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EC number: 254-599-0 | CAS number: 39711-79-0
- 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:
- chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- data from handbook or collection of data
- Justification for type of information:
- Data is from WHO Food addtivies series
Data source
Reference
- Reference Type:
- review article or handbook
- Title:
- Repeated dose oral toxicity study of the test chemical
- Author:
- Abott et al
- Year:
- 2 006
- Bibliographic source:
- WHO FAS
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- other: as mentioned below
- Principles of method if other than guideline:
- A 22 week study was carried out on groups of 15 Sprague-Dawley (CFY) male/female rats with intake of the test chemical through gavage route to measure its effect on repeated exposure.
- GLP compliance:
- not specified
Test material
- Reference substance name:
- N-ethyl-2-(isopropyl)-5-methylcyclohexanecarboxamide
- EC Number:
- 254-599-0
- EC Name:
- N-ethyl-2-(isopropyl)-5-methylcyclohexanecarboxamide
- Cas Number:
- 39711-79-0
- Molecular formula:
- C13H25NO
- IUPAC Name:
- N-ethyl-2-(isopropyl)-5-methylcyclohexanecarboxamide
- Details on test material:
- - Name of test material: N-ethyl-2-isopropyl-5-methylcyclohexanecarboxamide
- Molecular formula: C13H25NO
- Molecular weight: 211.346 g/mol
- Smiles notation : C1[C@@H](CC[C@@H](C(C)C)[C@@H]1C(NCC)=O)C
- InChl : VUNOFAIHSALQQH-UHFFFAOYSA-N
- Substance type: Organic
- Physical state: Solid
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Remarks:
- CFY
- Details on species / strain selection:
- Not specified
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Not specified
Administration / exposure
- Route of administration:
- oral: gavage
- Details on route of administration:
- Not specifed
- Vehicle:
- not specified
- Details on oral exposure:
- Not specifed
- Analytical verification of doses or concentrations:
- not specified
- Details on analytical verification of doses or concentrations:
- Not specifed
- Duration of treatment / exposure:
- 22 weeks
- Frequency of treatment:
- Not specifed
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 other: mg/kg bw/day
- Dose / conc.:
- 100 other: mg/kg bw/day
- Dose / conc.:
- 300 other: mg/kg bw/day
- Dose / conc.:
- 725 other: mg/kg bw/day
- No. of animals per sex per dose:
- 3 groups of 15 Sprague-Dawley (CFY) rats of each sex
0 mg/Kg/day: 15 males and 15 females
100 mg/Kg/day: 15 males and 15 females
300 mg/Kg/day: 15 males and 15 females
725 mg/Kg/day: 15 males and 15 females - Control animals:
- yes, concurrent vehicle
- Details on study design:
- Not specified
- Positive control:
- Not specified
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Throughout the study period
- Cage side observations checked in table [No.?] were included. Clinical signs and behavioral changes
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Throughout the study period
BODY WEIGHT: Yes
- Time schedule for examinations: Throughout the study period
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations:
OPHTHALMOSCOPIC EXAMINATION: Yes - Time schedule for examinations:
- Dose groups that were examined:
HAEMATOLOGY: Yes
- Time schedule for collection of blood: No data
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: No data
- Parameters checked in table [No.?] were examined. Blood clotting times
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: No data
- Animals fasted: No data
- How many animals: No data
- Parameters checked in table [No.?] were examined. Plasma glucose and serum sodium levels, serum alkaline phosphatase activity and total serum protein levels
URINALYSIS: Yes
- Time schedule for collection of urine: No data
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked in table [No.?] were examined. No data
NEUROBEHAVIOURAL EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data
- Battery of functions tested: sensory activity / grip strength / motor activity / other: No data - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes - Other examinations:
- Not specified
- Statistics:
- Not specified
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- After initial dosing, but not thereafter, several males were lethargic and had mild hypothermia, ataxia and lachrymation, and two females at the highest dose were semi-comatose. Throughout the study, mild transient salivation was noted in rats at the highest dose and to a lesser extent in those at 300 mg/kg bw per day. At the end of the second week and for the remainder of the study, rats at the highest dose and a few at the intermediate dose showed reduced grooming activity. Several rats had mild sialodacryoadenitis during weeks 8-12.
