Indium

Endpoint summary

Description of key information

Information characterizing the toxicokinetics of indium metal in experimental animals is lacking. Several in vitro studies have evaluated the dissolution rates of indium metal. Data on the bioaccessibility of indium metal in different biological fluids as a surrogate for bioavailability are reported within section 7.1.1 of IUCLID (Brouwers et al, ECTX). Additional toxicokinetics data in humans were available.

Animal Studies:

Absorption:

Oral:

Based on limited animal studies, indium is considered to be poorly absorbed by the oral route. The intestinal absorption of indium in rats has been reported to be approximately 0.5% of the administered dose (0.38g or 0.8 g In/kg) given as trichloride solution with additional indium trichloride carrier (Smith et al, 1960).

Inhalation:

In rats intracheally instilled with 114In(OH)3 or 114In citrate, it was found that most of the administered dose was taken up by the tracheobronchial lymph nodes (Smith et al, 1957). Results observed by Leach et al (1961) showed in rats exposed through inhalation to In2O3 at an average indium concentration in dust of 64mg In2O3/m3, significantly mobilization of indium oxide to tracheobronchial lymph nodes, but little absorption was observed. The absorption of inhaled 114In sesquioxide particles (2.5mg In/m3) by rats has been estimated to be between 3 and 6% of the total dose after a single 1 -hour treatment, and approximately 18% for sequential 1-hour exposures on four successive days (Morrow et al 1958).

Metabolism:

In blood, indium is located essentially in the serum (90%) bound to transferrin and albumin.

Distribution:

The transport of indium in body fluids and tissues is determined by the chemical form. Ionic indium is transported in the blood bound to transferrin (Castronovo and Wagner, 1973; Hosain et al, 1969; Zhang et al, 2004) and has been found to be cleared within 3 days from the blood of mice given an intravenous injection. On the other hand, colloidal hydrated indium oxide injected intravenous (i.v.) was immediately cleared from the blood (Castronovo and Wagner, 1971, 1973)

The distribution of indium after administration of a single i.t, subcutaneous (s.c.), intramuscular (i.m.) and oral dose to rats was investigated by Smith et al (1960, 1957). Kidney, spleen, liver and salivary glands were target organs, but pelt, skeleton and muscle contained the largest absolute amounts. Distribution of indium in body tissues is largely determined by the metal's chemical form. Ionic indium is extensively accumulated by the kidney, whereas colloidal hydrated indium oxide is accumulated primarily by the liver, spleen, and other organs of the reticuloendothelial system (Castranovo and Wagener, 1973; Fowler, 2007). Castronovo and Wagner (1971) demonstrated that 3 days after a single intravenous injection, approximately 20% of a tracer dose and 30% of an LD₁₀₀ dose of ionic ¹¹⁴In was found in the kidneys of mice. In contrast mice injected with colloidal 114In concentrated approximately 64% of the tracer dose and 40% of the LD100 dose in their livers after 3 days. Similar results were reported by Van Hulle et al (2001, 2005) demonstrating that the major sites of deposition for respectively rats intraperitoneally injected with 114In as InCl3 or subcutaneously injected with 114In as InAs were the liver, kidneys, and the spleen. Intracellular fractionation demonstrated that most of the 114In was bound in the cytoplasmic fraction followed by the mitochondria. Most of the 114In was bound in the high-molecular-weight fractions of the serum and in the cytoplasmic fraction of the liver, kidneys and spleen.

Hoet et al (2012) observed 3 months after a single pharyngeal (p.a.) administration of In2O3 the highest In tissue concentration in the lungs, confirming a very slow pulmonary clearance of this compound.

Excretion:

The primary route of indium excretion from the body is determined by the chemical form administered. Ionic indium is mainly excreted in urine, whereas colloidal indium complexes are primarily excreted in the faeces. Mice have been found to excrete 52% of an administered dose of ionic indium through urine and 53% of a dose of colloidal indium through faeces (Castronova and Wagner, 1971, 1973).

