol and nerol, is on test at NTP. It has a
polar substituent that may provide an active site. Myrcene, which does not contain a
polar substituent, is the simplest member of the structurally related group. A summary
of information found in the available literature is presented in Table 2.
Table 2 . Summary of information on citronellol and structurally related
compounds
Chemical Name Carcinogenicity Data Mutagenicity Data
Citronellol
[106-22-9]
CH2 OH
CH3H3C
HH3C
modest inhibition of AOM-induced
adenocarcinomas of the duodenum
(Wattenberg, 1991)
unlikely to be carcinogenic in a
Computerized Optimized Molecular
Parametric Analysis of Chemical
Toxicity (COMPACT) evaluation
(Lewis et al., 1994)
negative in S. typhimurium strains
TA98 and TA100 with or without
S9 (Kono et al., 1995; Rockwell &
Raw, 1979)
negative in B. subtilis rec assay
(Oda et al., 1978)
Citronellal
[106-23-0]
CHO
CH3H3 C
CH3
unlikely to be carcinogenic in a
COMPACT evaluation (Lewis et
al., 1994)
negative in S. typhimurium strains
TA98 and TA100 with or without
S9 (Kasamaki et al., 1982)
induced chromosomal aberrations
in Chinese hamster B241 cells
(Kasamaki et al., 1982)
posttreatment did not influence
mitomycin C-induced sister
chromatid exchanges in Chinese
hamster ovary cells (Sasaki et al.,
1989)
Citral
[5392-40-5]
CHO
CH3H3 C
CH3
NTP prechronic studies in rats and
mice (microencapsulation in feed)
have been completed, and citral is
on test in rats and mice (NTP,
1997)
Several studies have predicted the
carcinogenic activity of citral in the
NTP bioassay. Six predicted it to
be noncarcinogenic: evaluation by
COMPACT, CASE/MULTICASE,
rule learning (RL), and DEREK as
well as two on chemical structure,
genotoxicity, and rodent toxicity
considerations. Three predicted it
to be carcinogenic based on
chemical structure, genotoxicity,
and rodent toxicity considerations.
Equivocal results were predicted by
the Rapid Screening of Hazard
(RASH) method (Ashby, 1996;
Benigni et al., 1996; Bootman,
1996; Huff et al., 1996; Jones &
Easterly, 1996; Lee et al., 1996;
Lewis et al., 1996; Marchant & The
DEREK Group, 1996; Tennant &
Spalding, 1996; Zhang et al.,
1996)
inhibited tumor promotion in a twostage skin-carcinogenesis study in
hairless mice (Connor, 1991)
negative in S. typhimurium strains
TA92, TA1535, TA100, TA1537,
TA94, and TA98 with or without
S9 (Lutz et al., 1982; Ishidate et
al., 1984; Zeiger et al., 1987)
did not demonstrate antimutagenic
potential against the activity of
several chemical mutagens in S.
typhimurium and E. coli or against
UV-induced mutagenesis in E. coli
(Ohta et al., 1986a,b)
negative for chromosomal
aberrations in Chinese hamster
fibroblast cells without S9 (not
tested with S9) (Ishidate et al.,
1984)
induced DNA repair in B. subtilis
(NLM, 1997b)
negative for chromosome
aberrations and positive for sister
chromatid exchanges in Chinese
hamster ovary cells (Givaudan
Corp., 1985)
Myrcene
[123-35-3]
CH2
CH3H3 C
CH2
oral administration did not inhibit
the production of DMBA-induced
mammary tumors in SpragueDawley rats (Russin et al., 1989)
negative in the Chinese hamster V79/6-thioguanine assay with or
without S9 (CCRIS, 1997)
negative for chromosomal
aberrations and SCEs in human
lymphocytes and for mutation at
the HPRT locus in V79 cells
(Roscheisen et al., 1992a)
negative in the in vivo bone
marrow chromosome aberration
test with rats (Roscheisen et al. ,
1992a)
reduced SCEs-induced by S9activated cyclophosphamide in
human lymphocytes and V79 cells;
also inhibited SCEs in V79 cells
induced by aflatoxin B1 but not by
BAP or DMBA (Roscheisen et al. ,
1992b)
Geranyl acetate
[cis=141-12-8]
[trans=105-87-3]
Food grade geranyl
acetate contains
29% citronellyl
acetate
[150-84-5]
CH3
CH2OCCH3
O
Mouse
no evidence of carcinogenic activity
in male and female B6C3F1 mice
gavaged with 500 or 1000 mg/kg
(food grade) 5 times a week for up
to two years; survival of high dose
