Nonan-2-one

Endpoint summary

Description of key information

Repeated dose toxicity- Oral:

In a repeated dose toxicity study, CD, COBS male rats treated with Methyl heptyl ketone ( IUPAC name: nonan-2-one) in the concentration of 0, 1000, 2000 and 4000 mg/kg/day orally by gavage for 3 weeks. Following two to four doses of 4000 mg/kg/day animals withsevear depressionwere died and significant decrease in body weight gain were observed in treated rats as compared to control. Slitdecrease in body weight gain in in 2000 mg/kg/day and significant increase in absolute and relative liver and relative kidney weight were observed in 1000 and 2000 mg/kg/day treated rats as compared to control. Increased mean absolute kidney weights were considered to be not statistically significantfor 1000 mg/kg/day dose group.In addition, Vascular congestion and hemorrhage in major organ andModerate hepatocyte hypertrophy with minimal focal hepatic necrosis and enlarged hepatocytes impinged on sinusoidal spaces reducing their volume and severe central nervous system depression and consequent failure to maintain normal pulmonary ventilation and perfusion were observed at 4000 mg/kg/day treated ratsandminorto moderate hepatocyte hypertrophy were observed at 2000 mg/kg/day treated rats as compared to control. Therefore, No Observed Adverse Effect Level (NOAEL) was considered to be 1000 mg/kg/day when CD, COBS male rats treated with Methyl heptyl ketone.

Repeated dose toxicity: Inhalation

In Combined repeated dose repro-devp. Screen test, Sprague Dawley male and female rats were exposed to 2 -Nonanone 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. 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 40 and 100 mg/kg/day dose group andreduction in food consumption during days 0 -7 in 100 mg/kg/day dose group were observed as compared to control. In addition, no effects were observed on organ weight, gross pathology, sperm parameter and histopathology of treated rats as compared to control. Therefore, the No Observed Adverse effect concentration (NOAEC) was considered to be 80 ppm (80 mg/L) (actual dose 78.6 mg/L) when Sprague-Dawley male and female rats treated with 2-Nonanone

Key value for chemical safety assessment

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:

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:

equivalent or similar to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Principles of method if other than guideline:

To evaluate the acute toxicity of Methyl heptyl ketone in COBS, CD (SD) BR male rats.

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

- Name of test material: Methyl heptyl ketone
- IUPAC name: nonan-2-one
- Molecular formula: C9H18O
- Molecular weight: 142.24g/mol
- Substance type: Organic
- Physical state: No data
- Impurities (identity and concentrations): 27.7 %

Species:

rat

Strain:

other: CD, COBS

Details on species / strain selection:

No data

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Lab; Wilmington, Mass
- Age at study initiation: No data available.
- Weight at study initiation: No data available.
- Fasting period before study: No data available.
- Housing: They were singly housed in solid floor cages covered by Ab-Sorb-Dri bedding to reduce the likelihood of wire mesh-induced pressure neuropathy.
- Diet (e.g. ad libitum): Purina Rodent Laboratory Chow 5001 was available ad libitum.
- Water (e.g. ad libitum): Water was available 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:

water

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS: Methyl heptyl ketone was dissolved in water to give a dose level of 0, 1000, 2000 or 4000 mg/kg

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): Water
- Concentration in vehicle: 0, 1000, 2000 and 4000 mg/kg
- Amount of vehicle (if gavage): No data available
- Lot/batch no. (if required): No data available
- Purity: 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:

3 Weeks

Frequency of treatment:

Once a day, 5 days per week

Remarks:

0, 1000, 2000 or 4000 mg/kg

No. of animals per sex per dose:

Total animals -18 male rats
0 mg/kg: 9 male rats
1000 mg/kg: 3 male rats
2000 mg/kg :3 male rats
4000 mg/kg :3 male rats

Control animals:

yes, concurrent vehicle

Details on study design:

No data

Positive control:

No data available.

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily
- Cage side observations checked in table [No.?] were included: Clinical conditions were observed.

DETAILED CLINICAL OBSERVATIONS: Yes - Time schedule: Twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: On 0, 3,7,14 and 21 day of treatment.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes ,
Time schedule: 0, 3,7,14 and 21 day of treatment.
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data available.


