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

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Study period:

Two publications - one from 1961 and second from 1994

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Amyl cinnamaldehyde is an alkyl-substituted cinnamaldehyde and therefore structurally similar enough to justify read-across from cinnamaldehyde. Additional read across justification is provided for a number of substances and is included as attachment to the "Assessment Reports" section. This is a published study which conformed to the basic requirements of the guideline, containing sufficient details to regard it as reliable for use in hazard assessment. Cinnamic acid is the initial metabolite of cinnamaldehyde. Further justification included as attachement within endpoint summary. One of the studies is very old and probably less reliable. Nevertheless they are included here as supporting data to the metabolism of cinnamaldehyde provided as weight of evidence in this endpoint.

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Metabolism of trans-cinnamic acid in the rat and the mouse and its variation with dose

Author:

Nutley BP, Farmer P, Caldwell J

Year:

1994

Bibliographic source:

Fd. Chem. Toxic. 32, 877-886

Reference 2

Reference Type:

publication

Title:

La prova da carico di ac. cinnamico nel nefropaziente

Author:

Quarto di Palo FM; Bertolini AM

Year:

1961

Bibliographic source:

Atti. Accad. Med. Lombarada 16, 180-183

Materials and methods

Principles of method if other than guideline:

No details provided

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Cinnamic acid

EC Number:

210-708-3

EC Name:

Cinnamic acid

Cas Number:

621-82-9

IUPAC Name:

3-phenylacrylic acid

Test material form:

not specified

Details on test material:

No available information

Radiolabelling:

yes

Remarks:

14C label

Test animals

Species:

other: rat, mouse and human

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

No information

Administration / exposure

Route of administration:

other: rats - oral; mice - i.p. and humans intravenous injection

Vehicle:

not specified

Details on exposure:

The effect of dose on the disposition of [3-14C]-cinnamic acid in F344 rats and CD1 mice has been studied [Nutley et al., 1994]. Five dose levels of cinnamic acid in the range from 0.0005 mmol/kg bw (0.072 mg/kg bw) to 2.5 mmol/kg bw (370 mg/kg bw) were given orally to groups of F344 rats (4/group) or by intraperitoneal injection to groups of CD1 mice (4/group). After 24 hours, 73-88% of the radioactivity was recovered in the urine of rats and 78-93% in the urine of mice. After 72 hours, 84¬97% of the radioactivity was recovered from rats mainly in the urine. In mice, the recovery was 89-100% within 72 hours. Only trace amounts of radioactivity were present in the carcasses, indicating that cinnamic acid was readily and quantitatively excreted at all dose levels. In both species the main urinary metabolite was hippuric acid although in the mouse, the excretion of cinnamoylglycine was significant at lower doses.

Eleven adult volunteers received single intravenous doses of cinnamic acid, equivalent to 5 mg/kg bw (Quarto di Palo et al, 1961). 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 the glycine conjugate of benzoic acid (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.

Duration and frequency of treatment / exposure:

Single administration to each species

Doses / concentrations

Remarks:

Doses / Concentrations:
rats and mice treated at a range of doses between 0.0005 to 2.5 mmol/kg bw (equivalent to 0.072 to 370 mg/kg bw).
humans dose was 5 mg/kg bw

No. of animals per sex per dose / concentration:

Numbers of rats and mice not specified. Eleven human volunteers used.

Control animals:

no

Positive control reference chemical:

No data

Details on study design:

The effect of dose on the disposition of [3-14C]-cinnamic acid in F344 rats and CD1 mice has been studied [Nutley et al., 1994]. Five dose levels of cinnamic acid in the range from 0.0005 mmol/kg bw (0.072 mg/kg bw) to 2.5 mmol/kg bw (370 mg/kg bw) were given orally to groups of F344 rats (4/group) or by intraperitoneal injection to groups of CD1 mice (4/group). After 24 hours, 73-88% of the radioactivity was recovered in the urine of rats and 78-93% in the urine of mice. After 72 hours, 84¬97% of the radioactivity was recovered from rats mainly in the urine. In mice, the recovery was 89-100% within 72 hours. Only trace amounts of radioactivity were present in the carcasses, indicating that cinnamic acid was readily and quantitatively excreted at all dose levels. In both species the main urinary metabolite was hippuric acid although in the mouse, the excretion of cinnamoylglycine was significant at lower doses.

