Bis(2-propylheptyl) phthalate

Endpoint summary

Description of key information

Based on cross-reading to structurally related C8/C9 or C10 Phthalate esters (NIEHS, 1988; Elsisi et al., 1989), dermal absorption is very low.

The main metabolites excreted in urine based on human volunteers are OH-MPHP and oxo-MPHP. The maximum in excretion is already reached after 3 - 4h. (Leng et al., 2014, Klein et al., 2018)

Key value for chemical safety assessment

Absorption rate - dermal (%):

4

Additional information

5 male volunteers were given a single dose of 50mg deuterium labelled DPHP. Urine was collected for the next 48h and three DPHP specific metabolites were analysed. Maximum urinary concentrations were reached within 3–4 h post dose for all three metabolites: mono-2-(propyl-6 -hydroxy-heptyl)-phthalate (OH-MPHP), mono-2-(propyl-6-oxoheptyl)-phthalate (oxo-MPHP) and mono-2 -(propyl-6-carboxy-hexyl)-phthalate (cx-MPHxP). Elimination half-lives were between 6 and 8 h. Within 48h app. 13.5% and 10.7% of the total DPHP dose were excreted as OH-MPHP and oxo-MPHP, respectively, the two major metabolites of DPHP. In comparison, cx-MPHxP accounted only for 0.48%. The bulk of 22.9% was excreted within 24h. After 48h, combined excretion summed up to 24.7% (Leng et al., 2014).

These data match the results obtained in a publication by Wittassek, 2007. Following oral application of DPHP to one human volunteer, 34 % of the oral dose was eliminated via urine as secondary metabolites. Considering the longer sampling time of 61h and the fact that further metabolites were included in the measurement, there is a good correlation to the 24.7% obtained after 48h in the study described above. Less than 1 % was excreted as the monoester MPHP.

In both studies, only a moiety of the substance applicated was recovered. However this is not remarkable and rather typical for human biomonitoring studies.

The same findings, with additional kinetic data, were observed in blood:

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-(2-propyl-6-carboxy-hexyl) 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 (Klein, 2016).

In another study of Klein (2018), DPHP and selected metabolites were monitored in blood and urine of 6 male volunteers over time following ingestion of a single DPHP dose (0.7 mg/kg body weight). Concentration-time courses in blood were obtained up to 24 h for DPHP, mono-(2-propylheptyl) phthalate (MPHP), mono-(2-propyl-6-hydroxyheptyl) phthalate (OH-MPHP), and mono-(2-propyl-6-oxoheptyl) phthalate (oxo-MPHP); amounts excreted in urine were determined up to 46 h for MPHP, OH-MPHP, oxo-MPHP, and mono-(2-propyl-6-carboxyhexyl) phthalate (cx-MPHP). AUCs were: DPHP > MPHP > oxo-MPHP > OH-MPHP. The amounts excreted in urine were: oxo-MPHP > OH-MPHP> > cx-MPHP > MPHP. The AUCs of MPHP, oxo-MPHP, or OH-MPHP could be estimated well from the cumulative amounts of urinary OH-MPHP or oxo-MPHP excreted within 22 h after DPHP intake.

Shih (2018, 2019 and 2019) identified many more minor metabolites in liver enzyme incubates and in a rat model in urine and in hair with an ultra sensitive technique based on Ultraperformance liquid chromatography coupled with Orbitrap high-resolution mass spectrometry. However they didn't quantify any metabolite and they also didn't clarify all structures.

Due to its extremely low vapour pressure, DPHP vapour phase concentrations may not attain high levels, even at the high temperatures used in some industrial conditions (e.g. processing, mixing, calendering). At 20°C DPHP has a vapour pressure of 0.000000037 hPa, even at 211 °C the vapor pressure is only 0.99 hPa. Thus only aersols may lead to inhalative uptake, which is assumed to be low.

Skin absorption of chemicals can be described using a simple model which depends only upon the size of the permeant and its octanol/water partition coefficient (Potts and Guy, 1992, Predicting skin permeability. Pharmaceut. Res. 9(5), 663-669.). The maximum penetrant flux decreases very rapidly for log P values greater than 2 (Guy and Hadgraft, 1988). The molecular weight is generally considered as presenting less influence (although there was very limited experience with high molecular weight substances), the diffusion coefficient being theoretically inversely proportional to the cube root of molecular weight (ECETOC, 1993). With its very marked lipophilicity (log PoW 10.7) and high molecular weight of 446g/mol, DPHP may be inferred to have a very low skin penetration. A comprehensive set of experimental data about dermal absorption properties of phthalates confirms that skin penetration of the structurally related DIDP (another C10 phthalate) is very low. Results specific to [14C]-DIDP (NIEHS, 1988; Elsisi et al., 1989, Dermal absorption of phthalate diesters in rats. Fund. Appl. Toxicol. 12, 70-77.) involved dermal absorption of phthalate diesters (DMP to DIDP) in F344 rats,in vivo. The dose applied to the skin was around 5-8 mg/cm2. The ring-labeled phthalates were applied dissolved in absolute ethanol, with in situ evaporation. The dosed back skin was covered by a circular plastic cap perforated with needle holes. Total excretion was measured at different times. This study shows that DIDP is markedly less absorbed (ca. 10 times, when comparing faecal + urinary excretions at day 7) by this route than DEHP. For DEHP, recovery after 7 days was 86% at the site of application, for a total recovery of 105%. After 5 days, cumulative excretion data indicate that 5% of the dose was recovered. For the structurally related DIDP, recovery was 75% at the site of application, for a total recovery of 82% after 7 days. Cumulative excretion data after 7 days indicate that 0.5% of the dose was recovered in feces. No radioactivity was recovered in urine. It is noticeable that only faecal elimination was found. The author implies a preference for biliary excretion when the length of the side chain increases but this is not consistent with the scheme of elimination observed with DINP and the two other routes where radioactivity was shared between urine and feces. High differences in total recovery hinder a quantitative comparison of data. Muscle, adipose tissue and skin contained most of the dose remaining in the body. The total absorbed dose after 7 days can be estimated to be 1%, however this value is possibly underestimated because of the low recovery. The skin application site was apparently not washed before evaluating DIDP residue. In all cases, dermal uptake decreased when the side chain length increased beyond four carbons. Skin absorption appeared to decrease with branched alkyl side chains.

 

In conclusion, a dermal absorption rate of 4 % is used for risk assessment on the dermal route.