9
Calcium and Zinc Molybdates

CALCIUM and zinc molybdates readily dissociate in the body into molybdenum compounds and calcium and zinc ions. Because little data exist on calcium and zinc molydates specifically, this chapter reviews the physical and chemical properties, toxicokinetics, toxicological, epidemiological, and exposure data on molybdenum compounds and zinc. The subcommittee used that information to characterize the health risk from exposure to calcium and zinc molybdates. The subcommittee also identified data gaps and recommended research relevant for determining the health risk from exposure to calcium and zinc molybdates.

PHYSICAL AND CHEMICAL PROPERTIES

The physical and chemical properties of calcium and zinc molybdates are presented in Table 9–1.

OCCURRENCE AND USE

Calcium and zinc molybdates are used as flame retardants in cellulosic materials and other polymers. Textile applications for calcium and zinc molybdates include furniture, draperies, upholstery seating in transportation vehicles, wall coverings, and carpets (FRCA 1998). Calcium and zinc molybdates are



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Toxicological Risks of Selected Flame-Retardant Chemicals 9 Calcium and Zinc Molybdates CALCIUM and zinc molybdates readily dissociate in the body into molybdenum compounds and calcium and zinc ions. Because little data exist on calcium and zinc molydates specifically, this chapter reviews the physical and chemical properties, toxicokinetics, toxicological, epidemiological, and exposure data on molybdenum compounds and zinc. The subcommittee used that information to characterize the health risk from exposure to calcium and zinc molybdates. The subcommittee also identified data gaps and recommended research relevant for determining the health risk from exposure to calcium and zinc molybdates. PHYSICAL AND CHEMICAL PROPERTIES The physical and chemical properties of calcium and zinc molybdates are presented in Table 9–1. OCCURRENCE AND USE Calcium and zinc molybdates are used as flame retardants in cellulosic materials and other polymers. Textile applications for calcium and zinc molybdates include furniture, draperies, upholstery seating in transportation vehicles, wall coverings, and carpets (FRCA 1998). Calcium and zinc molybdates are

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Toxicological Risks of Selected Flame-Retardant Chemicals TABLE 9–1 Physical and Chemical Properties of Calcium and Zinc Molybdates Property Value Reference Calcium molybdate Chemical formula CaMoO4 Budavari et al. 1989 CAS registry # 7789–82–4 Powmet 1999 Synonym Powellite Powmet 1999 Molecular weight 200.01 Budavari et al. 1989 Physical state Solid Powmet 1999 Melting point 965°C Powmet 1999 Solubility 0.005 g/100 mL in H2O at 25 °C Tsigdinos and Moore 1981 Density 4.38–4.53 g/cm3 Powmet 1999 Zinc molybdate Chemical formula ZnMoO4 Tsigdinos and Moore 1981 CAS registry no. 13767–32–3 Powmet 1999 Synonyms zinc molybdenum oxide, molybdic acid, zinc salt, Kemguard Powmet 1999 Molecular weight 225.31 Powmet 1999 Physical state Solid Powmet 1999 Solubility 0.5g/100 mL in H2O at 25°C Powmet 1999 Melting point 1,020°C Tsigdinos and Moore 1981 formed when calcium oxide (CaO) or zinc oxide (ZnO) is complexed with molybdenum trioxide (MoO3). These molybdates readily dissociate in the body, resulting in molybdemum (Mo) in various valence states, along with zinc and calcium ions (Stokinger 1981). Calcium molybdate can occur naturally as the ore Powellite (Stokinger 1981). Molybdenum (Mo) exists in six valence states. The most important valence states in biological systems are Mo3+, Mo4+, Mo5+, and Mo6+ (Lener and Bibr 1984). In general, higher oxidation states lead to oxygen binding while lower oxidation states favor sulfur or nitrogen binding (EPA 1979). The principal dissolved Mo species in the natural environment is molybdate (EPA 1979). The recommended daily intake of Mo is 75–250 µg/d (NRC 1989). Mo is important

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Toxicological Risks of Selected Flame-Retardant Chemicals biologically to humans, as it is an essential trace element in the Mo-flavoprotein enzyme xanthine oxidase (XO), where it functions as an electron transport agent. XO permits the oxidation of hypoxanthine and xanthine to uric acid. It is also a component of several other metalloenzymes, including aldehyde oxidase and sulfite oxidase (Tsongas et al. 1980). Zinc is an essential nutrient with a recommended daily allowance of 15 mg/d for males and 12 mg/d for females (NRC 1989). The toxicity of zinc in humans is considered to be quite low; toxicity normally occurs following ingestion of >2 g of zinc (Prasad 1976, as cited in ATSDR 1994). Calcium is an essential nutrient, with a recommended daily allowance of 800–1,200 mg/d depending upon a person’s age (NRC 1989). No adverse effects from consumption of levels of calcium up to 2,500 mg/d in healthy adults have been reported. High calcium intakes may induce constipation, cause increased risks of urinary stone formation in males, and may inhibit the intestinal absorption of iron, zinc, and other essential minerals. Ingestion of very large quantities of calcium may result in hypercalciuria, hypercalcemia, and deterioration of renal function in both sexes (NRC 1989). Additional toxicity data on calcium are not included in this document, because the recommended daily allowance is considerably higher than exposure estimates in flame retardants applied to upholstery fabric. TOXICOKINETICS Molybdenum Compounds There are no toxicokinetic data on Mo compounds following dermal exposure. Only limited data were located regarding the absorption, distribution, metabolism, and excretion by humans of inhaled or ingested Mo compounds. A case study of four humans injected intravenously with 99Mo showed that 5-d cumulative urinary excretion ranged from 16.6% to 27.2% of the dose (50–100 µCi), with the primary excretory pathway being the kidney. Fecal excretion was found to be 6.8% in one patient and less than 1% in another after 10 d (Rosoff and Spencer 1964). Studies by Fairhall et al. (1945) showed that Mo is rapidly absorbed and eliminated by the kidneys of experimental animals following oral exposure. Six guinea pigs were administered 50 mg of Mo orally, as molybdenum trioxide in a 10% gum arabic solution, and were observed for 4, 16, and 48 hr. The highest concentrations of Mo were excreted in the urine, while much smaller quantities were found in the feces. Rats dosed orally with molybdenum trioxide were