males and females (91 weeks) and
of low dose females may have been
inadequate for detection of late
appearing tumors (NTP, 1987)
Rat
negative in a B. subtilis rec-assay
(NTP, 1987)
negative in S. typhimurium strains
TA98, TA100, TA1535, and
TA1537 with or without S9 (NTP,
1987)
CH3H3C
trans-geranyl
acetate
CH3
CH3H3C
CH2OCCH3
O
citronellyl acetate
no evidence of carcinogenic activity
in male and female F344/N rats
gavaged with 1000 or 2000 mg/kg
(food grade) 5 times a week for
two years; reduced 2-year survival
in high dose males (18/50) lowered
sensitivity and the marginal
increases of squamous cell
papillomas of the skin and renal
tubular cell adenomas observed in
low dose male rats may have been
related to administration of geranyl
acetate (NTP, 1987)
REFERENCES
Anon. (1997) Chemical imports. Chem. Mark. Rep., 251(18), 25
Asano, M. & Yamakawa, T. (1950) The fate of branched-chain fatty acids in the body. 1. A
contribution to the problem of “Hildebrandt Acid.” J. Biochem. (Tokyo), 37 , 321-327
[cited in: FEMA (1994)]
Ashby, J. (1996) Prediction of rodent carcinogenicity for 30 chemicals. Environ. Health
Perspect., 104(S5), 1101-1104
Bauer, K., Garbe, D. & Surburg, H. (1988) Flavors and Fragrances. In: Gerhartz, W.,
Yamamoto, Y.S., Elvers, B., Rounsaville, J.F. & Schulz, G., eds., Ullmann’s
Encyclopedia of Industrial Chemistry, 5th rev. ed., Vol. A11, New York, VCH
Publishers, pp. 157-158
Bedoukian, P.Z. (1985) Perfumery and Flavoring Synthetics, 3rd. rev. ed., Wheaton, IL,
Allured Publishing Corp., pp. 127-137
Benigni, R., Andreoli, C. & Zito, R. (1996) Prediction of rodent carcinogenicity of further
30 chemicals bioassayed by the U.S. National Toxicology Program. Environ. Health
Perspect., 104(S5), 1041-1044
Bootman, J. (1996) Speculations on the rodent carcinogenicity of 30 chemicals under
evaluation in rat and mouse bioassays organised by the U.S. National Toxicology
Program. Environ. Mol. Mutagen., 27 , 237-243
Budavari, S., ed. (1996) The Merck Index, 12th ed., Whitehouse Station, NJ, Merck & Co.,
Inc., pp. 393-394
CCRIS (1997) Chemical Carcinogenesis Research Information System, National Library of
Medicine, Bethesda, MD, searched May 1997
Chadha, A. & Madyastha K.M. (1982) Omega-hydroxylation of acyclic monoterpene
alcohols by rat lung microsomes. Biochem. Biophys. Res. Commun., 108 , 1271-1277
Chadha, A. & Madyastha K.M. (1984) Metabolism of geraniol and linalool in the rat and
effects on liver and lung microsomal enzymes. Xenobiotica, 14 , 365-374
Connor, M.J. (1991) Modulation of tumor promotion in mouse skin by the food additive
citral (3,6-dimethyl-2,6-octadienal). Cancer Lett., 56 , 25-28
De Vincenzi, M., Castriotta, F., Di Folco, S., Dracos, A., Magliola, M., Mattei, R.,
Purificato, I., Stacchini, A., Stacchini, P. & Silano, B. (1987) A basis for estimation of
consumption: Literature values for selected food volatiles. Part II. Food Addit.
Contam., 4(2), 161-218
Diliberto, J.J., Usha, G. & Birnbaum, L.S. (1988) Disposition of citral in male Fischer rats.
Drug Metab. Dispos., 16 , 721-727 [cited in: FEMA (1994)]
FDA (1996) Food and Drugs. Code Fed. Regul., Title 21, Part 172.515, pp. 51-58
FEMA (1994) Monograph 2309: dl-Citronellol (FEMA No. 2309), Washington, DC, Flavor
and Extract Manufacturers’ Association, 4 pp.
FEMA (1997) FEMA Database: dl-Citronellol (FEMA No. 2309), Washington, DC, Flavor
and Extract Manufacturers’ Association, 31 pp.
Fischer, F.G. & Bielig, H.J. (1940) Hydration of unsaturated substances in animal
organisms. Hoppe-Seyler’s Z. Physiological Chem., 266 , 73-98 [cited in: FEMA
(1994)]
Givaudan Corp. (1985) National Toxicology Program Fiscal Year 1985 Annual Plan (EPA
OTS0516404)
Huff, J., Weisburger, E. & Fung, V.A. (1996) Multicomponent criteria for predicting
carcinogenicity: Dataset of 30 NTP chemicals. Environ. Health Perspect., 104(S5),
1105-1112
Ishida, T., Toyota, M. & Asakawa, Y. (1989) Terpenoid biotransformation in mammals. V.
