Registration Dossier

Administrative data

Description of key information

Repeated oral dose toxicity study ofAmyl cinnamic aldehyde was studied in CFE strain rats. Doses of test substance administered orally in diet were6.1, 29.9 and 287.3 mg/kg/day for males and 6.7, 34.9 and 320.3 mg/kg/day for females. Test substance was fed to groups of 15 male rats (body weight loo-125 g) and15 females (body weight 90-120 g) for 14 wk.Additional groups of five rats were fed with 6.1, 29.9 and 287.3 mg/kg/day for males and 6.7, 34.9 and 320.3 mg/kg/day for females. Animals were fed on Spillers laboratory small animal diet. Water is provided to animals throughout study. Hematological screening, serum analysis and urine analysis were done. After appropriate period of feeding the rats were killed by exsanguination under barbiturates anesthesia. Gross pathology and histopathology investigation were done.Apart from three rats, no abnormalities were seen in behavior or appearance of animal. No mortality was reported in the study.Animals were weigh initially and then weekly thereafter. Increase in body weight at each dose level was reported. There were no statistically significant differences between treated and control groups in rate of body-weight gain. There were no statistically significant differences between treated and control groups in food consumption. The mean intakes of amyl cinnamic aldehyde over the 14wk period were 6.1, 29.9 and 287.3 mg/kg/day by the males of the groups given 4, 20 and 200 mg/kg bw of test substance in the diet and 6.7, 34.9 and 320.3 mg/kg/day by the females. There were no statistically significant differences between treated and control groups in water consumption. The mean water consummation over 14wk period were 25.8, 25.8 and 27.5 ml/rat/day by the males and female, mean water consummation values were 24.9, 24.5 and 25 respectively.There were no significant differences between treated and control groups in the results of the hematological examinations. Hematological examinations were done on blood samples collected at 2, 6 and 14 week of study. Hemoglobin, Packed cell volume, RBC, Reticulocytes and Leucocytes were examined.A measurement of urinary concentrating ability was made during the final week of treatment by measuring the specific gravity and volume of urine produced in a 6-hr period of water deprivation. At the same time, samples of the urine were examined for appearance, microscopic constituents and content of cells, glucose, ketones, bile salts and blood. At wk 6 and 13, urine was also collected from the rats over a 2-hr period following a water load of 25 ml/kg and between 16 and 20 hr after the water load. The only statistically significant differences in the absolute organ weights of treated and control rats were seen after treatment of 6 week. These consisted of lower stomach weights in the males given 287.3 mg/kg bw amyl cinnamic aldehyde and lower small intestine weights in the females given 320.3 mg/kg bw. In the latter case, the difference was not significant when the organ weights were expressed relative to body weights. Patchy lungs in three male rats (two at 6.1 mg/kg bw of test substance level and one control) and pale kidneys in some male rats in all groups including controls. Small mammary adenomas were found in two treated female rats.   One female rat shows respiratory depression, on histopathological examination of tissue revealed pneumonia and an abscess of renal pelvis. Mammary adenomas were reported in two female rats. Vacuolation of some liver cells, protein casts in kidney tubules and sign of chronic lung infection. The incidence of these findings was low and was similar in both treated and control rats.One female rat shows respiratory depression, on histopathological examination of tissue revealed pneumonia and an abscess of renal pelvis. Mammary adenomas were reported in two female rats. Vacuolation of some liver cells, protein casts in kidney tubules and sign of chronic lung infection. The incidence of these findings was low and was similar in both treated and control rats. Therefore NOAEL were approximately 23 mg/kg bw in males and 36 mg/kg bw in females as per study.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
No data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Peer reviewed journal research article
Qualifier:
according to
Guideline:
other: Refer below principle
Principles of method if other than guideline:
Short term toxicity potential of Amyl Cinnamic Aldehyde was studied in CFE strain rats.
GLP compliance:
not specified
Limit test:
no
Specific details on test material used for the study:
- Name of test material (as cited in study report): Amyl cinnamic aldehyde
- Molecular formula (if other than submission substance): C14H18O
- Molecular weight (if other than submission substance): 202.2952 g/mol
- Substance type: Organic
- Physical state: No data
- Impurities (identity and concentrations): 3%
Species:
rat
Strain:
other: CFE
Details on species / strain selection:
No data
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: SPF breeding colony
- Age at study initiation: No data
- Weight at study initiation: Male: 100-125 g, Female: 90-120 g
- Fasting period before study: No data
- Housing: Animals housed in cages in animal room maintained at 21±1 °C with relative humidity 50-60%.
- Diet (e.g. ad libitum): Spillers Laboratory small animal diet, ad. libitum.
- Water (e.g. ad libitum): Water, ad. libitum.
- Acclimation period: No data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21±1 °C
- Humidity (%):50-60%
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light):
No data
IN-LIFE DATES: From: To: No data
Route of administration:
oral: feed
Details on route of administration:
No data
Vehicle:
other: Spillers Laboratory small animal diet
Details on oral exposure:
Details on oral exposure
PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): 4-5 days
- Mixing appropriate amounts with (Type of food): Spillers Laboratory Small Animal Diet
- Storage temperature of food: No data

