Stereochemical inversion of haloxyfop in the Fischer 344 rat

The 2-aryloxypropionate haloxyfop is currently being evaluated for use as a herbicide. This compound is structurally similar to a group of 2-arylpropionates that have been shown previously to undergo stereochemical inversion in a variety of mammalian species. To support the data obtained from a number of toxicity/oncongenicity studies, in which racemic haloxyfop was employed, the stereochemical disposition of this compound was examined in the Fischer 344 rat. After administration of racemic haloxyfop (11 mg/kg, po) to male and female Fischer 344 rats, the day 1-10 urine samples were fortified with D4-haloxyfop (center ring label) and extracted, and the haloxyfop enantiomers were converted to diastereomeric derivatives [(S)-phenylethylamine] and analyzed by gas chromatography-mass spectrometry (GC/MS). Fecal samples for days 1-10 were fortified with D4-haloxyfop, extracted, and purified by reverse phase high-pressure liquid chromatography prior to derivation and GC/MS analysis. In the female rat, 77.3% of the administered dose was recovered in the day 1-10 urine and feces as parent compound. The stereochemistry of the haloxyfop present in these samples was found to be nearly all (R)-enantiomer (greater than 98%). In the male rat, 52.2% of the dose was recovered in the day 1-10 urine and feces as haloxyfop. The stereochemistry of the parent compound present in these samples was similar to the results seen in the female rat [greater than 98% (R)]. These results show that (S)-haloxyfop undergoes rapid and nearly complete inversion to the (R)-enantiomer in the female Fischer 344 rat. The data also suggest a similar stereochemical inversion of haloxyfop in the male Fischer 344 rat.