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EC number: 907-672-2 | CAS number: -
Radiolabeled 14C-Tributyl phosphate was administered to Yucatan minipigs by intravenous and dermal dose routes in order to investigate its absorption, distribution, and excretion in this species. Measurements of radioactivity were made in samples of feces, urine, bladder and kidney following intravenous and dermal application. Radioactive material was recovered at more than 80% for all dose groups except the low dose dermal groups where about 60% was recovered. 14C-TBP was rapidely eliminated via the urine and within the first 6 hr of intravenous exposure. The dermal doses were very poorly absorbed (maximum amount absorbed was about 5% of dose) and it was again eliminated mostly via the urine. There were no apparent sex differences in this study.
The individual group mean recovery values for all groups except the dermal groups range from about 87 to 100%. The dermal groups had consistently lower recovery values which ranged from a low of 65.9% in the low dose males to a high of 80.2% in the low dermal dose females.
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 4. multiple oral dose.
The doses for the study were chosen based on a preliminary study using hematuria as the relevant observation. The low dose was chosen because no hematuria was observed after a 5 mg/kg intravenous dose; the high dose was chosen because hematuria was observed following a 50 mg/kg oral dose.
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 was the urine. Urinary excretion was always exceeded the secondary route of excretion, the feces, from 4x (intravenous dose - males) to 14x (multiple oral high dose - females).
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.
Read-across to Tributyl phosphate (TBP) was applied to evaluate the toxicokinetics of DBPP. Among the components of the DBPP reaction mass (DBPP, TBP and butyl diphenyl phosphate), TBP has the most favorable physico-chemical properties regarding dermal absorption. Apart from that it is also the only component classified as a skin irritant. The reaction mass itself is not irritanting to the skin. If a substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration.
Consequently, the absorption of TBP can be considered as worst case when applying read-across.
Two toxicokinetic studies were evaluated, one described the toxicokinetics in rats and the other in minipigs.
In the study with rats, the distribution, metabolism and excretion of TBP was studied in Sprague-Dawley rats using radiolabeled TBP (14C-TBP). The test substance was given to the animals via the following routes: intravenous, oral and dermal route.
Urine, feces, expired air and various organs and tissues were collected and analyzed for radioactivity. Recovery was about 90% or above in all treated groups except for the dermal dose groups.
The major excretory route was via the urine.
Analytical techniques were applied on urine and feces samples. Chromatography of fecal homogenates indicated that no single component was greater than 5% of the administered dose. Mass spectrometric analyses were performed on methylated ethyl acetate extracts of urine samples using both chemical ionization and electron impact techniques. The results indicated that phase I metabolism represented the major biotransformation pathway. Significant and representative metabolites identified in urine samples included dibutyl hydrogen phosphate, butyl hydroxybutyl hydrogen phosphate, and butyl butanoic acid hydrogen phosphate.
The parent chemical was typically less 1% of the excreted dose.
In the study with minipigs, radiolabeled TBP (14C-TBP) was administered to Yucatan®minipigs by intravenous and dermal dose routes in order to investigate its absorption, distribution and excretion in this species. Measurements of radioactivity were made in samples of feces, urine, bladder and kidney following intravenous and dermal application. Radioactive material was recovered at more than 80% for all dose groups except the low dose dermal groups where about 60% was recovered. 14C-TBP was rapidly eliminated primarily via the urine and within the first 6 h of intravenous exposure. The dermal doses were very poorly absorbed (maximum amount absorbed was about 5% of dose) and it was again eliminated mostly via the urine. There were no apparent sex differences in this study.
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