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Description of key information

Key study: Based on the read-across approach from experimental results on analogue butanone oxime, the NOAEL for butan-2-one-O,O',O''-(vinylsilanetriyl)oxime for 13 weeks repeated dose toxicity by oral route in rats was estimated to be 374.22 ppm (29.99 and 35.98 mg/kg bw/day for males and females respectively).

Supporting study: Based on the read-across approach from experimental results on analogue butanone oxime, the NOAEL for butan-2-one-O,O',O''-(vinylsilanetriyl)oxime for 13 weeks repeated dose toxicity by oral route in mice was estimated to be 749.64 ppm (131.94 mg/kg bw/day) for males and 1499.27 ppm (407.80 mg/kg bw/day) for females.

Key study: Based on the read-across approach from experimental results on analogue butanone oxime, the NOEL for butan-2-one-O,O',O''-(vinylsilanetriyl)oxime for 28 days repeated dose toxicity by oral route in rats was estimated to be 4.80 mg/kg/day.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

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:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
Butan-2-one O,O',O''-(vinylsilanetriyl)oxime undergoes rapid hydrolysis in aqueous to butanone oxime and the corresponding silanol. Silanetriols undergo continuous condensation reactions to produce higher molecular weight siloxanes which are considered biologically unavailable. Therefore, the observed toxicity is likely due to butanone oxime and their values are comparable.
See attached the reporting format.
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Key result
Dose descriptor:
NOAEL
Remarks:
(erythrotoxicity)
Effect level:
374.22 ppm
Based on:
other: (analogue subtance)
Sex:
male/female
Basis for effect level:
other: anemia
Remarks on result:
other: (based on read-across approach from experimental data on analogue butanone oxime)
Key result
Dose descriptor:
NOAEL
Remarks:
(nose)
Effect level:
1 499.27 ppm
Based on:
other: (analogue substance)
Sex:
male/female
Basis for effect level:
other: olfactory epithelium degeneration
Remarks on result:
other: (based on read-across approach from experimental data on analogue butatone oxime)
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
749.64 ppm
System:
haematopoietic
Organ:
other: red blood cells
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
not specified

The concentrations used in the study on the analogue substance and the read-across approch estimation are as follows:

Unit

Sex

MEKO

VOS

ppm

Male/female

312,00

374,22

625,00

749,64

1250,00

1499,27

2500,00

2998,55

5000,00

5997,09

mg/kg bw/day

Male 

25,00

29,99

50,00

59,97

100,00

119,94

175,00

209,90

280,00

335,84

mg/kg bw/day

Female 

30,00

35,98

65,00

77,96

120,00

143,93

215,00

257,87

335,00

401,81

See the "Data Matrix" and the "Reporting Format" attached.

Conclusions:
Based on the read-across approach from experimental results on analogue butanone oxime, the NOAEL for butan-2-one-O,O',O''-(vinylsilanetriyl)oxime for 13 weeks repeated dose toxicity by oral route in rats was estimated to be 374.22 ppm (29.99 and 35.98 mg/kg bw/day for males and females respectively) for erythrotoxicity and 1499.27 ppm (119.94 and 143.93 mg/kg bw/day for males and females respectively) for olfactory epithelium degeneration.
Executive summary:

A 90 days repeated dose toxicity test was performed on analogue substance butanone oxime in accordance with an equivalent method to OECD Guideline 408. After 13 weeks oral administration of analogue MEKO to rats up to 5000 ppm (up to 280 mg/kg bw/day in males and up to 335 mg/kg/bw/day), the NOAEL for erythrotoxicity was determined to be 312 ppm (25 and 30 mg/kg bw/day in males and females respectively) and the NOAEL for olfactory epithelium degeneration was determined to be 1250 ppm (100 and 120 mg/kg bw/day in males and females respectively).

Based on these results, the read-across approach was applied and the NOAEL for butan-2-one-O,O',O''-(vinylsilanetriyl)oxime for 13 weeks repeated dose toxicity by oral route in rats was estimated to be 374.22 ppm (29.99 and 35.98 mg/kg bw/day for males and females respectively) for erythrotoxicity and 1499.27 ppm (119.94 and 143.93 mg/kg bw/day for males and females respectively) for olfactory epithelium degeneration.

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.
Reason / purpose for cross-reference:
reference to other study
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
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).
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
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
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.
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.
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.
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
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).
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.

