11
Antimony Pentoxide and Sodium Antimonate

THIS chapter reviews the physical and chemical properties, toxicokinetics, toxicological, epidemiological, and exposure data on pentavalent antimony (antimony pentoxide and sodium antimonate). The subcommittee reviewed the available data on these compounds and determined that toxicological information necessary for risk assessment was mostly available for antimony pentoxide. The subcommittee used that information to characterize the health risk from exposure to pentavalent antimony. The subcommittee also identified data gaps and recommended research relevant for determining the health risk from exposure to pentavalent antimony.

PHYSICAL AND CHEMICAL PROPERTIES

The physical and chemical properties of antimony pentoxide and sodium antimonate are summarized in Table 11–1.

OCCURRENCE AND USE

Antimony pentoxide (Sb2O5) and sodium antimonate (NaSbO3) are the pentavalent forms of antimony most widely used as flame retardants. Pentavalent



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Toxicological Risks of Selected Flame-Retardant Chemicals 11 Antimony Pentoxide and Sodium Antimonate THIS chapter reviews the physical and chemical properties, toxicokinetics, toxicological, epidemiological, and exposure data on pentavalent antimony (antimony pentoxide and sodium antimonate). The subcommittee reviewed the available data on these compounds and determined that toxicological information necessary for risk assessment was mostly available for antimony pentoxide. The subcommittee used that information to characterize the health risk from exposure to pentavalent antimony. The subcommittee also identified data gaps and recommended research relevant for determining the health risk from exposure to pentavalent antimony. PHYSICAL AND CHEMICAL PROPERTIES The physical and chemical properties of antimony pentoxide and sodium antimonate are summarized in Table 11–1. OCCURRENCE AND USE Antimony pentoxide (Sb2O5) and sodium antimonate (NaSbO3) are the pentavalent forms of antimony most widely used as flame retardants. Pentavalent

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Toxicological Risks of Selected Flame-Retardant Chemicals TABLE 11–1 Physical and Chemical Properties of Antimony Pentoxide and Sodium Antimonate Property Value Reference Antimony pentoxide Chemical formula Sb2O5, Sb(V) Budavari et al. 1989 CAS Registry # 1314–60–9 Budavari et al. 1989 Synonyms Antimonic oxide, stibic anhydride, antimonic acid, antimonic (V) acid Budavari et al. 1989 Molecular weight 323.52 Budavari et al. 1989 Physical state Yellow powder Budavari et al. 1989 Solubility Slightly soluble in water; practically insoluble in HNO3; slowly dissolves in warm HCl or in warm KOH Budavari et al. 1989 Melting point 380°C Budavari et al. 1989 Density 3.78 g/cm3 Budavari et al. 1989 Sodium antimonate Chemical formula NaSbO3, Sb(V) Lide 1991–1992 CAS Registry # 15432–85–6 Lide 1991–1992 Synonyms Sodium (meta) antimonate Lide 1991–1992 Molecular weight 192.74 Lide 1991–1992 Physical state White, granular powder Lide 1991–1992 Solubility Slightly soluble in water; practically insoluble in HNO3; soluble in tartaric acid Lide 1991–1992 antimonates function primarily as a stable colloid or synergist with halogenated flame retardants. Antimony pentoxide retards flammability by forming halogenated antimony compound which excludes oxygen from the front of the flame (Gerhartz et al. 1985; ATSDR 1992). Sodium antimonate (NaSbO3) is used in industrial applications where special colors are required or when antimony trioxide may produce unwanted chemical reactions (IPCS 1997). TOXICOKINETICS Absorption Dermal No studies were found that examined the absorption of pentavalent antimonates following dermal exposure.

