Cinnamaldehyde

Carcinogenicity

Description of key information

Carcinogenicity Studies:

In a toxicity study, the carcinogenic effects of the test chemical was evaluated male and female F344/N rat for 16 days. The test chemical was administered by oral gavage once daily, five days per week for a total of 12 doses, ranging for a total of 16 days. Rats received a dose level of 0, 235, 470, 940, 1880 or 3750 mg/kg body weight per day of the test chemical in a volume of 5 ml/kg body weight. No effects were observed at the lowest dose level, while all animals in the two highest dose groups died within the first 7 days of dosing. The results showed minimal to moderate forestomach hyperplasia in males was observed at doses of ≥470 mg/kg. There were a clear evidence of distended gastro-intestinal tracts in animals at doses of 1880 or 3750 mg/kg, as well as slightly decreased body weights in females of the 940 mg/kg dose group. Therefore, NOAEL was considered to be 235 mg/kg body weight in male and female F344/N rats when exposed once daily, five days per week for a total of 12 doses to the test chemical by oral gavage.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Data is from peer reviewed journal

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

Principles of method if other than guideline:

A study of the test chemical's carcinogenic potential in rats after gavage administration.

GLP compliance:

not specified

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

Details on test animal and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories (Raleigh, NC, USA).
- Age at study initiation: 5 weeks
- Weight at study initiation: No data available
- Fasting period before study: No data available
- Housing: Animals were housed individually in polycarbonate cages with hardwood shavings.
- Diet (e.g. ad libitum): NIH-07 Rodent Chow, ad libitum
- Water (e.g. ad libitum): Water, ad libitum
- Acclimatization period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 72 ± 2⁰F
- Humidity (%): 50 ± 5%
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): 12-hr light/dark cycle

IN-LIFE DATES: From: To: No data available

Route of administration:

oral: gavage

Vehicle:

other: Mazola corn oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Gavage dosing solutions were prepared directly in Mazola corn oil.

DIET PREPARATION
- Rate of preparation of diet (frequency): No data available
- Mixing appropriate amounts with (Type of food): No data available
- Storage temperature of food: No data available

VEHICLE
- Justification for use and choice of vehicle (if other than water): Mazola corn oil
- Concentration in vehicle: 0, 235, 470, 940, 1880 or 3750 mg/kg bodyweight/day
- Amount of vehicle (if gavage): 5 ml/kg bodyweight
- Lot/batch no. (if required): No data available
- Purity: No data available

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

No data available

Duration of treatment / exposure:

16 days

Frequency of treatment:

Once daily, five days per week for a total of 12 doses

Post exposure period:

No data available

Remarks:

Doses / Concentrations:
0, 235, 470, 940, 1880 or 3750 mg/kg bodyweight/day
Basis:
actual ingested

No. of animals per sex per dose:

Total: 60 animals
0 mg/kg: 5 males, 5 females
235 mg/kg: 5 males, 5 females
470 mg/ kg: 5 males, 5 females
940 mg/ kg: 5 males, 5 females
1880 mg/ kg: 5 males, 5 females
3750 mg/ kg: 5 males, 5 females

Control animals:

yes, concurrent vehicle

Details on study design:

No data available

Positive control:

No data available

Observations and examinations performed and frequency:

Observation and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: No data available
- Cage side observations included: Mortality

DETAILED CLINICAL OBSERVATIONS: No data available
- Time schedule: No data available

DERMAL IRRITATION (if dermal study): No data available
- Time schedule for examinations: No data available

BODY WEIGHT: Yes
- Time schedule for examinations: At time of termination

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No data available
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data available
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data available

FOOD EFFICIENCY: No data available
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data available

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data available
- Time schedule for examinations: No data available

OPHTHALMOSCOPIC EXAMINATION: No data available
- Time schedule for examinations: No data available
- Dose groups that were examined: No data available

HAEMATOLOGY: No data available
- Time schedule for collection of blood: No data available
- Anaesthetic used for blood collection: No data available
- Animals fasted: No data available
- How many animals: No data available
- Parameters checked in table [No.?] were examined. No data available

