Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

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 %

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - dermal (%):
0.183

Additional information

Category approach:

Alpha-hexylcinnamaldehyde (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).

The 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 and cosmetics.

Based on 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).

Cinnamaldehyde 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.

 

Table 7.1/1: Comparison of the physico-chemical properties of α-Hexyl-Cinnamaldehyde, Cinnamaldehyde, Cinnamyl alcohol and Cinnamic acid

 

Chemicals / Properties

Alpha-Hexyl-Cinnamaldehyde

Cinnamaldehyde

Cinnamic alcohol

Cinnamic acid

CAS No.

165184-98-5

104-55-2

104-54-1

621-82-9

Molecular formula

C15H20O

C9H8O

C9H10O

C9H8O2

Structural formula

Molecular weight (g/mol)

216.32

132.16

134.17

148.16

Partition coefficient (log Kow)

5.3 (measured)a

1.9 (measured)b

1.95c

2.25c

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:

The 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.

The 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.

Key values used for safety assessment:

The oral 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).

 

The 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 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 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.

 

Conclusion:

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 attachment.

Discussion on absorption rate:

Cinnamaldehyde and α-Hexyl-Cinnamaldehyde (HCA) are grouped in the “Cinnamyl derivatives” category as previously explained (see §7.1).

Regarding 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.

This 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.

 Table 7.1.2/1: Comparison of the physico-chemical properties ofα-Hexyl-Cinnamaldehyde and Cinnamaldehyde

Chemicals

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

5.3a

(at 24°C)

 1.6a

(at 20°C)

Cinnamaldehyde

(CAS 104-55-2)

3-phenyl-2-propenal

(C9H8O)

132.16

1.9b

1420c

(at 20°C)

a: Data from §4.0 of this dossier

b: Data from Log Kow databank (CNC/CODATA)

c: Data from Reptox database (CSST)

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 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.