Single ingestion of di-(2-propylheptyl) phthalate (DPHP) by male volunteers: DPHP in blood and its metabolites in blood and urine (original) (raw)
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Toxicology Letters, 2016
Di-(2-propylheptyl) phthalate (DPHP) does not act as a reproductive toxicant or endocrine disruptor in contrast to other phthalates. Considering adverse effects of phthalates to be linked to their metabolism, it was the aim of the present study to investigate in the rat the blood burden of DPHP and its metabolites as a basis for understanding the toxicological behavior of DPHP. Rats were administered single oral doses of DPHP of 0.7 and 100 mg/kg body weight. Concentration-time courses of DPHP and metabolites were monitored in blood. The areas under the concentration-time curves in blood (AUCs), normalized for the dose of DPHP, showed the following order: DPHP < mono-(2-propyl-6-oxoheptyl) phthalate < mono-(2-propyl-6-hydroxyheptyl) phthalate = mono-(2-propylheptyl) phthalate < mono-(2propyl-6-carboxyhexyl) phthalate (cx-MPHP). Glucuronidation of the monoesters accounted for less than 5% of total compounds. The elimination half-lives of the compounds ranged from 2.3 h (DPHP) to 8.2 h (cx-MPHP). The normalized AUCs of the metabolites were lower at the high dose of DPHP than at the low one indicating saturation kinetics of intestinal DPHP hydrolysis. The absence of toxicity to reproduction of DPHP may be related to the comparatively low bioavailability of the parent compound and its metabolites. Abbreviations AUC, concentration-time curve in blood calculated for t→∞; b.w., body weight; cx-MPHP(-d4), non-or ring-deuterated mono-(2-propyl-6-carboxyhexyl) phthalate; cx-MPHP, mono-(2-propyl-6-carboxyhexyl) phthalate; cx-MPHP-d4, ring-deuterated mono-(2-propyl-6-carboxyhexyl) phthalate; DEHP, di-(2-ethylhexyl) phthalate; DINP, di-isononyl phthalate; DPHP(-d4), non-or ring-deuterated di-(2-propylheptyl) 3 phthalate; DPHP, di-(2-propylheptyl) phthalate; DPHP-d4, ring-deuterated di-(2propylheptyl) phthalate; MEHP, mono-(2-ethylhexyl) phthalate; MPHP(-d4), non-or ring-deuterated mono-(2-propylheptyl) phthalate; MPHP, mono-(2-propylheptyl) phthalate; MPHP-d4, ring-deuterated mono-(2-propylheptyl) phthalate; OH-MPHP(-d4), non-or ring-deuterated mono-(2-propyl-6-hydroxyheptyl) phthalate; OH-MPHP, mono-(2-propyl-6-hydroxyheptyl) phthalate; OH-MPHP-d4, ring-deuterated mono-(2propyl-6-hydroxyheptyl) phthalate; oxo-MPHP(-d4), non-or ring-deuterated mono-(2propyl-6-oxoheptyl) phthalate; oxo-MPHP, mono-(2-propyl-6-oxoheptyl) phthalate; oxo-MPHP-d4, ring-deuterated mono-(2-propyl-6-oxoheptyl) phthalate; t1/2, half-life of the elimination phase
Toxicology and Applied Pharmacology, 2012
The plasticizer di(2-ethylhexyl) phthalate (DEHP) is suspected to induce antiandrogenic effects in men via its metabolite mono(2-ethylhexyl) phthalate (MEHP). However, there is only little information on the kinetic behavior of DEHP and its metabolites in humans. The toxikokinetics of DEHP was investigated in four male volunteers (28-61 y) who ingested a single dose (645± 20 μg/kg body weight) of ring-deuterated DEHP (DEHP-D 4). Concentrations of DEHP-D 4 , of free ring-deuterated MEHP (MEHP-D 4), and the sum of free and glucuronidated MEHP-D 4 were measured in blood for up to 24 h; amounts of the monoesters MEHP-D 4 , ring-deuterated mono(2-ethyl-5-hydroxyhexyl) phthalate and ring-deuterated mono(2-ethyl-5-oxohexyl) phthalate were determined in urine for up to 46 h after ingestion. The bioavailability of DEHP-D 4 was surprisingly high with an area under the concentration-time curve until 24 h (AUC) amounting to 50% of that of free MEHP-D 4. The AUC of free MEHP-D 4 normalized to DEHP-D 4 dose and body weight (AUC/D) was 2.1 and 8.1 times, that of DEHP-D 4 even 50 and 100 times higher than the corresponding AUC/D values obtained earlier in rat and marmoset, respectively. Time courses of the compounds in blood and urine of the volunteers oscillated widely. Terminal elimination half-lives were short (4.3-6.6 h). Total amounts of metabolites in 22-h urine are correlated linearly with the AUC of free MEHP-D 4 in blood, the parameter regarded as relevant for risk assessment.
