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Toxicological Risks of Selected Flame-Retardant Chemicals 10 Antimony Trioxide THIS chapter reviews the physical and chemical properties, toxicokinetics, toxicological, epidemiological, and exposure data on antimony trioxide. The subcommittee used that information to characterize the health risk from exposure to antimony trioxide. The subcommittee also identified data gaps and recommended research relevant for determining the health risk from exposure to antimony trioxide. PHYSICAL AND CHEMICAL PROPERTIES The physical and chemical properties of antimony trioxide are summarized in Table 10–1. OCCURRENCE AND USE Antimony trioxide is formed by reacting antimony trichloride (SbCl3) with water. It is used in combination with some brominated flame retardants, and might also be used in conjunction with zinc borate, both within and outside the United States on commercial furniture, draperies, wall coverings, and carpets (R.C.Kidder, Flame Retardant Chemical Association, unpublished material, April 21, 1998). It is also used in enamels, glasses, rubber, plastics, adhesives, textiles, paper, and as a paint pigment (Budavari et al. 1989).
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Toxicological Risks of Selected Flame-Retardant Chemicals TABLE 10–1 Physical and Chemical Properties of Antimony Trioxide Characteristic Value Reference Chemical formula Sb2O3 Lide 1991–1992 CAS registry # 1309–64–4 Lide 1991–1992 Synonyms diantimony trioxide, flowers of antimony Budavari et al. 1989 Molecular weight 291.5 g/mol Lide 1991–1992 Physical state Crystal Budavari et al. 1989 Solubility Very slightly soluble in cold water; slightly soluble in hot water; soluble in KOH, HCl, tartaric acid, and acetic acid Lide 1991–1992 Vapor pressure 1×10−10 mm Hg Calculated from Lide 1991–1992 Melting point 656 °C Lide 1991–1992 Boiling point 1,550 °C Lide 1991–1992 Density 5.2 g/cm3 (senarmontite), 5.7 g/cm3 (valentinite) Lide 1991–1992 TOXICOKINETICS Absorption Systemic toxicity and death occurred in rabbits following dermal application of 8g/kg antimony trioxide (Myers et al. 1978), and application of an unspecified dose of antimony trioxide in a paste of “artificial acidic or alkalinic sweat” (Fleming 1938). Both studies indicate that antimony trioxide is absorbed dermally in rabbits. Elevated blood and urine antimony levels were reported in workers occupationally exposed to antimony, suggesting that antimony trioxide is absorbed following inhalation exposure (Cooper et al. 1968; Lüdersdorf et al. 1987; Kim et al. 1997). However, no quantitative correlation was found between the air concentrations of antimony and the antimony concentration measured in urine (Kim et al. 1997). Few quantitative data were found regarding the absorption of antimony trioxide following oral exposure. The International Commission on Radiological Protection (ICRP 1981) has recommended that a 1% absorption rate of antimony compounds (including antimony trioxide) be assumed when estimat-
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Toxicological Risks of Selected Flame-Retardant Chemicals ing exposure from the gastrointestinal (GI) tract. That recommendation is based on studies of various organic and inorganic antimony compounds. Toxicity is greater following exposure to 7.9 mg antimony trioxide/kg-d in 5% citric acid than to 101 mg antimony trioxide/kg-d in water, suggesting that solubility can affect antimony absorption (Fleming 1938). Distribution No studies were identified on the tissue distribution of antimony trioxide following dermal exposure. Retired workers occupationally exposed by the inhalation route to antimony were reported to have elevated concentrations of antimony in their lung tissue as compared to non-occupationally exposed individuals (Gerhardsson et al. 1982). Following intratracheal instillation of a single dose of 1.52 mg antimony trioxide/kg in Syrian golden hamsters, the highest concentrations of antimony were measured in the lungs and liver, with lower concentrations present in the kidney, stomach, and trachea (Leffler et al. 1984). No information was found on the tissue distribution of antimony in humans following oral exposure. In rats, high concentrations of antimony were measured in the thyroid and GI contents following chronic ingestion of 2% antimony trioxide in the feed (Gross et al. 1955a). Detectable levels were also found in the spleen, kidney, heart, bone, muscle, lungs, liver, and GI tissue. Following continuous treatment of rats for 40 d. Antimony was concentrated in the thyroid, with much lower levels found in the other tissues 40 d after cessation of chronic ingestion of 2% antimony trioxide in the feed (Gross et al. 1955a). Metabolism and Excretion No data were identified on the metabolism or excretion of antimony trioxide following dermal exposure. Intraperitoneal injection of rats with 800 µg antimony chloride/kg did not result in detectable levels of any organic form of antimony in the bile or urine, indicating that antimony is not methylated in vivo. Antimony can form a complex with glutathione in vivo (Bailly et al. 1991). McCallum (1963) reported elevated antimony concentrations in the urine of workers occupationally exposed via inhalation to antimony, indicating that excretion by this pathway occurs in humans.