FOOD EFFICIENCY: No data available
- 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 available.


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water studies): No data available.


OPHTHALMOSCOPIC EXAMINATION: No data available.


HAEMATOLOGY: Yes
- Time schedule for collection of blood: At the termination of study
- Anaesthetic used for blood collection: Yes, carbon dioxide were used
- Animals fasted: No data available.
- How many animals: All 18 rats were examined.
- Parameters checked in table [No.?] were examined: Hemoglobin concentration, haematocrits, and total and relative white blood cell counts were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At the termination of study
- Anaesthetic used for blood collection: Yes, carbon dioxide were used
- Animals fasted: No data available.
- How many animals: All 18 rats were examined.
- Parameters checked in table [No.?] were examined.-
Glutamic-oxaloacetic transaminase (SGOT), glutamic-pyruvic transaminase (SGPT), alkaline phosphatase (AP), and lactic dehydrogenase (LDH), Urea nitrogen and glucose were examined.

URINALYSIS: No data available.

NEUROBEHAVIOURAL EXAMINATION: No data available.

OTHER: Liver and kidney weights were recorded prior to fixation.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, Gross abnormalities were examined.

Tissues were fixed in 10% buffered formalin (pH 7.0), embedded in paraffin, sectioned at 5 pm, stained with hematoxylin-eosin, and examined by light microscopy.

Eyes were fixed in a modified Zenker’s (Russell’s) fixative.

HISTOPATHOLOGY: Yes,

Organ examined:
Trachea, lungs, thymus, heart, tongue, salivary glands, esophagus, stomach, small intestine, large intestine, kidneys, urinary bladder, adrenal glands, pituitary, thyroids, parathyroids, pancreas, testes, epididymides, accessory sex glands, spleen, mesenteric lymph nodes, bone marrow, medulla oblongata, pons, cerebellum, cerebral cortex, thalamus, basal ganglia and eyes were examined.

Other examinations:

No data

Statistics:

Statistical analyses included Bartlett’s test, one-way analysis of variance (ANOVA), and Duncan’s multiple range test as a significance level of 5%.

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Details on results:

Clinical signs and mortality:
Mortality:
When treated with 4000 mg/kg/day, following two to four doses animals were died as compared to control.

Clinical signs:
When treated with 4000 mg/kg/day, sevear depression was observed in treated rats as compared to control.

Body weight and weight gain: When treated with 4000 mg/kg/day, significant decrease in body weight gain was observed in treated rats as compared to control.

When treated with 2000 mg/kg/day, slit decrease in body weight gain was observed in treated rats as compared to control.

Food consumption and compound intake: No significant change was observed in 1000 and 2000 mg/kg/day treated group compare to control group.

Food efficiency: No data

Water consumption and compound intake: No data

Opthalmoscopic examination: No data

Haematology: No significant change was observed in 1000 and 2000 mg/kg/day treated group compare to control group.

Clinical chemistry: No significant change was observed in 1000 and 2000 mg/kg/day treated group compare to control group.

Urinanalysis: No data

Neurobehaviour: No data

Organ weights: When treated with 1000 and 2000 mg/kg/day, significant increase in absolute and relative liver and relative kidney weight were observed in treated rats as compared to control.

Increased mean absolute kidney weights were considered to be not statistically significant.

Gross pathology: Vascular congestion and hemorrhage in major organ in 4000 mg/kg/day treated rats.

Histopathology: Moderate hepatocyte hypertrophy with minimal focal hepatic necrosis and enlarged hepatocytes impinged on sinusoidal spaces reducing their volume and severe central nervous system depression and consequent failure to maintain normal pulmonary ventilation and perfusion were observed at 4000 mg/kg/day treated rats as compared to control.

Minor to moderate hepatocyte hypertrophy were observed at 2000 mg/kg/day treated rats as compared to control.

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: No adverse effect on survival, body weight and body weight gain, food consumption, haematology, clinical chemistry, organ weight, gross pathology and histopathology.