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Toxicological Risks of Selected Flame-Retardant Chemicals found to have Mo levels distributed uniformly in the critical organs within 4 hr, while higher levels of Mo were found in the blood and bile. Two rabbits, administered 100 mg of molybdenum trioxide each via a stomach tube, also demonstrated similar rapid absorption of Mo, with rapidly rising blood levels. Mo was found to be rapidly eliminated from the kidneys, with urinary levels returning to baseline values within 72 hr. Fecal elimination, which comprised about 50% of the urinary levels, also occurred within 72 hr. The authors noted that significant quantities of Mo were stored in the bone. Arrington and Davis (1955) studied the toxicokinetics of Mo99 (in the form of molybdenum trioxide) in Long-Evans rats (18/dose) that were consuming both normal and high-calcium diets. Rats were dosed once orally with 15 µC Mo99 at least 5 wk after initiation of the high-calcium diets. No significant differences in the absorption, retention, or excretion of Mo99 were observed between the groups of rats consuming the normal versus high-calcium diets. Mo99 was eliminated primarily by the kidney and excreted rapidly. Within 6 hr of oral administration of Mo99, about 25% of the dose was excreted in the urine. At 12 hr, 50% of the dose was present in the urine. Mo99 was distributed primarily in the kidneys and blood, with smaller amounts in the bone, liver, and muscle. Mo tissue levels were determined in guinea pigs following 25 d of inhalation exposure to calcium molybdate (121.5 mg/m3) or molybdenum trioxide (157 mg/m3) (Fairhall et al. 1945). The highest concentrations of Mo were found in lung, kidneys, spleen, and bone. Analysis 2 wk after termination of exposure to calcium molybdate showed approximately 50–75% of the Mo remained in the tissues. In contrast, 2 wk following exposure to molybdenum trioxide, 25–50% of Mo remained in the tissues. Zinc Absorption Agren (1991) (as cited in ATSDR 1994) reported that zinc was present in human interstitial fluid (site of application) following dermal application of zinc oxide (dissolved in gum resin or hydrocolloids) to human forearms. No evidence for absorption into systemic circulation was provided. Agren (1990) (as cited in ATSDR 1994) and Hallmans (1977) (as cited in ATSDR 1994) determined that zinc readily permeates intact and damaged human skin following dermal application. However, penetration of zinc into systemic circulation was not determined.

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Toxicological Risks of Selected Flame-Retardant Chemicals Keen and Hurley (1977) (as cited in ATSDR 1994) determined that when zinc (as zinc chromate) was dissolved in oil and topically applied to rats, absorption of zinc in the bloodstream occurred. No other animal studies were identified regarding dermal absorption of zinc. Data suggest that zinc is absorbed into systemic circulation via the lungs following inhalation exposures. Hamdi (1969) (as cited in ATSDR 1994) found that zinc blood levels were elevated in workers occupationally exposed to zinc fumes. Drinker and Drinker (1928) (as cited in ATSDR 1994) determined that inhalation exposure of cats to zinc oxide fumes for up to 3.25 hr resulted in increased levels of zinc in the pancreas, kidney, and liver. In both studies, oral absorption of zinc particles following ciliary clearance and swallowing could account for all, or a significant portion, of the absorbed zinc. In the Drinker and Drinker (1928) study (as cited in ATSDR 1994), the swallowing of zinc particles during grooming activities may have also accounted for the increased tissue zinc levels. The estimated rate of oral absorption of zinc in humans is between 8% and 81%, depending on an individual’s diet (ATSDR 1994). People who are not zinc-deficient will absorb about 20–30%, while individuals who are zinc-deficient absorb more (ATSDR 1994). Two studies measured the peak blood concentrations of zinc in volunteers following oral ingestion of zinc sulfate and determined that peak blood Zn2+ concentrations were reached within 3 hr (Neve et al. 1991, as cited in ATSDR 1994; Sturniolo et al. 1991, as cited in ATSDR 1994). The presence of cadmium, mercury, copper, or other trace metals can diminish zinc absorption by inhibiting zinc transport across the intestinal wall (ATSDR 1994). Zinc absorption in male Wistar rats was approximately 40–48% when diets contained 0.81 mg of radio-labeled zinc/kg as zinc chloride or zinc carbonate (Galvez-Morros et al. 1992). ATSDR (1994) noted that fractional absorption of zinc in immature organisms usually exceeds the fractional absorption of zinc in adults. Distribution No relevant human or animal studies were located that investigated the distribution of zinc following dermal exposure to zinc compounds. No inhalation studies were identified that investigated the distribution of zinc in humans. Cats exposed to zinc oxide (12–61 mg Zn2+/kg-d) for 3 hr, had increased zinc levels in the pancreas, liver, and kidneys, suggesting that absorption of zinc had taken place in the lungs (Drinker and Drinker 1928, as cited in

