Toxicological Risks of Selected Flame-Retardant Chemicals (2000)

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ZINC BORATE 149 8 Zinc Borate THERE is limited information in the literature on the toxicity of zinc borate. Zinc borate readily breaks down in the stomach to zinc oxide (ZnO) and boric acid (H3BO3). Therefore, this chapter reviews the physical and chemical properties, toxicokinetics, toxicological, epidemiological, and exposure data on both those compounds. When data on zinc oxide are lacking, data on other zinc compounds are reviewed. According to the International Programme on Chemical Safety (IPCS), at low concentrations and under the same conditions, an equivalent amount of boron as boric acid or borax has similar chemical and toxicological properties (IPCS 1998). Therefore, data from boric acid and borax are considered in this chapter. Regardless of the zinc or boron compound of exposure, body burdens are measured as the concentration of the element (zinc or boron), and are discussed as such in this review. Doses are given in boron and zinc equivalents for comparison between different zinc and boron compounds. The subcommittee used the toxicity, toxicokinetic, and exposure data on those compounds to characterize the health risk from exposure to zinc borate. The subcommittee also identified data gaps and recommended research relevant for determining the health risk from exposure to zinc borate. PHYSICAL AND CHEMICAL PROPERTIES The physical and chemical properties of zinc borate, zinc oxide, and boric acid are summarized in Table 8–1. 

ZINC BORATE 150 TABLE 8–1 Physical and Chemical Properties of Zinc Borate, Zinc Oxide, and Boric Acid Value Property Zinc Borate Zinc Oxide Boric Acid Reference Chemical formula 3ZnO:2B2O3 ZnO H3BO3 Lide 1991–1992 CAS registry # 138265–88–0 1314–13–2 10043–35–3 Lide 1991–1992 Synonyms — Zinc white, pigment Orthoboric acid, Budavari et al. 1989 white boracic acid, borofax Molecular weight 383.4 81.4 61.3 Lide 1991–1992 Physical state Crystal or white Crystal or white Transparent crystals or Budavari et al. 1989 powder powder white granules or powder Solubility Soluble in cold water; 0.00016 g/100 mL 6.35 g/100 mL water at Lide 1991–1992 crystal insoluble in water at 29°C; soluble 30°C; 27.6 g/100 mL HCl; amorphous in acid, alkaline, water at 100°C soluble in HCl ammonium chloride; insoluble in alcohol Melting point 980°C 1,975°C 169°C±1 Lide 1991–1992 Octonal/water ND ND 0.175 IPCS 1998 partition coefficient Density Crystal: 4.22 g/cm3; 5.6 g/cm3 1.435 g/mL at 15°C Lide 1991–1992 Powder: 3.64 g/cm3 Abbreviations: HCl, hydrochloric acid; ND, not determined OCCURRENCE AND USE Zinc borate is typically composed of 45% ZnO and 34% boric anhydride (B2O3), with 20% water of hydration. Zinc borate is used as a flame retardant 

ZINC BORATE 151 in conjunction with other chemicals, including antimony trioxide, magnesium hydroxide, alumina trihydrate, and some brominated flame retardants. Zinc borate is used as a flame retardant on commercial furniture, draperies, wall coverings, and carpets (R.C.Kidder, Flame Retardant Chemical Association, unpublished material, April 21, 1998). In addition, zinc borate is used as a fungicide. Zinc oxide is used as a pigment in paint, cosmetics, and dental and quick drying cements. Therapeutically, zinc oxide is used as an astringent and as a topical protectant. Boric acid is used in enamels, porcelain, soaps, cosmetics, and as an insecticide. Therapeutically, boric acid is used as an astringent and an antiseptic. TOXICOKINETICS Absorption Zinc Borate No studies were identified that investigate the toxicokinetics of zinc borate following dermal, inhalation, or oral exposure. Zinc Oxide Agren (1991) reported that zinc is present in human interstitial fluid at the site of application following dermal application of zinc oxide in gum resin or hydrocolloids to human forearms. No evidence for absorption into systemic circulation was provided. Zinc readily permeates intact and damaged human skin following dermal application; however, absorption of zinc into systemic circulation was not determined (Hallmans 1977; Agren 1990, as cited in ATSDR 1994; Agren et al. 1991, as cited in ATSDR 1994). Keen and Hurley (1977) determined that when zinc (as zinc chromate) was dissolved in oil and topically applied to rats, absorption of zinc into the bloodstream occurred. No other animal studies were identified that investigated the dermal absorption of zinc. Workers exposed occupationally (via inhalation) to zinc fumes (zinc compound not specified) had elevated blood zinc concentrations (Hamdi 1969). Exposure of cats to zinc oxide fumes for up to 3.25 hr resulted in increased concentrations of zinc in the pancreas, kidney, and liver (Drinker and Drinker 1928, as cited in ATSDR 1994). In both studies, oral absorption of zinc particles following ciliary clearance and swallowing could account for all, or a 

ZINC BORATE 152 significant portion, of the absorbed zinc. In the Drinker and Drinker (1928, as cited in ATSDR 1994) study, the swallowing of zinc particles during grooming activities might also account for the increased tissue zinc levels. No data are available on the oral absorption of zinc oxide. The estimated rate of oral absorption of zinc (all zinc compounds) in humans is between 8% and 81%, depending on an individual's diet (ATSDR 1994). People who are not deficient in zinc absorb about 20–30%, while zinc-deficient individuals absorb more (ATSDR 1994). Two studies measured the peak blood concentrations of zinc in volunteers following oral ingestion of zinc sulfate; peak blood Zn2+ concentrations were reached within 3 hr (Neve et al. 1991; 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 (as zinc chloride or zinc carbonate) per kg of body weight (Galvez-Morros et al. 1992). ATSDR (1994) noted that the fraction of ingested zinc absorbed in immature organisms usually exceeds the fraction of ingested zinc absorbed in adult organisms. Boric Acid Wester et al. (1998) exposed the back of the hand of volunteers to a 5% aqueous solution of boric acid or borax and measured urinary boron concentrations to determine the extent of absorption, the flux, and the permeability constants (Kp) for intact skin. Following exposure to boric acid, 0.23% of the applied dose was excreted, flux was calculated as 0.01 µg/cm2/hr and Kp was 1.9×10−7 cm/hr. Following exposure to borax, 0.21% of the applied dose was excreted, flux was calculated as 0.01 µg/cm2/hr, and Kp was 1.8×10−7 cm/hr. Draize and Kelly (1959) has also reported low dermal absorption of boric acid, with no increase in urinary boron concentrations following a 4-hr exposure in a volunteer. Blood boron concentrations did not increase in infants after treatment with ointment (3% boric acid), indicating a lack of dermal absorption of boric acid (Friis-Hansen et al. 1982). No absorption of boric acid (measured as boron in the blood) occurred 1–9 d after a single topical application of boric acid in an anhydrous, water-emulsifying ointment (Stuttgen et al. 1982). However, blood boron concentrations were increased within 2–6 hr after application of the same amount of boric acid in a water- based jelly, indicating that the vehicle in which boric acid is applied to the skin affects absorption. Boron was detected in the urine of infants who had moderate to marked diaper rash, but not in the urine of infants who had minor or no diaper rash, 

