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EC number: 203-937-5 | CAS number: 112-12-9
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- sub-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 peer reviewed publication
Data source
Referenceopen allclose all
- Reference Type:
- publication
- Title:
- Commercial-Grade Methyl Heptyl Ketone (5-Methyl-2-octanone) Neurotoxicity: Contribution-of 5Nonanone’
- Author:
- JOHN L. DONOGHUE
- Year:
- 1 982
- Bibliographic source:
- TOXlCOLOGY AND APPLIED PHARMACOLOGY, (1982)
- Reference Type:
- other: study report
- Title:
- Repeated Oral Administration of Five Ketones to Rats
- Author:
- Walter J. Krasavage
- Year:
- 1 994
- Bibliographic source:
- EASTMAN KODAK CO-Company report
Materials and methods
Test guideline
- 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:
- Chronic repeated dose toxicity study particularly the neurotoxic potential of methyl heptyl ketone was studied orally in CD, COBS rats.
- GLP compliance:
- not specified
- Limit test:
- no
Test material
- Reference substance name:
- Nonan-2-one
- EC Number:
- 212-480-0
- EC Name:
- Nonan-2-one
- Cas Number:
- 821-55-6
- Molecular formula:
- C9H18O
- IUPAC Name:
- nonan-2-one
- Reference substance name:
- Methyl heptyl ketone
- IUPAC Name:
- Methyl heptyl ketone
- Test material form:
- other: colorless to pale yellow clear oily liquid
- Details on test material:
- - Name of test material (as cited in study report): Methyl heptyl ketone
- Molecular formula (if other than submission substance): C9H18O
- Molecular weight (if other than submission substance): 142.24g/mol
- Substance type: Organic
- Physical state: colorless to pale yellow clear oily liquid
- Impurities (identity and concentrations): 27.7 %
Constituent 1
Constituent 2
- 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 %
Test animals
- 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.
Administration / exposure
- 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 or 2000 mg/Kg/day
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 and 2000 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:
- 90 days
- Frequency of treatment:
- Once a day, 5 days per week
Doses / concentrations
- Remarks:
- 0 or 2000mg/kg
- No. of animals per sex per dose:
- Total animals -16 male rats
0 mg/kg: 8 male rats
2000 mg/kg: 8male rats - Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Doses were select on the basis of 3 weeks range finding study. 0, 1000, 2000 and 4000 mg/kg doseof Methyl heptyl ketone were given to male rats orally by gavage once a day, 5 days per week for 3 weeks. At 4000 mg/kg/day dose group, after two to four doses animals with sevear depression were died and significant decrease in body weight gain were observed. Vascular congestion and hemorrhage in major organ and 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 dose group. Therefore, 2000 mg/kg/day dose group were selected for present study.
- Rationale for animal assignment (if not random): No data available
- Rationale for selecting satellite groups: No data available
- Post-exposure recovery period in satellite groups: No data available
- Section schedule rationale (if not random): No data available - Positive control:
- No data
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: No data available
- Cage side observations checked in table [No.?] were included. No data available
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Twice daily
BODY WEIGHT: Yes
- Time schedule for examinations: Weekly.
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
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data available
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 available.
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water studies): No data available.
OPHTHALMOSCOPIC EXAMINATION: No data available.
HAEMATOLOGY: Yes
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 16 rats were examined.
- Parameters checked in table [No.?] were examined: 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 16 rats were examined.
Parameters checked in table [No.?] were examined: Glucose level were examined.
URINALYSIS: No data available.
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: weekly
- Dose groups that were examined: 2000 mg/kg/day
- Battery of functions tested: sensory activity / grip strength / motor activity / other: Yes, posture, gait, and strength were observed.
OTHER:
Organ weight:
Liver, kidneys, brain, adrenal glands, testes, heart, and spleen weight were recorded. - 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.