CLINICAL CHEMISTRY: No data available
- Time schedule for collection of blood: No data available
- Animals fasted: No data available
- How many animals: No data available
- Parameters checked in table [No.?] were examined. No data available

URINALYSIS: No data available
- Time schedule for collection of urine: No data available
- Metabolism cages used for collection of urine: No data available
- Animals fasted: No data available
- Parameters checked in table [No.?] were examined. No data available

NEUROBEHAVIOURAL EXAMINATION: No data available
- Time schedule for examinations: No data available
- Dose groups that were examined: No data available
- Battery of functions tested: sensory activity / grip strength / motor activity / other: No data available

OTHER: Organ weight was noted for liver, right kidney and spleen

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
Organs and tissues were examined for gross lesions and fixed prior to histopathological examinations.

HISTOPATHOLOGY: Yes
Prior to microscopic examination, a standard battery of 34 organs and tissues were trimmed, embedded, sectioned and stained with haematoxylin and eosin.
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. Organs identified as potential target organs (forestomach, testis, prostate, seminal vesicle, epididymis, uterus and ovary) were examined to a no-effect level in lower exposure groups.

Other examinations:

No Data Available

Statistics:

Intergroup variations in all endpoints were analysed by one-way analysis of variance. In cases where a statistically significant F-statistic (P <0.05) in the ANOVA was observed, a multiiple comparison procedure was used. The procedure of choice was the Ryan Einot Gabriel-Welsh multiple range test, which controls thetype I experiment-wise error rate. A P-value <0.05 was considered significant.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

The animals dosed with concentrations of 1880 and 3750mg/kg/day died or were killed when moribund during the first 7 days of dosing. Clinical signs were absent in surviving rats.

Dermal irritation (if dermal study):

not specified

Mortality:

mortality observed, treatment-related

Description (incidence):

The rats receiving the dose concentrations of 1880 and 3750mg/kg/day were subjected to unscheduled sacrifice, since they were found in the moribund conditions.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Rats of both sexes in the 940 mg'kg'day groups had slightly decreased body weights relative to controls, although this decrease was statistically significant (P < 0.05) only for the females.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

The corn oil solution was found in the mid to lower sections of the gut in each rat, and the stomachs were full of food, indicating that the rats had been eating well after the dosing.

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):

There were no consistent differences in organ weights or organ weight:body weight ratios between surviving treated rats and controls.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

Gastro-intestinal tracts were distended in animals treated with 1880 or 3750 mg/kg. No other gross lesions were absent in surviving rats.

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Microscopic lesions included a minimal to moderate forestomach hyperplasia in males at doses of 470 mg/kg/day and higher. The hyperplastic alterations in the forestomach epithelium seen in animals dosed by gavage were considered to be the result of irritation of the gastric mucosa by the test chemical. Such hyperplasia has been described in studies of numerous other irritant chemicals administered by an oral route.

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Details on results:

Clinical sign and mortality
Clinical signs were absent in surviving rats.

Mortality:
All rats dosed by gavage with the test chemical at concentrations of 1880 and 3750mg/kg/day died. All remaining rats of both sexes in the 235, 470 and 940 mg/kg/day dose groups survived to the end of the study.

Body weight and weight gain
Body weight:
Rats of both sexes in the 940 mg/kg/day groups had slightly decreased body weights relative to controls, although this decrease was statistically significant (P < 0.05) only for the females.

Food consumption & compound intake
Food consumption:
The corn oil solution was found in the mid to lower sections of the gut in each rat, and the stomachs were full of food, indicating that the rats had been eating well after the dosing.

Food efficiency
No data available

Water consumption & compound intake
No data available

Ophthalmoscopic examination
No data available

Haematology
No data available

Clinical chemistry
No data available

Urinalysis
No data available

Neuro behavior
No data available

Organ Weights
There were no consistent differences in organ weights or organ weight: body weight ratios between surviving treated rats and controls.

