undecan-2-one; methyl nonyl ketone

Endpoint summary

Description of key information

Repeated dose toxicity: Oral

Based on the data available from different studies, the No Observed Adverse Effect Level (NOAEL) for test material was considered to be 1000 mg/kg/day for repeated dose oral toxicity study, when rodents were treated with test material orally by gavage.

Repeated dose toxicity: Dermal

A short-term toxicity study does not need to be conducted because exposure of humans via dermal in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment. Also, the acute dermal toxicity value for test chemical (as provided in section 7.2.3) is >2000 mg/kg body weight. Given the use of the chemical; repeated exposure by the dermal route is unlikely since the use of gloves is common practice in industries. Thus, it is expected that test chemical shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no data available that suggests that test chemical shall exhibit repeated dose toxicity by the dermal route. Hence this end point was considered for waiver.

Repeated dose toxicity: Inhalation

A short-term toxicity study does not need to be conducted because exposure of humans via inhalation in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment. Also, according to Annex IX of the REACH regulation, testing by the inhalation route is appropriate only if exposure of humans via inhalation is likely. Taking into account the low vapour pressure of the test chemical which is reported as 0.0414 mmHg at 20 C. Thus, exposure to inhalable dust, mist and vapour of the test chemical is highly unlikely. Therefore this study is considered for waiver

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:

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:

Repeated dose subacute toxicity study was performed to determine the toxic nature 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:

subchronic

Species:

rat

Quality of whole database:

Data is klimisch 2.

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Data waiving:

exposure considerations

Justification for data waiving:

a short-term toxicity study does not need to be conducted because exposure of humans via inhalation in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment

Endpoint conclusion

Quality of whole database:

waiver

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: dermal

Data waiving:

exposure considerations

Justification for data waiving:

a short-term toxicity study does not need to be conducted because exposure of humans via the dermal route in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment

Endpoint conclusion

Quality of whole database:

waiver

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Repeated dose toxicity: Oral

Data available from the various sources was reviewed to determine the toxic nature of the given test chemical. The studies are as mentioned below:

Study 1:

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.

Study 2:

Chronic repeated dose toxicity study particularly the neurotoxic potential was performed, CD, COBS male rats were treated with Methyl heptyl ketone in the concentration of 0 and 2000 mg/kg/day orally 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 hindpaw were 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 and decrease in glucose level were observed in treated rats. In addition, Depression, weakness, numbness and clinical neuropathy were 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, Low Observed Adverse Effect Level (LOAEL) was considered to be 2000 mg /kg for Methyl heptyl ketone (MHK) in Charles River CD, COBS male rats for 90 days study.

Study 3:

A 13-week oral gavage study was conducted in rats to assess the toxicity potential of the test chemical. Rats of both sexes of the CFE strain, obtained from an SPF breeding colony, were given ground Spillers' Laboratory Small Animal Diet and water ad lib. They were housed five per cage in animal rooms maintained at 21±1 °C with a relative humidity of 50-60%. Groups of 15 CFE rats/sex/dose were administered test chemical via oral intubation at doses of 0, 20, 100, or 500 mg/kg/day in corn oil. An additional 5 rats/sex/dose receiving daily doses of 0, 100, or 500 mg/kg/day test chemical were examined after 2 and 6 weeks. The rats were observed for changes in body weight, haematological, serum analysis, urinalysis parameters. At autopsy all the animals were examined for macroscopic abnormalities and the brain, pituitary, thyroid, heart, liver, spleen, kidneys, adrenals, gonads, stomach, small intestine and caecum were weighed. Samples of these organs and of salivary gland, trachea, aorta, thymus, lymph nodes, urinary bladder, colon, rectum, pancreas, uterus and skeletal muscle were preserved in 10% buffered formalin. Paraffin-wax sections of these tissues from the controls and from animals receiving 500 mg/kg for 13 wk were stained with haematoxylin and eosin for microscopic examination. There were no statistically significant differences between test and controls groups in the results of body weight gain, food intake, water intake, haematological parameter and serum analyses. There were statistically significant increases in the number of cells excreted in the urine of both males and females at the mid- and high-dose groups after 13 weeks and in the high-dose group after 6 weeks, along with pale kidneys observed in the animals. A significant increase in the absolute liver weight (females) and relative kidney weights (males) was reported at the mid-dose. A significant increase in the absolute and relative liver weights (males and females, and males at week 6), absolute and relative kidney weights (males), and absolute stomach weights (females) were reported at the high-dose. Although organ weight changes were observed in the mid- and high-dose groups, no histopathological alterations or clinical chemistry changes were noted that might also be reflective of renal or hepatic toxicity. The NOAEL was considered to be 20 mg/kg/day, based on the observed increase in urine cellularity and organ weight changes in the mid- and high-dose groups. The NOAEL value was a level approximately 100 times the estimated maximum likely intake in man. Hence, the test chemical can be regarded to be safe for consumption in humans.

Repeated dose toxicity: Dermal

A short-term toxicity study does not need to be conducted because exposure of humans via dermal in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment. Also, the acute dermal toxicity value for test chemical (as provided in section 7.2.3) is >2000 mg/kg body weight. Given the use of the chemical; repeated exposure by the dermal route is unlikely since the use of gloves is common practice in industries. Thus, it is expected that test chemical shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no data available that suggests that test chemical shall exhibit repeated dose toxicity by the dermal route. Hence this end point was considered for waiver.

Repeated dose toxicity: Inhalation

A short-term toxicity study does not need to be conducted because exposure of humans via inhalation in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment. Also, according to Annex IX of the REACH regulation, testing by the inhalation route is appropriate only if exposure of humans via inhalation is likely. Taking into account the low vapour pressure of the test chemical which is reported as 0.0414 mmHg at 20 C. Thus, exposure to inhalable dust, mist and vapour of the test chemical is highly unlikely. Therefore this study is considered for waiver

Justification for classification or non-classification

Based on the data available, the given test chemical does not exhibit toxic nature upon repeated exposure by oral route of exposure. Hence, it is not likely to classify as toxic as per the criteria mentioned in CLP regulation. For repeated inhalation and repeated dermal toxicity wavier was added so, not possible to classify