A two-phase excretion pattern is described and the biological half-time for indium depends somewhat on the chemical form administered. A whole-body biological half-time of indium in mice receiving an intravenous injection of 114 indium chloride has been reported to be 1.9 days for the fast-phase component representing approximately 50% of the body burden, and 69 days for the slow-phase component. Hydrated 114 indium oxide had a biological half-time of 2 days for the fast-phase component representing approximately 25% of the body burden, and 73.8 days for the slow phase after intravenous injection (Castronovo and Wagner, 1971, 1973). In accordance with the above observations were the results of Hoet et al (2012) which showed very high In-Pl measures after ip injection of InCl3 to rats and a biphasic excretion pattern with an initial fast component (half-time 2.8 days) and a subsequent slower component with a half-time of 60 days suggesting the existence of a depot in an internal organ. Smith et al (1957, 1960) reported that approximately 60% of an intracheal injection of radioactive indium left the lungs of rats within 16 days. Excretion of indium from the bodies of these animals was also biphasic. The biological half-time for inhaled indium sesquioxide particles has been found to be approximately 8 -10 days in rat lungs (Morrow et al 1958).

Human information:

Absorption

Oral:

The intestinal absorption of indium in humans has been studied by Heading et al (1971), showing that adult volunteers absorbed less than 2% of a 200 µCi dose of 113In as a diethylenetriaminepentaacetic acid (DPTA) complex. Coates et al (1973) reported no detectable absorption of a 500 µCi dose of 113In administrated to InCl3 to human adults.

Inhalation:

Isitman et al (1974) administered 111InCl3 or 111In-DPTA to adult humans by ultrasonic nebulisation and found deposition in the major airways with little (1.3 -4.4%) alveolar deposition. Some studies reported an elevation of concentration of indium in blood, serum and/or urine in workers exposed to indium (indium compounds slightly soluble or insoluble) during the production of indium tin oxide (concentration ranges of <0.1 -117µg/L serum in the exposed workers versus <0.1 -1.5 in the controls) (Hamaguchi et al , 2008, Chonan et al 2007), in optoelectronic industry (average concentration in blood: 0.22 µg/l in exposed versus 0.14 µg/l in controls (Liao et al 2004) and in the production of semi-conductors (concentration ranges of 3 -36 µg/l urine in workers vs 0.05 -7 µg/l in controls (Chen et al 2007).

The above-mentioned values were higher than those reported in other industrial facilities as In ingot manufacturing workers mainly exposed to In2O3 and In(OH)3 and metallic indium (concentration ranges of 0.22 -3.5 µg/l urine and 0.32 -12.6 µg/l serum in workers vs < 0.02 and <0.03 µg/l respectively in controls (Hoet et al 2012). Hoet et al demonstrated that neither In-U nor In-Pl significantly increased during the day or the week. A weekend-end without occupational exposure was not sufficient to reach the background In-Pl and In-U levels measured in controls. The results of the experimental investigations confirmed the hypothesis that inhalation of hardly soluble In compounds may cause accumulation of In in the body leading to a prolonged 'endogenous exposure' from both a lung depot of 'insoluble' particles that are progressively absorbed and from a retention depot in other internal organs. In-U and In-Pl are very sensitive to detect exposure and mainly reflect long-term exposure. In-Pl levels are particularly stable for a given individual. In-U might be more influenced than In-Pl by recent exposure. Both parameters remained high years after the withdrawal from exposure, indicating a possible endogenous exposure and a prolonged risk of pulmonary and systemic diseases even after work exposure has ceased.

Dermal:

Indium has poor or no human skin absorption because of Indium's precipitation at physiologic pH (Sullivan and Krieger, 2001).

