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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
4-weeks
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1995
Report date:
1995

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Deviations:
yes
Remarks:
number and sex of animals, humidity, dosage
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

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Char1 es River Breeding Laboratories, Inc., Kingston, New York
- Age at study initiation: 7 weeks
- Weight at study initiation: 159.9-184.7
- Fasting period before study: no
- Housing: Animals were doubly housed in elevated stainless steel wire mesh cages during the first week of acclimation and individual1y housed
thereafter.
- Diet (e.g. ad libitum): Certi f i ed Rodent chow@, No. 5002; Purina Mills Inc., St. Louis, MO; ad libitum; fresh food presented weekly.
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 14 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 15-62
- Photoperiod (hrs dark / hrs light): 12/12


Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE
- Amount of vehicle (if gavage): 10 ml/kg bw
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analyses to determine stability, homogeneity and concentration of the test and/or control materials with carriers under conditions of this study were performed.
Duration of treatment / exposure:
4 weeks
Frequency of treatment:
Daily
Doses / concentrationsopen allclose all
Dose / conc.:
250 mg/kg bw/day (actual dose received)
Dose / conc.:
500 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
15 males/dose
Control animals:
yes, concurrent vehicle
Details on study design:
The study was designed to assess any potential peroxisome proliferation, or any potential changes in hepatic glutathione levels or serum testosterone levels after oral administration of MEKO.


Positive control:
A positive control group recieved clofibric acid, 250 mg/kg bw/day; at a dose volume of 10 mL/kg.
A negative control group received distilled water at a dose volume of 10 mL/kg.

Examinations

Observations and examinations performed and frequency:
Physical observations and body weight measurements were performed on all animals three times pretest and weekly during treatment period. Serum testosterone levels were determined on test days 8, 15, and 29.

After 7, 14, and 28 days of treatment, 5 animals/group were sacrificed, selected organs were weighed and relative organ weight as well as organ/brain weight ratios determined. Liver tissue samples were analysed by light and electron microscopy. Liver homogenates were assayed for protein content, cyanide-insensitive palmitoyl-CoA oxidation activity and for total, reduced, and oxidised glutathione content.

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):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
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
Gross pathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Hepatocellular hypertrophy was seen microscopically after 14 and 28 days.
Histopathological findings: neoplastic:
not examined
Details on results:
MEKO did not produce any significant hepatic peroxisome proliferation in the rat, as indicated by a lack of effect on palmitoyl-CoA oxidation and by electron microscopy. The potential responsiveness of the animals used in this study was confirmed by the marked induction of palmitoyl-CoA in the rats treated with clofibric acid. No effects on testosterone levels were found.

While MEKO was not a peroxisome proliferator in the rat, significant increases in the levels of hepatic glutathione (primarily reduced glutathione) wereobserved in rats given 250 and 500 mg MEKO/kg bw/day for 14 days and 28 days. This lack of an effect after 7 days of dosing correlated with the hepatocellular hypertrophy which was seen microscopically after 14 and 28, but not 7 days of treatment.

Effect levels

Dose descriptor:
LOAEL
Effect level:
250 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Based on significant increases in hepatic glutathione (primarily reduced glutathione) observed after 14 and 28 days.

Target system / organ toxicity

Critical effects observed:
yes
Lowest effective dose / conc.:
250 mg/kg bw/day (actual dose received)
System:
hepatobiliary
Organ:
liver
Treatment related:
yes
Dose response relationship:
yes

Applicant's summary and conclusion

Conclusions:
In rats administered oral doses of MEKO at levels up to 500 mg/kg bw/day for 4 weeks, MEKO did not induce peroxisome proliferation. A significant increase in peroxisomes was produced by clofibric acid demonstrating the ability of the analytical procedures to detect this effect. Similarly, MEKO had no effect on serum testosterone levels. While MEKO was not a peroxisome proliferator in the rat, significant increases i n the levels of hepatic glutathione (primarily reduced glutathione) were observed in rats given 250 and 500 mg MEKOlkglday for 14 days. This lack of an effect after 7 days of dosing correlated with the hepatocellular hypertrophy which was seenmicroscopically after 14 and 28 but not 7 days of treatment.