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Toxicological Risks of Selected Flame-Retardant Chemicals Gerhardsson et al. (1982) measured post-mortem antimony levels in the lung tissue of workers occupationally exposed via inhalation to antimony. Levels were found to be elevated compared to a control population, even after workers had been retired for up to 20 yr, indicating a long half-life for lung clearance of antimony in humans. Toxicokinetic studies in adult male Syrian golden hamsters given a single, intratracheal instillation of antimony trioxide (1.52 mg/kg body weight) indicate that 20% of the instilled antimony was cleared from the lung in the first 20 hr (Leffler et al. 1984). Biological half-times of about 40 hr for the initial phase and 20–40 d for the second phase were calculated for lung tissue (Leffler et al. 1984). In rats exposed to 119 mg antimony trioxide dust/m3 for 80 hr, the majority of urinary excretion occurred within the first 3 d after exposure (Gross et al. 1955a). Following a single oral dose (200 mg antimony trioxide) of antimony trioxide to rats, 3% of the administered dose was recovered in the urine within 8 d. Only 0.15% was recovered 1 d after treatment, and 3% was recovered between d 2 and 5 post-treatment (Gross et al. 1955a). Following chronic exposure (2% antimony trioxide in the diet; 8 mo), approximately 99% of fecal excretion and the majority of urinary excretion occurred within 7 d after exposure ceased (Gross et al. 1955a). The large amount of antimony excreted in the feces soon after exposure suggests that a substantial portion of the compound is excreted without being absorbed systemically. That is consistent with the low absorption rate (1%) cited by the ICRP (ICRP 1981) (see Absorption section). HAZARD IDENTIFICATION1 Dermal Exposure Irritation Dermatitis was reported in workers occupationally exposed to 0.4–70.7 mg antimony/m3 (Renes 1953; McCallum 1963; Potkonjak and Pavlovich 1983; White et al. 1993). Although antimony trioxide in the work environment was believed to be responsible for the dermatitis, quantitative data on dermal exposure were not available, and the workers were also exposed to other elements such as arsenic. Therefore, the causative agent for the observed dermatitis could not be positively determined. 1 In this section, the subcommittee reviewed toxicity data on antimony trioxide, 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 In a controlled human study (Industrial Bio-Test Laboratories, Inc. 1973), 52 subjects received a series of nine dermal applications of antimony trioxide over a 3-wk period. The antimony trioxide was applied for 24 hr; the dose was not reported. Two wk after the series of applications, a single dose of antimony trioxide was applied. After each application, skin reactions were evaluated. No skin reactions were observed over the course of the study, suggesting that antimony trioxide is neither a skin irritant nor a sensitizer. Dermal exposure to antimony trioxide generally did not cause dermatitis in tested animals. Only mild skin irritation was observed even after repeated or prolonged exposure to large quantities of antimony trioxide (2–25 g antimony trioxide/kg) in rabbits (Gross et al. 1955a; Ebbens 1972). Skin edema was reported in one study in which antimony trioxide was applied to rabbits in corn oil (8 g antimony trioxide/kg for 24 hr) (Myers et al. 1978). However, that study is limited in that there was no solvent control group, and data on severity and number of animals responding was lacking. In a study by Haskell Laboratory (Haskell Laboratory 1970a), a suspension of 12, 31, or 61 mg antimony trioxide/kg in a fat/acetone/dioxane mixture was applied to intact shaved skin (all doses) or abraded skin (31-mg/kg group only) of 10 albino guinea pigs. The exposure duration was not reported. Irritation was not seen in any of the treated animals. In another study by Haskell Laboratory (1970b), 24 or 49 mg/kg antimony trioxide (suspended in a similar mixture as above) was applied to the intact shaved skin of guinea pigs. One day after the treatment, mild erythema was observed in 2/10 and 5/10 animals treated with 24 mg antimony trioxide/kg and 49 mg antimony trioxide/kg, respectively. All of the responses had disappeared 2 d after the initial dosing. Sensitization As mentioned under the Irritation section, no skin reactions were observed in the controlled human study conducted by Industrial Bio-Test Laboratories, Inc. (1973), indicating that antimony trioxide is not a skin sensitizer. Haskell Laboratory (1970a, b) treated groups of five guinea pigs with nine dermal applications of 31 mg antimony trioxide/kg (25%) or 49 mg antimony trioxide/kg (50%) in a fat/acetone/dioxane mixture on shaved and abraded skin, or four intradermal injections of 1 mg antimony trioxide in either acetonedimethyl phthalate or propylene glycol solutions, over the course of 3 wk. After a 2-wk rest period, each group of animals received challenge applications of the suspensions on both intact and abraded skin. Sensitization was not observed in any of the test animals.