Critical effects observed:

not specified

Table: TERMINAL BODY AND ORGAN WEIGHTS FOR RATS DOSED WITH COMMERCIAL-GRADE METHYL HEPTYL KETONE

Range finding study	Terminal body weight (g)	Liver		Kidneys
		g	% body weight	g	% body weight
2000 mg/Kg	302 a	13.80b	4.51b	2.82	0.93b
n: 3	23.2	0.770	0.178	0.412	0.064
1000 mg/Kg	311	11.98b	3.86b	2.90	o.94b
n: 3	26.0	0.805	0.064	0.189	0.087
Control	320	9.79	3.06	2.51	0.78
n: 9	15.8	0.652	0.147	0.283	0.057

a Values are listed as X + SD.

b Indicates a statistically significant difference from control p Y 0.05, one-way ANOVA.

Conclusions:

The No Observed Adverse Effect Level (NOAEL) was considered to be 1000 mg/kg/day when CD, COBS male rats treated with Methyl heptyl ketone.

Executive summary:

In a repeated dose toxicity study, CD, COBS male rats treated with Methyl heptyl ketone in the concentration of 0, 1000, 2000 and 4000 mg/kg/day orally by gavage for 3 weeks. Following two to four doses of 4000 mg/kg/day animals withsevear depressionwere died and significant decrease in body weight gain were observed in treated rats as compared to control. Slitdecrease in body weight gain in in 2000 mg/kg/day and significant increase in absolute and relative liver and relative kidney weight were observed in 1000 and 2000 mg/kg/day treated rats as compared to control. Increased mean absolute kidney weights were considered to be not statistically significantfor 1000 mg/kg/day dose group.In addition, Vascular congestion and hemorrhage in major organ andModerate hepatocyte hypertrophy with minimal focal hepatic necrosis and enlarged hepatocytes impinged on sinusoidal spaces reducing their volume and severe central nervous system depression and consequent failure to maintain normal pulmonary ventilation and perfusion were observed at 4000 mg/kg/day treated ratsandminorto moderate hepatocyte hypertrophy were observed at 2000 mg/kg/day treated rats as compared to control. Therefore, No Observed Adverse Effect Level (NOAEL) was considered to be 1000 mg/kg/day when CD, COBS male rats treated with Methyl heptyl ketone.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Data is from K2 peer reviewed publication

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: inhalation

Remarks:

combined repeated dose and reproduction / developmental screening

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

Data is from NTRL report

Qualifier:

according to guideline

Guideline:

other: OECD:TG- 421

Principles of method if other than guideline:

Combined repeated dose repro-devp. Screen of 2-Nonanone was performed usins Sprague-Dawley rats

GLP compliance:

no

Limit test:

no

Specific details on test material used for the study:

- Name of test material: 2-Nonanone
- IUPAC name: nonan-2 -one
- Molecular formula: C9H18O
- Molecular weight: 142.24g/mol
- Substance type: Organic
- Physical state: Liquid
- Impurities (identity and concentrations): 99% pure

Species:

rat

Strain:

Sprague-Dawley

Details on species / strain selection:

No data

Sex:

male/female

Details on test animals or test system and environmental conditions:

No data available.

Route of administration:

inhalation

Type of inhalation exposure:

not specified

Vehicle:

air

Remarks:

Fileterd room air

Remarks on MMAD:

MMAD / GSD: No data available

Details on inhalation exposure:

No data available.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

50 days

Frequency of treatment:

6 hours/day, 7 days/week

Remarks:

0, 80, 400 or 1000 ppm. (0, 80, 400 or 1000 mg/L)
Actual exposure concentrations: 0, 78.6, 405.8 or 1022.6 ppm (0, 78.6, 405.8 or 1022.6 mg/L)

No. of animals per sex per dose:

No data available

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: No data available
- Cage side observations checked in table [No.?] were included: Survival was observed.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: No data available

BODY WEIGHT: Yes
- Time schedule for examinations: No data available

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data available
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data available

FOOD EFFICIENCY: No data available
- 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 available

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data available
- Time schedule for examinations: No data available

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

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

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

URINALYSIS: No data available
- Time schedule for collection of urine: No data available
- Metabolism cages used for collection of urine: No data available
- Animals fasted: No data available
- Parameters checked in table [No.?] were examined. No data available

NEUROBEHAVIOURAL EXAMINATION: No data available
- Time schedule for examinations: No data available
- Dose groups that were examined: No data available
- Battery of functions tested: sensory activity / grip strength / motor activity / other: No data available

OTHER:
The testes and epididymis were also weighed

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes, The ovaries, vagina, uterus, Fallopian tubes, and testes, epididymis, and male accessory sex organs were examined histologically.