International Journal of Hygiene and Environmental Health, 2015
Please cite this article in press as: Schütze, A., et al., Bis-(2-propylheptyl)phthalate (DPHP) metabolites emerging in 24 h urine samples from the German Environmental Specimen a b s t r a c t Bis-(2-propylheptyl)-phthalate (DPHP) has been introduced as a substitute for other high molecular weight phthalates primarily used in high temperature applications (e.g. cable wires, roofing membranes). The aim of this study was to investigate how the increased usage of DPHP is reflected in urine samples collected over the last 14 years and to evaluate the current extent of exposure.
Urinary metabolites of diisodecyl phthalate in rats
Toxicology, 2007
Diisodecyl phthalate (DiDP) is an isomeric mixture of phthalates with predominantly 10-carbon branched-dialkyl chains, widely used as a plasticizer for polyvinyl chloride. The extent of human exposure to DiDP is unknown in part because adequate biomarkers of exposure to DiDP are not available. We identified several major metabolites of DiDP in urine of adult female Sprague-Dawley rats after a single oral administration of DiDP (300 mg/kg). These metabolites can potentially be used as biomarkers of exposure to DiDP. The metabolites extracted from urine were chromatographically resolved and identified by their chromatographic behavior and full scan negative ion electrospray ionization mass spectrum. The identity of metabolites with similar molecular weights was further examined in accurate mass mode. For some metabolites, unequivocal identification was done using authentic standards. Among these were the hydrolytic monoester of DiDP, monoisodecyl phthalate (MiDP), detected as a minor metabolite, and one oxidation product of MiDP, mono(carboxy-isononyl) phthalate (MCiNP), which was the most abundant urinary metabolite. We also tentatively identified other secondary metabolites of MiDP, mono(hydroxy-isodecyl) phthalate, mono(oxo-isodecyl) phthalate, mono(carboxyisoheptyl) phthalate, mono(carboxy-isohexyl) phthalate, mono(carboxy-isopentyl) phthalate, mono(carboxy-isobutyl) phthalate, and mono(carboxy-ethyl) phthalate. Oxidative metabolites of diisoundecyl phthalate (DiUdP) and diisononyl phthalate (DiNP) were also detected suggesting the presence of DiUdP and DiNP in the DiDP formulation. The urinary concentrations of all these metabolites gradually decreased in the 4 days following the administration of DiDP. MCiNP and other DiDP secondary metabolites are more abundant in urine than MiDP, suggesting that these oxidative products are better biomarkers for DiDP exposure assessment than MiDP. Additional research on the toxicokinetics of these metabolites is needed to understand the extent of human exposure to DiDP from the urinary concentrations of MCiNP and other DiDP secondary metabolites.
Urinary and serum metabolites of di-n-pentyl phthalate in rats
Chemosphere, 2011
Din -pentyl phthalate (DPP) is used mainly as a plasticizer in nitrocellulose. At high doses, DPP acts as a potent testicular toxicant in rats. We administered a single oral dose of 500 mg kg À1 bw of DPP to adult female Sprague-Dawley rats (N = 9) and collected 24-h urine samples 1 d before and 24-and 48-h after DPP was administered to tentatively identify DPP metabolites that could be used as exposure biomarkers. At necropsy, 48 h after dosing, we also collected serum. The metabolites were extracted from urine or serum, resolved with high performance liquid chromatography, and detected by mass spectrometry. Two DPP metabolites, phthalic acid (PA) and mono(3-carboxypropyl) phthalate (MCPP), were identified by using authentic standards, whereas mono-n-pentyl phthalate (MPP), mono(4-oxopentyl) phthalate (MOPP), mono(4-hydroxypentyl) phthalate (MHPP), mono(4-carboxybutyl) phthalate (MCBP), mono(2carboxyethyl) phthalate (MCEP), and mono-n-pentenyl phthalate (MPeP) were identified based on their full scan mass spectrometric fragmentation pattern. The x À 1 oxidation product, MHPP, was the predominant urinary metabolite of DPP. The median urinary concentrations (lg mL À1) of the metabolites in the first 24 h urine collection after DPP administration were 993 (MHPP), 168 (MCBP), 0.2 (MCEP), 222 (MPP), 47 (MOPP), 26 (PA), 16 (MPeP), and 9 (MCPP); the concentrations of metabolites in the second 24 h urine collection after DPP administration were significantly lower than in the first collection. We identified some urinary metabolic products in the serum, but at much lower levels than in urine. Because of the similarities in metabolism of phthalates between rats and humans, based on our results and the fact that MHPP can only be formed from the metabolism of DPP, MHPP would be the most adequate DPP exposure biomarker for human exposure assessment. Nonetheless, based on the urinary levels of MHPP, our preliminary data suggest that human exposure to DPP in the United States is rather limited.
