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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
DATA QUALITY: Study was conducted in accordance with a recognized scientific procedure for determining the developmental toxicity of a test substance when administered repeatedly via inhalation. Study was conducted in compliance with GLP regulations. The study meets national and international scientific standards (OECD 414) and provides sufficient information to support the conclusions regarding the NOAEL and the LOAEL demonstrated from the study data.

Data source

Reference
Reference Type:
publication
Title:
Developmental toxicities of methacrylic acid, ethyl methacrylate, n-butyl methacrylate, and allyl methacrylate in rats following inhalation exposure.
Author:
Saillenfait AM, Bonnet P, Gallissot F, Peltier A, Fabries JF
Year:
1999
Bibliographic source:
Toxicol Sci 50: 136-145

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
ethyl methacrylate, purity: no data
Specific details on test material used for the study:
99% pure

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
SPECIES/SEX: Nulliparous female Sprague-Dawley rats, weighing 180-200  grams. AGE at Start of Test: sexually mature females; age not specified

Administration / exposure

Route of administration:
inhalation
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
 Exposures were whole  body and conducted in a 200 L chamber. Chamber temperature was 23 degrees  C, and the relative humidity was 50%. Air was passed through a heated  bubbler containing test material. The vaporized material was then  introduced into the exposure chambers. 
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Concentrations were monitored  continuously with a GC, and were determined once during each 6 hr  exposure by collecting the material and analyzing against a standard using  GC.    
Duration of treatment / exposure:
days 5 - 20 of gestation
Frequency of treatment:
6 hours per day
Duration of test:
days 6-20 of gestation
Doses / concentrationsopen allclose all
Dose / conc.:
600 ppm
Remarks:
corresponds to 2844 mg/m3 (OECD SIAR)
Dose / conc.:
1 200 ppm
Remarks:
corresponds to 5688 mg/m3 (OECD SIAR)
Dose / conc.:
1 800 ppm
Remarks:
corresponds to 8532 mg/m3 (OECD SIAR)
Dose / conc.:
2 400 ppm
Remarks:
corresponds to 11376 mg/m3 (OECD SIAR)
No. of animals per sex per dose:
22-25 pregnant females per dose
Control animals:
other: yes, concurrently to filtered air
Details on study design:
CAGING/HOUSING: 2-3 females were caged with one male rat for mating. The  onset of gestation was based upon the presence of sperm in the vaginal  smear and this was designated gestation day 0. After confirmation of  mating, females werere turned to an individual cage. Mated females were  housed inclear polycarbonate cages with stainless steel wire lids and  hardwood shavings for bedding. Food and water available adlibitum except  during exposures.
STUDY METHOD: Females were mated with males overnight and the presence of  sperm in the vaginal smear was considered gestation day 0. Mated females  were exposed via inhalation to test material for 6 hrs/day on gestation  days 6 through 20 and then sacrificed on day 21.

Examinations

Maternal examinations:
CAGESIDE OBSERVATIONS: Food consumption was measured for the intervals  GDs 6-13, and 13-21. Maternal body weights were recorded on GDs 0, 6, 13  and 21. Animals were observed daily for behavioral changes. 
Ovaries and uterine content:
ORGAN WEIGHTS: The uterus was removed and weighed. GROSS PATHOLOGY: At necropsy, the uterine horns and ovaries were exposed  to count the C.L., implantation sites, resorption sites, and viable and  dead fetuses. 
Fetal examinations:
Live fetuses were weighed, sexed, and examined for external  anomalies. 50% of the live fetuses were preserved in Bouin's solutionand  examined for internal soft-tissue changes. The remaining fetuses were  fixed in ethanol (70%), eviscerated and then processed for skeletal  staining with alizarin red S. 
Statistics:
STATISTICAL METHODS: The number of CL, implantation sites, and live  fetuses, maternal food consumption and various body weights were analyzed  by ANOVA, followed by Dunnett'st-test. the percentage of non-live  implant, resorptions,and males and the proportion of fetuses with  alterations ineach litter were evaluated by Kruskal-Walles test followed  by Dixon-Massey test. Rates of pregnancy and percentage of litters with  any malformations or external, visceral, or skeletal variations were  analyzed using Fisher's test. Where appropriate, least squares analysis  was performed. The level of significance was p < 0.05.
Indices:
FERTILITY AND REPRODUCTIVE PERFORMANCE: The following data were recorded  for each group of numbers of CL, and implantation sites 
- number of   resorptions and viable and dead fetuses. 
- mean fetal body weights 
- fetuses examined for gross malformations and skeletal abnormalities of  sex and of fetuses.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
not specified
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Maternal body weight gain was significantly reduced during the first half of exposures at 1200 and 1800 ppm and throughout the whole exposure period at 2400 ppm. The overall weight gain between GD 6 and GD 21 was significantly depressed
at 1200, 1800, and 2400 ppm. There was a concentration related decrease in absolute weight gain, which was statistically significantly different from control at 1200 ppm and above.
Exposure to 2400 ppm was associated with maternal weight loss when the gravid uterus weight was subtracted from the body weight change for GDs 6-21.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
A slight but statistically significant decrease in food consumption was seen at 600 ppm during the first half of exposure. Food consumption was significantly less than control for the entire exposure period at 1200 ppm and above.
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed

Effect levels (maternal animals)

Dose descriptor:
LOAEC
Remarks:
maternal toxicity
Effect level:
600 ppm
Based on:
test mat.
Basis for effect level:
food consumption and compound intake
Remarks on result:
other: corresponding to 2844 mg/m3;

Maternal abnormalities

Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
Fetal body weight was significantly reduced at 1200 ppm (males) and at higher concentrations (all, male and female fetuses) These decreases amounted to 6-7% of the control values at 2400 ppm.
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
External malformations:
no effects observed
Description (incidence and severity):
Single cases of malformations were seen in all groups with no indication of adverse effects due to EMA exposure
Skeletal malformations:
no effects observed
Description (incidence and severity):
There were no significant differences in the incidences of external, visceral (primarily distended ureter), or skeletal variations (primarily incompletely ossified stemebrae and/or vertebrae, and/or supernumerary ribs) between the control and treated groups.
Visceral malformations:
no effects observed
Description (incidence and severity):
There were no significant differences in the incidences of external, visceral (primarily distended ureter), or skeletal variations (primarily incompletely ossified stemebrae and/or vertebrae, and/or supernumerary ribs) between the control and treated groups.
Details on embryotoxic / teratogenic effects:
There was no significant effect of treatment on the mean number of implantations and live fetuses, on the incidences of non-live implants and resorptions, or on the fetal sex ratio.

Effect levels (fetuses)

open allclose all
Dose descriptor:
NOAEC
Remarks:
fetotoxicity
Effect level:
600 ppm (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
fetal/pup body weight changes
Remarks on result:
other: corresponding to 2844 mg/m3;
Dose descriptor:
NOAEC
Remarks:
teratogenicity
Effect level:
2 400 ppm (nominal)
Based on:
test mat.
Sex:
male/female
Remarks on result:
other: corresponding to 11376 mg/m3; no adverse effects observed

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
In a valid guideline study, n-BMA resulted in fetal toxicity, but no teratogenicity, at concentrations that also produced maternal toxicity.
Executive summary:

In a valid guideline study, n-BMA resulted in fetal toxicity, but no teratogenicity, at concentrations that also produced maternal toxicity.

The OECD SIAR concluded for this study: “EMA was studied, using a method equivalent to OECD Guideline 414, ingroups of 19-25 pregnant female rats (whole-body inhalation exposure for 6 hr/day, during days 6 to 20 of gestation), at exposure concentrations of 0, 600, 1200, 1800 or 2400 ppm (0, 2844, 5688, 8532 or 11376 mg/m3). No maternal deaths were observed. Maternal toxicity (decreased body weight gain) was shown at 1200 ppm (5688 mg/m3) and above. Feed consumption was decreased at 600 ppm (2844 mg/m3) and above. There was no significant effect of treatment on the mean number of implantations and live fetuses, or on the fetal sex ratio. Fetal body weight was significantly reduced at 1200 ppm (8532 mg/m3) (males only) and higher concentrations (both sexes). Single cases of malformations were seen in all groups (including controls) with no indication of adverse effects due to EMA exposure. There were no significant differences between the control and treated groups for external(morphological), visceral (primarily distended ureter), or skeletal variations (primarily incompletely ossified sternebrae and/or vertebrae, and/or supernumerary ribs). EMA produced no embryo/fetal lethality or fetal malformations at exposure concentrations producing overt maternal toxicity. The NOAEC for developmental toxicity was considered to be 600 ppm (2844 mg/m3) EMA (Saillenfait et al., 1999).”