Registration Dossier
Registration Dossier
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EC number: 222-294-1 | CAS number: 3407-42-9
Endpoint summary
Administrative data
Description of key information
Repeated dose toxicity: Oral
The test chemical was given to 7 rats per sex per dose level at 0 (vehicle; corn oil), 125, 375 and 1125 mg/kg/day. The study was performed according to GLP and according to OECD 407 with some additional reproductive-related endpoints included.Results:All animals survived to planned death and there were no clinical signs attributed to the test chemical. No significant changes in body weight were observed, except for a slight increase in male body weight at 1125 mg/kg on day 8 of treatment (mean, 248 g) compared to the control group (mean 237 g). This effect was considered incidental and not toxicologically significant. No significant changes in food intake or water intake were observed. No significant changes in locomotor activity were observed. No abnormalities were found during the ophthalmic examinations. Significant changes in haematology were as follows: significant increase in % monocytes in males treated at 125 mg/kg; significant increase in % basophils in males treated at 125 mg/kg; significant increases in white blood cell counts in females treated at 375 and 1125 mg/kg; significant decreases in red blood cell counts in females treated at 375 and 1125 mg/kg; significant decrease in haematocrit counts in females treated at 1125 mg/kg; significant increase in MCV in females treated at 1125 mg/kg; and significant increases in MCH in females treated at 375 and 1125 mg/kg. The observed changes in haematology were considered not toxicologically relevant due to lack of dose relationship and due to lack of associated histopathological findings. Significant changes in clinical chemistry were as follows: significant increase in total cholesterol in male rats treated at 1125 mg/kg; significant increase in creatinine in male rats treated at 125 mg/kg; significant increase in glucose in male rats treated at 375 mg/kg; significant increases in total proteins in male rats treated at 375 and 1125 mg/kg; significant increase in potassium in female rats treated at 1125 mg/kg; significant increase in sodium in female rats treated at 1125 mg/kg; significant increase in SGPT in female rats treated at 375 and 1125 mg/kg; significant decrease in glucose in female rats treated at 1125 mg/kg; significant increase in total protein in female rats treated at 1125 mg/kg; significant increases in urea nitrogen in female rats treated at 375 and 1125 mg/kg; and a significant increase in bile acid in female rats treated at 375 mg/kg. No significant changes in serum testosterone or serum oestrogen were observed. The observed changes in clinical chemistry were considered not toxicologically relevant due to lack of dose relationship and due to lack of associated histopathological findings. No significant changes in absolute organ weight were observed, with the exception of significant increases in liver weight in female rats treated at 375 and 1125 mg/kg. Significant changes in relative organ weight included a significant decrease in relative heart weight in male rats treated at 125 mg/kg and two significant increases in relative liver weight in female rats treated at 375 and 1125 mg/kg. In male rats, no gross pathological findings were observed. In female rats, gross pathological findings were limited to a slightly increased stomach at 1125 mg/kg and an enlarged uterus with uterine fluid at 1125 mg/kg. Histopathology performed at 0 and 1125 mg/kg showed excess of lymphocytes in the lungs of 2/7 control males, 1/7 high-dosed males, 1/7 control females, and 1/7 high-dosed females and reactive spleens in 3/7 control males, 1/7 high-dosed males, 2/7 control females, and 1/7 high-dosed females. These histopathological findings were consistent with the historical control data of the test facility and were therefore not considered to be toxicologically relevant. The histopathologic examinations did not reveal any significant effects on spermatogenesis.Conclusion:NOAEL was considered at 1125 mg/kg bw/day.
Repeated dose toxicity: Inhalation
The test substance 3-(5,5,6-trimethylbicyclo[2.2.1]hept-2-yl)cyclohexan-1-ol has very low vapor pressure (0.00162 Pa), so the potential for the generation of inhalable vapours of 3-(5,5,6-trimethylbicyclo[2.2.1]hept-2-yl)cyclohexan-1-ol is low. Also the normal conditions of use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be unlikely to occur, and therefore this end point was considered for waiver
Repeated dose toxicty: Dermal
The results for acute toxicity by the dermal route indicate the LD50 value to be greater than 2000 mg/kg body weight. In addition, the skin sensitization also indicates negative skin sensitization potential by the chemical 3-(5,5,6-trimethylbicyclo[2.2.1]hept-2-yl)cyclohexan-1-ol. Also considering the use of the chemical as a fragrance chemical and considering the low volatility absorption by the dermal route is not likely to be significant. Thus, given the above considerations, it is assumed that 3-(5,5,6-trimethylbicyclo[2.2.1]hept-2-yl)cyclohexan-1-ol shall not exhibit repeated dose toxicity by the dermal route.