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting 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.
Reason / purpose for cross-reference:
reference to other study
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
Species:
mouse
Strain:
B6C3F1
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: Mice were housed individually: 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: 14 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: 19 February 1991 To: 21 May 1991 (males), 22 May 1991 (females).
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
Dose / conc.:
0 ppm
Remarks:
nominal
Dose / conc.:
625 ppm
Remarks:
Equivalent to 110 and 145 mg/kg-bw/day in male and female mice respectively
Dose / conc.:
1 250 ppm
Remarks:
Equivalent to 200 and 340 mg/kg-bw/day in male and female mice respectively
Dose / conc.:
2 500 ppm
Remarks:
Equivalent to 515 and 630 mg/kg-bw/day in male and female mice respectively
Dose / conc.:
5 000 ppm
Remarks:
Equivalent to 755 and 1010 mg/kg-bw/day in male and female mice respectively
Dose / conc.:
10 000 ppm
Remarks:
Equivalent to 1330 and 3170 mg/kg-bw/day in male and female mice respectively
No. of animals per sex per dose:
10 animals per sex and per dose.
Control animals:
yes, concurrent no treatment
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.
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 10000 ppm. In addition to gross lesions and tissue masses, the following tissues were examined: adrenal gland, brain, clitoral gland, esophagus, gallbladder (mice), 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 female mice were: bone with marrow, liver, nose, spleen and urinary bladder. The kidney was examined in 0, 625, 5000, and 1,000 ppm male mice, and in 0 and 10000 ppm female mice. Organs examined in 0, 625, 2500, 5000, and 10000 ppm male mice were: liver, nose, and spleen. The bone with marrow was examined in 0, 625, 5000, and 10000 ppm male mice.
Other examinations:
SPERM MOBILITY AND VAGINAL CYTOLOGY:
At the end of the 13-week studies, sperm samples were collected from all male mice in the 0, 2500, 5000, and 10000 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 mice in the 0, 2500, 5000, and 10000 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.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Clinical findings were observed in males and females exposed to 10000 ppm; six males and four females were thin, and four males and one female appeared to be dehydrated.
Mortality:
mortality observed, treatment-related
Description (incidence):
All mice 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 male mice in the 625 and 1250 ppm groups and females in the 625 ppm group were slightly greater than the control values (statistically not significant). The final mean body weights and body weight gains of male and female mice in the 10000 ppm groups were less than the control values.
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 the 10000 ppm males was generally less than that by the control group throughout the study (not statistically significant). Drinking water concentrations of 625, 1250, 2500, 5000, or 10000 ppm resulted in average daily doses of approximately 110, 200, 515, 755, or 1330 mg methyl ethyl ketoxime/kg body weight to males and 145, 340, 630, 1010 or 3170 mg/kg to females.
Ophthalmological findings:
not examined
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Heart weights in males exposed to 10000 ppm methyl ethyl ketoxime were greater than the controls.
Absolute spleen weights of males exposed to 5000 or 10000 ppm were greater than that of the controls; the relative spleen weight of males exposed to 10000 ppm was significantly greater than that of the controls. Spleen weights of females in the 10000 ppm group were greater than the controls.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
At necropsy, gross findings attributed to methyl ethyl ketoxime treatment were found only in the 10000 ppm groups and consisted of enlarged and darkened spleens in male and female mice, as well as darkened livers in most of the same mice.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Microscopically, treatment-related effects were present in the spleen, bone marrow, kidney, liver, nose, and urinary bladder. Most of these effects were related to enhanced destruction of red blood cells and the resultant compensatory response.
In the spleen, increased hematopoietic cell proliferation in both male and female mice and correlated with increased spleen weights. This change was characterized by an increased number of hematopoietic cells, primarily of the erythroid series, in the splenic red pulp of treated animals relative to those seen in controls in all mice exposed to 5000 or 10000 ppm. An increase in the number of macrophages containing golden-brown granular pigment (hemosiderin) accompanying the increased hematopoiesis in 10000 ppm males and females was also observed. The incidence of hemosiderin pigmentation was also increased in the bone marrow of all mice exposed to 10000 ppm, although no increase in hematopoiesis was apparent in this tissue. Hemosiderin was also present in the proximal convoluted tubules of the kidney in 10000 ppm males.
In the liver, accumulation of hemosiderin pigment in the cytoplasm of sinusoidal Kupffer cells was present in the 10000 ppm mice, and phagocytosis of red blood cells (erythrophagocytosis) was observed in many of these same mice. In 10000 ppm females only, small foci of hematopoietic cell proliferation within the hepatic sinusoids were observed.
Treatment effects not apparently related to red blood cell destruction included degeneration of the nasal epithelium, cytoplasmic alteration of hepatocytes, and hyperplasia of urinary bladder epithelial cells. In the nose, degeneration was a minimal to moderate change of the olfactory epithelium in males exposed to 5000 or 10000 ppm and in females exposed to 2500 ppm or greater. The lesion was located primarily in the dorsal meatus of the mid- and posterior-level nasal sections and was characterized by decreased height, reduced cell number, and cytologic disorganization of the neuroepithelial architecture.
In the liver, cytoplasmic alteration was a mild tinctorial change that occurred in males and females exposed to 10000 ppm and was characterized primarily by increased cytoplasmic eosinophilia of centrilobular hepatocytes. Slight enlargement of these altered cells was evident in some mice.
Changes in the urinary bladder were hyperplasia of the transitional epithelial lining (increased number of cell layers and slight enlargement of the lining cells) in association with infiltration of inflammatory cells (lymphocytes) into the underlying submucosa. Incidences of cellular infiltration were significantly increased in males and females exposed to 2500 ppm or greater and the incidences of epithelial hyperplasia were significantly increased in males exposed to 1250 ppm or greater and in females in the 10000 ppm group.
