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Endpoint:
basic toxicokinetics in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
Read Across to an analogue based on structural similarity. An analogue justification is attached to section 13 of the dataset.
Reason / purpose for cross-reference:
read-across source
Type:
excretion
Results:
Curve fitting by least squares gave an effective half-life of 25 days for 113Sn activity and 21 days for labeled indium, with coefficients of determination of 0.93 and 0.80, respectively.
Details on excretion:
The injection of the unlabeled tin into two mice which had been injected with 113Sn had no apparent effect upon the observed whole-body counts. The decrease in whole-body counts with time was the same for both injected and noninjected mice containing labeled inorganic tin. Labeled tin has a half-life of 118 days and labeled indium, 1.7 hours.
Test no.:
#1
Toxicokinetic parameters:
half-life 1st: 29 days

The injection of unlabeled tin into mice which had been injected with 113Sn 6 days earlier had no apparent effect upon the observed whole-body counts. The decrease in the whole-body counts with time was the same for both injected and noninjected mice containing labeled inorganic tin.

Twenty-three days for 113Sn activity based on the average of the observed values for labeled tin and labeled indium. This half-life is the result of the biological and physical decay. Using 118 days for the physical half-life, it is estimated that the biological half-life in the mouse would be 29 days.

Conclusions:
The effective half-life of labeled tin in the mouse is expected to be 23 days, the average of the observed values for labeled tin and labeled indium. This half-life is the result of the biological and physical decay. Using 118 days for the physical half-life, it is estimated that the biological half-life in the mouse would be 29 days.
The injection of unlabeled tin into mice which had been injected with radiolabeled tin 6 days earlier had no apparent effect upon the observed whole-body counts. The decrease in the whole-body counts with time was the same for both injected and noninjected mice containing labeled inorganic tin.
Executive summary:

The injection of the unlabeled tin into two mice which had been injected with 113Sn 6 days earlier had no apparent effect upon the observed wholebody counts. The decrease in the wholebody counts with time was the same for both injected and noninjected mice containing labeled inorganic tin.

Endpoint:
basic toxicokinetics in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
Read Across to an analogue based on structural similarity. An analogue justification is attached to section 13 of the dataset.
Details on absorption:
Blood levels after intravenous injection appear to decay in a triphasic manner with half‑lives of 0.19 ± 0.11 hrs, 6.6 ± 3.9 hrs, and 117 ± 47 hrs. After oral administration, peak blood levels were achieved after 15 or 30 minutes, and also declined triphasically with half‑lives similar to what had been estimated from intravenous administration (0.32 ± 0.04 hrs, 6.8 ± 3.5 hrs, and 98.2 ± 32.8 hrs). Dermal application resulted in slower absorption with peak blood levels occurring 5.7 ± 0.4 hours after application and a half‑life of 3.2 ± 0.1 hr. Elimination was biphasic with half-lives of 4.2 ± 0.2 and 251 ± 135 hrs.
Details on excretion:
Approximately 72-75% of the oral dose was excreted in the urine within 24 hours. Little radioactivity (<10%) was excreted after 24 hours. The dose influenced the rate of excretion such that 50% of the radioactivity was excreted in the first 8 hours after the 100 mg/kg dose versus 20% after the 1000 mg/kg dose. Fecal excretion accounted for 7-12% in both cases. Slightly less radioactivity was excreted as either urine (64%) or feces (2%) after intravenous injection. Repeated dosing with unlabeled 2-ethylhexanoic acid altered excretion of radioactivity to approximately 55% in urine and 15% in feces within the first 24 hours. After dermal application, approximately 30% of the dose was excreted in the urine during the first 24 hours followed by an additional 8 or 17% from 24-96 hours for the 100 and 1000 mg/kg doses, respectively. Fecal excretion was 7% regardless of the dose level. Dermal absorption was estimated to be 63-70% relative to intravenous administration.
Metabolites identified:
yes
Details on metabolites:
Analysis of urine indicated three major peaks: one as a glucuronide conjugate of 2‑ethylhexanoic acid; one as a glucuronide conjugate of hydroxylated and diacid derivatives of 2-ethylhexanoic acid, possibly 2-ethyl-6-hydroxyhexanoic acid and 2‑ethyl-1,6-hexanedioic acid; and the last as unmetabolized 2-ethylhexanoic acid. No sulfate derivatives were detected. The percentages of each metabolite changed with the dose and route of administration (see Table in remarks on results section).