Key value for chemical safety assessment
- Toxic effect type:
- dose-dependent
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: oral
- Remarks:
- 28-days repeated dose toxicity study with extended reproductive parameters
- 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 a study report
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Version / remarks:
- Adopted in 3 October, 2008
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- - Source: Central Animal Facility (CAF), NIPER, 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 - 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:
- Once per day.
- 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:
- 7 rats per sex per dose.
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- No data available
- Positive control:
- No positive control was included.
- Observations and examinations performed and frequency:
- Mortality, clinical signs (once per day), detailed clinical signs (once per week), body weight (treatment days 1, 8, 15, 22, 28, 29) food intake (once per week), water intake (once per week), ophthalmology (4th week of treatment), locomotor activity (4th week of treatment), hematology (end of treatment), clinical chemistry (end of treatment)
Hematologic parameters: Haemoglobin, RBC, Total and differential leucocyte count, Haematocrit, Mean corpuscular volume (MCV), Mean corpuscular haemoglobin (MCH), Mean corpuscular haemoglobin concentration (MCHC), and Platelet count
Clinical chemistry parameters: Sodium, 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. - Sacrifice and pathology:
- The following organs were weighed: liver, adrenals, spleen, heart, kidney, brain, testes, epididymides, ovaries, thymus. The following organs/tissues were examined microscopically: brain, stomach, large intestine, small intestine, liver, kidney, adrenal gland, spleen, heart, thymus, lungs, testis, ovaries, uterus, lymph nodes, perihperal nerve, bone marrow, and gross lesions (if any).
- 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.
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no clinical signs attributed to the test item. 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 to planned death.
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No significant changes in body weight were observed, except for a slight increase in male body weight at 1125 mg/kg on day 8 of treatment (mean, 248 g) compared to the control group (mean 237 g). This effect was considered incidental and not toxicologically significant.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- No significant effects were observed in the study.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Description (incidence and severity):
- No significant effects were observed in the study.
- Ophthalmological findings:
- no effects observed
- Description (incidence and severity):
- No significant effects were observed in the study.
- Haematological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Significant changes in haematology were as follows: significant increase in % monocytes in males treated at 125 mg/kg; significant increase in % basophils in males treated at 125 mg/kg; significant increases in white blood cell counts in females treated at 375 and 1125 mg/kg; significant decreases in red blood cell counts in females treated at 375 and 1125 mg/kg; significant decrease in haematocrit counts in females treated at 1125 mg/kg; significant increase in MCV in females treated at 1125 mg/kg; and significant increases in MCH in females treated at 375 and 1125 mg/kg. The observed changes in haematology were considered not toxicologically relevant due to lack of dose relationship and due to lack of associated histopathological findings.
- Clinical biochemistry findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Significant changes in clinical chemistry were as follows: significant increase in total cholesterol in male rats treated at 1125 mg/kg; significant increase in creatinine in male rats treated at 125 mg/kg; significant increase in glucose in male rats treated at 375 mg/kg; significant increases in total proteins in male rats treated at 375 and 1125 mg/kg; significant increase in potassium in female rats treated at 1125 mg/kg; significant increase in sodium in female rats treated at 1125 mg/kg; significant increase in SGPT in female rats treated at 375 and 1125 mg/kg; significant decrease in glucose in female rats treated at 1125 mg/kg; significant increase in total protein in female rats treated at 1125 mg/kg; significant increases in urea nitrogen in female rats treated at 375 and 1125 mg/kg; and a significant increase in bile acid in female rats treated at 375 mg/kg. No significant changes in serum testosterone or serum oestrogen were observed.
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- No significant changes in locomotor activity were observed.