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Toxicological Risks of Selected Flame-Retardant Chemicals Systemic Effects Death occurred in one out of four rabbits following a single dermal exposure to 8 g/kg antimony trioxide (Myers et al. 1978), and in one out of four rabbits exposed to 2 g/kg antimony trioxide (Ebbens 1972). Systemic toxicity and death occurred in three out of eight rabbits, but not in rats, following short-term exposure (20–21 d) to an unspecified dose of antimony trioxide (Fleming 1938). Gross pathologies were seen in the liver, lung, stomach, and kidney. Other Systemic Effects No studies were identified that investigated the immunological, neurological, reproductive, developmental, or carcinogenic effects of antimony trioxide following dermal exposure to antimony trioxide. Inhalation Exposure Systemic Effects In humans, the lungs are the primary targets following inhalation exposure to antimony trioxide. Several studies of antimony smelter workers show that workers developed pneumoconiosis, chronic cough, and upper airway inflammation following chronic exposure to antimony trioxide (McCallum 1963, 1967; Cooper et al. 1968; Potkonjak and Pavlovich 1983). In addition, one study reported systemic effects following inhalation exposure in smelter workers, including weight loss, nausea, vomiting, nerve tenderness, and tingling (Renes 1953). In those studies, however, a causal role for antimony trioxide in the observed human health effects could not be confirmed because of the lack of individual exposure data for the workers and exposure to other compounds, including arsenic, lead, and alkali, that could be confounders. The lungs are also the primary target tissues in animals following inhalation exposure (see Table 10–2). All experimental inhalation studies were conducted using whole-body exposure. Details of particle size and purity are provided in footnotes. Guinea pigs exposed to antimony trioxide2 (average concentration: 45.4 mg antimony trioxide/m3, 2–3 hr/d, 6 mo) developed pneumonitis, liver and spleen effects, and decreased white blood cell counts (Dernehl 1945). Similarly, pneumonia was seen following exposure of rats (100–125 mg antimony trioxide/m3, 100 hr/mo, 14.5 mo) and rabbits (89 mg antimony 2 Assumed particle size <1 µm and 99.8% pure based on production technique.
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Toxicological Risks of Selected Flame-Retardant Chemicals TABLE 10–2 Toxic Effects of Antimony Trioxide Following Inhalation Exposure Species, Strain, Number Exposurea (mg/m3); Duration Duration-adjusted Concentrations (mg/m3)b Effects NOAEL/LOAEL (mg/m3) RDDR HEC NOAEL/ LOAEL Reference Rat, NS, 50 100–125; 100 hr/mo for 14.5 mo 13.9–17.4 Diffuse, interstitial fibrosis; 18% died of pneumonia LOAEL: 13.9 ND ND Gross et al. 1955b Rabbit, NS, 20 89; 100 hr/mo for 10 mo 12.4 85% died of pneumonia LOAEL: 12.4 ND ND Gross et al. 1955b Guinea pig, NS, 24 45.4 (average); 2–3 hr/d, 7 d/wk for 6 mo 3.8–5.7 Pneumonitis, liver and spleen effects, decreased white blood cell counts LOAEL: 3.8 ND ND Dernehl 1945 Rat, Wistar, 90/sex 45.5; 7 hr/d, 5 d/wk for 52 wk; 20-wk observation 9.4 Interstitial fibrosis, alveolar-wall cell hypertrophy and hyperplasia, and cuboidal and columnar cell metaplasia of the lungs LOAEL: 9.4 ND LOAEL: 5 Groth et al. 1986 Rat, Fischer 344, 55/sex 0.25, 1.08, 4.92, or 23.46; 6 hr/d, 5 d/wk for 13 wk; 27-wk observation 0.04, 0.19, 0.88, 4.19 6% decrease in body weight Increased lung weight NOAEL: 0.88 (M) LOAEL: 4.19 (M) NOAEL: 0.19 LOAEL: 0.88 0.324 0.585 ND NOAEL: 0.006 LOAEL: 0.51 ND Newton et al. 1994 Newton et al. 1994
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Toxicological Risks of Selected Flame-Retardant Chemicals Species, Strain, Number Exposurea (mg/m3); Duration Duration-adjusted Concentrations (mg/m3)b Effects NOAEL/LOAEL (mg/m3) RDDR HEC NOAEL/ LOAEL Reference Chronic interstitial inflammation, granulomatous inflammation, increased alveolar macrophages NOAEL: 0.19 (F) 0.88 (M) LOAEL: 0.88 (F) 4.19 (M) ND ND Newton et al. 1994 Rat, Fischer 344, 65/sex) 0.06, 0.51 or 4.5; 6 hr/d, 5 d/wk for 1 yr; 1-yr observation 0.01, 0.09, 0.80 Increased alveolar macrophage LOAEL: 0.01 0.435 LOAEL: 0.004 Newton et al. 1994 Interstitial inflammation and granulomatous inflammation NOAEL: 0.09 LOAEL: 0.80 BMC (F): 0.16 0.435 0.46 NOAEL: 0.039 LOAEL: 0.348 BMC(F): 0.074 Newton et al. 1994 Newton et al. 1994 Rat, Wistar, 50F 1.9, 5.0; 6 hr/d, 5 d/wk for 1 yr 0.3, 0.9 Discoloration and increased alveolar macrophages LOAEL: 0.3 ND ND Watt 1983