VEHICLE
- Justification for use and choice of vehicle (if other than water): No data
- Concentration in vehicle: 0,6.1,29.9 and 287.3 mg/kg/day for males
0,6.7, 34.9 and 320.3 mg/kg/day for females
- Amount of vehicle (if gavage): No data
- Lot/batch no. (if required): No data
- Purity: No data
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data
Duration of treatment / exposure:
14 weeks
Frequency of treatment:
Daily
Remarks:
0,6.1,29.9 and 287.3 mg/kg/day for males (0, 80, 400, 4000 ppm )
Remarks:
0,6.7, 34.9 and 320.3 mg/kg/day for females ((0, 80, 400, 4000 ppm )
No. of animals per sex per dose:
15 male and 15 female/dose
Test control: 15 male and 15 female
Satellite Control: 5 male and 5 female

Control animals:
yes, concurrent vehicle
Details on study design:
No data
Positive control:
No data
Observations and examinations performed and frequency:

Observations and examinations performed & frequency
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: No data
- Cage side observations checked in table [No.?] were included. respiratory distress and weight loss were observed

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: No data

BODY WEIGHT: Yes
- Time schedule for examinations:
Animals were weigh initially and then weekly up to 14 weeks.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes , The food consumption were measured over the 24-hr period
preceding each weighing.

- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

FOOD EFFICIENCY:
- 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

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: ml/rat/day at 0, 5, 9, 14 week

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

HAEMATOLOGY: Yes
- Time schedule for collection of blood: 2, 6, 14 week
- Anesthetic used for blood collection: Yes (Barbiturates anesthesia)
- Animals fasted: No data
Parameters checked in table [No.?] were examined: Yes, The hematological investigations consisted of measurement of hemoglobin ,content, packed cell volume, and counts of erythrocytes, total leucocytes and
individual types of leucocytes. Reticulocytes were counted in the samples from control rats
and those fed the highest level of amyl Cinnamic aldehyde .

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: 2, 6, 14 week
- Animals fasted: No data
- Parameters checked in table [No.?] were examined: Yes, Serum was analyzed for the content of urea, glucose, total protein and albumin and for the activities of glutamio oxalacetic and glutamic-pyruvic transaminases and of lactic dehydrogenase.

URINALYSIS: Yes
- Time schedule for collection of urine: 6,12 and Final week of treatment.
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked in table [No.?] were examined. Yes , the specific gravity and volume of urine produced in a 6-hr period
of water deprivation. At the same time, samples of the urine were examined for appearance,
microscopic constituents and content of cells, glucose, ketones, bile salts and blood. At wk 6
and 13, urine was also collected from the rats over a 2-hr period following a water load of
25 ml/kg and between 16 and 20 hr after the water load.

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

OTHER: organ weight; Organ stomach, small intestine and caecum were weighed.
Sacrifice and pathology:
Sacrifice and pathology
GROSS PATHOLOGY: Yes, the rats were killed by exsanguinations under barbiturate anesthesia. Samples of salivary gland, trachea, aorta, thymus, lymph nodes, urinary bladder, colon, rectum, pancreas, uterus, skeletal muscle were observed

HISTOPATHOLOGY: Yes , The tissue that appeared to be abnormal were fixed in 10 %
buffered formalin. Pa&En-wax sections of these tissues were stained with haematoxylin and
eosin for microscopic examination.

Statistics:
No data
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
No statistically significant change were observed at all dose group compare to control.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
No statistically significant change were observed at all dose group compare to control.

Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
No statistically significant change were observed at all dose group compare to control.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
effects observed, non-treatment-related
Description (incidence and severity):
No statistically significant change were observed at all dose group compare to control.
Ophthalmological findings:
not specified
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
No statistically significant change were observed at all dose group compare to control.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
No statistically significant change were observed at all dose group compare to control.
Urinalysis findings:
effects observed, non-treatment-related
Description (incidence and severity):
No statistically significant change were observed at all dose group compare to control.
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
The only statistically significant differences in the absolute organ weights of treated and control rats were seen after treatment of 6 week. These consisted of lower stomach weights in the males given 287.3 mg/kg bw amyl cinnamic aldehyde and lower small intestine weights in the females given 320.3 mg/kg bw. In the latter case, the difference was not significant when the organ weights were expressed relative to body weights.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Patchy lungs in three male rats (two at 6.1 mg/kg bw of test substance level and one control) and pale kidneys in some male rats in all groups including controls. Small mammary adenomas were found in two treated female rats.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
One female rat shows respiratory depression, on histopathological examination of tissue revealed pneumonia and an abscess of renal pelvis. Vacuolation of some liver cells, protein casts in kidney tubules and sign of chronic lung infection. The incidence of these findings was low and was similar in both treated and control rats.
Histopathological findings: neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
Mammary adenomas were reported in two female rats.
Key result
Dose descriptor:
NOAEL
Effect level:
23 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: No significant change were observed on the clinical sign/food consumption,body weight, hematological examinations,clinical chemistry,urine analysis ,organ weight, gross pathology and histopathology
Remarks on result:
other: No significant change were observed on the clinical sign/food consumption,body weight, hematological examinations,clinical chemistry,urine analysis ,organ weight, gross pathology and histopathology
Key result
Dose descriptor:
NOAEL
Effect level:
36 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: No significant change were observed on the clinical sign/food consumption,body weight, hematological examinations,clinical chemistry,urine analysis ,organ weight, gross pathology and histopathology
Remarks on result:
other: No significant change were observed on the clinical sign/food consumption,body weight, hematological examinations,clinical chemistry,urine analysis ,organ weight, gross pathology and histopathology
Critical effects observed:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Table. Mean body weights and consumption of food and water for rats fed amyl cinnamic aldehyde at 0-200 mg/kg bw of the diet for 14 wk

Dietary level

(ppm)

Body Weight (g) at week

Weight gain (g) at 14 week

Food Consumption (g/rat/day) at Week

Mean food consumption (g/rat/day)

0

5

9

14

0

5

9

14

Males

 

 

 

 

 

0

113

352

435

494

381

17.1

22.1

22.7

19.9

22.1

80

118

356

449

509

391

16.9

25.9

23.7

20.5

22.3

400

114

353

440

502

388

15.0

23.4

23.5

20.7

21.8

4000

116

343

428

490

374

16.6

21.8

22.1

19.7

20.6

Female

 

 

 

 

 

0

104

226

267

297

193

15.4

16.5

18.4

14.7

17.8

80

106

232

274

305

199

14.9

18.6

20.4

16.1

17.6

400

104

238

280

311

207

14.7

19.4

21.6

14.0

18.6

4000

104

225

264

292

188

14.3

17.3

19.3

15.1

16.4

                                                                                                                                  

 


 

 

Dietary level

(ppm)

Water Consumption (ml/rat/day) at wk

Mean water consumption (ml/rat/day)

0

5

9

14

Males

0

20.3

28.3

27.6

30.1

26.9

80

20.2

28.7

26.5

29.8

25.8

400

18.3

27.9

28.0

30.5

25.8

4000

20.1

27.7

28.1

29.3

27.5

Female

0

20.9

23.7

23.3

23.5

23.0

80

22.6

27.0

27.2

27.5

24.9

400

21.6

27.0

27.4

24.5

24.5

4000

20.1

27.2

26.1

25.6

25.0

 

 

 

 

 

 

 

 

 

Table: Hematological values of rats fed 0-200 mg/kg bw amyl cinnamic aldehyde in the diet for 2, 6 or 14 wk

Sex and Dietary level (ppm)

 

Leucocytes

No. of rats

Hb

(g/100 ml)

 

PCV (%)

RBC (106/mm3)

Retics (% of RBS)

Total

(103/mm3)

Differential (%)

 