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- One male and one female at the highest dose died at week 4; however, the deaths were probably the result of an intubation error. Another male at the highest dose was killed because of ocular haemorrhage after orbital blood sampling. One male at the intermediate dose was found dead during week 12 with signs of lung congestion. An additional 11 treated rats died during the last 3 weeks of the study, probably due to blood sampling error.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Significantly reduced body-weight gain was also reported in females at the highest dose, and rats at the highest dose continued to show lower weight gain during the last 9 weeks.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- No significant variations were found in food consumption between test and control rats; however, during the first 3 months, males at the two higher doses had a dose-related reduction in growth rate.
- Food efficiency:
- effects observed, treatment-related
- Description (incidence and severity):
- The reduced body-weight gain observed at the highest dose was accompanied by a reduction in feed use efficiency from week 5 of the study.
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- no effects observed
- Description (incidence and severity):
- No abnormalities of the eye were reported.
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- The only variations in haematological parameters reported were in males at weeks 12, 13, 15 and 22, which showed increased blood clotting times in thrombo tests in comparison with controls; however, this effect was thought to be a result of tissue fluid contamination, and therefore additional blood samples were collected by cardiac puncture at weeks 21 and 22. At week 21, the thrombo test values for rats at the two lower doses were below the upper normal limit; although the values for animals at the highest dose remained above the normal limits of variation, the values were markedly reduced from previous weeks. At week 22, a further improvement was noted in thrombotest values in blood collected by cardiac puncture in comparison with values in blood obtained from the orbital sinus.
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Statistically significant variations in clinical chemistry at week 6 were limited to a reduction in serum alkaline phosphatase activity in animals at the highest dose in comparison with controls; however, the values were within the normal limits of variation. Clinical chemistry parameters examined at week 12 revealed the following statistically significant changes: increased plasma glucose and serum sodium levels, decreased serum alkaline phosphatase activity in males at the highest dose and increased total serum protein levels in both sexes. In an extension of the study, serum protein was also increased in rats of each sex at the two lower doses.
- Urinalysis findings:
- effects observed, treatment-related
- Description (incidence and severity):
- At weeks 6 and 7, urine samples from controls and animals at the two higher doses contained leukocytes; however, none were seen at week 12. Epithelial cells were reported in urine samples taken at weeks 6 and 7, but not at week 12. Females at the highest dose had a dose-related increase in specific gravity with no change in urine volume at weeks 7 and 12, whereas males had an increase in volume output with no change in specific gravity. An increased urinary volume was observed in males at the intermediate dose at week 13. Additionally, reducing substances were found in the urine of females with increasing frequency over the test period.
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Dose-related variations in organ weights were limited to significant increases in the absolute and relative liver weights of females in all test groups in comparison with controls ,and significantly elevated relative liver weights in males at the highest dose. All other variations in organ weights were considered to be incidental or to reflect body weight differences and, as such, were not deemed to be toxicologically significant.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- The results of gross examinations were unremarkable
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Although histopathological examination revealed some changes in cardiac and pulmonary tissues and in the livers in all groups of animals, the changes were typical of this strain of laboratory rat and considered not to be related to treatment
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
- Details on results:
- Not specified
Effect levels
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 300 other: mg/Kg bw/day
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: No significant effects were noted at the mentioned dose level
- Dose descriptor:
- LOAEL
- Effect level:
- 100 other: mg/kg bw/day
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- organ weights and organ / body weight ratios
- urinalysis
Applicant's summary and conclusion
- Conclusions:
- The no observed adverse effect level (NOAEL) for the test chemical to Sprague Dawley male rat was considered to be 300 mg/kg bw/day while to female rat it was considered to be <100 mg/kg bw/day after repeated exposure via oral route.