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Toxicological Risks of Selected Flame-Retardant Chemicals Interstitial inflammation and granulomatous inflammation NOAEL: 0.9 LOAEL: 0.3 ND ND Watt 1983 Swine, Sinclair S-1, 3F 1.9, 5.0; 6 hr/d, 5 d/wk for 1 yr 0.3, 0.9 Minimal lung fibrosis ND ND ND Watt 1983 Rat, NS, 6–7 0.027, 0.082, 0.27; 24 hr/d for 21 d of gestation 0.027, 0.082, 0.27 Pre-implantation loss, fetal growth retardation, and pre-and post-implantation embryo death NOAEL: 0.027 LOAEL: 0.082 ND ND Grin et al. 1987 BMC, benchmark concentration; F, female; HEC, human equivalent concentration; LOAEL, lowest-observed-adverse-effect level; M, male; ND, not determined; NOAEL, no-observed-adverse-effect level; RDDR, regional deposited dose ratio. aAll inhalation exposures were whole body. bConcentrations are adjusted for continuous exposure.
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Toxicological Risks of Selected Flame-Retardant Chemicals trioxide/m3, 100 hr/mo, 10 mo) to antimony trioxide3 (Gross et al. 1955b). Interstitial flbrosis, hypertrophy, and hyperplasia were seen in male and female Wistar rats (90/sex-group) exposed to antimony trioxide4 (45.5 mg antimony trioxide/m3, 7 hr/d, 5 d/wk for 1 yr, followed by a 20-wk observation period) (Groth et al. 1986); those effects were more pronounced in the females. Watt (1983) investigated the effects of exposure to antimony trioxide5 (1.6 or 4.2 mg Sb/m3, equivalent to 1.9 or 5.0 mg antimony trioxide/m3, 6 hr/d, 5 d/wk for 1 yr) in female CDF Fischer rats (148 animals divided into three dose groups) and Sinclair S-1 miniature swine (eight animals divided into three dose groups). In rats, blood urea nitrogen (BUN) was consistently elevated at the high concentration, but was statistically significant only after 6 mo of exposure. No other changes in hematology, serum biochemistry or histology were reported. A concentration-related increase in lung weight was also observed in the rats. Swine were examined immediately after the treatment, at which time there was minimal fibrosis and no other statistically significant effects were observed. Newton et al. (1994) conducted a preliminary, subchronic study in which male and female F-344 rats (55/sex/group) were exposed to antimony trioxide6 (concentrations of 0.25, 1.08, 4.92, and 23.46 mg antimony trioxide/m3) 6 hr/d, 5 d/wk for 13 wk followed by a 27-wk observation period. A decrease in body weight was seen in the males at the highest concentration tested and an increase in absolute lung weight was seen at the two highest exposure concentrations. Minimal-to-moderate microscopic pathologies were seen in the highest exposure group. The Newton et al. (1994) pilot study was followed by a 1-yr chronic study 3 Average particle size by electron micrograph=0.6 µm, few particles up to 1 µm; calculated average particle size by weight=0.4 µm; purity not reported. 4 It was noted by the authors that they had difficulty generating the target concentration of 50 mg antimony trioxide/m3; the mean daily time-weighted average (TWA)=45.5 mg/m3; the range was 0–191.1 mg antimony trioxide/m3; particle size: median circular area equivalent diameter=0.347 µm, mass median diameter (MMD) =1.23 µm, mass median aerodynamic diameter (MMAD) =2.80 µm, analyzed using a scanning electron microscope and image analyzer; purity: 80% antimony by proton-induced X-ray emission, 0.04 mg arsenic/g and 2.3 mg lead/g. 5 Particle size averaged 0.44 µm (geometric standard deviation [SD] =2.23) and 0.40 µm (geometric SD=2.13) for low and high concentration, respectively; purity=99.4% antimony, 0.02% arsenic, 0.2% lead. MMAD, a critical parameter in inhalation studies, could not be directly derived from the data in this study. 6 Test material not milled; particle size: count median diameter=0.485–0.62 µm, MMD=1.49–2.50 µm, MMAD=3.05–5.7 µm; purity=99.68±0.10%, contaminants not reported.