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- No significant changes in absolute organ weight were observed, with the exception of significant increases in liver weight in female rats treated at 375 and 1125 mg/kg. Significant changes in relative organ weight included a significant decrease in relative heart weight in male rats treated at 125 mg/kg and two significant increases in relative liver weight in female rats treated at 375 and 1125 mg/kg.
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- In male rats, no gross pathological findings were observed. In female rats, gross pathological findings were limited to a slightly increased stomach at 1125 mg/kg and an enlarged uterus with uterine fluid at 1125 mg/kg.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Histopathology performed at 0 and 1125 mg/kg showed excess of lymphocytes in the lungs of 2/7 control males, 1/7 high-dosed males, 1/7 control females, and 1/7 high-dosed females and reactive spleens in 3/7 control males, 1/7 high-dosed males, 2/7 control females, and 1/7 high-dosed females. These histopathological findings were consistent with the historical control data of the test facility and were therefore not considered to be toxicologically relevant. The histopathologic examinations did not reveal any significant effects on spermatogenesis.
- Histopathological findings: neoplastic:
- no effects observed
- Key result
- 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: neoplastic
- histopathology: non-neoplastic
- mortality
- ophthalmological examination
- organ weights and organ / body weight ratios
- water consumption and compound intake
- Key result
- Critical effects observed:
- no
- Conclusions:
- NOAEL was considered to be 1125 mg/kg bw/day in both male and female SD rats.
- Executive summary:
The test chemical was given to 7 rats per sex per dose level at 0 (vehicle; corn oil), 125, 375 and 1125 mg/kg/day. The study was performed according to GLP and according to OECD 407 with some additional reproductive-related endpoints included.Results:All animals survived to planned death and there were no clinical signs attributed to the test chemical. No significant changes in body weight were observed, except for a slight increase in male body weight at 1125 mg/kg on day 8 of treatment (mean, 248 g) compared to the control group (mean 237 g). This effect was considered incidental and not toxicologically significant. No significant changes in food intake or water intake were observed. No significant changes in locomotor activity were observed. No abnormalities were found during the ophthalmic examinations. Significant changes in haematology were as follows: significant increase in % monocytes in males treated at 125 mg/kg; significant increase in % basophils in males treated at 125 mg/kg; significant increases in white blood cell counts in females treated at 375 and 1125 mg/kg; significant decreases in red blood cell counts in females treated at 375 and 1125 mg/kg; significant decrease in haematocrit counts in females treated at 1125 mg/kg; significant increase in MCV in females treated at 1125 mg/kg; and significant increases in MCH in females treated at 375 and 1125 mg/kg. The observed changes in haematology were considered not toxicologically relevant due to lack of dose relationship and due to lack of associated histopathological findings. Significant changes in clinical chemistry were as follows: significant increase in total cholesterol in male rats treated at 1125 mg/kg; significant increase in creatinine in male rats treated at 125 mg/kg; significant increase in glucose in male rats treated at 375 mg/kg; significant increases in total proteins in male rats treated at 375 and 1125 mg/kg; significant increase in potassium in female rats treated at 1125 mg/kg; significant increase in sodium in female rats treated at 1125 mg/kg; significant increase in SGPT in female rats treated at 375 and 1125 mg/kg; significant decrease in glucose in female rats treated at 1125 mg/kg; significant increase in total protein in female rats treated at 1125 mg/kg; significant increases in urea nitrogen in female rats treated at 375 and 1125 mg/kg; and a significant increase in bile acid in female rats treated at 375 mg/kg. No significant changes in serum testosterone or serum oestrogen were observed. The observed changes in clinical chemistry were considered not toxicologically relevant due to lack of dose relationship and due to lack of associated histopathological findings. No significant changes in absolute organ weight were observed, with the exception of significant increases in liver weight in female rats treated at 375 and 1125 mg/kg. Significant changes in relative organ weight included a significant decrease in relative heart weight in male rats treated at 125 mg/kg and two significant increases in relative liver weight in female rats treated at 375 and 1125 mg/kg. In male rats, no gross pathological findings were observed. In female rats, gross pathological findings were limited to a slightly increased stomach at 1125 mg/kg and an enlarged uterus with uterine fluid at 1125 mg/kg. Histopathology performed at 0 and 1125 mg/kg showed excess of lymphocytes in the lungs of 2/7 control males, 1/7 high-dosed males, 1/7 control females, and 1/7 high-dosed females and reactive spleens in 3/7 control males, 1/7 high-dosed males, 2/7 control females, and 1/7 high-dosed females. These histopathological findings were consistent with the historical control data of the test facility and were therefore not considered to be toxicologically relevant. The histopathologic examinations did not reveal any significant effects on spermatogenesis.Conclusion:NOAEL was considered at 1125 mg/kg bw/day.