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Toxicological Risks of Selected Flame-Retardant Chemicals Inhalation Elevated blood and urine antimony levels were reported in workers occupationally exposed to antimony compounds (pentoxide and trioxide) suggesting that antimony is absorbed by the inhalation route (Cooper et al. 1968). Inhalation studies in Syrian hamsters indicate that antimony is absorbed and distributed to various tissues following exposure to pentavalent aerosols derived from an antimony-tartrate complex (Felicetti et al. 1974). Oral The International Commission on Radiological Protection (ICRP 1981) has recommended that a 1% absorption rate of antimony compounds (including antimony pentoxide and sodium antimonate) be assumed when estimating exposure from the gastrointestinal tract. This recommendation is based on studies of various organic and inorganic antimony compounds, some of which have a pentavalent valence state. Oral exposure studies in Syrian hamsters with an antimony-tartrate complex found only minute amounts of antimony were absorbed through the gastrointestinal tract (Felicetti et al. 1974). Distribution The distribution of antimony in the body is affected by the valence states of the particular antimony species. Pentavalent antimony has less affinity for liver tissue and accumulates to a greater extent in the spleen of hamsters than do the trivalent forms (Gellhorn et al. 1946, as cited in ATSDR 1992). Human (Otto et al. 1947) and hamster (Felicetti et al. 1974) erythrocytes concentrate the trivalent form but not the pentavalent form of antimony. Additionally, skeletal uptake in hamsters is greater for pentavalent antimony than the trivalent form. In a retrospective study on deceased smelter workers exposed to a number of metals (including antimony), elevated levels of antimony were found in their lung tissues as compared with those in non-occupationally exposed individuals (Gerhardsson et al. 1982). Neither the form nor the valence state of the antimony exposure was reported. High levels of antimony were found in the liver, skeleton, and pelt (in non-lung tissue) of hamsters following inhalation exposure to pentavalent antimony as a tartrate (Felicetti et al. 1974).

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Toxicological Risks of Selected Flame-Retardant Chemicals Metabolism and Excretion Few data are available on the metabolism of pentavalent antimony. It is known that inorganic antimony is not methylated in vivo but can covalently bind to sulfhydryl groups and phosphate (Bailly et al. 1991). Pentavalent antimony can form conjugates with glutathione and be excreted in the bile (Bailly et al. 1991). Excretion of absorbed antimony in smelter workers exposed to pentavalent antimony occurs primarily in the urine. Rees et al. (1980) reported that more than 80% of pentavalent antimony (administered as sodium stibogluconate) is excreted in 6 hr in humans following intravenous or intramuscular injection. Following a single intramuscular injection, pentavalent antimony had a half-life of about 1 hr in hamsters (Berman et al. 1988). Experimental animals excrete trivalent antimony in the feces and to a lesser extent in the urine (Gross et al. 1955). HAZARD IDENTIFICATION1 There are inadequate toxicity data on antimony pentoxide and sodium antimonate from any route of exposure. Chapter 10 provides a detailed discussion of toxicity of antimony trioxide and other antimony compounds. This chapter contains discussion only on antimony pentoxide and sodium antimonate. Dermal Exposure Male smelter workers (n=51) exposed to airborne dusts containing antimony trioxide and pentoxide were diagnosed with skin changes. Conjunctivitis was identified in 27% of the workers while dermatosis was identified in 63% of the 51 workers (Potkonjak and Pavlovich 1983). No actual exposure levels for these workers were given. The authors note that the affected persons worked in the factory from 9 to 31yr (mean=17.91), almost exclusively as smelters. No other dermal toxicity data were identified for any pentavalent antimonates. 1   In this section, the subcommittee reviewed toxicity data on antimony pentoxide and sodium antimonate, including the toxicity assessment prepared by the U.S. Consumer Product Safety Commission (Hatlelid 1999).

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Toxicological Risks of Selected Flame-Retardant Chemicals Inhalation Exposure Systemic Effects Male smelter workers (n=51) exposed to airborne dust containing antimony, arsenic, silica, and ferric oxides were evaluated for symptoms of antimoniosis (pneumoconiosis caused by antimony exposure) over a 2-yr reporting period (Potkonjak and Pavlovich 1983). All subjects had worked exclusively as smelters for a period of 9 to 31 yr (mean=17.91) and had shown positive X-ray findings of antimoniosis over a range of severity. Exposure was primarily to antimony trioxide (5.5–64 mg/m3) while exposure to the pentoxide form ranged from 0.27 to 5.0 mg/m3. Other pulmonary symptoms included chronic coughing (60.8%), upper airway inflammation (35.3%), and conjunctivitis (27.5%). Pulmonary function tests did not find an increased incidence of any obstructive changes. Fibrosis was not detected in any of the subjects, and no other symptoms of systemic antimony poisoning were reported. However, the results of this study cannot be used to attribute the observed effects to antimony exposure because of the confounding exposure to other contaminants. In an acute inhalation exposure study, the LC50 for male and female Sprague-Dawley rats (5/sex) exposed to colloidal antimony pentoxide for 4 hr at concentrations of 2.64, 5.01, or 8.62 mg/L was found to be 6.14 mg/L for males and 8.62 mg/L for females. The generated particles had a mass median aerodynamic diameter (MMAD) of 2.95–3.54 microns with a geometric standard deviation of 2.15 to 2.39. Survivors did not have any findings at necropsy that were not incidental or spontaneous postmortem changes (Hazelton Laboratories 1989). No F-344 rats died or developed abnormal gross pathology that were intratracheally instilled with a suspension of antimony pentoxide (3.5 µg /kg body weight) for 6 mo (American Biogenics Corp. 1987). No significant differences in body weight were seen when compared to control animals. It is not known whether histopathological analysis was conducted on these animals. Macrophage cytotoxicity was also determined for cultured F-344 rat alveolar macrophages (American Biogenics Corp. 1986). Antimony trioxide, antimony pentoxide-A, and antimony pentoxide-ZTA concentrations tested were 0.02, 0.2, 2, and 20 mM for 20 hr. The viability indices, expressed as an EC50, were 0.55, 1.14, and 25.44, respectively, for the trioxide, pentoxide-A, and pentoxide-ZTA. Other Systemic Effects There are no data on the immunological, neurological, reproductive, or developmental effects of pentavalent antimonates following inhalation exposure.

