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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
Data is from study report

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2015
Report date:
2015

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Principles of method if other than guideline:
Repeated Dose 28- Days Oral Toxicity Study of Test chemical in Sprague Dawley (SD) Rats
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
3-(5,5,6-trimethylbicyclo[2.2.1]hept-2-yl)cyclohexan-1-ol
EC Number:
222-294-1
EC Name:
3-(5,5,6-trimethylbicyclo[2.2.1]hept-2-yl)cyclohexan-1-ol
Cas Number:
3407-42-9
Molecular formula:
C16H28O
IUPAC Name:
3-(5,5,6-trimethylbicyclo[2.2.1]hept-2-yl)cyclohexanol
Details on test material:
- Name of test material (as cited in study report): Iso bornyl cyclo hexanol (or 3-(5,5,6-trimethylbicyclo[2.2.1]hept-2-yl)cyclohexan-1-ol)
- Substance type:Organic
- Physical state:Liquid
-SMILES:C1(C)(C)C(C)C2C(C3CC(O)CCC3)CC1C2

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
- Source: Central Animal Facility (CAF), NIPER, Sector-67, S.A.S. Nagar, 160 062, Punjab, India.
- Age at study initiation: 7 to 8 weeks old
- Weight at study initiation: Males: 200.20-241.22 g; Female: 194.30-220.28 g
- Fasting period before study: Yes, 2 hrs fasted before dose administration.
- Housing: Animals were housed in sterilized solid bottom polypropylene cages with stainless steel grill tops with bedding of clean paddy husk in a controlled environment.
- Diet (e.g. ad libitum): Standard laboratory sterile extruded pelleted rodent feed, ad libitum.
- Water (e.g. ad libitum): Potable tap water filtered through Reviva Reverse Osmosis System (water filter cum purifier) of Eureka Forbes, ad libitum.
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±3º C
- Humidity (%): 30-70 %
- Air changes (per hr): 25±5 air changes per hour
- Photoperiod (hrs dark / hrs light): 12-hrs dark/12-hrs light

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: The test chemical was dissolved in corn oil prior to treatment.

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): Corn oil
- Concentration in vehicle: 0, 125, 375 or 1125 mg/kg/day
- Amount of vehicle (if gavage): 5 ml/kg
- 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:
The test item (125, 375 and 1125 mg) was weighed on balance and dissolved in 5 ml of corn oil. An aliquot was taken from three different layers of the dose mixtures and was extracted in methanol for GCMS analysis. The concentration of the test item in each layer was calculated using the standard curve (5 mg IBC / ml methanol).
Duration of treatment / exposure:
28 days
Frequency of treatment:
Daily
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Dose / conc.:
125 mg/kg bw/day (actual dose received)
Dose / conc.:
375 mg/kg bw/day (actual dose received)
Dose / conc.:
1 125 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
Total : 56 rats
Control: 7 males, 7 females
125 mg/kg/day: 7 males, 7 females
375 mg/kg/day: 7 males, 7 females
1125 mg/kg/day: 7 males, 7 females
Control animals:
yes, concurrent vehicle
Details on study design:
No data available
Positive control:
No data available

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily
- Cage side observations included: Mortality and morbidity.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily

BODY WEIGHT: Yes
- Time schedule for examinations: On day 1, 8, 15, 22, 28 and 29 (before sacrifice)

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes, weekly

- 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

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes

- Time schedule for examinations: Weekly

OPHTHALMOSCOPIC EXAMINATION: Yes

- Time schedule for examinations: In the fourth week of treatment
- Dose groups that were examined: All groups of rats.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Prior to necropsy on the day of termination.
- Anaesthetic used for blood collection: Yes, a slight anesthesia was used.
- Animals fasted: Yes, overnight
- How many animals: All groups of rats
.- Parameters examined: Haemoglobin (Hb), RBC, Count Total and differential leucocyte count (TLC / DLC), Haematocrit (Hct / PCV), Mean corpuscular volume (MCV), Mean corpuscular haemoglobin (MCH), Mean corpuscular haemoglobin concentration (MCHC), and Platelet count

.CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Prior to necropsy on the day of termination.
- Animals fasted: Yes, overnight
- How many animals: All groups of rats.
- Parameters examined: Sodium and Potassium Glucose, Total cholesterol, Blood urea, Creatinine, Total protein, Albumin, SGPT (Serum glutamic pyruvic transaminase) /ALT, SGOT (Serum glutamic oxaloacetic transaminase) /AST, Hormones analysis (testosterone and estrogen) and Total bile acids.