Reference
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 |
|
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 |
|
3.04 |
2.92 |
|||
7 |
375 |
Mean |
|
216.32 |
229.87 |
241.52 |
245.76 |
244.45 |
|
SD |
|
10.03 |
8.61 |
8.94 |
10.81 |
10.71 |
|||
SEM |
|
3.79 |
3.25 |
3.38 |
4.08 |
4.05 |
|||
8 |
1125 |
Mean |
|
206.34 |
219.92 |
232.85 |
234.80 |
233.05 |
|
SD |
|
6.45 |
10.36 |
6.51 |
7.95 |
7.58 |
|||
SEM |
|
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
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 1 125 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- Klimisch 1
Repeated dose toxicity: inhalation - systemic effects
Link to relevant study records
- Endpoint:
- repeated dose toxicity: inhalation
- Data waiving:
- exposure considerations
- Justification for data waiving:
- a short-term toxicity study does not need to be conducted because exposure of humans via inhalation in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment
- Critical effects observed:
- not specified
Reference
Endpoint conclusion
- Endpoint conclusion:
- no study available
- Quality of whole database:
- Waiver
Repeated dose toxicity: inhalation - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - systemic effects
Link to relevant study records
- Endpoint:
- repeated dose toxicity: dermal
- Data waiving:
- study scientifically not necessary / other information available
- Justification for data waiving:
- a short-term toxicity study does not need to be conducted because exposure of humans via the dermal route in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment
- Critical effects observed:
- not specified
Reference
Endpoint conclusion
- Endpoint conclusion:
- no study available
- Quality of whole database:
- Waiver
Repeated dose toxicity: dermal - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
Data available for the target chemical was reviewed to determine the toxic nature of the test chemical. The studies are as mentioned below:
Repeated dose toxicity: Oral
Various studies have been reviewed to evaluated the toxic properties of the test chemical when dosed repeatedly via oral for longer durations. These include in vivo experimental studies perfomed on rats for the test chemical. The results are mentioned below:
A short term (28-day) repeated dose toxicity study (OECD TG 407)was performed on Sprague Dawley rats to assess the toxic properties of the test chemical following repeated oral administration. A total of 56 male and female Sprague Dawley rats were used for the study. The test chemical was dissolved in corn oil administered by oral gavage in the concentrations of 0, 125, 375, or 1125 mg/kg/day. No mortality was observed in both treated and control groups during test chemical administration. Some abnormalities, such as nasal discharge, slight dullness, hunched posture, sneezing, and red crust around the nostrils, were observed in both treated and control groups. The mean body weight food and water consumptions were comparable in treated and control groups in both sexes. No adverse effect was noted during the ophthalmoscopic examination and locomotor activity assessment at any doses tested. The haematology of female rats revealed a significant increase in the White Blood Cell Count (WBC) at 375 and 1125 mg/kg. However, the increase showed no dose-dependence, and the percent of lymphocytes, monocytes, neutrophils, eosinophils, basophils were comparable in all treated and control groups. Also, the Red Blood Cell (RBC) count values decreased significantly at 375 and 1125 mg/kg, and the haematocrit value dropped significantly at the highest dose. Although these changes were statistically significant, the decrease was minimal, less than 10% of the control value, and therefore, their biological significance is considered negligible. Also, the mean corpuscular hemoglobin (MCH) and the mean corpuscular volume (MCV) values significantly increased at 375 and 1125 mg/kg when compared to the control; however, the changes were minimal (MCH: 5.4% and 8,1% of increase at 375 and 1125 mg/kg, respectively, MCV: 3,9% of increase at 1125 mg/kg) and the mean corpuscular hemoglobin concentration (MCHC), as well as the percent of hemoglobin, remained unchanged in dose groups when compared to the control. In males, no changes in haematological parameters, attributable to the test chemical administration, were observed as only incidental alterations of percent monocytes and basophils were detected at the lowest dose. Blood biochemistry of both male and female rats revealed significant changes in potassium, sodium, total cholesterol, and glucose values; however, the changes were minimal (around or less than 10% of the control values) and inconclusive and unequally distributed between sexes. The significant increase in the total protein (albumin and globulin) values at 375 mg/kg in males and 1125 mg/kg in both sexes could indicate infection or inflammatory condition in dosed rats. However, the histopathological examination of lung, spleen, and lymph nodes did not reveal any sign of chronic inflammation in groups treated with the test chemical. The blood urea nitrogen (BUN) increased at 375 and 1125 mg/kg in females, but the changes showed no dose-dependence. In