Cinnamaldehyde

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

Data is from peer reviewed journal

Data source

Reference

Reference Type:

publication

Title:

Repeated dose oral toxicity study of the test chemical

Author:

Hebert et al

Year:

1994

Bibliographic source:

Food and Chemical Toxicology

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: Refer below principle

Principles of method if other than guideline:

Subacute toxicity of the test chemical was assessed by oral gavage in B6C3F1 mice in a 14-day study.

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Cinnamaldehyde

EC Number:

203-213-9

EC Name:

Cinnamaldehyde

Cas Number:

104-55-2

Molecular formula:

C9H8O

IUPAC Name:

3-phenylacrylaldehyde

Details on test material:

- Name of test material (as cited in study report): Cinnamaldehyde
- Molecular weight: 132.1612 g/mol
- Molecular formula: C9H8O
- Substance type: Organic

Test animals

Species:

mouse

Strain:

B6C3F1

Sex:

male/female

Details on test animals or test system and environmental conditions:

Details on test animal
- Source: Charles River Laboratories
- Age at study initiation: 28 days
- Housing: Animals were housed individually in polycarbonate cages with hardwood shavings in a controlled environment.
- Diet (e.g. ad libitum): NIH-07 Rodent Chow
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS

- Temperature (°C): 72+2°F
- Humidity (%): 50 + 5%
- Photoperiod (hrs dark / hrs light): 12-hr light/dark cycle

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: Mazola corn oil

Details on oral exposure:

Details on oral exposure
- Amount of vehicle (if gavage) : 10mL/Kg bw/day

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

14 days (2 weeks: 5 days/week for a total of 12 doses)

Frequency of treatment:

Daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 656, 1310, 2620, 5250 or 10500 mg/kg/day
Basis:
other: in corn oil

No. of animals per sex per dose:

Control: 5 mice
656 mg/kg/day: 5 mice
1310 mg/kg/day: 5 mice
2620 mg/kg/day: 5 mice
5250 mg/kg/day: 5 mice
10500 mg/kg/day: 5 mice

Control animals:

yes, concurrent vehicle

Details on study design:

The test chemical was administered to B6C3F1 mice in corn oil as vehicle on a daily basis by gavage route at dose concentration of 0, 656, 1310, 2620, 5250 or 10500 mg/kg/day for 14 days. Animals were humanely killed with CO2 when sacrificed. A complete autopsy was performed on all animals that died early, and at the termination of each study on all treated and control animals.

Positive control:

No data

Examinations

Observations and examinations performed and frequency:

BODY WEIGHT: Yes
Body weights were determined.

ORGAN WEIGHT: Yes
Weight of the liver, right kidney and spleen were determined.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
Organs and tissues were examined for gross lesions and fixed in 10% neutral buffered formalin.

HISTOPATHOLOGY:
Complete histopathological examinations were carried out on all control animals, all early death animals, all animals in the highest dose group with at least 60% survivors and all animals in higher dose groups.

Other examinations:

OTHER:
A standard battery of 34 organs and tissues were trimmed, embedded in paraffin, sectioned, stained with hematoxylin and eosin, and examined microscopically. Organs identified as potential target organs (forestomach, testis, prostate, seminal vesicle, epididymis, uterus and ovary) were examined.
Organs identified as potential target organs (fore stomach, testis, prostate, seminal vesicle, epididymis, uterus, and ovary) were examined to a no-effect level in lower exposure groups

Statistics:

Statistics
Intergroup variations in all endpoints were analyzed by one-way analysis of variance. In cases where a statistically significant F-statistics in the ANOVA was observed, a multiple comparison procedure was used. The procedure of choice was the Ryan Einot Gabriel-Welsh multiple range test, which controls the type I experiment-wise error rate.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Description (incidence and severity):

No clinical signs were visible in these mice.

Mortality:

mortality observed, treatment-related

Description (incidence):

All mice gavaged withtest chemical at doses of 5250 and 10,500 mg/kg/day, as well as all female mice and three male mice dosed with 2620 mg/kg/day, died within the first 2 days of dosing. The cause of death could not be determined.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No statistically significant differences were observed in body weight

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

No statistically significant differences were observed in liver weight, spleen weight, kidney weight, or organ : body weight ratios between surviving treated mice and control mice.

Gross pathological findings:

no effects observed

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Minimal to mild fore stomach hyperplasia in both sexes and a minimal kidney nephropathy at doses of 1310 mg/kg/day was observed. The severity of the fore stomach hyperplasia was not related to dose or sex.

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

656 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Mortality, body weight, organ weight and histopathological examinations

Remarks on result:

not determinable due to absence of adverse toxic effects

2

Dose descriptor:

LOAEL

Effect level:

1 310 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Body weight, organ weight and histopathological examinations.

Remarks on result:

not determinable due to absence of adverse toxic effects

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Based on all the available results, it was concluded that the no observed adverse effect level (NOAEL) of the test chemical was considered to be 656 mg/kg/day in B6C3F1 mice and the low observed adverse effect level (LOAEL) of the test chemical was considered to be 1310 mg/kg/day in B6C3F1 mice.

Executive summary:

The purpose of this study was to examine the relative toxicity of the test chemical in B6C3F1 mice when administered in corn oil by gavage. The test chemical was administered on a daily basis at dose concentration of 0, 656, 1310, 2620, 5250 or 10500 mg/kg/day for 14 days. No statistically significant differences in body weight, liver weight, spleen weight and kidney weight was observed. In addition, no statistically significant differences in organ:body weight ratios between surviving treated mice and control mice was observed. All mice from two highest dose group as well as all female mice and three male mice from the 2620 mg/kg/day dose group died within the first 2 days of dosing. No clinical signs or gross lesions were observed in surviving mice and dead mice. Only a minimal to mild forestomach hyperplasia in both sexes and a minimal kidney nephropathy at doses of 1310 mg/kg/day and higher was shown. Hence, the no observed adverse effect level (NOAEL) of the test chemical was considered to be 656 mg/kg/day inB6C3F1 mice. The low observed adverse effect level (LOAEL) of the test chemical was considered to be 1310 mg/kg/day in B6C3F1 mice.