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Toxicological Risks of Selected Flame-Retardant Chemicals (Bio/dynamics 1990, as cited in EPA 1999). In that study, F-344 rats (65/sex/ exposure level) were exposed to antimony trioxide7 (measured concentrations were 0, 0.06, 0.51, or 4.5 mg antimony trioxide/m3) 6 hr/d, 5 d/wk for 1 yr, followed by a 1-yr observation period. Five rats/sex/group were killed after 6 and 12 mo of exposure, and at 6 mo postexposure. All survivors were killed 12 mo after the end of the exposure period. Animal body weights were monitored. Complete gross and histopathological examinations were performed on all animals. The sections of the lungs examined included both the right lobes and the major bronchi. The only exposure-related changes occurred in the lungs and included chronic interstitial inflammation, granulomatous inflammation, and increased alveolar macrophages. Pinpoint black foci, thought to be aggregates of macrophages laden with antimony trioxide, were seen in the lungs of exposed animals, most frequently during the post-exposure observation period. In a subsequent analysis performed by the EPA (1999), it was noted that in the low- and mid-exposure groups, there was no indication that the particle-laden macrophages were anything but part of a normal, compensatory response. However, the clearance half-time of the high-exposure group was more than three times that of the mid-exposure group, indicating that clearance mechanisms were severely compromised. In some instances, clearance of particles is slowed by high lung burdens of inert particles, which leads to high lung particle burdens for extended periods (months to years), and pathologies that cannot be directly attributed to the toxicity of the chemical (Witschi and Last 1996). However, in this study (Newton et al. 1994), the decreased clearance appeared to be due to the inherent toxicity of antimony trioxide, rather than a particle overload phenomenon. Newton et al. (1994) reported a 50% increase in the clearance time of antimony trioxide at a dust volume of 270 nanoliter (nL), but benign dust particles have to be at about 1,000 nL to have that effect on clearance (Muhle et al. 1990, as cited in EPA 1999). However, some scientists believe that particle overload could account for the increased clearance time rather than inherent toxicity of antimony trioxide. Despite those observations, the subcommittee considered this study to be appropriate for calculation of an RfC. Based on additional statistical analysis (EPA 1999) of the male and female rats that died spontaneously or were killed at 18 and 24 mo, a LOAEL for interstitial inflammation and granulomatous inflammation of 4.5 mg antimony trioxide/m3 and a NOAEL of 0.51 mg antimony trioxide/m3 (NOAEL[HEC] of 0.042 mg antimony trioxide/m3) were identified from this study. 7 MMAD=3.7 µm, geometric S.D.=1.7; purity=99.68±0.10%, contaminants not reported.