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Toxicological Risks of Selected Flame-Retardant Chemicals ATSDR 1994). Oral absorption through swallowing or grooming, however, cannot be ruled out. Absorption rates were not estimated in this study. The distribution of zinc to tissues has not been measured in humans following ingestion. However, there are a number of studies in rodents that have investigated the distribution of zinc following oral exposure to zinc compounds. Weigand and Kirchgessner (1992) (as cited in ATSDR 1994) determined that rats fed 1.1 mg Zn2+/kg-d for an unspecified amount of time, had greater amounts of zinc distributed primarily to the kidneys and pancreas than to the liver. Administration of zinc acetate to rats (191 mg Zn2+/kg-d in food for 3 mo) increased zinc levels in the heart, spleen, kidneys, liver, bone, and blood (Llobet et al. 1988). Mice fed either 76.9 mg Zn2+/kg-d as zinc sulfate (Schiffer et al. 1991, as cited in ATSDR 1994) or 38 mg Zn2+/kg-d as zinc nitrate (Cooke et al. 1990, as cited in ATSDR 1994) for 1 mo had increased levels of Zn2+ in the kidneys and liver. Newborn, young, or adult mice that received a single oral dose of 4.6 mg Zn2+/kg as zinc chloride generally had the highest level of zinc in the liver, kidneys, lungs, bone, and muscle 1 d after dosing (He et al. 1991, as cited in ATSDR 1994). Metabolism Although zinc is not metabolized in the body, it can bind to many molecules in the body. For instance, zinc induces and binds to metallothionein (a metal binding protein) in vivo. Metallothionein therefore acts as a protective mechanism against zinc toxicity (Goyer 1996). Indirect evidence suggests that zinc also complexes with reduced glutathione in the liver in rats following intraperitoneal injection (Alexander et al. 1981, as cited in ATSDR 1994). Excretion No studies were located that investigated the excretion of zinc in humans or animals following dermal application of zinc compounds. Following inhalation exposures, elevated levels of zinc were found in the urine of workers exposed to zinc oxide fumes containing unknown levels of Zn2+(Hamdi 1969, as cited in ATSDR 1994). No other studies were identified that investigated the excretion of zinc following inhalation of zinc compounds. Following oral exposure, the primary route of zinc excretion in humans and rats is the feces. Zinc can also be excreted in the urine, saliva, hair, and sweat (ATSDR 1994). Malnutrition or low dietary levels of zinc may promote in-

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Toxicological Risks of Selected Flame-Retardant Chemicals creased levels of urinary zinc excretion and are thought to result from increased levels of tissue breakdown and catabolism (ATSDR 1994). HAZARD IDENTIFICATION1 Dermal Exposure Irritation Molybdenum Compounds No human data on the effects of dermal exposure to Mo compounds were identified. No irritation effects were seen when Mo compounds were applied to intact or abraded skin of rabbits (Stokinger 1981). Zinc There are two case studies in the scientific literature that suggest that occupational dermal exposure to zinc at high levels may cause or contribute to a skin condition referred to as “zinc oxide pox” which is described as itchy papular-pustular eruptions that occur in the pubic region, inner surface of the thigh, axilla, and inner surface of the arms. Turner (1921) (as cited in ATSDR 1994) found that 14 out of 17 men developed zinc oxide pox at least once during their employment in the bagging or packaging of zinc oxide. The incidence of zinc oxide pox in the study by Turner (1921) (as cited in ATSDR 1994) has been attributed to poor hygiene among the workers, and not necessarily zinc oxide exposure. In a similar study, Batchelor et al. (1926) (as cited in ATSDR 1994) found that only 1 of a total of 24 workers occupationally exposed to zinc dusts developed zinc oxide pox. Agren (1990) (as cited in ATSDR 1994) reported that application of patches containing 25% zinc oxide (dose=2.9 mg Zn2+/m3) to the skin of human volunteers did not produce dermal irritation following 48 hr of exposure. The dermal irritancy of several zinc compounds in aqueous solution or suspension has been investigated in mice, rabbits, and guinea pigs (Lansdown 1991, as cited in ATSDR 1994). In this study, animals were treated topically 1   In this section, the subcommittee reviewed toxicity data on calcium and zinc molybdates, including the toxicity assessment prepared by the U.S. Consumer Product Safety Commission (Hatlelid 1999).

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Toxicological Risks of Selected Flame-Retardant Chemicals once a day for 5 consecutive days with one of the following zinc compounds (w/v): zinc oxide (20% suspension in Tween 80), zinc chloride (1% aqueous solution), zinc sulfate (1 % aqueous solution), zinc pyrithione (20% suspension), and zinc undecylenate (20% suspension). In open patch tests, zinc chloride was a potent irritant in all three species and caused the formation of epidermal hyperplasia and ulceration. All other compounds produced less severe erythema than zinc chloride, and none of the compounds caused ulceration or scaling over the 5-d test period. These compounds were also tested in a second group of rabbits using occlusive bandages at the test site. Occlusive patch testing with zinc chloride produced severe dermal irritation in rabbits within 3–5 d of application. Occlusive patch testing of zinc acetate produced moderate irritation. Occlusive patch testing with zinc oxide, sulfate, pyrithione, or undecylenate produced little dermal irritation. Histological examination of skin samples from animals treated with zinc chloride or zinc acetate showed evidence of acanthosis, parakeratosis, hyperkeratosis, and inflammatory changes in the epidermis and in the more superficial aspects of the dermis. Systemic Effects Molybdenum Compounds No data were identified on systemic effects of Mo compounds following dermal exposure. Zinc DuBray (1937) (as cited in ATSDR 1994) reported that a worker developed microcytic anemia and had low platelet counts after being exposed to zinc chloride solutions. The concentration of zinc was not reported. No systemic effects following dermal exposures of animals to zinc were identified. Inhalation Exposure Systemic Effects Molybdenum Compounds Twenty-five workers in a Mo roasting plant (where Mo sulfide is converted to molybdenum oxides) in Colorado were estimated to be exposed to soluble

