1.1. Properties of Antimony(III) Trioxide and Other Antimony Compounds

Antimony(III) trioxide exists as an odorless white powder or polymorphic crystals (HSDB 2013). It is slightly soluble in water, dilute sulfuric acid, dilute nitric acid, or dilute hydrochloric acid. It is soluble in solutions of alkali hydroxides or sulfides and in warm solutions of tartaric acid or of bitartrates. Figure 1-1 shows the chemical structure for antimony(III) trioxide and Table 1-1 presents its physical and chemical properties.

Figure 1-1

Structure for Antimony(III) Trioxide

Table 1-1

Physical and Chemical Properties for Antimony(III) Trioxide.

Physical and chemical properties for other antimony compounds discussed in this monograph are listed in Table 1-2 together with their structures; the compounds listed are those with carcinogenicity (Sections 4 and 5), mechanistic (Section 6), or disposition (Section 3) data. In addition to elemental antimony (valence = 0), most antimony compounds have valences of either +3 (11 compounds) or +5 (6 compounds) although one compound with valence −3 is also included in the table. Compounds with +3 valence are likely to share more similarity with antimony(III) oxide but as discussed in Sections 2 and 3, interconversion between antimony(III) and antimony(V) occurs during manufacturing processes, in the environment, and in vivo. Both the +3 and +5 valence states include both inorganic antimony compounds, e.g., antimony(III) trisulfide and antimony(V) pentasulfide, and organic antimony compounds, primarily those used as anti-leishmanial drugs, such as sodium antimony 2,3-mesodimercaptosuccinate (the active ingredient in Astiban) and sodium stibogluconate(V) (the active ingredient in Pentostam).

Table 1-2

Physical and Chemical Properties for Metallic (Elemental) Antimony and Other Antimony Compounds with Carcinogenicity or Mechanistic Data.

Solubilization of some water-insoluble compounds may be enhanced in biological fluids at low pH and in the presence of binding proteins (IARC 2006), and this information may provide better understanding of potential absorption of an antimony compound than solubility in water. Because in vivo bioavailability testing can be cost prohibitive and time consuming, solubility of compounds in artificial fluids (i.e., bioaccessibility) can be estimated using synthetic equivalents of gastric fluid (for ingestion exposure), interstitial and lysosomal fluids (for inhalation exposure), perspiration fluids (for dermal exposure), and human blood serum (for transport within the body). The solubility of antimony(III) trioxide and other antimony compounds in these different fluids, which have pH ranging from 1.6 for gastric fluid to 7.4 for lung interstitial fluid and human blood serum are listed in Table 1-3. European Union Registration, Evaluation and Authorisation of CHemicals (REACH) data for bioaccessibility for antimony(III) trioxide, antimony(V) pentoxide, and antimony(III) sulfide in simulated human fluids is expressed as percent solubility in simulated human fluids at various pH values (ECHA 2017). For these three antimony compounds, in fluids simulating physiologic pH, bioaccessibility after 24 hours of exposure was highest for antimony(III) trioxide and lowest for antimony sulfide, with antimony pentoxide occupying an intermediate position. Antimony(III) trioxide had the highest percent solubility in artificial alveolar lysosomal fluid (pH = 4.5), which may be representative of the lung tissue contacted by inhaled antimony(III) trioxide (see Section 2) (ECHA 2017). Intermediate values were reported for artificial sweat (pH = 6.5), interstitial fluid within the deep lung (pH = 7.4), and human blood serum (pH = 7.4). The lowest value reported was for artificial gastric fluid (pH = 1.6).

Table 1-3

Bioaccessibility of Antimony(III) Trioxide and Other Antimony Compounds.