ZINC BORATE 153 after application of a commercial talcum powder containing 5% boric acid (Mulinos et al. 1953, as cited in Moore 1997; Vignec and Ellis 1954, as cited in IPCS 1998). In rabbits, intact skin acts as a barrier to dermal absorption of boric acid, whereas absorption was much greater through damaged skin (Draize and Kelly 1959). In an in vitro absorption assay, 0.05%, 0.5%, or 5% boric acid solution were applied to human skin, and 1.2%, 0.28%, and 0.7%, respectively, of the boric acid was absorbed (Wester et al. 1998). From those data, flux values of 0.25, 0.58, and 14.58 µg/cm2/hr, and permeability constants (Kp) of 5.0×10−4, 1.2 ×10−4, and 2.9×10−4 cm/hr for the 0.05%, 0.5%, and 5.0% boric acid solutions, respectively, were calculated (Wester et al. 1998). In contrast to the lack of dermal absorption, boric acid is readily absorbed following inhalation and oral exposure. Kent and McCance (1941, as cited in Moore 1997) demonstrated in two female subjects that at least 90% of ingested boric acid is absorbed and excreted in the urine. More recently, Jansen et al. (1984) demonstrated greater than 90% recovery of administered boron in the urine of six male volunteers following ingestion of boric acid. An occupational study of workers involved in packaging and shipping borax (Na2B4O7• 10H2O) showed elevated boron levels in the urine after inhalation exposure (Culver et al. 1994). Metabolism and Distribution Zinc Borate Zinc borate is metabolized to zinc oxide and boric acid prior to being absorbed. Zinc Oxide No relevant human or animal studies were identified that investigated the distribution of zinc following dermal exposure to zinc compounds. No inhalation exposure studies were identified that investigated the distribution of zinc compounds in humans. Cats exposed to zinc oxide fumes (12–61 mg Zn2+/kg-d) for 3 hr had increased zinc levels in the pancreas, liver, and kidneys (Drinker and Drinker 1928, as cited in ATSDR 1994), however, oral absorption through swallowing or grooming cannot be ruled out. There are no data on the metabolism and distribution of zinc oxide following oral exposure. Weigand and Kirchgessner (1992) demonstrated that more zinc is distributed to the kidneys and pancreas than to the liver in rats fed 1.1 mg 

ZINC BORATE 154 Zn2+/kg-d (duration unspecified). Administration of zinc acetate to rats (191 mg Zn2+/kg-d in feed for 3 mo) increased zinc levels in the heart, spleen, kidneys, liver, bone, and blood (Llobet et al. 1988). Mice fed 76.9 mg Zn2+/kg-d as zinc sulfate for 1 mo had increased levels of Zn2+ in the kidneys and liver (Schiffer et al. 1991). Newborn, young, and adult mice given a single oral dose of 4.6 mg zinc/kg as zinc chloride generally had the highest level of zinc in the liver, kidneys, lungs, bone, muscle, and carcass 1 d after dosing (He et al. 1991, as cited in ATSDR 1994). Once in the body, zinc induces and binds to metallothionein (a metal binding protein) (Goyer 1996). Retention of zinc bound to metallothionein in tissues provides a source of zinc for essential cell functions even when zinc intake is deficient. In humans and rats, zinc and metallothionein are distributed throughout the body, with a linear relationship between zinc and metallothionein concentrations in the liver (Heilmaier et al. 1987). Boric Acid In humans, boron has been measured in the brain and liver following boric acid poisonings (see review, Moseman 1994). No other data were found on the distribution of boron in humans following exposure to boric acid or borax. In Fischer rats fed 9,000 ppm boron as boric acid (93–96 mg boric acid/kg-d) in the diet, boron was distributed throughout the soft tissues. Accumulation occurred in the bone, but not in the testis or the brain (Ku et al. 1991). Regardless of the compound or route of exposure, once in vivo, boron can form weak complexes with hydroxyl, amino, or thiol groups (Moore 1997). No data were found demonstrating that boron interacts with metallothionein. Excretion Zinc Borate No data were identified that investigated the excretion of zinc borate in humans or animals following any route of exposure. Zinc Oxide No studies were identified that investigated the excretion of zinc in humans or animals following dermal application of any zinc compounds. Elevated levels of zinc were found in the urine of workers exposed to zinc 

ZINC BORATE 155 oxide fumes containing unknown concentrations of Zn2+ (Hamdi 1969). No other studies were identified that investigated the excretion of zinc following inhalation of zinc compounds. Following oral exposure to zinc compounds, 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 can promote urinary zinc excretion, possibly as a result of increased levels of tissue breakdown and catabolism (ATSDR 1994). Boric Acid As discussed in the section on Absorption, boron has been detected in the urine after exposure to boric acid via the dermal, inhalation, and oral routes. Following ingestion of boric acid by six male volunteers, greater than 90% of an ingested dose was excreted in the urine within 96 hr (Jansen et al. 1984). HAZARD IDENTIFICATION1 Dermal Exposure Irritation and Sensitization Zinc Borate Zinc borate produced only mild conjunctivitis in albino rabbits in the eye irritation test and is not considered to be an irritant or corrosive (U.S. Borax 1996). Zinc borate was negative in the guinea pig sensitization test (U.S. Borax 1996). Zinc Oxide There are two case studies in the literature that suggest that dermal occupational exposure to zinc oxide might cause or contribute to a skin condition 1In this section, the subcommittee reviewed toxicity data on zinc borate, including the toxicity assessment prepared by the U.S. Consumer Product Safety Commission (Hatlelid 1999). 

ZINC BORATE 156 referred to as “zinc oxide pox” (itchy papular-pustular eruptions that occur in the pubic region, inner surface of the thigh, and 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. However, that effect has been attributed to poor hygiene among the workers, and not necessarily exposure to zinc oxide. In a similar study, Batchelor et al. (1926, as cited in ATSDR 1994) found that only 1 out of a total of 24 workers with occupational exposure to zinc dusts developed zinc oxide pox. Agren (1990, as cited in ATSDR 1994) reported that application of patches containing 25% zinc oxide (equivalent to 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 has been investigated in mice, rabbits, and guinea pigs (Lansdown 1991). Animals were treated topically once a d for 5 consecutive days with zinc oxide (20% suspension in Tween 80), zinc chloride (1% aqueous solution), zinc sulfate (1% aqueous solution), zinc pyrithione (20% suspension), or zinc undecylenate (20% suspension). In open patch tests, zinc chloride was a strong irritant in all three species, and caused the formation of epidermal hyperplasia and ulceration. All other compounds produced less severe erythema than zinc chloride. None of the compounds caused ulceration or scaling over the 5-d test period. Zinc chloride produced severe dermal irritation in rabbits within 3–5 d of application in occlusive patch tests, zinc acetate produced moderate irritation, and little dermal irritation was caused by the other zinc compounds. 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. No studies were identified that investigated the ability of zinc oxide to act as a senzitizer. Boric Acid Dermatitis has been reported following occupational exposure to borax (Birmingham and Key 1963). Boric acid (5 mL, 10% w/v in water) and borax (10 mL, 5% w/v in water) were found to be moderate and mild irritants, respectively, in guinea pigs. Both were mildly irritating to abraded skin after 24–72 hr in rabbits (Roudabush et al. 1965). No studies were identified that investigated the ability of boric acid to act as a skin sensitizer. 