females, the alanine transferase (SGPT) concentrations increased significantly at 375 and 1125 mg/kg, which was accompanied by increased absolute and relative liver weights. However, the gross pathological and detailed histopathological analyses of the liver did not reveal any changes of pathological significance, which can be related to the test chemical administration. Therefore the liver hypertrophy and the increased liver enzyme production indicate an adaptive metabolic and physiological changes which are not considered to be toxicologically significant or adverse.In conclusion, the oral administration of test chemical did not produce adverse health effects in the experimental animals including toxicologically significant changes which have affected the function or morphology of a tissue/organ or have produced severe changes to the biochemistry or haematology of the organism, when male and female SD rats were orally administered up to 1125 mg/kg bw/day
This result is supported by a study where the test chemical was tested in a 13-week subchronic toxicity study to evaluate its toxicological properities.The test chemical dissolved in corn oil was administered daily to groups of 15 male and 15 female CFE rats by gastric intubation in doses of 0 (control), 15, 90 or 270 mg/kg body weight/day for 13 weeks. Also, groups of five rats of each sex received daily doses of 0, 90 or 270 mg/kg/day for 2 to 6 weeks. The bodyweight of the animals and their intake of food and water were measured weekly. Urine samples were collected from all rats during the final week of treatment and, additionally, during week 6 from five rats of each sex of each group of the main study. The urine samples were examined for appearance, microscopic constituents, and content of glucose, ketones, bile salts, and blood. A concentration and dilution test was carried out on the same rats. At week 2 this was limited to measuring the volume and specific gravity of urine produced during a 6-hour period of water deprivation. At weeks 6 and 13, similar measurements were made on the urine produced in 2 hours after a water load of 25 ml/kg and in a 4-hour period after 16 hours without water.No deaths and no abnormalities in behaviour or appearance occurred during the study. There was no difference between treated and control animals in the rate of body weight gain and food intake. Throughout the study, water consumption was increased in males given 270 mg/kg/day but not in females. Haematological and serum analysis performed at week 2, 6 (5 male and 5 females rats) and week 13 (all rats) did not reveal any effect attributable to the test chemical administration in any dose groups. The urine of all rats was of normal colour and free from glucose, blood, bile, and ketones. The females treated with the test substance gave results similar to those of female controls. In males, there were no differences between control and treated rats at week 2, but at week 6 cell excretion was increased in rats receiving 270 mg/kg/day, and at week 13 this effect was also seen in animals receiving 90 mg/kg/day. The males given 270 mg/kg/day also showed an impairment of urine concentrating ability. At week 6 this was seen only after prolonged (16-20 hour) water deprivation, but at week 13 it was also noted after dehydration for 6 hours. At the lower dosage levels, there were no significant changes in the results of the concentration test. The relative weight of the kidney was increased at week 6 in males and at week 13 in both sexes in the 270 mg/kg dose group. The relative liver weight was increased in both sexes of rats given 270 mg/kg/day for 13 weeks. There were no changes in liver weight at week 2 or 6. Both absolute and relative caecal weights were increased at week 13 at the highest level of treatment. Histological changes associated with the test chemical treatment were confined to treatment at the 270 mg/kg level. In the kidneys, there was an increased incidence of focal tubular degeneration and atrophy and, in males only, vacuolation of the tubular epithelium. Vacuolation of the epithelial cells of the intrahepatic bile ducts was also seen in males.The data presented in this study demonstrated that the test chemical was without effect in rats (both males and females) at a daily dose level of 15 mg/kg. At 270 mg/kg, the histopathological analyses revealed lesions in both sexes. Increased cell excretion in the urine was found at 90 and 270 mg/kg/day only in males. Although the test chemical-induced vacuolation of the epithelial cells of the intrahepatic bile-ducts in males treated with 270 mg/kg, the liver function remained unaffected based on the unaltered liver enzyme levels. In females, the increased liver weight observed at 270 mg/kg was not accompanied by histopathological abnormalities or alteration of liver enzyme level in the serum. Also, the authors pointed out that the possible oral intake of the test chemical is at most 7.5 mg/person/day, with a mean intake of about 2 mg/person/day (0.12 and 0.03 mg/kg/day, respectively). Thus the no-effect level found in this study, 15 mg/kg/day, was more than 100 times the estimated maximum intake. Hence, the test chemical can be regarded as safe for consumption.