Histopathological findings: neoplastic:
not specified
Other effects:
effects observed, treatment-related
Description (incidence and severity):
There were no differences in sperm parameters, male reproductive organ weights, or estrous cycle lengths between controls and mice exposed to 2500, 5000, or 10000 ppm methyl ethyl ketoxime.
Key result
Dose descriptor:
NOAEL
Remarks:
(erythrotoxicity)
Effect level:
2 500 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Based on hematopoietic cell proliferation.
Key result
Dose descriptor:
NOAEL
Remarks:
(nose)
Effect level:
2 500 ppm
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Based on olfactory epithelium degeneration.
Key result
Dose descriptor:
NOAEL
Remarks:
(nose)
Effect level:
1 250 ppm
Based on:
test mat.
Sex:
female
Basis for effect level:
other: Based on olfactory epithelium degeneration.
Key result
Dose descriptor:
NOAEL
Remarks:
(urinary bladder)
Effect level:
625 ppm
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Based on hyperplasia of the urinary bladder transitional epithelium.
Key result
Dose descriptor:
NOAEL
Remarks:
(urinary bladder)
Effect level:
5 000 ppm
Based on:
test mat.
Sex:
female
Basis for effect level:
other: Based on hyperplasia of the urinary bladder transitional epithelium.
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
5 000 ppm
System:
haematopoietic
Organ:
other: red blood cells
Treatment related:
yes
Dose response relationship:
not specified
Relevant for humans:
not specified
Conclusions:
The NOAEL after 90 days exposure to methyl ethyl ketoxime by drinking water was determined to be 625 ppm (110 mg/kg bw/day) for male mice and 1250 ppm (635 mg/kg bw/day) for female mice.
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. 10 mice per sec and per dose were given drinking water containing 0 (control), 625, 1,250, 2,500, 5,000, or 10,000 ppm test substance. Clinical findings, individual body weights and water consumption were recorded periodically. 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 10000 ppm. Furthermore, at the end of the, sperm samples were collected from all male rats in the 0, 2500, 5000, and 10000 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, 2500, 5000, and 10000 ppm for vaginal cytology evaluations. All mice survived until the end of the study. Mean body weights and body weights gains of the 10000 ppm males and females were less than those of the controls. Spleen weights were generally significantly greater than those of the controls in the male and female mice exposed to 10000 ppm. Microscopically, there were exposure related increases in the incidences and severities of hematopoietic cell proliferation in the spleen at exposure concentrations of 5000 ppm or greater in males and females. Liver Kupffer cell erythrophagocytosis and hemosiderin pigmentation, as well as renal tubule hemosiderin pigmentation, occurred in exposed mice at 10000 ppm. Other lesions observed included hyperplasia of the transitional epithelial lining of the urinary bladder in male mice at 1250 ppm or greater and in female mice at 2500 ppm or greater. There was degeneration of the nasal olfactory epithelium of the dorsal meatus in male mice exposed to 5000 ppm or greater and in female mice exposed to 2500 ppm or greater. There were no differences in sperm parameters, male reproductive organ weights, or estrous cycle lengths between controls and mice exposed to 2500, 5000, or 10000 ppm methyl ethyl ketoxime. The NOAEL after 90 days of exposure to methyl ethyl ketoxime and based on the most sensitive parameter was determined to be 625 ppm (110 mg/kg bw/day) for male mice (basis for effect: hyperplasia of the urinary bladder transitional epithelium) and 1250 ppm (635 mg/kg bw/day) for female mice (basis for effect: infiltration of inflammatory cells into the underlying submucosa in the urinary bladder and degeneration of the olfactoy epithelium).
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:
mouse
Strain:
B6C3F1
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: Mice were housed individually: 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: 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: 7 December 1990 To: 21 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 30 and 35 mg/kg-bw/day in male and female mice respectively
Dose / conc.:
312 ppm
Remarks:
Equivalent to 70 and 130 mg/kg-bw/day in male and female mice respectively
Dose / conc.:
625 ppm
Remarks:
Equivalent to 140 and 215 mg/kg-bw/day in male and female mice respectively
Dose / conc.:
1 250 ppm
Remarks:
Equivalent to 300 and 370 mg/kg-bw/day in male and female mice respectively
Dose / conc.:
2 500 ppm
Remarks:
Equivalent to 475 and 635 mg/kg-bw/day in male and female mice 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
Mortality:
no mortality observed
Description (incidence):
All mice survived until the end of the study.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The final mean body weight of males exposed to 2500 ppm was significantly less than that of 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 the 2500 ppm male and female groups was generally less than that by the controls.
Drinking water concentrations of 106, 312, 625, 1250, or 2500 ppm resulted in average daily doses of approximately 30, 70, 140, 300, or 475 mg methyl ethyl ketoxime/kg body weight to males and 35, 130, 215, 370, or 635 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:
no effects observed
Description (incidence and severity):
There were no biologically significant differences in organ weights
Gross pathological findings:
no effects observed
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Key result
Dose descriptor:
NOAEL
Effect level:
1 250 ppm
Based on:
test mat.
Sex:
male
Basis for effect level:
body weight and weight gain
Key result
Dose descriptor:
NOAEL
Effect level:
> 2 500 ppm
Based on:
test mat.
Sex:
female
Basis for effect level:
other: Based on no adverse effect observed at the highest dose testes.
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
2 500 ppm
System:
other: Body weight gain in male mice
Treatment related:
not specified
Dose response relationship:
no
Relevant for humans:
not specified
Conclusions:
The 14 d-NOAEL oral exposure for methyl ethyl ketoxime was determined to be 1250 ppm in males (300 mg/kg bw/day, actual ingested) based on body weight gain and >2500 ppm in females (635 mg/kg bw/day) based on no adverse effects observe at the highest dose tested.
Executive summary:

In the 14-day repeated dose toxicity study, groups of five male and five female mice were given drinking water containing 0, 106, 312, 625, 1250, or 2500 ppm methyl ethyl ketoxime. The final mean body weight of male mice in the 2500 ppm group was also less than that of the controls. No chemical-related gross lesions were observed. The 14 d-NOAEL oral exposure for methyl ethyl ketoxime was determined to be 1250 ppm in males (300 mg/kg bw/day, actual ingested) based on body weight gain and >2500 ppm in females (635 mg/kg bw/day) based on no adverse effects observe at the highest dose tested.

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
Test method according to an accepted guideline. GLP study.
Qualifier:
according to guideline
Guideline:
other: Guidelines for 28-day repeat dose toxicity testing for chemicals (Japan)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source:
- Age at study initiation:
- Weight at study initiation: 163.3-165.9 g (males); 136.6-141.0 (females)
- Fasting period before study:
- Housing:
- Diet (e.g. ad libitum):
- Water (e.g. ad libitum):
- Acclimation period:

ENVIRONMENTAL CONDITIONS
- Temperature (°C):
- Humidity (%):
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light):

IN-LIFE DATES: From: To:
Route of administration:
oral: gavage
Vehicle:
olive oil
Details on oral exposure:
Volume: 10 mg/kg.
Concentration of tes item (v/v %): 0 (control), 0.04, 0.2 and 1 % (v/v).
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
28 days
Frequency of treatment:
Daily
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Dose / conc.:
4 mg/kg bw/day (actual dose received)
Dose / conc.:
20 mg/kg bw/day (actual dose received)
Dose / conc.:
100 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
7 animals per sex and per dose.
Satellite groups: 7 animals per sex and per dose at the control and 100 mg/kg bw/day groups
Control animals:
yes, concurrent vehicle
Details on study design:
- Post-exposure recovery period in satellite groups: 14 days
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes
- Time schedule for examinations:
Exposure period: Days 1, 2, 7, 14, 21 and 28.
Recovery period: Days 1, 2, 7 and 14.

