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Description of key information

Short description of key information on bioaccumulation potential result: 
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

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 total 14C label in blood.

 

After intravenous administration of 1 mg/kg 14C-EHA, the blood concentration of radiolabeldeclined 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. It is reported that 72 -75% of the administered oral dose was absorbed and excreted as metabolites. Thus 72% adsorption was observed in rats. 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.

Radioactivity was eliminated in the urine and feces after each dose of 14C-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 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 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 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 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%).

Discussion on bioaccumulation potential result:

Little information is available on tin bis(2 -ethylhexanoate) and on tin salts. The biological half-life of 113Sn 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.