ZINC BORATE 157 Systemic Effects Zinc Borate The LD50 in male and female albino rabbits following dermal exposure to zinc borate is estimated to be >10 g/kg (U.S. Borax 1996). Zinc Oxide DuBray (1937, as cited in ATSDR 1994) reported that a worker developed microcytic anemia and had low platelet counts after making zinc chloride solutions. The dose of zinc was not reported. No systemic effects were identified following dermal exposures of animals to zinc oxide. Boric Acid No studies were found on the systemic effects of boric acid following dermal absorption. Other Systemic Effects No studies were found that investigated the immunological, neurological, reproductive, developmental, or carcinogenic effects of zinc borate, zinc oxide, or boric acid following dermal exposure in humans or experimental animals. Inhalation Exposure No data were found on toxic effects of zinc borate following inhalation exposure. Data on the toxic effects of zinc oxide and boric acid following inhalation exposure are discussed below. Systemic Effects Zinc Oxide Although “metal fume fever” has been reported after exposure to zinc oxide, this syndrome is seen following exposure to extremely high concentrations in 

ZINC BORATE 158 the occupational setting and is not relevant to exposures from zinc borate-treated upholstered furniture. A number of deaths have been reported in humans following inhalation exposure to airborne mixtures containing very high concentrations of zinc. Ten out of 70 people died within 4 d of exposure to a smoke mixture containing approximately 33,000 mg Zn2+/kg as zinc chloride, in addition to unknown concentrations of hexachloroethane, calcium silicate, and an igniter (Evans 1945, as cited in ATSDR 1994). Milliken et al. (1963, as cited in ATSDR 1994) and Hjortso et al. (1988) reported fatalities after exposure to high, but unknown concentrations of a smoke mixture generated from zinc chloride smoke bombs. Autopsies revealed diffuse micro vascular obliteration, widespread occlusion of the pulmonary arteries, and extensive interstitial and intra-alveolar fibrosis of the lungs (Hjortsu et al. 1988). Although zinc oxide is associated with metal fume fever, and a large amount of research has been carried out in that area, those results are not a focus of this report because exposure to such fumes created by welding are not relevant to our exposure scenario. Nausea has been reported following exposure to high concentrations of zinc oxide in humans (Hammond 1944, as cited in ATSDR 1994; Rohrs 1957, 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, but Hamdi (1969) reported that workers exposed to zinc compounds had normal red blood cell counts. Routine blood analysis did not reveal liver disease among 12 workers with 4–21 yr of exposure to zinc oxide (Hamdi 1969). Pulmonary toxicity and reduced survival 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). However, the smoke contained a number of other toxic chemicals (e.g., carbon tetrachloride), therefore, the effects can not be attributed to zinc. A single exposure in rats and rabbits to 88–482 mg zinc/m3 as zinc oxide resulted in pulmonary congestion and leukocytic infiltration (Drinker and Drinker 1928; as cited in ATSDR 1994). Amdur et al. (1982) demonstrated a decreased lung compliance following exposure of guinea pigs to 0.73 mg zinc/m3 as zinc oxide for 1 hr. Lam et al. (1982) did not see an effect on ventilation, but did see an effect on functional residual capacity after exposure of guinea pigs to 6.3 mg zinc/m3 as zinc oxide for 3 hr. Deficits in lung function were seen in guinea pigs exposed to zinc oxide dust (3.7–5.6 me zinc/m3) 3 hr/d for up to 6 d (Lam et al. 1985, 1988). No effects were seen at a concentration of 2.2 mg zinc/m3 as zinc oxide (Lam et al. 1988). However, guinea pigs appear to be more sensitive to the pulmonary effects of zinc oxide than humans because of differences in lung structure (Lam et al. 1982). 

ZINC BORATE 159 Boric Acid In the occupational setting, toxic effects following exposure to boron are generally acute, and include nosebleed, nasal irritation, sore throat, cough, and shortness of breath (IPCS 1998). Garabrant et al. (1984) found an increase in reports of eye irritation, dry mouth, nose or throat irritation, and productive cough in workers in a borax mining and refining plant. Chronic bronchitis, without any abnormal regions on a chest X-ray or impairment of pulmonary function, was also found in the borax plant (Garabrant et al. 1985). In a prospective study of workers exposed to sodium borate dust in a mine and processing plant, Wegman et al. (1994) found increased nasal, eye, and throat irritation, cough, and breathlessness. No long-term effects were found in that study. Exposure to boric acid 6 hr/d, 5 d/wk had no effect on body weight gain, hematology, blood chemistry, urinalysis, or microscopic analysis in rats (77 mg/m3 for 24 wk; 175 mg/m3 for 12 wk, or 470 mg/m3 for 20 wk) or dogs (57 mg/m3 for 23 wk) (Wilding et al. 1959, as cited in ATSDR 1992). Immunological Effects No studies were identified that investigated immunological effects of boric acid following inhalation exposure. Data from three case reports suggest that inhalation exposure to high concentrations of zinc-containing compounds stimulates changes in immune parameters. Farrell (1987) reported that a worker developed hives and angioedema (suggestive of an immediate or delayed IgE response) following exposure to a low dose of zinc oxide fumes. The symptoms reappeared in a challenge test, suggesting a sensitization to zinc compounds. A correlation between exposure to zinc oxide and the proportion of activated helper-, inducer-, suppressor-, and killer-T-cells was observed among 14 welders approximately 20 hr after exposure to zinc oxide (77–153 mg Zn2 +/m3) (Blanc et al. 1991, as cited in ATSDR 1994). Ameille et al. (1992) reported elevated levels of lymphocytes in the bronchoalveolar lavage fluid of a smelter worker exposed to unknown concentrations of zinc fumes. Cytokine responses have been observed in bronchoalveolar lavage after inhalation of zinc oxide fumes from welding (Blanc et al. 1993; Kuschner et al. 1995, 1997). Marrs et al. (1988) did not observe abnormalities in the lymph nodes, thymus, or spleen tissue of female rats, mice, or guinea pigs killed 18 mo after a 20-wk exposure to zinc oxide/hexachloroethane smoke at concentrations as high as 119.3 or 121.7 mg Zn2+/m3 for 1 hr/d, 5 d/wk. 

ZINC BORATE 160 Reproductive and Developmental Effects Zinc Oxide No studies were identified in humans that investigated reproductive or developmental effects after inhalation exposure to zinc compounds. Pathological examination 17 mo after exposure of rats, guinea pigs, and mice to zinc oxide/hexachloroethane smoke (1 hr/d, 5 d/wk for 20 wk) did not demonstrate any treatment-related abnormalities in mammary glands, ovaries, or fallopian tubes (Marrset al. 1988). Boric Acid Reproductive effects of boron compounds have been investigated after occupational exposure. The number of live births in employees at a boron mine was not statistically different than the number of live births in the general U.S. population (Whorton et al. 1994). However, that study has been criticized because of its limitations and a lack of sensitivity (Moore 1997). A study (Tarasenko et al. 1972), summarized by Moore (1997), found a decrease in sexual activity in 28 workers exposed to very high concentrations of boron (10 mg/m3). Examination of the semen from six of the workers demonstrated a reduction in semen volume, a decrease in the number of spermatozoa, and decreased sperm motility. Cancer No studies were identified that investigated the carcinogenicity of boric acid. Excess lung cancer mortality was detected among persons living in an abandoned zinc/lead mining area in the midwestern United States as compared with state and national age- and sex-specific lung cancer rates (Neuberger and Hollowell 1982). However, potential confounding factors (such as smoking) were not controlled for. Logue et al. (1982) investigated mortality among a cohort of 4,802 male workers from two zinc and seven copper refining plants. Overall mortality and death from specific cancers were not elevated for the whole cohort. Cancer mortality rates, however, were not computed separately for the 978 zinc refinery workers. Marrs et al. (1988) found that female mice, but not female rats or guinea pigs, exposed to 1.3, 12.8, or 121.7 mg zinc/m3 as zinc oxide/hexachloroethane 

