Registration Dossier

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: see 'Remark'
Remarks:
Guideline study with acceptable restrictions (tabulated results not available; exposure at gestation day 6-15). Read across to Methylvinylether (CAS 107-25-5) was done. Both substances are vinylethers only differing in the side chain. Thus, read across is justified.

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1994
Report Date:
1994
Reference Type:
study report
Title:
Unnamed
Year:
2005
Report Date:
2005

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes
Remarks:
Bushy Run Research Center
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: liquid

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
- Source: Charles River Lab
- Animals per dose: 25 time-pregnant rats per dose level
- Acclimatisation: 2 weeks prior to mating
- Mean body weight range at gestation day 0 225-227 g
- Food and water: Tap water and certified diet ad libitum (not during exposure)
- Housind: Dams housed singly
- Temperature: 66-77°F
- Light: day/night cycle: 12/12 h
- Humidity: rel. air humidity: 40-70%

Administration / exposure

Route of administration:
inhalation
Type of inhalation exposure (if applicable):
whole body
Vehicle:
other: air
Details on exposure:
The rats were exposed to vinyl methyl ether vapour or filtered air for 6 h/d on gestational days 6 through 15 in stainless steel inhalation chambers. The chamber volume was 900 l, the airflow 200 l/min (13 changes/h). Target concentrations were 0; 5000; 10000 or 19500 ppm. Temperature and humidity were recorded.
MVE vapour introduced directly into the chambers from MVE cylinder (flowmeter control) after dilution with air.
Temperature: ranged from 21.1 to 22.4°C
Relative humidity: ranged from 37.4 to 46.2%
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The concentration of MVE in each chamber was monitored twice per hour during each 6-hour exposure by gas chromatography.
Details on mating procedure:
One male mated with one female; vaginal plugs controlled daily; gestation day (GD) 0 was the day the vaginal plug was detected.
Duration of treatment / exposure:
GD 6-15
Frequency of treatment:
Once daily, 6 hours/day
Duration of test:
GD 21
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0; 5000; 10000; 19500 ppm (12; 24; 47 mg/L)
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
0, 4946+-216, 10249+-465, and 19407+-796 ppm
Basis:
analytical conc.
average +- standard deviation
No. of animals per sex per dose:
25 pregnant dams
Control animals:
yes, concurrent vehicle
Details on study design:
Randomisation based on body weight at GD0

Examinations

Maternal examinations:
Twice daily clinical observations
Body weight GD 0, 6, 9, 12, 15, 18, 21
Food and water consumption measured GD 0-21 in 3-day intervals
The dams were necropsied on gestational day (gd) 21 and evaluated for body weight. Maternal liver, kidneys, and lungs were weighed and retained in fixative.
Ovaries and uterine content:
Gravid uterine weight and pregnancy status determined;
Fetal examinations:
All fetuses were dissected from the uterus, counted, weighed, examined for determination of gender and for external variations and malformations (including cleft palate). Approximately one-half of the live fetuses in each litter were examined for visceral and craniofacial malformations and variations. The remaining one-half of the fetuses were examined for skeletal malformations and variations after staining with alizarin red S.
Statistics:
The data for quantitative continuous variables were intercompared for the exposure groups and the control group by use of Levene's test homogeneity of variance, by ANOVA, and by t-tests. T-tests were used if the ANOVA was significant to delineate which groups differed from the controls. If Levene's test indicated homogeneous variances, the groups were compared by ANOVA for equal variances. If Levene's test indicated heterogeneous variances, groups were compared by an ANOVA for unequal variances, followed, when appropriate, by t-tests. Frequency data were compared using Fisher's exact test. All statistical tests, except the frequency comparisons, were performed using computer software. The probability value of p<0.05 (two-tailed) was used as the critical level of significance for all tests.
Historical control data:
yes