Overview of metabolite excretion
Route Dose Percentage excreted as
Oral 1000 mg/kg 45% glucuronide-2-ethylhexanoic acid
  (single) 7% glucuronide-diacid or hydroxylated 2-ethylhexanoic acid
    2% unmetabolized 2-ethylhexanoic acid
Oral 100 mg/kg 20% glucuronide-2-ethylhexanoic acid
  (single) 14% glucuronide-diacid or hydroxylated 2-ethylhexanoic acid
    7% unmetabolized 2-ethylhexanoic acid
Oral 100 mg/kg 12% glucuronide-2-ethylhexanoic acid
  (repeated) 12% glucuronide-diacid or hydroxylated 2-ethylhexanoic acid
    5% unmetabolized 2-ethylhexanoic acid
Dermal 1000 mg/kg 17% glucuronide-2-ethylhexanoic acid
  3% glucuronide-diacid or hydroxylated 2-ethylhexanoic acid
    3% unmetabolized 2-ethylhexanoic acid
Dermal 100 mg/kg 4% glucuronide-2-ethylhexanoic acid
  9% glucuronide-diacid or hydroxylated 2-ethylhexanoic acid
    2% unmetabolized 2-ethylhexanoic acid
Conclusions:
After intravenous administration of 1 mg/kg 14C-ERA, the blood concentration of 14C declined triexponentially. After oral administration of 100 mg/kg 14C-EHA, the mean peak blood level of 85.1 µg equivalents EHA/g was detected at 15 or 30 min. After dermal application of 100 mg/kg 14C-EHA, the mean peak blood level of 8.5 µg equivalents EHA/g was attained at 5.7 hr. The bioavailability of 14C after dermal application was 60-70% relative to the bioavailability of 14C after intravenous administration. The terminal half-lives of 14C after intravenous, oral and dermal administration were 117 hr, 98 hr and 251 hr, respectively.

Urinary metabolites were separated using a Waters HPLC system with a reversed phase (C-18) column and a mobile phase of aqueous formic acid and acetonitrile. Radioactively labeled components were detected using a radioactivity monitor. Radioactivity was eliminated in the urine and feces after each dose of 14C-EBA, primarily within the first 24 hr of dosing. At the 100 mg/kg and 1000 mg/kg single oral dose levels, 79.3% and 82,332, respectively, of the 14C was excreted in the urine and 12.4% and 6.7%, respectively, was excreted in the feces. After repeated oral dosing of the test compound at 100 mg/kg, 60.6% of the 14C was excreted in the urine and 14.9% was excreted in the feces. After dermal application of 100 mg/kg or 1000 mg/kg of 14C-EHA, 41.7% and.46.6%, respectively, of the 14C was excreted in the urine and 7.5% and 7.1%, respectively, was excreted in the feces. After intravenous administration of the test compound at 1 mg/kg, 66.6% of the 14C was excreted in the urine and 3.6% was excreted in the feces. The major urinary metabolites of EHA were the glucuronic acid conjugate of EHA, 2- ethylhexanedioic acid, isomers of hydroxy-2-ethylhexanoic acid and two isomeric metabolites of MU 142, proposed to be lactones. The parent compound was present in the urine at approximately 1.5 to 6.7% of the dose, depending upon the dose level and route of administration.
Executive summary:

The study was conducted to determine the metabolic fate and disposition of EHA in female rats following single oral gavage, repeated oral gavage, dermal or intravenous administration. Groups of 4 or 8 female Fischer 344 [CD®-(F-344)/CrlBR] rats weighing 115 g to 150 g were administered [2-14Chexyl] EHA (14C-EHA): 1) by a single oral gavage dose (100 mg/kg or 1000 mg/kg), 2) after fourteen daily oral gavage doses (100 mg/kg) of unlabeled EHA, 3) by dermal exposure (100 mg/kg or 1000 mg/kg) and 4) by intravenous injection (1 mg/kg). Urine, feces and cage rinsings were collected at intervals for 96 hr. Blood was collected from selected animals at intervals for 96 hr, and pharmacokinetic parameters were derived for the total 14C label in blood.