Eleven adult volunteers received single intravenous doses of cinnamic acid, equivalent to 5 mg/kg bw (Quarto di Palo et al, 1961). 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 the glycine conjugate of benzoic acid (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.

Details on dosing and sampling:

The effect of dose on the disposition of [3-14C]-cinnamic acid in F344 rats and CD1 mice has been studied [Nutley et al., 1994]. Five dose levels of cinnamic acid in the range from 0.0005 mmol/kg bw (0.072 mg/kg bw) to 2.5 mmol/kg bw (370 mg/kg bw) were given orally to groups of F344 rats (4/group) or by intraperitoneal injection to groups of CD1 mice (4/group). After 24 hours, 73-88% of the radioactivity was recovered in the urine of rats and 78-93% in the urine of mice. After 72 hours, 84¬97% of the radioactivity was recovered from rats mainly in the urine. In mice, the recovery was 89-100% within 72 hours. Only trace amounts of radioactivity were present in the carcasses, indicating that cinnamic acid was readily and quantitatively excreted at all dose levels. In both species the main urinary metabolite was hippuric acid although in the mouse, the excretion of cinnamoylglycine was significant at lower doses.

Eleven adult volunteers received single intravenous doses of cinnamic acid, equivalent to 5 mg/kg bw (Quarto di Palo et al, 1961). 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 the glycine conjugate of benzoic acid (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.

Statistics:

No data

Results and discussion

Preliminary studies:

No data

Toxicokinetic / pharmacokinetic studies

Details on absorption:

No data

Details on distribution in tissues:

No data

Details on excretion:

After 24 hours, 73-88% of the radioactivity was recovered in the urine of rats and 78-93% in the urine of mice.
After 72 hours, 84¬97% of the radioactivity was recovered from rats mainly in the urine.
In mice, the recovery was 89-100% within 72 hours.

Only trace amounts of radioactivity were present in the carcasses, indicating that cinnamic acid was readily and quantitatively excreted at all dose levels.
In both species the main urinary metabolite was hippuric acid although in the mouse, the excretion of cinnamoylglycine was significant at lower doses.

Analysis of the human 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 the glycine conjugate of benzoic acid (hippuric acid), cinnamoylglucuronide, and benzoylglucuronide present in a ratio of 74:24.5:1.5. These data demonstrate that cinnamic acid is rapidly oxidized to benzoic acid metabolites, and excreted in the urine of humans.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

In both rat and mouse species the main urinary metabolite was hippuric acid although in the mouse, the excretion of cinnamoylglycine was significant at lower doses.

human data demonstrate that cinnamic acid is rapidly oxidized to benzoic acid metabolites, and excreted in the urine of humans.

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:

No information

Any other information on results incl. tables

No information

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
Cinnamic acid is readily excreted in rat, mouse and human. The main urinary metabolite is hippuric acid.

Executive summary:

The effect of dose on the disposition of [3-14C]-cinnamic acid in F344 rats and CD1 mice has been studied [Nutley et al., 1994]. Five dose levels of cinnamic acid in the range from 0.0005 mmol/kg bw (0.072 mg/kg bw) to 2.5 mmol/kg bw (370 mg/kg bw) were given orally to groups of F344 rats (4/group) or by intraperitoneal injection to groups of CD1 mice (4/group). After 24 hours, 73-88% of the radioactivity was recovered in the urine of rats and 78-93% in the urine of mice. After 72 hours, 84¬97% of the radioactivity was recovered from rats mainly in the urine. In mice, the recovery was 89-100% within 72 hours. Only trace amounts of radioactivity were present in the carcasses, indicating that cinnamic acid was readily and quantitatively excreted at all dose levels. In both species the main urinary metabolite was hippuric acid although in the mouse, the excretion of cinnamoylglycine was significant at lower doses.

Eleven adult volunteers received single intravenous doses of cinnamic acid, equivalent to 5 mg/kg bw (Quarto di Palo et al, 1961). 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 the glycine conjugate of benzoic acid (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.