CINNAMALDEHYDE
Explanation
Cinnamaldehyde was reviewed at the eleventh meeting of the Joint
FAO/WHO Expert Committee on Food Additives, specifications were
prepared, and a conditional acceptable daily intake for man (ADI) of
0-1.25 mg/kg bw was established (FAO/WHO, 1967; FAO/WHO, 1968).
Since this previous review, new data on cinnamaldehyde and
closely related compounds have become available and are included in
this monograph.
BIOLOGICAL DATA
BIOCHEMICAL ASPECTS
Cinnamaldehyde administered intraperitoneally to a rabbit was
excreted in the urine as cinnamic acid, cinnamoylglycine, benzoic acid
and hippuric acid (Friedman & Mai, 1931).
Since cinnamaldehyde is oxidized in vivo to cinnamic acid
(Friedman & Mai, 1931; F.E.M.A., 1978), a consideration of the data on
the toxicity and metabolism of cinnamic acid is pertinent to the
evaluation of cinnamaldehyde. In this regard, considerable information
is available on cinnamic acid (Opdyke, 1978; F.E.M.A., 1978).
The oral LD50 for rats varies from 2.5 g/kg to greater than
5.0 g/kg. Values greater than 5.0 g/kg have been reported for mice and
guinea-pigs. The dermal LD50 for rabbits is greater than 5.0 g/kg
(Opdyke, 1978; F.E.M.A., 1978).
Cinnamic acid was administered orally in repeated daily doses of
5 or 50 mg/kg to pregnant rats for the entire course of pregnancy.
Sacrifice and examination of a half of the animals on day 20 of
gestation revealed no embryotoxic effects as judged by body weight,
rate of survival, bone development, and determination of hepatic
nucleic acids. Offspring produced from the other half of the animals
were normal with respect to body weight, size, survival, and general
development at birth and one month later (Zaitsev & Maganov, 1975).
When (3-14C) cinnamic acid was injected into female rats, 48% of
the label was excreted in the urine and 25% in the faeces; there was
negligible incorporation in tissues and respiratory CO2; no urinary
phenolic metabolites were detected. Identifiable metabolites included
hippuric and benzoic acids, together with unchanged cinnamic acid
(Teuchy & Van Sumere, 1971).
In the rabbit cinnamic acid is excreted almost entirely as
hippuric acid, there being no formation of cinnamoylglycine (Williams,
1959).
In the dog, considerable excretion of glucuronide, probably of
benzoyl glucuronide, has been observed and beta-phenyl-beta-
oxopropionic acid, cinnamoylglycine and acetophenone were found as
minor metabolites (Williams, 1959).
Following the administration of single oral doses (6-6.7 g) of
cinnamic acid or sodium cinnamate to humans, 60-90% was excreted in
the urine as hippuric acid; a minor amount was accounted for as
cinnamoyl glucuronide (Snapper et al., 1940; Snapper & Saltzman,
1948).
TOXICOLOGICAL STUDIES
Special studies on carcinogenicity
In a 24-week screening test, groups of 15 male and 15 female A/He
mice received in the first eight weeks of the test period, a total
dose of 0.8 or 4.0 g/kg bw of cinnamaldehyde in 24 thrice-weekly i.p.
injections. The higher dose had previously been calculated to be the
maximum tolerated dose. There was no increase in the incidence of
tumours of the lung, liver, kidney, spleen, thymus, intestine, or
salivary or endocrine glands. Survival was reduced in high-dose males
to 60% and in high-dose females to 75%, but survival in the low-dose
groups was unaffected (Stoner et al., 1973).
Special studies on pharmacological aspects
Intraperitoneal injection of either a 250 or 500 mg/kg dose of
cinnamaldehyde to mice resulted in ataxia, analgesia, hypothermia, a
decrease in spontaneous motor activity, antagonism of methamphetamine-
induced hyperactivity, and prolongation of sodium hexobarbital-induced
anaesthesia. A 500 mg/kg dose was also observed to reduce development
of a tonic convulsion in a nicotine-induced convulsion. Administration
of a 125 mg/kg dose intraperitoneally produced hypothermia,
antipyretcosis, and a prolongation of hexobarbital-induced anaesthesia
(Harada & Osaki, 1972).
