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EC number: 639-566-4
CAS number: 165184-98-5
Short description of key information on bioaccumulation potential result: Cinnamaldehyde, cinnamic alcohol and cinnamic aldehyde are rapidly absorbed from the gut, metabolized and excreted primarily in the urine and, to a minor extent, in the faeces. Rodent and humans studies for cinnamaldehyde and alpha-substituted cinnamaldehydes indicate that cinnamyl derivatives are absorbed, metabolized and excreted as polar metabolites within 24 hours and this is largely independent of species, sex, and mode of administration.Oral absorption of HCA is considered as 10% as a worst-case for DNELs derivation.Short description of key information on absorption rate: WoE approach: dermal absorption rate of HCA = 0.183 %
(HCA) has been evaluated within the "Cinnamyl derivatives" category by
the Flavor and Fragrance High Production Volume Consortia in its
submission to the US Environmental Protection Agency (Submission dated
05Mar2005, see attached document “FFHPVC” §7.1.1), and by the World
Health Organisation in its Cinnamyl Alcohol and Related Substances
review presented in the WHO Food Additives Series 46 (see attached
document, WHO §7.1.1).
grouping of Cinnamaldehyde, HCA and alpha-Amylcinnamaldehyde (ACA), into
the “Cinnamyl derivatives” category is based on their structural
relationships and the resulting similarities of their physico-chemical
(as described in Table 7.1/1) and toxicological properties (see FFHPVC,
2005). The three compounds are naturally occurring substances, used as
common component of traditional foods and generally recognized as safe
(GRAS) as flavoring substances by the U.S. Food and Drug Administration
(US FDA) and as food additives by the World Health Organization (WHO).
HCA and ACA are also used in fragranced consumer products such as soaps
this grouping approach, studies on Cinnamaldehyde, its tautomer alcohol
(Cinnamic alcohol) and their corresponding acid (cinnamic acid) were
considered reliable to assess the toxicological profile of HCA (see
attached figure “Metabolism of cinnamaldehyde derivatives” in §7.1.1).
is predominantly present in the environment as trans-cinnamaldehyde (CAS
No 14371-10-9) whereas the available studies are on cis-cinnamaldehyde
(CAS No 104-55-2). However, EPA considers the use of data for the
trans-isomer appropriate to supplement the data for the cis-isomer.
7.1/1: Comparison of the physico-chemical properties of α-Hexyl-Cinnamaldehyde,
Cinnamaldehyde, Cinnamyl alcohol and Cinnamic acid
Chemicals / Properties
Molecular weight (g/mol)
Partition coefficient (log Kow)
Water solubility (mg/L)
1.62 at 20°C (measured)a
1420 at 20°C (measured)b
1800 at 20°Cd
546 at 20°Ce
Vapor pressure (Pa)
0.068 at 25°C (measured)a
3.853 at 20°C (measured)b
1.599 at 25°C (estimated)f
0.628 at 25°C estimated)f
a: Data from
§4.0 of this dossier
b: Data from
Initial Risk-Based Prioritization of High Production Volume (HPV)
Chemicals “Cinnamyl Derivatives Category” (US EPA, 2009)
c: Data from
Log Kow databank (CNC/CODATA)
d: Data from
Gestis substance database (IFA)
e: Data from
Reptox database (CSST)
f: Data from
the Good Scents Company
toxicokinetic profile of HCA is derived from read-across with
Cinnamaldehyde. HCA, similarly to others “Cinnamyl derivatives” is
rapidly absorbed from the gut, metabolized and excreted primarily in the
urine (within 24 hours) and, to a minor extent, in the faeces. No
bioaccumulation potential is anticipated.
position and size of the substituent do not significantly affect the
pathways of metabolic detoxication of cinnamyl derivatives. Cinnamyl
derivatives containing α-alkylmethyl
substituents, are mainly metabolizedvia β-oxidation
followed by cleavage leading to the corresponding hippuric acid
conjugate excreted in the urine. However, larger substituents located at
the alpha-position (like HCA) inhibits beta-oxidation to
some extent and are excreted primarily unchanged or as the conjugated
form of the cinnamic acid derivative.
values used for safety assessment:
bioavailability of Cinnamaldehyde is low, i.e.from 10% to 17%.
The lowest oral absorption rate (10%) is considered as a worst-case to
calculate the DNEL for HCA using route-to-route extrapolation,e.g.,
from oral to inhalation or from oral to dermal route (see §7.1.1).
skin absorption potential of HCA is derived from weight of evidence. It
is estimated to be 0.183% (see § 7.1.2).
