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Suggested Citation:"1 Antimony." National Research Council. 2008. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/12527.
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Suggested Citation:"1 Antimony." National Research Council. 2008. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/12527.
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Suggested Citation:"1 Antimony." National Research Council. 2008. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/12527.
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Suggested Citation:"1 Antimony." National Research Council. 2008. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/12527.
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Appendix

1 Antimony Raghupathy Ramanathan, Ph.D. Toxicology Group Habitability and Environmental Factors Division Johnson Space Center National Aeronautics and Space Administration Houston, Texas INTRODUCTION NASA is concerned about the potential for antimony contamination of wa- ter because several experimental payloads will contain science materials that use antimony alloys with dopants. Also, numerous semiconductors and electronic equipment that can be found on a spacecraft, as well as materials with flame retardants, may contain antimony. In addition, some future experiments will involve soldering. NASA is concerned because the U.S. Environmental Protec- tion Agency (EPA) maximum contamination level (MCL) for antimony is rela- tively low (6 parts per billion). OCCURRENCE AND USE Antimony is a semi-hard, silvery-white, brittle metal. It exists in the earth’s crust mostly as a sulfide, from which antimony is extracted for commer- cial use. Antimony is not usually acted upon by air and is only slightly affected by dilute acids and alkalis. It resembles arsenic, both chemically and biologi- cally, and both exist as the trivalent and the pentavalent element. When burnt, antimony becomes brilliant, producing antimony (III) oxide (Sb2O3). This prop- erty makes it a desirable compound for making firecrackers. Antimony is also used in making bullets and cable sheathing, and, when mixed with lead and zinc, it is used to prepare alloys. Antimony salts are used in pigments and abrasives, as well as for flame-proofing fabrics. Antimony is extensively used in various industries and in large quantities for several applications, such as in making paints and enameling glass (Budavari et al. 1989; ATSDR 1992). One of the most noted uses of Sb2O3 is as a flame retardant added to textiles, plastics, and 13

14 Spacecraft Water Exposure Guidelines rubber (NRC 2000a). General physical and chemical properties of metallic an- timony and of two soluble antimony compounds are included in Table 1-1. Antimony has been used for more than 50 years in the preparation of drugs to treat cutaneous and visceral leishmaniasis, an endemic parasitic disease spread by the bite of infected blood-sucking sand flies. Pentavalent salts of an- timony (sodium stibogluconate [Pentostam] and meglumine antimonite [Glucan- time]) are used parenterally to treat schistosomiasis and leishmaniasis. Another of the most commonly used antimony-containing chemicals is a trivalent anti- monial called antimony potassium tartrate (APT), also known as tartar emetic. This compound has been used as an emetic, as well as an antischistosomal and antifilarial drug. Exposure to antimony results mostly from exposure to environmental dis- charges from the metal alloy industries and smelters. Water usually becomes contaminated with antimony as a result of exposure to sediments containing particulates from industrial pollution and as a result of runoff industrial waste from the paint, ceramics, and plastics industries. In the battery industries that use antimony in combination with lead and zinc, worker exposure to antimony oc- curs through antimony hydride (SbH3) (stibene gas), a very hazardous material that is produced when a battery overcharges and when antimony comes into contact with acid plus a reducing substance such as zinc. Stibine is used as a dopant in the microelectronics industry. In the semiconductor industries, anti- mony is used in making infrared detectors and diodes. Antimony exposure also comes from soldering, in which lead is being replaced with antimony. Several compounds of antimony are known; the most common are anti- mony pentasulfide (Sb2S5, a pentavalent compound), antimony trisulfide (Sb2S3, a trivalent compound), antimony pentoxide (Sb2O5, a pentavalent compound), APT (C8H4K2O12Sb2⋅3H2O, a trivalent compound), antimony trichloride (SbCl3, a trivalent compound), antimony trioxide (Sb2O3, a trivalent antimony com- pound), and antimony hydride (SbH3, a trivalent compound). Sodium anti- monate (NaSbO3), a pentavalent form of antimony [Sb(V)], is also widely used as a flame retardant. TABLE 1-1 Physical and Chemical Properties of Antimony and Two Soluble Antimony Compounds Antimony Potassium Antimony Parameter Metallic Antimony Tartrate⋅3H2O Trichloride Chemical formula Sb C8H4K2O12Sb2⋅3H2O SbCl3 Valence Sb(III) Sb(III) CAS no. 11071-15-1 28300-74-5 10025-91-9 Molecular weight 121.75 668 228 Solubility in water (at Insoluble 83 g/L 100 g/L room temperature) Percent Sb 100% 36% 53% Abbreviation: g/L = grams per liter.

Antimony 15 Recently, NASA has been testing the water compatibility of new water storage and transfer bags (bladder bags), which are composed of multilayer mats of a Japanese-made material called Cefral Soft. The bags will be used in the H-II transfer vehicle, an automated, uncrewed vehicle developed by the Japan Aero- space Exploration Agency (JAXA) as a cargo transportation system for the In- ternational Space Station. It was found that starting as early as 2-wk, material from the bag was leaching into the water. Analysis showed that one of the con- taminants was antimony, although the exact form of antimony in the storage and transfer bags and in the water has not been analyzed. In the initial 90-d stability test, the antimony concentration was about 8 parts per billion. As this is higher than the EPA MCL, the NASA Johnson Space Center toxicology group was charged with deriving a spacecraft water exposure guideline (SWEG) for anti- mony. According to EPA (1992), the concentration of antimony in drinking water is normally less than 5 micrograms per liter. Because a derivation of acceptable concentrations (ACs) for antimony compounds in drinking water is the main purpose of this document, descriptions of adverse effects and discussions are limited to soluble antimony compounds and studies dealing with ingestion of such compounds. Although the exact form of the soluble compound in spacecraft drinking water is not known at this time, it is not expected that insoluble forms of anti- mony will be found in the water. Hence, data from several experiments dealing with the ingestion of antimony oxides in the diet are not used to derive the AC because antimony oxide has very poor solubility (0.0014 gram per 100 millili- ters) in water. In addition, toxicity studies in which less soluble or insoluble an- timony compounds were administered are not included because use of data from such compounds could result in ACs that would underestimate the toxicity of antimony. PHARMACOKINETICS AND METABOLISM The most commonly used antimony compounds are oxides that are only minimally soluble in water. Limited data are available on the absorption, distri- bution, excretion, and elimination kinetics of soluble antimony compounds ad- ministered orally. Several studies in the literature involve the treatment of parasitic infec- tions through the administration of antimonial drugs, such as sodium stiboglu- conate and stibosamine, via intravenous (i.v.), intraperitoneal (i.p.), and intra- muscular (i.m.) routes, and these studies focused on measuring pharmacokinetic parameters to optimize the dosage for therapeutic purposes. Part of the reason these drugs must be administered parenterally is that they are poorly absorbed from the gastrointestinal (GI) tract, and doses must be high to obtain therapeuti- cally effective levels. At these doses, drugs orally administered would be very toxic to the GI tract. This includes both trivalent and pentavalent antimonial

16 Spacecraft Water Exposure Guidelines drugs. Many of these studies involve different antimonial drugs given to patients with cutaneous leishmaniasis (see Al-Jaser et al. 1995; Nieto et al. 2003) or to animals experimentally infected with leishmania parasites. Thus, pharmacoki- netic data from these studies may not be applicable to healthy individuals. Similarly, data on antimony concentrations in blood and tissues from occupationally exposed industrial workers are the result of inhalation exposure to dust and fumes and, to a minor extent, from dermal absorption. These data are of limited use in describing the fate of antimony administered orally. Absorption Lauwers et al. (1990) estimated that absorption of the trivalent antimonial APT (tartar emetic) is 5% in humans, while APT was absorption is at about 20% in mice (Dieter et al. 1991). The existing animal studies indicate that antimony can be absorbed from the GI tract whether it is in a soluble form or a very spar- ingly soluble form. This is evident from the results of the following two studies, both of which used the soluble form of the antimony compound. Felicetti et al. (1974) studied the metabolism, differential tissue distribution, and retention ki- netics of two valence states of antimony in hamsters using radioactive APT (124Sb tartrate) after administering the dose by gavage. They also studied the absorption of antimony by delivering the dose by gastric tube. Some hamsters received the trivalent antimony and some received the pentavalent antimony. The results indicated that 7% to 15% was absorbed for both tri- and pentavalent antimony. In a study using SbCl3 in mice, Gerber et al. (1982) estimated that about 7% of the ingested antimony was absorbed. The International Commission on Radiological Protection (ICRP 1981) suggested using a 10% absorption rate for antimony tartrate and 1% for other antimony compounds (including Sb2O3) when estimating exposure from the GI tract. Distribution No data are available on the tissue distribution of antimony in humans who ingested antimony compounds orally. However, Sumino et al. (1975) col- lected autopsy data for antimony in several tissues and body fluids from unex- posed Japanese individuals. Similarly, Lauwers et al. (1990) noted that, in a pa- tient who died from accidental poisoning by ingesting antimony tartrate, the total body pool was only about 5% of the ingested dose, with the highest con- centrations in liver, gall bladder, and GI mucosa. Results are available from several animal studies in which the distribution of antimony was measured after inhalation exposure, but few studies are avail- able in which it was measured after oral ingestion. Animal studies indicate that the distribution of absorbed antimony varies with its valence state. A significant observation is that trivalent compounds seem to bind more extensively to red