Intraperitoneal injection of a single 250 mg/kg dose of
cinnamaldehyde to mice produced an inhibition of intestinal propulsion
while simultaneously protecting against the generation of stress-
induced gastric erosion (Harada & Yano, 1975).
Dog
Intravenous infusion of single 5-10 mg/kg doses of cinnamalde to
anaesthetized dogs resulted in a 0-40% decrease in blood pressure for
periods of one to seven minutes (Harada & Yano, 1975).
Intravenous administration of 2.7-44.4 mg/kg cinnamaldehyde to
dogs invoked, primarily, a depressor response exhibiting an initial
significant sharp fall in blood pressure for a short period. This was
followed by a slight rise in blood pressure over a longer period
(Wingard et al., 1955).
Acute toxicity
LD50
Animal Route mg/kg bw References
Mouse i.p. 610 Harada & Ozaki, 1972
Mouse oral 2 225 Harada & Ozaki, 1972
Mouse oral 3 400 Zaitsev & Rakhmanina, 1974
Rat oral 3 400 Zaitsev & Rakhmanina, 1974
Rat oral 2 220 Jenner et al., 1964
Guinea-pig oral 3 400 Zaitsev & Rakhmanina, 1974
Guinea-pig oral 1 160 Jenner et al., 1964
Short-term studies
Rat
A 12-week feeding study was carried out on groups of 12 male and
12 female weanling rats using a blend of five related compounds
(cinnamic aldehyde, methyl cinnamate, ethyl cinnamate, cinnamyl
cinnamate, and alpha methyl cinnamic aldehyde), providing an estimated
daily intake for cinnamaldehyde of 103.5 mg/kg bw (with a total daily
intake for the blend of 115 mg/kg bw). No adverse effects were
observed in rats of either sex as judged by appearance, behaviour,
food intake, presence of sugar or albumin in the urine, blood
haemoglobin, liver, kidney and brain weights, or gross pathology.
However, the efficiency of food utilization was depressed in both
sexes, and the growth of males (but not females) was moderately
retarded (but not significantly as shown by statistical analysis)
(Oser, 1967).
In a second 12-week feeding study, groups of five male and five
female weanling rats were maintained on diets containing only
cinnamaldehyde at levels resulting in daily intakes of 58, 114 or
227 mg/kg. No adverse effects were observed (at any of the dietary
levels of cinnamaldehyde) on appearance, behaviour, growth, food
consumption, efficiency of food utilization, presence of sugar or
albumin in the urine, blood haemoglobin, liver and kidney weights, or
gross pathology (Oser, 1967).
Since no adverse effects were observed in this experiment on
cinnamaldehyde, alone, the authors concluded that the effects on
growth (males) and on efficiency of food utilization (both sexes)
observed in the earlier experiment, using a blend of five substances,
must have been due to components of the blend other than
cinnamaldehyde (Oser, 1967).
Groups of 10 male and 10 female rats were maintained for 16 weeks
on diets containing cinnamaldehyde at levels of 0, 1000, 2500 and
10 000 ppm (approximately equivalent to 50, 125 and 500 mg/kg/day).
Neither body weight gains, haematology, nor examination of the major
organs revealed significant differences between the test and control
animals at levels of either 1000 or 2500 ppm. None of the above
parameters revealed adverse effects following a dietary intake of
10 000 ppm for 16 weeks, with the exception of a "slight hepatic cell
swelling" and a "slight hyperkeratosis of squamous portion" of the
stomach, noted upon microscopic examination (Hagan et al., 1967).
Comments
Cinnamaldehyde was reviewed at the eleventh JECFA and a
conditional ADI of 0-1.25 mg/kg bw was established. There was further
data available on two short-term feeding studies. However, as these
did not include histopathology they could not be employed to set an
ADI. The previous conditional ADI was converted to a temporary ADI.
A monograph was prepared.
