Reaction mass of butyl diphenyl phosphate and dibutyl phenyl phosphate and tributyl phosphate

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Well documented GLP study.

Objective of study:

absorption

distribution

excretion

Qualifier:

according to guideline

Guideline:

other: EPA Metabolism and Pharmacokinetic Test Guidelines (40 CFR 798)

GLP compliance:

yes

Radiolabelling:

yes

Species:

guinea pig

Strain:

other: Yucatan

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratory (Windham, Maine)
- Diet: ad libitum (Lab Mini-Pig Chow Starter)
- Water: ad libitum (Kansas City municipal water)
- Acclimation period: during the quarantine period, the pigs were acclimated to the dosing slings and individual steel cages 2 to 3 days for 1 to 5 h each day

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16-24
- Humidity (%): 30-60

Route of administration:

other: intravenous or dermal absorption

Details on absorption:

- Dermal treatment group:
The major part of all the dermal doses (> 90% of the dose recovered) in both high and low dose treatment groups was found in the dose wash, dose site and dose site wrappings.

Details on distribution in tissues:

- Intravenous dose group:
Little or no radioactivity was observed in the kidney and bladder tissue.
- Dermal treatment group:
Little or no radioactivity was observed in the kidney and bladder tissue.

Details on excretion:

- Intravenous dose group:
The primary route of excretion is via the urine and the portion of the administered dose excreted via the kidneys was about 80% and that found in the feces was only 2 to 3%. The majority of urinary excretion occurred during the first 6 h after dosing.
- Dermal treatment group:
< 1% of dose was found in the urine and feces of the high dermal dose group and that expected in the urine and feces in the low dermal dose group ranged from about 2.5% to 6.6% of dose.

Metabolites identified:

no

Conclusions:

When administered by intravenous injection radiolabelled tributyl phosphate (TBP) is rapidly eliminated from the body of Yucatan minipigs via the urine. Dermal applications of radiolabelled TBP are poorly absorbed in the minipig in both high and low dose levels. On average, about 3 to 4% of the low dose appeared in the urine and feces whereas less than 1% of the high dose appeared in the excreta. Radiolabelled TBP did not appear to bioaccumulate in the bladder or kidney tissue of Yucatan minipigs.

Executive summary:

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.

Reference 2

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Study period:

1992

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Well documented GLP study.

Qualifier:

according to guideline

Guideline:

other: EPA Metabolism and Pharmacokinetic Test Guidelines (40 CFR 798)

GLP compliance:

yes

Radiolabelling:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories Inc. (Portage, Michigan)
- Age at study initiation: young adult
- Individual metabolism cages: yes (after determining that 14CO2 < 1% of the administered dose, rats were moved from glass to stainless steel metabolism cages for the remainder of the study)
- Diet: ad libitum (Purina Certified Rodent Chow (No. 5002, Ralston Purina Company, Richmond, Indiana))
- Water: ad libitum (Kansas City municipal water)
- Acclimation period: ≥ 24 h

Route of administration:

other: intravenous, dermal and oral

Remarks:

Doses / Concentrations:
5 mg/kg intravenous, 10 mg/kg dermal,

Details on absorption:

24 to 43% of the dermal dose remained on the skin and was found in the dermal dose wash.

Details on distribution in tissues:

The radioactive dose residing in the tissues in all groups is very small and did not exceed 1% of dose for any tissue. All carcas radioactivity recoveries were < 1.5% of the dose in all groups.

Details on excretion:

The major portion of the recoverable intravenous, dermal and oral dose (single or multiple) was eliminated within 48 h in urine and feces of male and female rats. The quantity of radioactivity excreted in urine exceeded that found in feces in all groups.
Percentages of radioactive dose found in expired air (derived from both CO2 and volutile metabolites) ranged from 1.56% in females of the low dermaldose group to 8.3% of dose in males of the single high oral dose group.

Metabolites identified:

yes

Details on metabolites:

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 < 1% of the excreted dose. Phase II metabolism was not considered a significant route of biotransformation of TBP.

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.

Executive summary:

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.

Additional information

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.

To summarize the results of this study, 14C-TBP is poorly absorbed across the skin of Yucatan® minipigs, is rapidly eliminated via the urine, and does not appear to bioaccumulate in the bladder or kidneys.