Metabolite Profiles of Di-n-butyl Phthalate in Humans and Rats
Environmental Science & Technology, 2007
Din -butyl phthalate (DBP) is widely used in consumer products. In humans and in rats, DBP is metabolized to monon-butyl phthalate (MBP). MBP may also further oxidize to other metabolites of DBP. We studied the metabolic profiles of DBP in rats and humans to evaluate the similarities between the two species and between different exposure scenarios. In rats administered DBP by oral gavage, we identified MBP and three urinary oxidative metabolites of DBP: mono-3-oxo-n-butyl phthalate, mono-3-hydroxyn-butyl phthalate (MHBP), and mono-3-carboxypropyl phthalate (MCPP). MBP, MHBP, and MCPP were also present in serum, albeit at lower levels than in urine. Statistically significant correlations (p < 0.01) existed between the concentrations of MBP and the concentrations of MHBP (Pearson correlation coefficient r) 0.82 [urine] and r) 0.96 [serum]) and MCPP (r) 0.77 [urine] and r) 0.97 [serum]). However, the concentrations of these metabolites in urine collected 6 h after dosing and in serum 24 h after dosing were not correlated, suggesting continuous metabolism of DBP and/or individual differences among rats. Serum DBP metabolite concentrations increased with the dose, whereas urinary concentrations did not. We also identified MBP, MHBP, and MCPP in the urine of four men exposed to DBP by taking a prescription medication containing DBP, and MBP and MCPP in 94 adults with no documented exposure to DBP. In the human samples, we observed statistically significant correlations (p < 0.01) among the urinary concentrations of MBP and MCPP, although the correlation was stronger for the four exposed men (r) 0.99) than for the adults without a documented exposure to DBP (r) 0.70). Our results suggest that regardless of species and exposure scenario, MBP, the major DBP metabolite, is an optimal biomarker of exposure to DBP. In addition to MBP, MCPP and MHBP may be adequate biomarkers of exposure to DBP in occupational settings or in potential high-exposure scenarios.
Pharmacokinetics of Dibutyl Phthalate (DBP) in the Rat Determined by UPLC-MS/MS
International Journal of Molecular Sciences, 2013
Dibutyl phthalate (DBP) is commonly used to increase the flexibility of plastics in industrial products. However, several plasticizers have been illegally used as clouding agents to increase dispersion of aqueous matrix in beverages. This study thus develops a rapid and validated analytical method by ultra-performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS) for the evaluation of pharmacokinetics of DBP in free moving rats. The UPLC-MS/MS system equipped with positive electrospray ionization (ESI) source in multiple reaction monitoring (MRM) mode was used to monitor m/z 279.25→148.93 transitions for DBP. The limit of quantification for DBP in rat plasma and feces was 0.05 µg/mL and 0.125 µg/g, respectively. The pharmacokinetic results demonstrate that DBP appeared to have a two-compartment model in the rats; the area under concentration versus time (AUC) was 57.8 ± 5.93 min μg/mL and the distribution and elimination half-life (t 1/2,α and t 1/2,β ) were 5.77 ± 1.14 and 217 ± 131 min, respectively, after DBP administration (30 mg/kg, i.v.). About 0.18% of the administered dose was recovered from the feces within 48 h. The pharmacokinetic behavior demonstrated that DBP was quickly degraded within 2 h, suggesting a rapid metabolism low fecal cumulative excretion in the rat.
Toxicology letters, 2009
Phthalates like di-n-butyl phthalate (DnBP) and diisobutyl phthalate (DiBP) are commonly used as plasticisers, enteric coatings in medications and their metabolites (MnBP respectively MiBP) are suspect of adverse endocrine activities. The aim of this study was to determine kinetical data in humans after the application of a drug containing 3600 microg of DnBP and to quantify main metabolites of DnBP and DiBP with and without glucuronidase treatment. Since commonly glucuronides do not exhibit endocrine activity it is of interest to determine the potentially active metabolite like free MnBP and MiBP for a valid risk assessment. After the application of one capsule containing 3600 microg of DnBP to 17 volunteers 78% (median of 2248 microg of total MnBP) of administered DnBP was found within 24h in urine. After 24h the levels of MnBP in urine were comparable to concentrations before administration showing a fast elimination. In contrast to controls in all urine samples collected within ...