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Description of key information

Repeated dose oral:

The no observed adverse effect level (NOAEL) for test substance when administered orally by intubation to male rats was 10 mg/kg/day daily in 16 days study period.

The study does not conclude higher dose value. Hence it is acceptable to take such low NOAEL .

Repeated dose inhalation:

The No Observed Adverse effect concentration (NOAEC) was considered to be  in a dose range of 80 ppm (80 mg/L) (actual dose 78.6 mg/L or 78600 mg/m3) - 6.6mg/m3 when rodents were  treated with test substance.

Repeated dose dermal:

The No observed adverse effect level (NOAEL) is 400 mg/kg in chronic dermal toxicity study when rats were exposed to  test substance for 21 weeks.

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
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 peer reviewed publication
Qualifier:
according to guideline
Guideline:
other: as mentioned below
Principles of method if other than guideline:
The repeated dose toxicity test was conducted on rats to determine the toxic nature of test substance by oral route of administration
GLP compliance:
not specified
Limit test:
no
Specific details on test material used for the study:
- Name of test material: 2-octanone
- IUPAC name: octan-2-one
- Molecular formula: C8H16O
- Molecular weight: 128.2134 g/mol
- Substance type: Organic
- Physical state: Liquid
- Impurities (identity and concentrations): No data available
Species:
rat
Strain:
Sprague-Dawley
Details on species / strain selection:
No data
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Zivic Miller, Allison Park, Pa.)
- Age at study initiation:No data available
- Weight at study initiation: No data available
- Fasting period before study: No data available
- Housing:
- Diet (e.g. ad libitum): Purina lab chow ad libitum
- Water (e.g. ad libitum): water ad libitum
- Acclimation period: No data available

ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data available
- Humidity (%):No data available
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): No data available

IN-LIFE DATES: From: To: No data available
Route of administration:
oral: gavage
Details on route of administration:
No data
Vehicle:
other: carboxymethylcellulose- H20 (1% CMC) solution
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: 2-octanone was suspended in 1% carboxymethylcellulose- H20 (1% CMC) and homogenized at dose level of 0 or 10 mg/Kg/day

DIET PREPARATION
- Rate of preparation of diet (frequency): No data
- Mixing appropriate amounts with (Type of food): No data
- Storage temperature of food: No data

VEHICLE
- Justification for use and choice of vehicle (if other than water): 1% carboxymethylcellulose- H20 (1% CMC)
- Concentration in vehicle: 10 mg/Kg/day
- Amount of vehicle (if gavage): No data
- Lot/batch no. (if required): No data
- Purity: No data
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data
Duration of treatment / exposure:
16 days
Frequency of treatment:
Daily at 11:00 am
Remarks:
0 or 10 mg/kg/day
No. of animals per sex per dose:
Total: 16
0 mg/Kg day: 8
10 mg/Kg day: 8
Control animals:
yes, concurrent vehicle
Details on study design:
Controls were given 1%CMC(carboxymethylcellulose-H20)
Positive control:
No data available
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Not specified
- Time schedule: Not specified
- Cage side observations checked in table [No.?] were included. Not specified

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Not specified

BODY WEIGHT: Yes
- Time schedule for examinations: Not specified

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Not specified
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Not specified
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Not specified

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: Not specified

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Not specified
- Time schedule for examinations: Not specified

OPHTHALMOSCOPIC EXAMINATION: Not specified
- Time schedule for examinations: Not specified
- Dose groups that were examined: Not specified

HAEMATOLOGY: Not specified
- Time schedule for collection of blood: Not specified
- Anaesthetic used for blood collection: Not specified
- Animals fasted: Not specified
- How many animals: Not specified
- Parameters checked in table [No.?] were examined. Not specified

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: On day 4, 10 and 16 after the last dose (24 hr)
- Animals fasted: Not specified
- How many animals: Not specified
- Parameters checked in table [No.?] were examined. Serum cholesterol level and Hypocholesterolemic Activity was observed

URINALYSIS: Not specified
- Time schedule for collection of urine: Not specified
- Metabolism cages used for collection of urine: Not specified
- Animals fasted: Not specified
- Parameters checked in table [No.?] were examined. Not specified

NEUROBEHAVIOURAL EXAMINATION: Not specified
- Time schedule for examinations: Not specified
- Dose groups that were examined: Not specified
- Battery of functions tested: sensory activity / grip strength / motor activity / other: Not specified

IMMUNOLOGY: Not specified
- Time schedule for examinations: Not specified
- How many animals: Not specified
- Dose groups that were examined: Not specified
- Parameters checked in table [No.?] were examined. Not specified

