Heptanal, 2-(phenylmethylene)-, (2E)-

Endpoint summary

Description of key information

Based on read across data, cinnamaldehyde is 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. While the oral absorption of hexyl cinnamic aldehyde was found to be very low  (<1%), the urinary excretion of cinnamaldehyde was typically very high (greater than 80%) and consequently the oral absorption for amyl cinnamic aldehyde, based on urinary excretion values was assumed to be equivalent to the mid-range of the higher absorption values.  83% oral absorption was considered to be a reasonable, if conservative, estimate.

Dermal absorption was assessed in two studies, one used as weight of evidence compared the rate of absorption for hexyl and amyl cinnamaldehyde, concluding a dermal absorption rate for HCA of 0.183 % and approximately 87-fold higher absorption for the substituted cinnamaldehyde. The study was not considered reliable due to the methodologies used and the study of Smith was used to derive a working estimate of dermal absorption. Based on the findings of this study, dermal absorption of amyl cinnamaldehyde is assumed to be 16%.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

83

Absorption rate - dermal (%):

16

Absorption rate - inhalation (%):

100

Additional information

There is sufficient weight of evidence from various sources to elucidate the toxicokinetic profiles of hexylcinnamaldehyde and its metabolites, cinnamic acid and use to address data gaps for amyl cinnamic aldehyde by means of read-across between structural analogues.  Hexylcinnamaldehyde (HCA) has been assessed within the Cinnamyl Derivatives category by the Flavor and Fragrance High Production Volume Consortia in its submission to the US Environmental Protection Agency (EPA) and by the World Health Organisation (WHO) in its Cinnamyl Alcohol and Related Substances review presented in the WHO Food Additives Series 46. Cinnamaldehyde, α-hexyl-cinnamaldehyde (HCA) and α-amyl-cinnamaldehyde (ACA), as alkyl-substituted cinnamaldehydes, are grouped together because of their structural relationships (3 -phenyl-2 -propenal backbone) and the resulting similarities of their physicochemical and toxicological properties including their absorption, distribution, metabolism and excretion after oral exposure. The toxicokinetic profile of cinnamaldehyde has been investigated in male rats (Yuan & Deiter,1992). Plasma levels of cinnamaldehyde (<0.1 µg/mL) and cinnamic acid (<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 <10 µg/mL, respectively. The bioavailability of cinnamaldehyde was calculated to be less than 20% at both dose levels. A dose-dependent increase in the excretion of 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 was studied in male rats (Sapienza et al., 1993). Following pre-treatment with single daily oral dose levels of 5, 50, or 500 mg/kg bw of cinnamaldehyde by gavage for seven days and a single oral dose of [3-14C]-cinnamaldehyde 24 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 pre-treatment group, the major urinary metabolite was hippuric acid, accompanied by small amounts of cinnamic and benzoic acid. In the high dose pre-treatment 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 and mice (Peters & 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 faeces (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 administration. 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 370 mg/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 benzoylglucuronide, 3-hydroxy-3-phenyl propionic acid, benzoic acid, cinnamic acid, and in addition, cinnamoylglycine and acetophenone in mouse only.

In a further study, 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 & 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 detoxification of cinnamyl derivatives. Cinnamyl derivatives containing alpha-alkyl substituents (e.g. alpha-methylcinnamaldehyde) are extensively metabolised 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 & 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. It is anticipated that alpha-hexylcinnamaldehyde will undergo beta-oxidation and cleavage to eventually yield the corresponding benzoic acid derivative that is excreted in the urine mainly as the glycine (hippurate) conjugate.

Conclusion based on read -across to hexyl cinnamaldehyde:

Cinnamaldehyde is rapidly absorbed from the gut, metabolised 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. The oral bioavailability of cinnamaldehyde is low, i.e. from 10% to 17%, but consistently over a large dose range of circa 1 -350 mg/kg bw/day in several different test species the urinary excretion recovery was greater than 80%. The percent dose eliminated was in the range of 73 -93% and a conservative estimate of oral absorption can be considered to be the mid-point, 83%.