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
Mortality: No mortality occurred during the study. Pregnancy rate was equivalent for all groups and ranged form 96 - 100 %. No females aborted or delivered early. At scheduled necropsy, one female each from 5000 and 10000 ppm group was not pregnant.
Clinical signs of toxicity: There were no exposure-related clinical signs observed in any exposure group.
Body weights: body weight decreases were noted as described below. p<0.05 indicates statistically significant differences compared to the control animals group. 19500 ppm group: slightly decreased on gd 9; (p<0.05) on gd 12 and 15; slightly on gd 18 and 21. 10000 ppm group: slightly decreased on gd 12; (p<0.05) on gd 15; 5000 ppm group: slightly decreased on gd 12; (p<0.05) on gd 15; Body weight gain was significantly reduced in the 19500 ppm group on most of the 3-days intervals, and in the 10000 and 5000 ppm groups on some of the 3-day intervals. Following the exposure period, body weight gain was comparable or slightly higher in the exposure groups when compared to the controls.
Food consumption was decreased in the 195000 and 10000 ppm groups during the exposure period. Food consumption was also reduced in the 5000 ppm group early in the exposure period (gd 6-9).
Maternal water consumption was increased, but the effect was not dose-related.
Terminal maternal body weight were slightly reduced, and corrected weight change was clearly reduced in all treatment groups. Gravid uterine weight and absolute and relative weights of lungs and kidneys were equivalent across groups. Absolute liver weights were slightly increased (2, 3, and 6% for the 5000m, 10000, and 19500 ppm groups, respectively. Increased relative liver weight was noted in all exposure groups.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
LOAEC
Effect level:
5 000 ppm
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEC
Effect level:
5 000 ppm
Basis for effect level:
other: developmental toxicity
Dose descriptor:
LOAEC
Effect level:
10 000 ppm
Basis for effect level:
other: developmental toxicity

Results (fetuses)

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

Details on embryotoxic / teratogenic effects:
Reproductive parameters: there were no effect of exposure on gestational parameters including resorptions, pre- and postimplantation losses, percentages of live fetuses, and sex ratios. There was no effect of exposure on fetal body weight/litter.
Pups
There were no significant effects of exposure on the incidence of visceral, skeletal, or external malformations by category or in total malformations. An increased incidence of one common external variation, ecchymosis in the trunk region, was noted in the 19500 ppm group. In addition, several skeletal variations involving various regions of the skeleton were observed for the 19500 and 10000 ppm groups. These included: unossified and poorly ossified cervical centra, reduced number of (ossifying) caudal segments, unossified anterior arch of the atlas, and poorly ossified sternebra. In addition increased incidences of all unossified proximal phalanges (forelimb and hindlimb), and some unossified metatarsals (hindlimb) occurred only in the 19500 ppm group. Overall, maternal toxicity was observed at all concentration levels used in this study. No embryolethality or teratogenic effects were observed. However, a concentration-dependent profile of delayed skeletal developmental was observed in all dose groups. Based on these results a NOAEL for maternal toxicity could not be established. Fetotoxicity was noted at all dose levels, thus a NOAEC for fetotoxicity could not be established in the main study. The NOAEC for teratogenicity/ embryolethality was 5000 ppm.
Re-analysis of this NOAEC for developmental toxicity see "Overall Remarks" (below).

Effect levels (fetuses)

Dose descriptor:
NOAEC
Effect level:
19 500 ppm
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Variations of the anterior arch of the atlas

Re-analysis of available data (see Overall Remarks)

Combined incidence of all 3 arch variations

% of litters at 0, 5000, 10000, 19500 ppm was 100, 100, 100, 100, respectively

% of fetuses was 95.2, 88.6, 95.8, 97.0 at 0, 5000, 10000, 19500 ppm, respectively

Conclusion: no statistically or biologically significant effects

Applicant's summary and conclusion

Conclusions:
Maternal toxicity: LOAEC = 5000 ppm or 12 mg/L.
Developmental toxicity: NOAEC = 5000 ppm or 12 mg/L.
Teratogenicity: NOAEC = 19500 ppm or 47 mg/L.
Executive summary:

Guideline study with acceptable restrictions (tabulated results not available).

In this developmental toxicity study 25 pregnant Sprague-Dawley rats were exposed (whole body) 6 h/day to 0, 5000, 10000, or 19500 ppm (12; 24; 47 mg/L) at gestation day 6 -15. The dams were sacrificed at gestation day 21. Maternal toxicity was noted at all dose levels. Signs of toxicity included decreased maternal body weights, body weight gain, and food consumption during the exposure period. In addition, relative maternal liver weight was increased in treated animals (questionable relevance). Reproductive parameters were not affected at any dose level. Developmental toxicity was noted at the mid and high dose levels, taking into account the above cited re-evaluation of the skeletal findings, substantiated by the increased incidence of skeletal variations, mostly resulting from retarded ossification. The incidence of malformations was not increased, thus no teratogenicity was noted.

Conclusion: Maternal toxicity: LOAEC = 5000 ppm or 12 mg/L. Developmental toxicity: NOAEC = 5000 ppm or 12 mg/L. Teratogenicity: NOAEC = 19500 ppm or 47 mg/L.