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Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1989
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study design deviates from OECD Guidelines, but is still scientifically valid and well reported, for read-across substance
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1991
Report date:
1989

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
other: NTP study design
Deviations:
yes
Remarks:
non-pregnant females included to test for maternal effects
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Reference substance name:
Methyl ethyl ketone
IUPAC Name:
Methyl ethyl ketone
Constituent 2
Chemical structure
Reference substance name:
Butanone
EC Number:
201-159-0
EC Name:
Butanone
Cas Number:
78-93-3
Molecular formula:
C4H8O
IUPAC Name:
butan-2-one
Test material form:
other: clear colorless liquid
Details on test material:
> 99.9% purity

Test animals

Species:
mouse
Strain:
CD-1
Details on test animals or test system and environmental conditions:
Housing: stainless steel cages - sexes separated
Food and water: Ad libitum
Room temperature: 72 - 78 F
Relative humidity: 40-70%
Light cycle: 12 hours
Pathogen screen: yes - 10 animals sacrificed during quarantine to ensure absence of significant pathogens/lesions.

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
Virgin females were added in addition to the treated and concurrent controls to test the effect of pregnant status on maternal toxicity.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Test material concentration was monitored every 4 hours, with a gas chromatographic system having a detection limit of 0.5 ppm, and a precision of 1%.
Details on mating procedure:
Not provided
Duration of treatment / exposure:
10 days
Frequency of treatment:
7 hours/day, 7 days/week
Duration of test:
16 days
No. of animals per sex per dose:
10 (controls)
30 (MEK treatment groups)
Control animals:
yes, sham-exposed

Examinations

Maternal examinations:
Body weights were obtained throughout the study period, and uterine and fetal body weights were obtained at sacrifice on the 18th gestational day.
Ovaries and uterine content:
Uterine implants were enumerated and their status recorded.
Fetal examinations:
Live fetuses were sexed and examined for gross, visceral, skeletal, and soft-tissue craniofacial defects.
Statistics:
Means and standard deviations analysed using SAS General Linear Models. ANOVA with Tukey's T-test was used to separate treatment-related effects. The litter was used as the basis for analysis of fetal variables.
Indices:
* Implantations/dam
* Live fetuses/litter
* Resorptions/litter
* Dead fetuses/litter
* Litters with resorptions
* % males
* No. live malformed fetuses/litter
* No. litters with malformed fetuses
Historical control data:
Not shown

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
Exposure of pregnant mice to these concentrations of MEK did not result in overt maternal toxicity although there were treatment-related increases in relative liver and kidney weights which was statistically significant for the 3000-ppm group.

Effect levels (maternal animals)

Dose descriptor:
NOAEC
Effect level:
1 000 ppm (nominal)
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
Mild developmental toxicity was evident at 3000-ppm as a reduction in mean fetal body weight. This reduction was statistically significant for the males only, although the relative decrease in mean fetal body weight was the same for both sexes.

There was no increase in the incidence of intrauterine death in the fetuses of mice exposed to MEK, but there was an increased incidence of misaligned sternebrae (a variation) which was correlated to increasing exposure concentration. The increase was statistically significant for the 3000-ppm group. Although there were no significant increases in the incidence of malformations, several malformations were present at a low incidence which were not observed in the O-ppm group or in the contemporary control data; cleft palate (1 fetus), fused ribs (2), missing vertebrae (1), and syndactyly (5 [all in the same litter]).

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

There were no differences in MEK toxicity observed between pregnant and non-pregnant females, and all shown comparisons were limited to pregnant animals.

Applicant's summary and conclusion

Conclusions:
In summary, pregnant Swiss (CD-1) mice appear to be relatively insensitive to the toxic effects of MEK at the exposure levels employed in this study. However, the offspring of the mice exhibited significant signs of toxicity at the 3000-ppm exposure level. Neither maternal nor developmental toxicity were observed at 1000 ppm MEK or below.

Executive summary:

Swiss (CD-1) mice were exposed to 0, 400, 1000 or 3000 ppm MEK vapors for 7 hours/day, 7 days/week for 10 consecutive days (GD 6 -15). Groups consisted of ten virgin females and 30 plug-positive females.

Exposures to these concentrations of MEK did not result in overt maternal toxicity although there were slight, treatment-related increases in relative liver and kidney weights which was statistically significant for the 3000 ppm group. Mild developmental toxicity was evident at 3000 ppm as a slight reduction in mean fetal body weight. This reduction was statistically significant for the males only, although the relative decrease in mean fetal body weight was the same for both sexes.

There was no increase in the incidence of intrauterine death in the fetuses of mice exposed to MEK, but there was an increased incidence of misaligned sternebrae (a variation) which was correlated to increasing exposure concentration. The increase was statistically significant for the 3000 ppm group. Although there were no significant increases in the incidence of malformations, several malformations were present at a low incidence which were not observed in the O-group or in the contemporary control data; cleft palate (1 fetus), fused ribs (2), missing vertebrae (1), and syndactyly (5 [all in the same litter]).

In summary, pregnant Swiss (CD-1) mice appear to be relatively insensitive to the toxic effects of MEK at the exposure levels employed in this study. However, the offspring of the mice exhibited significant signs of toxicity at the 3000 ppm exposure level. Neither maternal nor developmental toxicity were observed at 1000 ppm MEK or below.