EVALUATION
Level causing no toxicological effect
Rat: ppm in the diet equivalent to 125 mg/kg bw.
Estimate of temporary acceptable daily intake for man
0-0.7 mg/kg bw.
FURTHER WORK OR INFORMATION
Required by 1981.
Two 90-day studies in rodent and non-rodent.
REFERENCES
Boyland, E. & Mawson, E. H. (1938) Experiments on the chemotherapy of
cancer, Biochem. J., 32, 1982-1987
FAO/WHO (1967) Toxicological evaluation of some flavouring substances
and non-nutritive sweetening agents, FAO Nutrition Meetings
Report Series No. 44a; WHO/Food Add./68.33
FAO/WHO (1968) Specifications for the identity and purity of food
additives and their toxicological evaluation: some flavouring
substances and non-nutritive sweetening agents, Eleventh Report
of the Joint FAO/WHO Expert Committee on Food Additives, FAO
Nutrition Meetings Report Series No. 44; Wld Hlth Org. techn.
Rep. Ser. No. 383
F.E.M.A. (1978) Scientific literature review of cinnamyl alcohol and
related substances on flavor usage. Published by the National
Information Services under contract with the Food and Drug
Administration
Friedman, E. & Mai, H. (1931) Behaviour of cinnamyl acetic acid and of
cinnamaldehyde in the animal body, Biochem. Z., 242, 282-287
(in German)
Hagan, E. C. et al. (1967) Food flavourings and compounds of related
structure. II. Subacute and chronic toxicity, Food Cosmet.
Toxicol., 5, 141-157
Harada, M. & Osaki, Y. (1972) Pharmacological studies on Chinese
cinnamon. I. Central effects of cinnamaldehyde, Yakugaku
Zasshi, 92 (2), 135-140 (in Japanese)
Harada, M. & Yano, S. (1975) Pharmacological studies on Chinese
cinnamon. II. Effects of cinnamaldehyde on the cardiovascular and
digestive systems, Chem. Pharm. Bull., 23 (5), 941-947
Jenner, P. M. et al. (1964) Food flavourings and compounds of related
structure. I. Acute oral toxicity, Food Cosmet. Toxicol., 2,
327-343
Opdyke, D. L. J. (1978) Fragrance raw materials monographs, Food
Cosmet. Toxicol., 16, Suppl. 1, 687-689
Oser, B. L. (1967) Unpublished report
Snapper, I., Yu, T. F. & Chiang, Y. T. (1940) Cinnamic acid metabolism
in man, Proc. Soc. Exp. Biol. Med., 44, 30-34
Snapper, I. & Saltzman, A. (1948) Excretion of glucuronates after
ingestion of benzoic acid or cinnamic acid as a test of liver
function, Conf. on Liver Injury, Trans. 7th Conf., pp. 77-85
(discussion, pp. 85-86) (cited by F.E.M.A., 1978)
Teuchy, H. & Van Sumere, C. F. (1971) The metabolism of (1-14C)
phenylalanine, (3-14C) cinnamic acid, and (2-14C) ferulic acid
in the rat, Arch. Int. Physiol. Biochem., 79 (3), 589-618
Williams, R. T. (1959) Detoxication mechanisms, The metabolism and
detoxication of drugs, toxic substances and other compounds,
London, Chapman & Hall Ltd, 2nd ed.
Wingard, C., Hitchcock, P. & Teague, R. S. (1955) A survey of the
aldehydes with respect to their action on the blood pressure,
Arch. Int. Pharmacodyn., 102, 65-84
Zaitsev, A. N. & Rakhmanina, N. L. (1974) Toxic properties of
phenylethanol and cinnamic alcohol derivatives, Vopr. Pitan.,
5, 48-53 (in Russian)
Zaitsev, A. N. & Maganova, N. B. (1975) Embryotoxic effects of some
aromatizers for food products, Vopr. Pitan., 3, 64-68 (in
Russian)
See Also:
Toxicological Abbreviations
Cinnamaldehyde (FAO Nutrition Meetings Report Series 44a)
CINNAMALDEHYDE (JECFA Evaluation)