FOOD CONSUMPTION (g/day):
- Time schedule for examinations:
Exposure period: Days 1, 2, 7, 14, 21 and 28.
Recovery period: Days 1, 2, 7 and 14.

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the end of 28-day exposure and 14-day recovery period.
- How many animals: all animals.
- Parameters checked: RBC, Ht., Hb., MCV, MCH, MCHC, WBC, Plat., Ret., CT, PT, APTT, Hemogram of WBC (Neutro, Eos., Bas., Monocyte, Lymphocyte, others).
- Other: Myelogram: at the end of 28-day exposure and 14-day recovery period.
- How many animals: all animals from control and 100 mg/kg bw/day groups.
- Parameters checked: Nucleated, Erythrobals, Myeloid cells, M/E, Lymphocyte, Monocyte, Megakaryocyte, others.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the end of 28-day exposure and 14-day recovery period.
- How many animals: all animals
- Parameters checked: TP, Alb. A/G, Protein fractions (Alb, Globulin), GOT, GPT, ALP, LDH, γ-GTP, T-BIL, Glu, T-Cho, TG, BUN, Crea, Na, K, Cl, Ca, P

URINALYSIS: Yes
- Time schedule for collection of urine: In the final week of 28-day exposure period and 14-day recovery period.
- Metabolism cages used for collection of urine: Yes / No / No data
- Animals fasted: Yes / No / No data
- Parameters checked: pH, Pro, Glu, Ket, Uro, Bil, occult blood, color, urinary sediments (RBD, WBC, epitherlial cells, others), specific gravity, volume, Na, K, Cl, Ca, P.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
Gross findings and absolute and relative organ weights:
- Time schedule: at the en of 28-day exposure and 14-day recovery period.
- How many animals: all animals
- Organ weighs: Brain, pituitary gland, thymus, thyroid (right and left), lung, heart, liver, kidney (right and left), spleen, adrenal (right and left), testis (right and left), ovaries (right and left)
- Organ findings and spleen swelling.

HISTOPATHOLOGY: Yes
- Time schedule: at the en of 28-day exposure and 14-day recovery period.
- How many animals: all animals
- Organs checked: liver, kidney, spleen, heart, lung (bronchus), cerebrum, cerebellum, spinal cord, sciatic nerve, eyeball, Harder's gland, thyroid, parathyroid, thymus, submandibular lymph node, mesenteric lymph node, pancreas, adrenal, submandibular gland, sublingual gland, parotid gland, pituitary gland, larynx, trachea, aorta, tongue, esophagus, forestomach, glandular stomach, duodenum, jejunum, ileum, cecum, colon, sternum, femur, mammary gland, skin, skeletal muscle, urinary bladder, rectum, testis, prostate, epididymis, seminal vesicle, ovary, uterus or vagina.
Clinical signs:
no effects observed
Mortality:
no mortality observed
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:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Hematological examination revealed an increase in reticulocyte ratio in males and females given 20 mg/kg and above, an increase in the platelet count in females given 20 mg/kg and above, decreases in the red blood cell count, hematocrit value and hemoglobin concentration in males given 100 mg/kg and in females given 20 mg/kg and above, and increases in mean corpuscular volume, mean corpuscular hemoglobin and white blood cell count in males and females given 100 mg/kg.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Blood chemical examination revealed an increase in the potassium level in males and females given 100 mg/kg, increases in the albumin/globulin ratio and albumin fraction, a decrease in the Al-globulin fraction, and increases in total bilirubin and total cholesterol in males given 100 mg/kg.
Urinalysis findings:
effects observed, treatment-related
Behaviour (functional findings):
not examined
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Absolute and relative spleen weights were increased in females given 20 mg/kg and above and in males given 100 mg/kg, relative lung weights were increased in males given 100 mg/kg, and relative heart weights were increased in females given 100 mg/kg.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Autopsy revealed hypertrophy of the spleen in males given 20 mg/kg and above and in females given 100 mg/kg.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Histopathologically, hypertrophy of Kupffer cells with phagocytosed hemosiderin granules in the liver was observed in males given 100 mg/kg and in females given 20 mg/kg and above. Extramedullary hematopoiesis in the liver and deposition of lipofuscin-like substance in the renal tubular epithelium were observed in males and females given 100 mg/kg. Congestion, an increase in extramedullary hematopoiesis and an increase in hemosiderin granules were observed in the spleens of males and females given 20 mg/kg and above.
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed
Description (incidence and severity):
Myelopraphy: No effects were observed.
Key result
Dose descriptor:
NOEL
Effect level:
4 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
haematology
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
20 mg/kg bw/day (actual dose received)
System:
haematopoietic
Organ:
other: red blood cells
Treatment related:
yes
Dose response relationship:
not specified
Relevant for humans:
not specified

Most of the changes observed had disappeared or were decreased their degrees 14 days after withdrawal.