N

E

L

M

Week 2

Male

0

5

13

43

6.20

1.80

6.67

9

1

89

1

400

5

13.3

42

6.20

-

5.16

7

0

91

2

4000

5

13.5

43

6.41

1.72

6.09

7

1

90

2

Female

0

5

12.4

41

5.99

0.90

3.95

10

0

88

1

400

5

12.8

43

6.16

-

3.89

9

1

88

2

4000

5

12.8

43

6.45

1.69

3.47

7

2

89

2

Week 6

Male

0

5

14.1

44

6.81

0.64

7.52

13

1

84

2

400

5

14.3

45

7.13

-

6.66

14

0

85

1

4000

5

13.9

45

6.94

0.93

6.19

12

1

86

1

 

 

 

 

 

 

 

 

 

 

 

Female

0

5

13.4

43

6.16

1.06

4.33

18

2

79

1

400

5

13.3

42

6.14

-

4.33

16

2

80

2

4000

5

13.6

43

6.18

1.46

2.93

13

2

83

2

Week 14

Male

0

15

15.3

44

7.15

0.80

6.20

21

2

76

1

80

15

14.9

44

7.10

-

6.46

15

2

82

1

400

15

15.1

44

7.00

-

6.21

17

2

80

1

4000

15

15.1

44

7.32

0.49

6.55

14

1

84

1

Female

0

15

14.4

43

6.58

0.69

3.55

16

2

81

1

80

15

14.6

44

6.70

-

3.91

18

3

78

1

400

15

14.5

43

6.65

-

3.34

12

2

85

1

4000

15

14.1

43

6.63

0.71

3.21

16

2

81

1

Hb = Haemoglobin PCV = Packed cell volume RBC = Red blood cells Reties = Reticulocytes N = Neutrophils E = Eosinophils L = Lymphocytes M= Monocytes

 

Table. Values of serum analyses for rats treated with 0-200 mg/kg bw amyl cinnamic aldehyde in the diet for 2, 6 or 14 Week

Sex and Dietary level (ppm)

No. of rats

GOT (IU)

GPT (IU)

 

LDH (IU)

Glucose (mg/100 ml)

 

Urea (mg/100 ml)

Protein

(g/100 ml)

Albumin (g/100 ml)

Week 2

Male

0

5

46

6

897

-

15

5.9

5.5

400

4

43

6

945

-

13

5.8

5.4

4000

5

41

6

875

-

16

5.8

5.5

Female

0

5

51

7

1169

105

17

-

4.2

400

4

59

6

1280

115

17

-

4.0

4000

5

52

7

971

113

16

-

4.1

Week 6

Male

0

5

56

8

974

81

18

7.1

3.5

400

5

52

7

1071

81

15

7.1

4.0

4000

5

57

12

988

70

18

7.4

3.6

Female

0

5

46

9

941

75

19

7.3

3.8

400

5

45

6

907

88

19

7.1

4.1

4000

4

46

7

897

50

20

7.3

4.2

                                                          Week 14

Male

0

15

46

10

769

141

15

7.4

3.7

80

15

43

9

783

124

16

7.4

4.0

400

15

43

10

794

112

18

7.4

4.0

4000

15

46

9

811

121

19

7.4

4.1

Female

0

15

45

7

803

115

18

7.5

4.4

80

15

45

8

790

111

19

7.8

4.6

400

15

43

9

845

126

15

7.6

4.2

4000

15

44

7

860

120

15

7.6

4.2

 

 

 

 

 

 

 

 

 

 


Table. Mean value of renal concentration/ dilution tests and urinary cell excretion in rats fed amyl cinnamic aldehyde at 0-200 mg/kg bw amyl cinnamic aldehyde in the diet for 2, 6 or 14 week.

Sex and dietary level (ppm)

No. of rats

 

 

Cell excretion (103/hr)

Concentration test

Dilution Test

(2 hr)

 

Specific gravity

Volume (ml)

Specific Gravity

Volume (ml)

0-6 hr

16-20 hr

0-6 hr

16-20 hr

 

 