OTHER: Not specified
Sacrifice and pathology:
No data available
Other examinations:
No data available
Statistics:
The number of animals in a group, expressed as N, the mean of the percent of control, and standard deviation, expressed as x± S.D.,are noted. The probable significant level ( p ) was determined by the Student's t test according to the procedure of Snedecor.
Clinical signs:
no effects observed
Description (incidence and severity):
No observable toxic effects were noted
Mortality:
not specified
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No significant changes in body weight change was observed.
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Test substance as found to reduce serum choleterol to 34% of control
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Dose descriptor:
NOAEL
Effect level:
10 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: No significant changes were observed at the mentioned dose level
Remarks on result:
other: No toxic effect were observed
Critical effects observed:
not specified

Table I. Hypocholesterolemic Activity of 2-ooctanone at 10 mg/kg/day in Sprague-Dawley Rats

 

Serum cholesterol as % of control on day

% body weight increase

4

10

16

 

Control(1% CMC)

100±7

100±12

100±8

100±4

2-octanone (10 mg/Kg/day)

74±11

59±7

34±8

100±5

Conclusions:
The no observed adverse effect level (NOAEL) for test substance when administered orally by intubation to male rats was 10 mg/kg/day daily in 16 days study period.

Executive summary:

Subacute toxicity study was performed to determine the toxic nature of test substance upon repeated exposure by oral intubation route. The test substance was administered to male Sprague-Dawley rats daily for 16 days using 0.2cc oral intubation needle. The animals were observed for clinical signs if any, changes in body weight, and after the last dose (24 hr), blood was collected by tail vein bleeding and analyzed for serum cholesterol content. Test substance was found to reduce serum choleterol level to 34% of control. No significant changes were were noted in body weight and no observable toxic effects were observed. Hence, the no observed adverse effect level (NOAEL) for test substance when administered orally by intubation to male rats was 10 mg/kg/day daily in 16 days study period.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
10 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The data is K2 peer reviwed publication

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
78 600 mg/m³
Study duration:
subchronic
Species:
rat
Quality of whole database:
Weight of evidence prepared from various publication

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key 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 peer reviewed publication
Qualifier:
according to guideline
Guideline:
other: Refer below principle
Principles of method if other than guideline:
The repeated dose dermal toxicity test was conducted on Donryu rats exposed for 21 weeks subcutaneously with dose concentration of 400 mg/kg/day of test substance.
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
other: Donryu
Details on species / strain selection:
No data
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: No data available
- Age at study initiation: No data available
- Weight at study initiation: 200-300 gm
- Fasting period before study: No data available
- Housing: No data available
- Diet (e.g. ad libitum): Standard pellet diet (Nihon Nosan, MR-3-A) ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: : No data available

ENVIRONMENTAL CONDITIONS
- Temperature (°C): : No data available
- Humidity (%):: No data available
- Air changes (per hr): : No data available
- Photoperiod (hrs dark / hrs light): : No data available
Type of coverage:
other: Subcutaneous injections
Vehicle:
not specified
Details on exposure:
No data available
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data
Duration of treatment / exposure:
21 weeks
Frequency of treatment:
5 days per week for 21 weeks
Remarks:
0 or 400 mg/kg/day
No. of animals per sex per dose:
Total: 37
0 mg/Kg/day: 30
400 mg/Kg/day: 7 male rats
Control animals:
yes, concurrent vehicle
Details on study design:
No data available
Positive control:
No data available
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Every third day
- Cage side observations checked in table [No.?] were included. No data

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Every third day

DERMAL IRRITATION (if dermal study): No data
- Time schedule for examinations: No data

BODY WEIGHT: Yes
- Time schedule for examinations: Every third day

FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: 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: No data

WATER CONSUMPTION: No data
- Time schedule for examinations: No data

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

HAEMATOLOGY: No data
- 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. No data

CLINICAL CHEMISTRY: No data
- Time schedule for collection of blood: No data
- Animals fasted: No data
- How many animals: No data
- Parameters checked in table [No.?] were examined. No data

URINALYSIS: No data
- 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: Yes
- Time schedule for examinations: No data
- Dose groups that were examined: 400 mg/kg
- Battery of functions tested: sensory activity / grip strength / motor activity / other: Neurological signs and maximum conductioin velocities of motor and sensory fibres (MCV and SCV)

OTHER: The skin temperature of the tail inguinal regions was measured at the beginning of each measurement
Sacrifice and pathology:
No data
Other examinations:
No data available
Statistics:
Statistical significance of difference between mean values for the treated and control group was tested by student’s t test
Clinical signs:
no effects observed
Dermal irritation:
not specified
Mortality:
not specified
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Details on results:
Clinical signs and mortality :
Clinical signs: No appreciable clinical evidence in parameters like effect on growth, Dullness in movement, Difficulty in walking, paralysis in hind limbs were noted. No salivation was observed in test group.