Metabolism of (+)-citronellal, 7-hydroxycitronellal, citral, (-)-perillaldehyde, (-)myrtenal, cuminaldehyde, thujone, and carvone in rabbits. Xenobiotica, 19 , 843-855
Ishidate, M., Sofuni, T., Yoshikawa, K., Hayashi, M., Nohmi, T., Sawada, M. &
Matsuoka, A. (1984) Primary mutagenicity screening of food additives currently used in
Japan. Food Chem. Toxicol., 22(8), 623-636
Jones, T.D. & Easterly, C.E. (1996) A RASH analysis of National Toxicology Program data:
Predictions for 30 compounds to be tested in rodent carcinogenesis experiments.
Environ. Health Perspect., 104(S5), 1017-1030
Kasamaki, A., Takahashi, H., Tsumura, N., Niwa, J., Fujita, T. & Urasawa, S. (1982)
Genotoxicity of flavoring agents. Mutat. Res., 105 , 387-392
Kono, M., Yoshida, Y., Itaya, Y., Shimobo, K., Yoshikawa, K., Terashita, T. &
Shishiyama, J. (1995) Antimicrobial activity and mutagenicity of allyl isothiocyanate and
several essential oils from spices. Mem. Fac. Agr. Kinki Univ., 28 , 11-19
Lee, Y., Buchanan, B.G. & Rosenkranz, H.S. (1996) Carcinogenicity predictions for a
group of 30 chemicals undergoing rodent cancer bioassays based on rules derived from
subchronic organ toxicities. Environ. Health Perspect., 104(S5), 1059-1063
Lewis, D.F.V., Ioannides, C., Walker, R. & Parke, D.V. (1994) Safety evaluations of food
chemicals by "COMPACT" 1. A study of some acyclic terpenes. Food Chem. Toxicol.,
32(11) 1053-1059
Lewis, D.F.V., Ioannides, C. & Parke, D.V. (1996) COMPACT and molecular structure in
toxicity assessment: A prospective evaluation of 30 chemicals currently being tested for
rodent carcinogenicity by the NCI/NTP. Environ. Health Perspect., 104(S5), 10111016
Lide, D.R., ed. (1995) CRC Handbook of Chemistry and Physics, 76th ed., Boca Raton,
FL, CRC Press, p. 3-234
Lutz, D., Eder, E., Neydecker, T. & Henschler, D. (1982) Structure-mutagenicity
relationship in alpha,beta-unsaturated carbonylic compounds and their corresponding
allylic alcohols. Mutat. Res., 93 , 305-315
Marchant, C.A. & The DEREK Group (1996) Prediction of rodent carcinogenicity using the
DEREK system for 30 chemicals currently being tested by the National Toxicology
Program. Environ. Health Perspect., 104(S5), 1065-1073
Millenium Specialty Chemicals (1995a) Product Data Sheet: Citronellol Terpenes,
Jacksonville, FL
Millenium Specialty Chemicals (1995b) Product Data Sheet: Citronellol Select, Jacksonville,
FL
Millenium Specialty Chemicals (1995c) Product Data Sheet: Citronellol 80, Jacksonville, FL
Millenium Specialty Chemicals (1995d) Product Data Sheet: Citronellol Prime, Jacksonville,
FL
Millenium Specialty Chemicals (1995e) Product Data Sheet: Citronellol AJ, FCC,
Jacksonville, FL
Moreno, O.M. (1973) Acute toxicity studies on rats and rabbits. (Unpublished) [cited in:
FEMA (1994)]
NLM (1997a) RTECS (Registry of Toxic Effects of Chemical Substances), Bethesda, MD,
National Library of Medicine, searched May, 1997 [Record No. 53763]
NLM (1997b) RTECS (Registry of Toxic Effects of Chemical Substances), Bethesda, MD,
National Library of Medicine, searched May, 1997 [Record No. 53745]
Northover, B.J. & Verghese, J. (1962) The pharmacology of certain terpene alcohols and
oxides. J. Sci. Res. Sect. C., 21 , 342-345
Nozawa, Y. (1952) A report on studies of anthelminthic actions of principles of volatile oils.