Excretion:

Isitman et al (1974) reported the biphasic half-times for 111InCl3 or 111In-DPTA in lung of adult human subjects exposed to an aerosol to be 16 and 35 minutes, respectively. After a prolonged exposure it is likely that the accumulation of insoluble indium particles in the lungs is followed by a slowly resorption which is responsible for a prolonged elimination with half-times ranging from some days to several years. This can explain the observations of elevated indium concentrations in plasma/serum and urine of workers not anymore exposed to indium (Chonan et al 2007)

CONCLUSION SUMMARY:

For indium salts and its various compounds, systemic toxicity is attributed to the indium ion and differences in toxicity are principally linked to bioavailability. The bioelution data (for details see IUCLID section 7.1.1) are summarized below and have been incorporated into read-across assessments for In and In compounds. Further details related to the specific endpoints for which read-across approach was used, is summarized in section 13 of IUCLID (read across justification report). The bioelution data in lysosomal fluid was considered inconclusive and not used in the read-across approach. Due to the high citric acid in lysosomal fluid there is a complexation effect of citric acid inducing high solubility (e.g. indium metal; also seen with other metal compounds).

Table- Bio-elution data on indium and indium compounds measured in different physiological fluids

Test substance	Gastric Bioaccessibility pH 1.5 2 hours as % In released of total In content	Lysosomal Bioaccessibility pH 4.5 24- 168 hours as % In released of total In content	Interstitial Bioaccessibility pH 7.4 24- 168 hours as % In released of total In content	Sweat Bioaccessibility pH 6 24- 168 hours as % In released of total In content
InCl3	102	93.2-92.8	0.0034-0.00	0.00-0.00
In(NO)3	99	/	0.00-0.00	0.00-0.00
In	9.3	76-91	0.00-0.00	0.00-0.00
In(OH)3	5.1	1.60-5.40	0.00-0.00	0.00-0.00
In2O3	0.15	0.09-0.55	0.00-0.00	0.00-0.00
In2S3	0.45	0.27-0.51	/	0.00-0.00

 

The toxicokinetics of In compounds is likely dependent upon the form (solubility) of the compound administered, the dose, and the route of administration.

Absorption:

Indium and indium compounds are poorly absorbed by the oral route (0.5 -<2%) and moderately by the inhalation route (up to 18%). The absorption rate of indium is very likely a function of the chemical form. More indium can be absorbed in the lungs and tracheobronchial lymph nodes than in the gastrointestinal tract, likely due to the longer retention time when indium is deposited in the lungs.

Following inhalation or intracheal instillation, indium salts are retained in the lung and rapidly absorbed, having half-lives of approximately 1h; insoluble indium compounds, like In2O3 are absorbed slowly, with half-lives of approximately 2 months (Smith et al 1978). For poorly water-soluble particles, only a few percent of inhaled particles may reach the systemic circulation by the slow dissolution and progressive absorption; a further fraction may be translocated as particles to the tracheobronchial lymph nodes and from there to the systemic circulation (Hoet et al., 2012).

Distribution and elimination:

Ionic indium is concentrated in the kidneys, producing renal failure; colloidal indium is taken up by the reticuloendothelial system, causing damage to the liver and spleen. Ionic indium is excreted primarily in urine while fecal elimination is the predominant route for the removal of colloidal indium. A biphasic pattern of excretion and a whole-body biological half-time in the order of 2 weeks have been reported for ionic and colloidal forms of indium.

The most common routes of exposure for the general population are inhalation and ingestion; for occupationally exposed persons it is inhalation.

References :

-Smith GA, Thomas RG and Scott JK 1960: The metabolism of indium after administration of a single dose to the rat by intracheal, subcutaneous, intramuscular and oral injection (publication), Health Physics Pergamon Press. 4: 101-108.

-Smith GA, Thomas RG, Black B and Scott JK 1957: The metabolism of indium 114m administered to the rat by intracheal intubation (publication), The university of Rochester Atomic Energy Report No. UR-500. Testing laboratory: University of Rochester, Rochester, N.Y.