Conclusions:
The NOEL for ethyl methyl ketoxime after a 28 days repeated dose oral exposition in rats was determined to be 4 mg/kg bw/day.
Executive summary:

A 28 days repeated dose toxicity test was performed on ethyl methyl ketoxime on Crj:CD (SD) rats according to Guidelines for 28 -day Repeat Dose Toxicity Testing for Chemicals (Japan). 7 rats per sex and per dose were orally exposed to test item at 0 (control), 4, 20 and 100 mg/kg bw/day doses during 28 days. Satellites groups were in place (7 animals per sex and dose) at the control and 100 mg/kg bw/day groups. Post-exposure recovery period in these satellite groups were 14 days. Ethyl methyl ketoxime caused effects on the erythrocyte series as follows: an increase in reticulocyte ratio in males and females given 20 mg/kg and above, and decreases in the red blood cell count, hematocrit value and hemoglobin concentration, increases in mean corpuscular volume, mean corpuscular hemoglobin and total serum bilirubin in males or females given 20 mg/kg and or 100 mg/kg. An increase in platelet count was also noted in females given 20 mg/kg and above and an increase in the white blood cell count in males and females given 100 mg/kg. Absolute and relative spleen weights were increased and hypertrophy of the organ was observed macroscopically in males or females given 20 mg/kg and above. Histopathologically, congestion, an increase in extramedullary hematopoiesis and an increase in hemosiderin granules were observed in males and females given 20 mg/kg and above. In the liver, hypertrophy of Kupffer cells with phagocytosed hemosiderin granules was observed in males given 100 mg/kg and in females given 20 mg/kg and above, and extramedullary hematopoiesis was noted in males and females given 100 mg/kg. In the kidney, deposition of lipofuscin-like substance in the tubular epithelium was observed in males and females given 100 mg/kg. Increases in the A/G ratio, albumin fraction and total cholesterol and a decrease in the A1-globulin fraction in males given 100 mg/kg were suggestive of effects on hepatic function. Relative lung weights were increased in males given 100 mg/kg and relative heart weights were increased in females given 100 mg/kg. These changes disappeared or were decreased in their degrees 14 days after withdrawal. The NOEL for repeat dose toxicity for both males and females was considered to be both 4 mg/kg/day.

Endpoint:
sub-chronic toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
Butan-2-one O,O',O''-(vinylsilanetriyl)oxime undergoes rapid hydrolysis in aqueous to butanone oxime and the corresponding silanol. Silanetriols undergo continuous condensation reactions to produce higher molecular weight siloxanes which are considered biologically unavailable. Therefore, the observed toxicity is likely due to butanone oxime and their values are comparable.
See attached the reporting format.
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Key result
Dose descriptor:
NOAEL
Remarks:
(erythrotoxicity)
Effect level:
2 998.55 ppm
Based on:
other: (analogue substance)
Sex:
male/female
Basis for effect level:
other: basis for effect: hematopoietic cell proliferation
Remarks on result:
other: (based on read-across approach from experimental data on analogue butanone oxime)
Key result
Dose descriptor:
NOAEL
Remarks:
(nose)
Effect level:
2 998.55 ppm
Based on:
other: (analogue substance)
Sex:
male
Basis for effect level:
other: basis for effect: olfactory epithelium degeneration
Remarks on result:
other: (based on read-across approach from experimental data on analogue butatone oxime)
Key result
Dose descriptor:
NOAEL
Remarks:
(nose)
Effect level:
1 499.27 ppm
Based on:
other: (analogue substance)
Sex:
female
Basis for effect level:
other: basis for effect: olfactory epithelium degeneration
Remarks on result:
other: (based on read-across approach from experimental data on analogue butanone oxime)
Key result
Dose descriptor:
NOAEL
Remarks:
(urinary bladder)
Effect level:
749.64 ppm
Based on:
other: (analogue substance)
Sex:
male
Basis for effect level:
other: basis for effect: hyperplasia of the urinary bladder transitional epithelium
Remarks on result:
other: (based on read-across approach from experimental data on analogue butanone oxime)
Key result
Dose descriptor:
NOAEL
Remarks:
(urinary bladder)
Effect level:
5 997.09 ppm
Based on:
other: (analogue substance)
Sex:
female
Basis for effect level:
other: basis for effect: hyperplasia of the urinary bladder transitional epithelium
Remarks on result:
other: (based on read-across approach from experimental data on analogue butanone oxime)
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
5 997.09 ppm
System:
haematopoietic
Organ:
other: red blood cells
Treatment related:
yes
Dose response relationship:
not specified
Relevant for humans:
not specified

