Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
publication
Title:
WHO Expert Committee on Food Additives
Author:
WHO
Year:
1997
Bibliographic source:
Study report to be retrieved

Materials and methods

Principles of method if other than guideline:
Several Guidelines followed
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid
Radiolabelling:
yes

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
In groups of male Fischer 344 rats, 83% of an oral dose of 2.5 mmol/kg bw of [3-14C-d5]-cinnamyl alcohol (335 mg/kg bw), 77% of a dose of [3-14C-d5]-cinnamaldehyde (330 mg/kg bw), and 79% of a dose of [3-14C-d5]-cinnamic acid (370 mg/kg bw) were excreted mainly in the urine within 24 h. Excretion in the faeces accounted for only minor amounts of the administered alcohol (6.1%), aldehyde (16%), and acid (0.9%). More than 90% of the administered dose of any of the three substances was recovered in the urine and faeces within 72 h. Administration of the same doses of the parent alcohol, aldehyde, or acid to groups of CD-1 mice by intraperitoneal injection resulted in a similar pattern of excretion in the urine and faeces at 24 h (75%, 80%, and 93%, respectively) and 72 h (> 93%) (Nutley, 1990).

The tissue distribution and excretion of cinnamaldehyde (No. 656) were studied in groups of eight male Fischer 344 rats pretreated with single daily oral doses of 5, 50, or 500 mg/kg bw of cinnamaldehyde by gavage for 7 days and the same single oral dose of [3-14C]cinnamaldehyde 24 h later. Further groups received no pretreatment but the same single doses. The radiolabel was distributed primarily to the gastrointestinal tract, kidneys, and liver in all groups. After 24 h, > 80% of the radiolabel was recovered in the urine and < 7% in the faeces from all rats, regardless of dose. In all groups, a small amount of the dose was distributed to fat. Radiolabel was still present in animals killed 3 days after receiving 50 or 500 mg/kg bw. In animals pretreated with the two lower doses, the main urinary metabolite was hippuric acid, with small amounts of cinnamic and benzoic acid. In those pretreated with the high dose, benzoic acid was the major metabolite, suggesting that saturation of the glycine conjugation pathway occurs with repeated high doses of cinnamaldehyde (Sapienza et al., 1993).
The effect of dose and sex on the disposition of [3-14C]cinnamaldehyde was studied in Fischer 344 rats and CD-1 mice. More than 85% of doses of 2.0 and 250 mg/kg bw administered to groups of four male and four female rats and six male and six female mice by intraperitoneal injection was recovered in the urine and faeces within 24 h, and > 90% was recovered by 72 h. Of a dose of 250 mg/kg bw of [3-14C]cinnamaldehyde administered orally to Fischer 344 rats, 98% was recovered from the urine (91%) and faeces (7%) within 24 h (Peters & Caldwell, 1994). The effect of dose on the disposition of [3-14C-d5]-cinnamic acid was also studied in Fischer 344 rats and CD-1 mice. Five doses of cinnamic acid in the range 0.0005–2.5 mmol/kg bw were given orally to groups of four rats or by intraperitoneal injection to groups of four mice. After 24 h, 73–88% of the radiolabel was recovered in the urine of rats and 78–93% in the urine of mice; after 72 h, 85–100% of the radiolabel was recovered from rats and 89–100% from mice, mainly in the urine (Caldwell & Nutley, 1986). Only trace amounts of radiolabel were present in the carcass, indicating that cinnamic acid was readily and quantitatively excreted at all doses. The parent alcohol, aldehyde, and acid therefore appear to undergo rapid absorption, metabolism, and excretion, independently of dose up to 250 mg/kg bw, species, sex, and mode of administration (Nutley et al., 1994).
Eleven persons each received a single intravenous dose of cinnamic acid (No. 657) equivalent to 5 mg/kg bw. Analysis of blood showed that 100% of the dose was present within 2.5 min and none after 20 min (Quarto di Palo & Bertolini, 1961).
An oral dose of 1.5 mmol/kg bw (240 mg/kg bw) methyl cinnamate (No. 658) was rapidly and almost completely (95%) absorbed from the gut in rats. The agent was partially hydrolysed to cinnamic acid in the stomach (9%) and gut (40%), and the rate of absorption of cinnamic acid and methyl cinnamate from the gut was similar. No ester was detected in the peripheral blood of dosed rabbits or rats. Only traces were detected in portal and heart blood taken from the rats, indicating that almost complete hydrolysis of methyl cinnamate had occurred during intestinal absorption (Fahelbum & James, 1977).
After administration of a single oral dose of 57 mg of ring-deuterated 3-phenyl-propionic acid to one person, deuterobenzoic acid corresponding to 110% of the dose was isolated from alkaline hydrolysed urine within 100 min (Pollitt, 1974).
These studies indicate that cinnamyl derivatives can be anticipated to be rapidly absorbed, metabolized, and excreted, mainly in the urine, within 24 h.
Details on excretion:
Cinnamyl derivatives containing alpha-methyl substituents (e.g. alpha-methylcinnamaldehyde, are extensively metabolized via beta-oxidation and 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).