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Toxicological Risks of Selected Flame-Retardant Chemicals Mo compounds (primarily molybdenum trioxide) at a concentration of 9.5 mg/m3 for an 8-hr time-weighted average exposure. Exposure concentrations were estimated from respirable dust samples taken at the plant. Workers showed large increases in serum ceruloplasmin (50.5 mg/dL versus 30.5 mg/dL in controls) (Walravens et al. 1979). Controls consisted of 24 students and research personnel at the University of Colorado Medical Center. Workers were employed at the plant from 0.5 to 20 yr, with the average employment being 4 yr. Plasma and urine Mo levels were elevated in the workers compared with controls (0.9–36.5 µg/dL vs. 0–3.4 µg/dL in plasma and 120–11,000 µg/L vs. 4–347 µg/L in urine). No other adverse health effects were reported. The authors hypothesized that elevated serum ceruloplasmin levels stemmed from mobilization of tissue copper reserves within the hepatocyte, with subsequent ceruloplasmin synthesis and release to prevent intracellular copper toxicity. A study conducted on 73 workers from a Russian copper-molybdenum processing plant found increased levels of uric acid in the blood (Akopyan 1964). Additional details on the exposure levels of these workers were not provided. Review articles (Stokinger 1981; ACGIH 1991) reported elevated serum uric acid levels and signs of gout, including pain and deformities of joints in workers and inhabitants in Mo-rich areas in Armenia. Lener and Bibr (1984), in a review article, reported an increased incidence of nonspecific symptoms, including weakness, fatigue, headache, anorexia, and joint and muscle pains among mining and metallurgy workers exposed to 60–600 mg/m3 Mo. No other reports of effects from industrial Mo exposure were cited. Mogilevskaya (1967) reported that 3 of 19 workers exposed to Mo compounds (Mo and molybdenum trioxide) at two industrial facilities showed early signs of pneumoconiosis on X-ray examination. These three individuals had worked at the facilities for 4–7 yr and their exposures, although variable, were reported to range from 1–19 mg/m3. Fairhall et al. (1945) observed that 5/24 guinea pigs died following exposure via inhalation to 195 mg/m3 CaMoO4 (125 mg Mo/m3) dust for 1 hr/d, 5 d/wk for 5 wk, but no other signs of toxicity were observed. Guinea pigs (51 animals, sex not reported), who were exposed to 250 mg MoO3/m3 (164 mg Mo/m3) using the same exposure regime, experienced severe eye and nasal irritation, loss of appetite and weight, diarrhea, muscular incoordination, and loss of hair. Following the 10th exposure, 26/51 animals died. Two 13-wk studies were conducted by NTP (1997) in which F-344/N rats and B6C3F1 mice (10/sex/group) were exposed to molybdenum trioxide for 6.5 hr/d, 5 d/wk at concentrations of 0, 1, 3, 10, 30, or 100 mg/m3. All rats and mice survived to the end of the study. Significant increases in liver copper concentrations were observed in female mice exposed to 30 mg/m3 and in male and female mice exposed to 100 mg/m3 (males: 11.51 µg/g in the 100-mg/m3 exposure group versus 8.19 µg/g in controls; females: 6.51 and 6.98 µ/g in the 30-

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Toxicological Risks of Selected Flame-Retardant Chemicals and 100-mg/m3 dose groups, respectively, versus 5.68 µ/g in controls). The increased copper concentrations were not regarded as being an adverse effect relevant for deriving a LOAEL and a NOAEL. No other clinical findings were observed in either rats or mice. Additionally, no significant differences in absolute or relative organ weights, sperm counts, or motility were noted in rats or mice. In the same NTP study (1997), rats (F344/N) and mice (B6C3F1) (50/sex/ dose) exposed for 6 hr/d, 5 d/wk at concentrations of 0, 10, 30, or 100 mg/m3 molybdenum trioxide for 2 yr experienced a significant exposure-dependent increase in blood Mo concentrations. Male and female rats exposed to 30 or 100 mg/m3 experienced significantly increased incidences of chronic alveolar inflammation. Incidences of hyaline degeneration in the nasal respiratory epithelium in male rats exposed to 30 or 100 mg/m3 and in all exposed groups of females rats were significantly greater than those of the control groups. Incidences of hyaline degeneration in the nasal olfactory epithelium of all exposed groups of females were also statistically significant. For male mice, the incidences of histiocyte cellular infiltration in all exposed groups were significant. Incidences of hyaline degeneration of the respiratory epithelium of the nasal cavity in female mice at 100 mg/m3 were significantly greater than those in the controls (NTP 1997). Based on the 2-yr NTP study, the LOAEL is 10 mg/m3 for increased incidences of hyaline degeneration in the nasal respiratory epithelium and nasal olfactory epithelium in female rats. Zinc There are a number of case reports of deaths in humans following high inhalation exposures to airborne mixtures containing zinc. Ten of 70 persons died within four d following intense exposure to a smoke mixture containing approximately 33,000 mg Zn2+/kg as zinc chloride along with other compounds (Evans 1945, as cited in ATSDR 1994). These mixtures were thought to include unknown concentrations of hexachloroethane, calcium silicate, and an igniter. Milliken et al. (1963) (as cited in ATSDR 1994) describes the case of a fireman who died following exposure to a high but unknown concentration of a smoke mixture generated from a zinc chloride smoke bomb. Two soldiers developed severe respiratory distress syndrome and died 25–32 d following exposure to a high concentration of zinc chloride smoke mixture generated from a zinc chloride smoke bomb (Hjortso et al. 1988). No exposure levels were reported in this study. Autopsies performed on the soldiers revealed diffuse microvascular obliteration, widespread occlusion of the pulmonary arteries, and extensive interstitial and intra-alveolar fibrosis of the lungs. Nausea has been reported