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Toxicological Risks of Selected Flame-Retardant Chemicals TABLE 10–6 Inhalation Reference Concentration for Antimony Trioxide Critical Effect Species Effect Level (mg/m3) Uncertainty Factors RfC (µg/m3) Reference Pulmonary toxicity Rats BMC10: (ADJ, HEC) 0.074 UFA: 3 UFH: 10 UFS: 3 UFD: 3 Total: 300 0.2 Newton et al. 1994 BMC10, concentration corresponding to an extra risk of 10% (adjusted for intermittent exposure and calculated as the human equivalent concentration); RfC, reference concentration; UFA, extrapolation from animals to humans; UFH, intraspecies variability; UFS, extrapolation from a study of less-than-lifetime duration; UFD, inadequate or deficient toxicity database. of 10 for intraspecies variation, a factor of 3 for database inadequacies, and a factor of 3 for a less-than-lifetime exposure that was longer than the standard subchronic study. Division of BMC10 (ADJ, HEC) by the composite uncertainty factor resulted in an RfC of 0.2 µg antimony trioxide/m3. The key study used for the derivation of the inhalation RfC was assigned a medium confidence level. Although it was well conducted and well documented, it is not a lifetime exposure study. Confidence in the database is medium because of the absence of adequate developmental or reproductive toxicity studies. Therefore, confidence in the RfC is medium. Oral RfD The database for developing an oral reference dose (RfD) for antimony trioxide is limited to one high-quality subchronic feeding study in rats (Hext et al. 1999). That study is supported by data from a subchronic study in rats (Sunagawa 1981), and short-term studies in rats (Smyth and Thompson 1945) and dogs (Fleming 1938). Overall, those data indicate that the hematological system (increased serum enzymes), the liver (increased liver weights), and the gastrointestinal tract are the target organs for antimony trioxide. Based on the weight of evidence, the subcommittee considered the increases in serum enzymes in females and the increase in liver weight in males and females at 1,879 mg Sb2O3/kg bw-d to be adverse effects (Hext et al. 1999). Therefore, the LOAEL for that study is 1,879 mg antimony trioxide/kg-d and the NOAEL is 494 mg antimony trioxide/kg-d. A composite uncertainty factor of 3,000 is
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Toxicological Risks of Selected Flame-Retardant Chemicals applied to that NOAEL to yield an RfD of approximately 0.2 mg antimony trioxide/kg-d. The composite uncertainty factor comprises a factor of 10 for interspecies extrapolation; a factor of 10 to for intraspecies variability; a factor of 10 for extrapolation from a subchronic to a chronic study; and a factor of 3 for data base deficiencies (i.e., lower than the default of 10 because there is some data that indicate there is no progression in severity of effects). A summary of the derivation of that oral RfD is provided in Table 10–7. The key study used for the derivation of the RfD was conducted according to current testing guidelines and is well documented; therefore, confidence in the key study is high. However, confidence in the overall database is low, because there are no adequate data on developmental or reproductive effects. Several additional studies are needed to complete the database, including a bioassay in a second species, a multigeneration reproduction study, and developmental toxicity studies in two species. Longer-term assays would also be informative. As a result, the confidence for the derived RfD is low to medium. Cancer Dermal The carcinogenicity of antimony trioxide by the dermal route of exposure cannot be determined because of lack of data. Inhalation Based on the weight of evidence (from animal studies), the subcommittee concludes that the data are suggestive of carcinogenicity following inhalation TABLE 10–7 Oral Reference Dose for Antimony Trioxide Critical Effect Species Effect Level (mg/kg-d) Uncertainty Factors RfD (mg/kg-d) Reference Increases in serum enzymes; increased liver weight Female rats NOAEL=494 UFA: 10 UFH: 10 UFS: 10 UFD: 3 Total: 3,000 0.2 Hext et al. 1999 NOAEL, no-observed-adverse-effect level; RfD, reference dose; UFA, extrapolation from animals to humans; UFH, intraspecies variability; UFS, extrapolation from a study of less-than-lifetime duration; UFD, inadequate or deficient toxicity database.