III. Toxicity for mice and the efficacy against pig ascaria and earthworm muscles.
Sapporo Igaku Zasshi, 3(3-4), 73-77 [cited in: FEMA (1997)]
NTP (1987) Carcinogenesis Studies of Food Grade Geranyl Acetate (71% Geranyl Acetate,
29% Citronellyl Acetate) (CAS No. 105-87-3) in F344/N Rats and B6C3F1 Mice
(Gavage Studies) (Technical Report Series No. 252; NIH Publ. No. 88-2508), Research
Triangle Park, NC, National Toxicology Program
NTP (1997) Management Status Report (05/14/97), Research Triangle Park, NC, National
Toxicology Program, p. 39
Oda, Y., Hamano, Y., Inoue, K., Yamamoto, H., Nihara, T. & Kunita, N. (1978)
Mutagenicity of food flavors in bacteria. 1. Osaka-Furitsu Koshu Eisei Kenkyu Hokoku
Shokuhin Eisei, 9 , 177-181
Ohta, T., Watanabe, M., Tsukamoto, R., Shirasu, Y. & Kada, T. (1986a) Antimutagenic
effects of 5-fluorouracil and 5-fluorodeoxyuridine on UV-induced mutagenesis in
Escherichia coli. Mutat. Res., 173 , 19-24
Ohta, T., Watanabe, M., Watanabe, K., Shirasu, Y. & Kada, T. (1986b) Inhibitory effects
of flavourings on mutagenesis induced by chemicals in bacteria. Food Chem. Toxicol.,
24(1), 51-54
Oser, B.L. (1967) Private communication to FEMA. [cited in: FEMA (1994)]
Parke, D.V., Rahman, K.M. & Walker, R. (1974) The disposition of linalool in rats.
Biochem. Soc. Transact., 2 , 612-615
Paxéus, N. & Schröder, H.F. (1996) Screening for non-regulated organic compounds in
municipal wastewater in Göteborg, Sweden. Water Sci. Technol., 33(6), 9-15
Phillips, J.C., Kingsnorth, J., Gangolli, S.D. & Gaunt, I.F. (1976) Studies on the
absorption, distribution and excretion of citral in the rat and mouse. Food Chem.
Toxicol., 14 , 537-540 [cited in: FEMA (1994)]
Rockwell, P. & Raw, I. (1979) A mutagenic screening of various herbs, spices, and food
additives. Nutr. Cancer, 1(4), 10-15
Roscheisen, C., Zamith, H., Vidal, M., Paumbartten, F.J. & Speit, G. (1992a)
Antimutagenic effects of beta-myrcene. Mutat. Res., 271(2), 180 [Abstract]
Roscheisen, C., Zamith, H., Paumbartten, F.J. & Speit, G. (1992b) Myrcene: A specific
inhibitor of the cytochrome P450 system? Mutagenesis, 7(2), 166-167 [Abstract]
Russin, W.A., Hoesly, J.D., Elson, C.E., Tanner, M.A. & Gould, M.N. (1989) Inhibition
of rat mammary carcinogenesis by monoterpenoids. Carcinogenesis, 10(11), 21612164
Sasaki, Y.F., Imanishi, H., Ohta, T. & Shirasu, Y. (1989) Modifying effects of components
of plant essence on the induction of sister-chromatid exchanges in cultured Chinese
hamster ovary cells. Mutat. Res., 226 , 103-110
Tennant, R.W. & Spalding, J. (1996) Predictions for the outcome of rodent carcinogenicity
bioassays: Identification of trans-species carcinogens and noncarcinogens. Environ.
Health Perspect., 104(S5), 1065-1100
Wallace, L.A., Nelson, W.C., Pellizzari, E., Raymer, J.H. & Thomas, K.W. (1991)
Identification of Polar Organic Compounds in Consumer Products and Common
Microenvironments (EPA/600/D-91/074; NTIS PB91-182865), Research Triangle Park,
NC, Research Triangle Institute, 16 pp.
Wattenberg, L.W. (1991) Inhibition of azoxymethane-induced neoplasia of the large bowel
by 3-hydroxy-3,7,11-trimethyl-1,6,10-dodecatriene (nerolidol). Carcinogenesis, 12(1),
151-152
Zeiger, E., Anderson, B., Haworth, S., Lawlor, T., Mortelmans, K. & Speck, W. (1987)
Salmonella mutagenicity tests: III. Results from the testing of 255 chemicals. Environ.
Mutagen., 9(S9), 1-110
Zhang, Y.P., Sussman, N., Macina, O.T., Rosenkranz, H.S. & Klopman, G. (1996)
Prediction of the carcinogenicity of a second group of organic chemicals undergoing
carcinogenicity testing. Environ. Health Perspect., 104(S5), 1045-1050

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