Spinal cord, sciatic-plantar nerves, and dorsal root ganglia were collected in formalin. Plantar interosseous muscles of the hindpaw were collected in Bouin’s fixative. Portions of the medulla oblongata and the cerebellum and an entire sciatic-plantar nerve were fixed with 5% glutaraldehyde in 0.1 M phosphate buffer, pH 7.4, at O”C, postfixed in Dalton’s chrome-osmium solution, dehydrated in a series of ethanol solutions and propylene oxide, and embedded in epoxy resin.
Sections cut at 1 pm were stained with toluidine blue and examined by light microscopy.
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, Spinal cord, medulla oblongata, pons, cerebellum, cerebral cortex, sciatic-plantar nerves, and dorsal root ganglia, thalamus, basal ganglia and eyes , Quadriceps femoris muscle, calf musculature, and plantar interosseous muscles of the hindpaw 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%.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Mortality:
- not specified
- Body weight and weight changes:
- effects observed, treatment-related
- 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:
- effects observed, treatment-related
- Clinical biochemistry findings:
- effects observed, treatment-related
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- effects observed, treatment-related
- 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:
No data available
Clinical signs:
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 in treated rats as compared to control.
The observed sign were considered to be neurotoxic signs.
Body weight and weight gain: 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.
Food consumption and compound intake: Food consumption:
Minor decreases in food consumption were observed in treated rats as compared to control.
Compound intake:
No data available
Food efficiency: No data
Water consumption and compound intake: No data
Opthalmoscopic examination: No data
Haematology: Minor decrease in total white blood cell count was observed in treated rats as compared to control.
Clinical chemistry: Decrease in glucose level was observed in treated rats as compared to control.
Urinanalysis: No data
Neurobehaviour: Depression, weakness and numbness were observed in treated animals as compare to control.
Clinical neuropathy was also observed in treated rats.
Organ weights: 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 were observed in treated rats as compared to control.
Gross pathology: Generalized adipose tissue and hindlimb musculature atrophy evident in affected muscles by flaccidity, pallor, and reduction in total muscle mass were observed in treated rats as compared to control.
Histopathology: 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.
Sites of axonal damage in increasing order of severity were the cerebellum, medulla oblongata, spinal cord, and peripheral nerves.
Effect levels
- Dose descriptor:
- LOAEL
- Effect level:
- 2 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: Effect on clinical sign, gross pathology, histopathology and neurotoxicity
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
Table: TERMINAL BODY AND ORGAN WEIGHTS FOR RATS DOSED WITH COMMERCIAL-GRADE METHYL HEPTYL KETONE
90- day study |
Terminal body weight (g) |
Liver |
Kidneys |
Brain |
Adrenal gland |
Testes |
Heart |
||||||
g |
% body weight |
g |
% body weight |
g |
% body weight |
g |
% body weight |
g |
% body weight |
g |
% body weight |
||
2000 mg/Kg |
337 ab |
16.48 |
4.87b |
3.48 |
1.04b |
1.79b |
0.54b |
0.057 |
0.017b |
3.40 |
1.02b |
1.14b |
0.39 |
n: 8 |
50.0 |
3.066b |
0.341 |
0.541 |
0.100 |
0.071 |
0.0074 |
0.0053 |
0.0032 |
0.264 |
0.112 |
0.153 |
0.039 |
Control |
495 |
13.33 |
270 |
3.10 |
0.63 |
2.05 |
0.42 |
0.053 |
0.011 |
3.16 |
0.64 |
1.74 |
0.35 |
n: 8 |
40.3 |
1.336 |
0.126 |
0.276 |
0.030 |
0.070 |
0.034 |
0.0054 |
0.0009 |
0.690 |
0.157 |
0.427 |
0.071 |
a Values are listed as X + SD.
b Indicates a statistically significant difference from control p ≤ 0.05, one-way ANOVA.
Applicant's summary and conclusion
- Conclusions:
- The 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.
- Executive summary:
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.
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