The concentrations used in the study on the analogue substance and the read-across approch estimation are as follows:

Unit

Sex

MEKO

VOS

ppm mice

Male/female

625,00

749,64

1250,00

1499,27

2500,00

2998,55

5000,00

5997,09

10000,00

11994,18

mg/kg bw/day

Male

110,00

131,94

200,00

239,88

515,00

617,70

755,00

905,56

1330,00

1595,23

mg/kg bw/day

Female

145,00

173,92

340,00

407,80

630,00

755,63

1010,00

1211,41

3170,00

3802,16

See the "Data Matrix" and the "Reporting Format" attached.

Conclusions:
Based on the read-across approach from experimental results on analogue butanone oxime, the NOAEL for butan-2-one-O,O',O''-(vinylsilanetriyl)oxime for 13 weeks repeated dose toxicity by oral route in mice was estimated to be 749.64 ppm (131.94 mg/kg bw/day) for male mice (basis for effect: hiperplasia of the urinary bladder transitional epithelium) and 1499.27 ppm (407.80 mg/kg bw/day) for female mice (basis for effect: infiltration of inflammatory cells into the underlying submucosa in the urinary bladder and degeneration of the olfactoy epithelium).
Executive summary:

A 90 days repeated dose toxicity test was performed on analogue substance butanone oxime in accordance with an equivalent method to OECD Guideline 408. After 13 weeks oral administration of analogue MEKO to mice up to 10000 ppm (up to 1330 mg/kg bw/day in males and up to 3170 mg/kg/bw/day). Based on the most sensitive parameter the NOAEL was determined to be 625 ppm (110 mg/kg bw/day) for male mice (basis for effect: hyperplasia of the urinary bladder transitional epithelium) and 1250 ppm (635 mg/kg bw/day) for female mice (basis for effect: infiltration of inflammatory cells into the underlying submucosa in the urinary bladder and degeneration of the olfactoy epithelium).

Based on these results, the read-across approach was applied and the NOAEL for butan-2-one-O,O',O''-(vinylsilanetriyl)oxime for 13 weeks repeated dose toxicity by oral route in mice was estimated to be 749.64 ppm (131.94 mg/kg bw/day) for male mice (basis for effect: hiperplasia of the urinary bladder transitional epithelium) and 1499.27 ppm (407.80 mg/kg bw/day) for female mice (basis for effect: infiltration of inflammatory cells into the underlying submucosa in the urinary bladder and degeneration of the olfactoy epithelium)

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
Butan-2-one O,O',O''-(vinylsilanetriyl)oxime undergoes rapid hydrolysis in aqueous to butanone oxime and the corresponding silanol. Silanetriol undergo continuous condensation reactions to produce higher molecular weight siloxanes which are considered biologically unavailable. Therefore, the observed toxicity is likely due to butanone oxime and their values are comparable.
See attached the reporting format.
Reason / purpose for cross-reference:
read-across source
Key result
Dose descriptor:
NOEL
Effect level:
4.8 mg/kg bw/day (actual dose received)
Based on:
other: (analogue subtance)
Sex:
male/female
Basis for effect level:
haematology
Remarks on result:
other: (based on read-across approach from experimental data on analogue butanone oxime)
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
23.99 mg/kg bw/day (actual dose received)
System:
haematopoietic
Organ:
other: red blood cells
Treatment related:
yes
Dose response relationship:
not specified
Relevant for humans:
not specified

The concentrations used in the study on the analogue substance and the read-across approch estimation are as follows:

Unit

Sex

MEKO

VOS

TOS

mg/kg bw/day

Male/female

4,00

4,80

4,28

20,00

23,99

21,38

100,00

119,94

106,90

See the "Data Matrix" and the "Reporting Format" attached.

