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Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1991
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Remarks:
NTP study. Test method was similar to OECD Guideline 408. GLP study.
Cross-reference
Reason / purpose for cross-reference:
reference to other study
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1990-1991
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
NTP study. Range-finding for the 90 days repeated dose toxicity study (test method similar to OECD Guideline 408).
Reason / purpose for cross-reference:
reference to other study
Principles of method if other than guideline:
A 14 days range finding study was performed prior to 90 days repeated dose toxicity test. Groups of five male and five female rats were given drinking water containing 0, 106, 312, 625, 1,250, or 2,500 ppm methyl ethyl ketoxime. Clinical findings and individual body weights were recorded on days 1 and 8 and at the end of the studies. Water consumption was recorded twice per week and at the end of the studies. The animals were sacrificed after 14 day of exposure by CO asphyxiation. Necropsies were performed on all animals. The liver and spleen were weighed at necropsy.
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: Taconic Farms, Germantown, NY
- Age at study initiation: 6 weeks
- Housing: 5 animals per cage: polycarbonate (Lab Products, Inc., Rochelle Park, NJ), rotated twice per week; stainless steel racks, sani-chips bedding changed twice per week.
- Diet (e.g. ad libitum): NIH-07 Open Formula pelleted diet (Zeigler Brothers, Inc., Gardners, PA), available ad libitum, changed weekly.
- Water (e.g. ad libitum): Deionized water via glass sipper tube water bottles (Allentown Caging Corporation, Allentown, NJ), available ad libitum, changed twice per week.
- Acclimation period: 16 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.5-23.8
- Humidity (%): 50 +/-15%
- Air changes (per hr): at least 10 per hour
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: Date of First Exposure: 6 December 1990 To: 20 December 1990
Route of administration:
oral: drinking water
Vehicle:
water
Remarks:
(deionized water)
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Dose formulations and animal room samples were analyzed by gas chromatography. The analytical results for all dose formulations were within 10% of the theoretical concentrations.
Duration of treatment / exposure:
14 days.
Frequency of treatment:
Daily, ad libitum
Dose / conc.:
0 ppm
Remarks:
nominal
Dose / conc.:
106 ppm
Remarks:
Equivalent to 10 and 15 mg/kg-bw/day in male and female rats respectively
Dose / conc.:
312 ppm
Remarks:
Equivalent to 30 and 40 mg/kg-bw/day in male and female rats respectively
Dose / conc.:
625 ppm
Remarks:
Equivalent to 70 and 80 mg/kg-bw/day in male and female rats respectively
Dose / conc.:
1 250 ppm
Remarks:
Equivalent to 130 and 140 mg/kg-bw/day in male and female rats respectively
Dose / conc.:
2 500 ppm
Remarks:
Equivalent to 280 and 220 mg/kg-bw/day in male and female rats respectively
No. of animals per sex per dose:
5 animals per sex and per dose.
Control animals:
yes, concurrent no treatment
Observations and examinations performed and frequency:
Observed twice daily for mortality/moribundity. Clinical findings and individual body weights were recorded on days 1 and 8 and at the end of the studies. Water consumption was recorded twice per week and at the end of the studies.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
The animals were sacrificed after 14 day of exposure by CO asphyxiation. Necropsies were performed on all animals. The liver and spleen were weighed at necropsy.

