Ethyl methyl ketoxime

エチルメチルケトキシム

[CAS No. 96-29-7]

2-Butanone oxime

2-ブタノンオキシム

Molecular formula: C4H9NO Molecular weight: 87.12

ABSTRACT

Ethyl methyl ketoxime was studied for oral toxicity in rats in a 28-day repeat dose toxicity test at doses of 0, 4, 20 and 100 mg/kg/day. In the repeat dose toxicity test, 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 α1-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 is considered to be both 4 mg/kg/day.

Ethyl methyl ketoxime was not mutagenic to Salmonella typhimurium TA100, TA98, TA1535, TA1537 and Escherichia coli WP2 uvrA, with or without an exogeneous metabolic activation system.

Ethyl methyl ketoxime induced neither structural chromosomal aberrations nor polyploidy in CHL/IU cells up to the limit concentration of 10 mM (0.87 mg/ml), in the absence or presence of an exogenous metabolic activation system.

SUMMARIZED DATA OF THE STUDIES

1. Repeat Dose Toxicity １）

Purity:99.0%
Test species/strain:Rat/Crj:CD (SD)
Test method:Guidelines for 28-Day Repeat Dose Toxicity Testing for Chemicals (Japan)
　Route:Oral (gavage)
　Doses:0 (vehicle), 4, 20, 100 mg/kg/day
　Number of animals/group
　Administration period:Males and females, 14, 7, 7 and 14/group for the 0, 4, 20 and 100 mg/kg cases, respectively
　Recovery period:Males and females, 7 and 7/group for the 0 and 100 mg/kg cases, respectively
　Vehicle:Olive oil
　Administration period:Males and females, 28 days
　Terminal kill:Days 29 or 43
GLP:Yes

　Test results:

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. 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 α1-globulin fraction, and increases in total bilirubin and total cholesterol in males given 100 mg/kg. 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. Autopsy revealed hypertrophy of the spleen in males given 20 mg/kg and above and in females given 100 mg/kg. 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. No effects were detected in terms of general condition, body weights, food consumption or myelography. Most of the changes observed had disappeared or were decreased their degrees 14 days after withdrawal. The NOELs for repeat dose toxicity for males and for females are considered to be both 4 mg/kg/day.

2. Genetic Toxicity

2-1. Bacterial test ２）

Purity:99.98%
Test species/strains:Salmonella typhimurium TA100, TA1535, TA98, TA1537, Escherichia coli WP2 uvrA
Test methods:Guidelines for Screening Mutagenicity Testing of Chemicals (Japan) and OECD (471 and 472)
　Procedures:Plate incorporation method
　Solvent:Acetone
　Positive controls:-S9 mix, 2-(2-Furyl)-3-(5-nitro-2-furyl)acrylamide (TA100, WP2, TA98), Sodium azide (TA1535)and 9-Aminoacridine (TA1537),
+S9 mix, 2-Aminoanthracene (five strains)
　Doses:0, 313, 625, 1250, 2500 and 5000 μg/plate in five strains, -S9 mix and +S9 mix.
　S9:Rat liver, induced with phenobarbital and 5,6-benzoflavone
　Plates/test:3
　Number of replicates:2
GLP:Yes

　Test results:
This chemical did not induce gene mutations in the S. typhimurium and E. coli strains. Toxicity was not observed at 5000 μg/plate in five strains with either without S9 mix or with S9 mix.

Genetic effects:
Salmonella typhimurium TA100, TA1535, TA98, TA1537
+?-
Without metabolic activation: [ ][ ][*]
With metabolic activation: [ ][ ][*]

Escherichia coli WP2 uvrA
+?-
Without metabolic activation: [ ][ ][*]
With metabolic activation: [ ][ ][*]

2-2. Non-bacterial in vitro test (chromosomal aberration test) ２）

Purity:99.98%
Type of cell used:Chinese hamster lung (CHL/IU) cells
Test method:Guidelines for Screening Mutagenicity Testing of Chemicals (Japan)
　Solvent:Acetone
　Positive controls:-S9 mix, Mitomycin C
+S9 mix, Cyclophosphamide
　Doses:-S9 mix (continuous treatment): 0, 0.22, 0.44, 0.87 mg/ml
-S9 mix (short-term treatment): 0, 0.22, 0.44, 0.87 mg/ml
+S9 mix (short-term treatment): 0, 0.22, 0.44, 0.87 mg/ml
　S-9:Rat liver, induced with phenobarbital and 5,6-benzoflavone
　Plates/test:2
GLP:Yes

　Test results:
This chemical did not induce structural chromosomal aberrations with and without an exogeneous metabolic activation system under the conditions of this experiment.