Other examinations:

No data

Statistics:

Homogeneity of data were evaluated by Bartlett's test (p, 0.01), analysis of variance (ANOVA, <0.05), and Dunnett's test (p, 0.05). When the variances of the means were not considered equal by Bartlett's test, the data were evaluated by Kruskal-Wallis H-test (p, 0.05) followed by Mann-Whitney U-test (p<0.05). The reproductive performance of dams and fertility and fecundity indices were evaluated in contingency tables, using Chi-square test (p,0.05). The total number of pups per litter (live and dead) and the total number of live pups per litter were evaluated by a linear regression model.

Clinical signs:

effects observed, treatment-related

Mortality:

no mortality observed

Description (incidence):

No effects were observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

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:

no effects observed

Gross pathological findings:

no effects observed

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Details on results:

Clinical signs and mortality:
Mortality:
No effect on survival of treated rats was observed as compared to control.

Clinical sign:
Minimal reductions in activity level were observed in 40 and 100 mg/kg/day dose group.

No other abnormalities were observed in treated rats as compared to control.

Body weight and weight gain :No effect were observed on body weight and weight gain of treated rats as compared to control

Food consumption and compound intake:
Food consumption:
In male rats, reduction in food consumption during days 0-7 hen treated with 100 mg/kg/day as compared to control.

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 data available

Organ weights: No effect was observed on organ weight of treated rats as compared to control.

Gross pathology: No gross pathological changes were observed in treated rats as compared to control.

Histopathology: No histopathological changes in organs were observed in treated rats as compared to control.

Other: Sperm parameter:
No change in Mean sperm motility and mean epididymal spermatozoan and testicular spermatid counts were observed in treated male rats as compared to control.

Dose descriptor:

NOAEC

Remarks:

F0

Effect level:

80 mg/L air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No advarse effect on survival clinical sign, body weight and body weight gain, food consumption, sperm parameter, gross pathology and histopathology

Dose descriptor:

NOAEC

Remarks:

F1

Effect level:

1 000 mg/L air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse effect on clinical signs, weight gain and gross pthology

Critical effects observed:

not specified

Conclusions:

The No Observed Adverse effect concentration (NOAEC) was considered to be 80 ppm (80 mg/L) (actual dose 78.6 mg/L) when Sprague-Dawley male and female rats treated with 2-Nonanone

Executive summary:

In Combined repeated dose repro-devp. Screen test, Sprague Dawley male and female rats were exposed to 2 -Nonanone 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. 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 40 and 100 mg/kg/day dose group andreduction in food consumption during days 0 -7 in 100 mg/kg/day dose group were observed as compared to control. In addition, no effects were observed on organ weight, gross pathology, sperm parameter and histopathology of treated rats as compared to control. Therefore, the No Observed Adverse effect concentration (NOAEC) was considered to be 80 ppm (80 mg/L) (actual dose 78.6 mg/L) when Sprague-Dawley male and female rats treated with 2-Nonanone

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

80 mg/m³

Study duration:

subchronic

Species:

rat

Quality of whole database:

Data is from K4 company report

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Repeated dose toxicity- Oral:

Various peer reviewed publications were removed to determine the toxic nature of 2 -Nonanone ( IUPAC name: nonan-2-one) upon repeated application by oral route of exposure.