HISTOPATHOLOGY: No.
Statistics:
The Fisher exact test, a procedure based on the overall proportion of animals with specific lesions, was used to determine significance. Two approaches were employed to assess the significance of pairwise comparisons between exposed and control groups in the analysis of continuous variables. Organ and body weight data, which have approximately normal distributions, were analyzed with the parametric multiple comparisons procedures of Dunnett (1955) and Williams (1971, 1972). Hematology, spermatid, and epididymal spermatozoal data, which typically have skewed distributions, were analyzed with the nonparametric multiple comparison methods of Shirley (1977) and Dunn (1964). Jonckheere’s test (Jonckheere, 1954) was used to assess the significance of exposure-related trends and to determine whether a trend-sensitive test (Williams’ or Shirley’s test) was more appropriate for pairwise comparisons than a test that does not assume a monotonic exposure-related trend (Dunnett’s or Dunn’s test). Prior to statistical analysis, extreme values identified by the outlier test of Dixon and Massey (1951) were examined by NTP personnel, and implausible values were eliminated from the analysis. Because vaginal cytology data are proportions (the proportion of the observation period that an animal was in a given estrous stage), an arcsine transformation was used to bring the data into closer conformance with a normality assumption. Treatment effects were investigated by applying a multivariate analysis of variance (Morrison, 1976) to the transformed data to test for simultaneous equality of measurements across exposure concentrations.
Clinical signs:
no effects observed
Description (incidence and severity):
No clinical findings were noted in male rats. One female rat in the 1,250 ppm group had nasal/eye discharge.
Mortality:
no mortality observed
Description (incidence):
All rats survived until the end of the study.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Male rats exposed to 2,500 ppm had a lower mean body weight gain than the controls.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
Average water consumption by male and female rats exposed to 1250 or 2500 ppm was generally less than that by the controls during the last week of the study. Drinking water concentrations of 106, 312, 625, 1250, or 2500 ppm resulted in average daily doses of approximately 10, 30, 70, 130, or 280 mg methyl ethyl ketoxime/kg body weight to males and 15, 40, 80, 140, or 220 mg/kg to females
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Spleen weights were significantly greater than the control values for males and females exposed to 1250 or 2500 ppm.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No chemical-related gross lesions were observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
625 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Based on spleen weight increase.
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
1 250 ppm
System:
haematopoietic
Organ:
spleen
Treatment related:
yes
Dose response relationship:
not specified
Relevant for humans:
not specified
Conclusions:
The NOAEL for 14 days repeated dose exposure of methyl ethyl ketoxime in rats was determined to be 625 ppm (70 mg/kg bw/day males and 80 mg/kg bw/day female, actual ingested) based on spleen weigh increase.
Executive summary:

In the 14-day repeated dose toxicity study, groups of five male and five female rats were given drinking water containing 0, 106, 312, 625, 1250, or 2500 ppm methyl ethyl ketoxime. The mean body weight gain of male rats in the 2500 ppm group was significantly less than that of the controls. Spleen weights were increased in male and female rats in the 1250 and 2500 ppm groups. No chemical-related gross lesions were observed. The 14 d-NOAEL oral exposure for methyl ethyl ketoxime was determined to be 625 ppm (70 mg/kg bw/day males and 80 mg/kg bw/day female, actual ingested) based on spleen weigh increase.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1999

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:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Butanone oxime
EC Number:
202-496-6
EC Name:
Butanone oxime
Cas Number:
96-29-7
Molecular formula:
C4H9NO
IUPAC Name:
butan-2-one oxime
Test material form:
liquid
Details on test material:
- Name of test material (as cited in study report): Methyl ethyl ketoxime
- Supplier: supplied by Pfaltz and Bauer (Waterbury, CT) and obtained from the Radian Corporation (Morrisville, NC).
- Physical state: Liquid

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Taconic Farms, Germantown, NY
- Age at study initiation: 6 weeks
- Housing: 5 animals per cage: polycarbonate (Lab Products, Inc., Rochelle Park, NJ), rotated twice per week; stainless steel racks, Sani-Chip beddings changed twice per week.
- Diet (e.g. ad libitum): NIH-07 Open Formula pelleted diet, Zeigler Brothers, Inc., Gardners, PA, available ad libitum, changed weekly
- Water (e.g. ad libitum): Deionized water via glass sipper tube water bottles (Allentown Caging Corporation, Allentown, NJ), available ad libitum, changed twice per week.
- Acclimation period: 16-17 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.5-23.8
- Humidity (%): 50 +/-15%
- Air changes (per hr): at least 10 per hour
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: Date of First Exposure: 21 February 1991 (males), 22 February 1991 (rats). To: 23 May 1991 (males), 24 May 1991 (females).

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Remarks:
(deionized water)
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Dose formulations and animal room samples were analyzed by gas chromatography. The analytical results for all dose formulations were within 10% of the theoretical concentrations.
Duration of treatment / exposure:
13 weeks.
Frequency of treatment:
Daily, ad libitum
Doses / concentrationsopen allclose all
Dose / conc.:
0 ppm
Dose / conc.:
312 ppm
Remarks:
Equivalent to 25 and 30 mg/kg-bw/day for male and female rats respectively
Dose / conc.:
625 ppm
Remarks:
Equivalent to 50 and 65 mg/kg-bw/day for male and female rats respectively
Dose / conc.:
1 250 ppm
Remarks:
Equivalent to 100 and 120 mg/kg-bw/day for male and female rats respectively
Dose / conc.:
2 500 ppm
Remarks:
Equivalent to 175 and 215 mg/kg-bw/day for male and female rats respectively
Dose / conc.:
5 000 ppm
Remarks:
Equivalent to 280 and 335 mg/kg-bw/day for male and female rats respectively
No. of animals per sex per dose:
10 animals per sex and per dose.
Control animals:
yes, concurrent no treatment

Examinations

Observations and examinations performed and frequency:
OBSERVATIONS:
Observed twice daily for mortality/moribundity. Clinical findings were recorded weekly. Individual body weights were recorded at the start of the studies, weekly thereafter, and at the end of the studies. Water consumption was recorded twice per week and at the end of the studies.

