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The toxicokinetics of DTDP have not been examined. However, the toxicokinetics of other high molecular weight phthalates, DINP and DIDP, have been studied and can provide an assessment for DTDP as read-across information. 

 

The acute exposure toxicokinetic studies conducted in F344 rats by oral administration showed that, at a low dose (50 mg/kg), approximately half of the DINP was excreted in the urine within about 24 hours. The remainder of the dose was excreted in the feces within 96 hours. At the high dose (500 mg/kg) the fraction excreted in the urine was about 40% of the administered dose. In the repeated dose studies (5 daily doses of 50, 150, and 500 mg/kg) approximately 60% of the administered dose was excreted at all doses, suggesting an elevation of esterase activity and more rapid conversion to monoester following repeated treatment. Based on these urinary excretion data, the half-time for elimination of absorbed phthalate was about 7 hours. The dermal absorption study (approximately 0.2 ml/rat), by contrast, indicated that absorption was very slow, with 2-4% of the applied dose being absorbed within 7 days. However, the data indicated that DINP was rapidly metabolized and excreted once it was absorbed; the approximate biological half life is 7 hours (McKee et al., 2002).

 

As shown in McKee et al (2002), most of the orally administered DINP was recovered in urine (52-59%) and feces within 48 hours of administration. Urinary metabolites were primarily oxidation products of MINP (monoisononyl phthalate) and phthalic anhydride. There was little, if any, un-metabolized DINP or MINP in the urine. The majority of the material recovered from the feces was unmetabolized DINP. Measurements of phthalate (as total radioactivity) in tissue indicated that the majority of the absorbed material went into the blood, liver and kidney compartments with little radioactivity elsewhere. In the liver, the major metabolites were MINP and oxidized MINP. In general, the highest levels of radioactivity in these compartments were found 2 to 4 hours after oral dosing, and declined thereafter. Estimated elimination half-times from the blood and tissue compartments were 3.5 to 4.5 hours. Repeated dosing caused no accumulation of DINP and/or its metabolites in blood and tissue, but resulted in increased formation and elimination of the monoester-oxidation products. Similar results have been observed in other studies (Silva et al., 2006a). 

 

The fate of DIDP was evaluated in 6 male Sprague Dawley rats (mean body weight 200 g) receiving head only exposure to 14C-DIDP aerosol atmosphere nominal concentration: 100 mg/m3 for 6 hours (General Motors Research Laboratories, 1981). Total body burden following the exposure was 6.75 µmole equivalents or approximately 3 mg.  Radioactivity derived from 14C -DIDP was excreted in urine and feces during the 72-hour post-exposure collection period: 45.3% and 41%, respectively, of the total body burden. At the end of the collection period following exposure, 9.4% of the absorbed dose of radioactivity was recovered from carcass and tissues, 2.4% from skin and 1.6% from cage. The distribution of radioactivity in rat tissues immediately following exposure, indicated the highest concentration of radioactivity was in lung followed by GIT, liver and kidney. The remaining tissues contained far lesser amounts. Radioactivity was below detection limit in brain, spleen and testes.  After 72 hours the concentration was decreased in all tissues. The highest level of radioactivity was still found in lung which contained 27% of the content of radioactivity present immediately following exposure. The pulmonary load decreased to a lesser extent than all the tissues except fat which did not appear to change. Radioactivity derived from 14C -DIDP was excreted in urine and feces during the 72-hour post-exposure collection period: 45.3% and 41%, respectively, of the total body burden. The excretion of radioactivity in urine during the 72-hour collection period following inhalation exposure was best described using first order kinetics. Based on 12-hour interval excretion data, the half-life (T¿) of elimination was 16 hours with an elimination rate constant Ke of 0.042/hour. Radioactivity derived from 14C -DIDP was excreted in urine (45.3%) and feces (41.3%) during the 72-hour post-exposure collection period. An additional 1.6% was recovered in washings of the metabolic cage collection surfaces and was derived from urine and fecal contamination. From these data 88% of the total absorbed dose of the radioactivity was excreted from the body, and the carcass retention data imply that a small fraction of DIDP or metabolites was retained in the body for a longer period of time. Using total recovered radioactivity to represent body content or body burden of 14C immediately following exposure, and given urinary and fecal interval excretion data, an estimate of the disappearance of radioactivity from the whole body with time can be obtained. The decline in body burden was linear with an apparent first order elimination rate constant (Ke) of 0.027/h and a T¿ of 26 hours .

 

Urinary metabolites of DINP have also been quantified in several human studies for use as biomarkers of exposure. In a single subject human metabolism study of DINP (Koch and Angerer., 2007), it was observed that metabolites included the urinary excretion of the simple monoester, mono-iso-nonylphthalate (MINP), and oxidized isomers with hydroxy (OH-MINP), oxo (oxo-MINP) and carboxy (carboxy-MINP) functional groups. Within 48 h, 43.6% of the applied dose in urine was recovered as the above DINP metabolites: 20.2% as OH-MINP, 10.7% as carboxy-MINP, 10.6% as oxo-MINP and 2.2% as MINP. Elimination followed a multi-phase pattern; elimination half-lives in the second phase (beginning 24 h post-dose) can only roughly be estimated to be 12 h for the OH- and oxo-MINP-metabolites and 18 h for carboxy-MINP metabolites. After 24 h, the carboxy-MINP metabolites replaced the OH-MINP metabolites as the major urinary metabolites. With regard to ambient exposure to DINP, studies that examined urinary metabolites identified MINP and oxidative metabolites (Silva et al., 2004, 2006b), in agreement with the work of Koch and Angerer (2007). Thus, in humans, as in animals, approximately half the ingested DINP is absorbed and then rapidly metabolized and excreted in urine and feces. 

 

In summary, studies in both laboratory animals and humans demonstrate that DINP and DIDP are rapidly absorbed from an oral route of exposure and quickly metabolized into the corresponding mono-esters (MINP and MIDP, respectively) which can then be further transformed into oxidative metabolites. It is expected that DTDP will exhibit similar properties.

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