ZINC BORATE 161 smoke (1 hr/d, 5 d/wk for 20 wk) had a statistically significant trend in the prevalence of alveologenic carcinoma, with the frequency of this tumor reaching significance in the high-dose group at 13 mo postexposure. However, the effects cannot be attributed to zinc oxide because the smoke contained a number of other chemicals, including carbon tretrachloride, which is known to be an animal carcinogen. Other Systemic Effects No studies were found that investigated the neurological effects of zinc oxide and boric acid following inhalation exposure. Oral Exposure Systemic Effects Zinc Borate U.S. Borax (1996) lists an acute oral LD50 for zinc borate in male rats of>10 g/kg. Zinc Oxide A summary of oral toxicity studies on zinc compounds is presented in Table 8–2. When considering the oral toxicity of zinc compounds, it is important to note that zinc is an essential nutrient. NRC (1989) established recommended dietary allowances for zinc of 15 mg/d for males and 12 mg/d for females. However, chronic supplementation of more than 15 mg/d is not recommended without medical supervision because zinc can aggravate copper deficiency in individuals who are already marginally copper deficient (NRC 1989). No human studies report death following ingestion of high zinc concentrations and toxicity normally occurs only after ingestion of more than 2 grams of zinc (Prasad 1976, as cited in ATSDR 1994; NRC 1989). Vomiting, abdominal cramps, and diarrhea have been observed following ingestion of high levels of zinc sulfate. A wk after an English school girl ingested 440 mg zinc sulfate-d (2.6 mg zinc/kg-d) in capsules (a medically prescribed treatment for acne), she was admitted to the hospital, diagnosed with anemia, and had indications of gastrointestinal bleeding (Moore 1978). Gastrointestinal 

ZINC BORATE 162 TABLE 8–2 Selected Animal Toxicity Data for Boron, Zinc, and Zinc Borate Species, Strain, Dose Duration, Route Effects NOAEL/LOAEL Reference Sex BORON Rat, Sprague- Boric acid: Gestation d 0– No maternal deaths NOAEL Price et al. 1996a Dawley, F 3.3, 6.6, 20, diet or overt signs of (developmental (pregnant) 9.6, 13.3, toxicity. Significant toxicity): 9.6 mg 25 mg/kg-d reduction in fetal boron/kg-d LOAEL body weight (developmental observed in dams toxicity): 13.3 mg treated with 13.3 and boron/kg-d 25 mg/kg-d. Significant increasing trend in percentage of fetuses with skeletal malformations/litter in two highest dose groups (short XII- or wavy ribs). Rabbit, New Boric acid: Gestation d 6– Prenatal survival NOAEL Price et al. 1996b Zealand, F 10.9, 21.9, 19, gavage decreased and (developmental (pregnant) 43.7 mg/kg- number of toxicity): 21.9 mg/kg- d malformations d LOAEL (mainly (developmental cardiovascular) was toxicity): 43.7 mg increased in high boron/kg-d dose group. Rat, Sprague- Boric acid: Gestation d 0– Incidence of skeletal ND Heindel et al. Dawley, F 3.3, 6.5, 20, diet malformations was 1992 (pregnant) 9.8, 12.9, increased in the low- 25.3 mg/kg- and high-dose groups d on postnatal d 21, along with clinical signs of maternal toxicity. The incidence of short rib was increased at postnatal d 21. There was no association between treatment and wavy rib at postnatal d 21. Mouse, CD-1, F Boric acid: Gestation d 0– Dose-dependent NOAEL Heindel et al. (pregnant) 43, 79, 175 17, diet decrease in fetal body (developmental 1992 mg/kg-d weight at the two toxicity): 43 mg highest doses; boron/kg-d LOAEL increased skeletal (developmental malformations were toxicity): 79 mg also seen. Maternal boron/kg-d toxicity was also seen at those doses. 

ZINC BORATE 163 Mouse, CD-1 and Boric acid: 27 wk, diet Testicular atrophy, NOAEL (testicular Fail et al. field, M 1,000, 4,500, decreased effects): 4,500 mg/ 1989, as cited 9,000 mg/kg-d spermatogenesis, in kg-d in field mice in Moore 1997 4,500- and 9,000-mg/kg- NOAEL for d dose groups in CD-1 testicular effects mice. Same effects not established for observed at the high dose CD-1 mice in wild field mice. Mouse, B6C3F1, Boric acid: 91 d, diet Decreased weight gain in NOAEL (weight NTP 1987 M/F 1,200, 2,500 both sexes at the three loss): 2,500 ppm 5,000, 10,000, highest doses. Increased boric acid in feed 20,000 ppm mortality in the highest LOAEL (weight dose group. loss): 5,000 ppm Extramedullary boric acid in feed hematopoiesis of the spleen occurred in all groups except 20,000 ppm group. Stomach hyperkeratosis and/or acanthosis in both sexes at 20,000 ppm. Testicular degeneration and atrophy of seminiferous tubules in three highest dose groups. Mouse, B6C3F1, Boric acid: 2 yr, diet Survival decreased in LOAEL (systemic NTP 1987 M/F 2,500, 5,000 males of both dose effects): 2,500 ppm ppm groups. Decreased weight boric acid in feed gain in high dose group (400–500 mg/kg-d) for both sexes. Increased incidence of lung hemorrhage in high-dose females. Dose-related increase in incidence of testicular atrophy and interstitial cell hyperplasia in male mice. Rat, Sprague- Boric acid: 117, 2 yr, diet Decreased food NOAEL (systemic Weir and Dawley, M/F 350, 1,170 ppm consumption and effects): 350 ppm Fisher 1972 suppressed growth, rough LOAEL (systemic fur coat, swollen paws, toxicity): 1,170 ppm other gross signs of toxicity in all animals in high-dose group. Increased incidence of testicular and seminiferous atrophy in males in high-dose group. Dog, beagle, M/F Boric acid: 58, 38 wk, diet Seminiferous tubular NOAEL (systemic Weir and 117, 350, 1,170 atrophy and decreased effects): 1,170 ppm Fisher 1972 ppm spermatogenesis (8.8 mg/kg-d) observed in 1,170 dose group at 38 wk. See note in text about expert committee findings, i.e., Moore (1997). 

ZINC BORATE 164 Species, Strain, Dose Duration, Route Effects NOAEL/ Reference Sex LOAEL BORON Rat, NS, M/F Boron: 500 mg/ 21–27 d, diet Reduced weight ND Dani et al. 1971 kg-d gain; effect on nucleotide levels in numerous tissues. ZINC COMPOUNDS Healthy adult 50 mg/kg-d as 10 wk, oral Serum zinc ND Yadrick et al. human zinc gluconate (capsules) significantly 1989 volunteers, F increased. Significant decrease in erythrocyte superoxide dismutase activity, serum ferritin, and hematocrit values. Guinea pig, Zinc oxide 1 hr/d, 5 d/wk, No increase in ND Marrs et al. 1988 Dunkin-Hartley, F smokea (20% inhalation (100 tumor frequency. Zn by weight): exposures; high High death rate in 1.3 ±0.4, 12.8 ± dose guinea pigs high-dose group. 2.6, 119.3± 31.7 received 15 mg/m3 exposures) Rat, Wistar, F Zinc oxide 1 hr/d, 5 d/wk, No increase in ND Marrs et al. 1988 smokea (20% inhalation (100 tumor frequency. Zn by weight): exposures) 1.3 ±0.4, 12.8 ± 2.6, 21.7±17.8 mg/m3 Mice, Porton, F Zinc oxide 1 hr/d, 5 d/wk, Treatment-related, LOAEL (lung Marrs et al. 1988 smokea (20% inhalation (100 fatty changes in the tumors): 21.7 Zn by weight): exposures) liver in the middle- ±17.8 mg/m3 1.3 ±0.4, 12.8± and high-dose NOAEL (lung 2.6, 21.7±17.8 groups. Statistically tumors): 12.8 mg/m3 significant trend in ±2.6 mg/m3 the prevalence of alveologenic carcinoma, with the frequency of this tumor reaching significance in the high-dose group at 13 mo postexposure. 