Mortality: No data available

Dermal Irritation: No data available

Body weight and weight gain: No data available

Food consumption and compound intake: No data available

Food efficiency: No data available

Water consumption and compound intake: No data available

Opthalmoscopic examination: No data available

Haematology: No data available

Clinical chemistry: No data available

Urinanalysis No data available

Neurobehaviour: No effect of chemical on nerve conduction velocity and motor distal latency was observed as compared to control

Organ weights: No data available

Gross pathology: No data available

Histopathology: No data available
Dose descriptor:
NOAEL
Effect level:
400 mg/kg bw/day
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: No signs of clinical or neurophysiological evidence of neuropathy was noted
Remarks on result:
other: No toxic effects were observed
Critical effects observed:
not specified

Table: Neurobehavioral changes noted

 

Motor conduction velocity

Sensory conduction velocity

Distal latency

 

 

Whole

proximal

Distal

 

Control

100

100

100

100

100

2-octanone

100

102

101

103

92

Conclusions:
The No observed adverse effect level (NOAEL) is 400 mg/kg in chronic dermal toxicity study when rats were exposed to test substance for 21 weeks.
Executive summary:

Repeated dose chronic toxicity study was performed to determine the dermal toxic nature of test substance . The test substance in, 200 -300 g weighing male Donryu rats were injected subcutaneously with 0 or 400 mg/Kg/day 2 -octanone 5 days/weeks for 21 weeks. The treated animals were observed for clinical signs, body weight and food intake changes and neurological signs and maximum conduction velocities of motor and sensory fibres (MCV and SCV). Treated animals failed to show any appreciable changes in clinical signs like effect on growth, dullness in movement, difficulty in walking, paralysis in hind limbs. No salivation was observed in test group, and neurophysiological evidence of neuropathy was not observed. Hence, the No observed adverse effect level (NOAEL) is 400 mg/kg in chronic dermal toxicity study when rat were exposed to test substance for 21 weeks.

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

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

 

Peer reviewed publication of test substance was reviewed to determine the toxic nature of 2 -octanone (IUPAC name: octan-2-one CAS NO: 111-13-7) upon repeated exposure by oral route. The summary is as mentioned below:

Repeated dose toxicity: Oral

Subacute toxicity study was performed to determine the toxic nature of test substance upon repeated exposure by oral intubation route. The test substance was administered to male Sprague-Dawley rats daily for 16 days using 0.2cc oral intubation needle. The animals were observed for clinical signs if any, changes in body weight, and after the last dose (24 hr), blood was collected by tail vein bleeding and analyzed for serum cholesterol content. Test substance was found to reduce serum choleterol level to 34% of control. No significant changes were were noted in body weight and no observable toxic effects were observed. Hence, the no observed adverse effect level (NOAEL) for test substance when administered orally by intubation to male rats was 10 mg/kg/day daily in 16 days study period.

The study does not conclude higher dose value. Hence it is acceptable to take such low NOAEL .

 

In a 28 days repeated dose toxicity study, the effect of test chemical was evaluated in male and female Sprague Dawley rats. The test chemical was administered by oral gavage in the concentration of 0, 250, 500 and 1000 mg/kg/ body weight/day. The results showed no effect on mortality, no changes were in food consumption and ophthalmology. Changes were observed in clinical signs like soft stool, nasal discharge, red crust around nostrils, perineum soiled with fecal matter were observed. Significant decreased were observed in water consumption and locomotor activity of female rat in 1000 mg/kg dose group. Bodyweight was increased significantly in male and female rats. Significant increase in MCV, Lymphocyte, Basophils level and significant decrease in WBC, platelet, monocytes, neutrophils and eosinophils were observed in male and female rats. Significant changes were observed in the level of testosterone, sodium, total proteins, total cholesterol, SGOT, SGPT, albumin, Blood urea nitrogen (BUN) and Creatinine when treated with 500 and 1000 mg/kg/day. Significant changes were observed in absolute and relative weight of brain, adrenals, spleen, thymus, epididymides, heart, kidneys, ovaries, uterus and liver in 500 and 1000 mg/kg/day. In addition, minimal to mild gross pathological and histopathological changes were observed in liver, spleen and intestine. However, the biological significance of these findings are not related to test chemical. Therefore, the No Observed Adverse Effect Level (NOAEL) was considered to be 1000 mg/kg/day when Sprague-Dawley rat exposed to test substance orally.

