Cyclopentanone

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The study was well conducted. The protocol and the results were detailed. The cyclohexanone purity was known and confirmed by analysis. The GLP were not mentioned.

Data source

Reference

Reference Type:

publication

Title:

Chronic toxicity study of cyclohexanone in rats and mice.

Author:

Lijinsky W, Kovatch RM

Year:

1986

Bibliographic source:

J Nat Cancer Inst, 77, 941-949

Materials and methods

Principles of method if other than guideline:

Sub-chronic toxicity study in drinking water

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Cyclohexanone

EC Number:

203-631-1

EC Name:

Cyclohexanone

Cas Number:

108-94-1

Molecular formula:

C6H10O

IUPAC Name:

cyclohexanone

Details on test material:

Cyclohexanone (CAS 108-94-1)
- Details on test material:
* Molecular formula: C6-H10-O
* Molecular weight: 98.14 g
* Smiles notation: O=C(CCCC1)C1
* Substance type: pure active substance
* Physical state: liquid
* Analytical purity: 96 %
* Impurities: 3 % water, 1% unidentified compounds
* Purity test date: data not available
* Lot/batch No: data not available
* Expiration date of the lot/batch: data not available
* Stability under test conditions: stable
* Storage condition of test material: stored at 5 °C

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

* TEST ANIMALS:
- Source: Animal Production Facility of the NCI-Frederick Cancer Reasearch Facility
- Age at study initiation: 7 to 8 weeks old
- Weight at study initiation: the weight of the male rats averaged 162 g (139-180 g), that of the female rats 126 g (107-143 g)
- Fasting period before study: data not available
- Housing: 5 to a cage
- Diet: Wayne Sterilizable Lab Meal, ad libitum
- Water: data not available

Acclimation period: data not available

* ENVIRONMENTAL CONDITIONS:
- Temperature: 22 to 24 °C
- Air changes: 15 times per hour
- Humidity, photoperiod: data not available

IN-LIFE DATES: data not available

Administration / exposure

Route of administration:

oral: drinking water

Vehicle:

other: acidified water

Details on oral exposure:

* PREPARATION OF DOSING SOLUTIONS: cyclohexanone was dissolved in acidified water (pH 2.5) and stored at 5 °C. The solution was prepared every 2 weeks, stored at 5 °C.

* VEHICLE:
Justification for use and choice of vehicle: water was acidified to suppress bacterial growth

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Analysis of the solution at intervals and after 28 days showed that there was no detectable decomposition during this time. Cyclohexanone was also
completely stable at room temperature for at least 4 days.

Duration of treatment / exposure:

For 25 weeks

Frequency of treatment:

daily

Doses / concentrations

Remarks:

Doses / Concentrations:
190 ppm (29 mg/kg bw), 400 ppm (61 mg/kg bw), 800 ppm (122 mg/kg bw), 1600 ppm (246 mg/kg bw), 3300 ppm (508 mg/kg bw), 4700 ppm (723 mg/kg bw), 6500 ppm (1000 mg/kg bw). The ppm doses would provide approximately mg/kg bw/day doses.
Basis:

No. of animals per sex per dose:

5

Control animals:

yes, concurrent vehicle

Details on study design:

* Dose selection rationale: based on a LD50 at 1.6 g/kg bw
* Rationale for animal assignment: data not available

Positive control:

no

Examinations

Observations and examinations performed and frequency:

* CAGE SIDE OBSERVATIONS: No data
* DETAILED CLINICAL OBSERVATIONS: No data
* BODY WEIGHT: Yes
Time schedule for examinations: once a week and at the end of the study
* WATER CONSUMPTION AND COMPOUND INTAKE: No data
* OPHTHALMOSCOPIC EXAMINATION: No data
* HAEMATOLOGY: No data
* CLINICAL CHEMISTRY: No data
* URINALYSIS: No data
* NEUROBEHAVIOURAL EXAMINATION: No data

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Other examinations:

no data

Statistics:

no data

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Details on results:

- Clinical signs and mortality: no effects
Up to the termination study at 25 weeks, cyclohexanone did not affect survival, even in the rats exposed to 6500 ppm concentration.
There was moderate chronic respiratory disease in all animals, cyclohexanone-treated and control rats.

- Body weight and weight gain: yes: a depression of body weight gain (10% less than controls) was noted in both male and female rats exposed to
cyclohexanone at 6500 ppm for the 25 weeks exposure.

- Histopathology: non-neoplastic: yes: the only histopathological change observed was a mild degenerative change in the thyroid gland of 2/5 male
rats exposed to 4700 ppm but not seen in other animals.

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

4 700 ppm

Sex:

male/female

Basis for effect level:

other: Depression of body weight gain / 4700 ppm correspond to 723 mg/kg b.w./day.

2

Dose descriptor:

LOAEL

Effect level:

6 500 ppm

Sex:

male/female

Basis for effect level:

other: Depression of body weight gain / 6500 ppm correspond to 1000 mg/kg b.w./day.

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Executive summary:

In a sub-chronic toxicity study (Lijinsky W, 1986) Cyclohexanone (96% purity) was administered to 5 F344 rat/sex/dose in water at dose levels of 0, 190, 400, 800, 1600, 3300, 4700, 6500 ppm (equiv. to ca. 29, 61, 122, 246, 508, 723, 1000 mg/kg bw/day).
Up to the end of the study at 25 weeks, cyclohexanone did not affect survival, even in the rats exposed to 6500 ppm concentration. However, the body weight gain was 10% lower than controls in both male and female rats at the highest dose. It was concluded that in absence of significant histopathologic findings, the MTD was 6500 ppm, dose also considered as the LOAEL in Fisher 344 rats. The NOAEL was 4700 ppm (723 mg/kg bw).