ZINC BORATE 165 Healthy adult 4.3 mg/kg-d 6 wk, oral Impaired mitogenic LOAEL (immune Chandra 1984 human as zinc response elicited from effects): 4.3 mg/kg-d volunteers, M gluconate peripheral blood lymphocytes. Impaired chemotactic and phagocytic responses of polymorphonuclear leukocytes. Healthy adult 50 mg/kg-d as 6 wk, oral Serum zinc significantly LOAEL (enzyme Fischer et al. human zinc gluconate (capsules) increased at wk 2. inhibition): 50 mg/ 1984 volunteers, M Significant decrease in kg-d erythrocyte superoxide dismutase activity (15%). Rat, Sprague- 160, 320, 640 90 d, drinking No effects observed on ND Llobet et al. Dawley, M/F mg/kg-d as water hematocrit or 1988 zinc acetate hemoglobin levels, serum glucose Mink, F 20.8 mg/kg-d Diet No effects on gestation ND Bleavins et al. (pregnant) as zinc sulfate length or litter size 1983 Mice, NS, M/F 10, 104, 1,110 90 d, diet Decreased leukocyte NOAEL (hematocrit Maita et al. mg/kg-d as count in male mice in values): 10 mg/kg-d 1981 zinc sulfate the high-dose group. LOAEL (hematocrit Significantly lower values): 104 mg/kg-d hematocrit values and hemoglobin concentrations in the two highest-dose groups. Regressive kidney lesions in female mice of the highest dose group. Rats, NS, M/F 100, 200 mg/ 21 d before to 4–29% increase in LOAEL Schlicker and kg-d as zinc mating resorptions during (developmental Cox 1968 oxide through gestation in 200 mg/kg- toxicity): 200 mg/ gestation, diet d dose group. kg-d NOAEL (developmental toxicity): 100 mg/ kg-d F, female; LOAEL, lowest-observed-adverse-effect level; M, male; ND, not determined; NOAEL, no-observed-adverse-effect level; NS, not specified. aAuthors note that zinc oxide smoke also contained animal carcinogens carbon tetrachloride and hexachloroethane. 

ZINC BORATE 166 upset (abdominal cramps, vomiting, nausea) was reported in 26 out of 47 healthy volunteers following ingestion of zinc sulfate tablets (150 mg Zn2+ in three divided doses/d; 2 mg zinc/kg-d) for 6 wk (Samman and Roberts 1987). Yadrick et al. (1989) investigated the effects of oral zinc supplements on copper and iron balance in a 10- wk clinical study in 18 healthy women. Women were given supplements (as capsules) of 50 mg zinc/d as zinc gluconate. Erythrocyte superoxide dismutase (ESOD) activity declined over the 10-wk period and after 10 wk were significantly decreased (p<0.05) compared to ESOD activity during the pretreatment period. Serum ferritin and hematocrit values were also significantly lower than pre-treatment values after 10 wk. Serum zinc was significantly increased. Ceruloplasmin levels were not altered. Fischer et al. (1984) reported that zinc supplementation in healthy adult male volunteers (50 mg zinc/d as zinc gluconate) for 6 wk significantly decreased ESOD activity (15%). There were no differences in serum copper levels or ceruloplasmin activity in the exposed group as compared to the controls. Serum zinc levels were significantly increased in the exposed group after 2 wk. No oral LD50 value has been reported for zinc oxide, but LD50 values for other zinc compounds range from 237 to 623 mg zinc/kg-d in rats, and 86 to 390 mg zinc/kg-d in mice. Ferrets that ingested 390 mg zinc/kg-d as zinc oxide for 2 wk experienced intestinal hemorrhages and a 75% reduction in food intake (Straube et al. 1980). Mice fed a diet containing 1,110 mg zinc/kg-d developed ulcers in the forestomach. No gastrointestinal effects were observed in rats fed 565 mg zinc/kg-d (Maita et al. 1981). Llobet et al. (1988) fed zinc acetate dihydrate to 40 Sprague-Dawley rats in drinking water at levels of 0, 160, 320, or 640 mg/kg-d for 3 mo. No significant differences were observed in hematocrit and hemoglobin levels between dose groups. The concentrations of glucose and enzymes in plasma were within the normal range in treated and untreated animals. Zaporowska and Wasilewski (1992, as cited in ATSDR 1994) identified a LOAEL of 12 mg zinc/kg-d as zinc chloride in a 4-wk drinking water study in 2-mo-old rats, based on decreased hemoglobin (85% of control values). Maita et al. (1981) fed mice (12/sex/group) zinc sulfate at 0, 300, 3,000, and 30,000 ppm (equivalent to 0, 10, 104, 1,110 mg zinc/kg-d) in the diet for 13 wk. Significantly lower hematocrit and hemoglobin concentrations were measured in the 3,000- and 30,000-ppm groups compared to controls, however, no dose-dependent relationship was observed. Leukocyte counts in male mice exposed to 30,000 ppm were also decreased. Several animal studies have demonstrated renal effects in animals exposed to zinc oxide, zinc sulfate, and zinc acetate. Zinc sulfate caused an increase in absolute and relative kidney weights, and kidney lesions in female mice fed 

ZINC BORATE 167 1,110 mg zinc/kg-d, but not 565 mg zinc/kg-d, as zinc sulfate in the diet for 13 wk (Maita et al. 1981). Rats exposed to 191 mg zinc/kg-d as zinc acetate for 3 mo had epithelial cell damage in the glomerulus and proximal convoluted tubules, and increased plasma creatinine and urea levels (Llobet et al. 1988). A NOAEL 95 mg zinc/ kg-d was identified. Boric Acid The free ion of boric acid, boron, is an essential nutrient for plants, and there is some evidence supporting essentiality in animals, including humans (see reviews, Woods 1994; Nielsen 1996). The essentiality of boron in humans is under consideration by the Institute of Medicine; however, no dietary intakes are currently recommended. Information on the acute toxicity of boron compounds, including boric acid, in humans comes from severe poisonings, often related to old medical treatments or accidental exposures. Following ingestion of large amounts of boric acid, gastrointestinal symptoms occur first (nausea, vomiting, and diarrhea), followed by erythema, exfoliation, and desquamation of the skin (Moore 1997). No consistent lethal dose of boric acid has been reported in adults, but lethal doses in infants and children of 2–3 g and 5–6 g, respectively, have been reported (Moore 1997). Death occurred following ingestion of a large amount of boric acid (2.5% solution), which was accidently used instead of water to prepare an infant's formula (Wong et al. 1964, as cited in Moore 1997). A review of recent reports of boric acid poisoning at a number of poison centers indicate that acute boric acid ingestion generally produces minimal or no toxicity, with no cases of severe toxicity out of 784 poisonings. See Table 8–2 for a summary of oral toxicity studies of boric acid. Weir and Fisher (1972) determined LD50 values for boric acid of 3.45, 4.08, and 3.16 g/kg (equivalent to 0.60, 0.71, and 0.55 g boron/kg) in male and female Sprague-Dawley rats, and male Long-Evans rats, respectively. The corresponding LD50 values for borax were 4.5,5.0, and 6.1 g/kg (equivalent to 0.51, 0.56, and 0.69 g boron/kg). Administration of boric acid in the diet reduced weight gain and affected nucleotide levels in numerous tissues in rats treated with 10,000 ppm (500 mg boron/kg-d) for 21–27 d (Dani et al. 1971). Changes in spermatogenesis were seen after a 14-d treatment with approximately 1 g/kg-d boron as boric acid (Silaev et al. 1977). Dose- and duration-dependent changes were seen in the activities of enzymes found in spermatogenic cells in male Sprague-Dawley rats treated with 60 or 125–131 mg boron/kg-d for 30 or 60 d (Lee et al. 1978). In F-344 rats fed boric acid (0 or 60.9 mg boron/kg-d), inhibition of spermia 

