title: Identification of potential biomarkers of exposure to di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH), an alternative for phthalate plasticizers.
abstract: Di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH) is used as an alternative for some phthalate plasticizers. In rats, DINCH mostly eliminates in feces as cyclohexane-1,2-dicarboxylic acid (CHDA), mono isononyl ester (MINCH) or in urine as CHDA. However, CHDA is not a specific biomarker of DINCH and measuring MINCH in feces is impractical. To identify additional potential biomarkers, we administered DINCH (500 mg/kg body weight) in a single subcutaneous (SC) or oral dose to four adult female Sprague-Dawley rats. We collected 24-h urine samples before dosing (to be used as controls) and 24-h and 48-h after dosing, and serum at necropsy after 48 h. We positively identified and accurately quantified CHDA and cyclohexane-1,2-dicarboxylic [corrected] acid, mono hydroxyisononyl ester (MHNCH) using authentic standards. Moreover, we tentatively identified MINCH and 12 oxidative metabolites, including 4 cyclohexane ring oxidation products, based on their mass spectrometric-fragmentation patterns. CHDA and MHNCH levels were higher in the urine collected 24 h after oral than SC administration. By contrast, 48-h after dosing, CHDA urinary levels were similar regardless of the exposure route. We detected all but two of the urine metabolites also in serum. Levels of CHDA and MHNCH in serum were lower than in the two post-dose urine collections. Our results suggest that several urinary oxidative metabolites, specifically CHDA, mono oxoisononyl ester and MHNCH may be used as specific biomarkers of DINCH exposure in humans.
authors.affiliation: Division of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, Georgia 30341, USA.
authors.forename: Manori J
authors.initials: MJ
authors.lastname: Silva
authors.forename: Johnathan
authors.initials: J
authors.lastname: Furr
authors.forename: James L
authors.initials: JL
authors.lastname: Preau
authors.forename: Ella
authors.initials: E
authors.lastname: Samandar
authors.forename: L Earl
authors.initials: LE
authors.lastname: Gray
authors.forename: Antonia M
authors.initials: AM
authors.lastname: Calafat
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood* / Q000652:urine*; D003509:Cyclohexanecarboxylic Acids / Q000008:administration & dosage / Q000097:blood* / Q000378:metabolism* / Q000652:urine*; D003998:Dicarboxylic Acids / Q000008:administration & dosage / Q000097:blood* / Q000378:metabolism* / Q000652:urine*; D005260:Female; D013058:Mass Spectrometry; D010795:Phthalic Acids; D010968:Plasticizers; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D015415:Biomarkers; D003509:Cyclohexanecarboxylic Acids; D003998:Dicarboxylic Acids; D010795:Phthalic Acids; D010968:Plasticizers; C534517:cyclohexane-1,2-dicarboxylic acid; C558012:diisononyl 1,2-cyclohexanedicarboxylic acid; C032279:phthalic acid