URINALYSIS: No data available

NEUROBEHAVIOURAL EXAMINATION: No data available
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
Complete necropsy was carried out on all the animals to score the gross lesions and organ weight (inkl. epididymides, ovaries and testes). Tissues were collected from all animals and preserved in 10% formal saline. However, testes, ovaries and uterus were first fixed in Bouin’s fixative for short duration then transferred to 10% formal saline. The following tissues were collected at necropsy for histological analysis: Brain, Stomach, Large intestine, Small intestine, Liver, Kidneys, Adrenal gland(s), Spleen, Heart, Thymus, Lungs, Testis / Ovary, Uterus, Lymph nodes, Peripheral nerve (Sciatic), Bone marrow, and Gross lesions, if any.

HISTOPATHOLOGY: Yes The histological examination was conducted on the tissues ffom the control and the high-dose group animals based on double blind analysis by using Olympus Trinocular Microscope, (Model BX-51) at magnification of 10x, 20x and 100x.
Other examinations:
The locomotor activity assessment was performed for all groups of rats in the fourth week of treatment. Each animal from different groups was placed in Digital Photoactometer for 5 minutes and the scores were recorded.
Statistics:
Statistical analysis was carried out by using Microsoft Excel and IBM SPSS statistics version-20.0. All analyses and comparisons were evaluated at the 5 % level, statistically significant differences (p≤0.05) indicated by appropriate notation. The focus was to examine the mean differences and their significance between control and low dose group, control and mid dose group and control and high dose group. The statistical decision was taken by preparing the univariant GLM MODEL procedure was used to check the significance between above mentioned groups. For multiple comparisons Turkey’s HSD test was applied.

Results and discussion

Results of examinations

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
Some abnormalities like nasal discharge, slight dullness, hunched posture, fore paw stained red, sneezing, red crust around the nostrils, perineum wet were common to all the groups.
Mortality:
no mortality observed
Description (incidence):
All animals survived throughout the treatment period of 28 days.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
In male animals, a significant increase has been noticed in the body weight of 1125 mg/kg/day as compared to control animals on day 8. However, no change was noticed in the body weight of female animals taken at different time periods.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No difference was observed among any groups of male as well as female animals.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
No difference was observed among any groups of male as well as female animals in water consumption as compared to control.
Ophthalmological findings:
no effects observed
Description (incidence and severity):
No abnormalities were found in the ophthalmological examination (control vs. 1125 mg/kg/day treated group).
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
When treated with 1125 mg/kg/day, in male rat significant increased were observed in percentage of monocytes and basophils.

In female rat, significant increase were observed in WBC count, MCV and MCH levels and significant decreased in RBC count and Hct level as compare to control.

When treated with 375 mg/kg/day, in female rat significant increase were observed in WBC count and MCH level and significant decreased in RBC count as compare to control.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
When treated with 1125 mg/kg/day, in male rat significant increase were observed in total protein and total cholesterol.

In female rat, significant increasewere observed in sodium, potassium, total proteins, BUN levels. And activity of SGPT and significant decreased were observed in Glucose level as compare to control.

When treated with 375 mg/kg/day, in male rat significant increase were observed in glucose and total proteins leve.
In female rat, significant increase were observed in SGPT activity, BUN level and decreased TBA level as compare to control.

When treated with 125 mg/kg/day, in male rat significant increase were observed in creatinine level as compare to control.
Urinalysis findings:
not specified
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
No significant change was observed in the test compound treated groups as compared to control animals.
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
In female rat, teatement with 375 and 1125 mg/kg/day absolut and relative liver weight were significantly increased as compared to control.

