4-methylpentan-2-one

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1986

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Well documented. According to acceptable guidelines.

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1986

Report date:

1986

Reference 2

Reference Type:

secondary source

Title:

TOXICOLOGICAL REVIEW OF METHYL ISOBUTYL KETONE (CAS No. 108-10-1). In Support of Summary Information on the Integrated Risk Information System (IRIS)

Author:

EPA (U.S. Environmental Protection Agency)

Year:

2003

Bibliographic source:

http://www.epa.gov/iris/toxreviews/0173tr.pdf

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

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

Deviations:

yes

Remarks:

- humidity was >70% in 2 instances

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

4-methylpentan-2-one

EC Number:

203-550-1

EC Name:

4-methylpentan-2-one

Cas Number:

108-10-1

Molecular formula:

C6H12O

IUPAC Name:

4-methylpentan-2-one

Test material form:

other: liquid

Details on test material:

- Name of test material (as cited in study report): Methyl isobutyl ketone
- Lot/batch No.: A13A
- Stability under test conditions: Stable for at least 12 days at the concentrations tested
- Storage condition of test material: Stored in original container at room temperature and ambient humidity

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

7 days/week

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 50, 250, or 1000 mg/kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

30/sex/dose

Control animals:

yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:

Non-fasted body weights recorded on Test Day 1 and weekly thereafter.

Individual food consumption data were collected on a weekly basis.

Moribundity/mortality checks were performed twice daily (morning and afternoon).

Test animals were examined once/week for clinical signs of toxicity.

Ophthalmology examinations were performed during the quarantine period and in Test Week 13.

Hematology, clinical chemistry, and urinalysis were performed on 10 rats/sex/dose during Test Week 7 (interim clinical pathology) and on Test Week 14.

Sacrifice and pathology:

Necropsy evaluations were performed on 10 rats/sex/dose during Test Week 7 (interim necropsy) and on all remaining animals on Test Week 14.

Histological tissue examinations were conducted on the control and high-dose animals.

Statistics:

Statistics: one-way ANOVA with Dunnett's t-test.

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):

effects observed, treatment-related

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

no effects observed

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

effects observed, treatment-related

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY
Reversible lethargy was observed in rats of both sexes receiving 1000 mg/kg-day (but not at lower dose levels) for a few hours following dosing and reportedly decreased in incidence and severity during the study.
Two female rats administered 1000 mg/kg bw/d died during the study (one during Test Week 6 and the other during Test Week 13. These animals demonstrated mottled lungs at gross necropsy. In addition, the liver and kidneys were dark red for one of the animals). A control female also was found dead on Test Week 5.

BODY WEIGHT AND WEIGHT GAIN
Males in the high-dose group showed a slight (9%) but significantly decreased mean body weight gain as compared to controls during the last 2 weeks of exposure, whereas female body weight gain was significantly increased during 5 of the last 6 weeks of exposure.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Both male and female food consumption was significantly increased during the second half of the exposure period.

OPHTHALMOSCOPIC EXAMINATION
No ophthalmic lesions were noted.

HAEMATOLOGY
The only potentially exposure-related hematological effects observed were slight but statistically significant increases in hemoglobin (+6%) and hematocrit (+8%) at terminal sacrifice in females administered 1000 mg/kg-day and a 15% decrease in lymphocyte count in high-dose males at terminal sacrifice.

CLINICAL CHEMISTRY
250 mg/kg-day: increased (+39%) serum glutamic-pyruvic transaminase (SGPT) in female rats at the terminal sacrifice.
1000 mg/kg-day: increased SGPT (+73%, interim; +34%, terminal) in females as compared to controls, increased serum alkaline phosphatase (+84%, interim) in females, increased serum cholesterol in males (+30%, interim) and females (+59%, interim; +65%, final), decreased albumin/globulin ratio in males (-16%, interim), and minimally increased serum total protein in females (+9%, interim; +10%, terminal), increased blood-urea-nitrogen (BUN) in males (+37%, interim), increased serum potassium in males (+34%, terminal), decreased serum glucose in males (-27%, terminal), and a reported increase in urinary protein and ketones in males and females at terminal sacrifice (summary data were not provided).

URINALYSIS
Increased quantities of urinary protein and ketones and elevated specific gravity were generally seen for high-dose and, to a lesser extent, mid-dose animals of both sexes at both the interim and teminal kill periods. An elevated number of epithelial cells also occurred for high- and mid-dose males at the interim kills.

NEUROBEHAVIOUR
No data

ORGAN WEIGHTS
- 250 mg/kg bw/d
Liver: increased terminal absolute (+34%, males; +39%, females) and relative (+42%, males; +38%, females) weights
Kidneys: increased terminal absolute or relative kidney weights in males and females, ranging from 6 to 12% over controls

- 1000 mg/kg bw/d
Liver: increased terminal absolute (+34%, males; +39%, females) and relative (+42%, males; +38%, females) liver weights,
Kidneys: increased terminal absolute and relative kidney weights (from 25 to 34% in males and from 20 to 22% in females) as compared to controls
Adrenals: increased relative weights in male (+29%) and female (+11%) rats
Testis: slightly increased relative weights (+9%) in males

GROSS PATHOLOGY
Gross necropsy failed to suggest treatment-related lesions.

