Report Date: March 1992
The following abstract presents results of a study conducted by a contract laboratory for the National Toxicology Program. The findings may not have been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by NTP in March 2009. For more information, see the Explanation of Levels of Evidence for Developmental Toxicity. The findings and conclusions for this study should not be construed to represent the views of NTP or the U.S. Government.
This study was conducted to assess the potential for orally administered N,N'-methylenebisacrylamide to cause developmental toxicity. The oral route of administration corresponds to a hazardous potential human route of exposure to BAC. The CD-1 mouse was selected as the test animal for this study based on evidence for acrylamide-induced toxicity in other strains/ stocks of mice in the literature, and to correspond with other teratology and reproductive toxicology studies of the parent compound and congeners sponsored by the National Toxicology Program.
N,N'-Methylenebisacrylamide (BAC. CAS No. 110-26-9) was administered by gavage to timed-pregnant Swiss (CD-1) mice (13-25/group) on gestational days 6-17. The dose levels administered were 0, 30, 60, 120, or 180 mg/kg/day (Replicate I) or 0, 3, 10, or 30 mg/kg/day (Replicate II). Dose levels were adjusted between replicates due to excessive maternal toxicity at greater than or equal to 60 mg/kg/day. Animals were observed daily (gd 6-17) for clinical signs of toxicity. Food and water weights and body weights were determined on gd 0, 3, 6, 9, 12, 15, and 17. All animals were killed on gd 17 and examined for maternal body weight, implant status, fetal weight, sex, and morphological development.
Females exposed to 3-30 mg/kg/day BAC (Replicates I and II, combined) did not exhibit any significant clinical signs of toxicity, including any signs of neurotoxicity. Maternal food and water consumption (g/kg/day) was comparable to controls for most time points. Maternal body weights did not differ significantly between the control group and any of the BAC-treated groups (0, 3, 10, and 30 mg/kg/day) on gd 0 through 9. Maternal body weight was significantly depressed on gd 12 at 3 and 10 mg/kg/day, and on gd 15 at 10 mg/kg/day. In addition, relative maternal liver weight was increased, and gravid uterine weight was depressed at 10 mg/kg/day. These effects appeared to be replicate-dependent, although evidence of reduced gravid uterine weight was observed in Replicate II. On gd 15 and 17, maternal body weight in the 30 mg/kg/day groups was depressed below the control group. Maternal body weight change during treatment and gestation, and corrected maternal body weight were decreased at 30 mg/kg/day: gravid uterine weight was decreased at 30 mg/kg/day, and relative maternal liver weight was increased at 30 mg/kg/day. Thus, 10 mg/kg/day BAC was the maternal no-observed-adverse-effect-level based on the absence of any persistent effect on maternal status when this group was compared to concurrent controls. Maternal toxicity, observed as reduced corrected maternal weight gain. was observed at 30 mg/kg/day. Thus, 30 mg/kg/day BAC was the maternal low-observed-adverse-effect-level.
Average fetal body weight was depressed at 30 mg/kg/day BAC indicating clear developmental toxicity. There was no effect of treatment on the incidence of malformations at any dose level. The incidence of fetal variations per litter was increased at 10 and 30 mg/kg/day.
In summary, 10 mg/kg/day BAC was a no observed adverse effect level for maternal toxicity and a low observed adverse effect level for developmental toxicity. At 30 mg/kg/day, both developmental and maternal toxicity were observed.
|Body Weight (gd 12)||⇓||⇓|
|Body Weight (gd 15 and 17)||⇓||⇓|
|Body Weight Gain (Treatment)||⇓|
|Body Weight Gain (Gestation)||⇓|
|Body Weight Gain (Corrected)||⇓|
|Gravid Uterine Weight||⇓||⇓|
|Relative Liver Weight||⇑||⇑|
|Mean male fetal weight/litter||⇓|
|Mean female fetal weight/litter||⇓|
|% Fetuses with variations/litter||⇑||⇑|
[a] Pregnancy rates were 92-100% per group on gd 17; thus, each group contained 24-25 confirmed-pregnant females. No maternal deaths. clinical signs or treatment-related alterations in food/water intake-were observed.
⇓Significantly increased relative to control (p<0.05).
⇑Significantly decreased relative to control (p<0.05).