In male rats, treatement with 125 mg/kg/day significantly decreased in relaive heart weight were observed as compare to control.

The significant change in organ weight did not corroborate with the individual histological findings of the animals.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
When treated with 1125 mg/kg/day, in female rat enlarged uterus with uterine fluid and Slightly enlarged stomach were observed in one of the rat.

Above changes produced in organs might be due to the adaptive metabolic and physiological changes, anoxic / hypoxic conditions during anesthesia and terminal sacrifice of the animals, which affect the normal structure of the organs and were considered to be dose independent. So, these findings were considered to be of no toxicological significance.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
No remarkable changes were observed in control and in 1125 mg/kg /day-treated animals.

A few microscopic findings were observed in 1125 mg/kg/day-treated animals included reactive spleen and excess of lymphocytes in lungs.

These types of findings may be considered to be within the range of normal background lesions which may be seen in rats of this strain and age of this study type and were considered incidental in nature with carbon dioxide inhalation and terminal changes at sacrifice, reflecting the usual individual variability.

However, 1125 mg/kg/day group animals did not reveal any toxic lesions on histological examinations when compared with the respective control group, hence further histological investigation was not extended to the two other lower dose (low-dose and mid-dose) treatment groups
Histopathological findings: neoplastic:
not specified
Other effects:
not specified

Effect levels

Dose descriptor:
NOAEL
Effect level:
1 125 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
behaviour (functional findings)
body weight and weight gain
clinical biochemistry
clinical signs
food consumption and compound intake
gross pathology
haematology
histopathology: non-neoplastic
mortality
ophthalmological examination
organ weights and organ / body weight ratios
water consumption and compound intake
other: No effect observed

Target system / organ toxicity

Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Any other information on results incl. tables

SUMMARY OF DAY-WISE MORTALTY DATA

MALE

Groups

1

2

3

4

Days

 

 

 

 

 

1

0/7

0/7

0/7

0/7

2

0/7

0/7

0/7

0/7

3

0/7

0/7

0/7

0/7

4

0/7

0/7

0/7

0/7

5

0/7

0/7

0/7

0/7

6

0/7

0/7

0/7

0/7

7

0/7

0/7

0/7

0/7

8

0/7

0/7

0/7

0/7

9

0/7

0/7

0/7

0/7

10

0/7

0/7

0/7

0/7

11

0/7

0/7

0/7

0/7

12

0/7

0/7

0/7

0/7

13

0/7

0/7

0/7

0/7

14

0/7

0/7

0/7

0/7

15

0/7

0/7

0/7

0/7

16

0/7

0/7

0/7

0/7

17

0/7

0/7

0/7

0/7

18

0/7

0/7

0/7

0/7

19

0/7

0/7

0/7

0/7

20

0/7

0/7

0/7

0/7

21

0/7

0/7

0/7

0/7

22

0/7

0/7

0/7

0/7

23

0/7

0/7

0/7

0/7

24

0/7

0/7

0/7

0/7

25

0/7

0/7

0/7

0/7

26

0/7

0/7

0/7

0/7

27

0/7

0/7

0/7

0/7

28

0/7

0/7

0/7

0/7

FEMALE

Groups

5

6

7

8

Days

 

 

 

 

 

1

0/7

0/7

0/7

0/7

2

0/7

0/7

0/7

0/7

3

0/7

0/7

0/7

0/7

4

0/7

0/7

0/7

0/7

5

0/7

0/7

0/7

0/7

6

0/7

0/7

0/7

0/7

7

0/7

0/7

0/7

0/7

8

0/7

0/7

0/7

0/7

9

0/7

0/7

0/7

0/7

10

0/7

0/7

0/7

0/7

11

0/7

0/7

0/7

0/7

12

0/7

0/7

0/7

0/7

13

0/7

0/7

0/7

0/7

14

0/7

0/7

0/7

0/7

15

0/7

0/7

0/7

0/7

16

0/7

0/7

0/7

0/7

17

0/7

0/7

0/7

0/7

18

0/7

0/7

0/7

0/7

19

0/7

0/7

0/7

0/7

20

0/7

0/7

0/7

0/7

21

0/7

0/7

0/7

0/7

22

0/7

0/7

0/7

0/7

23

0/7

0/7

0/7

0/7

24

0/7

0/7

0/7

0/7

25

0/7

0/7

0/7

0/7

26

0/7

0/7

0/7

0/7

27

0/7

0/7

0/7

0/7

28

0/7

0/7

0/7

0/7

  

