Tris(2-ethylhexyl) phosphate

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: No OECD guideline or GLP defined.

Objective of study:

metabolism

Principles of method if other than guideline:

other: Radiotracer Inhalation Study

GLP compliance:

no

Radiolabelling:

yes

Remarks:

32P radiolabel (for metabolism study only)

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

All species were adapted to laboratory conditions prior to use for one to two weeks. Animals were housed in cages with screen bottoms elevated above the droppings.

Route of administration:

oral: gavage

Vehicle:

not specified

Details on exposure:

Radiotracer study- in rats (inhalation)

Nine rats were subjected to a single exposure of radioactive TOF, disseminated as an aerosol from a Laskin generator 7 into a tubular exposure apparatus. The median particle size produced was approximately 4 um. The exposure tube, constructed of clear plastic, measured 3 X 3 X 30 inches long and was provided with four ports through which the animals' heads protruded into the lumen. The outlet of the tube led to an absorption train consisting of three gas washing bottles charged with trichlorethylene, a rotameter, and exhaust pump. A filter paper sampling holder was arranged in parallel and could be substituted for the absorption train by manipulation of stopcocks. After exposure, the rats were maintained in metabolism cages and then sacrificed by exsanguination at various time intervals.

Duration and frequency of treatment / exposure:

sinlge exposure of radiolabelled TEHP for 20 mins (aerosol).

Remarks:

Doses / Concentrations:
nominal air flow concentration was 1.45 mg/L- actual determined to be 0.72 - 0.91 mg/L.

Mean recoveries of radioactiviy from rat tissues suggest that each rat retained ca 1.13 mg

No. of animals per sex per dose / concentration:

various- see exposure section

Control animals:

no

Positive control reference chemical:

no

Details on study design:

Radiotrace inhalation study

Details on dosing and sampling:

rats were sacrificied by exsanguination after the following time intervals post exposure: 5 minutes, 30 minutes, 1, 4, 17, 18, 24, 48, and 70 hours. The brain, lungs, liver, spleen, kidneys, stomach and stomach contents, fat, muscle, bone, urine, blood, and feces were analyzed for radioactivity. The head skin was also removed and examined for surface radioactivity.

Details on absorption:

the test substance is well absorbed after 20-minute inhalation exposure

Details on distribution in tissues:

the test substance is rapidly distributed in tissues, mainly in the lung, liver and brain

Observation:

other: the test substance is rapidly distributed in tissues, mainly in the lung, liver and brain

Details on excretion:

fecal excretion high

Toxicokinetic parameters:

other: maximum retention in tissue after the first few hours

Metabolites identified:

yes

Details on metabolites:

In studying the excretion of radioactive test substance or its metabolites, urine and feces samples from the rat sacrificed at 48 hours were utilized.

RM-Freetext:
Radiotracer inhalation study with rats: 9 male rats, single
head exposure, 20 minutes, aerosol, sacrifice after 5 min,
30 min, 1, 4, 17, 18, 24, 48, or 70 h:analytcal
concentration 0.72 to 0.91 mg/l, maximum retention in tissue
after the first few hours, fecal excretion high.

Executive summary:

In an old and limited documented radiotracer inhalation study nine male rats received a single head exposure of an aerosol of [32P] labeled test substance (median particle size 4 nm) for 20 minutes. The animals were sacrificed by exsanguinisation after the following intervals post exposure: 5 minutes, 30 minutes, 1, 4, 17, 18, 24, 48, and 70 hours. The brain, lungs, liver, spleen, kidneys, stomach and stomach contents, fat, muscle, bone, urine, blood, and feces were analyzed for radioactivity. The head skin was also removed and examined for surface radioactivity. Analytical concentrations, obtained from the analysis of filter paper samples, revealed that the nominal concentration of the test substance levels ranged between 0.72 and 0.91 mg/liter. An estimate of the total amount of radioactive test substance in the rat sacrificed five minutes after exposure, obtained by summing all tissue radioactivities, came to 1.13 mg. On analysis for radioactivity, it was found that most tissues exhibited a maximum retention in the first few hours, followed by a progressive decay. Thus, the lungs retained a peak of 13% of the total radioactivity in the animal at five minutes, with a subsequent gradual decline. Peak activity was seen in the brain and liver at 30 minutes and corresponded to retentions of 9% and 16%, respectively. Other organs and tissues (i.e., spleen, kidneys, bone, muscle, and fat) retained less than 2% of the radioactivity at any time. A high level of radioactivity, representing 50% to 64% retention, was found during the first hour in the stomach contents, but this declined rapidly thereafter. Urinary and fecal excretions, first determined at the 17-hour point, were moderately high, 7%, and then declined steadily. Finally, carcass radioactivity increased to a peak corresponding to 81% retention at 48 hours post exposure, followed by a progressive decrease. In studying the excretion of radioactive test substance or its metabolites, urine and feces samples from the rat sacrificed at 48 hours were utilized. Ascending chromatography of filter paper strips 54 cm long for 48 hours was performed. The strip was cut into segments and these were counted for three minutes. The fecal sample exhibited very high activity but only slight activity was detectable in the urine sample. The results obtained with the isopropyl ether-formic acid solvent system was the only solvent that yielded evidence of excretion of a metabolite product of the test substance.

