Acetone oxime

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The study was conducted according to OECD guidelines under GLP conditions

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1990

Report date:

1990

Reference 2

Reference Type:

publication

Title:

Developmental toxicity studies of methyl ethyl ketoxime (MEKO) in rats and rabbits.

Author:

Derelanko, Michael J., Rinehart, W.E. and Rodwell, Dean E.

Year:

2003

Bibliographic source:

Drug and Chemical Toxicology 26(3): 147-168, 2003.

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Butanone oxime

EC Number:

202-496-6

EC Name:

Butanone oxime

Cas Number:

96-29-7

IUPAC Name:

butan-2-one oxime

Test material form:

other: liquid

Details on test material:

- Name of test material (as cited in study report): Methyl ethyl ketoxime (MEKO), from Allied-Signal Inc., Morristown, NJ
- Physical state: Liquid
- Analytical purity: >99%
- Lot/batch No.: 912012
- Stability under test conditions: Stability and homogeneity of the test material in the vehicle were determined at concentrations of 1 and 100 mg/mL using gas chromatography.
- Storage condition of test material: room temperature

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Inc., Kingston, NY
- Age at study initiation: 90 days old
- Weight at study initiation: 222 - 291 g
- Housing: Individually in wire-mesh stainless steel cages
- Diet (e.g. ad libitum): Purina Certified Rodent Meal No. 5002
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 13 days prior to mating

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17.7 - 26.1
- Humidity (%): 64-70
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

Dosage solutions were administered orally by gavage as a single dose daily from gestation day 6 through gestation day 15. Individual doses were calculated using the most recent body weight data. Dose levels were 0 (distilled water control), 60, 200 or 600 mg MEKO/kg body weight. The dose volume was 10 mL/kg.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The test substance, MEKO, was analyzed for purity and the test solutions were analyzed for homogeneity and stability by a gas chromatographic
procedure using a Poropack P column and a flame ionization detector. Overall the material used was > 99% pure and recoveries were ~ 99-100%.
Stability over the course of the dosing period was > 93%.

Details on mating procedure:

Selected females were cohabitated with male rats of the same strain and source. Evidence of mating was determined by the presence of a copulatory plug in the vagina or a sperm positive vaginal smear. The day evidence of copulation was observed was designated day 0 of gestation and the female rats were assigned consecutively, in a block design, to study groups.

Duration of treatment / exposure:

Gestation Days 6-15.

Frequency of treatment:

Daily.

Duration of test:

Until sacrifice on Gestation Day 20.

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 60, 200 or 600 mg/kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

25 females/dose

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Dose levels for this rat developmental toxicity studies were based on results of a range finding study in which groups of 6 pregnant rats received MEKO at levels of 25, 100, 200 or 400 mg/kg bw/day on gestation days 6-15. Hematological status was evaluated by measuring methemoglobin and reticulocyte levels. Mothers were sacrificed on gestation day 20 for Cesarean ection evaluations. Fetal evaluations in the range finding study were limited to external observations. All dams survived treatment. Clinical signs of toxicity were observed at 400 mg/kg bw/day including transient central nervous system depression. Dose-related increases in the levels of reticulocytes and methemoglobin occurred at all dose levels throughout gestation. Methemoglobin levels at 400 mg/kg bw/day were as high as 39%. Enlarged black/purple spleens were found at dose levels of 100 mg/kg bw/day and above. These effects suggested anemia was induced by the treatment. No adverse effects on gestational parameters such as the number of resorptions, viable fetuses and fetal weights were found. No fetal external malformations or developmental variations were observed. Statistical analyses were not performed in the range finding study.

Examinations

Maternal examinations:

- During the experimental period, all animals were observed daily for clinical signs of toxicity including physical or behavioral abnormalities.
- Mortality checks were perfomed twice daily, in morning and afternoon.
- During the dosing period, the females were observed between one-half hour and two hours following dosing for overt signs of toxicity.
- Body weights of individual animals were measured and recorded on gestation days 0, 6, 9, 12, 16 and 20. Body weight changes were calculated for the following gestation intervals: 0.-6, 6-9, 9-12, 12-16, 16-20, 6-16 and 0-20.
- Food consumption was measured (as g/animal/day and g/kg/day) during gestation days 0-6, 6-9, 9-12, 12-16 and 16-20.

Ovaries and uterine content:

After sacrifice on day 20, the uterus was removed from the body, examined externally, weighed, and then opened fo an internal examination. The number of viable and nonviable fetuses, early and late resorptions was recorded beginning with the left distal uterine horn, noting the position of the cervix, and continuing with the right uterine horn. Corpora lutea were counted and recorded for each ovary. Uteri with no macroscopic evidence of implants were placed in 10% aqueous ammonium sulfide for detection of early embryolethality.

Fetal examinations:

Fetuses were examined for external, visceral and skeletal abnormalities. Developmental malformations and variations were classfied based on the severity of the anatomical change(s) and their potential interference with organ and/or body functions.

Statistics:

Statistical analyses were performed by a Digital Vax 11/730 computer. All analyses were two-tailed with a minimal significance level of 5%. One-way analysis of variance followed by Dunnett's test was used to analyze maternal and fetal data including body weights, food consumption, number of viable fetuses, implantation sites, and corpora lutea. The Mann-Whitney U test was used to compare post-implantation loss, dead fetuses, and resorptions. Fetal sex ratios were analyzed using the Chi-Square test. Fisher's Exact test was used to analyze the incidence and number of fetal malformations. and variations utilizing the dam (litter) as the experimental unit.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
Clinical signs of toxicity were observed at 200 and 600 mg/kg bw/day. These clinical signs (signs of general nervous system depression) were generally transient and had disappeared before dosing on the following day. Also, body weight losses and/or reduced body weight gain and reduced food consumption was seen in these dose groups. No treatment-related clinical signs were observed at the 60 mg/kg/day treatment level. Enlarged spleens were seen at necropsy in all MEKO-treated animals but not in the controls. Thus, the NOEL for the maternal animals was not established.

Effect levels (maternal animals)

1

Dose descriptor:

NOAEL

Effect level:

600 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

2

Dose descriptor:

LOAEL

Effect level:

60 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Maternal oral exposure to methyl ethyl ketoxime (MEKO) at concentrations up to 600 mg/kg bw/day during gestation days 6 through 15 did not induce developmental toxicity in rats. In this study, the NOEL for developmental toxicity in the rat was 600 mg/kg bw/day. Maternal toxicity was noted in all MEKO treated rats (60, 120 and 600 mg/kg bw/day).