Cyclopentanone

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The study was very old and performed before the GLP standard was established. However, the inhalation protocol and the results were well described.

Data source

Reference

Reference Type:

publication

Title:

The physiological response of animals to cyclohexane, mehtylcyclohexane, and certain derivatives of these compounds. II. Inhalation.

Author:

Treon JF, Crutchfield WE, Kitzmiller KV

Year:

1943

Bibliographic source:

Journal of Industrial Hygiene and Toxicology, 25, 323-347

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Subchronic inhalation study

GLP compliance:

no

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:

no data

Test animals

Species:

rabbit

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

TEST ANIMALS:
- Acclimation period: 2 to 6 weeks
- Source, age at study initiation, weight at study initiation, fasting period before study, housing, diet, water: data not available

ENVIRONMENTAL CONDITIONS
- Temperature: 24 °C
- Humidity: controlled not to exceed 45%
- Air changes: 30-60 per hour
- Photoperiod (hrs dark / hrs light): data not available

IN-LIFE DATES: data not available

Administration / exposure

Route of administration:

inhalation

Type of inhalation exposure:

not specified

Vehicle:

other: no data

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
The prolonged inhalation of lower concentration was effected by the use of a battery of nine insulated plywood cages, each having a capacity of 600 litres and equipped with a front glass door. The rate of flow into the cage ranged from 350 to 800 L per minute. The equipment for conditioning the air in these cages has been described by Moore (1941). A special apparatus was used for constant vaporization of liquid with low vapour pressures and slow rates of evaporation such as cyclohexanone.

TEST ATMOSPHERE
The concentrations of cyclohexanone in air were determined colorimetrically by measuring in the air alcoholic extract compound the intensity of the pink colour produced by a reaction of the Zimmerman type, with m-dinitrobenzene.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Period of 10 weeks

Frequency of treatment:

5 days a week, 6 hours daily

Doses / concentrations

Remarks:

Doses / Concentrations:
190 ppm (0.75 mg/L), 309 ppm (1.21 mg/L), 773 ppm (3.04 mg/L), 1414 ppm (5.56 mg/L)
Basis:
no data

No. of animals per sex per dose:

4 per dose group

Control animals:

yes

Details on study design:

Post-exposure period: Observation for 2 months after the end of exposure

Examinations

Observations and examinations performed and frequency:

* CAGE SIDE OBSERVATIONS: No data
* DETAILED CLINICAL OBSERVATIONS: No data
* BODY WEIGHT: Yes
- Time schedule for examinations: daily
* FOOD CONSUMPTION: No data
* WATER CONSUMPTION: No data
* OPHTHALMOSCOPIC EXAMINATION: No data
* HAEMATOLOGY: Yes
- Time schedule for collection of blood: weekly
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: data not available
- Parameters: blood cell analysis (erythrocytes and leucocytes) and
hemoglobin concentration
* CLINICAL CHEMISTRY: No data
* URINALYSIS: Yes
- Time schedule for collection of urine: weekly
- Metabolism cages used for collection of urine: Yes / No / No data
- Animals fasted: Yes / No / No data
- Parameters: urine of rabbits exposed to 190 ppm, 309 ppm and 1414 ppm cyclohexanone were analysed for the excretion of organic and inorganic sulfates using a turbidimetric method. Urine of rabbits exposed to the lowest concentration ( 190 ppm = 0.75 mg/L) were analysed for their glucuronic-acid content using a naphthoresorcinol method.
* NEUROBEHAVIOURAL EXAMINATION: No data
* OTHER: rectal temperature was determined daily

Sacrifice and pathology:

* GROSS PATHOLOGY: Yes
* HISTOPATHOLOGY: Yes

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

Haematological findings:

effects observed, treatment-related

Urinalysis findings:

effects observed, treatment-related

Details on results:

- CLINICAL SIGNS AND MORTALITY:
At the lowest concentration (190 ppm = 0.75 mg/L) no abnormality in the behaviour of the animals was noted but degenerative changes in the liver and kidney were barely
demonstrated. These changes, not significative, were observed only at the lowest concentration and can not be considered as an effect of the test substance.
At the highest concentration (1414 ppm), slight lethargy, distention of the ear veins, salivation and conjunctival irritation manifested by congestion, lacrimation, and secretion of mucus were noted throughout the daily periods of exposure.
A lesser degree of ocular irritation resulted from exposure to the concentrations at 309 ppm and 773 ppm while slight salivation was observed under the latter conditions (773 ppm).
No mortality was observed.

- BODY WEIGHT AND WEIGHT GAIN: The rabbits gained in weight during exposure at the different concentrations.

- HAEMATOLOGY: No specific or general toxic effects upon the cellular elements of the peripheral blood were observed.

- URINALYSIS: The weekly variations in the percentage of inorganic sulfates (in relation to the total urinary sulfates) were normal before and immediately after the termination of exposures. However, some conjugation occurred during exposure to all but the lowest concentration (190 ppm = 0.75 mg/L), the mean value for this period being within normal limits (84.5%).
At this lowest concentration, there was an average daily out-put of 61 mg of glucuronic acid per rabbit during the period before exposure, with an increase to 222 mg per rabbit during exposure, and a decrease to 39 mg per rabbit after exposure had been terminated.

The changes in body temperature of the exposed animals were comparable to those observed in control animals.

Effect levels

1

Dose descriptor:

NOAEC

Effect level:

190 ppm

Sex:

not specified

Basis for effect level:

other: Local effects (ocular irritation) / 190 ppm correspond to 750 mg/m3.

2

Dose descriptor:

LOAEC

Effect level:

309 ppm

Sex:

not specified

Basis for effect level:

other: Local effects (ocular irritation) / 309 ppm correspond to 3040 mg/m3.

3

Dose descriptor:

NOAEC

Effect level:

773 ppm

Sex:

not specified

Basis for effect level:

other: Systemic effects / 773 ppm correspond to 3040 mg/m3

4

Dose descriptor:

LOAEC

Effect level:

1 414 ppm

Sex:

not specified

Basis for effect level:

other: Systemic effects / 1414 ppm correspond to 5560 mg/m3.

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The LOAEL was 309 ppm since only ocular irritation was observed at this concentration.

Executive summary:

In a subchronic inhalation toxicity study (Treon, 1943) cyclohexanone (purity unknown) was administered to rabbits (4/group), by exposure at concentrations of 0.75, 1.21, 3.04, 5.56 mg/L (190, 309, 773 and 1414 ppm) for 6 hours per day,  5 days/week for a total of 10 weeks.
At the lowest concentration (190 ppm), no depression in body weight gain, no changes in body temperature, no abnormality in the behavior of the animals and no specific or general toxic effects upon cellular elements of the peripheral blood were noted. However, barely demonstrated degenerative changes in the liver and kidney were observed in the rabbits exposed to 190 ppm. However, these changes were not significant and were not observed at higher doses. At the highest concentration (1414 ppm), slight lethargy, distention of the ear veins, salivation and conjunctival irritation manifested by congestion, lacrimation, and secretion of mucus were noted throughout the daily periods of exposure. A lesser degree of ocular irritation resulted from exposure to the concentrations at 309 ppm and 773 ppm while slight salivation was observed under the latter conditions (773 ppm). Based on this study, a NOAEC of 773 ppm (3.04 mg/L) can be identified for systemic effects (lethargy, distention of the ear veins) and a NOAEC of 190 ppm (0.75 mg/L) for local effect (eye irritation).