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Toxicological Risks of Selected Flame-Retardant Chemicals among persons following intense inhalation exposures to zinc chloride and zinc oxide (Hammond 1944, as cited in ATSDR 1994; Evans 1945, as cited in ATSDR 1994; Rohrs 1957, as cited in ATSDR 1994; Johnson and Stonehill 1961, as cited in ATSDR 1994; Schenker et al. 1981, as cited in ATSDR 1994). Routine blood chemistries and examinations revealed no liver disease among 12 workers involved in the manufacture of brass alloys, with 4–21 yr of exposure to zinc oxide (Hamdi 1969, as cited in ATSDR 1994). McCord et al. (1926) (as cited in ATSDR 1994) reported that several workers from the galvanized industry had decreased red blood cell counts. Workers investigated by Hamdi (1969) (as cited in ATSDR 1994) had normal red blood cell counts. Various adverse pulmonary effects and reduced survival rates were reported in female rodents following exposure to zinc oxide/hexachloroethane smoke (119 mg Zn2+/m3 for 1 hr/d, 5 d/wk for up to 20 wk) (Marrs et al. 1988). The authors noted that the zinc oxide/hexachloroethane smoke contained a number of toxic chemicals including carbon tetrachloride. Therefore, it is not certain whether the toxic effects observed in this study can be solely attributed to the inhalation of zinc particles. Immunological Effects Molybdenum Compounds No data were identified on the immunological effects of Mo compounds following inhalation exposure. Zinc There are three case reports in the literature that found that the inhalation of high concentrations of zinc-containing compounds appeared to stimulate changes in the immune system. Farrell (1987) reported a case study of a worker who developed hives and angioedema (suggestive of an immediate or delayed IgE response) following exposure to a low dose of zinc fumes. The signs and symptoms of toxicity were repeated in a challenge test, suggesting that the patient had developed sensitization to zinc compounds. A correlation between exposure to zinc oxide and the proportion of activated T-cells, T-helper cells, T-inducer cells, T-suppressor cells, and activated killer T-cells, was observed among 14 welders approximately 20 hr following exposure to zinc oxide (Blanc et al. 1991, as cited in ATSDR 1994). Zinc oxide exposure levels were estimated to be approximately 77–153 mg Zn2+/m3. Ameille et al. (1992) (as cited

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Toxicological Risks of Selected Flame-Retardant Chemicals Cancer Dermal No studies were identified regarding the carcinogenicity of calcium or zinc molybdates or other Mo compounds following dermal exposure in humans or in experimental animals. Therefore, the subcommittee concluded that the carcinogenicity of calcium and zinc molybdates cannot be determined based on available data. Inhalation Inhaled molybdenum trioxide was carcinogenic in male and female mice based on a single NTP study (NTP 1997). There was equivocal evidence for its carcinogenicity for male rats. Available data suggests that these compounds are not carcinogenic. Based on the data currently available, the subcommittee concluded that the weight of evidence suggests that calcium and zinc molybdates may be carcinogenic to humans. Therefore, the subcommittee derived a cancer slope factor for characterizing the carcinogenic risk from exposure to these chemicals. The cancer slope factor was derived using the multistage model (EPA 1996). Modeling was conducted using the adenoma/carcinoma incidence data (combined) in female mice (3/50, 6/50, 8/49, and 15/49 for the 0-, 10-, 30- and 100-mg/m3 exposure groups, respectively) (NTP 1997) (see Table 9–6). The female mice data were used instead of the male mice data because female mice were more sensitive. Exposure concentrations were normalized for continuous exposure and were converted to human equivalent concentrations (HEC) using the regional deposited dose ratios (RDDR) based on the aerodynamic particle size generated in the NTP (1997) study. Based on linear extrapolation, the unit risk of lung cancer is less than 2.6×10−5/µg/m3. Oral No studies were identified regarding the carcinogenicity of calcium or zinc molybdates or other Mo compounds following oral exposure in humans or experimental animals. Therefore, the subcommittee concluded that there are insufficient data to determine its carcinogencity.

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Toxicological Risks of Selected Flame-Retardant Chemicals TABLE 9–6 Calculation of LED10 and 0.1/LED10 for Molybdenum Trioxide Using Incidence of Lung Carcinoma and Adenoma in Female Mice (NTP 1997) Assay concentration (mg/m3)a Assay concentration (mg/m3), duration adjustedb HEC (mg/m3)c Tumor response (lung adenomas and carcinomas) LED10 (mg/m3)d 0.1/LED10 (per mg/m3) 0 0 0 3 3.8 0.026 10 1.75 1.8 6     30 5.25 5.4 8     100 17.5 17.7 15     HEC, human equivalent concentrations; LED10, the lower 95% confidence bound on the effective dose that causes a 10% tumor response in animals; MoO3, molybdenum trioxide. aFemale mice were exposed to air concentrations of particulate MoO3 for 6 hr/d, 5 d/wk for 103 wk. bMoO3 concentrations were normalized for continuous chronic exposure by multiplying by 6/24 hr and 5/7 d (EPA 1994). cNormalized assay concentrations were converted to HEC using the regional deposited dose ratios for the mouse pulmonary region as recommended by EPA (1994). Particulate mass median aerodynamic diameter (MMAD) and geometric standard deviations listed for each concentration by NTP (1997) were used (µm): 10 mg/m3: MMAD=1.3, σg=1.8; 30 mg/m3: MMAD=1.4, σg=1.8; 100 mg/m3: MMAD=1.5, σg=1.8. dLED10 calculated using the multistage model. EXPOSURE ASSESSMENT AND RISK CHARACTERIZATION Noncancer Dermal Exposure The assessment of noncancer risk for the dermal exposure route is based on 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 calcium or zinc molybdates and also assumes 1/4th of the upper torso is in contact with the upholstery and clothing presents no barrier. Calcium and zinc molybdates are considered to be ionic, and are essentially not absorbed through the skin. However, to be conservative, the subcommittee assumed that ionized calcium and zinc molybdates permeate the skin at the

