Cyclopentanone

Carcinogenicity

Description of key information

No carcinogenic data is available for cyclopentanone.

Cyclohexanone was negative in two carcinogenic studies performed in rats and mice by oral route. Therefore, by analogy, cyclopentanone
should not induce carcinogenic effects.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Qualifier:

no guideline followed

Principles of method if other than guideline:

Carcinogenicity studies

GLP compliance:

not specified

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS:
- Age at study initiation: 7-8 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: 4 to a cage
- Diet: Wayne Sterilizable Lab Meal, ad libitum
- Water: data not available
- Acclimation period: data not available

ENVIRONMENTAL CONDITIONS:
- Temperature (°C): 22-24 °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 exposure:

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

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

two years (= 104 weeks)

Frequency of treatment:

daily

Remarks:

Doses / Concentrations:
3300 ppm (500 mg / kg bw) and 6500 ppm (1000 mg / kg bw)
Basis:
nominal in water

No. of animals per sex per dose:

52 males and 52 females per group

Control animals:

yes, concurrent vehicle

Details on study design:

Post-exposure period: Animals were sacrified 3 weeks after the end of cyclohexanone exposure

Positive control:

no

Observations and examinations performed and frequency:

Observations and clinical examinations performed and frequency:
- Cage side observations: Yes
> Time schedule: twice daily (no other information available)
- Detailed clinical observations: No data
- Body weight: Yes
> Time schedule for examinations: once a week for the first 4 months, then once every 2 weeks for 4 months, then once a month
- Water consumption and compound intake: No data
- Ophtalmoscopic examination: No data
- Haematology: No data
- Clinical chemistry: No data
- Urinalysis: No data
- Neurobehavioural examination: No data

Sacrifice and pathology:

- Gross pathology: No data
- Histopathology: Yes: the following were fixed in Formalin, and slides were prepared and stained: brain, pituitary gland, lymph nodes, spleen, thyroid gland, parathyroid glands, salivary glands, lung, trachea, heart, diaphragm, esophagus, stomach, duodenum, jejunum-ileum, large intestine, pancreas, kidneys, adrenal glands, liver, skin, gonads, urinary bladder, prostate, uterus, mammary gland, femur with marrow, and any lesions or tissue masses.

Statistics:

Statistical methods used include life-table methods of Cox and Tarone

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

no effects observed

Details on results:

- Clinical signs and mortality: the effects of both exposure concentration on survival were not severe: at 6500 ppm, more than 85% of both male and female rats were alive at week 90, and 70% were alive at termination of the study (104 weeks). Survival of the 0.5 MTD-exposure groups was little different from the controls.

- Body weight and weight gain: At 6500 ppm (maximum tolerated dose = MTD), both male and female rats showed a considerably smaller weight gain throughout the experiment by comparison with the control rats. Rats exposed to 3300 ppm (0.5 MTD) failed also to reach the weight of the untreated animals, although they gained more than the MTD-exposed rats.

- Histopathology: neoplastic: Many neoplasms were found in the cyclohexanone-treated rats, but few of these differed in incidence from the untreated controls. Those that did included neoplasms of the mammary gland and stromal polyps of the uterus in females, which were fewer in the MTD-treated group than in the controls. The single tumor type that appeared at a significant higher incidence in the treated than untreated groups was adenoma
of the adrenal cortex in males. In the 0.5 MTD-treated group 7 of 52 rats had this neoplasm, compared with 1 o 52 controls (P = 0.03), but only 1 of 51 MTD-treated male rat had this neoplasm. Among historical controls adrenocortical adenomas had an incidence of 1% in male F344 rats. The
incidence of neoplasms of the liver, hepatocellular carcinomas and neoplastic nodules, did not differ significantly between cyclohexanone-treated
rats and untreated controls.

Relevance of carcinogenic effects / potential:

The patterns of survival and of the weight gain in the rats given 2 doses of cyclohexanone indicate that an MTD was administrated and that failure to
find significant increases in the incidence of neoplasms is not due to administration of doses too small to elicit an effect.
In male rats of the lower dose group (3300 ppm cyclohexanone in drinking water), there was a statistically significant increase in adenomas of the adrenal cortex, but there was no such increase in the group given a higher dose. The number of male rats with this lesion was small, 7 of 52 animals (13%). In historical surveys of the incidence of adrenocortical neoplasms in male F344 rats, the incidence was approximately 1%.
In the absence of a dose response, it is doubtful that this single observation of increased incidence of a benign neoplasm is indicative of a carcinogenic effect of cyclohexanone in F344 rats

Dose descriptor:

LOAEL

Effect level:

3 300 ppm

Sex:

male/female

Basis for effect level:

other: Body weight

Remarks on result:

other:

Remarks:

No NOAEL can be identifed because the body weight reduction has been noted at the two tested doses.

