title: Urinary biomarkers of di-isononyl phthalate in rats.
abstract: Commercial di-isononyl phthalate (DiNP) is a mixture of various branched-chain dialkyl phthalates mainly containing nine-carbon alkyl isomers. At high doses in rodents, DiNP is a carcinogen, and a developmental toxicant. After exposure, the diester isomers are de-esterified to form hydrolytic monoesters, monoisononyl phthalates (MiNP), which subsequently metabolize to form oxidative metabolites. These metabolites can be excreted in urine or feces. The urinary excretion of DiNP metabolites was monitored in adult female Sprague-Dawley rats after oral administration of a single dose (300 mg/kg) of commercial DiNP. The metabolites were extracted from urine, resolved with high performance liquid chromatography, analyzed by mass spectrometry, and tentatively identified based on their chromatographic separation and mass spectrometric fragmentation pattern. Because DiNP is an isomeric mixture, its metabolites were also isomeric mixtures that eluted from the HPLC column with close retention times. Mono(carboxy-isooctyl)phthalate (MCiOP) was identified as the major metabolite of DiNP; in addition, mono(hydroxy-isononyl)phthalate (MHiNP) and mono(oxo-isononyl)phthalate (MOiNP) were present. Furthermore, metabolites of di-isooctyl phthalate (DiOP) and di-isodecyl phthalate (DiDP) were also detected. Excretion toxicokinetics of the DiNP metabolites in urine followed a biphasic pattern with initial rapid decay in concentration. Despite potential differences in the metabolism of DiNP among species, MCiOP, MHiNP and MOiNP were detected in humans with no known exposure to DiNP at levels significantly higher than MiNP suggesting that these oxidative metabolites may be better urinary biomarkers of human exposure to DiNP than is MiNP.
authors.affiliation: Division of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA 30341, USA. zca2@cdc.gov
authors.forename: Manori J
authors.initials: MJ
authors.lastname: Silva
authors.forename: Kayoko
authors.initials: K
authors.lastname: Kato
authors.forename: Cynthia
authors.initials: C
authors.lastname: Wolf
authors.forename: Ella
authors.initials: E
authors.lastname: Samandar
authors.forename: Sathya S
authors.initials: SS
authors.lastname: Silva
authors.forename: Earl L
authors.initials: EL
authors.lastname: Gray
authors.forename: Larry L
authors.initials: LL
authors.lastname: Needham
authors.forename: Antonia M
authors.initials: AM
authors.lastname: Calafat
mesh_terms: D000284:Administration, Oral; D000818:Animals; D015415:Biomarkers / Q000737:chemistry / Q000652:urine; D005260:Female; D006801:Humans; D008658:Inactivation, Metabolic; D015394:Molecular Structure; D010795:Phthalic Acids / Q000737:chemistry / Q000652:urine*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D015415:Biomarkers; D010795:Phthalic Acids; C573544:mono(carboxy-isooctyl)phthalate; C012125:diisononyl phthalate