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Toxicological Risks of Selected Flame-Retardant Chemicals exposure to antimony trioxide. The cancer risk from antimony trioxide following inhalation exposure was estimated based on the study by Watt (1983). It should be noted, however, that the study by Watt (1983) is not published in the peer review literature and the results are controversial. A linear extrapolation from the observable region to the low-dose region is appropriate because there are insufficient data to suggest a nonlinear mode of action. The data by Watt (1983) was modeled using the linear multistage model. The three tumor end points from the Watt (1983) study that were modeled were bronchioalveolar adenomas, scirrhous carcinomas, and squamous-cell carcinomas.14 Concentrations were adjusted for discontinuous exposure (multiplied by 6 hr/24 hr×5 d/7 d), converted to a HEC using the regional deposited dose ratio (RDDR=1.8342) of particles for the thoracic region (MMAD=0.4 microns, sigma g=2.2), and adjusted for the less-than-lifetime exposure. The modeling results are listed in Table 10–8. Because all the tumors occurred in the bronchioalveolar region and appeared to be arising from the alveolar epithelial lining cells, the three tumor types were combined, and total bronchioalveolar tumors were also modeled for the LED10. Using the combined bronchioalveolar tumor incidence yields the most conservative (health-protective) estimate of the risk, with an LED10 of 0.14 mg antimony trioxide/m3. Based on a linear extrapolation, the unit risk (cancer potency factor) of lung cancer is 7.1×10−4/µg antimony trioxide/m3. Oral The carcinogenicity of antimony trioxide by the oral route of exposure cannot be determined because of lack of data. EXPOSURE ASSESSMENT AND RISK CHARACTERIZATION Noncancer Dermal The assessment of noncancer risk by the dermal route of exposure is based on the scenario described in Chapter 3. This exposure scenario assumes that an 14 The incidence of tumors in all animals was used in the hazard identification. However, since the concentration-response modeling is based on tumors following a lifetime exposure, and there were several interim kills in this study, only tumors in the animals sacrificed at study termination were used in the modeling.
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Toxicological Risks of Selected Flame-Retardant Chemicals TABLE 10–8 Results of Modeling for the Watt (1983) Study on Antimony Trioxide Multistage model (mg/m3) Risk by EPA methods (mg/m3)−1 End point ED10 LED10 0.1/ED10 0.1/LED10 Adenomas 0.51 0.24 0.185 0.417 Scirrhous carcinomas 0.35 0.21 0.286 0.476 Squamous-cell carcinomas 0.83 0.43 0.120 0.233 Bronchioalveolar tumor (combined) 0.24 0.14 0.417 0.714 ED10, effective dose corresponding to a 10% tumor response in test animals; LED10, lower 95% bound on the effective dose corresponding to a 10% tumor response in test animals. adult spends 1/4th of his or her time sitting on furniture upholstery treated with antimony trioxide, that 1/4th of the upper torso is in contact with the upholstery, and that clothing presents no barrier. Antimony trioxide is considered to be ionic, and is essentially not absorbed through the skin. However, to be conservative, the subcommittee assumed that ionized antimony trioxide permeates 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 antimony trioxide (2.5 mg/cm2), and Equation 1 in Chapter 3, the subcommittee calculated a dermal exposure level of 2.0×10−2 mg/kg-d. The oral RfD for antimony trioxide (0.2 mg/kg-d; see Oral RfD in Quantitative Toxicity section) was used as the best estimate of the internal dose for dermal exposure. Dividing the exposure level by the oral RfD yields a hazard index of 0.1. Thus it was concluded that antimony trioxide used as a flame retardant in upholstery fabric is not likely to pose a noncancer risk by the dermal route. Inhalation Particles The assessment of the noncancer risk by the inhalation route of exposure is based on the scenario described Chapter 3. This scenario corresponds to a person spending 1/4th of his or her life in a room with low air-change rate
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Toxicological Risks of Selected Flame-Retardant Chemicals (0.25/hr) and with a relatively large amount of fabric upholstery treated with antimony trioxide (30 m2 in a 30-m3 room), with this treatment gradually being worn away over 25% of its surface to 50% of its initial quantity over the 15-yr lifetime of the fabric. A small fraction, 1%, of the worn-off antimony trioxide is released into the indoor air as inhalable particles and is breathed by the occupant. Equations 4 through 6 in Chapter 3 were used to estimate the average concentration of antimony trioxide in the air. The highest expected application rate for antimony trioxide is 2.5 mg/cm2. The estimated release rate is 2.3× 10−7/d. Using those values, the estimated time-averaged exposure concentration for antimony trioxide is 0.24 µg/m3. Division of that exposure concentration (0.24 µg/m3) by the inhalation RfC (2×10−4 mg/m3; see Quantitative Toxicity Assessment section) results in a hazard index of 1.2, indicating that under the worst-case exposure scenario, antimony trioxide might possibly pose a noncancer risk via inhalation of particles. Vapors In addition to the possibility of release of antimony trioxide in particles worn from upholstery fabric, the subcommittee considered the possibility of its release by evaporation. However, because of antimony trioxide’s negligible vapor pressure at ambient temperatures, the subcommittee considered antimony trioxide not likely to pose a noncancer risk by exposure to vapors. Oral Exposure The assessment of the noncancer risk by the oral exposure route is based on the scenario described in Chapter 3. That exposure assumes that a child sucks on 50 cm2 of fabric backcoated with antimony trioxide daily for two yr, one hr/d. The highest expected application rate (per unit time) for antimony trioxide is about 2.5 mg/cm2. The fractional release rate of antimory trioxide is estimated as 0.001/d, based on the leaching of antimony from polyvinyl chloride cot mattresses (Jenkins et al. 1998). Using those assumptions and Equation 15 in Chapter 3, the average oral dose rate is estimated to be 0.00052 mg/kg-d. Division of that exposure estimate (0.00052 mg/kg-d) by the oral RfD (0.2 mg/kg-d; see Quantitative Toxicity Assessment section) results in a hazard index of 2.6×10−3. Therefore, under the worst-case exposure assumptions, antimony trioxide, used as a flame retardant in upholstery fabric, is not likely to pose a noncancer risk by the oral route of exposure.