ZINC BORATE 168 tion, significant loss of spermatocytes and spermatids from all tubules, and decreased testosterone concentrations occurred (Treinen and Chapin 1991). Krasovskii et al. (1976) dosed white random-bred rats (number of animals not given) with boric acid (0, 0.015, 0.05, and 0.3 mg boron/kg body weight) for 6 mo. Statistically significant decreases in mobility time, acid resistance, and osmotic resistance were seen at 0.3 mg boron/kg body weight. Mobility time and acid resistance were also decreased at 0.05 mg boron/kg body weight. The authors identified a NOAEL of 0.015 mg boron/kg and a LOAEL of 0.05 mg boron/kg. The effects of a 14-d exposure to 0, 600, 1,200, 2,400, 4,900, or 9,800 ppm boric acid, and 0, 6,200, 12,500, 25,000, 50,000, or 100,000 ppm in the diet of B6C3F1 mice (five/sex/group) were investigated in two studies conducted under the National Toxicology Program (NTP) (NTP 1987). No dietary intake levels were provided for those studies. Mortality and hyperplasia and/or dysplasia of the forestomach occurred at doses of 25,000 ppm or above. B6C3F1 mice (10/sex/group) were fed 0, 1,200, 2,500, 5,000, 10,000, or 20,000 ppm boric acid for 13 wk (NTP 1987). Unreliable feed consumption data precluded the estimation of the corresponding doses. Mortality was seen in the two highest concentration groups. The animals in the highest concentration group appeared nervous and dehydrated, and decreased weight gain occurred at the three highest doses. Mild-to-medium extramedullary hematopoiesis of the spleen occurred in all dose groups except the highest; stomach hyperkeratosis and/or acanthosis occurred in the highest dose group. Testicular degeneration or atrophy of the seminiferous tubules occurred at 5,000, 10,000, and 20,000 ppm boric acid. Weir and Fisher (1972) fed Sprague-Dawley rats (10/sex/group) 0, 52.5, 175, 525, 1,750, and 5,250 ppm boron as boric acid or borax in the diet (0, 2.6, 8.8, 26.3, 87.5, or 262.5 mg boron/kg-d). Hematological, biochemical, urinary, necropsy, and histological analyses were performed. Overt toxicity was seen in rats in the two highest dose groups, including rapid respiration, inflamed eyes, swollen paws, and desquamated skin on paws and tails. All animals in the highest-dose group, and one animal in the 2.6- and 87.5-mg boron/kg-d group died. Doses above 26.3 mg boron/kg-d decreased growth and food consumption. Body weights and some organ weights were altered at 26.3 mg boron/kg-d in females, and were consistently altered at the higher dose levels. Upon necropsy, congestion of liver and kidneys, bright red lungs, small gonads, and a thickened pancreas were seen in several animals. There was an increase in ovary weight at 2.6 mg boron/kg-d as borax, whereas 262.5 mg boron/kg-d, given as borax or boric acid, caused a decrease in ovary weight. At 262.5 mg boron/kg-d, both compounds decreased testis/brain weight ratios. Complete atrophy of the testis occurred in one male at 2.6 mg boron/kg-d, in four males 

ZINC BORATE 169 at 26.3 mg boron/kg-d as borax, and in all males dosed with 262.5 mg boron/kg-d as either compound. A LOAEL of 2.6 mg boron/kg-d was identified; no NOAEL was identified. Weir and Fisher (1972) fed beagle dogs (five/sex/group) 17.5, 175, or 1,750 ppm boron as boric acid or borax for 90 d and assessed most of the same end points as in the rat study. No overt toxicity was seen except for one dog in the high-dose group which died of diarrhea. In the high-dose group, two male and three female dogs had decreased packed cell volume and hemoglobin values. There was a decrease in spleen/body weight ratio in one dog at the lowest dose (borax), and decreased testes/body weight ratio in the 175-ppm group (boric acid). Both compounds significantly decreased thyroid/body and testes/body weight ratios in the 1,750 ppm group. No hematological, biochemical, or urinary effects were seen. No effects were seen upon necropsy. Upon histological examination, the animals in the highest-borax-dose group had severe testicular atrophy, degeneration of the spermatogenic epithelium, red blood cell destruction, slightly greater proprortion of solid epithelial nests and minute follicles, and an increased width of the zona reticularis in the adrenal gland. The highest dose of boric acid also increased the width of the zona reticularis and decreased the width of the zona fasciculata in the adrenal gland, caused lymphoid infiltration of the thyroid (two females), and caused thyroid atrophy (one female) (Weir and Fischer 1972). Weir and Fisher (1972) fed Sprague-Dawley rats diets containing 0 (70/sex), 117 (35/sex), 350 (35/sex), or 1,170 (35/sex) ppm boron in the diet as boric acid or borax (corresponding to 5.9, 17.5, and 58.5 mg boron/kg-d) for 2 yr. Hematological, biochemical, urinary and histopathological examinations, and a necropsy, were conducted as in the 90-d study (see above) on a subset of the animals. Animals treated with the highest dose of boric acid or borax had decreased food consumption, suppressed growth, overt evidence of toxicity, and some hematological disturbances. No histological effects were seen in the 117 ppm and 350 ppm groups. Atrophic testes and seminiferous epithelium, and decreased tubular size were seen in male rats dosed with 1,170 ppm boron as boric acid or borax. Testes weights and testes/body weight ratios were decreased at that dose. Brain/ body and thyroid/body weight ratios were increased in the high-dose group. Beagle dogs (four/sex/group) were fed 58, 117, and 350 ppm boron equivalents as boric acid or borax (Weir and Fisher 1972). There were no apparent effects on appearance, behavior, appetite, body weight, or food consumption. Organ weights and organ weight to body weight ratios were not changed from control levels, and the hematological and biochemical values in the treated animals were within the normal range of values. In a subsequent study, four dogs were exposed to 1,170 ppm boron equivalents as boric acid or borax for 