CLINICAL PATHOLOGY:
Blood was collected from the retroorbital sinus of supplemental rats on days 5 and 21 and on all core study rats at study termination (week 13). Hematology: automated and manual hematocrit, hemoglobin concentration; erythrocyte, reticulocyte, and nucleated erythrocyte counts; mean cell volume; mean cell hemoglobin; mean cell hemoglobin concentration; platelet counts; leukocyte count and differentials; and methemoglobin.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
At the end of the 13-week study, animals were sacrificed by CO asphyxiation. Necropsies were performed on all core-study animals. The heart, right kidney, liver, lungs, spleen, right testis, and thymus were weighed at necropsy.

HISTOPATHOLOGY: Yes
Histopathologic examinations were performed on all control and 5000 ppm rats. In addition to gross lesions and tissue masses, the following tissues were examined: adrenal gland, brain, clitoral gland, esophagus, heart, large intestine (cecum, colon, and rectum), small intestine (duodenum, jejunum, and ileum), lung, lymph nodes (mandibular and mesenteric), mammary gland (with adjacent skin), ovary, pancreas, parathyroid gland, pituitary gland, preputial gland, prostate gland, salivary gland, stomach (forestomach and glandular), right testis (with epididymis and seminal vesicle), thymus, thyroid gland, trachea, and uterus. Organs examined at all exposure concentrations in rats were: bone with marrow, liver, nose, spleen and kidney.
Other examinations:
SPERM MOBILITY AND VAGINAL CYTOLOGY:
At the end of the 13-week studies, sperm samples were collected from all male rats in the 0, 1250, 2500, and 5000 ppm groups for sperm motility evaluation. The following parameters were evaluated: spermatid heads per testis and per gram testis, spermatid counts, and epididymal spermatozoal motility and concentration. The left cauda epididymis, left epididymis, and left testis were weighed. Vaginal samples were collected for up to 12 consecutive days prior to the end of the studies from all female rats in the 0, 1250, 2500, and 5000 ppm for vaginal cytology evaluations. The parameters evaluated were the relative frequency of estrous stages and estrous cycle length.
Statistics:
The Fisher exact test, a procedure based on the overall proportion of animals with specific lesions, was used to determine significance. Two approaches were employed to assess the significance of pairwise comparisons between exposed and control groups in the analysis of continuous variables. Organ and body weight data, which have approximately normal distributions, were analyzed with the parametric multiple comparisons procedures of Dunnett (1955) and Williams (1971, 1972). Hematology, spermatid, and epididymal spermatozoal data, which typically have skewed distributions, were analyzed with the nonparametric multiple comparison methods of Shirley (1977) and Dunn (1964). Jonckheere’s test (Jonckheere, 1954) was used to assess the significance of exposure-related trends and to determine whether a trend-sensitive test (Williams’ or Shirley’s test) was more appropriate for pairwise comparisons than a test that does not assume a monotonic exposure-related trend (Dunnett’s or Dunn’s test). Prior to statistical analysis, extreme values identified by the outlier test of Dixon and Massey (1951) were examined by NTP personnel, and implausible values were eliminated from the analysis. Because vaginal cytology data are proportions (the proportion of the observation period that an animal was in a given estrous stage), an arcsine transformation was used to bring the data into closer conformance with a normality assumption. Treatment effects were investigated by applying a multivariate analysis of variance (Morrison, 1976) to the transformed data to test for simultaneous equality of measurements across exposure concentrations.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
All males and females in the 2500 and 5000 ppm groups had signs of toxicity including dark eyes and pale ears, tail, or appendages. Nasal/lacrimal discharge was observed in three animals at lower exposure concentrations.
Mortality:
mortality observed, treatment-related
Description (incidence):
All rats survived until the end of the study
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The final mean body weights and body weight gains of males in the 2500 and 5000 ppm groups were notably less than those of the controls, as were the mean body weight gains of males in the 1250 ppm group and females in the 2500 and 5000 ppm groups
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
Average daily water consumption by 5,000 ppm males and females was generally less than that by the controls throughout the study (not significant). Drinking water concentrations of 312, 625, 1,250, 2500, or 5000 ppm resulted in average daily doses of approximately 25, 50, 100, 175, or 280 mg methyl ethyl ketoxime/kg body weight to males and 30, 65, 120, 215, or 335 mg/kg to females.
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
On day 5, exposure concentration-dependent increases of methemoglobin concentration, indicating oxidative red cell injury, occurred in 2500 and 5000 ppm male and female rats. The increases in methemoglobin concentration ameliorated; on day 21, there were no differences between exposed and control rats. Methemoglobin concentrations were minimally increased in 2500 and 5000 ppm male rats at week 13.
An exposure concentration- and time-dependent anemia occurred in the exposed rats; the anemia was evidenced by mild to marked decreases in erythrocyte counts, hemoglobin concentrations, and/or hematocrit values.