Dose descriptor:

NOAEL

Effect level:

> 6 600 ppm

Sex:

male/female

Basis for effect level:

other: Histopathology

Remarks on result:

other:

Remarks:

The NOAEL for carcinogenic effect is higher than 6600 ppm. No neoplastic lesion attributed to the substance was observed. No dose-related and comparable to historical controls.

Conclusions:

Negative. No carcinogenic effect.

Executive summary:

Rats of both sexes (52 males and 52 females per group) were exposed by drinking water to 3300 ppm (508 mg/kg bw) or 6500 ppm (1000 mg/kg bw) for 104 weeks. The effects of both exposure concentration on survival were not severe since at 6500 ppm, 70% of the rats were alive at termination of the study and survival of the 3300 ppm exposure groups was little different from the control group. Histopathological examinations permitted to the authors to conclude that there were non-neoplastic lesions in the rats that differed significantly in incidence between exposed and control animals that could be attributed to the exposure to cyclohexanone.

Reference 2

Endpoint:

carcinogenicity: 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 well described. The cyclohexanone purity was known and confirmed by analysis. The GLP were not mentioned.

Qualifier:

no guideline followed

Principles of method if other than guideline:

Carcinogenic studies

GLP compliance:

not specified

Species:

mouse

Strain:

B6C3F1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS:
- Age at study initiation: 7-8 weeks old
- Weight at study initiation: the weight of the male mice averaged 23 g (20-26 g), that of the female mice 20 g (17-23 g)
- Fasting period before study: data not available
- Housing: 4 to a cage
- Diet: Wayne Sterilizable Lab Meal, ad libitum
- Water: data not available
- Acclimation period: data not available

ENVIRONMENTAL CONDITIONS:
- Temperature (°C): 22-24 °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 exposure:

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

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

two years (= 104 weeks)

Frequency of treatment:

/

Post exposure period:

Animals were sacrified 3 weeks after the end of cyclohexanone exposure

Remarks:

Doses / Concentrations:
6500 ppm (1625 mg/kg bw), 13000 ppm (3250 mg/kg bw), 25000 ppm (6250 mg/kg bw)
Basis:
nominal in water

No. of animals per sex per dose:

50 to 52 B6C3F1 mice, except the highest dose groups of male and female mice, which numbered 47 and 41 respectively.

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: based on a preliminary sub-chronic study, the MTD and the 0.5 MTD (maximum tolerated dose) were chosen.

Positive control:

no

Observations and examinations performed and frequency:

- Cage side observations: Yes
> Time schedule: twice daily (no other information available)
- Detailed clinical observations: No data
- Body weight: Yes
> Time schedule for examinations: once a week for the first 4 months, then once every 2 weeks for 4 months, then once a month
- Water consumption and compound intake: No data
- Ophtalmoscopic examination: No data
- Haematology: No data
- Clinical chemistry: No data
- Urinalysis: No data
- Neurobehavioural examination: No data

Sacrifice and pathology:

- Gross pathology: No data
- Histopathology: Yes: the following were fixed in Formalin, and slides were prepared and stained: brain, pituitary gland, lymph nodes, spleen, thyroid gland, parathyroid glands, salivary glands, lung, trachea, heart, diaphragm, esophagus, stomach, gallbladder, duodenum, jejunum-ileum, large intestine, pancreas, kidneys, adrenal glands, liver, skin, gonads, urinary bladder, prostate, uterus, mammary gland, femur with marrow, and any lesions or tissue masses

Statistics:

Statistical methods used include life-table methods of Cox and Tarone.

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Histopathological findings: neoplastic:

effects observed, treatment-related

Details on results:

- Clinical signs and mortality: Survival of mice of both sexes exposed to 6500 ppm cyclohexanone was little different from the controls and at the 13000 ppm dose, 80% of male mice survived at week 90. At 25000 ppm, only half of the female mice survived for 50 weeks and fewer than 20% were alive at 75 weeks. At 13000 ppm, about half female mice survived at 75 weeks and only 40% at 90 weeks.

- Body weight and weight gain: Female mice exposed to 6500 ppm of cyclohexanone in water showed no significant difference in weight from controls throughout the 2-year study. Female mice receiving 13000 ppm cyclohexanone had only a slight weight depression. Male mice exposed to 13000 ppm cyclohexanone and female mice exposed to 25000 ppm cyclohexanone had average weights 15-20% lower than those of controls during most of the study.

- Histopathology: neoplastic:
Proliferative lesions of the liver were observed in male mice. Combined benign and malignant hepatocellular neoplasms occurred as follows: control 16/52 (31%), 6500 ppm 25/51 (49%), and 13000 ppm 13/46 (28%). This response observed only in male mice exposed to cyclohexanone low dose (6500 ppm) and without a dose-related trend for these tumor incidences, did not suggest a carcinogenic effect.

