Toxicokinetic profile of N-(2-aminoethyl)ethanolamine in the female Wistar rat and distribution into the late gestation fetus and milk.

N-(2-aminoethyl)ethanolamine (AEEA) caused aneurysms of the great vessels in rats exposed in utero and during the first days post partum, exacerbated by postnatal treatment of the lactating dams (Moore et al., 2012). The purpose of this work was to examine the systemic availability of AEEA during gestation and early lactation. The absorption of AEEA was determined following oral administration to nonpregnant and pregnant female Wistar rats. A single dose administered by gavage (0.5 or 50 mg/kg) on gestation day 18 was rapidly and extensively (>90%) absorbed from the gastrointestinal tract (absorption t(1/2) = 0.1-0.2 hr). Elimination from the plasma followed a biphasic pattern, with a rapid elimination phase (t(1/2 α) = 1.6-1.8 hr) followed by a slower phase (t(1/2 ß) = 16.7-17.3 hr). Following repeated gavage administration during gestation day 17 to 19, (14) C-AEEA-derived radioactivity readily partitioned into the fetus and was evenly distributed therein, but cleared approximately twofold slower from the fetal blood and tissues than the maternal blood and chorioallantoic placenta. When administered to lactating dams during lactation days 1 to 12, (14) C-AEEA-derived radioactivity preferentially partitioned into the milk reaching levels that were between 1.6- and 2.5-fold higher than the maternal blood. Although the concentration of AEEA equivalents in the maternal blood remained quite consistent, the concentration in the milk fell by almost 40% between lactation days 4 and 12, probably reflecting an increase in milk production over this same period. We confirm exposure of the offspring to AEEA both in utero and during lactation, but that AEEA does not appear to specifically concentrate in the great vessels.

The effect of route, vehicle, and divided doses on the pharmacokinetics of chlorpyrifos and its metabolite trichloropyridinol in neonatal Sprague-Dawley rats.

There is a paucity of data on neonatal systemic exposure using different dosing paradigms. Male CD (Sprague-Dawley derived) rats at postnatal day (PND) 5 were dosed with chlorpyrifos (CPF, 1 mg/kg) using different routes of exposure, vehicles, and single versus divided doses. Blood concentrations of CPF and its primary metabolite, trichloropyridinol, were measured at multiple times through 24 h. Groups included were single gavage bolus versus divided gavage doses in corn oil (one vs. three times in 24h), single gavage bolus versus divided gavage doses in rat milk, and sc administration in dimethyl sulfoxide (DMSO). These data were compared with lactational exposure of PND 5 pups from dams exposed to CPF in the diet at 5 mg/kg/day for 4 weeks or published data from dams exposed to daily gavage with CPF at 5 mg/kg/day. Maternal blood CPF levels were an order of magnitude lower from dietary exposure than gavage (1.1 vs. 14.8 ng/g), and blood CPF levels in PND 5 pups that nursed dietary-exposed or gavage-exposed dams were below the limit of detection. Single gavage doses of 1 mg/kg CPF in corn oil vehicle in pups resulted in CPF blood levels of 49 ng/g and in milk vehicle about 9 ng/g. Divided doses led to lower peak CPF levels. A bolus dose of 1 mg/kg CPF in DMSO administered sc appeared to have substantially altered pharmacokinetics from orally administered CPF. To be meaningful for risk assessment, neonatal studies require attention to the exposure scenario, since route, vehicle, dose, and frequency of administration result in different systemic exposure to the test chemical and its metabolites.

The bioconcentration and metabolism of chlorpyrifos by the eastern oyster, Crassostrea virginica.

Eastern oysters (Crassostrea virginica) were exposed to [14C]chlorpyrifos (O,O-diethyl-O-[3,5,6-trichloro-2-pyridyl] phosphorothioate) at an average measured seawater concentration of 0.6 microg/L under flow-through conditions for 28 d. The compound O,O-diethyl-O-(3,5-dichloro-6-methylthio-2-pyridyl)phosphorothioate (DMP) was extracted and identified as the single metabolite observed, and this metabolite constituted the majority of the total [14C] activity in the oyster at all sampling times. Once oysters were exposed to clean water, both chlorpyrifos and DMP residues cleared rapidly from whole oysters, with elimination half-lives of <3 d. A simple two-compartment uptake/elimination model was adequate to describe total [14C] activity in whole oysters, edible tissue, and oyster liquor. The average bioconcentration factors (BCFs) for total [14C] activity in whole oysters, edible tissue, and oyster liquor were 565, 1,400, and 35 ml/g, respectively. The parent [14C]chlorpyrifos accumulated to a peak residue concentration of 135 microg/kg in whole oyster tissue, representing an empirical [14C]chlorpyrifos BCF value in the oyster of approximately 225 ml/ g; the BCF value for [14C]chlorpyrifos was lower than the BCF for total [14C] activity in whole oysters and edible tissue because of extensive metabolism to DMP and oyster elimination processes.