Genotoxic effects:
　clastogenicitypolyploidy
+?-+?-
Without metabolic activation: [ ][ ][*] [ ][ ][*]
With metabolic activation: [ ][ ][*] [ ][ ][*]

1)The tests were performed by the Safety Research Institute for Chemical Compounds Co., Ltd., 363-24, Shin-ei, Toyohira-ku, Sapporo, Hokkaido, 004, Japan. Tel +81-11-885-5031 Fax +81-11-885-5313
2)The tests were performed by the Hatano Research Institute, Food and Drug Safety Center, 729-5 Ochiai, Hadano-shi, Kanagawa, 257, Japan. Tel +81-463-82-4751 Fax +81-463-82-9627

Ethyl methyl ketoxime

エチルメチルケトキシム


[CAS No. 96-29-7]

2-Butanone oxime/Ethyl methyl ketone oxime

2-ブタノンオキシム/エチルメチルケトンオキシム

Molecular formula: C4H9NO　　　　　Molecular weight: 87.12

ABSTRACT

Ethyl methyl ketoxime was studied for oral toxicity in rats in an OECD preliminary reproductive toxicity screening test at doses of 0, 10, 30 and 100 mg/kg/day.

In the repeat dose toxicity, no dead animals were found in any groups. There were no adverse effects of test substance on general condition, body weight or food consumption throughout the administration period. The spleen weights of the animals in both sexes receiving 30 mg/kg or more showed significant increase compared with the control group values, and liver weights in males and heart weights in females of the 100 mg/kg group were also increased. In the necropsy findings, black and enlargement of spleen were observed in both sexes receiving 30 mg/kg or more of test substance. As histopathological findings, congestion, deposition of pigment and extramedullary hematopoiesis in the spleen, deposition of glycogen, deposition of pigment in Kupffer cells and extramedullary hematopoiesis in the liver and deposition of brown pigment in the kidney were observed in both sexes receiving 10 mg/kg or more. The incidences or degrees of these findings in the treatment groups were greater than those in the control group.

The NOEL for repeat dose toxicity in parent animals in both sexes is considered to be less than 10 mg/kg/day.

In terms of reproductive/developmental toxicity, delivery index in the 100 mg/kg group showed significant decrease compared with the control group value. With regard to the neonates, no adverse effects of the test substance were observed in any groups.

NOELs for reproductive/developmental toxicity are considered to be 100 mg/kg/day for males, 30 mg/kg/day for females, and 100 mg/kg/day for the F1 generation.

SUMMARIZED DATA FROM THE STUDIES

1. Repeat Dose and Reproductive/Developmental Toxicity１）

Purity:99.99 wt%
Test species/strains:Rat/Crj:CD(SD)
Test method:OECD Preliminary Reproductive Toxicity Screening Test
　Route:Oral(gavage)
　Doses:0(Vehicle), 10, 30, 100 mg/kg/day
　Number of animals:Males, 12; females, 12/group
　Vehicle:Distilled water for injection
　Administration period:Males, 48 days
Females, from 14 days before mating to day 3 of lactation
　Terminal kill:Male, day 48
Females, day 4 of lactation
GLP:Yes

　Test results:

<Repeat dose toxicity>

In the repeat dose study, no animals were found dead in any groups. There were no adverse effects of the test substance on general condition, body weight or food consumption throughout the administration period.

The spleen weights of the animals in both sexes receiving 30 mg/kg or more showed significant increase as compared with the control group values, and liver weights in males and heart weights in females of the 100 mg/kg group were also elevated. In the necropsy findings, black and enlargement of spleen were observed in both sexes receiving 30 mg/kg or more of the test substance. As histopathological findings, congestion, deposition of pigment and extramedullary hematopoiesis in the spleen, deposition of glycogen, deposition of pigment in Kupffer cells and extramedullary hematopoiesis in the liver and deposition of brown pigment in the kidney were observed in both sexes receiving 10 mg/kg or more. The incidences or degrees of these findings in treatment groups were greater than in the control group.

The NOEL for repeat dose toxicity in parent animals in both sexes is considered to be less than 10 mg/kg/day.

<Reproductive and Developmental toxicity>

As for the reproductive ability of parent animals, no effects were detected in males, while the delivery index in the 100 mg/kg group showed significant decrease compared with control group value. With regard to the effects on neonates, no adverse effects of the test substance were observed in any group.

On the basis of these findings , NOELs for reproductive/developmental toxicity are considered to be 100 mg/kg/day for males, 30 mg/kg/day for females,and 100 mg/kg/day for the F1 generation,

1)The tests were performed by the Biosafety Research Center, Foods, Drugs and Pesticides(An-pyo Center), Japan, 582-2 Shioshinden Arahama, Fukude-cho, Iwata-gun, Shizuoka, 437-1213, Japan. Tel +81-538-58-1266 Fax +81-538-58-1393