There was a negative trend for combined alveolar-bronchiolar adenomas and carcinomas of the lung of male mice with the result as follows: control 13/52 (25%), 6500 ppm 7/51 (14%), and 13000 ppm 3/47 (6%)
Malignant lymphoma were observed only in the female mice exposed to 6500 ppm cyclohexanone and without a dose-related trend: control 8/52 (15%); 6500 ppm 17/50 (34%); 13000 ppm 4/50 (8%); and 25000 ppm 0/41 (0%).
Lymphoid hyperplasia, lymphocytic inflammatory infiltrates, and/or malignant lymphoma were common to most cyclohexanone-treated and control female mice in this study. Lymphoid hyperplasia or lymphocytic infiltrates were common in lymph nodes, spleen, salivary gland, kidneys, pancreas, lungs, and meninges of the brain and spinal cord. These changes often involved more than a single organ system. No cause for these lymphoid hyperplasias and infiltrates was found histologically.

Relevance of carcinogenic effects / potential:

It can be concluded that an increase only at the lower dose level (6500 ppm) in female and in male of the already considerable incidence of lymphomas or hepatocellular neoplasms in these animals (lymphoma: female control 8/52; hepatocellular neoplasms: male control 16/52), was not suggestive of a carcinogenic effect of cyclohexanone in B6C3F1 mice.

Dose descriptor:

NOAEL

Effect level:

> 25 000 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Histopathology

Remarks on result:

other:

Remarks:

The NOAEL for carcinogenic effect is higher than 25 000 ppm (the higher tested dose). No neoplastic lesion attributed to the substance was noted. Not dose-related.

Conclusions:

Negative. No neoplastic lesion attributed to the substance was noted. No dose related.

Executive summary:

Groups of B6C3F1 mice (50-52 animals per group, excepted in the high dose group, 41-47) were exposed to 6500 ppm (1000 mg/kg bw), 13000 ppm (3250 mg/kg bw) or 25000 ppm (6250 mg/kg bw) for 104 weeks to detect carcinogenic effect in both sexes. The highest dose was very toxic since animals died during the 13-week exposure. Female mice exposed to 6500 ppm of cyclohexanone showed no significant difference in weight from controls throughout the 2-year study. Those receiving 13000 ppm cyclohexanone had only a slight weight depression. However, male mice exposed to 13000 ppm cyclohexanone and female mice exposed to 25000 ppm cyclohexanone had average weight 15-20% lower than those of controls almost all along the study. Survival of mice of both sexes exposed to 6500 ppm cyclohexanone was little different from the control group, and at 13000 ppm, 80% of male mice survived at week 90. At 25000 ppm, only 20% of the female mice survived for 75 weeks. At 13000 ppm, only 40% female mice survived at 90 weeks. Proliferative lesions of the liver (benign and malignant hepatocellular neoplasms) were observed in male mice. This response observed only in male mice exposed to cyclohexanone low dose (6500 ppm) and without a dose-related trend for these tumor incidences, did not suggest a carcinogenic effect. In the same way, malignant lymphoma were observed only in the female mice exposed to 6500 ppm cyclohexanone and without a dose-related trend.

Reference 3

Endpoint:

carcinogenicity: oral

Type of information:

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

Justification for type of information:

See attached document fo read-across justification.

Species:

mouse

Strain:

B6C3F1

Sex:

male/female

Route of administration:

oral: drinking water

Dose descriptor:

NOAEL

Effect level:

> 25 000 ppm

Sex:

male/female

Basis for effect level:

histopathology: neoplastic

Remarks on result:

other: The NOAEL for carcinogenic effect is higher than 25000 ppm (higher tested dose). No neoplastic lesion attributed to the substance was noted. Not dose-related.

Remarks:

Data on an analogue (cyclohexanone)

Executive summary:

Read accross with Cyclohexanonewas used for carcinogenicity.

Summary of the study by oral route:

Groups of B6C3F1 mice (50-52 animals per group, excepted in the high dose group, 41-47) were exposed to 6500 ppm (1000 mg/kg bw), 13000 ppm (3250 mg/kg bw) or 25000 ppm (6250 mg/kg bw) for 104 weeks to detect carcinogenic effect in both sexes. The highest dose was very toxic since animals died during the 13-week exposure. Female mice exposed to 6500 ppm of cyclohexanone showed no significant difference in weight from controls throughout the 2-year study. Those receiving 13000 ppm cyclohexanone had only a slight weight depression. However, male mice exposed to 13000 ppm cyclohexanone and female mice exposed to 25000 ppm cyclohexanone had average weight 15-20% lower than those of controls almost all along the study. Survival of mice of both sexes exposed to 6500 ppm cyclohexanone was little different from the control group, and at 13000 ppm, 80% of male mice survived at week 90. At 25000 ppm, only 20% of the female mice survived for 75 weeks. At 13000 ppm, only 40% female mice survived at 90 weeks. Proliferative lesions of the liver (benign and malignant hepatocellular neoplasms) were observed in male mice. This response observed only in male mice exposed to cyclohexanone low dose (6500 ppm) and without a dose-related trend for these tumor incidences, did not suggest a carcinogenic effect. In the same way, malignant lymphoma were observed only in the female mice exposed to 6500 ppm cyclohexanone and without a dose-related trend.