SUMMARY OF CLINICAL FINDINGS OF ANIMALS

MALE

GROUPS

DOSE (mg/kg)

Animals ID

Total occurance/total no. of animals

Remarks

1

0

2

1/7

Abnormal

2

125

11

1/7

Abnormal

3

375

17,18,21

3/7

Abnormal

4

1125

22,24,25

3/7

Abnormal

 

Female

GROUPS

DOSE (mg/kg)

Animals ID

Total occurance/total no. of animals

Remarks

5

0

30,31

2/7

Abnormal

6

125

-

7/7

Abnormal

7

375

47

1/7

Abnormal

8

1125

51,52,55,56

4/7

Abnormal

 

SUMMARY OF body-weights (g)

Male

Groups

Dose

(mg/kg)

 

Day 1

Day 8

Day 15

Day 22

Day 28

Terminal day·

 

1

 

0

Mean

218.32

237.41

262.26

277.80

289.58

287.90

SD

13.88

19.91

23.69

24.50

28.75

28.69

SEM

5.25

7.53

8.95

9.09

10.86

10.84

 

2

 

125

Mean

222.48

243.24

266.67

285.77

293.54

291.38

SD

7.73

11.32

18.07

22.09

23.33

23.23

SEM

2.92

4.28

6.83

8.35

8.82

8.78

 

3

 

375

Mean

230.02

255.17

280.56

296.58

303.07

300.22

SD

7.50

12.42

17.61

16.75

19.13

18.54

SEM

2.83

4.69

6.66

6.33

7.23

7.01

 

4

 

1125

Mean

230.90

248.17*

263.75

277.82

285.36

283.46

SD

7.83

20.67

25.55

25.44

24.82

25.15

SEM

2.96

7.81

9.66

9.62

9.38.

9.50

·:Significant at p≤0.05 in comparison to control group

*:Terminal body weight reflect the body weights of animals after overnight fasting on the day of necropsy

Female

Groups

Dose

(mg/kg)

 

Day 1

Day 8

Day 15

Day 22

Day 28

Terminal day·

 

5

 

0

Mean

204.43

217.45

230.94

244.10

250.12

247.75

SD

8.79

11.32

12.19

11.53

11.44

11.60

SEM

3.32

4.28

4.61

4.36

4.32

4.39

 

6

 

125

Mean

202.53

210.25

230.15

244.96

250.58

250.58

SD

6.53

5.48

7.68

7.22

8.05

7.72

SEM

2.47

2.07

2.90

 

2.73

3.04

2.92

 

7

 

375

Mean

207.56

216.32

229.87

241.52

245.76

244.45

SD

7.42

10.03

8.61

8.94

10.81

10.71

SEM

2.81

3.79

3.25

3.38

4.08

4.05

 

8

 

1125

Mean

204.30

206.34

219.92

232.85

234.80

233.05

SD

6.75

6.45

10.36

6.51

7.95

7.58

SEM

2.55

2.44

3.92

2.46

3.00

2.86

Terminal body weight reflect the body weights of animals after overnight fasting on the day of necropsy

SUMMARY OF FOOD CONSUMPTION (g)

Male

Groups

 

Dose (mg/kg)

 

Average Food Intake / Animal / Day

Week 1

Week 2

Week 3

Week 4

1

0

13.29

10.29

12.43

12.71

2

125

11.86

9.14

13.00

10.57

3

375

9.00

11.57

12.43

9.43

4

1125

9.14

11.57

14.14

8.57

 

Female

Groups

 

Dose (mg/kg)

 

Average Food Intake / Animal / Day

Week 1

Week 2

Week 3

Week 4

5

0

7.86

9.86

10.57

8.57

6

125

6.71

6.86

9.86

4.14

7

375

8.14

8.14

10.00

5.71

8

1125

6.86

10.29

10.00

5.14

 

