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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1973
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Published study which contains sufficient detail, including in results, to judge it reliable for hazard assessment purposes. Non GLP but close to guideline study and well documented.

Data source

Reference
Reference Type:
publication
Title:
Short-term toxicity of amyl cinnamic aldehyde in rats
Author:
Carpanini FMB, Gaunt IF, Wright MG, Grasso P, Gangolli SD
Year:
1973
Bibliographic source:
Fd. Cosmet. Toxicol. 11, 725-734

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
no opthalmological examination; No sensory reactivity determination; some serum determinations not conducted i.e. creatinine, cholesterol, sodium and potassium. Some organ histology not conducted .
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
The test material typically contains >94% of the trans (E) isomer and 4-5% of the cis (Z) isomer.

Test animals

Species:
rat
Strain:
other: CFE
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: SPF breeding colony (not clear whether sourced at BIBRA)
- Age at study initiation: no data
- Weight at study initiation: males 100-125g; females 90-120g
- Fasting period before study:
- Housing: 5 per cage
- Diet (e.g. ad libitum): Ad libitum. Spillers' Laboratory Small Diet.
- Water (e.g. ad libitum): Ad libitum.
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21+/-1C
- Humidity (%): 50-60%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data

IN-LIFE DATES: From: To: no data

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
The loss of amyl cinnamic aldehyde from the diet was determined prior to the study. This was done by the analysis (gas chromatography) of a diet which had been prepared with amyl cinnamic aldehyde at 10,000ppm and had been exposed in the animal room for 48, and compared to the same mixture in an air tight container. Only 1% of amyl cinnamic aldehyde was lost from the diet. Since this was not considered significant amyl cinnamic aldehyde was administered in food prepared every 4-5 days at the appropriate concentrations.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
14 weeks
Frequency of treatment:
Daily (continuous) dietary exposure
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 80, 400 or 4000 ppm
Basis:
nominal in diet
No. of animals per sex per dose:
15 for 14 weeks treatment (0, 80, 400, or 4000ppm)
Additional 5 for 2 weeks treatment (0, 400, or 4000ppm)
Additional 5 for 6 weeks treatment (0, 400, or 4000ppm)
Control animals:
yes, plain diet
Details on study design:
No information provided in publication
Positive control:
None

Examinations

Observations and examinations performed and frequency:
Body weights: At the beginning of the study and then weekly up to week 14.
Food and water consumption were measured over the 24hour period preceding each weighing.
Sacrifice and pathology:
At completion of the study the animals were necropsied. Any macroscopic abnormalities were noted.
The following organs were weighed: brain, pituitary, thyroid, heart, liver, spleen, kidneys, adrenals, gonads, stomach, small intestine and caecum.
Samples of the organs weighed were histologically examined. Also, tissues and samples from the following were histologically examined: salivary gland, trachea, aorta, thymus, lymph nodes, urinary bladder, colon, rectum, pancreas, uterus, skeletal muscle, and any other tissue that appeared to be abnormal.
Other examinations:
Blood samples were obtained before necropsy for haematological and serum chemistry investigations. In the final week of treatment, urine produced in a 6 hour period of water deprivation. At week 6 and 13, urine over a 2hr period was collected following a 25ml/kg of waterload and between 16 and 20hr after the water load.
Statistics:
Student's t-test. Significance p<0.05 or p<001

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
liver and kidney
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
One female in the 400ppm group died but histological and necropsy findings showed to be due to infection and therefore, unrelated to treatment.
Mammary adenomas were noted in two females (1 at 80ppm and 1 at 400ppm) during the last 3 week of the study. These were considered spontaneous and non-treatment related. Significant lower stomach weights in males given 400ppm and lower small-intestine weights in females given 4000ppm were observed after treatment for 6 weeks. The latter was not significant when expressed per body weight. Also, there were significant increases in relative liver weights in both sexes after 14week treatment and in males after 6 week treatement. Relative kidney weights were also increased after 14weeks at 4000ppm. There were some macroscopic and histological findings but none associated with substance intake. These were red, patchy lungs in three male rats (two at 80ppm, one in control), and pale kidneys in some male rats in all groups including controls. Also, vacuolation of some liver cells, protein casts in the kidney tubules and signs of chronic lung infection, with low and similar incidence in both treated and controls.

Effect levels

Dose descriptor:
NOAEL
Effect level:
400 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Liver and kidney enlargement observed at 4000 ppm

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

The increase in relative liver and kidney weights was not associated with any histological abnormality.

Mean intakes of amyl cinnamic aldehyde were 6.1, 29.9 and 287.3 mg/kg bw/d for males and 6.7, 34.9, and 320.3 mg/kg bw/d for females. The 400 ppm NOAEL corresponded to approximately 23 mg/kg bw/d in males and 36 mg/kg bw/d in females.

Applicant's summary and conclusion

Conclusions:
An oral NOAEL of approximately 30 mg/kg bw/d can be derived under the conditions of this study.
Executive summary:

Male and female rats were fed a diet containing amyl cinnamic aldehyde at 0, 80, 400 or 4000 ppm for 14 weeks. No differences were observed in body weight gain, haematology, urinary analysis, or clinical chemistry between control and treatment groups. Macroscopic and histological examination did not find any treatment-related changes. There were small mammary adenomas in two females from the two lowest doses which were considered spontaneous. At the end of the study there were a significant relative kidney weight increase in females and relative liver weight increase in male and females at the 4000 ppm dose and consequently a NOAEL of 400 ppm (approximately) 30 mg/kg bw/d can be established.