The cinnamyl derivatives used as flavouring substances are simple aromatic compounds with a propyl side-chain containing a primary oxygenated functional group, and they participate in common routes of absorption, distribution, and metabolism. The members of this group may be hydrolysed to yield the component alcohol, aldehyde, or acid. If the product is an alcohol or aldehyde, it is oxidized to yield the corresponding 3-phenylpropenoic acid or a 3-phenylpropanoic acid derivative which undergoes further side-chainbeta-oxidation and cleavage to yield mainly the corresponding benzoic acid derivatives (see attachment; Williams, 1959). The benzoic acid derivatives are conjugated with glycine and, to a lessor extent, glucuronic acid and excreted primarily in the urine (Snapper et al., 1940).ortho-Alkyl- andortho-alkoxy-substituted cinnamaldehyde derivatives undergobeta-oxidation to a minor extent, to yieldbeta-hydroxy-3-phenylpropanoic acid metabolites that are excreted as the glucuronic acid conjugates (Solheim & Scheline, 1973, 1976; Samuelsen et al., 1986).

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Cinnamyl derivatives containing alpha-methyl substituents (e.g. alpha-methylcinnamaldehyde, are extensively metabolized via beta-oxidation and 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)

Any other information on results incl. tables

The position and size of the substituent play a role in the metabolism of cinnamyl derivatives. Those containing alpha-methyl substituents (e.g. alpha-methylcinnamaldehyde) are extensively metabolized via beta-oxidation and 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). Larger substituents located at the alpha- or beta-position inhibited beta-oxidation to some extent (Deuel, 1957; Kassahun et al., 1991), in which case there may be direct conjugation of the carboxylic acid with glucuronic acid, followed by excretion. 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 observations 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.

References Cited

Kay, H. & Raper, H. (1924) The mode of oxidation of fatty acids with branched chains. III.Biochemistry,18, 153–160

Deuel, H.J. (1957) The oxidation and metabolism of triglycerides, fatty acids, and glycerol in the animal body. In:The Lipids, Their Chemistry and Biochemistry,: Wiley Interscience, Vol. III, pp. 71–99, 291–301

Kassahun, K., Farrell, K. & Abbott, F. (1991) Identification and characterization of the glutathione and N-acetylcysteine conjugates of (E)-2-propyl-2,4-pentadienoic acid, a toxic metabolite of valproic acid, in rats and humans.Drug Metab. Disposition,19, 525–535

Fischer, F.G. & Bielig, H.J. (1940) On the hydrogenation of unsaturated materials in the animal body.Z. Physiol. Chem.,266,73–98

Summary safety evaluations of cinnamyl alcohol and related flavouring agents

 Flavoring Agent  No. CAS Number   Does intake exceed the threshold for human intake Comments  Conclusion based on current intake 
 alpha-methylcinnamaldehyde 683  101 -39 -3  No; EU: 3, USA: 390   

Oxidized to cinnamic acid or its corresponding derivative and further oxidized to benzoic acid or its corresponding derivative, which is excreted as hippuric acid or its corresponding derivative

 No safety concern

Biological data

The cinnamyl derivatives used as flavouring substances are simple aromatic compounds with a propyl side-chain containing a primary oxygenated functional group, and they participate in common routes of absorption, distribution, and metabolism. The members of this group may be hydrolysed to yield the component alcohol, aldehyde, or acid. If the product is an alcohol or aldehyde, it is oxidized to yield the corresponding 3-phenylpropenoic acid or a 3-phenylpropanoic acid derivative which undergoes further side-chainbeta-oxidation and cleavage to yield mainly the corresponding benzoic acid derivatives (see attachment; Williams, 1959). The benzoic acid derivatives are conjugated with glycine and, to a lessor extent, glucuronic acid and excreted primarily in the urine (Snapper et al., 1940).ortho-Alkyl- andortho-alkoxy-substituted cinnamaldehyde derivatives undergobeta-oxidation to a minor extent, to yieldbeta-hydroxy-3-phenylpropanoic acid metabolites that are excreted as the glucuronic acid conjugates (Solheim & Scheline, 1973, 1976; Samuelsen et al., 1986).

Applicant's summary and conclusion

Conclusions:
Interpretation of results: no bioaccumulation potential based on study results
The position and size of the substituent play a role in the metabolism of cinnamyl derivatives. Those containing alpha-methyl substituents (e.g. alpha-methylcinnamaldehyde) are extensively metabolized via beta-oxidation and 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). Larger substituents located at the alpha- or beta-position inhibited beta-oxidation to some extent (Deuel, 1957; Kassahun et al., 1991), in which case there may be direct conjugation of the carboxylic acid with glucuronic acid, followed by excretion. 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 observations suggest that alpha-methylcinnam-aldehyde undergoes oxidation to benzoic acid, while higher homologues are excreted primarily unchanged or as the conjugated form of the cinnamic acid derivative.

Studies indicate that cinnamyl derivatives can be anticipated to be rapidly absorbed, metabolized, and excreted, mainly in the urine, within 24 h.