In a repeated dose toxicity study by Donoghue et al (Toxicology and applied pharmacology, 1982), CD, COBS male rats treated with Methyl heptyl ketone ( IUPAC name: nonan-2-one) in the concentration of 0, 1000, 2000 and 4000 mg/kg/day orally by gavage for 3 weeks. Following two to four doses of 4000 mg/kg/day animals withsevear depressionwere died and significant decrease in body weight gain were observed in treated rats as compared to control. Slitdecrease in body weight gain in in 2000 mg/kg/day and significant increase in absolute and relative liver and relative kidney weight were observed in 1000 and 2000 mg/kg/day treated rats as compared to control. Increased mean absolute kidney weights were considered to be not statistically significantfor 1000 mg/kg/day dose group.In addition, Vascular congestion and hemorrhage in major organ andModerate hepatocyte hypertrophy with minimal focal hepatic necrosis and enlarged hepatocytes impinged on sinusoidal spaces reducing their volume and severe central nervous system depression and consequent failure to maintain normal pulmonary ventilation and perfusion were observed at 4000 mg/kg/day treated ratsandminorto moderate hepatocyte hypertrophy were observed at 2000 mg/kg/day treated rats as compared to control. Therefore, No Observed Adverse Effect Level (NOAEL) was considered to be 1000 mg/kg/day when CD, COBS male rats treated with Methyl heptyl ketone.

In the same study by Donoghue et al (1982), Chronic repeated dose toxicity study particularly the neurotoxic potential was performed, CD, COBS male rats were treated with Methyl heptyl ketone ( IUPAC name: nonan-2-one) in the concentration of 0 and 2000 mg/kg/dayorally by gavage for 90 days.Peripheral neuropathy, Hind limb weakness, reduction in extension of the hind limbs and a tendency toward a base-wide stance and low or droop tail, dragging of at least one hindpawwere observed.Observed sign were considered to be neurotoxic signs. Minor differences in mean weekly body weight were observed in treated rats during the first 3 weeks of exposure, but the differences did not reach statistical significance until the fourth week as compared to control.Similarly,Minor decreases in food consumption, total white blood cell count anddecrease in glucose level were observed in treated rats.In addition, Depression, weakness, numbness and clinical neuropathywere observed.Significant increase in absolute and relative liver weight and absolute brain, adrenal and testes weight and relative kidney weight and decrease in relative heart weight,generalized adipose tissue and hindlimb musculature atrophy evident in affected muscles by flaccidity, pallor, and reduction in total muscle mass and Hepatocyte hypertrophy and increased hyalin droplet formation in the proximal renal tubular epithelium, higher degree of regenerating renal tubular epithelium and tubular dilation with casts, muscle fiber atrophy of tongue, quadriceps femoris, calf and hindpaw interosseous muscles were observed in treated rats. Atrophic changes were characterized by increased numbers of central myofiber nuclei, increased angular myofibers, foci of small myofibers, and coalescence of atrophic foci into large areas. “Giant” axons and degenerating axons were located in intramuscular nerves. Therefore, No Observed Adverse Effect Level (NOAEL) was considered to be > 2000 mg /kg for Methyl heptyl ketone (MHK) in Charles River CD, COBS male rats for 90 days study.

Another repeated dose oral toxicity study was reviewed. In a 90-Days Repeated dose toxicity study (Eastman Kodak Company, 1994), Charles River CD, COBS male rats treated with Methyl heptyl ketone (MHK; IUPAC name: nonan-2-one)orally by gavage in the concentration of 0 and 2000 mg/kg. Peripheral neuropathy, Hind limb weakness, reduction in extension of the hind limbs and a tendency toward a base-wide stance and low or droop tail were observed in treated rats.The observed sign were considered to be neurotoxic signs.Feed consumption was significantly reduced for the first week and then was comparable to control values except during weeks 10 and 12 when it was significantly lower. Body weight was the lowest from the fourth week and by the sixth week was significantly lower than all other groups.Significantly reduced total white cell count and glucose level. Statistically significant decreased in absolute and increased in relative liver weight, statistically significantly increased relative kidney, adrenal gland and testes weight and decreased absolute brain and heart weight and decreased relative spleen weights were observed as compared to control. In addition, Flaccidity, pallor and reduction in total muscle mass, generalized decrease in adipose tissue and atrophy of the hind limb musculature and Hyperkeratosis with pseudoepitheliomatous hyperplasia of the non-glandular mucosa of the stomach, hepatocyte hypertrophy, and increased hyalin droplet formation in the proximal renal tubular epithelium. Regenerating renal tubular epithelium and tubular dilation with casts. Muscle atrophy of tongues,quadriceps femoris muscle, calf musculature and hind limb interosseous muscles. Increased numbers of central myofiber nuclei, increased angular myofibers, and foci of atrophic myofibers and coalesence of atrophic myofibers into large areas of atrophy were observed in treated rats. "Giant" axons and degenerating axons were located in some intramuscular nerves. "Giant" axonal lesions in cerebellum, medulla oblongata, spinal cord and peripheral nerves were observed in treated rats characterized by multifocal axonal swelling with thinning of myelin sheath and paranodal myelin retraction. More severely affected axons showed fragmentation and myelin degeneration in the form of ovoids were observedas compared to control. Therefore, The No-observed-adverse-effect-level (NOAEL) was found to be >2000 mg /kg for Methyl heptyl ketone (MHK) in Charles River CD, COBS male rats for 90 days study.