Description of key information

The test substance is well absorbed in animals after 20-minute inhalational exposure and rapidly distributed in tissues, mainly in the lung, liver and brain in an old and limited documented radiotracer inhalation study. Maximal peak levels of 13% of the total radioactivity were reached in lungs five minutes after exposure, with a subsequent gradual decline. A high level of radioactivity (50% to 64%) was found in the stomach contents during the first hour and declined rapidly thereafter. Tris(2-ethylhexyl)phosphate is excreted mainly in the feces, and only to a small extent in urine. The test substance is presumably hydrolyzed in an initial metabolic step to 2-ethlhexanol and Bis(2-ethylhexyl)phosphate.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

In an old and limited documented radiotracer inhalation study nine male rats received a single head exposure of an aerosol of [32P] labeled test substance (median particle size 4 nm) for 20 minutes. The animals were sacrificed by exsanguinisation after the following intervals post exposure: 5 minutes, 30 minutes, 1, 4, 17, 18, 24, 48, and 70 hours. The brain, lungs, liver, spleen, kidneys, stomach and stomach contents, fat, muscle, bone, urine, blood, and feces were analyzed for radioactivity. The head skin was also removed and examined for surface radioactivity.

Analytical concentrations, obtained from the analysis of filter paper samples, revealed that the nominal concentration of the test substance levels ranged between 0.72 and 0.91 mg/liter. An estimate of the total amount of radioactive test substance in the rat sacrificed five minutes after exposure, obtained by summing all tissue radioactivities, came to 1.13 mg. On analysis for radioactivity, it was found that most tissues exhibited a maximum retention in the first few hours, followed by a progressive decay. Thus, the lungs retained a peak of 13% of the total radioactivity in the animal at five minutes, with a subsequent gradual decline. Peak activity was seen in the brain and liver at 30 minutes and corresponded to retentions of 9% and 16%, respectively. Other organs and tissues (i.e., spleen, kidneys, bone, muscle, and fat) retained less than 2% of the radioactivity at any time. A high level of radioactivity, representing 50% to 64% retention, was found during the first hour in the stomach contents, but this declined rapidly thereafter. Urinary and fecal excretions, first determined at the 17-hour point, were moderately high, 7%, and then declined steadily. Finally, carcass radioactivity increased to a peak corresponding to 81% retention at 48 hours post exposure, followed by a progressive decrease. In studying the excretion of radioactive test substance or its metabolites, urine and feces samples from the rat sacrificed at 48 hours were utilized. Ascending chromatography of filter paper strips 54 cm long for 48 hours was performed. The strip was cut into segments and these were counted for three minutes. The fecal sample exhibited very high activity but only slight activity was detectable in the urine sample. The results obtained with the isopropyl ether-formic acid solvent system was the only solvent that yielded evidence of excretion of a metabolite product of the test substance (MacFarland, 1966).

The metabolism of tris(2-ethylhexyl)phosphate has not been studied, but the major metabolites of trialkyl phosphates are generally bis- and monoalkyl phosphates plus the respective alcohols (Nomeir 1981, Nomeir 1983). The alcohol metabolite of tris(2-ethylhexyl)phosphate would be 2-ethylhexanol (Kluwe, 1983). A compound that is rapidly metabolized (NTP 1984).

Conclusion:

The test substance is well absorbed in animals after 20-minute inhalational exposure and rapidly distributed in tissues, mainly in the lung, liver and brain in an old and limited documented radiotracer inhalation study. Maximal peak levels of 13% of the total radioactivity were reached in lungs five minutes after exposure, with a subsequent gradual decline. A high level of radioactivity (50% to 64%) was found in the stomach contents during the first hour and declined rapidly thereafter. Tris(2-ethylhexyl)phosphate is excreted mainly in the feces, and only to a small extent in urine. The test substance is presumably hydrolyzed in an initial metabolic step to 2-ethlhexanol and Bis(2-ethylhexyl)phosphate.