Cyclopentanone

Endpoint summary

Description of key information

Based on the oral chronic toxicity study performed on cyclohexanone (rats) and considered as a key study (Lijinsky W, 1986) a NOAEL of 723 mg/kg b.w./day was identified in rats for cyclopentanone and for body weight decrease.
For inhalation, based on a study performed on cyclohexanone and on rabbits a NOAEC of 773 ppm (3040 mg/m3) was identified for systemic effects (lethargy, distention of the ear veins)

and a NOAEC of 190 ppm (750 mg/m3) for local effects (eye irritation) (Treon, 1943 - considered as a key study)for cyclopentanone.

Several studies both performed on cyclopentanone and cyclohexanone showed that the two substances induce similar effects and that cyclohexanone is more toxic than cyclopentanone (see justification for read-across).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

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.

Principles of method if other than guideline:

Sub-chronic toxicity study in drinking water

GLP compliance:

not specified

Limit test:

no

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

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

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

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

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.

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.

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.

Critical effects observed:

not specified

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).

Reference 2

Endpoint:

sub-chronic toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

see below attached justification for read-across

Reason / purpose for cross-reference:

read-across source

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Route of administration:

oral: drinking water

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

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.

Remarks on result:

other: results on an analogous (cyclohexanone)

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.

Remarks on result:

other: results on an analogous (cyclohexanone)

Critical effects observed:

not specified

Executive summary:

Read accross with Cyclohexanone was used for repeated dose toxicity.

Summary of the study by oral route:

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).

Based on this data and by analogy, Cyclopentanone is not classified for repeated dose toxicity and orale route.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

723 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Reference 1

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.

Qualifier:

no guideline followed

Principles of method if other than guideline:

Subchronic inhalation study

GLP compliance:

no

Limit test:

no

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

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

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

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

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.

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.

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.

Dose descriptor:

NOAEC

Effect level:

773 ppm

Sex:

not specified

Basis for effect level:

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

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.

Critical effects observed:

not specified

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).

 

Reference 2

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

see below attached justification for read-across

Reason / purpose for cross-reference:

read-across source

Species:

rabbit

Route of administration:

inhalation

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

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.

Remarks on result:

other: results on an analogous (cyclohexanone)

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.

Remarks on result:

other: results on an analogous (cyclohexanone)

Dose descriptor:

NOAEC

Effect level:

773 ppm

Sex:

not specified

Basis for effect level:

other: Systemic effects / 773 ppm correspond to 340 mg/m3

Remarks on result:

other: results on an analogous (cyclohexanone)

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

Remarks on result:

other: results on an analogous (cyclohexanone)

Critical effects observed:

not specified

Executive summary:

Read accross with Cyclohexanone was used for repeated dose toxicity.

Summary of the study by inhalation route:

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).

Based on this study and by analogy, Cyclopentanone is not classified for repeated dose toxicity by inhalation.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

3 040 mg/m³

Study duration:

subchronic

Species:

rabbit

System:

other: Systemic effect

Repeated dose toxicity: inhalation - local effects

Link to relevant study records

Reference

Reference 1

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.

Qualifier:

no guideline followed

Principles of method if other than guideline:

Subchronic inhalation study

GLP compliance:

no

Limit test:

no

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

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

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

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

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.

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.

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.

Dose descriptor:

NOAEC

Effect level:

773 ppm

Sex:

not specified

Basis for effect level:

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

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.

Critical effects observed:

not specified

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).

 

Reference 2

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

see below attached justification for read-across

Reason / purpose for cross-reference:

read-across source

Species:

rabbit

Route of administration:

inhalation

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

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.

Remarks on result:

other: results on an analogous (cyclohexanone)

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.

Remarks on result:

other: results on an analogous (cyclohexanone)

Dose descriptor:

NOAEC

Effect level:

773 ppm

Sex:

not specified

Basis for effect level:

other: Systemic effects / 773 ppm correspond to 340 mg/m3

Remarks on result:

other: results on an analogous (cyclohexanone)

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

Remarks on result:

other: results on an analogous (cyclohexanone)

Critical effects observed:

not specified

Executive summary:

Read accross with Cyclohexanone was used for repeated dose toxicity.

Summary of the study by inhalation route:

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).

Based on this study and by analogy, Cyclopentanone is not classified for repeated dose toxicity by inhalation.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

750 mg/m³

Species:

rabbit

Additional information

Read accross with Cyclohexanone was used for repeated dose toxicity.

Summary of the selected key studies by oral and inhalation route:

Oral route:

In a 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 (1000 mg/kg bw), dose also considered as the LOAEL in Fisher 344 rats. The NOAEL was 4700 ppm (723 mg/kg bw) based on body weight gain decrease.

In the same study (Lijinsky 1989) cyclohexanone (96% purity) was administered to 10 B6C3F1 mice/sex/dose in water at dose levels of 400, 2300, 6500,13000,25000,34000,47000ppm (equiv. to 100, 575, 1625, 3250, 6250, 8500,11750 mg/kg bw/day) for 13 weeks. Based on the body weight depression data and on the absence of histopathological findings, the authors considered that the MTD was 25000ppm (6250 mg/kg bw) in female and 13000ppm (3250 mg/kg bw) in male mice. For males a NOAEL of 13000ppm (3250 mg/kg) can be identified based on body weight gain decrease. For females the NOAEL was considered as 25000ppm (6250 mg/kg) based on the same effect.

Inhalation route:

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 and 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 (0.75 mg/L), no depression in body weight gain, no changes in body temperature, no abnormality in the behaviour of the animals and no specific or general toxic effects upon cellular elements of the peripheral blood were noted. Barely demonstrated degenerative changes in the liver and kidney were observed in the rabbits exposed to 0.75 mg/L. 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).

Repeated dose toxicity: inhalation - systemic effects (target organ) neurologic: behaviour

Justification for classification or non-classification

Based on cyclohexanone data:

- NOAEL = 723 mg/kg bw/day in rats for body weight gain decrease after oral route exposure (25 weeks)

- NOAEC = 773 ppm (3040 mg/m3) in rabbits for systemic effects (lethargy, distention of the ear veins) (10 weeks of exposure by inhalation)

- NOAEC = 190 ppm (775 mg/m3) in rabbits for local effects (eye irritation) (10 weeks of exposure by inhalation)

 

Cyclopentanone, by analogy, is not classified for repeated dose toxicity.