1,2-Benzenedicarboxylic acid, di-C8-10-branched alkyl esters, C9-rich

Endpoint summary

Additional information

Absorption

Dermal absorption of 14C-DINP was studied in male Fischer 344 rats in both conditioned (pretreatment with non-labeled DINP) and non-conditioned skin (ExxonMobil, 1983a; McKee et al., 2002). Following exposure, the dosed area was occluded. Under all conditions, the amount of DINP absorbed after 7 days ranged from 2 to 4% with approximately 93−99% of the administered radioactivity recovered at the site of application. Radioactivity in feces and gut of the exposed rats suggested some excretion occurred via the biliary route. These results are in agreement with the work published by Elsisi et al (1989) which demonstrated that dermal absorption decreases as carbon chain length increases.

          

Absorption of DINP via the gastrointestinal tract decreases as dose increases (49% at the low dose of 50 mg/kg compared to 39% at the high dose of 500 mg/kg; eliminated in urine) leading to an estimated absorption of approximately 50%. In addition, absorption of DINP seems to be of a saturable process. Increasing the dose results in an increased amount of unabsorbed compound being eliminated (fecal radioactivity associated with parent compound increased from 8% to 41% from a single low dose to the high dose).

 

Metabolism

Once absorbed, DINP is de-esterified to the monoester and then further metabolized by side-chain oxidation of the ester group or by hydrolysis to phthalic acid. Most of the 14C collected in the urine of rats following a single oral dose of 14C-DINP was in the form of phthalic acid or side-chain oxidation products of the monoester (MINP). The relative amount of phthalic acid in the urine decreased at the high dose. The monoester itself, as well as the diester, was present in only trace amounts. In feces, 8 and 41% of the radioactivity was associated with the diester following administration of a low (50 mg/kg) or a high (500 mg/kg) oral dose of 14C-DINP. This indicates saturation of metabolism at the high dose. The remainder of the fecal radioactivity was associated with the monoester or its side-chain oxidation products. Major metabolites in the liver were the monoester and its side-chain oxidation products. The same metabolites and phthalic acid were in testes. The fat compartments contained the monoester and its oxidation products. Repeated exposures revealed similar metabolites in the tissues. Repeated dosing did not result in accumulation of DINP and/or its metabolites in blood and tissue, but rather in increased formation and elimination of the monoester-oxidation products. In summary, in the rat, DINP was de-esterified to the monoester, which was further metabolized by side-chain oxidation of the ester group or by hydrolysis to phthalic acid. Formation of oxidation products appeared to increase following the high dose or repeated dosing, while the hydrolysis to phthalic acid decreased.

 

In humans, DINP is also rapidly metabolized to the simple monoester, mono-iso-nonylphthalate (MINP), and oxidized isomers with hydroxy (OH-MINP), oxo (oxo-MINP) and carboxy (carboxy-MINP) functional groups (Koch and Angerer., 2007). 

 

Distribution

In male and female Fischer 344 rats receiving single or repeated oral doses of 14C-DINP, radioactivity cleared from the tissues rapidly, but analysis of tissues within 1 hour after the exposure indicated that the highest levels were in liver (4.7% of administered dose), kidneys (0.31%), and blood (1.62 %). Fat and testes contained small amounts of metabolites. No bioaccumulation occurred over 72 hours post-dosing.

 

Excretion

DINP is rapidly excreted; the majority of orally administered material excreted in urine and feces within 24-48 hours, and less than 0.1% of radioactivity was recovered in tissues after 72 hours. The major routes of excretion for orally administered DINP in rats were urine and feces, with about equal amounts excreted by either route at low doses, but more excreted in feces at high doses. The biological half-life is approximately 7 hours. Repeated dosing did not cause accumulation of DINP or its metabolites in blood or tissue, but rather increased formation and elimination of the monoester side-chain oxidation products.

 

In humans, within 48 h of administration, 43.6% of the applied dose in urine was recovered as DINP metabolites: 20.2% as OH-MINP, 10.7% as carboxy-MINP, 10.6% as oxo-MINP and 2.2% as MINP (Koch and Angerer., 2007). 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.

 

A DINP PBPK model for rat and human was adapted (Campbell Jr. et al, 2020) from previously established models for DBP and DEHP. Species-specific pharmacokinetic data was used to parameterize the model. Pregnant rat and human data were used to address the hydrolysis of DINP in the testinal tract, plasma and liver, hepatic oxidative metabolism and conjugation of the monoester and primary oxidative metabolites. Rat and human data were used to inform the uptake and disposition of MINP and three primary oxidative metabolites (7-OH, 7-OXO and 7-COX). The simulated kinetics of DINP in this model provided a reliable fit to the adult and pregnant rat and human in vivo data, including primary oxidative metabolites measured in human population biomonitoring studies. The goal of this project was to establish a PBPK model for DiNP by substance specific adaptions to the preexisting PBPK models for DBP and DEHP and to confirm that simulated kinetics of DiNP in adult and pregnant rat and human fit with in vivo studies. Overall, the model provides reliable fit to the extensive kinetic dataset in rat and human, incoporates primary oxidative metabolites that were measured in human population biomonitoring studies and can serve as a tool to reduce uncertainty in animal to human extrapolation of a point of departure for risk assessment.

 

Campbell Jr, J.L., Otter, R., Anderson, W.A., Longnecker, M.P., Clewell, R.A., North, C. and Clewell III, H.J., 2020. Development of a physiologically based pharmacokinetic model of diisononyl phthalate (DiNP) in pregnant rat and human. Journal of Toxicology and Environmental Health, Part A, 83(19-20), pp.631-648.

 

Discussion on bioaccumulation potential result:

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 approximately 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). 

 

Urinary metabolites of DINP have also been quantified in several human studies with the hopes of using them 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 is rapidly absorbed from an oral route of exposure and quickly metabolized into the mono-ester (MINP) which can then be further transformed into oxidative metabolites.

 

Discussion on absorption rate:

The dermal absorption 14C-DINP was determined to be slow in rats, but it occurred at a steady rate as evidenced by the increased amounts of radioactivity recovered in urine, feces, and tissues. The total amounts absorbed during a 7-day period ranged from 2 to 4% of the applied doses. Therefore, there is a low potential for dermal absorption of DINP since most of the dose remains unabsorbed at the application site.