Week 2

Male

0

5

5.4

1.062

-

1.5

-

-

-

400

5

4.8

1.061

-

2.2

-

-

-

4000

5

3.1

1.066

-

1.2

-

-

-

Female

0

5

3.7

1.057

-

2.2

-

-

-

400

5

2.5

1.062

-

2.1

-

-

-

4000

5

4.3

1.060

-

1.6

-

-

-

Week 6

Male

0

5

3.7

1.049

1.068

2.3

0.7

1.010

7.2

400

5

4.0

1.054

1.076

2.9

0.9

1.012

5.5

4000

5

3.9

1.056

1.065

2.5

1.4

1.009

6.4

Female

0

5

2.6

1.049

1.072

1.4

0.8

1.010

3.2

400

5

2.8

1.037

1.075

1.6

0.6

1.007

3.6

4000

5

3.8

1.045

1.073

1.0

0.7

1.013

2.7

Week 14

Male

0

12

3.2

1.060

1.072

1.9

1.0

1.011

6.7

80

12

3.6

1.056

1.067

1.7

1.5

1.012

6.0

400

12

3.2

1.062

1.067

1.4

1.4

1.014

5.5

4000

12

3.6

1.060

1.065

1.6

1.4

1.012

6.7

Female

 

 

 

 

 

 

 

 

0

12

2.2

1.062

1.079

0.5

0.3

1.010

5.3

80

12

2.9

1.051

1.068

0.9

0.6

1.011

4.4

400

12

3.8

1.049

1.068

0.7

0.3

1.012

4.9

4000

12

4.1

1.051

1.063

1.2

1.1

1.008

5.3

 

 

 

 


Table: Relative organ weights of rats fed amyl cinnamic aldehyde at 0-200 mg/kg bw of the diet for 2, 6 or 14 weeks.

Sex and Dietary level (ppm)

No. of rats

Relative organ weights (g/100 g body weight)

Terminal Body Weight (g)

Brain

Heart

Liver

Spleen

Kidney

Stomach

Small

Intestine

Caecum

Adrenals+

Gonads

++

Pituitary

+

Thyroid

+

Week 2

Male

0

5

0.76

0.41

3.33

0.33

0.86

0.60

3.42

0.36

24.2

1.16

3.84

6.99

226

400

5

0.70

0.41

3.32

0.28

0.82

0.52

3.18

0.35

24.5

1.18

3.89

6.97

240

4000

5

0.75

0.40

3.73

0.30

0.87

0.55

3.21

0.34

25.1

1.21

4.02

8.02

229

Female

0

5

0.94

0.43

3.40

0.34

0.84

0.58

3.45

0.36

38.1

51.9

5.82

9.35

169

400

5

1.00

0.44

3.47

0.34

0.87

0.58

3.37

0.37

37.7

55.1

6.33

8.76

163

4000

5

0.97

0.43

3.51

0.35

0.86

0.57

3.38

0.37

36.6

46.0

5.84

9.52

167

Week 6

Male

0

5

0.51

0.34

2.77

0.25

0.69

0.44

1.80

0.24

18.6

1.00

3.40

4.68

372

400

5

0.51

0.35

2.80

0.24

0.71

0.39

1.91

0.23

16.9

0.94

3.56

5.43

369

4000

5

0.54

0.35

3.06

0.24

0.77

0.46

1.92

0.27

19.4

1.06

3.40

5.65

338

Female

0

5

0.76

0.35

2.75

0.28

0.67

0.51

2.64

0.38

35.2

59.3

4.51

7.77

223

400

5

0.76

0.33

2.56

0.24

0.65

0.62

2.47

0.32

34.7

41.4

4.41

8.40

213

4000

5

0.76

0.34

2.87

0.28

0.70

0.54

2.31

0.39

36.7

47.7

4.66

8.80

217

Week 14

Male

0

15

0.40

0.28

2.42

0.17

0.60

0.39

1.62

0.24

13.7

0.77

2.34

4.20

476

80

15

0.38

0.28

2.51

0.18

0.58

0.41

1.62

0.24

12.2

0.72

2.40

4.23

492

400

15

0.39

0.28

2.45

0.18

0.60

0.38

1.63

0.23

13.1

0.79

2.35

4.27

485

4000

15

0.40

0.27

2.66

0.17

0.64

0.38

1.67

0.25

13.5

0.79

2.44

4.48

467

Female

0

15

0.64

0.32

2.20

0.22

0.58

0.49

2.20

0.33

24.7

45.0

4.73

7.07

280

80

15

0.61

0.31

2.20

0.23

0.58

0.49

2.25

0.32

25.3

39.3

4.31

7.26

289

400

15

0.61

0.33

2.25

0.22

0.60

0.48

2.17

0.32

26.0

44.7

4.77

6.60

291

4000

15

0.63

0.32

2.35

0.24

0.61

0.51

2.15

0.36

25.7

47.4

4.70

6.90

276

 

+ Weights of this organ are expressed in mg/100 g body weight.