Discussion on bioaccumulation potential result:
The toxicokinetic profile of cinnamaldehyde
has been investigated in male rats (Yuan and Deiter,1992). Plasma
levels of cinnamaldehyde (less than 0.1 µg/mL) and cinnamic acid (less
than 1 µg/mL) were not measurable when rats were administered a single
oral dose of 50 mg/kg bw of cinnamaldehyde. At dose levels of 250 and
500 mg/kg bw, plasma levels of cinnamaldehyde and cinnamic acid were
approximately 1 and less than 10 µg/mL, respectively. The
bioavailability of cinnamaldehyde was calculated to be less than 20% at
both dose levels for neat and microencapsulated cinnamaldehyde (from 10%
to 17%). A dose-dependent increase in hippuric acid, the major urinary
metabolite, occurred 6 hours after gavage and continued over the next 18
hours. Only small amounts of cinnamic acid were excreted in the urine
either free or as the glucuronic acid conjugate. The urinary hippuric
acid recovered over 50 hours accounted for 72-81% over the dose range
from 50 to 500 mg/kg bw.
In another study the tissue distribution and
excretion of cinnamaldehyde has been studied in male rats (Sapienza et
al., 1993). Following pretreatment with single daily oral dose
levels of 5, 50, or 500 mg/kg of cinnamaldehyde by gavage for seven days
and a single oral dose of [3-14C]-cinnamaldehyde twenty-four
hours later, radioactivity was distributed primarily to the
gastrointestinal tract, kidneys, and liver. After 24 hours, more than
80% of the radioactivity was recovered in the urine and less than 7% in
the faeces from all groups of rats, regardless of dose level. At all
dose levels, a small amount of the dose was distributed to the fat. At
50 and 500 mg/kg bw, radioactivity could be measured in animals
terminated 3 days after dosing. Except for the high dose pretreatment
group, the major urinary metabolite was hippuric acid, accompanied by
small amounts of cinnamic and benzoic acid. In the high dose
pretreatment group, benzoic acid was the major metabolite, suggesting
that saturation of the glycine conjugation pathway occurs at repeated
high dose levels of cinnamaldehyde.
The effect of dose and sex on the
disposition of [3-14C]-cinnamaldehyde has been studied in
rats or mice (Peters and Caldwell, 1994). Greater than 80% of either a 2
or 250 mg/kg bw dose of cinnamaldehyde administered to groups of male
and female rats or mice by intraperitoneal injection was recovered in
the urine and faeces within 24 hours. Greater than 90% was recovered
after 72 hours. When 250 mg mg/kg bw of [3-14C]-cinnamaldehyde
was administered orally to rats, 98% was recovered from the urine (91%)
and feces (7%) within 24 hours. In both species, the major urinary
metabolite was hippuric acid, accompanied by small amounts of
metabolites including 3-hydroxy-3-phenylpropionic acid, benzoic acid,
and benzyl glucuronide. The glycine conjugate of cinnamic acid was
formed to a considerable extent only in the mouse. To a small extent,
glutathione conjugation of cinnamaldehyde competes with the oxidation
pathway. Approximately 6-9% of either dose was excreted in 24 hours as
glutathione conjugates of cinnamaldehyde. The authors concluded that the
excretion pattern and metabolic profile of cinnamaldehyde in rats and
mice are not systematically affected by sex, dose size, or route of
The elimination of cinnamic acid follows a
similar pathway in rat, mouse and humans.
The effect of dose on the disposition of [3-14C-d5]-cinnamic
acid in rats and mice has also been studied (Nutley et al., 1994). Five
dose levels of cinnamic acid in the range from 0.074 to 370mg/kg bw were
given orally to groups of rats or by intraperitoneal injection to groups
of mice. After 24 hours, 73-88% of the radioactivity was recovered in
the urine of rats and 78-93% in the urine of mice. Only trace amounts of
radioactivity were present in the carcasses after 72hrs, indicating that
cinnamic acid was readily and quantitatively excreted at all dose
levels. In both species and routes the main metabolite was hippuric acid
followed by benzoyl glucuronide, 3-hydroxy-3-phenyl propionic acid,
benzoic acid, cinnamic acid, and in addition, cinnamoylglycine and
acetophenone in mouse only.
Eleven adult human volunteers received
single intravenous doses of cinnamic acid, equivalent to 5 mg/kg bw. Analysis
of the blood plasma revealed cinnamic acid at 100% of the total dose
within 2.5 minutes declining to 0% after 20 minutes. Ninety
minutes after dosing, urinalysis revealed mainly hippuric acid,
cinnamoylglucuronide, and benzoylglucuronide present in a ratio of
74:24.5:1.5 (Quarto di Palo and Bertolini, 1961). These data demonstrate
that cinnamic acid is rapidly oxidized to benzoic acid metabolites, and
excreted in the urine of humans.