These results are further supported by a bioassay conducted for evaluatiing the possible carcinogenicity of the test chemical by administering of the test chemical in feed to Fischer 344 rats. Groups of 50 rats of each sex were administered with the test chemical in doses of 3750 or 7500 ppm (ca. 188 or 375 mg/kg bw/day)) for 103 weeks, then rats were kept without treatment for an additional 1 or 2 weeks. Matched controls consisted of 50 untreated rats of each sex. All surviving rats were killed at 105 weeks. The mean body weights of dosed rats were only slightly lower than those of the corresponding controls, but the decrease was not statistically significant. No other clinical signs related to the administration of the dl-menthol were noted in dosed groups. The survival rates of male rats at week 105 were 68%, 66%, and 62% in the high-dose, low dose, and control groups, respectively. In females, 76%, 70%, and 72% of the animals were alive at week 105 in the high dose, low dose, and control groups, respectively. Thus, sufficient numbers of rats of each sex were at risk for the development of late-appearing tumors. In male rats, no tumours occurred at incidences, which were considered to be related to the administration of the test chemical. In female rats, no tumours occurred at higher incidences in the dosed groups than in the control groups. Fibroadenomas of the mammary gland occurred at lower incidences in the low-dose (10/49) and high-dose (7/49) groups than in the control group (20/50), and alveolar/bronchiolar adenomas or carcinomas of the lung occurred only in the controls (3/50). Based on the observations of the present study and under the experimental conditions described, it was concluded that the test chemical, dl-menthol [CAS: 89-78-1; EC Number:201-939-0] was not carcinogenic and produced no systemic or specific organ toxicity when male and female Fischer 344 rats were fed diet supplemented with the test chemical up to 7500 ppm for 103 weeks. The NOAEL in this study can be considered 375 mg/kg bw/d for male and female rats
Based on this information, the test chemical is expected to be well-tolerated by standard test species when dosed repeatedly for longer durations viz 90 days and beyond. Also the NOAEL can be considered to be 1125 mg/kgbw/day.
Repeated dose toxicity: Inhalation
The test substance has very low vapor pressure (0.00162 Pa), so the potential for the generation of inhalable vapours of the test chemical is very low. Also the normal conditions of use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be unlikely to occur, and therefore this end point was considered for waiver
Repeated dose toxicty: Dermal
The results for acute toxicity by the dermal route indicate the LD50 value to be greater than 2000 mg/kg body weight. In addition, the skin sensitization also indicates negative skin sensitization potential by the chemical 3-(5,5,6-trimethylbicyclo[2.2.1]hept-2-yl)cyclohexan-1-ol. Also considering the use of the chemical as a fragrance chemical and considering the low volatility absorption by the dermal route is not likely to be significant. Thus, given the above considerations, it is assumed that 3-(5,5,6-trimethylbicyclo[2.2.1]hept-2-yl)cyclohexan-1-ol shall not exhibit repeated dose toxicity by the dermal route.
Based on the data available, the test chemical is not likely to be toxic upon repeated exposure by oral, dermal and inhalation route of exposure. Hence it is not likely to be a toxicant as per the criteria mentioned in CLP regulation.
Justification for classification or non-classification
In a OECD 407 study performed with the substance, no adverse effects were observed up to the highest dose tested of 1125 mg/kg bw/day. The substance is therefore regarded to be classified as Not Classified for repeated dose toxicity.
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