Supplementary information from toxicokinetic information

The toxicokinetic profile of cinnamaldehyde was studied in male rats. The animals were given single doses of cinnamaldehyde intravenously (5-25 mg/kg bw) or by gavage (50-2000 mg/kg bw). Following i.v. administration the half-life was determined to be 1.7 hours. Following oral administration the blood levels of cinnamaldehyde were very low (at around 1 µg/mL) but were maintained for over a 24 hour period after a dose of 500 mg/kg bw. At 50 mg/kg bw no cinnamaldehyde was detected in blood. The oral bioavailability of cinnamaldehyde was estimated at less than 20%. Cinnamaldehyde was oxidised rapidly into cinnamic acid in blood and the majority of cinnamaldehyde was excreted as hippuric acid in urine with only a small fraction as free cinnamic acid or beta glucuronide conjugated cinnamic acid. No bioaccumulation potential was identified in this study.

Excretion and the urinary metabolic profile of cinnamaldehyde were studied in F344 rats and CD1 mice. Single doses of 2 or 250 mg/kg bw of trans [14C]-cinnamaldehyde by i.p., in both male and female, rats and mice, and 250 mg/kg bw by gavage in males only were administered. Cinnamaldehyde was excreted rapidly with 80% and 87% of the dose in rat and mouse, respectively, eliminated in the first 24 hours following administration. The main urinary metabolite was hippuric acid but also 3 -hydroxy-3phenylpropionic acid, benzoic acid, cinnamoyl glycine and benzoyl glucuronide in both species. The excretion pattern and metabolic profile of cinnamaldehyde in rats and mice were not greatly affected by sex, dose size and route of administration.

Radiolabelled cinnamaldehyde was administered as a single oral dose or 24 hours after multiple oral doses (once a day for 7 days) of non radiolabelled cinnamaldehyde, to male F344 rats in order to study its distribution and elimination from tissues. The distribution of cinnamaldehyde into tissues is low and it is rapidly eliminated in urine. The main metabolites are hippuric acid and benzoic acid. No bioaccumulation potential was identified for cinnamaldehyde in this study. A similar pattern of response was confirmed in a second study in which radio-labelled cinnamic acid was acutely or repeatedly administered orally or by i.p. injection to rats and mice.

In dogs and rabbits, alpha-methylcinnamaldehyde undergoes oxidation to benzoic acid while higher homologues are excreted primarily unchanged or as the conjugated form of the cinnamic acid derivative. The alkyl chain in alkyl cinnamic derivatives does not significantly affect its detoxification.

Absorption rate

Cinnamaldehyde and α-Hexyl-Cinnamaldehyde (HCA), as alkyl-substituted cinnamaldehyde, were designated as Cinnamyl derivatives and grouped together because of their structural relationships and the resulting similarities of their physicochemical and toxicological properties including their absorption, distribution, metabolism and excretion.

 

Comparison of the physicochemical properties of α-Hexyl-Cinnamaldehyde and Cinnamaldehyde

Substance	Chemical formula	Molecular weight (g/mol)	Partition coefficient (log Kow)	Water solubility (mg/L)
αHexyl-Cinnamaldehyde (CAS 165184 -98-5)	2-hexyl-3 -phenyl-2 -propenal (C15H20O)	216.32	5.3 (at 24°C)	0.3 (at 20°C)
Cinnamaldehyde (CAS 104-55-2)	3-phenyl-2-propenal (C9H8O)	132.16	2.22**	1400**
Amyl cinnamaldehyde (CAS 122-40-7)	2-(phenyl methylene) heptanal (C14H18O)	202.30	4.7 (at 24°C)	9 (at 25°C)

**Data from IUCLID4 dataset for Cinnamaldehyde (2000)

 Regarding the dermal exposure to cinnamaldehyde and HCA, a weight of evidence approach is considered using two studies (Jimbo, 1983; Smith, 2000). In fact, the study of Jimbo (1983) does not provide a reliable penetration rate for HCA. In this experiment, low temperature (21°C) used, and the fact that amount within the epidermis was not determined, the likely low solubility of HCA in saline, and the potential loss of test substance through its determination by extraction process rather than radiolabelling may have contributed to the very low penetration rate reported for both, HCA and also for cinnamaldehyde. The integrity of the skin was not checked but in any case a loss of integrity would overestimate the penetration rate. Also, it is 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.  However, 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. This difference is consistent with their physicochemical 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 inducing a lower dermal absorption for HCA than for cinnamaldehyde . Therefore, 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). 

Finally, 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 cinnamaldehyde was evaluated at 16%.