Antimony 17 blood cells, whereas most of the absorbed pentavalent antimony is found in plasma (Goyer 1996; van der Voet and de Wolff 1996; Poon et al. 1998). Win- ship (1987) reported that, after oral administration (or after injection), significant concentrations of antimony could be found in liver, kidney, thyroid, adrenals, and bone. Though this may not be directly relevant to oral administration, dif- ferences in the distribution of antimony were observed between trivalent and pentavalent forms in the blood in a hamster study in which pentavalent and tri- valent antimony were administered as an aerosol inhalation (Felicetti et al. 1974). Metabolism and Excretion No direct human data on the metabolism of antimony compounds from oral doses are available. The i.p. injection of SbCl3 into adult male Sprague- Dawley rats did not result in detectable levels of any methylated antimony in the bile or urine; thus, it was concluded that, unlike arsenic, antimony is not methy- lated in vivo (Bailly et al. 1991). Antimony is excreted in the bile after conjuga- tion with glutathione (GSH), but a significant portion of antimony excreted in the bile undergoes enterohepatic circulation. It is also excreted in the urine as GSH conjugate. GSH seems to be one of the key components in the biliary ex- cretion and metabolism of antimony (Bailly et al. 1991). The evidence in hu- mans that no in vivo methylation takes place came from observation of one woman who ingested an unknown quantity of Sb2S3 and was admitted to a hos- pital within 1 h. Antimony was measured in whole blood, urine, bile, and gastric fluid for 160 h. On the basis of the type of urine analysis used, the authors con- cluded that antimony is not methylated in vivo (Bailly et al. 1991). No study of the pharmacokinetics of APT or any soluble antimony com- pounds administered orally could be located. It has been stated that in most rodents, trivalent antimony (APT) is ex- creted primarily in the feces and pentavalent antimony (from pentavalent anti- monials such as stibogluconate, also called Pentostam) is excreted primarily in the urine; in humans, both types are excreted in the urine (NRC 1980). These results were observed after i.v. injection of tri- and pentavalent antimonials, and they were based on studies by Otto et al. (1947) and Otto and Maren (1950). Similar excretion data are not available from rodents or humans who ingested APT. TOXICITY SUMMARY Numerous toxicity studies have been conducted in animals using relatively insoluble antimony oxides (Fleming 1938; Gross et al. 1955; Hext et al. 1999). The discussions and study descriptions below mostly focus on oral ingestion studies, but an abundant amount of literature on other routes of administration

18 Spacecraft Water Exposure Guidelines provides knowledge of the target organs and the nature of the toxicities. A re- view of the literature on the toxicity of antimony compounds indicates that tox- icity depends on the chemical form of the antimony compound and its relative solubility in water, its route of administration, and whether the antimony is triva- lent or pentavalent. The literature also indicates, from various experimental and occupational exposures and from clinical observations from case histories, that trivalent compounds are more toxic than pentavalent compounds and the soluble ones are more toxic than the poorly soluble ones. In fact, the way these com- pounds are used in the medical field is also based on the valence of antimony in the compound; for example, APT can cause inflammation and severe pain and tissue necrosis and thus has been replaced with other antimonial drugs that can be administered parenterally. Exposure to SbCl3 fumes is known to cause “anti- mony spots” in the skin around the sweat and sebaceous glands. Several investi- gators have reported serious toxic effects from the injection of pentavalent anti- monial medications. Data from their studies indicate that liver, kidney, and hematologic systems may be targets for antimony toxicity. Similar effects on kidney and liver have been shown in animals after i.p. injections of trivalent antimonials such as APT (Dieter 1992). Although acute toxicity primarily in- volves the GI system, causing GI irritation, vomiting and diarrhea, and death at high doses, chronic exposures to antimony can affect liver, kidney, heart, and hematologic systems. Acute Effects The literature shows the acute oral median lethal dose (LD50) for APT ranged from 115 milligrams per kilogram of body weight (mg/kg) in rats to 600 mg/kg in mice to 115 mg/kg in rabbits (PAN Pesticide Database). According to a German document (German Association for Gas and Water installation, DVGW 1985, 1988), although the oral LD50 for APT (the soluble salt of anti- mony) for rats is 115 mg/kg, the LD50 for Sb2O3 is 20,000 mg/kg, showing a vast difference between soluble and relatively insoluble forms of antimony compounds. The LD50 in rats for APT injected i.p has been reported to be only 30 mg/kg, or about 11 mg of antimony per kg (Bradley and Frederick 1941). In rodent LD50 oral studies, fatalities resulted from myocardial edema and hypere- mia. The oxides of antimony seem to be less toxic than APT, perhaps because APT has higher solubility and thus greater bioavailability. A major form of antimony toxicity after oral ingestion involved its GI ef- fects, such as abdominal cramps, diarrhea, and vomiting due to the strong irritat- ing effect of antimony on the gastric mucosa (Elinder and Friberg 1986). The vomit, in general, contained sloughed mucosal cells and most of the antimony. A reduced respiratory rate, hemorrhagic nephritis, and hepatitis may also occur (Venugopal and Luckey 1978, van der Voet and de Wolff 1996). Using anti- mony compounds of high purity and taking care that the arsenic content re-

Antimony 19 mained negligible, Bradley and Frederick (1941) showed that, among five anti- mony compounds administered by i.p. injection, Sb2O3 was the least toxic. Several examples of antimony poisoning have been cited in the literature, but in some cases the concentration of antimony that resulted in GI distress was not known. Dunn (1928) reported that several workers who drank lemonade contaminated with antimony tartrate that leached from an enamel bucket became very sick, and 50 to 60 of them had to be taken to the hospital. The concentra- tion of antimony was provided by the author as 0.013% or 130 mg/L. Werrin (1963) reported that 150 children who drank lemonade refrigerated for 20 h in a large agate pot experienced nausea, vomiting, and diarrhea. The symptoms were caused by antimony in the lining of the pot. Lauwers et al. (1990) reported on oral antimony intoxication in four adults who ingested cake mistakenly made with tartar emetic instead of cream of tartar. They had severe GI symptoms such as abdominal cramps, nausea, continuous vomiting, and watery diarrhea. Mod- erate leukocytosis and hemoconcentration and decreased extracellular volume were noted. The estimated dose of tartar emetic was 850 mg per person. The initial electroencephalograms of three subjects were abnormal; one person had severe GI bleeding and died from cardiac and respiratory failure (Lauwers et al. 1990). Bailly et al. (1991) reported that a 24-year-old woman suffered from epi- gastric pain and dysphagia after trying to commit suicide by ingesting an un- known quantity of Sb2S3. Flury (1927) conducted feeding experiments on rats, cats, and dogs using tartar emetic, Sb2O3, Sb2O5, and other antimonial com- pounds. Dogs were more sensitive to the emetic effect than cats; in dogs, the most toxic of these compounds as an emetic agent was APT at 4 mg of antimony per kg. Similarly, dogs were more sensitive than small rodents (rats) with re- spect to digestive upsets and diarrhea, and APT was the most toxic for these effects. GI effects resulted not only from the ingestion of antimony compounds by animals and humans, but also from inhalation exposures. Smelter workers, for example, inhaled compounds such as SbCl3 in fumes, resulting in abdominal pain, diarrhea, and vomiting (Winship 1987). Short-Term Exposure Dieter et al. (1991) conducted a toxicity and distribution study of APT in rats and mice after they were exposed via drinking water and i.p. injection. Only the drinking-water study data are included here. Toxicity and concentrations of tissue antimony were compared in F344/N rats and B6C3F1 mice (both sexes) given APT in drinking water for 14 d. For the 14-d drinking-water protocol, doses estimated from water consumption data were 0, 16, 28, 59, 94, or 168 mg/kg in rats and 0, 59, 98, 174, 273, or 407 mg/kg in mice. Antimony concen- trations in the blood, kidney, heart, liver, and spleen of rats and mice were measured at the end of the study. The animal tissues were also evaluated histopathologically. One of 10 females died in the mouse group that received the highest antimony dose

20 Spacecraft Water Exposure Guidelines (407 mg/kg). No mortalities were noted in any other group, indicating that rats tolerated a dose of at least 168 mg/kg and mice at least 273 mg/kg. The authors noted a change in water consumption that was inversely related to increasing dose, although the authors did not provide detailed dose versus water consump- tion data. Decreases in the weight of heart, spleen, thymus, and kidney were noted in the highest dose groups; body weight also decreased in these groups. Tissue histopathology indicated that in the male and female mice of the 407- mg/kg group, treatment-related gross lesions consisted of ulceration with necro- sis and inflammation of the forestomach squamous mucosal epithelium. In both male and female mice of the highest dose group (407 mg/kg), a minimal to moderate cytoplasmic vacuolization of hepatocytes was present; the male mice had more severe changes. The hepatocytes in the centrilobular region were slightly enlarged, with a loss of cytoplasmic staining. The authors did not pro- vide any quantitative data on the severity of these histopathologic lesions. In male rats given APT, cytoplasmic protein droplets normally present in the renal tubular epithelium stained slightly more prominently than those in control rats. The increases in the antimony concentrations in blood, liver, spleen, heart, and kidneys did not exhibit a clear dose-response trend (Dieter et al. 1991; Dieter 1992). Although the data from the 16-d APT i.p. injection study are not described here, the mortality and severity of histopathologic lesions in the study indicated that liver and kidney might be the target organs for antimony toxicity, and that toxicity of antimony administered orally is much lower than toxicity from the i.p. route. Subchronic Toxicity Studies In an old study, Bradley and Frederick (1941) administered APT in the diet to rats at a dose of 8 mg/kg/d. The study also involved feeding finely granu- lated metallic antimony at 8 or 40 mg/kg/d. The rats were treated for 4 or 12 months. They included a group in which the doses were raised to 100 mg/kg/d and to 1,000 mg/kg/d. The rats maintained normal growth, but abnormal histo- pathology findings were noted on examination of the kidney, liver, small intes- tine, and spleen. Congestion and polymorphonuclear leukocyte infiltration in liver, tubular necrosis of the kidneys (in addition to glomerular nephritis), hem- orrhage of the small intestine, and congestion of the spleen were observed (Bradley and Frederick 1941). Poon et al. (1998) studied the effects of APT on rats after a 90-d exposure via drinking water. Male and female Sprague-Dawley rats (127-135 g) were exposed to a soluble trivalent antimony salt, APT, in drinking water at antimony concentrations of 0.5, 5, 50, and 500 parts per million (ppm) for 13 wk. An addi- tional 10 male and 10 female rats were included in each of the control and 500- ppm groups and were given tap water for a further 4 wk as a recovery period after the 13-wk treatment period was completed. Body weight changes, water

Antimony 21 and food consumption, hematologic analysis, urine analysis, serum clinical chemistry (concentration of inorganic phosphate, glucose, cholesterol, creatinine, total protein, and activity of hepatotoxicity marker enzymes, such as aspartate aminotransferase, alkaline phosphatase, sorbitol dehydrogenase, creatinine kinase, and hepatic enzymes), and tissue histopathology were all de- termined. In addition, serum thyroxin and thyroid hormone binding ratio were determined. The authors determined the calculated mean intake doses of anti- mony as 0.06, 0.56, 5.58, and 42.17 mg/kg/d for males and 0.06, 0.64, 6.13, and 45.609 mg/kg/d for females, determined on the basis of water consumption. Poon et al. reported no overt clinical signs of toxicity. They provided no further explanation of what they meant by clinical signs of toxicity in the paper. The animals in the 500-ppm group consumed 30% less water than the controls, but water consumption returned to normal during the recovery period when APT was discontinued. Food consumption was also reduced 12% in the high-dose group. Starting at 6 wk, a significant depression in weight gain was observed in the males. This was noted in females starting at 12 wk. One male in the 5-ppm group and three in the 500-ppm group had gross hematuria; one male receiving this dose had a cirrhotic liver. A dose-related decrease in serum glucose in the females starting at 5 ppm, decreased creatinine and alkaline phosphatase in both male and female rats at 500 ppm, and decreased serum protein in females were noted. No treatment-related changes in serum aspartate aminotransferase or sor- bitol dehydrogenase activities were noted. Male rats from the 500-ppm dose group had decreased red blood cell and platelet counts and a slightly increased mean corpuscular volume. No treatment-related changes in total thyroid hor- mone, thyroxin, were reported. However, in the female rats, the thyroid hormone binding ratio (a measure of the level of thyroid hormone binding protein, a globulin) increased significantly at 50 and 500 ppm. In addition, in the 500-ppm groups, mild histologic changes were observed in the thyroid, such as reduced follicle size, increased epithelial height, and nu- clear vesiculation. Some of these did not return to normal during the recovery period. The relationship between the observed increase in the thyroid hormone binding ratio found in the serum of 50- and 500-ppm rats and the observed his- tologic changes in the thyroid is not clear. Collapsed thyroid follicles, not ob- served during the treatment period, were seen at the end of the recovery period. The authors declared that changes seen in the thyroid glands were adaptive and did not show a strong dose-response level (Poon et al. 1998). Poon et al. (1998) reported that in the liver of all male and female rats in the study, the severity of anisokaryosis (inequality in the size of the nuclei of cells) approached moderate in the groups receiving higher doses and was persis- tent even 2 wk after cessation of treatment. Similarly, the hyperchromicity of the nuclei was more pronounced at high doses. In the cytoplasm of hepatocytes, increased portal density and increased perivenous homogeneity were dose re- lated. However, two serum hepatotoxicity marker enzymes, aspartate ami- notransferase and sorbitol dehydrogenase, remained unaltered in males and fe- males even in the 500-ppm APT group.

22 Spacecraft Water Exposure Guidelines Poon et al. concluded that a 90-d no-observed-adverse-effect level (NOAEL) dose of 0.5 ppm APT (equivalent to an average of 0.06 mg of anti- mony per kg) can be identified for antimony in drinking water on the basis of the histologic and biochemical changes observed in the group treated with 5.0 ppm APT (a lowest-observed-adverse-effect level [LOAEL]). The Poon et al. study had some experiment design issues and other prob- lems that might limit the usefulness of some of its results for considering in the derivation of ACs for antimony. The details of these limitations are described later in this document (refer to section on 100-d AC for ingestion). Dieter et al. (1991) conducted a 90-d study of APT in rats and mice. How- ever, it was not an oral ingestion study; instead APT was injected i.p. Despite the fact that the data may not be directly useful for deriving an AC for drinking water, the study showed that the liver is a target organ for antimony exposure; hepatocellular degeneration and necrosis occurred in association with dose- related elevations in activities of the liver-specific serum enzymes sorbitol de- hydrogenase and alanine aminotransferase. Chronic Toxicity Studies Kanisawa and Schroeder (1969) and Schroeder et al. (1968) conducted a lifetime (from weaning until death) study in which groups of 55 male and 54 female Swiss CD-1 mice were exposed to 5 ppm antimony as APT in drinking water. Based on a nominal mouse body weight of 30 g and a water intake vol- ume of 5 mL/d, the antimony dose can be estimated to be 0.83 mg/kg/d. Body weights were measured weekly for the first 8 wk and monthly thereafter. Food consumption was not recorded. The number of days for 50%, 75%, and 90% of the animals to die was also determined. In this study, no hematologic or clinical chemistry variables or organ weights were measured. All animals were sub- jected to necropsy, during which gross lesions were recorded and only visible tumors were dissected. The lesions were graded only as pretumorous, benign, or malignant. Not all tissues were included in the histopathology. The authors con- cluded that there were no significant differences in the incidence of spontaneous tumors (tumors that develop in the absence of all experimental interference) or of treatment-related malignant tumors. Only results for liver, lung, adrenal, and mammary gland were reported and, for these organs, limited information was included. During the first year of treatment, antimony had no significant effect on growth rate. Weight losses were noted in male mice after 540 d and in fe- males after 12 months. No data indicated overt toxicity from antimony at this dose. Schroeder et al. (1970) performed a chronic (lifetime) toxicity study in which antimony, as APT, was administered in the drinking water at concentra- tions of 0 or 5 ppm to groups of 50 male and female Long-Evans rats from weaning to death. The antimony dose can be estimated to be 0.43 mg/kg/d based on a nominal rat body weight of 350 g and water consumption of 30 mL/d.

Antimony 23 Changes in growth rate, survival and longevity, serum glucose (fasting and non- fasting) and cholesterol, urinary glucose and protein content, and heart weights were measured. Gross lesions and visible tumors were dissected. Antimony con- tents of heart, lung, kidney, liver, and spleen were also determined. Body weight was measured weekly for the first 6 wk and monthly thereafter. Serum glucose was measured on days 718 and 698 for control male and female rats, respec- tively, but it was measured on days 853 and 859 for treated male and female rats. Similarly, serum cholesterol was measured on these days. It is important to note that serum glucose and cholesterol were not measured on the same days of the lifetime in control and treated rats. The body weight of APT-treated rats did not differ significantly from that of untreated controls, but the treated rats showed a significant reduction in lon- gevity (defined as the mean age at death of the oldest 10% of animals). Longev- ity was 1,160 ± 27.8 d for control males and 999 ± 7.8 d for treated males; it was 1,304 ± 36 d for control females and 1,092 ± 36 d for treated females. APT treatment did not affect mean body weight or body weight gain. Nonfasting glu- cose concentrations were reported to be significantly decreased in both males and females compared with controls. However, the nonfasting glucose concen- trations were lower than the fasting glucose levels. Only visible tumors were sectioned and the authors reported no treatment-related increase in tumor inci- dence. These studies by the investigator had some experiment design issues and other problems that might limit the usefulness of the results for considering in the derivation of ACs for antimony. The details of these limitations are de- scribed later in this document (refer to the section on 1000-d AC for ingestion). Genotoxicity Very few data are available on the mutagenic potential of antimony in vivo in humans. Also, a very high percentage of mutagenicity assessment stud- ies have been performed with the poorly soluble antimony oxides. Data from studies of patients therapeutically treated with pentavalent antimonials do not provide relevant data on genotoxicity. In general, even with high doses of these antimonials, studies have had negative results with respect to the genotoxicity of antimony (Hantson et al. 1996). Schaumloffel and Gebel (1998) found that, at a concentration of 5 µM, trivalent antimony compounds induced micronuclei in human lymphocytes in vitro, but the induction was not suppressed by coincuba- tion with catalase or superoxide dismutase, indicating that induction of oxidative stress may not be a key factor in the mechanism of DNA damage by trivalent antimony compounds. In an animal in vivo assay for genotoxicity, Gurnani et al. (1992 a, 1993) examined the bone marrow for chromosomal aberrations such as chromatid and isochromatid gaps and breaks after gavage doses of Sb2O3 to mice. The dose rates were 400, 670, and 1,000 mg/kg. The measurements were made after 7, 14,

24 Spacecraft Water Exposure Guidelines and 21 d of daily dosing. After a single dose, there was no change, but when the doses were administered multiple times, the frequencies of chromosomal aberra- tions induced were directly proportional to the dose used and the duration of exposure, indicating that Sb2O3 had cumulative effects on the animals. In this study, the authors also measured the frequency of sperm head abnormalities, but it was not found to be affected by any of the doses used. The authors (Gurnani et al. 1992b) also studied the genotoxic effects of SbCl3 given as a gavage dose in female Swiss mice in vivo. The doses were 70, 140, and 230 mg/kg. They exam- ined clastogenic effects by determining the number of chromosomal aberrations at 6, 12, 18, and 24 h postdose. Dose-related increases compared with controls were seen in the frequencies of both total chromosomal aberrations and breaks per cell. Kanematsu et al. (1980) observed in V79 cells that antimony oxide showed a positive response in Bacillus subtilis DNA-damaging capacity and mutagenicity (rec assay) and also in the sister chromatid exchange (SCE) assay. Kuroda et al. (1991) studied the genotoxicity of some antimony com- pounds in the bacterial DNA repair (rec), Salmonella mutagenicity, and SCE assays. In the rec assay, SbCl3, SbCl5, and Sb2O3 all had DNA-damaging activ- ity but were not mutagenic to Salmonella. In the SCE assays using V79 cells, SbCl3 and Sb2O3 significantly induced SCEs. Kuroda et al. also reported that Sb2O5 was negative for mutagenicity in various Salmonella strains up to 200 µg per plate, was also negative in the Bacillus subtilis assay, and did not induce SCEs in Chinese hamster ovary cells. In a 1985 Nissan Chemical Industries study in male and female CD-1 mice treated with Sb2O5 by gavage at doses of 2,500, 5,000, and 10,000 mg/kg (see NRC 2000a), no chromosome damage was induced. Elliott et al. (1998) extensively investigated the in vivo genotoxicity of Sb2O3 using single- and repeat-dose mouse bone marrow micronucleus tests and the rat liver unscheduled DNA synthesis assay. All three studies were negative, in contrast to the results of Gurnani et al. (1992a). Elliott et al. (1998) examined Sb2O3 in a range of in vitro and in vivo genotoxicity (bone marrow micronu- cleus) assays. They obtained negative results with the Salmonella microsome assay and the L5178Y mutation assay. They observed a positive response in the in vitro cytogenetic assay using isolated human peripheral lymphocytes. How- ever, in vivo, Sb2O3 was nonclastogenic in the mouse (male and female CD-1 mice) bone marrow micronucleus assay, after oral gavage administration for 1, 7, 14, and 21 days at doses up to 5,000 mg/kg (single dose) or 1,000 mg/kg (re- peat dose). They also obtained a negative result in the in vivo rat (male Alpk:APfSD rats) liver DNA repair (unscheduled DNA synthesis) assay after single oral gavage administration of doses up to 5,000 mg/kg. These data show no genotoxicity for Sb2O3 in vivo and do not confirm a previous report (Gurnani et al. 1993) of clastogenicity in the mouse on repeated dosing. As the purity of the compound used in the Gurnani studies is not known, some contaminants may have given rise to positive results. The study by Elliott et al. was conducted under the genetic toxicology protocol of the Organization for Economic Co-

Antimony 25 operation and Development with materials of established purity. It is concluded that Sb2O3 is not genotoxic in vivo and does not present a genotoxic hazard to humans. The lack of genotoxic activity could be due to poor solubility of the trioxide and, thus, the lack of uptake in the bacterial studies. De Boeck et al. (2003) showed that other trivalent and pentavalent anti- mony genotoxicity test systems usually gave positive results for Sb(III) and negative results for Sb(V) compounds. Recently, Andrewes et al. (2004) evalu- ated the in vitro genotoxicities of five antimony compounds—potassium anti- mony tartrate, stibine, potassium hexahydroxyantimonate, trimethylantimony dichloride, and trimethylstibine—using a plasmid DNA-nicking assay. Of these five antimony compounds, only stibine and trimethylstibine were genotoxic (significant nicking to pBR322 plasmid DNA). Cancer The International Agency for Research on Cancer concluded that Sb2O3 is possibly carcinogenic to humans (Group 2B) and that Sb2S3 is not classifiable as to its carcinogenicity to humans (Group 3). These conclusions are primarily based on evidence from inhalation studies with animals (IARC 1989). All tu- mors occurred in the bronchoalveolar region. NRC (2000a) determined that data from all potential routes of exposure, including oral (e.g., by a child sucking a garment coated with flame retardant), are not adequate to characterize the car- cinogenic risk from the use of Sb2O5 as a flame retardant. Despite the use of pentavalent antimonials in medications, no studies were found that assessed the oral carcinogenicity of antimony in humans. Similarly, no robust animal studies indicate that antimony compounds are carcinogenic by the oral route. The only lifetime studies were conducted by Kanisawa and Schroeder (1969) and Schroe- der et al. (1968, 1970) in rats and mice exposed to 5 ppm antimony as APT. None of these studies indicated any carcinogenic activity. However, the meth- odology and the lack of systematic tissue histopathology sampling, in addition to study design flaws, undermine the use of these studies as a definitive assessment for the risk of cancer (Lynch et al.1999). Reproductive and Developmental Toxicity No human data indicate that oral administration of antimony compounds resulted in reproductive or developmental toxicity. Rossi et al. (1987) studied the effect of prenatal and postnatal antimony exposure by the oral route on the development of vasomotor reactivity (func- tional development of cardiovascular system) in rat pups. Pregnant female rats were exposed to SbCl3 in drinking water at 0.1 and 1.0 milligram per deciliter (mg/dL) (equivalent to 1 and 10 ppm SbCl3) from the first day of pregnancy until the 22nd day after delivery. Thereafter, the pups weaned at 22 d were ex-

26 Spacecraft Water Exposure Guidelines posed to the same concentration of SbCl3 until the 60th day of age. The authors reported that exposure of pregnant mothers to SbCl3 did not affect the length of gestation or the number of newborn pups per litter. No macroscopic teratogenic effects were noted. The body weights of mothers at day 20 were significantly less than those of corresponding controls. In pups, prenatal and postnatal anti- mony exposure up to 60 d did not affect the hypertensive response to carotid occlusion. However, at day 60 after birth, the vasomotor response to l- noradrenaline and the hypotensive response to l-isoprenaline or acetylcholine were decreased in these pups. These studies indicated that 10 ppm SbCl3 af- fected the development of some pressor responses. Immunotoxicity No human or experimental animal data on changes in immune system pa- rameters from ingestion of soluble antimony compounds could be found in the toxicology literature. Toxicity studies conducted after administration of various antimony compounds via oral route have been summarized in Table 1-2. RATIONALE The following paragraphs provide a rationale for proposing 1-, 10-, 100-, and 1,000-d SWEG values for soluble antimony in NASA’s spacecraft water. The values listed were based on ACs developed according to Methods for De- veloping Spacecraft Water Exposure Guidelines (NRC 2000b). A summary of SWEGs for antimony derived for various durations using these guidelines has been listed in Table 1-3. Approaches by Other Organizations EPA determined an oral reference dose (RfD) for antimony (EPA 1991) based on the critical effects of decreased longevity and altered levels of blood glucose (decrease in nonfasted levels in treated males) and serum cholesterol changes in both males and females, reported by Schroeder et al. (1970) in a study in which 50 male and 50 female rats were administered 5 ppm of APT in their drinking water for their lifetime. The treated male and female rats survived fewer days than control rats at median life span. A NOAEL was not identified in this study, as only one dose was used. The dose rate corresponded to 0.35 mg/kg/d. EPA applied an uncertainty factor of 1,000 on the LOAEL of 0.35 mg/kg/d (10 for species, 10 for sensitive individuals, and 10 for LOAEL to NOAEL). An RfD of 0.0004 mg/kg/d was derived. EPA listed its confidence in

TABLE 1-2 Oral Toxicity Summary Compound Species, Route, Dose Observed Adverse Effects Reference Antimony trioxide Human (n = 50 to 60) Severe nausea, vomiting, and diarrhea; recovery was delayed Dunn 1928 (soluble due to citric Drinking a solution (contaminated in some workers acid in lemonade) lemonade) Sb concentration = 130 mg/L Antimony trioxide Children (n = 150) Nausea, vomiting, and diarrhea Werrin 1963 (soluble due to citric Drinking contaminated lemonade acid in lemonade) Amount/concentration unknown Antimony potassium Human (M) Abnormal EEG in 3 of 4 subjects; suffered severe gastroin- Lauwers et al. tartrate Ingestion of contaminated cake testinal symptoms such as abdominal cramps, nausea, con- 1990 Amount ingested estimated at 850 tinuous vomiting, and watery diarrhea; moderate leukocyto- mg/per person (contaminated piece of sis and hemoconcentration and decreased extracellular cake) volume; one person had gastrointestinal bleeding; recovery took a few days; thrombophlebitis in all subjects Antimony trisulfideHuman (F) Epigastric pain and dysphagia Bailly et al. A woman consumed an unknown 1991 amount and concentration of antimony trisulfide Antimony potassium Dog Vomiting Houpt et al. tartrate Gavage 1984 One dose of 13.2 mg/kg/d Antimony potassium Rat Decreased survival; minimum lethal dose Bradley and tartrate Gavage Frederick 1941 One dose of 300 mg/kg/d (Continued) 27

28 TABLE 1-2 Continued Compound Species, Route, Dose Observed Adverse Effects Reference Antimony potassium Rat, cat, dog Emesis, diarrhea; dogs more sensitive than rodents Flurry et al. tartrate Gavage 1927, cited in A LOAEL for dog is 4 mg/kg/d; one Bradley and dose Frederick 1941 Antimony potassium F344/N rat, B6C3F1 mouse (M, F) Decreased water consumption in mice and rats, as a function Dieter et al. tartrate Drinking water of dose; no deaths in rats at the maximum dose of 168 1991, Dieter Doses 0, 16, 28, 59 94, and 168 mg/kg mg/kg; 1/10 mice died at 407 mg of Sb/kg. In mice at this 1992 for rats; 0, 59, 98, 174, 273, and 407 dose, effects were gross lesions, consisting of ulceration with mg/kg for mice; duration 14 d necrosis and inflammation, in the forestomach; decreases in heart, spleen, thymus, and kidney weights; treatment-related lesions of forestomach; and minimal to moderate cytoplasmic vacuolization of hepatocytes, severe in male mice. Antimony trichloride Rats; drinking water; gestation day 0- Decreased development of some cardiovascular responses Rossi et al. 1987 21 and until 60th day after birth; pups; (decreased pressor response to l-noradrenaline and decreased 0.1 and 1 mg of SbCl3/dL hypotensive response to l-isoprenaline Antimony trichloride Rat (F) No change in maternal blood pressure, length of gestation, or Rossi et al. 1987 Drinking water number of newborn per litter; no macroscopic teratogenic 1 and 10 mg/L from day 1 of preg- effects nancy until 22n d after delivery Antimony potassium Sprague-Dawley rat (M, F) Starting at 5 ppm, a dose-related decrease in serum glucose Poon et al. 1998 tartrate Drinking water (0.5, 5, 50, and 500 in females; 30% less water consumption in 500-ppm group; ppm) depression in weight gain in males and females; increase in Calculated doses: the kidney-to-body weight ratio; decreased red blood cell 0.06, 0.56, 5.58, and 42.17 mg of and platelet counts and slightly increased mean corpuscular Sb/kg/d (M); 0.06, 0.64, 6.13, and volume in male rats of 500-ppm group; mild histologic 45.6 mg of Sb/kg/d (F); duration 90 d changes in thyroid, liver, and pituitary gland of both sexes,

and in spleen of male rats and thymus of female rats; liver histopathology still present after recovery period Antimony potassium Rat Normal growth; congestion and infiltration of polymor- Bradley and tartrate Diet phonuclear leukocytes in liver, tubular necrosis of kidneys in Frederick, 1941 8 or 40 mg/kg/d; duration 4 or 12 mo addition to glomerular nephritis, hemorrhage of small intes- tine, and congestion of spleen were observed Antimony potassium Swiss CD-1 mouse (M, F) Decreased median and 75% life span in female mice by 49 Kanisawa and tartrate 5 ppm of Sb (0.83 mg of Sb/kg/d) in and 86 d, respectively; no changes in incidence of spontane- Schroeder 1969, drinking water; duration = lifetime ous or malignant tumors in liver, lung, or adrenal or mam- Schroeder et al. mary gland; no other parameters measured to evaluate overt 1968 toxicity; no fatty degeneration of liver Antimony potassium Lifetime exposure; Long-Evans rats Increased serum cholesterol in males but decrease in fe- Schroeder et al. tartrate (M, F; 50/sex); 5 ppm as APT in males; decreased nonfasting serum glucose; median life span 1970 drinking water of treated males and females was about 106 d less than that of controls; significant reduction in LT90 especially in fe- males; no treatment-related tumor incidence; epidemic of virulent pneumonia struck the rat colony Abbreviations: APT = antimony potassium tartrate; EEG = electroencephalogram; F = female; LOAEL = lowest-observed-adverse-effect level; LT90 = 90% lethal time; M = male. 29

30 Spacecraft Water Exposure Guidelines TABLE 1-3 Spacecraft Water Exposure Guidelines (SWEGs) for Soluble Antimony (Salts) in Humans Duration SWEG (mg/L) Toxicity End Point Principal study 1d 4.0 mg/L Emetic effect Dunn 1928 10 d 4.0 mg/L Emetic effect Dunn 1928 (Adopted 1-d AC) 100 d 4.0 mg/L Emetic effect Dunn 1928 (Adopted 1- and 10-d AC) 1,000 d 2.0 mg/L Hematologic effects Poon et al. 1998 Note: Based on these SWEGs, the total daily intake of antimony would be 11.2, 11.2, 11.2, and 5.6 mg/d for 1-, 10-, 100-, and 1,000-d, respectively. Similarly, daily antimony doses can be calculated to be 0.16, 0.16, 0.16, and 0.08 mg/kg/d, respectively, for these durations. These are based on estimated water consumption of 2.8 L/d and an average adult body weight of 70 kg. the results of the Schroeder study, as well as the existing antimony toxicity data- base available for deriving RfD, as low. Current national standards, guidance levels, and cancer groupings from some organizations for antimony in drinking water are summarized in Table 1-4. The Agency for Toxic Substances and Disease Registry (ATSDR) did not derive an acute, intermediate, or chronic oral minimal risk level for antimony because it lacked robust data providing concentrations that led to the adverse toxic effects. The ATSDR toxicology profile for antimony is several years old (ATSDR 1992), and other studies have appeared in the literature since then—for example, the studies of Dieter et al. (1991) and Poon et al. (1998). 1-Day AC for Antimony Ingestion Some of the most important acute effects from ingestion of antimony com- pounds are GI system effects such as abdominal cramps, vomiting, and diarrhea. Several reports on toxicity from acute exposures were reviewed, including the LD50 data. The data came from reports on human ingestion of antimony com- pounds by accident or in suicide attempts and on administration of antimony compounds as medical therapy for some tropical diseases. For many of these cases, the amount ingested or the concentration is not available. The following studies were considered for 1-d AC derivation. Dunn (1928) reported that more than 50 workers who drank stored lemonade contaminated with antimony tartrate that leached from an enamel bucket became very sick and had to be taken to the hospital. Some recovered soon and others took longer to return to normal health. The concentration of antimony was provided by the author as 0.013% or 130 mg/L. Because the emetic effect is

Antimony 31 TABLE 1-4 Current Regulatory and Guideline Levels from Other Organizations for Oral Ingestion of Antimony Organization, Standard Regulatory and Guideline Levels Reference EPA EPA 2006 MCLGa 0.006 mg/L MCLa 0.006 mg/L Health Advisory, 1 d (10-kg child) 0.01 mg/L Health Advisory, 10 d (10-kg child) 0.01 mg/L Lifetime Health Advisory 0.006 mg/L DWEL 0.01 mg/L Cancer Grouping Group D RfD 0.0004 mg/kg/d EPA 1992 IARC IARC Cancer Grouping Sb2O3 Group 2B 1989 Cancer Grouping Sb2S3 Group 3 a The MCLG is a non-enforceable health goal, which is set at a level at which no known or anticipated adverse effect on the health of persons occurs and which allows an ade- quate margin of safety. The MCL is the highest level of a contaminant that is allowed in drinking water and is an enforceable standard. Abbreviations: DWEL, drinking-water equivalent level (assumes 100% contribution of the contaminant from water); EPA, U.S. Environmental Protection Agency; IARC, Inter- national Agency for Research on Cancer; Group D, not classifiable as to human carcino- genicity; Group 2B, possibly carcinogenic to humans; Group 3, not classifiable as to carcinogenicity in humans; MCL, maximum contaminant level; MCLG, maximum con- taminant level goal; RfD, oral reference dose. based on the concentration of antimony, the AC was calculated from the concen- tration and not from the dose. This is derived from human data and the number of individuals is large enough to consider using the data for setting the AC. With 130 mg/L as a LOAEL for antimony, a 1-d AC can be calculated after first ap- plying a factor of 3 to reduce the severity to a less severe LOAEL, and then a factor of 10 to convert the LOAEL to a NOAEL. Thus, the 1-d AC for antimony is derived as follows: 1-d AC(GI effects) = 130 mg/L(moderate LOAEL) × 1/3(moderate LOAEL to moderate NOAEL) × 1/10(LOAEL to NOAEL) = 4.33 m g/L, rounded to mg/L. The 1-d AC based on GI effect is 4 mg/L. A search of the medical literature for the emetic dose of antimony showed that it was reported in the medicinal substances supply table of the medical de- partment, U.S.Navy (Medical Front WWI 2007). The principal properties, uses, and dosage of APT are stated, and the emetic dose is listed as 0.03 to 0.065 g. Thus, the lower end of the effective dose for emesis is 30 mg (the amount and not the concentration). If one were to drink 400 mL of water during one session

32 Spacecraft Water Exposure Guidelines with APT added at a concentration of 4 mg/L, the amount of APT would be 1.6 mg, far lower than 30 mg. This supports the derived value of 4 mg/L as the AC for 1 d. The second study considered is that of Lauwers et al. (1990), also a human study. The authors reported on four adults who ingested cake mistakenly made with tartar emetic instead of cream of tartar and had severe abdominal cramps, nausea, continuous vomiting, and watery diarrhea. Moderate leukocytosis and hemoconcentration and decreased extracellular volume were noted. The esti- mated dose of tartar emetic ingested was 850 mg per person. Because the num- ber of subjects was very small, and the amount of antimony and the medical condition of some subjects were uncertain, the data could not be used for AC derivation. The data, however, seem to support the emetic effects found in the Dunn (1928) study. 10-Day AC for Antimony Ingestion No suitable human data are available that can be used to derive a 10-d AC for ingestion of antimony. Several studies have been conducted with patients receiving pentavalent organic antimonial therapeutic medications such as Pen- tostam (sodium stibogluconate) and Glucantime (megulmine antimoniate) to treat visceral leishmaniasis infection. In all these cases, the antimonial com- pound was administered i.m. or i.v. In addition, the subjects’ health was already compromised and data are of limited use. A few rodent studies were considered for the 10-d AC derivation. First, the Dieter et al. (1991) study was considered, in which F344/N male and female rats and B6C3F1 male and female mice were provided drinking water contain- ing APT for 14 days. The data were later published as a National Toxicology Program technical report (Dieter 1992). For the 14-d drinking-water protocol, doses estimated from water consumption data were 0, 16, 28, 59, 94, or 168 mg/kg for rats and 0, 59, 98, 174, 273, or 407 mg/kg for mice. In the male and female mice of the 407-mg/kg group, histopathologically identifiable lesions of forestomach (gross lesions consisting of ulceration with necrosis and inflamma- tion of the forestomach squamous epithelium) and liver (moderate cytoplasmic vacuolization of hepatocytes with a loss of cytoplasmic staining) were observed. A dose of 273 mg/kg can be identified as a NOAEL in mice. However, in the rat, the highest dose used was only 168 mg/kg/d, which did not affect any of the variables the investigators tested. So, the lower value for the rat NOAEL was used in the 10-d AC calculation. The authors did not mention whether the doses represent antimony or APT. Assuming that the dose is APT, a NOAEL of 168 mg /kg of APT equiva- lent to an antimony concentration of 58 mg/kg/d is identified. The 10-d antimony AC for hepatotoxicity can be calculated as follows:

Antimony 33 10-d AC(hepatotoxicity) = [58 mg/kg/d(NOAEL) × 70 kg(adult body weight) × 1/10(species)] ÷ 2.8 L/d (water ingestion/d) = 145 mg/L. In the same study, the reduction in drinking water consumption in rats and mice at the high dose was also considered. The authors stated that the water con- sumption was inversely proportional to the concentration of APT in the water. Calculation of the doses was based on water consumption. From the doses, it appears that APT at 59 mg/kg for the rat and 174 mg/kg for the mouse are LOAELs. To be on the conservative side, the NOAEL for APT was based on the rat, and a NOAEL of 28 mg/kg was identified, which corresponds to an anti- mony dose of 10 mg/kg/d. Using a NOAEL of 10 mg/kg/d, a 10-d AC for reduc- tion in water consumption can be calculated as follows: 10-d AC(reduction in water consumption) = [10 mg/kg/d(NOAEL) × 70 kg(adult body weight) × 1/10(species) × 1/3(spaceflight)] ÷ 2.8 L/dwater ingestion/d) = 8 mg/L. A taste threshold for antimony cannot be found in the literature, except it is stated that one can expect a brassy taste. NASA has not done taste tests on antimony in water. The levels derived will not affect the water consumption, as we already used a spaceflight factor for that risk, thus offering some margin of safety for taste. In addition, there is presumably a sufficient margin of safety in that we used a species factor of 10 for species extrapolation, implying that hu- mans are 10 times more sensitive to taste than rodents. In fact, it is possible that thresholds for sensory end points such as nasal irritation, odor, and taste aver- sion between humans and rodents may not be 10-fold. In any case, the antimony concentration of 8 mg/L calculated above might not be protective against GI effects considered in deriving the lower 1-d AC of antimony of 4 mg/L. Thus, the 1-d AC of 4 mg/L will be adopted for 10 d. The 10-d antimony AC for GI effects is 4 mg/L. 100-Day AC for Antimony Ingestion No human studies are suitable to use for calculating a 100-d AC. Some human studies involved several doses of pentavalent antimoniates given for therapeutic purposes to health-compromised subjects via different routes of ad- ministration, such as i.v. and i.m.,. Data from such studies may not be very use- ful for AC derivation considering the route of administration and the type of subjects. The Dieter et al. (1991) 14-d APT drinking-water study was not consid- ered, because a 90-d drinking-water study was available. The 90-d subchronic antimony drinking-water study by Poon et al. (1998) was considered for deriving a 100-d AC. In this study, male and female Spra-

34 Spacecraft Water Exposure Guidelines gue-Dawley rats (127-135 g), 15 animals per group, were exposed to APT in drinking water at concentrations of 0.5, 5, 50, and 500 ppm antimony for 13 wk. The animals in the 500-ppm group (the highest-dose group) consumed 35% less water than the controls. So, the authors calculated the mean intake doses of an- timony as 0.06, 0.56, 5.58, and 42.17 mg/kg/d for males and 0.06, 0.64, 6.13, and 45.7 mg/kg/d for females based on water consumption. Poon et al. (1998) reported that gross hematuria was seen in three males from the 500-ppm group. Also in the 500-ppm male rats, a decrease in red blood cells and an increase in mean corpuscular volume were noted, indicating hema- tologic effects, but the NOAEL of these effects was 50 ppm. A statistically sig- nificant decrease in the platelet counts of 500-ppm-dosed males was also noted. These effects were not seen in the female rats, however, there was a dose-related decrease in serum glucose starting at 5 ppm, which was only seen in the female rats. Histologic changes were scored as 1 = minimal, 2 = mild, 3 = moderate, and 4 = severe, and the authors presented average severity scores. Mild his- tologic changes were seen in the thyroid, liver, pituitary glands, spleen, and thymus in 500-ppm dose groups. The authors declared that the changes in the thyroids were adaptive and mild, lacked a strong dose-response relationship, and did not appear to affect thyroid function, even though the changes persisted after the 4-wk recovery period. Poon et al. (1998) proposed a LOAEL of 5 ppm (equivalent to an anti- mony intake of 0.6 mg/kg/d) and a NOAEL of 0.5 ppm (equivalent to 0.06 mg/kg/d) based only on glucose changes in the female rats. The authors consid- ered the change in glucose a credible adverse effect because similar reductions in glucose were reported in the 30-d i.m. injection study by al-Khawajah et al. (1992) and in the chronic drinking-water study by Schroeder et al. (1970). NASA first evaluated this for AC derivation. The changes in glucose showed a very poor dose-response profile, including the fact that the decrease was seen only for concentrations up to 50 ppm and the response leveled off between 50 and 500 ppm, which cannot be explained. NASA gathered that Poon et al. (1998) measured glucose in nonfasting animals for 4 h each morning over the course of several days and that, each day, animals from the different dose groups were measured in the same order, from controls to the highest-dose group. As a result, the glucose levels in the animals would be falling throughout the morn- ing, which would cause a trend for animals in higher dose groups to have lower glucose levels than controls and animals in lower dose groups. Hence, these changes were considered not to be compound related and it was decided not to use these data for AC derivation. The data were also criticized by Lynch et al. (1999) because no changes in glucose levels were seen in the Dieter et al. (1991) study in which APT was in- jected by the i.p. route and APT administered through this route was much more toxic. The liver histopathology data from the Poon et al. (1998) study was evalu- ated next. The authors reported their histopathology findings with a qualitative

Antimony 35 scale by which 0 = no changes, 1 = minimal changes, 2 = mild changes, 3 = moderate changes, and 4 = severe changes. Their assessment of the liver consid- ered nuclear anisokaryosis and hyperchromicity, and their cytoplasmic evalua- tion considered what they described as “increased portal density,” “increased perivenous homogeneity,” and fibrosis. The authors did not include photos to illustrate the nuclear lesions or cytoplasmic lesions other than fibrosis. In no case did they provide an illustration of the basis for ascertaining the scale of severity of the lesions. From a personal communication from the authors, we understand that the pathologist who interpreted the slides was aware of the dose group from which the slides were derived. Upon review of the liver histopathology data, the expert pathologist of the National Research Council (NRC) Spacecraft Exposure Guidelines (SEG) com- mittee stated that in assessing human hepatic pathology, nuclear anisokaryosis and hyperchromicity would rarely be mentioned in the absence of other substan- tial hepatic pathology. It is also not clear what the authors meant by “increased portal density” and “increased perivenous homogeneity.” These are not standard descriptors of hepatic pathology, and how they relate to more conventional terms of hepatic pathology is not clear. Fibrosis is a standard term and the one liver illustration reveals fibrosis. Although the data show progressive and dose-related increases in aniso- karyosis, hyperchromicity, “increased portal density,” and “increased perivenous homogeneity,” it is surprising that for doses ranging from 0.5 to 500 ppm there are only limited differences in all the parameters examined. In no case did any of the more obvious signs of hepatic toxicity appear, even as the dose of anti- mony was increased 1,000-fold, with the single exception of one liver with fi- brosis at the highest dose. The fact that the pathology review of the samples was not blinded and that no illustrations of the appearance of the lesions or the measures of the severity scale were included in the report makes one skeptical about the meaningfulness of the hepatic morphology aspect of the study in general. Thus, it is difficult to accept these findings as evidence of a substantial structural effect of antimony on the liver that would be interpreted as toxicity or other pathology. The NRC COT/SEG therefore recommended to NASA that the data on changes in serum glucose levels and changes in liver histopathology not be used in the derivations of AC. Next, the hematology data reported by Poon et al. (1998) were considered. Giving 500 ppm APT in drinking water to male rats resulted in a statistically significant reduction in the number of red blood cells, a reduction in mean cor- puscular volume (average volume of a red blood cell), and a reduction in platelet counts. These end points are also critical because three male rats from the 500- ppm dose group had hematuria. A NOAEL of 50 ppm APT (or antimony at 5.58 mg/kg/d) for hematologic effects could be identified. The dose-response data were processed by the benchmark dose (BMD) method, using the EPA BMD software (version 1.3.2) with the models for continuous data. There are four models for the continuous type in the EPA software, and BMD computation

36 Spacecraft Water Exposure Guidelines could be carried out only for the polynomial model and the power model. One standard deviation change in mean response was used as the benchmark re- sponse. The statistician from the NRC SEG committee recommended that NASA use the data from the power model, which would provide a more appro- priate model fit of the response. Figure 1-1 shows the BMD plots of two dose- response models for changes in red blood cells due to antimony ingestion. The results are summarized in Table 1-5. FIGURE 1-1 BMD model curves for changes in red blood cells due to ingestion of an- timony. Source: Data from Poon et al. 1998.

Antimony 37 TABLE 1-5 Summary of BMDs for Hematologic Effects of Antimony BMD BMDL Parameter Model (mg/kg/d) (mg/kg/d) Red blood cells Polynomial 41.77 35.65 Power 41.29 29.12 Mean corpuscular volume Polynomial 42.66 26.75 Power 42.10 29.55 Platelets Polynomial 49.35 12.95 Power 43.10 30.98 Note: Only male rat data included; female rat data were not statistically significant. Abbreviations: BMD, benchmark dose; BMDL, 95% lower confidence limit of BMD. The 100-d AC can be calculated using the statistically significant decrease in the amount of red blood cells as a critical end point in male rats ingesting 500 ppm of APT via drinking water (Poon et al. 1998). Using the BMD method, a BMD lower confidence limit (BMDL) for antimony of 29 mg/kg/d was ob- tained. The 100-d AC can thus be calculated as follows: 100-d AC(hematologic effects) = [29 mg /kg/d(BMDL) × 70 kg(adult body weight) × 1/10(species) × 1/3(spaceflight) × 90 d/100 d(time extrapolation)] ÷ 2.8 L/d(water ingestion/d) = 21.75 mg/L, rounded to 22 mg/L. Thus, the 100-d AC for hematologic effects is 22 mg/L. As the 100-d AC value of 22 mg/L is higher than the value of 4.0 mg/L derived for GI effects for 1- and 10-d ACs, to be protective of GI effects, the 1- and 10-d AC was adopted as the 100-d AC. Thus, the 100-d AC for GI effects is 4 mg/L. As has been discussed under the 1-d AC, this concentration is far below the threshold emetic level when water is consumed in separate boluses, and thus the 1-d value can be used for 100 d. 1,000-Day AC for Antimony Ingestion In the literature, no human subject study data are available that can be used to derive a 1,000-d AC. Only one laboratory has conducted lifetime chronic animal studies in which antimony was administered orally (Schroeder et al. 1968, Kanisawa and Schroeder 1969, Schroeder et al. 1970). It was conducted in the late 1960s and early 1970s on rats and mice. As NRC guidelines have not recommended the use of survival rate, growth rate, and organ weight changes for deriving ACs, the data from these studies could not be considered. In the lifetime (from weaning until natural death) mouse study by Kani- sawa and Schroeder (1969), groups of male and female Swiss CD-1 mice were

38 Spacecraft Water Exposure Guidelines given 5 ppm of antimony as APT in drinking water. With the intent of avoiding any influence on the results by the coexistence of other trace metals, the diet was rye, dried skim milk, and corn oil, which are normally low in trace elements, even though some trace elements are nutritionally important. Considering a nominal body weight of 30 g and water intake of 5 mL/d, the dose rate for anti- mony in water can be estimated to be 0.83 mg/kg/d. In the 1969 mouse study, sections of only a few tissues (liver, lung, adrenals, and mammary glands) were used and gross observations on tumors were made. The lesions were graded only as pretumorous, benign, and malignant. Not all tissues were included in the histopathology. The authors concluded from this study that antimony was not tumorigenic when given in drinking water. The numbers of epithelial tumors, nonepithelial tumors, and carcinomas found in the treated mice were not signifi- cantly different from those in the controls. No data suggested overt toxicity from antimony at this dose. In the 1968 mouse study (Schroeder et al. 1968) in which male and female CD-1 mice were exposed to 5 ppm of antimony in water as APT, growth rate, survival rate, tissue antimony levels, incidence of spontaneous tumors, and other physiological changes such as incidence and severity of hepatic fatty degenera- tion were reported. There was no evidence of increased fatty degeneration over the controls. Antimony was found to be not tumorigenic at this concentration. In the study of Schroeder et al. (1970), antimony was administered at a single concentration, 5 ppm, as APT in drinking water to groups of 50 male and female Long-Evans rats from weaning until natural death, and the antimony dose was estimated to be 0.43 mg/kg/d. Glucose and cholesterol were measured on days 718 and 698 for control males and females, respectively, and on days 853 and 859 for treated males and females; thus, control and treated groups were not evaluated at the same age. Nonfasting glucose levels of treated males and females were reported to be significantly lower than those of the controls. How- ever, the nonfasting glucose levels were lower than the fasting glucose levels; thus, the results are of questionable significance. The authors reported no treatment-related increase in tumor incidence, noted only as grossly visible tumors at necropsy. Such limited information pre- cludes consideration of these data for AC derivation. Most importantly, Schroeder et al. (1970) stated that male and female rats in control and treated groups had a high incidence of death due to an epidemic of virulent pneumonia that struck the rat colony during the 4 years of the ex- periment. Lynch et al. (1999), who critically evaluated all published subchronic and chronic studies that used APT by the oral route, concluded that the Schroe- der et al. (1970) study on antimony had numerous shortcomings, such as virulent pneumonia in the rat colony and the use of animals that survived for the comple- tion of the study, lack of detailed histopathology of tissues examined before de- claring that APT is not carcinogenic, biochemical measurements on controls and treated groups done with groups at different ages, and glucose being higher in fasted than in nonfasted animals. Thus, the data from this study were inappropri- ate for use in determining regulatory levels of water quality for antimony. In

Antimony 39 concurrence with this summary criticism, the data from the Schroeder et al. (1970) study were considered not acceptable to NASA for AC derivations. It must be pointed out that EPA derived an RfD for antimony with the data from the Schroeder et al. study, using longevity, blood glucose, and cholesterol, but EPA declared that its confidence in the RfD was low. Confidence in the chosen study was rated as low because only one species was used, only one dose was used, no NOAEL was determined, and gross pathology and histopathology were not well described. Confidence in the database was low because of a lack of adequate oral exposure investigations. In spite of criticisms and limitations ex- pressed by authors such as Lynch et al. (1999) on the principal study used by EPA, the organization has not revised the MCLs for antimony to date. In the absence of any other chronic toxicity study on soluble antimony compounds by the oral route, 1,000-d AC will use the observations of hema- tologic effects reported by Poon et al. (1998) from the subchronic antimony tar- trate drinking-water study. The 100-d AC derived from the BMDL of the dose- response curve for changes in red blood cells (with spaceflight factor applied) will be extrapolated with a time factor of 10 to derive a 1,000-d AC. This may be somewhat conservative, considering that the slope of the dose-response curve for hematologic changes seen in the Poon et al. study is rather low. The 1,000-d AC for antimony can be calculated as follows: 1,000-d AC(hematologic effects) = 22 mg/L(100-d AC) × 1/10(time factor) = 2.2 mg/L, rounded to 2.0 mg/L. Thus, the 1,000-d AC for antimony based on hematologic effects is 2.0 mg/L. Drinking water ACs for antimony for 1-, 10-, 100-, and 1,000-d and the SWEGs for these durations have been summarized in Table 1-6. RECOMMENDATIONS FOR ADDITIONAL RESEARCH Oral toxicity for only one soluble compound, APT, has been extensively reported in the literature, mainly for reasons of it having been used as an emetic agent. However, there are no oral toxicity data on even short-term durations for compounds such as SbCl3 and SbCl5, which are used in the dyeing industry, and antimony acetate, which is used in the synthetic fiber industry.

40 TABLE 1-6 Summary of Acceptable Concentrations and Spacecraft Water Exposure Guidelines for Antimony Uncertainty Factors Acceptable Concentrations, mg/L Toxicity End Point NOAEL/ LOAEL to Species Time Safety Reference and Chemical LOAEL Species NOAEL Factor Factor Factor 1d 10 d 100 d 1,000 d Study Induction of LOAEL = Human 10 1 1 3a 4.0 — — — Dunn 1928 vomiting: emetic 130 mg/L (beverage) stimulus (antimony mixture) Reduction in water NOAEL = Rat 1 10 1 3b — 8 — — Dieter et al. intake 10 mg/kg 1991 Hepatotoxicity NOAEL = Rat 1 10 1 1 — 145.0 — — Dieter et al. 58 mg/kg 1991 Hematotoxicity BMDL Rat NA 10 100 d/ 3 — — 22 — Poon et al. (reduction in 29 mg/kg 90 d 1998 RBCs) Hematotoxicity BMDL Rat NA 10 1,000 d/ 3 — — — 2 Poon et al. (reduction in 29 mg/kg 90 d 1998 RBCs) SWEG 4.0 4.0c 4.0d 2.0 a As the adverse effect seen was so serious that recovery took a few days, this factor was added to reduce the LOAEL. b Spaceflight factor to prevent astronauts from drinking less water. c The lowest concentration in the column under 10-d AC (8 mg/L) is higher than the levels that will cause gastrointestinal effects; thus, the lower 1-d AC value was adopted per recommendation of the committee. d 22 mg/L will not protect against gastrointestinal effects. Therefore, the 1-d AC of 4 mg/L is adopted. Abbreviations: BMDL, 95% lower confidence limit on the benchmark dose; LOAEL, lowest-observed-adverse-effect level; NA, not applicable; NOAEL, no-observed-adverse-effect level; RBC, red blood cell; —, not derived for this duration.

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Antimony 43 Kanematsu, N., M. Hara, and T. Kada. 1980. Rec assay and mutagenicity studies on metal compounds. Mutat. Res. 77(2):109-116. Kanisawa, M., and H.A. Schroeder. 1969. Life term studies on the effect of trace ele- ments on spontaneous tumors in mice and rats. Cancer Res. 29(4):892-895. 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. Lauwers, L.F., A. Roelants, P.M. Rosseel, B. Heyndrickx, and L. Baute. 1990. Oral anti- mony intoxications in man. Crit. Care Med. 18(3):324-326. Lynch, B.S., C.C. Capen, E.R. Nestmann, G. Veenstra, and J.A. Deyo. 1999. Review of subchronic/chronic toxicity of antimony potassium tartrate. Regul. Toxicol. Phar- macol. 30(1):9-17. Medical Front WWI. 2007. Materia Medica: The Medicinal Substances on the Supply Table of the Medical Department, U.S. Navy, and Their Principal Properties, Uses, and Dosage [online]. Available: http://www.vlib.us/medical/pharmacy/matmed. htm [accessed Jan. 4, 2008]. Nieto, J., J. Alvar, A.B. Mullen, K.C. Carter, C. Rodríguez, M.I. San Andrés, M.D. San Andrés, A.J. Baillie, and F. González. 2003. Pharmacokinetics, toxicities, and ef- ficacies of sodium stibogluconate formulations after intravenous administration in animals. Antimicrob. Agents Chemother. 47(9):2781-2787. NRC (National Research Council). 1980. Antimony. Pp. 24-39 in Mineral Tolerance of Domestic Animals. Washington, DC: National Academy of Sciences. NRC (National Research Council). 2000a. Antimony oxide. Pp. 229-261 in Toxicological Risks of Selected Flame Retardant Chemicals. Washington, DC: National Acad- emy Press. NRC (National Research Council). 2000b. Methods for Developing Spacecraft Water Exposure Guidelines. Washington, DC: National Academy Press. Otto, G.F., and T.H. Maren. 1950. Studies on the chemotherapy of filariasis. VI. Studies on the excretion and concentration of antimony in blood and other tissues follow- ing the injection of trivalent and pentavalent antimonials into experimental ani- mals. Am. J. Hyg. 51(3):370-385. Otto, G.F., T.H. Maren, and H.W. Brown. 1947. Blood levels and excretion rates of an- timony in persons receiving trivalent and pentavalent antimonials. Am. J. Hyg. 46(Sept.):193-211. Poon, R., I. Chu, P. Lecavalier, V.E. Valli, W. Foster, S. Gupta, and B. Thomas. 1998. Effects of antimony on rats following 90-day exposure via drinking water. Food Chem. Toxicol. 36(1):21-35. Rossi, F., R. Acampora, C. Vacca, S. Maione, M.G. Matera, R. Servodio, and E. Marmo. 1987. Prenatal and postnatal antimony exposure in rats: Effect on vasomotor reac- tivity development of pups. Teratog. Carcinog. Mutagen. 7(5):491-496. Schaumloffel, N., and T. Gebel. 1998. Heterogeneity of the DNA damage provoked by antimony and arsenic. Mutagenesis 13(3):281-286. Schroeder, H.A., M. Mitchener, J.J. Balassa, M. Kanisawa, and A.P. Nason. 1968. Zirco- nium, niobium, antimony and fluorine in mice: Effects on growth, survival and tis- sue levels. J. Nutr. 95(1):95-101. Schroeder, H.A., M. Mitchener, and A.P. Nason. 1970. Zirconium, niobium, antimony, vanadium and lead in rats: Life term studies. J. Nutr. 100(1):59-68. Sumino, K., K. Hayakawa, T. Shibata, and S. Kitamura. 1975. Heavy metals in normal Japanese tissues. Amounts of 15 heavy metals in 30 subjects. Arch. Environ. Health 30(10):487-494. van der Voet, G.B. and F.A. de Wolff. 1996. Human exposure to lithium, thallium, anti-

44 Spacecraft Water Exposure Guidelines mony, gold, and platinum: III. Antimony. Pp. 457-458 in Toxicology of Metals, L.W. Chang, ed. Boca Raton, FL: Lewis. Venugopal, B., and T.D. Luckey. 1978. Metal toxicity in mammals. Chemical Toxicity of Metals and Metalloids, Vol. 2. New York: Plenum Press. Werrin, M. 1963. Chemical food poisoning. Q Bull. Assoc. Food Drug Office 27:38-45. Winship, K.A. 1987. Toxicity of antimony and its compounds. Adverse Drug React. Acute Poisoning Rev. 6(2):67-90.

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NASA maintains an active interest in the environmental conditions associated with living and working in spacecraft and identifying hazards that might adversely affect the health and well-being of crew members. Despite major engineering advances in controlling the spacecraft environment, some water and air contamination is inevitable. Several hundred chemical species are likely to be found in the closed environment of the spacecraft, and as the frequency, complexity, and duration of human space flight increase, identifying and understanding significant health hazards will become more complicated and more critical for the success of the missions.

To protect space crews from contaminants in potable and hygiene water, NASA requested that the National Research Council NRC provide guidance on how to develop water exposure guidelines and subsequently review NASA's development of the exposure guidelines for specific chemicals. This book presents spacecraft water exposure guidelines (SWEGs) for antimony, benzene, ethylene glycol, methanol, methyl ethyl ketone, and propylene glycol.

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