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Toxicological Risks of Selected Flame-Retardant Chemicals Cancer Potkonjak and Pavlovich (1983) did not find any malignancies among 51 smelter workers exposed to antimony (as antimony trioxide and pentoxide). Workers had occupational exposure in the smelter industry from 9 to 31yr (mean=17.91). There are no data on the carcinogenicity of pentavalent antimonates in animals following inhalation exposure. Oral Exposure There are no carcinogenicity data on antimony pentoxide or sodium antimonate in humans or animals following oral exposure. Genotoxicity Antimony pentoxide did not induce chromosome damage or damage to chromosomal spindle apparatus in male or female CD-1 mice (five/sex/group) treated by gavage with antimony pentoxide at doses of 2,500, 5,000, or 10,000 mg/kg (Nissan Chemical Industries, Ltd. 1985). Antimony pentoxide was negative in the Bacillus subtilis assay (60 µg/disk) and did not induce sister chromatid exchanges (40 µg/mL) in Chinese hamster ovary cells (Kuroda et al. 1991). Antimony pentoxide was also negative for mutagenicity in various Salmonella strains at concentrations up to 200 µg/plate. Antimony trioxide was positive in the rec assay and induced SCE at doses 100 times lower than the pentoxide (Kuroda et al. 1991). QUANTITATIVE TOXICITY ASSESSMENT Noncancer Dermal, inhalation, and oral toxicity data on pentavalent antimonates are insufficient to derive RfDs or an RfC. Acute oral toxicity data for the pentavalent forms of antimony suggest that it is less toxic than the trivalent forms of antimony. Cancer There are insufficient cancer data on pentavalent antimonates from any route of exposure to calculate cancer potency factors.

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Toxicological Risks of Selected Flame-Retardant Chemicals EXPOSURE ASSESSMENT AND RISK CHARACTERIZATION Noncancer Dermal exposure to pentavalent antimony was estimated using the dermal exposure scenario described in Chapter 3. This exposure scenario assumes that an adult spends 1/4th of his or her time sitting on furniture upholstery treated with antimony pentoxide or sodium antimonate and also assumes 1/4th of the upper torso is in contact with the upholstery and clothing presents no barrier. The subcommittee believes that pentavalent antimony is an ionic substance and, therefore, is essentially not absorbed through the skin. However, to be conservative, the subcommittee assumed that ionized antimony pentoxide and sodium antimonate permeate the skin at the same rate as water, with a permeability rate of 10−3 cm/hr (EPA 1992). Using that permeability rate, the highest expected application rate for zinc borate of 2.5 mg/cm2, and Equation 1 in Chapter 3, the subcommittee calculated a worst-case dermal exposure level of 2.0×10−2 mg/kg-d. The dermal or oral RfDs for antimony pentoxide or sodium antimonate were not derived because of a lack of adequate toxicity data. As a result, the noncancer risk associated with dermal exposure to antimony pentoxide or sodium antimonate, used as a flame retardant, cannot be characterized at this time. Inhalation Exposure Particles The assessment of the noncancer risk from inhalation of upholstery particles containing pentavalent antimony is based on the inhalation exposure scenario described in Chapter 3. In this scenario, a person is exposed to upholstery particles containing pentavalent antimony. It is assumed that particles are formed from the wear of the upholstery and 50% of the pentavalent antimony present in 25% of the treated surface is released as particles over the 15-yr lifetime of the fabric. It is also assumed that only 1% of the worn-off pentavalent antimony is released into the indoor air as particles that may be inhaled and that a person spends 1/4th of his or her lifetime in a 30-m3 room that contains 30 m2 of treated upholstery with an air-change rate of 0.25/hr. Particle exposure was estimated using Equations 4 and 5 in Chapter 3. The subcommittee estimated an upholstery application rate (Sa) for pentavalent antimony of 2.5 mg/cm2. The release rate (µr) for pentavalent antimony from