- Executive summary:
In a 22-week study, groups of 15 Sprague-Dawley (CFY) rats of each sex were given the test chemical by gavage at a dose of 0, 100, 300 or 725 mg/kg bw. The parameters examined were mortality, Clinical signs, body weight, food efficiency, Urinalysis, Haematology, Biochemistry, organ weight, Opthalmoscopy, Gross pathology and histopathology. After initial dosing, but not thereafter, several males were lethargic and had mild hypothermia, ataxia and lachrymation, and two females at the highest dose were semi-comatose. Throughout the study, mild transient salivation was noted in rats at the highest dose and to a lesser extent in those at 300 mg/kg bw per day. At the end of the second week and for the remainder of the study, rats at the highest dose and a few at the intermediate dose showed reduced grooming activity. Several rats had mild sialodacryoadenitis during weeks 8-12. One male and one female at the highest dose died at week 4; however, the deaths were probably the result of an intubation error. Another male at the highest dose was killed because of ocular haemorrhage after orbital blood sampling. One male at the intermediate dose was found dead during week 12 with signs of lung congestion. An additional 11 treated rats died during the last 3 weeks of the study, probably due to blood sampling error. Significantly reduced body-weight gain was also reported in females at the highest dose, and rats at the highest dose continued to show lower weight gain during the last 9 weeks. No significant variations were found in food consumption between test and control rats; however, during the first 3 months, males at the two higher doses had a dose-related reduction in growth rate. The reduced body-weight gain observed at the highest dose was accompanied by a reduction in feed use efficiency from week 5 of the study. The only variations in haematological parameters reported were in males at weeks 12, 13, 15 and 22, which showed increased blood clotting times in thrombo tests in comparison with controls; however, this effect was thought to be a result of tissue fluid contamination, and therefore additional blood samples were collected by cardiac puncture at weeks 21 and 22. At week 21, the thrombo test values for rats at the two lower doses were below the upper normal limit; although the values for animals at the highest dose remained above the normal limits of variation, the values were markedly reduced from previous weeks. At week 22, a further improvement was noted in thrombotest values in blood collected by cardiac puncture in comparison with values in blood obtained from the orbital sinus. Statistically significant variations in clinical chemistry at week 6 were limited to a reduction in serum alkaline phosphatase activity in animals at the highest dose in comparison with controls; however, the values were within the normal limits of variation. Clinical chemistry parameters examined at week 12 revealed the following statistically significant changes: increased plasma glucose and serum sodium levels, decreased serum alkaline phosphatase activity in males at the highest dose and increased total serum protein levels in both sexes. In an extension of the study, serum protein was also increased in rats of each sex at the two lower doses. At weeks 6 and 7, urine samples from controls and animals at the two higher doses contained leukocytes; however, none were seen at week 12. Epithelial cells were reported in urine samples taken at weeks 6 and 7, but not at week 12. Females at the highest dose had a dose-related increase in specific gravity with no change in urine volume at weeks 7 and 12, whereas males had an increase in volume output with no change in specific gravity. An increased urinary volume was observed in males at the intermediate dose at week 13. Additionally, reducing substances were found in the urine of females with increasing frequency over the test period. Dose-related variations in organ weights were limited to significant increases in the absolute and relative liver weights of females in all test groups in comparison with controls ,and significantly elevated relative liver weights in males at the highest dose. All other variations in organ weights were considered to be incidental or to reflect body weight differences and, as such, were not deemed to be toxicologically significant. The results of gross examinations were unremarkable. Although histopathological examination revealed some changes in cardiac and pulmonary tissues and in the livers in all groups of animals, the changes were typical of this strain of laboratory rat and considered not to be related to treatment. Based on the observations made, no observed adverse effect level (NOAEL) for the test chemical to Sprague Dawley male rat was considered to be 300 mg/kg bw/day while to female rat it was considered to be <100 mg/kg bw/day after repeated exposure via oral route.
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