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Repeated dose toxicity: oral

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Administrative data

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

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

Constituent 1
Chemical structure
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
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 %
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, 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
Doses / concentrations
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.

Examinations

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%.

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
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.

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 adverse effect on survival, body weight and body weight gain, food consumption, haematology, clinical chemistry, organ weight, gross pathology and histopathology.

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

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.

Applicant's summary and conclusion

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.