Conclusions:
Based on the read-across approach from experimental results on analogue butanone oxime, the NOEL for butan-2-one-O,O',O''-(vinylsilanetriyl)oxime for 28 days repeated dose toxicity by oral route in rats was estimated to be 4.80 mg/kg/day.
Executive summary:

A 28 days repeated dose toxicity test was performed on analogue ethyl methyl ketoxime up to 100 mg/kg bw/day on Crj:CD (SD) rats according to Guidelines for 28 -day Repeat Dose Toxicity Testing for Chemicals (Japan). The NOEL for repeat dose toxicity for both males and females was considered to be both 4 mg/kg/day based on haematological effects. Based on these results, the read-across approach was applied and the NOEL for butan-2-one-O,O',O''-(vinylsilanetriyl)oxime for 28 days repeated dose toxicity by oral route in rats was estimated to be 4.80 mg/kg bw/day.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
30 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Three studies are available on an analogue substance (two 90d and a 28 day repeated dose toxicity studies) with a Klimisch score = 1. The overall quality of the database was determined as appropriate for assessment.

Additional information

ORAL Repeated dose toxicity study:

Key study: Read-across from experimental data on analogue butatone oxime: 90 days oral repeated dose toxicity study in rats (test method similar to OECD 408):

In the study performed on analogue butatone onxime, groups of 10 rats per sex were given drinking water containing 0, 312, 625, 1250, 2500, or 5000 ppm (25, 50, 100, 175, 175, 280 mg/kg bw/day in males and 30, 65, 120, 215, 335 mg/kg bw/day in females) of test item. All rats survived until the end of the study. NOAEL for the most sensitive parameter (erythrotoxicity) for rats after 90 days of exposure to butanone oxime was determined to be 312 ppm (25 mg/kg bw/day males and 30 mg/kg bw/day females). Based on these results, the read-across approach was applied and the NOAEL for butan-2-one O,O',O''-(vinylsilanetriyl)oxime was estimated to be 374.22 ppm (29.99 mg/kg bw/day in males and 35.98 mg/kg bw/day in females).

Supporting study: Read-across from experimental data on analogue substance butanone oxime: 90 days oral repeated dose toxicity study in mice (test method similar to OECD 408):

In the study performed on analogue butanone oxime, groups of 10 mice per sex were given drinking water containing 0 (control), 625, 1,250, 2,500, 5,000, or 10,000 ppm (110, 200, 515, 755, 1330 mg/kg bw/day in males and 145, 340, 630, 1010 and 3170 mg/kg bw/day in females) of test substance. All mice survived until the end of the study. The NOAEL after 90 days of exposure to butanone oxime based on the most sensitive parameter was determined to be 625 ppm (110 mg/kg bw/day) for male mice (basis for effect: hyperplasia of the urinary bladder transitional epithelium) and 1250 ppm (635 mg/kg bw/day) for female mice (basis for effect: infiltration of inflammatory cells into the underlying submucosa in the urinary bladder and degeneration of the olfactoy epithelium). Based on these results, the read-across approach was applied and the NOAEL for butan-2-one O,O',O''-(vinylsilanetriyl)oxime was estimated to be 749.64 ppm (131.94 mg/kg bw/day) for males and 1499.27 ppm (407.80 mg/kg bw/day) for females.

Key study: Read-across from experimental data on analogue substance butanone oxime: 28 days oral repeated dose toxicity study in rats (test method similar to OECD 407):

In the study performed by the Japanese authorities, 7 rats per sex and per dose were orally exposed to the analogue substance butanone oxime at 0 (control), 4, 20 and 100 mg/kg bw/day doses during 28 days. The NOEL for repeat dose toxicity for both males and females was considered to be both 4 mg/kg/day (basis for effect: effects on erythrocyte series, spleen weight increase, hemosiderin granules in the liver (only in females)). Based on these results, the read-across approach was applied and the NOEL for butan-2-one O,O',O''-(vinylsilanetriyl)oxime was estimated to be 4.80 mg/kg bw/day.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:

The study with the longest duration (90-days) performed and lowest NOAEL was chosen.

Justification for classification or non-classification

Based on available data and in accordance with CLP Regulation (EC) No 1272/2008, the substance butan-2-one O,O',O''-(vinylsilanetriyl)oxime is classified as STOT Rep. Exp. 2 since the significant toxic effects were observed in a 90-day repeated-dose study (oral) conducted in experimental animals within value ranges 10 -100 mg/kg bw/day.