After intravenous administration of 1 mg/kg 14C-ERA, the blood concentration of 14C declined triexponentially. After oral administration of 100 mg/kg 14C-EHA, the mean peak blood level of 85.1 µg equivalents EHA/g was detected at 15 or 30 min. After dermal application of 100 mg/kg 14C-EHA, the mean peak blood level of 8.5 µg equivalents EHA/g was attained at 5.7 hr. The bioavailability of 14C after dermal application was 60-70% relative to the bioavailability of 14C after intravenous administration. The terminal half-lives of 14C after intravenous, oral and dermal administration were 117 hr, 98 hr and 251 hr, respectively.

Urinary metabolites were separated using a Waters HPLC system with a reversed phase (C-18) column and a mobile phase of aqueous formic acid and acetonitrile. Radioactively labeled components were detected using a radioactivity monitor. Radioactivity was eliminated in the urine and feces after each dose of 14C-EBA, primarily within the first 24 hr of dosing. At the 100 mg/kg and 1000 mg/kg single oral dose levels, 79.3% and 82,332, respectively, of the 14C was excreted in the urine and 12.4% and 6.7%, respectively, was excreted in the feces. After repeated oral dosing of the test compound at 100 mg/kg, 60.6% of the 14C was excreted in the urine and 14.9% was excreted in the feces. After dermal application of 100 mg/kg or 1000 mg/kg of 14C-EHA, 41.7% and.46.6%, respectively, of the 14C was excreted in the urine and 7.5% and 7.1%, respectively, was excreted in the feces. After intravenous administration of the test compound at 1 mg/kg, 66.6% of the 14C was excreted in the urine and 3.6% was excreted in the feces. The major urinary metabolites of EHA were the glucuronic acid conjugate of EHA, 2- ethylhexanedioic acid, isomers of hydroxy-2-ethylhexanoic acid and two isomeric metabolites of MU 142, proposed to be lactones. The parent compound was present in the urine at approximately 1.5 to 6.7% of the dose, depending upon the dose level and route of administration.

A skin washing study was conducted to determine the efficiency of removal of dermally applied EHA from the skin surface by washing the skin with soapy water. The exposure site was washed five to ten minutes after dermal exposure to 14C-EHA at 1000 mg/kg. Essentially all of the 14C was recovered during the washing procedure (101.9%). 14C excreted in the urine and feces over 96 hr was negligible (less than 0.2%).

Description of key information

Following administration of EHA, the material is rapidly cleared within 24 hours by oxidative metabolism to diacids, hydroxyacids, lactones and glucuronic acid conjugates of these metabolites in urine and in feces. The biological half-life of 113Sn in mice was estimated to be 29 days after i.p.injection.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
75
Absorption rate - dermal (%):
70
Absorption rate - inhalation (%):
100

Additional information

There are no data available on the metabolic disposition of tin bis(2 -ethylhexanoate) following administration of this material to experimental animals. However, information is available on tin and on ethylhexanoic acid, the two hydrolysis products of tin bis(2 -ethylhexanoate).

Inorganic tin compounds generally have little systemic toxicity in animals because of limited absorption from the gastrointestinal tract, low accumulation in tissues, and rapid excretion, primarily in the faeces. (JECFA/ WHO FAS 46 and CICAD 56)

 

The distribution of 2-ethylhexanoic acid (2-EHA) was studied in mice and rats.

2-14C-EHA in rat blood, brain, liver and kidney was quanitated by liquid scintillation analysis and by wholebody autoradiography in mice. A single intraperitoneal dose of 2-14C-EHA was injected in both species. Techniques employed did not allow separation of radiolabeled EHA from its metabolites. Animals were sacrificed 30 min., 2 and 6 hr after the administration of 2-14C-EHA in autoradiography experiments. The highest uptake of 2-14CEHA was observed in the liver, kidney and blood of mice.In contrast, low uptake of 2-14C-EHA was seen in the brain. In rats, at 2 hr after administration the highest concentration of 2-14C-EHA occurred in blood (0.3% of the total dose/g tissue). By 6 hr, the radioactivity had decreased rapidly and was hardly measurable at 24 hr after the administration. The results suggest that 2-EHA is rapidly cleared from the tissues. [Pennanen and Mamminen, 1991]

 