On day 5, the anemia occurred in nearly all exposed groups, characterized as normocytic (absence of changes in mean cell volumes), hyperchromic (increases in mean cell hemoglobin concentrations in 2500 and 5000 ppm), and responsive (Increases in reticulocyte counts in 2500 and 5000 ppm female rats and in nucleated erythrocyte counts in the 2500 and 5000 ppm females and all exposed male groups).
On day 21, the anemia occurred in 1250 ppm or greater male groups and in 625 ppm or greater female groups, and was characterized as macrocytic (increases in mean cell volumes in male and female rats exposed to 1250 ppm or greater), hyperchromic (increase of cell hemoglobin concentration only in 5,000 ppmfemale rats), and responsive (exposure concentration-dependent increases in reticulocyte and nucleated erythrocyte counts occurred in male and female groups receiving 1250 ppm or greater; nucleated erythrocyte counts were also increased in 625 ppm female rats).
At the end of the study, anemia was seen in the 1250 ppm or greater male groups and 625 ppm or greater female groups, and was characterized as macrocytic (increases in mean cell volumes in 625 ppm or greater), normochromic (cell hemoglobin concentrations were similar to those of the control rats), and responsive (increase in reticulocyte and nucleated erythrocyte counts in the 1250 ppm or greater male and female groups; reticulocyte counts were also increased in 312 and 625 ppm female rats and mean cell hemoglobin generally increased).
Microscopic review of the erythrocyte morphology revealed a server exposure concentration-dependent and primarily observed changes in the 1250, 2500, and 5000 ppm groups at all time points. Minimal to marked increases in erythrocyte central pallor, basophilic stippling, and in the numbers of Heinz bodies, Howell-Jolly bodies, keratocytes, schistocytes, acanthocytes, and microcytes were observed at all time points.
A transient exposure concentration-related thrombocytosis, evidenced by increased platelet counts, occurred in male and female rats exposed to 625 ppm or greater. A mild to marked exposure concentration- and time-dependent leukocytosis, evidenced by increased total leukocyte counts, occurred in treated rats at all time points; very large increases occurred in the 2500 and 5000 ppm groups. The differences between the estimated and automated leukocyte counts were too great and suggest that the automated leukocyte counts may have been erroneously elevated related to the presence of reticulocytes (resistant to lysis), erythrocyte fragments, and/or Heinz bodies in the circulation.
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Spleen weights of males and females exposed to 1250, 2500, or 5000 ppm were generally greater than those of the controls. Absolute liver weights of male rats exposed to 1250, 2500, or 5000 ppm and relative liver weights of all groups of exposed males were greater than those of the controls. In females, absolute liver weights in the 2500 and 5000 ppm groups and relative liver weights in the 1250, 2500, and 5000 ppm groups were increased. Absolute kidney weights of male rats in the 5000 ppm group and relative kidney weights in males exposed to 1250 ppm or greater were increased. Kidney weights of females exposed to 625 ppm or greater were greater than those of the controls.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
At necropsy, gross findings attributed to methyl ethyl ketoxime exposure consisted of enlarged and darkened spleens and darkened kidneys in male and female rats in the 2500 and 5000 ppm groups.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Microscopically, treatment-related effects were present in the spleen, bone marrow, liver, kidney, and nose. Most of these effects were related to enhanced destruction of erythrocytes and the resultant compensatory response.
In the spleen, increased incidences of hematopoietic cell proliferation occurred at exposure concentrations of 625 ppm and greater in males and females. Increased hematopoiesis was sporadically accompanied by minimal to mild increases in the number of macrophages containing golden-brown granular pigment (hemosiderin) in males in the 5,000 ppm group and females exposed to 625 ppm or greater.
Increases in the incidences of hematopoietic cell proliferation in the bone marrow were observed in males and females at all exposure concentrations (statistically significant at >= 625 ppm).
In the liver, exposure was associated with several changes related to the destruction of red blood cells. Hematopoietic cell proliferation was significantly increased at >=625 ppm doses. At 2500 and 5000 ppm groups, changes of Kupffer cell changes consisted on phagocytosis of red blood cells (erythrophagocytosis) and cytoplasmic deposition of golden-brown pigment (hemosiderin).
In the kidney, brown pigment (hemosiderin) was present in the cytoplasm of renal tubule epithelial cells in all males in the 2500 and 5000 ppm groups and in all females exposed to 1250 ppm or greater.
Treatment effects not apparently related to red blood cell destruction included degeneration of the nasal epithelium in males and females in the 2500 and 5000 ppm groups and cytoplasmic alteration of hepatocytes in males in the 5000 ppm group
Histopathological findings: neoplastic:
no effects observed
Other effects:
effects observed, treatment-related
Description (incidence and severity):
SPERM MOBILITY AND VAGINAL CYTOLOGY:
There were no significant differences in sperm parameters or male reproductive organ weights between control and exposed male rats. Females in the 2,500 and 5,000 ppm groups had significantly shorter estrous cycle lengths than the concurrent controls; however, these shorter cycle lengths were still within the normal range for controls.