In the same study mentioned above, Subacute repeated dose toxicity study (Eastman Kodak Company, 1994) was also performed. CD, COBS male rats were treated with Methyl heptyl ketone ( IUPAC name: nonan-2-one) in the concentration of 0, 1000, 2000 or 4000 mg/kg orally by gavage for 3 weeks. 3 rats died within 24 to 28 hours and depression and prostration were observed in 4000 mg/kg treated rats as compared to control. No effects were observed on Body weight and weight gain,food consumption and haematology of treated rats as compared to control. Significant increase in absolute and relative liver weight and slightly increased absolute and relative kidney weight were observed in 1000 and 2000 mg/kg. in addition, serosal hemorrhage in the jejunum, porphyrin stained tears, congestion of the liver and a small contracted spleen and minor acute bronchitis and severe congestion, edema and atelectasis, moderate congestion and interstitial pneumonia in lung, moderate hyperplasia of the epithelium of the non-glandular mucosa of the stomach, moderate hepatocyte hypertrophy, characterized by an increase in the absolute volume of the cytoplasm, a decrease in basophilic grandular cytoplasm and enlarged, vesicular nuclei with prominent nucleoli and Enlarged hepatocytes impinged on the sinusoidal space reducing its volume in liver, dilatation of the lumena of the renal tubules and multiple hemorrhages into the lamina propria and submocosa of the urinary bladder, congested and cells of the zona fasiculata were hypertrophied in adrenal gland, congestion in Bone marrow and brain, Atrophy of the mesenteric adipose tissue were observed in 4000 mg/kg dose group. Minor to severe degree of hyperplasia of the epithelium of the nonglandular mucosa was observed in stomach and minor to moderate degree of hepatocyte hypertrophy were observed in 2000 mg/kg treated rats as compared to control. Therefore, No-observed-adverse-effect-level (NOAEL) was considered to be 1000 mg/kg when CD, COBS male rats treated with Methyl heptyl ketone

Repeated dose toxicity: Inhalation

Data for repeated inhalation toxicity was reviewed to determine the toxic nature of 2 -Nonanone ( IUPAC name: nonan-2-one) upon repeated exposure by inhalation route. The summary is as mentioned below:

In Combined repeated dose repro-devp. Screen test (Eastman Kodak Company, 1994), Sprague Dawley male and female rats were exposed to 2 -Nonanone 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. 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 40 and 100 mg/kg/day dose group andreduction in food consumption during days 0 -7 in 100 mg/kg/day dose group were observed as compared to control. In addition, no effects were observed on organ weight, gross pathology, sperm parameter and histopathology of treated rats as compared to control. Therefore, the No Observed Adverse effect concentration (NOAEC) was considered to be 80 ppm (80 mg/L) (actual dose 78.6 mg/L) when Sprague-Dawley male and female rats treated with 2-Nonanone

Based on the information observed for the target chemical, it is summarized that 2 -Nonanone does not exhibit repeated oral and inhalation toxicity. Thus, the chemical is not likely to classify as a toxicant upon repeated exposure by oral and inhalation route of exposure.

Justification for classification or non-classification

Based on the information observed for the target chemical, it is summarized that 2 -Nonanone does not exhibit repeated oral and inhalation toxicity. Thus, the chemical is not likely to classify as a toxicant upon repeated exposure by oral and inhalation route of exposure.