Pennanen et al [1991] also characterized the metabolites of EHA excreted in urine. Male Wistar rats were given 2-ethylhexanoic acid (2-EHA) in drinking water (600 mg/kg daily) for nine weeks, and then urine specimens were collected and analyzed. The compounds were identified by gas chromatography-mass spectrometry in both electron-impact mode and chemical ionization mode. In addition to 2-EHA, ten different 2-EHA-related metabolites were found in the urine of 2-EHA-treated rats. The main metabolite was 2-ethyl-l,6-hexanedioic acid. Urine also contained 2-ethyl-6-hydroxyhexanoic acid and five other hydroxylated metabolites and two lactones. At least part of the 2-EHA is present in urine as a glucuronide conjugate.

 

The following study [Eastman Kodak, 1987] was conducted to determine the metabolic fate and disposition of EHA in female rats following single oral gavage, repeated oral gavage, dermal or intravenous administration. Groups of 4 or 8 female Fischer 344 [rats weighing 115 g to 150 g were administered [2-14C-hexyl]EHA (14C-EHA): 1) by a single oral gavage dose (100 mg/kg or 1000 mg/kg), 2) after fourteen daily oral gavage doses (100 mg/kg) of unlabeled EHA, 3) by dermal exposure (100 mg/kg or 1000 mg/kg) and 4) by intravenous injection (1 mg/kg). Urine, feces and cage rinsings were collected at intervals for 96 hr. Blood was collected from selected animals at intervals for 96 hr, and pharmacokinetic parameters were derived for the total14C label in blood.

 

After intravenous administration of 1 mg/kg14C-EHA, the blood concentration of radiolabeldeclined triexponentially. After oral administration of 100 mg/kg14C-EHA, the mean peak blood level of 85.1 μg equivalents EHA/g was detected at 15 or 30 min. It is reported that 72 -75% of the administered oral dose was absorbed and excreted as metabolites. Thus, at least 72% adsorption was observed in rats. After dermal application of 100 mg/kg14C-EHA, the mean peak blood level of 8.5 μg equivalents EHA/g was attained at 5.7 hr. The bioavailability of14C after dermal application was 60-70% relative to the bioavailability of14C after intravenous administration. The terminal half-lives of14C after intravenous, oral and dermal administration were 117 hr, 98 hr and 251 hr, respectively.

Radioactivity was eliminated in the urine and feces after each dose of14C-EHA, primarily within the first 24 hr of dosing. At the 100 mg/kg and 1000 mg/kg single oral dose levels, 79.3% and 82.3%, respectively, of the14C was excreted in the urine and 12.4% and 6.7%, respectively, was excreted in the feces. After repeated oral dosing of the test compound at 100 mg/kg, 60.6% of the14C was excreted in the urine and 14.9% was excreted in the feces. After dermal application of 100 mg/kg or 1000 mg/kg of14C-EHA, 41.7% and.46.6%, respectively, of the14C was excreted in the urine and 7.5% and 7.1%, respectively, was excreted in the feces. After intravenous administration of the test compound at 1 mg/kg, 66.6% of the14C was excreted in the urine and 3.6% was excreted in the feces.

 

The major urinary metabolites of EHA were the glucuronic acid conjugate of EHA, 2-ethylhexanedioic acid, isomers of hydroxy-2-ethylhexanoic acid and two isomeric metabolites proposed to be lactones. The parent compound was present in the urine at approximately 1.5 to 6.7% of the dose, depending upon the dose level and route of administration.

 

A skin washing study was conducted to determine the efficiency of removal of dermally applied EHA from the skin surface by washing the skin with soapy water. The exposure site was washed five to ten minutes after dermal exposure to14C-EHA at 1000 mg/kg. Essentially all of the14C was recovered during the washing procedure (101.9%).14C excreted in the urine and feces over 96 hr was negligible (less than 0.2%).

Discussion on bioaccumulation potential result:

Little information is available ontin bis(2 -ethylhexanoate)and on tin salts. The biological half-life of113Sn in mice was estimated to be 29 days.

 

EHA metabolic disposition and toxicokinetics have been investigated in rats. Following administration of EHA, the material is rapidly cleared within 24 hours by oxidative metabolism to diacids, hydroxyacids, lactones and glucuronic acid conjugates of these metabolites in urine and in feces.