-Leach LJ, Scott JK, Armstrong RD, Steadman LT, Maynard EA 1961: The inhalation toxicity of indium sesquioxide in the rat. (publication), The university of Rochester Atomic Energy Report No. UR-590. Testing laboratory: University of Rochester, Rochester, N.Y.

-Morrow PE, Gibb FR, Cloutier R, Casarett LJ and Scott JK 1958: Fate of indium sesquioxide and of indium114 trichloride hydrolysate following inhalation in rats (publication), The university of Rochester Atomic Energy Report No. UR-508. Testing laboratory: University of Rochester, Rochester, N.Y.

-Castronovo FP, Jr., Wagner HN, Jr. 1973: Comparative toxicity and pharmacodynamics of ionic indium chloride and hydrated indium oxide. (publication), J Nucl Med 14:677-682.

-Castronovo FP, Wagner HN (1971) Factors affecting the toxicity of the element indium. British journal of experimental pathology 52:543-559

-Hosain F, McIntyre PA, Poulose K, Stern HS, Wagner HN, Jr. (1969) Binding of trace amounts of ionic indium-113m to plasma transferrin. Clinica chimica acta; international journal of clinical chemistry 24:69-75.

​-Zhang M, Gumerov DR, Kaltashov IA, Mason AB (2004) Indirect detection of protein-Metal binding: Interaction of serum transferrin with In3+ and Bi3+. Journal of the American Society for Mass Spectrometry 15:1658-1664.​

-Van Hulle M, De Cremer K, Vanholder R and Cornelis R 2001: In vivo distribution and speciation of [114mIn]InCl3 in the Wistar rat (publication), Journal of Environmental Monitoring 3: 86-90. ​

-Van Hulle M, De Cremer K, Vanholder R and Cornelis R 2005: In vivo distribution and fractionation of indium in rats after subcutaneous and oral administration of [114mIn]InAs (publication), Journal of Environmental Monitoring 7:365-370. ​

-Hoet P, De Graef E, Swennen B, Seminck T, Yakoub Y, Deumer G, Haufroid V and Lison D. 2012: Occupational exposure to indium: what does biomonitoring tell us? (publication), Toxicology Letters 213(1):122-128.

-Heading RC, Tothill P, Laidlaw AJ, Shearman DJ (1971) An evaluation of indium DTPA chelate in the measurement of gastric emptying by scintiscanning. Gut 12:611-615.

-Coates G, Gilday DL, Cradduck TD, Wood DE 1973: Measurement of the rate of stomach emptying using Indium-113m and a 10-crystal rectilinear scanner (publication), Canadian Medical Association journal 108:180-183.​

-Isitman AT, Manoli R, Schmidt GH, Holmes RA 1974: An assessment of alveolar deposition and pulmonary clearance of radiopharmaceuticals after nebulization. (publication), The American journal of roentgenology, radium therapy, and nuclear medicine 120:776-781.

-Hamaguchi T, Omae K, Takebayashi T, Kikuchi Y, Yoshioka N, Nishiwaki Y, Tanaka A, Hirata M, Taguchi O, Chonan T (2008) Exposure to hardly soluble indium compounds in ITO production and recycling plants is a new risk for interstitial lung damage. Occupational and environmental medicine 65:51-55.

-Chonan T, Taguchi O, Omae K (2007) Interstitial pulmonary disorders in indium-processing workers. Eur Respir J 29:317-324.

-Liao YH, Yu HS, Ho CK, Wu MT, Yang CY, Chen JR, Chang CC (2004) Biological monitoring of exposures to aluminium, gallium, indium, arsenic, and antimony in optoelectronic industry workers. Journal of occupational and environmental medicine / American College of Occupational and Environmental Medicine 46:931-936.

-Chen HW (2007) Exposure and health risk of gallium, indium, and arsenic from semiconductor manufacturing industry workers. Bulletin of environmental contamination and toxicology 78:5-9.

-Sullivan and Krieger, editors (2001) Clinical environmental health and toxic exposures, second edition