ZINC BORATE 170 38 wk. In that study, seminiferous tubular atrophy and decreased spermatogenesis were observed. A NOAEL of 8.8 mg boron/kg-d was identified. However, an expert committee (Moore 1997) that had access to the data from that study, noted a high incidence of effects in the control dogs (three out of four), including seminiferous tubule degeneration, decreased spermatogenesis, and atrophy. Therefore, the usefulness of that study (Weir and Fisher 1972) for quantitative risk assessment is questionable. Research by Fail et al. (1989, as cited in ATSDR 1994) in CD-1 mice demonstrated testicular atrophy and decreased spermatogenesis after a 27-wk exposure to 4,500 or 9,000 mg boric acid/kg, but not 1,000 mg boric acid/kg. Fertility was also decreased in the middle-dose group, and the high-dose group was infertile. Fail et al. (1989, as cited in ATSDR 1994) also treated wild deer mice with the same concentrations of boric acid as the CD-1 mice; infertility was seen at the highest-dose group, along with decreased testis and accessory sex organ weights. LOAELs of 9,000 mg boric acid/kg and 4,500 mg boric acid/kg were identified in field mice and CD-1 mice, respectively. The NOAEL in field mice was 4,500 mg boric acid/kg; no NOAEL was established in the CD-1 mice. Linder et al. (1990) investigated the dose- and time-response relationship for male reproductive effects in rats. Rats were dosed with a single dose and killed at various times following dosing (2, 14, 28, or 57 d), or dosed with a single dose at different concentrations (44, 87, 175, or 350 mg boron/kg) and killed after 14 d. Effects on epididymal sperm, testicular and seminiferous tubule spermatids, and spermiation were seen 14 d after exposure to 175 or 350 mg boron/kg. Those effects reversed when the exposure had been stopped for 57 d. Other studies in F-344 rats indicate that some reproductive effects of boron, such as inhibition of spermiation, are reversible, while others, such as focal atrophy, were not reversed when the exposure had been stopped for 32 wk (Ku et al. 1993). In a 2-yr chronic bioassay by NTP (1987), B6C3F1 mice (50/sex/group) were fed 0, 2,500, or 5,000 ppm boric acid (400–500 or 1,100–1,200 mg boric acid/kg). Survival was decreased in the low- and high-dose males and body weight gain was decreased in the high-dose males and females. No chemically related clinical symptoms were observed. All organs and tissues were examined by necropsy for gross lesions and histology was conducted. There were slight increases in non-neoplastic lesions in both sexes. The increases were not dose- dependent and were not found in both sexes, therefore it was concluded that they were not chemically related. There was a statistically significant increase in lung hemorrhage (control, 2/50; low dose, 5/50; and high dose, 12/50) in the high-dose females. Testicular atrophy (control 3/49; low dose, 6/50; high dose, 27/47; at 0, 2,500, and 5,000 ppm boric acid) and interstitial cell hyperplasia 

ZINC BORATE 171 (0/49; 0/50; 7/47) occurred in male mice. The LOAEL for systemic effects in that study is 2,500 ppm. No NOAEL was identified. Reproductive and Developmental Effects Zinc Borate No studies on the reproductive or developmental effects of zinc borate following oral exposure were identified. Zinc Oxide In humans, no developmental effects were reported in newborns following ingestion of zinc compounds by mothers during the last two trimesters of pregnancy (Kynast and Saling 1986; Mahomed et al. 1989, as cited in ATSDR 1994; Simmer et al. 1991). Schlicker and Cox (1968) administered 200 mg zinc/kg-d (as zinc oxide) in the diet of rats for 21 d prior to mating and during gestation. In the treated group, the incidence of resorptions was 4.3% compared with 0% in controls. When the dose was reduced to 100 mg zinc/kg-d, 21 d prior to mating, no fetal resorptions, malformations, or growth reduction were reported. Administration of 200 mg zinc/kg-d (as zinc oxide) to dams throughout gestation resulted in decreased growth and decreased tissue levels of copper and iron in fetal rats (Cox et al. 1969; Schlicker and Cox 1968). No measurable effect on gestational length or litter size was reported when female mink were fed a time-weighted average dose of 20.8 mg zinc/kg-d as zinc sulfate for 25 wk (Bleavins et al. 1983). Mice fed 1,110 mg zinc/kg-d for 13 wk did not have any histological alterations in the testes or ovaries (Maita et al. 1981). Boric Acid In a three-generational study, Weir and Fisher (1972) fed boric acid and borax (117, 350, and 1,170 ppm boron; calculated as 5.9, 17.5, and 58.5 mg boron/kg-d) to Sprague-Dawley rats (8 males and 16 females/group). Animals were dosed for 14 wk prior to mating. Doses of 117 and 350 ppm had no effect on litter size, weight of progeny, or general appearance, but the overall fertility index was increased in those two groups as compared with controls. No pregnancies occurred in animals in the highest-dose group. Decreased fertility, 

ZINC BORATE 172 decreased live births, and decreased offspring survival (no offspring survived to weaning) occurred when treated females were mated with control males. The LOAEL from that study is 1,170 ppm (58.5 mg boron/kg-d) and the NOAEL is 350 ppm (17.5 mg boron/kg-d). NTP has conducted multigenerational continuous-breeding studies in Swiss CD-1 mice (NTP 1990; Fail et al. 1991). Male and female mice (F0) were fed boric acid (control, 1,000, 4,500, or 9,000 mg/kg feed; equivalent to 0, 19.2, 104.7, and 222.1 mg boron/kg-d for males and 0, 31.9, 148.1, and 290.5 mg boron/kg-d for females) for 27 wk. Animals (F0) in the mid-dose group had decreased numbers of litters/pair, decreased live pups per litter, and decreased pup weight; animals in the high-dose group were infertile. Cross-mating experiments indicated that the decreased fertility was associated with adverse reproductive effects on the male. Treated animals (F0) had decreased sperm motility at all dose levels. Significant increases in uterine weight, and kidney plus adrenal weight were seen in the female offspring (F1) of the low-dose animals, and a decrease in birth weight (3.3%) was seen in the F2 offspring of this dose group. A LOAEL of 19.2 mg boron/kg-d was identified in this study based on effects in the low-dose males. No NOAEL could be identified. Heindel et al. (1992) investigated developmental effects in Sprague-Dawley rats with boron as boric acid in feed (0, 13.6, 28.5, or 57.7 mg boron/kg-d) on gestational d 0–20. Another treatment group received 94.2 mg boron/kg-d on gestational d 6–15. Maternal effects (increased liver and kidney weights relative to body weights) were seen at and above 28.5 mg boron/kg-d. Fetal body weight was decreased in a dose-dependent manner, with significant decreases seen at all doses. Significant fetal malformations, including effects on the eyes, central nervous system, cardiovascular system, and axial skeleton, occurred at and above 28.5 mg/kg-d. The percentage of malformations per litter was reduced relative to controls in the 13.6 and 28.5 mg boron/kg-d dose groups. However, skeletal effects were significantly increased at 94.2 mg boron/kg-d. Treatment for part of gestation with 94.2 mg boron/kg-d resulted in increased prenatal mortality. The lowest dose in that study, 13.6 mg boron/ kg-d, is a LOAEL in the study. Price et al. (1996a) conducted a follow-up study to the study by Heindel et al. (1992). The study consisted of one phase to determine a NOAEL and a second phase to investigate the reversibility of the effects of boric acid on fetal body weight. Both phases consisted of two replicate studies. In each replicate of the phase 1 study, pregnant Sprague-Dawley rats (14–17/group) were fed diets containing boric acid (0, 3.3, 6.3, 9.6, 13.3, or 25 mg boron/kg-d) on gestational d 0–20. There were no maternal deaths or overt signs of maternal toxicity from the treatments. A slight increase in relative maternal right kidney weight was seen, but only on gestational d 20. Boric acid did not affect mater 