The position and size of the substituent do
not significantly affect the pathways of metabolic detoxication of
cinnamyl derivatives. Cinnamyl derivatives containing alpha-alkyl
substituents (e.g.alpha-methylcinnamaldehyde) are extensively
metabolized via beta-oxidation followed by cleavage to yield mainly the
corresponding hippuric acid derivative. A benzoic acid metabolite was
isolated from the urine of dogs given either alpha-methylcinnamic
acid or alpha-methylphenylpropionic acid (Kay and Raper, 1924).
While alpha-methylcinnamic acid undergoes oxidation to benzoic
acid, alpha-ethyl- and alpha-propylcinnamic acids are
excreted unchanged (Carter, 1941). Alpha-Ethylcinnamic alcohol
and alpha-ethylcinnamaldehyde administered orally to rabbits
resulted in urinary excretion of alpha-ethylcinnamic acid and of
small amounts of benzoic acid (Fischer & Bielig, 1940). These
studies suggest that alpha-methylcinnamaldehyde undergoes
oxidation to benzoic acid while higher homologues are excreted primarily
unchanged or as the conjugated form of the cinnamic acid derivative.
Cinnamaldehyde, cinnamic alcohol and
cinnamic acid, are rapidly absorbed from the gut, metabolized and
excreted primarily in the urine and, to a minor extent, in the faeces.
Rodent and humans studies for cinnamaldehyde and alpha-substituted
cinnamaldehydes indicate that cinnamyl derivatives are absorbed,
metabolized and excreted as polar metabolites within 24 hours and this
is largely independent of species, sex, and mode of administration.
It is anticipated that larger
substituents located at the alpha-position (like HCA) inhibitsbeta-oxidation
to some extent and are excreted primarily unchanged or as the conjugated
form of the cinnamic acid derivative.
The oral bioavailability of Cynnamaldehyde
is low, i.e. from 10% to 17%. The lowest oral absorption rate (10%) is
considered as a worst-case to calculate the DNEL for HCA using
route-to-route extrapolation (e.g., from oral to inhalation or from oral
to dermal route).
The proposed metabolism pathway for the
cinnamaldehyde derivatives is illustrated in the figure included as
Discussion on absorption rate:
and α-Hexyl-Cinnamaldehyde (HCA)
are grouped in the “Cinnamyl derivatives” category as previously
explained (see §7.1).
the dermal exposure to Cinnamaldehyde and HCA, a weight of evidence
approach is considered using two studies (Jimbo, 1983; Smith, 2000).
However, the study of Jimbo (1983) does not provide a reliable
penetration rate for HCA. Indeed, in this experiment several factors may
have contributed to the very low penetration rate reported for both HCA
and Cinnamaldehyde: a low temperature (21°C) was used and the amount
within the epidermis was not determined. Moreover, the solubility of HCA
in saline is likely low, and the test substance was potentially loss
through its determination by extraction process rather than
radiolabelling. The integrity of the skin was not checked but in any
case a loss of integrity would have overestimated the penetration rate.
It is also considered that, although the absolute dermal absorption
levels for HCA (0.002%) and Cinnamaldehyde (0.175%) may not be accurate,
the relative penetration rates for these two substances are likely to be
reliable to some extent and, therefore, the data may still be used
within a weight of evidence approach. This study showed a significant
difference in the dermal absorption between Cinnamaldehyde and HCA
(0.175% vs 0.002%) representing an absorption ratio of 87.5-fold, even
if the absolute dermal absorption is low in both cases.
difference is consistent with their physico-chemical properties since
HCA has a slightly higher lipophilic character (i.e., higher log Kow)
than Cinnamaldehyde together with lower water solubility and higher
molecular weight (see Table 7.1.2/1) inducing a lower dermal absorption
for HCA than for Cinnamaldehyde.
7.1.2/1: Comparison of the physico-chemical properties ofα-Hexyl-Cinnamaldehyde
b: Data from
Log Kow databank (CNC/CODATA)
c: Data from
Reptox database (CSST)
this difference can be considered to extrapolate the HCA dermal
absorption from the Cinnamaldehyde dermal absorption by applying the
calculated ratio of 87.5 (see above).
several studies are available in which the skin penetration of
Cinnamaldehyde have been studied and all results showed far higher
penetration rates than the Cinnamaldehyde dermal absorption rate
determined in the study of Jimbo (1983). In the second study considered
as a weight of evidence (Smith, 2000) the skin penetration of neat
Cinnamaldehyde was evaluated at 16%. Therefore, using this value and
applying the calculated ratio of 87.5 described above (16/87.5), the
dermal absorption for HCA can be extrapolated at 0.183.
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