SUMMARY OF WATER CONSUMPTION (ml)

Male

Groups

 

Dose (mg/kg)

 

Average water consumption / Animal / Day

Week 1

Week 2

Week 3

Week 4

1

0

27.14

21.43

30.00

28.57

2

125

27.14

25.71

24.29

37.14

3

375

30.00

31.43

31.43

32.86

4

1125

32.86

28.57

27.14

35.71

Female

Groups

 

Dose (mg/kg)

 

Average water consumption / Animal / Day

Week 1

Week 2

Week 3

Week 4

5

0

26.43

21.43

25.71

28.57

6

125

21.43

17.14

24.29

27.14

7

375

25.71

20.00

22.86

24.29

8

1125

28.57

27.14

25.71

38.57

 SUMMARY OF LOCOMOTOR ACTIVITY SCORES

Male

Groups

Dose (mg/kg)

 

Activity during 4thweek of treatment

 

1

 

0

Mean

347.71

SD

26.18

SEM

9.90

 

2

 

125

Mean

331.71

SD

20.45

SEM

7.73

 

3

 

375

Mean

365.57

SD

49.75

SEM

18.80

 

4

 

1125

Mean

376.29

SD

18.32

SEM

6.92

 

 Female

Groups

 

Dose (mg/kg)

 

 

Activity during 4thweek of treatment

 

5

 

0

Mean

387.00

SD

53.51

SEM

20.23

 

6

 

125

Mean

396.71

SD

39.46

SEM

14.92

 

7

 

375

Mean

14.92

SD

47.11

SEM

17.81

 

8

 

1125

Mean

376.57

SD

54.16

SEM

20.47

SUMMARY OF HEMATOLOGY DATA

MALE

            Groups / Dose

 

 

WBC (x103/ mm3)

 

RBC (x106/ mm3)

 

PLT (x103/ mm3)

 

Hct (%)

 

Hgb (g/dl)

 

MCV (fl)

 

MCH (pg)

 

MCHC (g/dl)

 

Lym (%)

 

Mon (%)

 

Nut (%)

 

Eos (%)

 

Bas (%)

 

 

1/0

(mg/kg)

 

Mean

9.34

7.44

549.14

36.70

14.66

49.40

19.74

39.99

63.84

4.53

28.84

1.19

0.87

SD

2.44

0.46

202.40

2.10

0.71

1.58

0.95

1.90

9.15

0.30

9.73

1.84

0.21

SEM

0.92

0.17

76.50

0.79

0.27

0.60

0.36

0.72

3.46

0.11

3.68

0.70

0.08

 

2/125

(mg/kg)

 

Mean

10.78

7.29

508.71

36.61

14.53

50.24

19.93

39.66

62.54

5.06*

29.49

1.10

1.10*

SD

0.89

0.39

77.48

2.16

0.87

0.61

0.42

0.49

9.06

0.68

9.34

2.25

0.15

SEM

0.33

0.15

29.28

0.82

0.33

0.23

0.16

0.18

3.43

0.26

3.53

0.85

0.06

 

3/375

(mg/kg)

 

Mean

10.36

7.57

653.29

37.53

14.79

49.67

19.59

39.44

73.17

4.24

20.61

0.21

1.11

SD

1.29

0.54

227.12

2.06

0.80

1.76

0.67

0.77

3.03

0.41

3.00

0.15

0.26

SEM

0.49

0.20

85.85

0.78

0.30

0.67

0.25

0.29

1.14

0.16

1.13

0.06

0.10

 

4/1125 (mg/kg)

 

Mean

9.10

7.35

715.71

36.30

14.04

49.40

19.17

38.77

54.36

4.66

39.06

0.37

0.84

SD

3.65

0.36

166.93

1.41

0.60

1.02

0.73

0.77

20.45

0.82

20.16

0.38

0.36

SEM

1.38

0.14

63.09

0.53

0.23

0.39

0.28

0.29

7.73

0.31

7.62

0.14

0.14

* Significant at p ≤ 0.05 in comparison to control group

FEMALE

            Groups / Dose

 

