Tributyl phosphate

Endpoint summary

Description of key information

The distribution, metabolism, and excretion of TBP was studied in Sprague-Dawley rats using 14C-labeled TBP. The test substance was given to the animals via the following routes and schedules: 1. intravenous, 2. dermal, 3. single oral dose, and 4. multiple oral doses.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

56

Additional information

Plasma concentrations of tributyl phosphate (TBP) were measured in rats as a function of time using radiolabeled TBP and following different doses and 3 routes of exposure: 1. intravenous 2. dermal (low and high doses, 10 and 350 mg/kg), and 3. oral (single and multiple doses at both low and high doses). Urine, feces, and expired air were collected from all dose groups at 6, 12, 24, 48, and 72 h after dosing. Urine and feces were then collected at 96, 120, 144, and 168 h after dosing. After the least collection, all of the rats in a dose group were sacrificed for tissue distribution analysis. The excreta of 2 males and 2 females from each dose group were also analyzed for metabolites.

The major excretory route for the radio label was the urine. Urinary excretion always exceeded the secondary raute of excretion, the feces, from 4-fold (i.v. dose-males) to 14-fold (multiple-oral high dose-females). No gender differences were apparent nor were these changes associated with single or multiple dose regimens. More radioactivity was excreted in the feces in the oral dose groups than in the other dose groups.

Intravenous administration was followed by a rapid removal of TBP from plasma with a half-life of about 1.3 hr in both males and females. Based on the urinary excretion data , the mean terminal half-live was considerably higher (~ 29 h). This suggests that TBP/metabolites rapidly disappear from plasma due to tissue uptake, followed by slower excretion into the urine.

For the oral single or multiple dose a bioavailability of 100 % was found, with a half-life of about 25 h.

Urinary excretion data from dermal application demonstrated a mean terminal half-life of about 20 h. The extent of absorption was about 40% in the low dermal dose group and about 56% in the high dermal dose group.

The results indicated that phase I metabolism (oxidation and hydrolysis) represented the major biotransformation pathway. Significant and representative metabolites identified in urine sample included dibutyl hydrogen phosphate (DBP), butyl hydroxybutyl hydrogen phosphate, and butyl butanoic acid hydrogen phosphate. Fifteen other metabolites were also observed which contained oxidized (acid, keto, hydroxyl) tri, di, and monobutyl substituted phosphoric acids. The parent chemical was typically less than 1% of the excreted dose. Phase II metabolism was not considered a significant route of biotransformation of TBP (SOCMA).

 

When rats were given a single oral dose of 14C-labeled tributyl phosphate at 14 mg/kg, 50, 10, and 6% of the applied 14C were excreted in urine, exhaled air and feces, respectively, within 1 day. On the other hand, when rats were given a single intraperitoneal dose (same amount), 70, 7, and 4% of the applied 14C were excreted in urine, exhaled air, and feces respectively, within 1 day.

After a single intraperitoneal dose of tributyl phosphate at 250 mg/kg, 11 phosphorus-containing metabolites were identified in the 24 -h urine. Major metabolites were dibutyl hydrogen phosphate, butyl dihydrogen phosphate, and butyl bis(3 -hydroxybutyl)phosphate as well as small amounts of derivatives hydroxylated at the butyl moieties.

In a follow up study rats were given a single intraperitoneal dose of tributyl phosphate. Several S-containing metabolites were identified in the urine. The main metabolites were (3-oxobutyl)- and (3-hydroxybutyl)mercapturic acids, and traces of (2-oxobutyl)- and (2-hydroxybutyl)mercapturic acid (Suzuki, 1984).

 

In another study the rate of metabolism of tributyl phosphate and the nature of the metabolites produced were determined in in-vitro tests on rat liver homogenate. It was found that rat liver microsomal enzymes rapidly metabolized TBP in the presence of NADPH (within 30 min), but only slight metabolic breakdown occured in the absence of NADPH. Dibutyl(3 -hydroxybutyl) phosphate was obtained as a metabolite in the first stage of the test. The extended incubation time in the second stage of the test yielded 2 further metabolites, butyl di(3 -hydroxybutyl) phosphate and dibutyl hydrogen phosphate, which were produced from the primary metabolite dibutyl (3 -hydroxybutyl) phosphate (Sasaki, 1984).