1.2. Antimony Speciation and Variability of Valence

The form of antimony (i.e., its speciation) affects its toxicity, mobility, and transformation in the environment, and antimony speciation depends on pH and redox potential (Herath et al. 2017). Similar to many other metallic elements, antimony toxicity is thought to be exerted through its ions (EU 2008), and ions of antimony are capable of performing redox reactions in biological systems (Beyersmann and Hartwig 2008). In general, antimony(III) species have been reported to be more toxic than antimony(V) species (Filella et al. 2002a; Herath et al. 2017); however, the European Union (2008) noted that there is no evidence to support a firm conclusion on toxicity differences for the two valences, and ORoC was also unable to identify data showing a clear difference in toxicity based on valence.

Elemental antimony exists in four primary oxidation states; −3, 0, +3, and +5; Sb(III) (trivalent form) and Sb(V) (pentavalent form) are the most common in environmental, biological, and geochemical systems. Thermodynamic equilibrium calculations indicate that antimony(V) predominates in oxic systems, and antimony(III) predominates in anoxic systems. However, antimony(III) concentrations at higher than calculation-predicted values have been detected in oxic systems; similarly, higher than calculation-predicted antimony(V) concentrations have been detected in anoxic systems (Filella et al. 2002a). Both trivalent (III) and pentavalent (V) antimony ions hydrolyze readily. When any form of antimony dissolves in water, it exists as the hydroxide forms, Sb(OH)₃ (uncharged) or Sb(OH)₆⁻ (charged) (Herath et al. 2017). Antimony(III) is present as the neutral species Sb(OH)₃ (or H₃SbO₃) for pH values from 2 to approximately 10 (Krupka and Serne 2002) and antimony(V) is present as the anion Sb(OH)₆⁻ (or H₂SbO₄⁻) for pH values from 2.7 to 10.4 (EU 2008; Herath et al. 2017). As shown in Figure 1-2, these forms are the major ones at physiologic pH around 7.4. Figure 1- 2 also illustrates antimony speciation for antimony(III) and antimony(V) species over a pH range of 0 to 12. Positively charged species are reported to generally exist only under very acidic conditions (i.e., pH < 2) (Herath et al. 2017).

Figure 1-2

Antimony Speciation for Antimony(III) and Antimony(V) Species over a Range of pH Values

The evidence for formation of these hydroxide forms in cellular or extracellular fluids is limited; however, the presence of Sb(III) in oxic water at higher than predicted levels has been proposed to be related to the presence of organic matter, particularly organic acids that also occur in plasma, such as citric acid, pyruvic acid, and fumaric acid (Filella et al. 2002a; 2002b).

Inorganic forms generally are found more often than organic forms in many environmental systems (EU 2008; Herath et al. 2017). However, antimony can form organic compounds via biological methylation (i.e., the chemical combination of methyl groups with metals or metalloids through the action of a living organism such as bacteria, fungi, or plants) (Filella et al. 2007). Evidence for in vivo methylation of antimony in mammals is limited (see Section 3).

1.3. Detection of Antimony and Antimonial Species

Measurements in both environmental and biological samples (Table 1-4) can include total antimony, the oxidation state of antimony, and methylated species (Belzile et al. 2011).

Table 1-4

Methods for Detection of Antimony and Antimonial Species in Environmental and Biological Samples.

1.4. Summary

Elemental antimony is a metalloid that exists in four primary oxidation states: −3, 0, +3, and +5. The most common forms in environmental, biological, and geochemical systems are Sb(III) (the trivalent form) and Sb(V) (the pentavalent form). Antimony speciation can affect its toxicity, mobility, and transformation in the environment. Detection of antimony species depends on chromatographic separation of Sb(III) from Sb(V) followed by determination of elemental antimony by methods such as atomic absorption spectrometry after destruction of the chemical compound at high temperatures or conversion to the hydride.

Antimony(III) trioxide is the oxide of trivalent (+3) antimony that exists as an odorless white powder or polymorphic crystals (HSDB 2013). It is only slightly soluble in water, but it is bioaccessible in artificial body fluids, especially lysosomal fluid of lung cells where more than 80% dissolves in 24 hours. In solution, antimony(III) trioxide exists primarily as the uncharged hydroxide form, Sb(OH)₃.