Cyclohexanone oxime

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1985

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Equivalent to guidellne with limited documentation

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1985

Report date:

1985

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Cyclohexanone oxime

EC Number:

202-874-0

EC Name:

Cyclohexanone oxime

Cas Number:

100-64-1

Molecular formula:

C6H11NO

IUPAC Name:

cyclohexanone oxime

Test material form:

not specified

Details on test material:

- Name of test material (as cited in study report): cyclohexanone oxime
- Analytical purity: 99,5%

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles
River Breeding Laboratories (Kingston, NY, USA)
- Housing: individually

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2
- Humidity (%): 50 +/- 5

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS: with distilled water

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

90 days (main study)
30, 60 days (satellite groups)

Frequency of treatment:

5 days/week

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 0.25, 2.5 or 25 mg/kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

20 (main study)
10 (satellite groups)

Control animals:

yes, concurrent vehicle

Details on study design:

- Post-exposure recovery period in satellite groups: no

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: days -14, 7, 0 (start of exposure), 1, 4, 7 and weekly thereafter

FOOD CONSUMPTION:
- Time schedule for examinations: weekly

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: days -7, 7 and monthly thereafter
- Dose groups that were examined: all

HAEMATOLOGY: Yes
- Time schedule for collection of blood: on morning of necropsy
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes
- How many animals: all
- Parameters: white blood cells (WBC), red blood cells, hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) , mean corpuscular hemoglobin concentration, white cell differential count, platelet count, and reticulocyte count
Osmotic fragilities determined in 5 animals per sex and group

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: on morning of necropsy
- Animals fasted: Yes
- How many animals: all
- Parameters: calcium, chloride, blood urea nitrogen, glucose, total protein, albumin, total bilirubin, serum glutamicoxaloacetic transaminase, creatinine phosphokinase, lactate dehydrogenase, sodium, potassium, phosphorus

URINALYSIS: Yes
- Time schedule for collection of urine: 19 h sample prior to necropsy
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters: volume, sodium, potassium, chloride, pH, protein, glucose, specific gravity, phosphorus, and osmolality

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: daily
- Dose groups that were examined: all
- Battery of functions tested: observational screen

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
Complete necropsy


HISTOPATHOLOGY: Yes
Brain (three levels), eyes with optic nerves, pituitary, cervical spinal cord, major salivary glands, cervical lymph nodes, heart, thymus and mediastinal contents, larynx with thyroid and parathyroid, trachea, lungs, esophagus, stomach, duodenum, ileum, lymph nodes, adrenals, pancreas, liver, spleen, kidneys, bladder, testes with epididymis, prostate, ovaries, uterus, femur with marrow, sternebrae with marrow, and skeletal muscle from proximal hind limb

Other examinations:

Organ weights: brain, lung with trachea, heart, liver, spleen, each kidney, each testis with epididymis, and each ovary. Organ and terminal body weights were used to calculate organ/body weight ratios

Statistics:

Continuous variables: Bartlett's homogeneity of variance, analysis of variance, and Duncan's multiple range test.
If Bartlett's test indicated heterogeneous variance or where data were ranked or suspected to be nonparametric, Kruskall-Wallis nonparametric analysis of variance and Wilcoxan rank sum tests were used.

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

see details on results below

Mortality:

mortality observed, treatment-related

Description (incidence):

see details on results below

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

effects observed, treatment-related

Description (incidence and severity):

see details on results below

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

see details on results below

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

see details on results below

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

see details on results below

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY
Through the first 9 weeks of the study: Highest dose males: persistent red nasal discharge, chromodacryorrhea and swollen conjuntiva (also mid dose), the effects gradually subsided and had disappeared by the end of the study
Females after 2 weeks of exposure: chromodacryorrhea (high dose) and corneal opacity (high and mid dose), which both gradually subsided but persisted at study termination

Three females of the high dose died (additionally on female of low dose group due to dosing accident)

OPHTHALMOSCOPIC EXAMINATION
Corneal opacity (transiently in males of all treated groups, persistent in females at >= 2.5 mg/kg bw /day))

HAEMATOLOGY
Dose-related decreases in erythrocyte counts, haemoglobin, increase in MCV, nucleated erythrocytes, lymphocytes (significant at highest dose in both sexes), increased white blood cell counts (significant at >= 2.5 mg/kg bw/day in males, at highest dose in fermales)
Increase in reticulocyte counts and Howell-Jones bodies, anisocytosis and poikilocytosis (significant in all treated males, at highest dose in females)

ORGAN WEIGHTS
Increased spleen weights in males and kidney weights in females (significant at highest dose)

GROSS PATHOLOGY
Splenomegaly in high dose males

HISTOPATHOLOGY: NON-NEOPLASTIC
Spleen: increased haemosiderin pigmentation, extramedullary haematopoesis; increased erythropoesis also in bone marow, all treated males

Effect levels

1

Dose descriptor:

LOAEL

Remarks:

90-days study

Effect level:

0.25 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: Haematotoxicity, extramedullary erythropesis in spleen, increased erythropoesis in bone marrow

2

Dose descriptor:

LOAEL

Remarks:

60-days study

Effect level:

25 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: Haematotoxicity, increased spleen weight

3

Dose descriptor:

NOAEL

Remarks:

60-days study

Effect level:

2.5 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

4

Dose descriptor:

LOAEL

Remarks:

30-days study

Effect level:

25 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Haematotoxicity, increased spleen weight

5

Dose descriptor:

NOAEL

Remarks:

30-days study

Effect level:

2.5 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Similar effects were oberved in the satellite groups with 30 or 60 days of exposure, but to a lesser extent. However, the increase in spleen weight was also significant in the male animals of the highest dose group; significant haematological alterations were restricted to the highest dose group. Therefore the LOAEL and NOAEL of the 30- and 60 -days studies are 25 and 2.5 mg/kg bw/day, respectively.

Applicant's summary and conclusion

Conclusions:

Under the conditions of this study the test substance was haematotoxic at all dose levels, especially in males (LOAEL 0.25 mg/kg bw/day).

Executive summary:

Groups of F-344 rats (20 per sex per dose) were treated by oral gavage with the test substance for 5 days/w for 90 days at doses of 0, 0.25, 2.5 or 25 mg/kg body weight. Satellite groups with 10 animals per sex and dose were exposed for 30 and 60 days. The 30-days study revealed increased spleen weights and haematotoxicity at the highest dose, with a NOAEL of 2.5 mg/kg bw/day. In the main study, there were no significant effects on either body weight or food consumption; mortality occurred at the highest dose (3 female rats). In males, treatment-related clinical effects were observed (red nasal discharge, highest dose only; chromodacryorrhea and swollen conjunctiva (2.5 mg/kg bw/day and above), and corneal opacity (all doses)). These effects gradually subsided and disappeared by the end of the study. In females, clinical signs included chromodacryorrhea (high dose) and corneal opacity (high and mid dose), both of which gradually subsided but persisted at study termination. There was a dose-related decrease in erythrocytes, hemoglobin and hematocrit, accompanied by an increase in circulating reticulocytes and nucleated erythrocytes, the appearance of Howell-Jones bodies, anisocytosis and poikilocytosis. This was confirmed by the observation of haemosiderose, extramedullary erythropoesis in all exposed males and splenomegaly at the highest dose. According to the authors, all observed effects are a compensatory increase in erythropoesis following erythrocyte destruction, were considered "to be not severe and recovery could be expected". No other organs or tissues were adversely affected, including reproductive organs.

Based on dose-related haematotoxic effects, observable at all dose levels, the LOAEL of this 90-days study is 0.25 mg/kg bw/day and a NOAEL could not be determined.