Gross Pathology
Gastro-intestinal tracts were distended in animals treated with 1880 or 3750 mg/kg.

Histopathology: non-neoplastic
Microscopic lesions included a minimal to moderate forestomach hyperplasia in males at doses of 470 mg/kg/day and higher. The hyperplastic alterations in the forestomach epithelium seen in animals dosed by gavage were considered to be the result of irritation of the gastric mucosa by the test chemical. Such hyperplasia has been described in studies of numerous other irritant chemicals administered by an oral route.

Histopathology: neoplastic
No data available

Dose descriptor:

NOAEL

Effect level:

235 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No occurrence of hyperplastic lesions or forestomach hyperplasia.

Remarks on result:

other:

Remarks:

Effect type: other: Not tumorogenic (migrated information)

Critical effects observed:

yes

Lowest effective dose / conc.:

470 mg/kg bw/day (nominal)

System:

gastrointestinal tract

Organ:

stomach

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

not specified

Conclusions:

Based on all the observations and results, the NOAEL for the test chemical was observed to be 235 mg/kg bw/day.

Executive summary:

In a toxicity study, the carcinogenic effects of the test chemical was evaluated male and female F344/N rat for 16 days. The test chemical was administered by oral gavage once daily, five days per week for a total of 12 doses, ranging for a total of 16 days. Rats received a dose level of 0, 235, 470, 940, 1880 or 3750 mg/kg body weight per day of the test chemical in a volume of 5 ml/kg body weight. No effects were observed at the lowest dose level, while all animals in the two highest dose groups died within the first 7 days of dosing. The results showed minimal to moderate forestomach hyperplasia in males was observed at doses of ≥470 mg/kg. There were a clear evidence of distended gastro-intestinal tracts in animals at doses of 1880 or 3750 mg/kg, as well as slightly decreased body weights in females of the 940 mg/kg dose group. Therefore, NOAEL was considered to be 235 mg/kg body weight in male and female F344/N rats when exposed once daily, five days per week for a total of 12 doses to the test chemical by oral gavage.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

235 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Data is from a Klimisch 2 source and provides a robust study summary.

System:

other: Not Specified

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

In summary, dietary exposure to trans-cinnamaldehyde is not associated with an increased risk of cancer according to two-year studies involving rats and mice. In shorter studies (90 days) minimal to moderate forestomach epithelial hyperplasia has been observed at high concentrations of trans-cinnamaldehyde. This effect was likely an adaptive response to mucosal irritation caused by the chemical at high concentrations. Based on the presented data, cinnamaldehyde is regarded to be classified as Not Classified for Carcinogenicity.

Additional information

Carcinogenicity Studies:

The data from different carcinogenicity studies is as follows:

Study 1:

In a toxicity study, the carcinogenic effects of the test chemical was evaluated male and female F344/N rat for 16 days. The test chemical was administered by oral gavage once daily, five days per week for a total of 12 doses, ranging for a total of 16 days. Rats received a dose level of 0, 235, 470, 940, 1880 or 3750 mg/kg body weight per day of the test chemical in a volume of 5 ml/kg body weight. No effects were observed at the lowest dose level, while all animals in the two highest dose groups died within the first 7 days of dosing. The results showed minimal to moderate forestomach hyperplasia in males was observed at doses of ≥470 mg/kg. There were a clear evidence of distended gastro-intestinal tracts in animals at doses of 1880 or 3750 mg/kg, as well as slightly decreased body weights in females of the 940 mg/kg dose group. Therefore, NOAEL was considered to be 235 mg/kg body weight in male and female F344/N rats when exposed once daily, five days per week for a total of 12 doses to the test chemical by oral gavage.