Effect levels

open allclose all
Key result
Dose descriptor:
NOAEL
Remarks:
(erythrotoxicity)
Effect level:
312 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Based on anemia.
Key result
Dose descriptor:
NOAEL
Remarks:
(nose)
Effect level:
1 250 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Based on olfactory epithelium degeneration.

Target system / organ toxicity

Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
625 ppm
System:
haematopoietic
Organ:
other: red blood cells
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
not specified

Applicant's summary and conclusion

Conclusions:
The NOAEL after 90 days exposure to methyl ethyl ketoxime by drinking water was determined to be 312 ppm (25 mg/kg bw/day males and 30 mg/kg bw/day females) for both male and female rats.
Executive summary:
A 90 days repeated dose toxicity test was performed on test item methyl ethyl ketoxime in accordance with an equivalent method to OECD Guideline 408. Groups of 10 male and 10 female rats were given drinking water containing 0, 312, 625, 1250, 2500, or 5000 ppm of test item. Clinical findings, individual body weights and water consumption were recorded periodically. Blood was collected from the retroorbital sinus of supplemental rats on days 5 and 21 and on all core study rats at study termination. At the end of the study, animals were sacrificed and necropsies were performed on all core-study animals. The heart, right kidney, liver, lungs, spleen, right testis, and thymus were weighed at necropsy. Histopathologic examinations were performed on all control and 5000 ppm. Furthermore, at the end of the, sperm samples were collected from all male rats in the 0, 1250, 2500, and 5000 ppm groups for sperm motility evaluation. Vaginal samples were collected for up to 12 consecutive days prior to the end of the studies from all female rats in the 0, 1250, 2500, and 5000 ppm for vaginal cytology evaluations.
All rats survived until the end of the study: The final mean body weights and body weight gains of the 2500 and 5000 ppm males were less than those of the controls as were the mean body weight gains of males in the 1250, 2500 and 5000 ppm groups and females in the 2500 and 5000 ppm groups. Hematology indicated a methemoglobinemia and a responsive Heinz body anaemia. Liver and spleen weights were generally significantly greater than those of the controls in the male and female rats exposed to 1250 ppm and higher. Kidney weights were significantly increased in males at 5000 ppm and females at 1250 ppm and above. Microscopically, there were exposure related increases in the incidences and severities of hematopoietic cell proliferation in the spleen at exposure concentrations of 625 ppm or greater in males and females. A significant increase in the incidence of hematopoietic proliferation in the bone marrow was observed in both sexes exposed to 625 ppm and greater. Liver Kupffer cell erythrophagocytosis and hemosiderin pigmentation, as well as renal tubule hemosiderin pigmentation, occurred in exposed rats. Degeneration of the nasal olfactory epithelium occurred in male and female rats in the 2500 and 5000 ppm groups. There were no significant differences in sperm parameters or male reproductive organ weights between control and exposed male rats. Females in the 2500 and 5000 ppm groups had significantly shorter estrous cycle lengths than the concurrent controls; however, these shorter cycle lengths were still within the normal range for controls. The NOAEL for the most sensitive parameter (erythrotoxicity) for rats after 90 days of exposure to methyl ethyl ketoxime was determined to be 312 ppm (25 mg/kg bw/day males and 30 mg/kg bw/day females).