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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1990
Report date:
1990

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
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:
(NE)-N-butan-2-ylidenehydroxylamine
Test material form:
liquid

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Kingston, NY
- Age at study initiation: 6 weeks
- Weight at study initiation: Males 113-139 g; Females 93-106 g
- Fasting period before study: no
- Housing: Individually housed in suspended stainless steel wire mesh cages
- Diet (e.g. ad libitum): Purina Rodent Laboratory Chow Brand Animal Diet #5001, ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 15 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-24
- Humidity (%): 17-90
- Photoperiod (hrs dark / hrs light): 12/12


Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Remarks on MMAD:
MMAD / GSD: Particle size distribution determinations indicated that there was no measurable amounts of MEKO present as an a aerosol.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
MEKO exposure levels were analyzed using a MIRAN Ambient Air Analyzer equipped with an Omniscribe strip chart recorder. The test atmosphere was drawn through a Balston@ filter, via 1/4" Teflon aline in to the MIRAN. A General Electric pump was used to draw the sample through the MIRAN in to a Marsh Vacuum gauge and a Dwyer@ flowmeter regulated by a Nupro metering valve. The MIRAN was wrapped with a Foxboro heating jacket control1ed by a Fenwall thermocouple (set at 50°C). Samples were withdrawn hourly during each exposure from the normal sampling portal. The resultant absorbance was read off of a Micronta@ LCD Bench Top digital multimeter. The exposure levels were then determined by compar.ison of the resultant absorbance to a calibrated response curve constructed using the same instrument settings.
Duration of treatment / exposure:
4 weeks (total of 20 exposures)
Frequency of treatment:
6 hours/day, 5 days/ week
Doses / concentrationsopen allclose all
Dose / conc.:
30 ppm (nominal)
Remarks:
25 ppm (analytical concentration); 90 mg/m³
Dose / conc.:
101 ppm (nominal)
Remarks:
102 ppm (analytical concentration); 360 mg/m³
Dose / conc.:
340 ppm (nominal)
Remarks:
404 ppm (analytical concentration); 1440 mg/m³
No. of animals per sex per dose:
10/sex/dose
Control animals:
yes, sham-exposed

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily in morning and afternoon

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Pretest and weekly thereafter.

BODY WEIGHT: Yes
- Time schedule for examinations: Three times pretest, weekly thereafter and at termination.

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean weekly diet consumption calculated as g food/kg body weight/week: Yes

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Just prior to termination
- Anaesthetic used for blood collection: Yes
- Animals fasted: Yes
- How many animals:10 animals per sex per group
- Parameters examined: Methemoglobin concentration, hemoglobin concentration, hematocrit, eythrocytes count, reticulocyte count, platelet count, mean corpuscular volume calculated, mean corpuscular hemoglobin calculated, mean corpuscular hemoglobin concentration calculated, and total and ifferential leukocyte counts.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, performed on all animals dying accidentally or killed at the scheduled sacrifice interval . Examinations included the external surface, all orifices, the cranial cavity, carcass, the external and sectioned surfaces of the brain and spinal cord, the thoracic, abdominal and pelvic cavities and their viscera and cervical tissues and organs. Animals were fasted prior to scheduled sacrifice.
ORGANS WEIGHED: adrenal s; brain, heart, kidneys, liver, lungs, ovaries, spleen, and testes
HISTOPATHOLOGY: Yes, the livers of all animals were examined.
Statistics:
Body weights, food consumption, hematology parameters, organ weights, organ/body and organ/brain weight ratios were analyzed. Mean values of all exposure groups were compared to control at each time interval. Statistically significant differences from control were indicated.

Results and discussion

Results of examinations

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:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Exposure to 404 ppm produced significant changes in most hematology parameters for both male and female rats (including incresead methemoglobin, three fold increase in reticulocytes, 30% increase in platelets, 10% increase in MCV and MCH and a 13% increase in total leucocyte counts). Changes also included an appr. 10% decrease in hemoglobin, hematocrit, erythrocytes and MCHC. Methemoglobin was also increased in the 102 ppm female rat group.
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Absolute and relative weights of liver and spleen were increased in male and female rats of the 400 ppm group.
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No related histological effects were observed.
Histopathological findings: neoplastic:
no effects observed
Details on results:
Exposure to 404 ppm produced significant changes in most hematology parameters for both male and female rats (including incresead methemoglobin, three fold increase in reticulocytes, 30% increase in platelets, 10% increase in MCV and MCH and a 13% increase in total leucocyte counts). Changes also included an appr. 10% decrease in hemoglobin, hematocrit, erythrocytes and MCHC. Methemoglobin was also increased in the 102 ppm female rat group. Absolute and relative weights of liver and spleen were increased in male and female rats of the 400 ppm group. However, no related histological effects were observed.

Effect levels

Dose descriptor:
NOAEC
Effect level:
90 mg/m³ air (analytical)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Based on increased methaemoglobin in female rats and increased absolute or relative organ weights (liver and spleen) of male and female rats

Target system / organ toxicity

Critical effects observed:
yes
Lowest effective dose / conc.:
360 mg/m³ air (analytical)
System:
haematopoietic
Organ:
blood
Treatment related:
yes
Dose response relationship:
yes

Applicant's summary and conclusion

Conclusions:
All animals exposed to vapors of methyl ethyl ketoxime (MEKO) at concentrations up to 404 ppm for 4 weeks survived the duration o f the study. There were no gross external signs of toxicity or changes in body weight or food consumption in animals exposed to MEKO. Exposures to 404 ppm produced significant changes in hematology parameters of both male and female rats involving increased methemoglobin levels, reticulocytosis and decreased hemoglobin, hematocrit and erythrocyte counts. Methemoglobin levels were also slightly elevated in the 102 ppm-exposed female rats. Increased absolute or relative organ weights were observed in the liver of male and female rats, and in the spleen of male and female rats. Gross postmortem aberrations were unremarkabl e and microscopic examination o f the livers found no MEKO-related changes.