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Toxicological Risks of Selected Flame-Retardant Chemicals upholstery fabric was estimated to be 2.3×10−7/d yielding a room airborne particle concentration (Cp) of 0.95 µg/m3 and a short time-averaged exposure concentration of 0.24 µg/m3. The time-averaged exposure concentration for particles was calculated using Equation 6 in Chapter 3. An inhalation RfC is currently not available for pentavalent antimony. As a result, the noncancer risk associated with the inhalation of particles containing antimony pentoxide cannot be characterized at this time. However, a structurally similar compound, antimony trioxide, was found to be a possible concern for noncancer effects. Therefore, the subcommittee recommends that exposure levels for these compounds be measured. Vapors Antimony pentoxide has negligible vapor pressure at ambient temperatures. Therefore, inhalation of antimony pentoxide vapor is not anticipated to pose a noncancer toxic risk when incorporated into furniture upholstery. Oral Exposure The assessment of noncancer risk from oral exposure to antimony pentoxide or sodium antimonate is based on the oral exposure scenario described in Chapter 3. This scenario assumes a child is exposed to pentavalent antimony by sucking on 50 cm2 of fabric treated with pentavalent antimony, 1 hr/d for 2 yr. The subcommittee estimated an upholstery application rate (Sa) for pentavalent antimony of 2.5 mg/cm2 and a fractional rate of pentavalent antimony extraction (µa) by saliva of 0.001/d based on levels reported by Jenkins et al. (1998). Oral exposure was calculated using Equation 15 in Chapter 3. Using the above equation, the worst-case average oral daily dose for antimony pentoxide was estimated as 0.00052 mg/kg-d. An oral RfD is not currently available for antimony pentoxide; therefore the noncancer risk associated with the estimated worst-case daily dose cannot be characterized at this time. Cancer There are inadequate data to characterize carcinogenic risk from the use of antimony pentoxide as a flame retardant from the dermal, inhalation, or oral routes of exposure.

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Toxicological Risks of Selected Flame-Retardant Chemicals RECOMMENDATIONS FROM OTHER ORGANIZATIONS The Threshold Limit Value recommended by the American Conference of Governmental Industrial Hygienists for antimony and its compounds is 0.5 mg/m3 (ACGIH 1999). The subcommittee is not aware of any other regulatory exposure limits for antimony pentoxide or sodium antimonate. DATA GAPS AND RESEARCH NEEDS There are no subchronic or chronic toxicity studies in the literature on pentavalent forms of antimony from any route of exposure. Additionally, there are no studies on the toxic effects of pentavalent antimony on reproduction or development. There are no exposure measurements from any route of exposure. Based on the lack of toxicological data and possible concern from exposure to a structurally similar compound, antimony trioxide, the subcommittee recommends that the release rates into saline solution and air from fabrics treated with antimony pentoxide or sodium antimonate be investigated. REFERENCES ACGIH (American Conference of Government Industrial Hygienists). 1999. Threshold Limit Values and Biological Exposure Indices. Cincinnati, OH: American Conference of Government Industrial Hygienists, Inc. American Biogenics Corp. (American Biogenics Corporation). 1986. Evaluation of the Cytotoxicity of Antimony Trioxide and Two Antimony Pentoxides Using Cultured Alveolar Macrophages. Study No. 420–2630. Decatur, IL. American Biogenics Corp. (American Biogenics Corporation). 1987. A Six-month Intratracheal Toxicity Study of Antimony Oxides in Albino Rats. Study no. 420–2211 (Draft). Decatur, IL. ATSDR (Agency for Toxic Substances and Disease Control). 1992. Toxicological Profile for Antimony. Agency for Toxic Substances and Disease Registry, U.S. Department of Health and Human Services, Public Health Service, Atlanta, GA. Bailly, R., R.Lauwerys, J.P.Buchet, P.Mahieu, and J.Konings. 1991. Experimental and human studies on antimony metabolism: Their relevance for the biological monitoring of workers exposed to inorganic antimony. Br. J. Ind. Med. 48(2):93–97. Berman, J.D., J.F.Gallalee, and J.V.Gallalee. 1988. Pharmacokinetics of pentavalent antimony (Pentostam) in hamsters. Am. J. Trop. Med. Hyg. 39(1):41–45. Budavari, S., M.J.O’Neil, A.Smith, and P.E.Heckelman. 1989. The Merck Index, Eleventh Ed. S.Budavari, M.J.O’Neil, A.Smith, and P.E.Heckelman, eds. Rahway, NJ.: Merck & Co., Inc. Cooper, D.A., E.P.Pendergrass, A.J.Vorwald, R.L.Mayock, and H.Brieger. 1968.

