6-chlorohexan-2-one

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Data source

Reference

Reference Type:

publication

Title:

Commercial-Grade Methyl Heptyl Ketone (5-Methyl-2-octanone) Neurotoxicity: Contribution-of 5Nonanone’

Author:

JOHN L. ‘DONOGHUE,* WALTER J. KRASAVAGE, GEORGE D. DIVINCENZO, AND DONALD A. ZIEGLER

Year:

1982

Bibliographic source:

TOXlCOLOGY AND APPLIED PHARMACOLOGY 62,307-316 (1982)

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:

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

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Nonan-2-one

EC Number:

212-480-0

EC Name:

Nonan-2-one

Cas Number:

821-55-6

IUPAC Name:

nonan-2-one

Constituent 2

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 (est)
- Impurities (identity and concentrations): 27.7 %

Test animals

Species:

rat

Strain:

other: COBS, CD(SD)BR

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):
- Humidity (%):
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light):

IN-LIFE DATES: From: To: No data available.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

not specified

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

3 Weeks

Frequency of treatment:

5 days per week

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 1000, 2000 and 4000 mg/kg
Basis:

No. of animals per sex per dose:

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

It was a range finding study.

Positive control:

No data available.

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: No data available.

DETAILED CLINICAL OBSERVATIONS: Yes - Time schedule: Twice daily

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

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes ,
Time schedule: 0, 3,7,14 and 21day of treatment.
- 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 , the rats were anesthetized with carbon dioxide, bled for hematologic determinations
- Parameters checked in table [No.?] were examined.- Blood samples were analyzed for hemoglobin concentration, haematocrits, and total and relative white blood cell counts by standard methods.

CLINICAL CHEMISTRY: Yes, the rats were anesthetized with carbon dioxide, bled for clinical chemistry determinations.
- Parameters checked in table [No.?] were examined.- Serum clinical chemistries
including glutamic-oxaloacetic transaminase (SGOT), glutamic-pyruvic transaminase (SGPT), alkaline
phosphatase (AP), and lactic dehydrogenase (LDH) were determined with a Beckman Enzyme Activity
Analyzer System TR (Beckman Instruments, Inc., Fullerton, Calif.). Urea nitrogen and glucose were determined by a Technicon Auto analyzer.

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 , the rats were anesthetized with carbon dioxide, bled for hematologic and clinical chemistry
determinations, and necropsied, HISTOPATHOLOGY: Yes , The following 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: 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, and basal ganglia. Eyes were fixed in a modified Zenker’s (Russell’s) fixative and handled similarly.

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:

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

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Details on results:

Mortality –Mortality was observed at 4000 mg/kg/day.
At 1000 and 2000mg/kg/day no mortality was observed.

Clinical signs- At 4000 mg/kg/day depression and consequent failure to maintain normal pulmonary ventilation and perfusion was obsrved.
Rats receiving 1000 and 2000 mg/kg/day showed no adverse clinical signs .

Body weight and weight gain Body weight gain over 20 days was 42% for control animals, 34% for the 2000 mg/ kg /day group, and 28% for the 1000 mg/kg/day group. The 4000 mg/kg group lost 18% of their body weight over 3 days.

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 available.

Water consumption and compound intake: No data available.

Opthalmoscopic examination No data available.

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 available.

Neurobehaviour: No data available.

Organ weights Both absolute and relative liver and relative kidney weights were statistically higher than control values for test 1000 and 2000 mg/kg/day groups. Mean absolute kidney weights were also increased, but the difference was not statistically significant.

Gross pathology: No data available.

Histopathology: At 4000 mg/kg/day compound-related pathological findings included vascular congestion and/or hemorrhage in major organ systems. The most striking change was observed in the livers of all three rats. Moderate hepatocyte hypertrophy with minimal focal hepatic necrosis was observed in two rats. One rat showed severe hypertrophy. Enlarged hepatocyte impinged on sinusoidal spaces reducing their volume.

At 2000 mg/kg/day hepatocyte hypertrophy was absent in one rat, minor in a second, and moderate in the third.

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

Details on results: No data available.

Effect levels

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: No significant changes were observed in clinical sign, mortality, gross pathology and histopathology.

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

NOAEL was found to be1000mg/kg for Methyl heptyl ketone in Charles River CD, COBS male rats for 3weeks study.

Executive summary:

In repeated dose toxicity study for Methyl heptyl ketone by oral (gavage) at dose concentration of 1000, 2000 and 4000 mg/kg in Charles River CD, COBS male rats for 3weeks.As test compounds produced clinical evidence of depression and prostration; particularly depression and prostration was followed by death at the high dose of 4000 mg/kg. Significant gross or histopathological compound related changes were found at 2000 and 4000 mg/kg dose level. No significant gross or histopathological compound related changes were found at 1000 mg/kg dose level. Therefore NOAEL was found to be 1000 mg/kg for Methyl heptyl ketone by oral (gavage) for subacute study.