Repeated dose oral toxicity study with reproductive and developmental screening was conducted to investigate the repeated dose toxicity of the test material. The chemical was administered by oral gavage route of exposure to dose groups, each of 13 male and 13 female Crj:CD (SD) strain rats upto forty-three days at dose levels of 0, 100, 300 or 1000 mg/kg/day. A control group of 13 males and 13 females was dosed with vehicle alone (corn oil). As a result, in males, abnormalities in death cases and general conditions were not observed in any treated animal. There was also no change in body weight and food consumption suggesting the effect of test chemical administration. Necropsy, histopathological examination, hematology examination, and blood biochemical examination after repeated administration of 42 times also showed no findings or abnormal values suggesting the effect of test chemical administration. In females, there were no deaths in any test chemical administration group. In addition, no change was observed in general condition, body weight and food intake. Necropsy at 4 days postpartum and histopathological examination also did not show findings suggestive of the effect of test chemical administration. On the reproductive and developmental toxicity, test chemical dose up to 1000 mg / kg did not affect mating rate and conception rate. In addition, changes suggesting the effect of test chemical administration on the pregnancy period, birth rate, labor condition and nursing condition of the mother animals were not observed. No treatment related adverse effects were found in either dose group 0, 100, 300 or 1000 mg/kg/day, though some slight changes were observed in blood biochemistry and histopathology in testes. Thus, on the basis of overall discussion of the study, the 'No Observed Effect Level' (NOEL) for repeated dose toxicity by oral route is to be 1000 mg/kg/day.

Repeated dose inhalation:

In subchronic test, Sprague Dawley male and female rats were exposed to test substance by inhalation in the concentration of 0, 80, 400 and 1000 ppm (0, 80, 400 or 1000 mg/L). Actual exposure concentrations is 0, 78.6, 405.8 or 1022.6 ppm (0, 78.6, 405.8 or 1022.6 mg/L) for 6 hours/day, 7 days/week for 50 days. All adult animals survived to study termination and there were no test substance-related changes in mean terminal body weight. For the 1000 mg/L male group, there was a reduction in food consumption during days 0-7. No effect on survival, body weight and weight gain were observed in treated rats as compared to control. Minimal reductions in activity level were observed in 400 and 1000 mg/L dose group and reduction in food consumption during days 0 -7 in 100 mg/L dose group were observed as compared to control. Mean sperm motility and mean epididymal spermatozoan and testicular spermatid counts were comparable among the groups. No test substance-related gross pathology was observed for adult animals from any group. No exposure-related changes were observed during histological examination of the reproductive organs of any of the test substance-exposed animals. Therefore, the No Observed Adverse effect concentration (NOAEC) was considered to be 80 ppm (80 mg/L) (actual dose 78.6 mg/L or 78600 mg/m3) when Sprague-Dawley male and female rats treated with test substance.

Repeated dose oral toxicity was evaluated for test substance using authoritative database. The study assumed the use of rabbits in a subacute study for 30 days .Opthalmoscopic examinations was observed. Since no significant changes were noted, the No observed adverse effect concentration (NOAEC) for test substance in rabbits is estimated to be 6.6 mg/m3/2H after repeated exposure via inhalation route.

 

Repeated dose toxicity: Dermal

Repeated dose chronic toxicity study was performed to determine the dermal toxic nature of test substance . The test substance in, 200 -300 g weighing male Donryu rats were injected subcutaneously with 0 or 400 mg/Kg/day 2 -octanone 5 days/weeks for 21 weeks. The treated animals were observed for clinical signs, body weight and food intake changes and neurological signs and maximum conduction velocities of motor and sensory fibres (MCV and SCV). Treated animals failed to show any appreciable changes in clinical signs like effect on growth, dullness in movement, difficulty in walking, paralysis in hind limbs. No salivation was observed in test group, and neurophysiological evidence of neuropathy was not observed. Hence, the No observed adverse effect level (NOAEL) is 400 mg/kg in chronic dermal toxicity study when rat were exposed to test substance for 21 weeks.

Repeated dose chronic dermal toxicity study was performed to determine the dermal toxic nature of test substance upon repeated applcatioin by dermal route of exposure. The test chemical was administered subcutaneously in daily dose of 400 mg/kg into the back of seven rats, weighing 290g, 5 days per week for a period of 21 weeks. The animals were observed for clinical signs, changes in body weight and neurophysiological changes. Treated animals failed to exhibit apparent clinical and neurophysiologic evidence except for a slight inhibition of weight gain and narcotic effects after treatment. Hence, the No observed adverse effect level (NOAEL) for test substance in rats exposed for 21 weeks is 400 mg/kg.

Based on the data available from the test chemical, 2 -octanone (IUPAC name: octan-2-one CAS NO: 111-13-7) not likely to exhibit repeated dose oral ,inhalation and dermal toxicity. Hence the test chemical is not likely to classify as per the criteria mentioned in CLP regulation.

 

 

 

Justification for classification or non-classification

Based on the data available from the test chemical, 2 -octanone (IUPAC name: octan-2-one CAS NO: 111-13-7) not likely to exhibit repeated dose oral ,inhalation and dermal toxicity. Hence the test chemical is not likely to classify as per the criteria mentioned in CLP regulation.