HISTOPATHOLOGY: NON-NEOPLASTIC
1000mg/kg bw/d: increased incidence of male rats with mild nephropathy (multifocally distributed swollen or hyperchromatic and flattened renal cortical tubular epithelial cells) at 1000 mg/kg-day (16/20) as compared to controls (4/20) but no increase in such lesions in females.

Effect levels

1

Dose descriptor:

NOEL

Effect level:

50 mg/kg bw/day (actual dose received)

Sex:

male/female

Basis for effect level:

other: No treatment-related effects of any kind

2

Dose descriptor:

NOAEL

Effect level:

250 mg/kg bw/day (actual dose received)

Sex:

male/female

Basis for effect level:

other: Increases in relative kidney weights for male and females rats administered MIBK at doses of 250 mg/kg bw/d but without histological lesions

3

Dose descriptor:

LOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Sex:

male/female

Basis for effect level:

other: Based on kidney changes, hepatomegaly and alterations in clinical chemistry and urinalysis parameters

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The NOAEL was estimated to be 250 mg/kg bw/d, based on increases in relative kidney weights for male and female rats administered MIBK at doses of 250 mg/kg bw/d but without histological lesions. Effects at higher doses included kidney changes, hepatomegaly and alterations in clinical chemistry and urinalysis parameters. No treatment-related effects of any kind were observed at 50 mg/kg-day.

Executive summary:

Groups of 30 male and 30 female Sprague-Dawley rats were administered MIBK by gavage in corn oil at daily dose levels of 0 (vehicle control), 50, 250, or 1000 mg/kg-day for 13 consecutive weeks and evaluated for exposure-related changes in body weight, food consumption, mortality, clinical signs, ophthalmological parameters, and terminal organ weights (heart, liver, spleen, brain, kidney, gonads, adrenals, thyroid, and parathyroid). The following evaluations were conducted in rats from each exposure level at interim (week 7) and final sacrifices: hematology, clinical chemistry, urinalysis, and comprehensive gross pathology. All tissue samples collected during gross necropsy in high-dose and control rats were evaluated for histopathologies, and kidney samples were also histologically evaluated in mid-dose rats.

Reversible lethargy was observed in rats of both sexes receiving 1000 mg/kg-day (but not at lower dose levels) for a few hours following dosing and reportedly decreased in incidence and severity during the study. Males in the high-dose group showed a slight (9%) but significantly decreased mean body weight gain as compared to controls during the last 2 weeks of exposure, whereas female body weight gain was significantly increased during 5 of the last 6 weeks of exposure. Both male and female food consumption was significantly increased during the second half of the exposure period. The only potentially exposure-related hematological effects observed were slight but statistically significant increases in hemoglobin (+6%) and hematocrit (+8%) at terminal sacrifice in females administered 1000 mg/kg-day and a 15% decrease in lymphocyte count in high-dose males at terminal sacrifice.

The lowest hepatic effect level that was observed in the oral exposure studies was 250 mg/kg-day for increased (+39%) serum glutamic-pyruvic transaminase (SGPT) in female rats at the terminal sacrifice. The following changes suggestive of adverse liver effects were observed at 1000 mg/kg-day at either interim and/or final sacrifice: increased SGPT (+73%, interim; +34%, terminal) in females as compared to controls, increased serum alkaline phosphatase (+84%, interim) in females, increased serum cholesterol in males (+30%, interim) and females (+59%, interim; +65%, final), increased terminal absolute (+34%, males; +39%, females) and relative (+42%, males; +38%, females) liver weights, decreased albumin/globulin ratio in males (-16%, interim), and minimally increased serum total protein in females (+9%, interim; +10%, terminal).

The only renal effect occurring at 250 mg/kg-day was increased terminal absolute or relative kidney weights in males and females, ranging from 6 to 12% over controls. The following changes suggestive of adverse kidney effects were observed at 1000 mg/kg-day: increased terminal absolute and relative kidney weights (from 25 to 34% in males and from 20 to 22% in females) as compared to controls, increased blood-urea-nitrogen (BUN) in males (+37%, interim), increased serum potassium in males (+34%, terminal), decreased serum glucose in males (-27%, terminal), and a reported increase in urinary protein and ketones in males and females at terminal sacrifice (summary data were not provided). Histological examination of kidney tissues revealed an increased incidence of male rats with mild nephropathy (multifocally distributed swollen or hyperchromatic and flattened renal cortical tubular epithelial cells) at 1000 mg/kg-day (16/20) as compared to controls (4/20) but no increase in such lesions in females.

Significantly increased relative adrenal weights in male (+29%) and female (+11%) rats and slightly increased relative testis weights (+9%) in males were also observed at 1000 mg/kgday. No exposure-related histopathologic lesions were evident in the liver or adrenal glands nor in any other tissue that was examined, aside from the kidney. The NOAEL was estimated to be 250 mg/kg bw/d, based on increases in relative kidney weights for male and female rats administered MIBK at doses of 250 mg/kg bw/d but without histological lesions. Effects at higher doses included kidney changes, hepatomegaly and alterations in clinical chemistry and urinalysis parameters. No treatment-related effects of any kind were observed at 50 mg/kg-day.