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Toxicological Risks of Selected Flame-Retardant Chemicals 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 calcium and zinc molybdates (2 mg/cm3), and Equation 1 in Chapter 3, the subcommittee calculated a dermal exposure level of 6.3×10−3 mg/kg-d. The oral RfD for calcium and zinc molybdates (6.0×10−4; 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 10. Therefore it was concluded that calcium and zinc molybdates used as flame retardants in upholstery fabric may pose a non-cancer risk by the dermal route at the specified concentration and under the given worst-case exposure scenario. Inhalation Exposure Particles Inhalation exposure estimates for calcium and zinc molybdates were calculated using the exposure scenario described in Chapter 3. This scenario assumes that a person spends a quarter of his or her life in a room with low air-change rates (0.25/hr) and with a relatively large amount of fabric upholstery treated with calcium or zinc molybdate (30 m2 in a 30 m3 room), with this calcium or zinc molybdate treatment gradually being worn away over 25% of its surface to 50% of its initial quantity over the 15-yr lifetime of the fabric. A small fraction, 1%, of the worn-off calcium or zinc molybdate, is released into the indoor air as inhalable particles, and may be breathed by the occupant. Particle exposure was estimated using Equations 4 through 6 in Chapter 3. The release rate (µr) for calcium and zinc molybdates for upholstery, 2.3× 10−7/d (Equation 5), was used in conjunction with the upholstery application rate (Sa) for calcium and zinc molybdates of 2 mg/cm2 to calculate a room airborne particulate concentration of 0.76 µg/m3 (Equation 4). Factoring in the fraction of a day a person spends in the room containing upholstery (0.25), the time-average exposure concentration was determined to be 0.19 µg/m3 (Equation 6). The inhalation RfC for calcium or zinc molybdate is 2×10−3 mg/m3 (see Inhalation RfC section). A hazard index was calculated as the ratio of the time-averaged exposure concentration to this estimated RfC, yielding a value of 0.095. This indicates that calcium or zinc molybdates, used as upholstery flame retardants, are not likely to pose any noncancer risk via inhalation in the particulate phase.

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Toxicological Risks of Selected Flame-Retardant Chemicals Vapors Calcium and zinc molybdates have negligible vapor pressures at ambient temperatures. Therefore calcium or zinc molybdates used as upholstery-fabric flame retardants are not likely to pose any noncancer risks, when exposure occurs in the vapor phase. Oral Exposure The assessment of the noncancer risk for the oral exposure route is based on the scenario described in Chapter 3. This scenario assumes a child is exposed to calcium and zinc molybdates through sucking on 50 cm2 of fabric daily for two yr, 1 hr/d. The dose rate to the child was calculated using Equation 15 in Chapter 3. Parameters specific to calcium and zinc molybdates that were used in this calculation included an upholstery application rate (Sa) of 2 mg/cm2 and an extraction rate (µa) by saliva of 0.0004/d. This extraction rate was based on data from US Borax on zinc and boron extraction from polymer films (PVC and paint film) (Borax 1996). Using these values, the average oral dose rate was estimated to be 1.7×10−4 mg/kg-d. The oral dose rate (1.7×10−4 mg/kg-d) was divided by the oral RfD of 0.0006 mg/kg-d, giving a hazard index of 0.28. The subcommittee concluded that calcium or zinc molybdate used as an upholstery fabric flame retardant is not likely to pose any noncancer risk by the oral route. Cancer Dermal Exposure Based on inadequate data on the carcinogencity of calcium and zinc molybdates via the dermal route, the subcommittee concludes that there are insufficient data to assess its carcinogencity. Inhalation Exposure Particles The average room-air concentration and average exposure concentration to calcium or zinc molybdate were obtained as described in the Noncancer sec-

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Toxicological Risks of Selected Flame-Retardant Chemicals tion. Using the inhalation unit risk of 2.6×10−5/µg/m3, the lifetime risk estimate from exposure to calcium or zinc molybdate in the particulate phase is 5.0 ×10−6 (see Table 9–6). Vapors Calcium and zinc molybdates have negligible vapor pressures at ambient temperatures. Therefore, calcium or zinc molybdate used as an upholstery-fabric flame retardant is not likely to pose any cancer risk via inhalation in the vapor phase. Oral Exposure Based on inadequate data on the carcinogencity of calcium and zinc molybdates via the oral route, the subcommittee concludes that there are insufficient data to assess its carcinogencity. RECOMMENDATIONS FROM OTHER ORGANIZATIONS The OSHA permissible exposure limit (PEL) recommended for this compound is 5 mg/m3 for soluble compounds. The TLV-TWA (Threshold Limit Value-time weighted average) established by the American Conference of Governmental Industrial Hygienists (ACGIH) is also 5 mg/m3 (ACGIH 1991) for soluble Mo compounds. Additionally, several other countries have adopted a permissible exposure level of 5 mg/m3 for soluble Mo including Australia, Federal Republic of Germany, Sweden, and the United Kingdom. The EPA, as detailed in IRIS, has established an oral RfD of 5×10−3 mg/kg-d for Mo and an oral RfD for zinc of 3×10−1 mg/kg-d. The National Research Council has established RDAs for Mo of 75–250 µg/d (1.07–3.57 µg/kg-d for a 70-kg person) and for zinc of 12–15 mg/d (0.17–0.21 mg/kg-d of zinc for a 70-kg person), respectively. DATA GAPS AND RESEARCH NEEDS There is a substantial amount of data available on zinc, calcium, and molybdates. For instance, the oral RfD, inhalation RfC, and cancer potency factor determined by the subcommittee for calcium and zinc molybdates are based on molybdenum. Because of the calculated inhalation lifetime cancer risk for