Based on this study and by analogy cyclopentanone is not considered to be carcinogenic.

Reference 4

Endpoint:

carcinogenicity: oral

Type of information:

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

Justification for type of information:

See attached document for justification of the read-across.

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Route of administration:

oral: drinking water

Dose descriptor:

LOAEL

Effect level:

3 300 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

Remarks on result:

other: Body weight was reduced at the two tested doses.

Remarks:

data on an analogue (cyclohexanone).

Dose descriptor:

NOAEL

Effect level:

> 6 600 ppm

Sex:

male/female

Basis for effect level:

histopathology: neoplastic

Remarks on result:

other: No neoplastic lesion attibuted to the tested substance has been identifed. No dose-related and comparable to historical controls.

Remarks:

Data on a analogue (cyclohexanone).

Executive summary:

Read accross with Cyclohexanone was used for carcinogenicity.

Summary of the study by oral route:

Rats of both sexes (52 males and 52 females per group) were exposed by drinking water to 3300 ppm (508 mg/kg bw) or 6500 ppm (1000 mg/kg bw) of cyclohexanone for 104 weeks. The effects of both exposure concentration on survival were not severe since at 6500 ppm, 70% of the rats were alive at termination of the study and survival of the 3300 ppm exposure groups was little different from the control group. Histopathological examinations permitted to the authors to conclude that there were non-neoplastic lesions in the rats that differed significantly in incidence between exposed and control animals that could be attributed to the exposure to cyclohexanone.

Based on this study and by analogy with cyclohexanone, cyclopentanone is not considered to induce carcinogenic effect.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Justification for classification or non-classification

Based on two studies, cyclohexanone induces no carcinogenic effects in rats and mice after oral long term exposure. Therefore, by analogy, cyclopentanone is not considered as carcinogenic.

 

Additional information

Read accross with Cyclohexanone was used for Carcinogenicity.

Summary of the selected key study:

In a study (Lijinsky, 1986) with reliability 2 according to Klimisch rating, rats of both sexes (52 males and 52 females per group) were exposed by drinking water to 3300 ppm (508 mg/kg bw) or 6500 ppm (1000 mg/kg bw) to cyclohexanone for 104 weeks. The effects of both exposure concentration on survival were not severe since at 6500 ppm, 70% of the rats were alive at termination of the study and survival of the 3300 ppm exposure groups was little different from the control group. Histopathological examinations permitted to the authors to conclude that there were non-neoplastic lesions in the rats that differed significantly in incidence between exposed and control animals that could be attributed to the exposure to cyclohexanone.

In an another study (Lijinsky, 1986) with reliability 2 according to Klimisch rating, groups of B6C3F1 mice (50-52 animals per group, excepted in the high dose group, 41-47) were exposed to 6500 ppm (1000 mg/kg bw), 13000 ppm (3250 mg/kg bw) or 25000ppm (6250 mg/kg bw) of cyclohexanone for 104 weeks to detect carcinogenic effect in both sexes. The highest dose was very toxic since animals died during the 13-week exposure. Female mice exposed to 6500 ppm of cyclohexanone showed no significant difference in weight from controls throughout the 2-year study. Those receiving 13000 ppm cyclohexanone had only a slight weight depression. However, male mice exposed to 13000 ppm cyclohexanone and female mice exposed to 25000 ppm cyclohexanone had average weight 15-20% lower than those of controls almost all along the study. Survival of mice of both sexes exposed to 6500 ppm cyclohexanone was little different from the control group, and at 13000 ppm, 80% of male mice survived at week 90. At 25000 ppm, only 20% of the female mice survived for 75 weeks. At 13000 ppm, only 40% female mice survived at 90 weeks. Proliferative lesions of the liver (benign and malignant hepatocellular neoplasms) were observed in male mice. This response observed only in male mice exposed to cyclohexanone low dose (6500 ppm) and without a dose-related trend for these tumor incidences, did not suggest a carcinogenic effect.

In the same way, malignant lymphomas were observed only in the female mice exposed to 6500 ppm cyclohexanone and without a dose-related trend.