Study 2:

In a toxicity study, the carcinogenic effects of the test chemical was evaluated male and female B6C3F1mice for 16 days. The test chemical was administered by oral gavage once daily, five days per week for a total of 12 doses, ranging for a total of 16 days. Mice received a dose level of 0,656, 1310, 2620, 5250 or 10500 mg/kg body weight per day of the test chemical in a volume of 10 ml/kg body weight. All mice dosed with 5250 or 10500 mg/kg, as well as all female mice and 3 male mice at 2620 mg/kg, died within the first two days of dosing. The results also showed a minimal to mild fore stomach hyperplasia in both sexes and a minimal kidney nephropathy at doses of ≥1310 mg/kg. However, the severity of the fore stomach hyperplasia was regarded not to be related to dose or sex. Therefore, NOAEL was considered to be 656 mg/kg body weight in male and femaleB6C3F1micewhen exposed once daily, five days per week for a total of 12 doses to the test chemical by oral gavage.

Study 3:

In a 2-year combined repeated and carcinogenicity study of the test chemical, groups of 50 male and 50 female F344/N rats were fed diets containing 1,000, 2,100, or 4,100 ppm microencapsulated test chemical for 2 years. Additional groups of 50 male and 50 female rats received untreated feed (untreated controls) or feed containing placebo microcapsules (vehicle controls). Dietary concentrations of 1,000, 2,100, or 4,100 ppm delivered average daily doses of approximately 50, 100, or 200 mg/kg to males and females. Survival of 4,100 ppm males was greater than that of the vehicle controls. Mean body weights of 4,100 ppm males were less than those of the vehicle controls throughout the study, mean body weights of 2,100 ppm males were less after week 94, and mean body weights of 4,100 ppm females were less after week 18. Feed consumption by 2,100 and 4,100 ppm males and 4,100 ppm females was less than that by the vehicle controls at the beginning and end of the study. The incidences of adenoma of the preputial gland (vehicle control, 5/50; 1,000 ppm, 1/49; 2,100 ppm, 2/50; 4,100 ppm, 0/50) and prostate gland (4/50, 0/49, 0/49, 0/50) in 4,100 ppm males were significantly decreased compared to those in the vehicle controls. The incidences of preputial gland adenoma in the exposed and vehicle control groups were within the historical range in controls (all routes) given NTP-2000 diet [45/907 (4.2% ± 3.5%), range 0%-13%]. Similarly, the incidences of carcinoma of the preputial gland (1/50, 2/49, 3/50, 1/50) were within the historical range in controls given NTP-2000 diet [27/907 (3.3% ± 3.0%), range 0%-10%]. The incidence of prostate gland adenoma in the vehicle controls (4/50) exceeded the historical control range [13/906 (1.4% ± 1.7%), range 0%-4%]. Thus, based on all the observations and results, the NOAEL for the test chemical was found to be 205 mg/kg bw/day.

Study 4:

In a 2-year carcinogenicity study, the carcinogenic effects of the test chemical was evaluated in male and females B6C3F1mice. The test chemical was administered microencapsulated test chemical in diet at a dosage of 0, 1000, 2100 or 4100 ppm (0, 125, 270 or 540 (males)/570 (females) mg/kg body weight) for 2 years. The results showed that the survival of4100 ppm males and females were generally less than those of the vehicle controls throughout the study. Feed consumption by 2100 or 4100 ppm males and 4100 ppm females were less than that by the vehicle controls at the beginning and end of the study. When examining pathology, the results showed no neoplasms or non-neoplastic lesions that were attributed to exposure to the test chemical. Survival of males in the 2100 ppm group was less than that of the vehicle control group. Mean body weights of 2100 and 4100 ppm males and 4100 ppm females were generally less than those of the vehicle controls throughout the study, and mean body weights of 1000 ppm males were less after week 74. Feed consumption by exposed mice was similar to that by the vehicle controls. The incidences of olfactory epithelial pigmentation in 4100 ppm males and in 2100 and 4100 ppm females were significantly greater than those in vehicle controls. As compared to historical ranges, no neoplasms attributed to exposure to the test chemical were seen. Therefore, NOAEL was considered to be 4100 ppm (540 (males)/570 (females) mg/kg body weight) when male and female B6C3F1mice were exposed to the test chemical.