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Toxicological Risks of Selected Flame-Retardant Chemicals Pneumoconiosis among workers in an antimony industry. Am. J. Roentgenol. Radium Ther. Nucl. Med. 103(3):495–508. EPA (U.S. Environmental Protection Agency). 1992. Dermal Exposure Assessment: Principles and Applications. EPA/600/8–91–011B. Office of Health and Environmental Assessment, U.S. Environmental Protection Agency, Washington, DC. Felicetti, S.A., R.G.Thomas, and R.O.McClellan. 1974. Metabolism of two valence states of inhaled antimony in hamsters. Am. Ind. Hyg. Assoc. J. 35(5):292–300. Gellhorn, A., N.A.Tupikova, and H.B.van Dyke. 1946. The tissue distribution and excretion of four organic antimonials after single or repeated administration to normal hamsters. J. Pharmacol. Exp. Ther. 87:169–180. Gerhardsson, L., D.Brune, G.F.Nordberg, and P.O.Wester. 1982. Antimony in lung, liver and kidney tissue from deceased smelter workers. Scand. J. Work Environ. Health 8(3):201–208. Gerhartz, W., Y.S.Yamamoto, F.T.Campbell, R.Pfefferkorn, and J.F.Rounsaville, eds. 1985. Pp. 124–125 in Ullman’s Encyclopedia of Industrial Chemistry, Vol. Al. Weinheim, Germany: VCH. Gross, P., J.H.U.Brown, M.L.Westrick, R.P.Srsic, N.L.Butler, and T.F.Hatch. 1955. Toxicologic study of calcium halophosphate phosphors and antimony trioxide. I. Acute and chronic toxicity and some pharmacologic aspects. Arch. Ind. Health 11:473–478. Hatlelid, K. 1999. Toxicity Review for Calcium Molybdate and Zinc Molybdate. Memorandum, dated March 2, 1999, from Kristina Hatlelid, Toxicologist, Division of Health Sciences, to Ronald Medford, Assistant Executive Director for Hazard Identification and Reduction, U.S. Consumer Product Safety Commission, Washington, DC. Hazleton Laboratories (Hazelton Laboratories America, Inc.). 1989. Acute Inhalation Toxicity Study with Colloidal Antimony Pentoxide in the Rat. HLA Study No. 2096–169. Hazelton Laboratories America, Inc., Rockville, MD. ICRP (International Commission on Radiological Protection). 1981. Metabolic data for antimony. Pp. 46–49 in Radiation Protection, ICRP Publication 30, Part 3, Including Addendum to Parts 1 and 2, Limits for Intakes of Radionuclides by Workers. International Commission on Radiological Protection. Elmsford, NY: Pergamon Press. IPCS (International Programme on Chemical Safety). 1997. Environmental Health Criteria 192 Flame Retardants: A General Introduction. Geneva: World Health Organization. Jenkins, R.O., P.J. Craig, W. Goessler, and K.J. Irgolic. 1998. Antimony leaching from cot mattresses and sudden infant death syndrome (SIDS). Hum. Exp. Toxicol. 17(3):138–139. Kuroda, K., G. Endo, A. Okamoto, Y.S. Yoo, and S. Horiguchi. 1991. Genotoxicity of beryllium, gallium, and antimony in short-term assays. Mutat. Res. 264(4): 163–170. Lide, D.R. 1991–1992. Handbook of Chemistry and Physics, 72nd Ed. Boca Raton, FL.:CRC Press. Nissan Chemical Industries, Ltd. 1985. Micronucleus Test with Sb2O5 in Mice. Report No. 85–32–02803. Saitama-ken, Japan.

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Toxicological Risks of Selected Flame-Retardant Chemicals Otto, G.F., T.H.Maren, and H.W.Brown. 1947. Blood levels and excretion rates of antimony in persons receiving trivalentand pentavalent antimonials. Am. J. Hyg. 46:193–211. Potkonjak, V. and M.Pavlovich. 1983. Antimoniosis: A particular form of pneumoconiosis. I. Etiology, clinical and X-ray findings. Int. Arch. Occup. Environ. Health 51(3): 199–207. Rees, P.H., M.I.Keating, P.A.Kager, and W.T.Hockmeyer. 1980. Renal clearance of pentavalent antimony (sodium stibogluconate). Lancet 2(8188):226–229.