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EC number: 222-294-1 | CAS number: 3407-42-9
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data

Repeated dose toxicity: oral
Administrative data
- 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
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 015
- 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)
- Version / remarks:
- Adopted in 3 October, 2008
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- 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
- Test material form:
- liquid
- 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)
- Molecular Formula: C16H28O
- Molecular Weight: 236.396 g/mol
- Substance type:Organic
- Physical state:Liquid
-SMILES:C1(C)(C)C(C)C2C(C3CC(O)CCC3)CC1C2
Constituent 1
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, 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:
- Once per day.
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:
- 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.
Examinations
- 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.
Results and discussion
Results of examinations
- 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
Effect levels
- 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
Target system / organ toxicity
- Key result
- Critical effects observed:
- no
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 |
|
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
Applicant's summary and conclusion
- 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.
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