Cyclohexanone oxime

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1989

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Similar to guideline with acceptable deviations and limited documentation

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1989

Report date:

1989

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

yes

Remarks:

fewer animals per group, longer exposure period, positive control group

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

IUPAC Name:

cyclohexanone

Test material form:

other: vapour

Details on test material:

- Name of test material (as cited in study report): cyclohexanone
- Molecular formula (if other than submission substance): C6H10O
- Analytical purity: 99.8%

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Simonsen Laboratories, Gilfroy, CA, USA
- Housing: individually
- Diet (ad libitum): standard rat chow (except daily exposure period)
- Water (ad libitum): tap water (except daily exposure period)

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-25
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

whole body

Vehicle:

air

Details on exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: solvent vapour generating system
- Method of holding animals in test chamber: individually in cages
- Source and rate of air: purified
- Method of conditioning air: desired concentrations by mixing with purified air
- Temperature, humidity, pressure in air chamber: 22-25 °C, not stated, 1 inch of water below atmospheric pressure

TEST ATMOSPHERE
- Brief description of analytical method used: Continuous monitoring by infrared gas analyser
- Samples taken from breathing zone: not stated

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Continuous monitoring by infrared gas analyser

Details on mating procedure:

not stated

Duration of treatment / exposure:

16 days (gestation days 5 -20)

Frequency of treatment:

7 h/day

Duration of test:

17 days sacrifice on day 21)

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0, 100, 250 or 500 ppm (408, 1020 or 2040 mg/m3)
Basis:
analytical conc.

Doses / concentrations 2

Remarks:

Doses / Concentrations:
0, 300 or 400 µL/kg
Basis:
actual ingested
via gavage, positive control 2-ethoxyethanol

No. of animals per sex per dose:

10 pregant rats per exposure groups, 15 in control groups (5 each in concurrent controls to 3 test substance concentration groups) and 15 in positive control groups (5 each in concurrent groups to 3 test substance concentration groups)

Control animals:

yes, concurrent vehicle

other: positive control: 2-ethoxyethanol (by gavage)

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: start and end of exposure

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21
- Organs examined: gross pathology, see also ovaries and uterus content

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes

Fetal examinations:

- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: Yes: half per litter
- Fetal body weight, sex: Yes

Statistics:

A t-test statistic for multiple comparisons was used.

Indices:

not calculated

Historical control data:

not stated

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
Slight, not significant reduction in maternal body weight gain (actual and corrected by gravid uterus weight) in all treated groups, significant actual reduction in all positive control groups
grey mottling of lungs in several dams at >= 250 ppm
No effects on implantation or number of corpora lutea (also in positve control groups)

Effect levels (maternal animals)

1

Dose descriptor:

LOAEC

Effect level:

1 020 mg/m³ air

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

NOAEC

Effect level:

408 mg/m³ air

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

3

Dose descriptor:

NOAEC

Effect level:

>= 2 040 mg/m³ air

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No significant increase in the mean percent of rudimentary ribs/ litter was observed in the treated groups.
No significant increase in numbers of external, skeletal or visceral malformations were noted, and no significant differences were evident between the treated and control groups in fetal weight, resorption sites, fetal death or sex ratio.

The positve controls revealed a markedly higher, significant percentage of resorptions and reduced fetal weight. The malformation rate was significantly higher than in controls.

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Under the conditions of this study cyclohexanone was toxic to the dams, but not a developmental toxicant.

Executive summary:

Pregnant Sprague-Dawley rats (10 per exposure groups, 15 (combined) in 3 separate concurrent control groups and 15 (combined) in 3 separate concurrent positive control groups) were exposed to 0, 100, 250 and 500 ppm cyclohexanone (408, 1020 and 2040 mg/m3) on gestation days 5-20 for 7 h/d. Positive controls (3 concurrent groups) were exposed via gavage to 300 or 400 µL/kg 2 -ethoxyethanol. Animals were sacrificied at gestation day 21. The maternal weight gain of the animals of the exposure groups was only slightly lower than in control groups (not significant). Grey mottling of the lung was seen in several of the exposed dams at 250 and 500 ppm. No significant differences between treated and control groups were observed with respect to fetal weight, resorption sites, fetal death or sex ratio, as well as external visceral or skeletal malformations or variations.

The positive controls showed a significantly increased percentage of resorptions and reduced fetal weight. The malformation rate was significantly higher than in controls.

Under the conditions of this study the maternal LOAEC and NOAEC was 250 and 100 ppm (1020 and 408 mg/m3), respectively. The developmental NOAEL was >= 500 ppm in this study (2040 mg/m3).