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Toxicological Risks of Selected Flame-Retardant Chemicals calcium and zinc molybdates, the subcommittee believes that the potential of these chemicals to be released as particles from fabric needs to be investigated. Because of a dermal hazard index greater than 1, the dermal absorption of calcium and zinc molybdates from treated fabric should be investigated. REFERENCES ACGIH (American Conference of Government Industrial Hygienists). 1991. Molybdenum and Compounds. Pp. 1051–1054 in Documentation of the Threshold Limit Values and Biological Exposure Indices, 6th Ed. Cincinnati, OH: American Conference of Government Industrial Hygienists, Inc. Agren, M.S. 1990. Percutaneous absorption of zinc from zinc oxide applied topically to intact skin in man. Dermatologica 180(1):36–39. Agren, M.S., M.Kusell, and L.Frazen. 1991. Release and absorption of zinc from zinc oxide and zinc sulfate in open wounds. Acta Derm. Venereol. 71:330–333. Akopyan, O.A. 1964. Some biochemical shift in workers having contact with molybdenum-containing dust. [Abstract]. Pp. 65–67 in Materials from the 2nd Summary Scientific Conference on Labor Hygiene and Work-Related Pathology of the Institute of Labor Hygiene and Work-Related Illnesses. Alexander, J., J.Aaseth, and T.Refsvik. 1981. Excretion of zinc in rat bile—a role of glutathione. Acta Pharmacol. Toxicol. (Copenh.) 49(3): 190–194. Amacher, D.E., and S.C.Paillet. 1980. Induction of trifluorothymidine-resistant mutants by metal ions in L5178Y/TK+/− cells. Mutat. Res. 78(3):279–288. Ameille, J., J.M.Brechot, P.Brochard, F.Capron, and M.F.Dore. 1992. Occupational hypersensitivity pneumonitis in a smelter exposed to zinc fumes. Chest 101(3):862–863. Arrington, L.R., and G.K.Davis. 1955. Metabolism of phosphorus32 and molybdenum99 in rats receiving high calcium diets. J. Nutr. 55(2):185–192. ATSDR (Agency for Toxic Substances and Disease Registry). 1994. Toxicological Profile for Zinc (Update). U.S. Department of Health and Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry, Atlanta, GA. TP-93/15. 230pp. Batchelor, R.P., J.W.Fehnel, R.M.Thompson, et al. 1926. A clinical and laboratory investigation of the effect of metallic zinc, of zinc oxide, and of zinc sulphide upon the health of workmen. J. Ind. Hyg. 8:322–363. Bauchinger, M., E.Schmid, H.J.Einbrodt, and J.Dresp. 1976. Chromosome aberrations in lymphocytes after occupational exposure to lead and cadmium. Mutat. Res. 40(1):57–62. Blanc, P., H.Wong, M.S.Bernstein, and H.A.Boushey. 1991. An experimental human model of metal fume fever. Ann. Intern. Med. 114(11):930–936. Bleavins, M.R., R.J.Aulerich, J.R.Hochstein, T.C.Hornshaw, and A.C.Napolitano. 1983. Effects of excessive dietary zinc on the intrauterine and postnatal development of mink. J. Nutr. 113(11):2360–2367.

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Toxicological Risks of Selected Flame-Retardant Chemicals Ketcheson, M.R., G.P.Barren, and D.H.Cox. 1969. Relationship of maternal dietary zinc during gestation and lactation to development and zinc, iron and copper content of the postnatal rat. J. Nutr. 98(3):303–311. Kovalsky, V.V., G.A.Yarovaya, and D.M.Shmavonyan. 1961. Changes of purine metabolism in humans and animals in molybdenum-rich biogeochemical provinces. [Article in Russian]. Zh. Obshch. Biol. 22(3):179–191. Kowlaska-Wochna, E.J.Moniuszko-Jakoniuk, E.Kulikowska, et al. 1988. The effect of orally applied aqueous solutions of lead and zinc on chromosome aberrations and induction of sister chromatid exchanges in the rat (Rattus sp.) Genetica Polonica 29(2):181–189. Kozik, M.B., L.Maziarz, and A.Godlewski. 1980. Morphological and histochemical changes occurring in the brain of rats fed large doses of zinc oxide. Folia Histochem. Cytochem. 18:201–206. Kozik, M.B., G.Gramza, and M.Pietrzak. 1981. Neurosecretion of the hypothalamohypophyseal system after intragasrric adminstration of zinc oxide. Folia Histochem. Cytochem. 10:115–122. Kynast, G., and E.Saling. 1986. Effect of oral zinc application during pregnancy. Gynecol. Obstet. Invest. 21(3):117–123. Lansdown, A.B. 1991. Interspecies variations in response to topical application of selected zinc compounds. Food Chem. Toxicol. 29(1):57–64. Lener, J., and B.Bibr. 1984. Effects of molybdenum on the organism (A review). J. Hyg. Epidemiol. Microbiol. Immunol. 29(4):405–419. Llobet, J.M., J.L.Domingo, M.T.Colomina, E.Mayayo, and J.Corbella. 1988. Subchronic oral toxicity of zinc in rats. Bull. Environ. Contam. Toxicol. 41:36–43. Logue, J.N., M.D.Koontz, and M.A.W.Hattwick. 1982. A historical prospective mortality study of workers in copper and zinc refineries. J. Occup. Med. 24(5):398–408. Mahomed K., D.K.James, J.Golding, and R.McCabe. 1989. Zinc supplementation during pregnancy: A double blind randomised controlled trial. BMJ 299(6703): 826–833. Maita, K., M.Hirano, K.Mitsumori, K.Takahashi, and Y.Shirasu. 1981. Subacute toxicity studies with zinc sulfate in mice and rats. J. Pesticide Sci. 6:327–336. Marrs, T.C., H.F.Colgrave, J.A.Edington, R.F.Brown, and N.L.Cross. 1988. The repeated dose toxicity of a zinc oxide/hexachloroethane smoke. Arch. Toxicol. 62(2–3):123–132. Marzin, D.R., and H.V.Phi. 1985. Study of the mutagenicity of metal derivatives with Salmonella typhimurium TA102. Mutat. Res. 155(1–2):49–51. McCord, C.P., A.Friedlander, W.E.Brown, et al. 1926. An occupational disease among zinc workers. Arch. Intern. Med. 37:641–659. Milliken, J.A., D.Waugh, and M.E.Kadish. 1963. Acute interstitial pulmonary fibrosis caused by a smoke bomb. Can. Med. Assoc. J. 88:36–39. Mogilevskaya, O.Y. 1967. Experimental studies on the effect on the organism of rare, dispersed and other metals and their compounds used in industry: Molybdenum. Pp. 12–28 in Toxicology of the Rare Metals. [Translated from Russian] Z.I.Izrael’son, ed. Israel Program for Scientific Translations, Jerusalem. Moore. R. 1978. Bleeding gastric erosion after oral zinc sulfate. BMJ 1(6115):754.

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Toxicological Risks of Selected Flame-Retardant Chemicals Murphy. J.V. 1970. Intoxication following ingestion of elemental zinc. JAMA 212(12):2119–2120. Neuberger, J.S., and J.G.Hollowell. 1982. Lung cancer excess in an abandoned lead-zinc mining and smelting area. Sci. Total Environ. 25(3):287–294. Neve, J., M.Hanocq, A.Peretz, F.Abi Khalil, F.Pelen, J.P.Famaey, and J.Fontaine. 1991. Pharmacokinetic study of orally administered zinc in humans: Evidence for an enteral recirculation. Eur. J. Drug Metab. Pharmacokinet. 16(4):315–323. Nishioka, H. 1975. Mutagenic activities of metal compounds in bacteria. Mutat. Res. 31(3):185–189. NRC (National Research Council). 1989. Recommended Dietary Allowances, 10th Ed., Washington, DC: National Academy Press. NTP (National Toxicology Program). 1997. Toxicology and Carcinogenesis Studies of Molybdenum Trioxide (CAS No. 1313–27–5) in F344/N Rats and B6C3F1 Mice. (Inhalation Studies). National Toxicology Program, Research Triangle Park, NC. Philipp, R., A.O.Hughes, and M.C.Robertson. 1982. Stomach cancer and soil metal content. Br. J. Cancer 45(3):482. Powmet (Powmet, Inc.). 1999. Material Safety Data Sheet, Calcium Molybdate. Powmet, Inc., Rockford, IL. Prasad, A.S. 1976. Deficiency of zinc in man and its toxicity. In Trace Elements in Health and Disease. Vol. 1, Zinc and Copper, A.S.Prasad, ed. New York: Academic Press. Prasad, A.S., G.J.Brewer, E.B.Schoomaker, and P.Rabbani. 1978. Hypocupremia induced by zinc therapy in adults. JAMA 240(20):2166–2168. Rohrs, L.C. 1957. Metal-fume fever from inhaling zinc oxide. Arch. Ind. Health 16:42–7. Rosoff, B., and H.Spencer. 1964. Fate of molybdenum-99 in man. Nature 202(4930):410–411. Samman, S., and D.C.Roberts. 1987. The effect of zinc supplements on plasma zinc and copper levels and the reported symptoms in health volunteers. Med. J. Aust. 146(5):246–249. Schenker, M.B., F.E.Speizer, and J.O.Taylor. 1981. Acute upper respiratory symptoms resulting from exposure to zinc chloride aerosol. Environ. Res. 25(2):317–324. Schiffer, R.B., F.W.Sunderman, Jr., R.B.Braggs, J.A.Moynihan. 1991. The effects of exposure to dietary nickel and zinc upon humoral and cellular immunity in SJL mice. J. Neuroimmunol. 34(2–3):229–239. Schlicker, S.A., and D.H.Cox. 1968. Maternal dietary zinc, and development and zinc, iron, and copper content of the rat fetus. J. Nutr. 95(2):287–94. Simmer, K., L.Lort-Phillips, C.James, and R.P.Thompson. 1991. A double-blind trial of zinc supplementation in pregnancy. Eur. J. Clin. Nutr. 45(3): 139–144. Stocks, P., and R.I.Davies. 1964. Zinc and copper content of soils associated with the incidence of cancer of the stomach and other organs. Br. J. Cancer 18:14–24. Stokinger, H.E. 1981. The metals. Pp. 1806–1820 in Patty’s Industrial Hygiene and Toxicology. G.D.Clayton, and F.E.Clayton, eds. New York: John Wiley and Sons. Straube E.F., N.H.Schuster, and A.J.Sinclair. 1980. Zinc toxicity in the ferret. J. Comp. Pathol. 90(3):355–361.

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