 

WBC (x103/ mm3)

 

RBC (x106/ mm3)

 

PLT (x103/ mm3)

 

Hct (%)

 

Hgb (g/dl)

 

MCV (fl)

 

MCH (pg)

 

MCHC (g/dl)

 

Lym (%)

 

Mon (%)

 

Nut (%)

 

Eos (%)

 

Bas (%)

 

 

5/0

(mg/kg)

Mean

6.32

7.94

523.29

39.21

14.26

49.43

17.97

36.31

67.73

3.56

26.90

0.21

1.06

SD

1.96

0.24

135.99

0.96

0.43

1.23

0.77

1.37

3.38

0.77

3.27

0.20

0.25

SEM

0.74

0.09

51.40

0.36

0.16

0.46

0.29

0.52

1.28

0.29

1.24

0.07

0.09

 

6 / 125 (mg/kg)

Mean

9.13

7.73

424.29

38.90

14.19

50.40

18.33

36.39

69.43

3.40

25.30

0.23

1.06

SD

3.84

0.28

51.81

1.14

0.45

0.65

0.48

0.59

7.04

0.42

6.47

0.19

0.14

SEM

1.45

0.11

19.58

0.43

0.17

0.24

0.18

0.22

2.66

0.16

2.45

0.07

0.05

 

7/ 375 (mg/kg)

Mean

10.99**

7.60*

427.57

38.27

14.43

50.36

18.94*

37.66

70.74

4.03

21.96

1.40

1.24

SD

1.58

0.25

111.75

1.77

0.67

2.27

0.88

0.86

8.05

0.99

8.03

1.96

0.21

SEM

0.60

0.09

42.24

0.67

0.25

0.86

0.33

0.33

3.04

0.37

3.03

0.74

0.08

 

8 / 1125 (mg/kg)

Mean

10.57*

7.19***

394.29

36.93*

13.97

51.40**

19.43**

37.83

68.56

4.14

25.20

0.29

1.24

SD

2.17

0.25

99.97

1.38

0.24

1.01

0.61

1.19

4.11

0.43

3.74

0.19

0.23

SEM

0.82

0.09

37.78

0.52

0.09

0.38

0.23

0.45

1.55

0.16

1.41

0.07

0.09

* Significant at p ≤ 0.05 in comparison to control group

**Significant at p ≤ 0.01 in comparison to control group

*** Significant at p ≤ 0.001 in comparison to control group

Applicant's summary and conclusion

Conclusions:
The no observed adverse effect level (NOAEL) was considered to be 1125 mg/kg body weight/day for the test chemical when administered orally by gavage to male and female Sprague-Dawley rats.
Executive summary:

In a repeated dose oral toxicity study, the effects of the test chemical was evaluated in male and female Sprague Dawley rats. The test chemical was administered by oral gavage in the concentration of 0, 125, 375 or 1125 mg/kg/day. The results showed that Iso Bornyl Cyclo Hexanol (IBC) significantly change the percentage of monocytes and basophils, WBC count, MCV and MCH levels in hematology, total protein and total cholesterol, sodium, potassium, total proteins, BUN levels in clinical biochemistry. Absolute and relative liver and heart weight was changed as compared to control. The significant change in organ weight did not corroborate with the individual histological findings of the animals.While no effects were observed in water consumption, opthalmoscopic examination or locomotor activity. At 1125 mg/kg/day, in female rat enlarged uterus with uterine fluid and Slightly enlarged stomach were observed in one of the rat.Above changes produced in organs might be due to the adaptive metabolic and physiological changes, anoxic / hypoxic conditions during anesthesia and terminal sacrifice of the animals, which affect the normal structure of the organs and were considered to be dose independent. So, these findings were considered to be of no toxicological significance. Histopathology performed on organs after treatment with 1125 mg/kg/day did not reveal any toxic lesions as compared to control. Hence, the no observed adverse effect level (NOAEL) was considered to be 1125 mg/kg/day when male and female Sprague Dawley rats were exposed daily to the test chemical by oral route for 28 days.