++ Weights of female gonads are expressed in mg/100 g body weight.

Conclusions:
The repeated dose oral toxicity study of Amyl cinnamic aldehyde was studied in CFE strain rats by administering doses of test substance in diet for male 0,6.1,29.9 and 287.3 mg/kg/day and for female 0,6.7, 34.9 and 320.3 mg/kg/day .Therefore NOAEL were 23 mg/kg bw/day in males and 36 mg/kg bw/day in females as insited by study.
Executive summary:

Repeated oral dose toxicity study ofAmyl cinnamic aldehyde was studied in CFE strain rats. Doses of test substance administered orally in diet were6.1, 29.9 and 287.3 mg/kg/day for males and 6.7, 34.9 and 320.3 mg/kg/day for females. Test substance was fed to groups of 15 male rats (body weight loo-125 g) and15 females (body weight 90-120 g) for 14 wk.Additional groups of five rats were fed with 6.1, 29.9 and 287.3 mg/kg/day for males and 6.7, 34.9 and 320.3 mg/kg/day for females. Animals were fed on Spillers laboratory small animal diet. Water is provided to animals throughout study. Hematological screening, serum analysis and urine analysis were done. After appropriate period of feeding the rats were killed by exsanguination under barbiturates anesthesia. Gross pathology and histopathology investigation were done.Apart from three rats, no abnormalities were seen in behavior or appearance of animal. No mortality was reported in the study.Animals were weigh initially and then weekly thereafter. Increase in body weight at each dose level was reported. There were no statistically significant differences between treated and control groups in rate of body-weight gain. There were no statistically significant differences between treated and control groups in food consumption. The mean intakes of amyl cinnamic aldehyde over the 14wk period were 6.1, 29.9 and 287.3 mg/kg/day by the males of the groups given 4, 20 and 200 mg/kg bw of test substance in the diet and 6.7, 34.9 and 320.3 mg/kg/day by the females. There were no statistically significant differences between treated and control groups in water consumption. The mean water consummation over 14wk period were 25.8, 25.8 and 27.5 ml/rat/day by the males and female, mean water consummation values were 24.9, 24.5 and 25 respectively.There were no significant differences between treated and control groups in the results of the hematological examinations. Hematological examinations were done on blood samples collected at 2, 6 and 14 week of study. Hemoglobin, Packed cell volume, RBC, Reticulocytes and Leucocytes were examined.A measurement of urinary concentrating ability was made during the final week of treatment by measuring the specific gravity and volume of urine produced in a 6-hr period of water deprivation. At the same time, samples of the urine were examined for appearance, microscopic constituents and content of cells, glucose, ketones, bile salts and blood. At wk 6 and 13, urine was also collected from the rats over a 2-hr period following a water load of 25 ml/kg and between 16 and 20 hr after the water load. The only statistically significant differences in the absolute organ weights of treated and control rats were seen after treatment of 6 week. These consisted of lower stomach weights in the males given 287.3 mg/kg bw amyl cinnamic aldehyde and lower small intestine weights in the females given 320.3 mg/kg bw. In the latter case, the difference was not significant when the organ weights were expressed relative to body weights. Patchy lungs in three male rats (two at 6.1 mg/kg bw of test substance level and one control) and pale kidneys in some male rats in all groups including controls. Small mammary adenomas were found in two treated female rats.   One female rat shows respiratory depression, on histopathological examination of tissue revealed pneumonia and an abscess of renal pelvis. Mammary adenomas were reported in two female rats. Vacuolation of some liver cells, protein casts in kidney tubules and sign of chronic lung infection. The incidence of these findings was low and was similar in both treated and control rats.One female rat shows respiratory depression, on histopathological examination of tissue revealed pneumonia and an abscess of renal pelvis. Mammary adenomas were reported in two female rats. Vacuolation of some liver cells, protein casts in kidney tubules and sign of chronic lung infection. The incidence of these findings was low and was similar in both treated and control rats. Therefore NOAEL were approximately 23 mg/kg bw in males and 36 mg/kg bw in females as per study.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
23 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Data is from K2 publication

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Repeated dose oral toxicity:

Various experimental studies were reviewed to determine the toxic nature of alpha-Amyl cinnamaldehyde (122-40-7) upon repeated exposure by oral route. The studies are as mentioned below:

Repeated oral dose toxicity study ofAmyl cinnamic aldehyde was studied in CFE strain rats. Doses of test substance administered orally in diet were6.1, 29.9 and 287.3 mg/kg/day for males and 6.7, 34.9 and 320.3 mg/kg/day for females. Test substance was fed to groups of 15 male rats (body weight loo-125 g) and15 females (body weight 90-120 g) for 14 wk.Additional groups of five rats were fed with 6.1, 29.9 and 287.3 mg/kg/day for males and 6.7, 34.9 and 320.3 mg/kg/day for females. Animals were fed on Spillers laboratory small animal diet. Water is provided to animals throughout study. Hematological screening, serum analysis and urine analysis were done. After appropriate period of feeding the rats were killed by exsanguination under barbiturates anesthesia. Gross pathology and histopathology investigation were done.Apart from three rats, no abnormalities were seen in behavior or appearance of animal. No mortality was reported in the study.Animals were weigh initially and then weekly thereafter. Increase in body weight at each dose level was reported. There were no statistically significant differences between treated and control groups in rate of body-weight gain. There were no statistically significant differences between treated and control groups in food consumption. The mean intakes of amyl cinnamic aldehyde over the 14wk period were 6.1, 29.9 and 287.3 mg/kg/day by the males of the groups given 4, 20 and 200 mg/kg bw of test substance in the diet and 6.7, 34.9 and 320.3 mg/kg/day by the females. There were no statistically significant differences between treated and control groups in water consumption. The mean water consummation over 14wk period were 25.8, 25.8 and 27.5 ml/rat/day by the males and female, mean water consummation values were 24.9, 24.5 and 25 respectively.There were no significant differences between treated and control groups in the results of the hematological examinations. Hematological examinations were done on blood samples collected at 2, 6 and 14 week of study. Hemoglobin, Packed cell volume, RBC, Reticulocytes and Leucocytes were examined.A measurement of urinary concentrating ability was made during the final week of treatment by measuring the specific gravity and volume of urine produced in a 6-hr period of water deprivation. At the same time, samples of the urine were examined for appearance, microscopic constituents and content of cells, glucose, ketones, bile salts and blood. At wk 6 and 13, urine was also collected from the rats over a 2-hr period following a water load of 25 ml/kg and between 16 and 20 hr after the water load. The only statistically significant differences in the absolute organ weights of treated and control rats were seen after treatment of 6 week. These consisted of lower stomach weights in the males given 287.3 mg/kg bw amyl cinnamic aldehyde and lower small intestine weights in the females given 320.3 mg/kg bw. In the latter case, the difference was not significant when the organ weights were expressed relative to body weights. Patchy lungs in three male rats (two at 6.1 mg/kg bw of test substance level and one control) and pale kidneys in some male rats in all groups including controls. Small mammary adenomas were found in two treated female rats.   One female rat shows respiratory depression, on histopathological examination of tissue revealed pneumonia and an abscess of renal pelvis. Mammary adenomas were reported in two female rats. Vacuolation of some liver cells, protein casts in kidney tubules and sign of chronic lung infection. The incidence of these findings was low and was similar in both treated and control rats.One female rat shows respiratory depression, on histopathological examination of tissue revealed pneumonia and an abscess of renal pelvis. Mammary adenomas were reported in two female rats. Vacuolation of some liver cells, protein casts in kidney tubules and sign of chronic lung infection. The incidence of these findings was low and was similar in both treated and control rats. Therefore NOAEL were approximately 23 mg/kg bw in males and 36 mg/kg bw in females as per study.

The data available for the target chemical alpha-Amyl cinnamaldehyde (122-40-7)is insufficient to classify the chemical as toxic. Also the NOAEL value range can be close to 23 mg/kg bw in males and 36 mg/kg bw in females. Based on the observations made, alpha-Amyl cinnamaldehyde does not exhibit toxicity upon repeated exposure by oral route. Hence the test chemical is not likely to classify as a toxicant upon repeated exposure by oral route. Further testing is required to clearly judge the test chemical as toxic upon repeated exposure.

 

Justification for classification or non-classification

Thus based on the above annotation and CLP criteria for the target substance, alpha-Amyl cinnamaldehyde does not exhibit toxicity upon repeated exposure by oral route. Hence the test chemical is not likely to classify as a toxicant upon repeated exposure by oral route. Further testing is required to clearly judge the test chemical as toxic upon repeated exposure.