Registration Dossier

Toxicological information

Developmental toxicity / teratogenicity

Currently viewing:

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:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP compliant guideline study, no restrictions, fully adequate for assessment. The study is included as a read across to a similar substance to include data on a non-rodent species (rabbit.)

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Developmental toxicity evaluation of methyl tertiary-butyl ether (MTBE) by inhalation in mice and rabbits.
Author:
Bevan C, Tyl RW, Neeper-Bradley TL, Fisher LC, Panson RD, Douglas JF & Andrews LS
Year:
1997
Bibliographic source:
Journal of Applied Toxicology, 17, S21-9.
Reference Type:
study report
Title:
Unnamed
Year:
1989

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
EPA OTS 798.4350 (Inhalation Developmental Toxicity Screen)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): MTBE
- Physical state: liquid
- Analytical purity: at least 99% (determined by gas chromatography)

Test animals

Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hazleton-Dutch Laboratories
- Weight at study initiation: at least 2.5 kg
- Housing: individual
- Diet: ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 70-74
- Humidity (%): 48-85
- Air changes (per hr): 14
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
All exposures were conducted in 4.3 m3 stainless-steel and glass inhalation chambers. Airflow in each chamber was approximately 1000 L/min (14 air changes per hour). For the generation of atmospheres, liquid MTBE was metered from a piston pump into a heated glass evaporator. The tempearture was maintained at the lowest level sufficient to vapourize liquid. The resulting vapour was carried into the chamber by a countercurrent air stream that entered the bottom of the evaporator.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Each chamber was analysed for MTBE once every 20 minutes during each 6-hour exposure. A Perkin-Elmer gas chromatograph equipped with a flame ionization detector was used for the measurements.
Details on mating procedure:
Female rabbits were naturally bred to proven fertile males (in-house rabbits from the same supplier) and the day of observed mating (presence of a vaginal plug) was designated gestation day 0.
Duration of treatment / exposure:
gestation days 6-18
Frequency of treatment:
6 hours/day
Duration of test:
29 days
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
1000, 4000 and 8000 ppm
Basis:
other: target concentration
Remarks:
Doses / Concentrations:
1021 (161), 4058 (41) and 8021 (161) ppm (SD between brackets)
Basis:
analytical conc.
No. of animals per sex per dose:
15 females
Control animals:
yes
Details on study design:
The selection of exposure levels was based on a pilot study conducted at concentrations of 0, 1000, 4000 and 8000 ppm. Reduced body weight gain and food consumption was observed at 8000 ppm, as well as a slight reduction in fetal body weight.

Examinations

Maternal examinations:
Clinical observations and food consumption recording were conducted daily and maternal body weight was recorded on gestation day 0, 6, 9, 12, 15, 18, 24 and 29.
All maternal livers were weighed and liver sections were fixed in 10% buffered formalin.
The abdominal and thoracic cavities were examined grossly.
Ovaries and uterine content:
The reproductive organs were examined grossly. Corpora lutea were counted and gravid uterine weight as well as the number of live and and dead fetuses and resoprtion sites were recorded. Apparent non-gravid uteri were placed in a 10% ammonium sulfide solution for detection of early resorptions.
Fetal examinations:
Live fetuses were weighed, their sex determined and inspected for external malformations (including cleft) palate and variations. The fetuses from each litter were inspected for visceral abnormalities by longitudinal dissection. The heads of the fetuses were fixed in Bouin's solution and analysed. The remaining intact fetuses were eviscerated, fixed in ethanol and processed with alizarin red S for skeletal examination.
Statistics:
The unit of comparison was the pregnant female of the litter. Quantitative continuous variables were statistically analyzed by means of Levene's test for equal variances, ANOVA and t-tests with Bonferroni probabilities for pairwise comparisons. Non-parametric data were analyzed using the Kruskal-Wallis test followed by the Mann-Whitney U test.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
None of the dams aborted or died during the study. The highest dose group suffered from a negative weight development (p<0.01) on gestation days 6-18, which was the treatment period. This was associated with the reduced food consumption during this time. When the maternal weight changes were corrected for gravid uterine weight they were substantially but not statistically significantly lowered when compared to controls. The only treatment related effect found on maternal rabbits was 15% increased liver weight in the 8000 ppm group and over 70% reduced food consumption. Gestation parameters and other reproduction data were similar along all the groups.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEC
Effect level:
8 000 ppm
Basis for effect level:
other: developmental toxicity
Dose descriptor:
NOAEC
Effect level:
4 000 ppm
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
The pregnancy rates remained between 80%-100% in all groups.

There were no significant effects of treatment on any gestational parameters, including number of ovarian corpora lutea, number of total, non-viable (early or late resorptions or dead fetuses) or viable implantations, per cent pre- or post-implantation loss or sex ratio (% male fetuses). Fetal body weights per litter were statistically equivalent across all groups. There were no treatment-related changes in the incidence of external visceral, skeletal or total malformations. There were also no significant differences in the incidence of external visceral skeletal or total variations.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion