7
Magnesium Hydroxide

THIS chapter reviews the physical and chemical properties, toxicokinetics, toxicological, epidemiological, and exposure data on magnesium hydroxide, Mg(OH)2. The subcommittee used that information to characterize the health risk from exposure to Mg(OH)2. The subcommittee also identified data gaps and recommended research relevant for determining the health risk from exposure to Mg(OH)2.

PHYSICAL AND CHEMICAL PROPERTIES

Magnesium hydroxide, Mg(OH)2, is one of a number of inorganic compounds that has been used as a flame retardant (FR) in furniture upholstery. The physical and chemical properties of Mg(OH)2 are listed in Table 7–1.

OCCURRENCE AND USE

Mg(OH)2 is most commonly used as an antacid and is the active ingredient in the laxative milk of magnesia. It is also used as a residual fuel-oil additive, an alkali drying agent in food, a color-retention agent, an ingredient of tooth-



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Toxicological Risks of Selected Flame-Retardant Chemicals 7 Magnesium Hydroxide THIS chapter reviews the physical and chemical properties, toxicokinetics, toxicological, epidemiological, and exposure data on magnesium hydroxide, Mg(OH)2. The subcommittee used that information to characterize the health risk from exposure to Mg(OH)2. The subcommittee also identified data gaps and recommended research relevant for determining the health risk from exposure to Mg(OH)2. PHYSICAL AND CHEMICAL PROPERTIES Magnesium hydroxide, Mg(OH)2, is one of a number of inorganic compounds that has been used as a flame retardant (FR) in furniture upholstery. The physical and chemical properties of Mg(OH)2 are listed in Table 7–1. OCCURRENCE AND USE Mg(OH)2 is most commonly used as an antacid and is the active ingredient in the laxative milk of magnesia. It is also used as a residual fuel-oil additive, an alkali drying agent in food, a color-retention agent, an ingredient of tooth-

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Toxicological Risks of Selected Flame-Retardant Chemicals TABLE 7–1 Physical and Chemical Properties of Magnesium Hydroxide Property Value Reference Chemical formula Mg(OH)2 HSDB 1998 CAS registry no. 1309–42–8 HSDB 1998 Synonyms Caustic magnesite, magnesia magma, magnesium dihydroxide, magnesium hydrate, magnesium hydroxide gel, magnesium oxide, Marinco H, Marinco H 1241, Milk of magnesia, Mint-o-mag, Nemalite HSDB 1998 Molecular weight 58.34 HSDB 1998 Physical state White very fine powder HSDB 1998 Solubility 0.0009 g in 100 cm3 of H2O at 18°C 0.004 g in 100 cm3 of H2O at 100°C HSDB 1998 pH 9.5–10.5 (aqueous slurry) HSDB 1998 Temperature of decomposition 350°C HSDB 1998 Density 2.36 HSDB 1998 paste and frozen desserts, a clarifier in sugar refining, and a neutralizing agent in the chemical industry (HSDB 1998). Mg(OH)2 is categorized by the U.S. Food and Drug Administration (FDA) as a GRAS (generally recognized as safe) food ingredient and is approved for use as a nutritional supplement and a pH-control agent in foods (FDA 1999). Mg(OH)2 is used as an FR in commercial furniture applications in the United States and in commercial and residential furniture in the United Kingdom (Fire Retardant Chemicals Association 1998). The stability of Mg(OH)2 at temperatures above 300°C allows it to be incorporated into several polymers (IPCS 1997). Market-volume data published in 1993 suggest increasing the use of Mg(OH)2 as a FR. About 2,000 and 3,000 tons of Mg(OH)2 were marketed as an FR in the United States in 1986 and 1993, respectively (IPCS 1997). Mg2+ is the fourth most abundant cation in the human body (Rude and Singer 1981). The average adult’s body contains about 24 g of magnesium (Sutton and Dirks 1986; Elin 1987). The normal range of magnesium in human serum is 1.5–2.5 mEq/L (18.2–30.3 mg/L) and about two-third of magnesium is present as free cation and one-third is bound to plasma proteins (Elin 1987).

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Toxicological Risks of Selected Flame-Retardant Chemicals TOXICOKINETICS Absorption Dermal No information was found on the dermal absorption of Mg(OH)2 in humans or experimental animals. Inhalation Absorption of Mg2+ from inhalation exposure has been shown to take place in male Wistar rats after inhalation of MgSO4/5Mg(OH)2 • 3H2O filaments (Hori et al. 1994). That few filaments were detected in the rat lungs after 1 d of exposure suggested to the authors that the filaments were dissolved and absorbed through the alveolar capillaries. An intratracheal-instillation experiment in hamsters showed that the half-life for pulmonary clearance of short filaments (4.9 mm) was 17.6 min (Oberdörster 1996). However, this experiment could not determine whether fibers were removed from the lungs by alveolar macrophages or were absorbed by alveolar capillaries. Oral When administered orally, Mg(OH)2 dissociates in stomach acids to Mg2+ cations. About 5–15% of the dissociated Mg2+ cations are absorbed (HSDB 1998) through the epithelial lining of the small intestine (Sutton and Dirks 1986; Elin 1987). Absorption of Mg2+ can be affected by the presence of food or other substances that readily complex with Mg2+ cations. Mg(OH)2 and MgO, which have relatively low solubilities at neutral and alkaline pH, are less completely absorbed than the more water-soluble Mg2+compounds-magnesium chloride (MgCl2), magnesium citrate, and magnesium lactate (Benech et al. 1998; Brunton 1996). Determination of increased plasma or urinary Mg2+ cations after oral administration of Mg(OH)2 is not possible, because of rapid homeostasis of exogenous Mg2+ in humans (Benech et al. 1998). A single study in human volunteers measured the oral absorption of Mg2+ cations (Benech et al. 1998). In that study, six healthy males were administered a single oral dose of 360 mg of 26Mg2+ as magnesium lactate or citrate and absorption of Mg2+ over 5 d was found to be 34.5%±18.8% and 39.8%±

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Toxicological Risks of Selected Flame-Retardant Chemicals 24.3% (mean±SD) based on urinary excretion. Absorption of Mg2+ was 25.6% ±34.5%; this estimate was based on fecal excretion. Distribution Dermal and Inhalation No studies were found that investigated distribution of Mg2+ cations following dermal or inhalation exposure of humans or experimental animals to Mg(OH)2. Oral Twelve volunteers that received a single oral dose of 16 mmol of MgCl2 (389 mg of magnesium) exhibited a rise in serum magnesium during the first 4 hr after ingestion accompanied by an increase in urinary magnesium excretion (White et al. 1992). In another study, 23 women and 12 men (21–50 yr old) received two oral doses of 400 mg of MgO/d (476 mg Mg2+/d) for 60 d and had no change in serum magnesium (Marken et al. 1989). Metabolism No studies were found that investigated the biotransformation of Mg(OH)2 in humans or animals after exposure by any route. Mg(OH)2 probably does not undergo biotransformation by the liver, lungs, skin, or intestinal epithelium after oral, dermal, or inhalation exposure. Excretion Dermal and Inhalation No studies were found that investigated excretion of Mg2+ cations following dermal or inhalation exposure of humans or experimental animals to Mg(OH)2. Oral Following oral exposure, undissolved Mg(OH)2 antacids pass through the intestines and are eliminated in the feces (Brunton 1996). Unabsorbed Mg2+ is

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Toxicological Risks of Selected Flame-Retardant Chemicals excreted unchanged in the feces (Brunton 1996). When 19 normal volunteers were given Mg(OH)2 for 4 d in addition to magnesium in their normal diet (total magnesium, 27, 54, or 107-mmol/d), soluble Mg2+ output in feces reached a maximum of 14.6 mmol/d mg/kg-d (Fine et al. 1991). The average fecal output of soluble Mg2+ in these volunteers was 5.06. Urinary excretion is the major route of elimination of absorbed Mg2+ when kidney function is normal. Urinary excretion accounts for about 80–90% of Mg2+ under steady-state conditions (Sutton and Dirks 1986). However, much of the absorbed dose of Mg2+ enters Mg2+ pools within the body and is not readily eliminated. Only about 7.4%±4% of a 50-mg intravenous dose of soluble Mg2+ or 2.22%±0.43% of an oral dose of 360 mg of soluble Mg2+ was excreted in urine over 5 d in six healthy male volunteers. White et al. (1992) measured a 22% increase in urinary magnesium in 12 healthy volunteers (nine men and three women, 23–46 yr old) during the first 8 hr after ingestion of MgCl2 of Mg2+ at 5.6 mg/kg-d. HAZARD IDENTIFICATION1 The toxicology database on Mg(OH)2 is sparse. Therefore, the subcommittee decided that this review should also include toxicity data on magnesium salts that are expected to dissociate in stomach acid to Mg2+ cations. These include MgCl2, magnesium lactate, and magnesium citrate. Dermal Exposure No studies were found on the toxic effects of Mg(OH)2 following dermal exposure. Inhalation Exposure Systemic Effects No human studies were found that investigated the toxic effects of Mg(OH)2 following inhalation exposure. Exposure of male Wistar rats to short (4.9× 0.31 mm) or long (12×0.44 mm) MgSO4/5Mg(OH)2 • 3H2O filaments by 1   In this section, the subcommittee reviewed the toxicity data on Mg(OH)2, including the toxicity assessment prepared by the U.S. Consumer Product Safety Commission (Ferrante 1999).

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Toxicological Risks of Selected Flame-Retardant Chemicals inhalation, 6 hr/d, 5 d/wk for up to a year was associated with a slight increase in the incidence of pulmonary lesions 1 yr after cessation of exposure (Hori et al. 1994). A year after cessation of exposure, histopathological examination of treated animals revealed a slight increase in segmental calcification of the pulmonary artery and thickening of the lung pleura in rats exposed to either short or long filaments for 4 wk or 1 yr. Differences between exposed and unexposed animals were statistically significant. No significant differences in body, lung, liver, kidney, or spleen weights were detected between animals sacrificed 1 d or 1 yr after a 1-yr exposure to short or long filaments. No significant differences in survival were observed between animals sacrificd 1 d or 1 yr after a 1-yr exposure to short or long filaments. Other Systemic Effects No inhalation toxicity studies were found that investigated the immunological, neurological, reproductive, or developmental effects of Mg(OH)2. Cancer The incidence of all cancers among 2,391 Norwegian males who worked between 1951 and 1974 in a factory producing magnesium metal was not significantly increased when compared with cancer incidence for the Norwegian national population of the same age (Heldaas et al. 1989). The number of cases of lip, as well as stomach, and lung cancers were significantly increased. Workers in this study were also exposed to magnesium oxide dust, coal dust, chlorine gas, hydrochlorine aerosols, chlorinated aromatics, and sulphur dioxide. Therefore, it is not possible to determine whether exposure to magnesium dust alone is responsible for the observed elevations in cancer incidence. Exposure of male Wistar rats to short (4.9×0.31 mm) or long (12×0.44 mm) MgSO4/5Mg(OH)2 • 3H2O filaments by inhalation (6 hr/d, 5 d/ wk for 1 yr) was not associated with an increase in the incidence of any tumor types in animals sacrificed 1 d or 1 yr after cessation of exposure (Hori et al. 1994). One yr after exposure, one pulmonary adenoma was observed in animals that had been exposed to long filaments for 4 wk and none in controls. One yr after exposure, neoplastic lesions were observed in control animals and short- and long-filament treated rats that had been exposed for 1 yr. Two pulmonary adenomas were observed in the exposed animals and one in control animals. No hepatocellular adenomas or carcinomas occurred in controls, one hepatocellular adenoma was found in the long-filament group, and one hepatocellular carcinoma was found in the short-filament group, respectively.

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Toxicological Risks of Selected Flame-Retardant Chemicals Oral Exposure Systemic Effects Human Data Most available toxicity data on Mg(OH)2 describe effects of acute exposure to Mg(OH)2 or of prolonged exposure to antacid or laxative products containing Mg(OH)2. Magnesium intoxication has been reported in infants (2–42 d old) that received Mg2+-containing oral laxatives at Mg2+ doses of 224–917 mg/kg-d for 2–11 d (Alison and Bulugahapitiya 1990, Brand and Greer 1990, Humphrey et al. 1981, Mofenson and Caraccio 1991). Whereas normal serum magnesium ranges from 1.4 to 2.4 mEq/L, these infants had concentrations of 3.5–11.7 mEq/L. In one case, Mg2+ body burden was high enough to cause perforation of the bowel (Mofenson and Caraccio 1991). In adults, serious toxic effects associated with excess magnesium intake occur at very high intake levels equating to serum concentrations of 4 mEq/L (Mordes and Wacker 1978; Rude and Singer 1981). Toxicity has been limited to persons with intestinal or renal disease (Poisindex 1998). The Hazardous Substance Data Bank (HSDB) entry for Mg(OH)2 states that the probable oral lethal dose of Mg(OH)2 in humans is 5–15 g/kg in a 70-kg person (HSDB 1998). Cardiac arrest has been reported at serum Mg2+ concentrations of 15–16 mEq/L (Dreisbach 1977). Respiratory depression, depression of the central nervous system, and coma occur in adult patients with plasma Mg2+ concentrations of 10–14 mEq/L (Ferdinandus et al. 1981). Hypotension, nausea, and vomiting occur at plasma concentrations of 3–8 mEq/L. In its review of clinical studies, the Institute of Medicine (IOM 1997) concluded that Mg2+ in the diet is never high enough to cause adverse effects. The IOM set a “tolerable upper intake level” (TUL)2 for the ingestion of magnesium (Mg2+) supplements of 5 mg/d for anyone over 1 yr old. The TUL was based on the approximate no-observed-adverse-effects level (NOAEL) for osmotic diarrhea in humans reported by Marken et al. (1989), Fine et al. (1991), Ricci et al. (1991), and Bashir et al. (1993). Gastrointestinal discomfort occurred in six of 21 patients with stable congestive heart failure who received 15.8 mmol MgCl2/d (5.5 mg/kg-d) for 6 wk (Bashir et al. 1993). Five of the six patients reported epigastric burning or distension and two reported diarrhea. Five of 50 pregnant women developed adverse gastrointestinal effects (nau- 2   A tolerable upper intake level is the maximal total chronic daily intake of a nutrient or food component that is unlikely to pose risks of adverse effects.

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Toxicological Risks of Selected Flame-Retardant Chemicals sea, soft stool, or diarrhea) given intravenous and oral doses of Mg2+ to suppress preterm delivery (Ricci et al. 1991). The women were initially given a 4-g bolus dose of MgSO4 by intravenous injection followed by intravenous infusion of MgSO4 at a dose of 2 g/hr for 12 hr. This approximates to a minimum dose of 353 mg/kg (assuming a female body weight of 55 kg). Increases in the incidence of adverse neonatal outcomes were observed in women that ingested MgCl2 tablets (7 mg/kg-d over an average of 29 d) as compared with controls given no MgCl2 tablets (Ricci et al. 1991). Eleven of 25 neonates in treated mothers were diagnosed with jaundice as compared with 6 out of 25 infants born to control mothers. One fatal case of respiratory distress syndrome, one case of intraventricular hemorrhage, and 2 cases of necrotizing enterocolitis occurred in women taking MgCl2 tablets as compared with no cases among infants born to control mothers. These increases were judged not to be statistically significant by the study investigators. Diarrhea occurred in 18 of 50 (36%) healthy adult volunteers who received magnesium (as MgO) doses of 476 mg/d for 60 d (Marken et al. 1989). Diarrhea was also observed in 14 healthy male subjects who ingested Mg(OH)2 at a dose rate of 16.7, 33.3, or 67 mg/kg-d for 4 d (Fine et al.1991). Animal Data The key oral toxicity studies for Mg(OH)2 are summarized in Table 7–2. Decreased body weight was found to be the critical effect in B6C3F1 mice fed diets containing 0%, 0.3%, 0.6%, 1.25%, 2.5% or 5% MgCl2 • 6H2O for 13 wk (Tanaka et al. 1994). Intake of Mg2+ added to the diet was calculated to be 73, 146, 322, 650, or 1,368 mg/kg-d in treated males and 92, 190, 391, 817, and 1,660 mg/kg-d in treated females (the amount of magnesium in the basal diet was not provided). The 5%-treatment group of both sexes showed a significant decrease in weight gain (15% in males and 10% in females). Males in the 2.5 and 5% group exhibited an increased incidence of renal tubular vacuolation. The authors determined that the LOAEL for this study was 650 mg/kg-d. Decreased body weight and increased renal vacuolation were observed in male, but not female B6C3F1 mice fed a diet that contained 5% MgCl2 • 6H2O (Mg2+ at 840 mg/kg-d) for 13 wk (Kurata et al. 1989). No treatment-related effects were reported for male and female mice fed a diet containing 0, 0.3, 0.6, 1.25, or 2.5% MgCl2 • 6H2O for 13 wk. The NOAEL for Mg2+ in this study was determined to be 587 mg/kg-d for females and 420 mg/kg-d for males. Decreased body weight gain (about 25% at termination of the exposure) and increases in relative brain, heart, and kidney weights compared with controls were observed in female B6C3F1 mice fed diets for 96 wk that contained 2%

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Toxicological Risks of Selected Flame-Retardant Chemicals TABLE 7–2 Selected Oral Animal Toxicity Data on Magnesium Hydroxide Species, strain, sex Dose or concentration, Mg2+ Duration Effects NOAEL/LOAEL (Mg2+) Reference ORAL EXPOSURE Mouse, B6C3F1, M/F M: 73, 146, 322, 650, 1,368 mg/kg-d F: 92, 190, 391, 817, 1,660 mg/kg-d 90 d Significant decrease in weight gain in high-dose groups for both males and females. Increased incidence of renal tubular vacuolation in male mice in the high- and 650 mg/kg-d dose groups. LOAEL: 650 mg/kg-d Tanaka et al. 1994 Mouse, B6C3F1, M/F 0.3, 0.6, 1.25, 2.5% 90 d Significant decrease in weight gain and increased incidence of renal tubular vacuolation in males in the high-dose group (840 mg/kg-d). NOAEL: 587 mg/kg-d (F) 420 mg/kg-d (M) Kurata et al. 1989 Mouse, B6C3F1, M/F M: 68, 336 mg/kg-d F: 87, 470 mg/kg-d 96 wk In high-dose females, significant body weight gains, increases in food and water consumption, and increases in relative brain, heart, and kidney weights compared to controls at 96 wk. No treatment-related effects in male mice. LOAEL: 470 mg/kg-d (F) Kurata et al. 1989 Rat, Wistar, F 24, 47, or 96 mg/kg-d Gestation d 6–15 No treatment-related effects reported. NOAEL: >96 mg/kg-d Usami et al. 1996 F: female; LOAEL: lowest-observed-adverse-effect level; M: male; ND: not determined; NOAEL: no-observed-adverse-effect level.

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Toxicological Risks of Selected Flame-Retardant Chemicals MgCl2 • 6H2O (470 mg Mg2+/kg-d) (Kurata et al. 1989). No treatment-related effects were observed in male mice fed diets that contained 0.5% or 2% of MgCl2 • 6H2O (68, or 336 mg/kg-d) or female mice fed diets that contained 0.5% of MgCl2 • 6H2O (87 mg/kg-d) for 96 wk. Histopathological examination after 104 wk of exposure revealed no treatment-related changes. Urinary, hematological, and clinical chemistry parameters and histopathological measures were not affected by treatment, except for a significant increase in serum albumin in high-dose females. Survival rates were comparable between treated and control animals. The LOAEL for this study is 470 mg/kg-d based on the treatment-related effects in high-dose female mice. Immunological and Neurological Effects No studies were found that investigated the immunological or neurological effects of Mg(OH)2 from oral exposures. Reproductive and Developmental Effects There are no studies in humans that evaluated reproductive or developmental effects associated with the ingestion of Mg(OH)2. Oral administration of MgCl2 solution caused no toxic signs in pregnant Wistar rats and no increases in the incidences of fetal malformations that were given doses of 0, 200, 400, or 800 mg/kg-d (Mg2+ at 0, 24, 47, and 96 mg/kg-d) on d 6 through 15 of pregnancy (Usami et al. 1996). Pregnant dams were killed on d 20 of pregnancy and all fetuses underwent pathological examination for skeletal and visceral malformations. No malformations were observed at any dose tested. The authors concluded that the NOAEL for developmental and maternal toxicity was over 800 mg/kg-d (equivalent to 96 mg Mg2+/kg-d) in this study. Cancer The subcommittee found no oral chronic toxicity studies or epidemiological studies that investigated the carcinogenicity of Mg(OH)2 in rodents or humans. Mice fed 0.5% or 2% of aqueous MgCl2 in their diet for 96 wk (68, or 336 mg/kg-d for males; 87 or 470 mg/kg-d for females) showed no significant change in the incidence of malignant lymphoma and leukemia (Kurata et al. 1989). Dose-related increases in incidence of malignant lymphoma and leukemia occurred in male mice (controls, five of 50; low dose, seven of 50; high

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Toxicological Risks of Selected Flame-Retardant Chemicals dose, eleven of 50), but not in females (controls, nine of 49; low dose, 17 of 50; high dose, 11 of 50). The incidence of hepatocellular carcinomas in male mice was decreased in a dose-related manner (controls, 13 of 50; low dose, six of 50; high dose, four of 50) and the incidence in high-dose males was significantly different from that in controls. Toxicity in female mice (i.e., decreased body weight) suggests that the study was conducted at or near the maximum tolerated dose (MTD) for females. Several studies in rats have shown that dietary Mg(OH)2 can protect against chemically induced bowel carcinogenesis by suppressing hyperproliferation of the colon epithelium. Dietary levels of 250 ppm Mg(OH)2 inhibited the incidence of colon adenoma and adenocarcinoma in rats given carcinogens methylazoxymethanol acetate (MAM acetate) or 1, 2-dimethylhydrazine (Tanaka et al. 1989; Morishita et al. 1991; Mori et al. 1993). Administration of Mg(OH)2 in the diet and the bowel carcinogen cholic acid reduced cell proliferation in bowel tissue (Wang et al. 1994). Dietary Mg(OH)2 also prevented the expression of c-myc gene in colon mucosa cells of MAM acetate-treated rats (Wang et al. 1993). Genotoxicity The subcommittee found no mutagenicity data on Mg(OH)2. However, there are studies that have investigated the genotoxicity of other magnesium salts. Most of theses studies report negative genotoxicity findings for these compounds. MgCl2 was judged to be a nonmutagen in the Ames assay when tested with and without metabolic activation and it did not induce chromosomal aberrations in Chinese hamster fibroblast cells in vitro (Ishidate et al. 1984, as cited in Tanaka et al. 1994). Chromatid gaps, breaks, and exchanges were observed in Chinese hamster lung fibroblasts treated with MgCl2 at concentrations of 8.0 and 12.0 mg/ml but not at or below concentrations of 4 mg/mL (Ashby and Ishidate 1986). Since positive results occurred at only high concentrations, the authors suggest that the clastogenic effects observed may be an artifact induced by hypertonic solutions. MgCl2 did not induce mutations in mouse lymphoma L5178/TK+/− cells at concentrations of 5.7–18.1 mg Mg2+/ml (Amacher and Paillet 1980). MgSO4 was not mutagenic in Salmonella typhimurium (strains TA100, TA1535) and Escherichia coli WP2 uvrA at concentrations of 313–5,000 mg/plate (Oguma et al. 1998). MgSO4 was not mutagenic in Salmonella strain TA98 tested without metabolic activation and strain TA1537 tested with metabolic activation at a concentration of 156–5000 mg/plate (Oguma et al. 1998).

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Toxicological Risks of Selected Flame-Retardant Chemicals QUANTITATIVE TOXICITY ASSESSMENT Noncancer Dermal Assessment There are no adequate studies that investigated the subchronic or chronic toxicity of Mg(OH)2 administered by the dermal route of exposure. Therefore, the subcommittee did not estimate a dermal RfD for Mg(OH)2. Inhalation RfC One study investigated the chronic toxicity of manufactured mineral filaments that contain Mg(OH)2 (Hori et al. 1994). However, the subcommittee concluded that this study is not useful for deriving an inhalation RfC for Mg(OH)2, because of the threefold difference in solubility between Mg(OH)2 and the composite mineral filaments and the great variation in the size and shape of Mg(OH)2 particles as opposed to the composite filaments used in the study. Therefore, the subcommittee concludes that there are inadequate human or animal data on the inhaled toxicity of Mg(OH)2 to derive an inhalation RfC. Oral RfD There are inadequate toxicity data on Mg(OH)2 from oral exposure studies. However, the Institute of Medicine’s Committee on Recommended Dietary Allowance (IOM 1997) has derived a tolerable upper limit (TUL) for intake of Mg2+ (from nonfood sources) based on the LOAEL for osmotic diarrhea based on the results of several studies in adults (Marken et al. 1989; Fine et al. 1991; Ricci et al. 1991; Bashir et al. 1993). The TUL for Mg2+ is 5 mg/kg-d (0.21 mmol/kg-d) for all population groups 1 yr old and older (see Hazard Identification section for more detail). In its calculation, IOM (IOM 1997) used an uncertainty factor of 1.0 reasoning that diarrhea is a mild and reversible toxic effect. Based on differences in molecular weight, the equivalent TUL for Mg(OH)2 is estimated to be about 2.4 times that of Mg2+ or 12 mg/kg-d. The subcommittee believes that this TUL can be safely assumed to also be the oral RfD. Carcinogenicity There are insufficient data to assess the carcinogenicity of Mg(OH)2. EPA,

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Toxicological Risks of Selected Flame-Retardant Chemicals the National Toxicology Program (NTP), and the International Agency for Research on Cancer (IARC) have not evaluated the carcinogenicity of Mg(OH)2. A chronic study in mice exposed to Mg(OH)2 filaments did not find evidence of carcinogenicity. Studies in rats suggest that Mg(OH)2 incorporated into the diet can protect against some chemically induced cancers (Tanaka et al. 1989; Morishita et al. 1991; Mori et al. 1993; Wang et al. 1993, 1994). The subcommittee is not aware of any mutagenicity data on Mg(OH)2. However, genotoxicity studies conducted with several magnesium salts have all been negative. On the basis of the data available, the subcommittee concludes that there are insufficient data on oral carcinogenicity of Mg(OH)2 to determine its carcinogenicity. EXPOSURE ASSESSMENT AND RISK CHARACTERIZATION Noncancer Dermal Exposure Dermal exposure to Mg(OH)2 was estimated using the dermal exposure scenario described in Chapter 3. This exposure scenario assumes that an adult spends 1/4th of his or her time sitting on furniture upholstery treated with Mg(OH)2 and also assumes that 1/4th of the upper torso is in contact with the upholstery and clothing presents no barrier. The subcommittee concluded that Mg(OH)2 is an ionic substance and, therefore, is essentially not absorbed through the skin and should not pose a health risk from the dermal route of exposure when used as an FR in furniture upholstery. However, to be conservative, the subcommittee assumed that ionized Mg(OH)2 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 Mg(OH)2 of 4 mg/cm2 and Equation 1 in Chapter 3, the subcommittee calculated a worst-case dermal exposure level of 1.7×10−3 mg/kg–d. The oral RfD for Mg(OH)2 (12 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 1.4×10−4. Thus, it was concluded that Mg(OH)2 used as an FR in upholstery fabric is not likely to pose any noncancer risk by the dermal route.

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Toxicological Risks of Selected Flame-Retardant Chemicals Inhalation Exposure Particles The characterization of the noncancer health risk from the inhalation of upholstery particles containing Mg(OH)2 is based on the inhalation exposure scenario described in Chapter 3. In this scenario, a person is exposed to upholstery particles containing Mg(OH)2. It is assumed that particles are generated from wear of the upholstery and 50% of the Mg(OH)2 present in 25% of the treated surface are released as particles over the 15-yr lifetime of the fabric. It is also assumed that only 1% of the worn-off Mg(OH)2 is released into the indoor air as particles that may be inhaled and that a person spends 1/4th of his or her life in a 30-m3 room that contains 30 m2 of treated upholstery with an air-change rate of 0.25/hr. Particle exposure was estimated using Equations 4 and 5 in Chapter 3. The subcommittee estimated an upholstery application rate (Sa) for Mg(OH)2 of 4 mg/cm2. The release rate (µr) for Mg(OH)2 from upholstery fabric was estimated to be 2.3×10−7/d, yielding a room airborne particle concentration (Cp) of 1.5 µg/m3. These values were used in Equation 8 in Chapter 3 to yield a short-time-average exposure concentration of 0.38 µg/m3. The time-averaged exposure concentration for particles was calculated using Equation 6 in Chapter 3. There are inadequate human or animal data on the inhaled toxicity of Mg(OH)2 to derive an inhalation RfC. However, for the purpose of estimating a hazard index for characterizing the noncancer risk from the inhalation of Mg(OH)2, a provisional inhalation RfC was derived from the TUL, which in this case is considered to be equivalent to the oral RfD (see Chapter 4 for the rationale). A provisional inhalation RfC of 42 mg/m3 was derived for Mg(OH)2 using the oral RfD and Equation 7 in chapter 3. Division of the time-average exposure concentration of 0.38 µg/m3 by the provisional inhalation RfC of 42 mg/m3 results in a hazard index of 9.1×10−6. This ratio suggests that under the worst-case human-exposure assumptions, Mg(OH)2, when used as a FRs in upholstery, is not likely to pose a noncancer risk by the inhalation route of exposure. Vapors Mg(OH)2 has negligible vapor pressure at ambient temperatures. Therefore, inhalation of Mg(OH)2 vapor is not anticipated to pose a noncancer toxic risk when incorporated into furniture upholstery.

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Toxicological Risks of Selected Flame-Retardant Chemicals Oral Exposure The characterization of noncancer health risk from oral exposure to Mg(OH)2 is based on the oral exposure scenario described in Chapter 3. This scenario assumes a child is exposed to Mg(OH)2 by sucking on 50 cm2 of fabric treated with Mg(OH)2, 1 hr/d for 2 yr. The subcommittee estimated an upholstery application rate (Sa) for Mg(OH)2 of 4 mg/cm2 and a fractional rate of Mg(OH)2 extraction (µa) by saliva of 0.025/d based on levels reported by Jenkins et al. (1998). Oral exposure was calculated by using Equation 15 in Chapter 3. The average oral daily dose for Mg(OH)2 was estimated as 0.021 mg/kg-d. Division of the dose estimate by the oral TUL (RfD) for Mg(OH)2 of 12 mg/kg-d results in the hazard index of 1.7×10−3. Therefore, the subcommittee concluded that Mg(OH)2 is not likely to pose a noncancer risk at the worst-case exposure levels from upholstered furniture. Cancer The subcommittee concludes that Mg(OH)2 is not likely to be carcinogenic to humans by the oral route. No adequate data are available to assess the carcinogenicity of Mg(OH)2 by the dermal or inhalation or routes of exposure. RECOMMENDATIONS FROM OTHER ORGANIZATIONS The current threshold limit value (TLV) for magnesium oxide is 10 mg/m3 (ACGIH 1999). The subcommittee is not aware of any recommended exposure limits for Mg(OH)2. DATA GAPS AND RESEARCH NEEDS There are inadequate subchronic or chronic toxicity data from dermal or inhalation exposure to Mg(OH)2. There are no exposure data from dermal, inhalation, or oral routes of exposure to Mg(OH)2 when used as an FR. Because the hazard indices for noncancer effects for dermal, inhalation, and oral routes of exposure are less than 1, the subcommittee concludes that no further research is needed for assessing health risks from Mg(OH)2.

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