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EC number: 203-227-5
CAS number: 104-68-7
rat plasma and urine samples were screened for the relevant biomarkers
following dietary consumption of rodent feed prepared to deliver
diethylene glycol mono phenyl ether DiEPH doses of 0, 250, 500 and 1000
mg/kg/day. The relevant biomarkers were identified as (DiEPH),
2-(2-Phenoxyethoxy) acetic acid (PEAA) and Phenoxyacetic acid (PAA).
Plasma and urine (following acid hydrolysis) samples were analyzed for
these biomarkers by high performance liquid chromatography (HPLC),
negative/positive ion electrospray ionization (-/+ESI), with mass
spectrometry detection operating in multiple reaction ion monitoring
(MRM) mode. PAA and PEAA were quantified using stable isotope internal
standard calibration and diethylene glycol phenyl ether was analyzed
using external standard calibration.
Metabolic Biomarker Identification - A series of analytical screening
experiments were conducted to determine the relevant biomarkers in rat
plasma and urine following dietary administration of DiEPh at dose
levels of 0, 250, 500, or 1000 mg/kg/day. The proposed metabolic scheme
of DiEPh presented in the attachment Figure 1 which shows the likely
metabolic pathways and related biomarkers that were screened. These
target analytes included: ethylene glycol (EG), diethylene glycol (DEG),
phenoxy ethanol (PE), phenol, hydroxylethoxy acetic acid (HEAA),
diglycolic acid (DGA), glycolic acid (GA), and oxalic acid (OA),
diethylene glycol mono phenyl ether (DiEPh), phenoxyethoxy acetic
(PEAA), and phenoxy acetic acid (PAA). These screening experiments
identified the relevant biomarkers as DiEPh, PEAA, and PAA. The levels
of the other potential biomarkers were low relative to both background
PEAA or PAA levels. Therefore, no definitive quantitative data was
generated for EG, DEG, PE, HEAA, DGA, GA, or OA.
Toxicokinetic Assessment - DiEPh was not present at levels above the
lower limit of quantitation (LLQ) in most of the blood samples. The two
metabolites, PEAA and PAA, were present at higher levels in the blood.
PEAA was present well above the limit of quantitation and in nearly all
of the blood samples from exposed animals, while PAA was present in 50
percent of the blood samples For this reason, systemic exposure (AUC24h)
and elimination half-life (t½) values could only be calculated for PEAA.
PEAA systemic exposure (AUC24h) values were dose-proportional in both
males and females. Half-life values based on PEAA blood levels were
approximately 7.4 hours, on average, and ranged 3.9-15.6 hours.
PEAA, and PAA all were present at concentrations above the LLQ in all
urine samples from treated animals. On average, only 1.3 percent of the
dose was excreted as DiEPh in the 24 hour urine, whereas 39.3 percent of
the dose was excreted as PEAA and 4.3 percent of the dose was excreted
as PAA. Urine levels of all three analytes were dose-proportional. These
data suggest DiEPh was rapidly metabolized at all dose levels. A major
portion of the dose was metabolized to PEAA (≥ 39.3% of the administered
dose, 87.5% of the recovered dose). A smaller portion was metabolized to
PAA (≥ 4.3% of the administered dose, 9.6% of the recovered dose). There
was no apparent saturation of absorption, distribution or elimination at
any dose level. Thus, DiEPh exhibits linear kinetics up to, and
including, 1000 mg/kg/day.
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