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Toxicological Risks of Selected Flame-Retardant Chemicals Cancer There are inadequate data to assess the carcinogenicity of antimony trioxide from dermal or oral exposures. Inhalation (Particles) The average room-air concentration and average exposure concentration for antimony trioxide were obtained as described for the noncancer risk assessment of particles. The estimated time-averaged exposure concentration is 0.24 µg/m3. Using the inhalation unit cancer risk (cancer potency factor) of 7.1×10−4/µg antimony trioxide/m3, the lifetime excess cancer risk estimate from exposure to antimony trioxide as particles is 1.7×10−4. However, the inhalation unit risk (cancer potency factor) of antimony trioxide is itself suspect (see Hazard Identification Section). Furthermore, even if the reservations concerning the study by Watt (1983) are discounted and the inhalation unit risk is considered to be accurate, better exposure assessment is required before any definitive conclusions can be drawn about the carcinogenic risk from antimony trioxide via inhalation in the particulate phase. Inhalation (Vapors) Antimony trioxide has negligible vapor pressure at ambient temperatures, so antimony trioxide used as a flame retardant in upholstery fabric is not likely to pose a cancer risk for exposure to vapors. RECOMMENDATIONS FROM OTHER ORGANIZATIONS The American Conference of Governmental Industrial Hygienists (ACGIH) has established a Threshold Limit Value (TLV) for antimony trioxide of 0.5 mg antimony/m3 (AGCIH 1999). The Occupational Safety and Health Administration (OSHA) and the National Institute for Occupational Safety and Health (NIOSH) do not have standards for exposure to antimony trioxide. EPA’s inhalation RfC of 0.2 µg antimony trioxide/mg3 is the same as that of the subcommittee.
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Toxicological Risks of Selected Flame-Retardant Chemicals DATA GAPS AND RESEARCH NEEDS There are little data on the toxicity of antimony trioxide following dermal exposure. The hazard index of 0.1 indicates that antimony trioxide is not likely to pose a non-cancer risk from dermal exposure. Therefore, the subcommittee does not recommend further research on the effects of antimony trioxide from dermal exposure for the purposes of flame-retarding upholstery furniture. The subcommittee’s risk characterization indicates that antimony trioxide might possibly pose a risk for noncancer and cancer end points via inhalation in the particulate phase. Therefore, better exposure information is essential to accurately assess the risks of antimony trioxide use as a flame retardant in upholstery fabric. If that research shows that actual exposures are substantially lower than the subcommittee’s estimated levels, there will be a reduced need to perform toxicity studies. One study indicated that there are reproductive effects following inhalation of antimony trioxide. However, the purity of the antimony trioxide in that study is not known, and studies of other antimony compounds show no reproductive effects (Reprotox 1999). The study on which the quantitative toxicity assessment for cancer is based is suspect, and further studies would clarify if antimony indeed poses a cancer risk following inhalation exposure. There are no studies that evaluated the chronic toxicity of antimony trioxide from the oral route of exposure. There are no studies that have measured exposure from the oral route. The hazard index of 2.6×10−3 indicates that antimony trioxide is not likely to pose a noncancer risk from oral exposure. Therefore, the subcommittee does not recommend further studies of antimony trioxide following oral exposure for the purposes of its use as a flame retardant in upholstery furniture fabric. With respect to cancer, the effects following inhalation exposure are portalof-entry specific (i.e., only occur in the lung), and, therefore, the subcommittee does not recommend carcinogenic studies following other routes of exposure. Based on an inhalation hazard index greater than one and a potential cancer risk following inhalation exposure, the subcommittee recommends that the potential for particle release from treated fabric 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.
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Representative terms from entire chapter: