Dose Range-finding Prenatal Developmental Toxicity Study:

Groups of 10 time-mated female rats were administered 0, 250, 500, or 1,000 mg dimethylaminoethanol bitartrate/kg body weight per day (mg/kg/day) in sterile water by gavage from GD 6 to GD 20. Vehicle control (0 mg/kg) animals received sterile water.

There were no indications of maternal or fetal toxicity in the dose range-finding study. All animals survived to study termination. There were no dose-related effects on maternal body weights, body weight gains, body weights corrected for live litter size, or feed consumption. The number of pregnant females, mean number of corpora lutea, dead fetuses, early and late resorptions, and fetal sex ratio were similar across all treatment groups. There was a significant positive trend in the mean number of live female fetuses per litter relative to dose. There were no exposure-related fetal findings.

Prenatal Developmental Toxicity Study:

As no maternal toxicity was observed in the dose range-finding study, groups of 25 time-mated female rats were administered 0, 250, 500, or 1,000 mg/kg/day in sterile water by gavage from GD 6 to GD 20. Vehicle control (0 mg/kg) animals received sterile water. In this study, dimethylaminoethanol bitartrate was well tolerated and there were no significant effects on mortality, maternal body weights, body weight gains, body weights corrected for litter size, or feed consumption during gestation. In the 1,000 mg/kg/day group, one dam was euthanized moribund (GD 21) and one was found dead (GD 10); however, those deaths were not considered dose-related. Clinical observations were limited to single or sporadic incidences with the exception of brown or red vaginal discharge, which was observed between GD 14 and GD 21 in 10/20, 3/20, 4/20, and 10/24 dams in the 0, 250, 500, and 1,000 mg/kg/day groups, respectively. There were no notable placental or other maternal gross observations at necropsy except for a significant, but not biologically relevant, positive trend in mean absolute liver weight.

The number of pregnant females, mean number of corpora lutea, implantations, litter size, live fetuses per litter, and fetal sex ratio were similar across all treatment groups.

External and visceral malformations were limited to common background findings and singular or sporadic incidences. There were no observed incidences of fetal head, specifically brain, abnormalities. Skeletal malformations and variations occurred predominantly in the ribs. A significant increase in the incidence of absent innominate artery (a variation) and total, short thoracolumbar ribs (a variation) was observed in the 1,000 mg/kg group, along with a significant positive trend. Additionally, there was a significant increase in the number of supernumerary sites, or ossification sites, in the skull in 1,000 mg/kg fetuses as well as a significant positive trend across all exposed groups. These effects might be reversible (supernumerary ribs) or of uncertain biological significance (supernumerary sites in the skull); however, in the absence of maternal toxicity or effects on fetal body weight, the increased incidences of extra ossification sites in two separate locations, each occurring through two different skeletal developmental pathways, suggest that these effects could be related to dimethylaminoethanol bitartrate exposure.

Conclusions:

Under the conditions of the prenatal study, there was equivocal evidence^† of developmental toxicity of dimethylaminoethanol bitartrate in Sprague Dawley (Hsd:Sprague Dawley^® SD^®) rats attributable to increased incidences of absent innominate artery, short thoracolumbar ribs, and supernumerary sites in the skull in the absence of overt maternal toxicity.

Synonyms: 2-Dimethylaminoethanol bitartrate; 2-dimethylaminoethanol tartrate; dimethylethanolamine bitartrate; N,N-dimethylethanolamine- tartaric acid salt; ethanol, 2-(dimethylamino)-, [R(R*,R*)]-2,3-dihydroxybutanedioate; ethanol, 2-(dimethylamino)-, tartrate

^†See Explanation of Levels of Evidence for Developmental Toxicity.