ZINC BORATE 173 nal weight gain, liver weight, or percentage of dams delivering pups, the number of ovarian corpora lutea-dam, implantation sites/litter, live litter size, percentage of resorptions, or late fetal deaths. On gestational d 20, significant reductions in fetal body weight were seen at the two highest dose levels (6% at 13.3 mg boron/kg-d and 12% at 25 mg boron/kg-d). A low incidence of external malformations, and visceral malformations and variations occurred on gestational d 20. A significant increasing trend in the percentage of fetuses with skeletal malformations per litter was seen at the two highest dose levels, but there were no significant differences in the overall incidence of skeletal variations. However, at the two highest doses, there was a significant increase in short rib XIII and wavy ribs. In phase 2 of the study, dams and offspring were kept alive until postnatal d 21. There was no difference in body weight between boron exposed and control animals on postnatal d 21. Overall incidence of skeletal malformations was increased in the low- and high-dose groups on postnatal d 21. A dose- dependent increase in the incidence of short rib occurred at postnatal d 21, but the authors concluded that this effect was treatment related only at the highest dose. There was no association between treatment and wavy rib at postnatal d 21. Based on phase 1 effects, Price et al. (1996a) identified a LOAEL of 13.3 mg boron/kg-d and a NOAEL of 9.6 mg boron/kg-d. Developmental toxicity studies were also conducted in mice (Heindel et al. 1992). Mice fed boric acid in their diet (0, 43, 79, or 175 mg boron/kg-d) had a dose-dependent decrease in fetal body weight, with statistically significant decreases at the two highest doses. Increased skeletal malformations also occurred at those doses. However, maternal toxicity was also seen at those doses. A LOAEL of 79 mg boron/kg-d and a NOAEL of 43 mg boron/kg-d were identified for developmental effects in mice. Price et al. (1996b) gavaged New Zealand white rabbits with 0, 10.9, 21.9, or 43.7 mg boron/kg-d. Prenatal survival decreased and the number of malformations increased at 43.7 mg boron/kg-d. Cardiovascular defects contributed the most to the malformations. The LOAEL was 43.7 mg boron/kg-d and the NOAEL was 21.9 mg/ kg-d. Developmental and reproductive end points are the most sensitive effects for boron compounds following oral exposure. The lowest NOAEL identified was 8.8 mg boron/kg-d in the dog study by Weir and Fisher (1972). However, in the report by Moore (1997), questions were raised about that study due to a high level of abnormalities in the control group. The number of animals was also quite small in that study. Therefore, the study by Price et al. (1996a), which provided the next lowest values, with a LOAEL of 13.3 mg boron/kg-d and a NOAEL of 9.6 mg boron/kg-d, based on developmental effects, is the critical study for the reproductive and developmental effects of boron. 

ZINC BORATE 174 Immunological Effects No studies were identified that investigated the immunological effects of zinc borate or boric acid following oral exposure. Eleven healthy adult men who ingested 4.3 mg zinc/kg-d for 6 wk experienced impaired mitogenic response elicited from peripheral blood lymphocytes and impaired chemotactic and phagocytic responses of polymorphonuclear leukocytes. No effects were observed on total number of lymphocytes or relative number of T cells or B cells (Chandra 1984). Zinc deficiency is generally associated with adverse effects on the immune system in humans and animals (see Prasad et al. 1978; Thurnham 1997; Shankar and Prasad 1998 for reviews). Neurological Effects No studies were identified that investigated the neurological effects of zinc borate or boric acid following oral exposure. Murphy (1970) reported that a 16-yr-old boy developed symptoms of lethargy, light-headedness, staggering, and difficulty in writing clearly following ingestion of about 86 mg zinc/kg-d (as metallic zinc) over a 2-d period in an effort to promote the healing of a wound. Limited data were located on neurological effects of zinc compounds in animals. Rats dosed with 487 mg zinc/kg-d as zinc oxide for 10 d (Kozik et al. 1980; as cited in ATSDR 1994) experienced minor neuronal degeneration and proliferation of oligodendroglia. Kozick et al. (1981; as cited in ATSDR 1994) reported that rats receiving 472 mg zinc/kg-d as zinc oxide for 10 d had increased levels of secretory material in the neurosecretory nuclei of the hypothalamus. Cancer Zinc Borate No studies were located that investigated the carcinogenicity of zinc borate following oral exposure. Zinc Oxide Two epidemiological studies report conflicting results on the association between high zinc soil levels and cancer. In a survey of cancer registry data 

ZINC BORATE 175 (1954–1978) in Shipham, Somerset (Great Britain), an area with a high soil zinc-to-copper ratio ( 17:1), the gastric cancer incidence rate was significantly lower than the regional rate (Philipp et al. 1982). In contrast, Stocks and Davies (1964, as cited in ATSDR 1994) found an association between an excess rate of gastric cancer in people of North Wales and high zinc-to-copper ratios ( 30:1) in the soil of household gardens. Walters and Roe (1965) reported no increased incidence of tumors following exposure of mice to 951 mg zinc/kg-d as zinc sulfate in drinking water for 1 yr compared to controls. However, the report of that study lacked important details and the study had several limitations, including a high mortality rate in control mice. Boric Acid Weir and Fisher (1972) conducted a 2-yr study in which they fed Sprague-Dawley rats (35/sex/group) 0, 117, 350, or 1,170 ppm of boron (0, 67, 200, and 669 mg boron/kg-d) as boric acid or borax. That study, however, was not designed as a cancer bioassay (see Systemic Effects section for study details). A limited number of tissues were examined histopathologically, and the report failed to even mention tumor findings. Following dose-finding studies (see Systemic Effects section), the NTP conducted a chronic cancer bioassay (NTP 1987). B6C3F1 mice (50/sex/group) were fed diets containing 0, 2,500, or 5,000 ppm boric acid (0, 400–500, or 1,100–1,200 mg/kg-d as measured by NTP). In males dosed with 400–500 mg/kg-d, there was an increase (not statistically significant) in hepatocellular carcinomas (5/50, 12/50, and 8/49 at 0, 400–500, and 1,100–1,200 mg/kg-d, respectively) and hepatocellular adenomas or carcinomas (14/50, 19/50, and 15/49 at 0, 400–500, and 1,100–1,200 mg/kg-d, respectively). Since the increases were not statistically significant and they did not occur in a dose-dependent manner, and since there is variability in historical controls for that tumor type, the NTP did not consider those tumors to be related to boric acid. NTP concluded that there was no evidence of carcinogenicity for boric acid (NTP 1987). Genotoxicity Zinc Borate Zinc borate was not mutagenic in the Ames Salmonella mutagenicity bioassay, with or without metabolic activation (U.S. Borax 1996). 

ZINC BORATE 176 Zinc Oxide Bauchinger et al. (1976) found an increased incidence of chromosomal aberrations in 24 workers in a zinc smelting plant compared with controls. However, those workers also had increased blood levels of lead and cadmium; authors attributed the increase in the incidence of chromosome aberrations to cadmium exposure. A number of in vivo studies have reported that zinc salts are clastogenic when administered by various routes of exposure (Table 8–3). Many of those studies were carried out with high exposures (>10 mg Zn/kg/d) or with intraperitoneal injection. Inhalation exposure of mice to zinc oxide induced chromosomal aberrations in bone marrow cells, but no exposure concentrations were given (Voroshilin et al. 1978; as cited in ATSDR 1994). Zinc sulfate and zinc chloride have been found to be negative for mutagenic activity in in vitro bacterial and mammalian systems (ATSDR 1994). TABLE 8–3 Genotoxicity of Zinc Compounds In Vivo Species Zinc Compound Genotoxicity End Point Results Reference Mouse Zinc salts Chromosomal aberrations Positive Vilkina et al. 1978, as cited in ATSDR 1994 Mouse Zinc chloride Micronucleus test Positive Gocke et al. 1981 Mouse Zinc chloride Chromosomal aberrations Positivea Deknudt and Gerber 1979 Mouse Zinc chloride Chromosomal aberrations Positive Gupta et al. 1991 Rat Zinc chlorate Chromosomal aberrations Positive Kowalska-Wochna et al. 1988, as cited in ATSDR 1994 Rat Zinc chlorate Sister chromatid exchange Positive Kowalska-Wochna et al. 1988, as cited in ATSDR 1994 Drosophila Zinc chloride Sex-linked recessive lethal mutations Negative Gocke et al. 1981 aZinc chloride was genotoxic only when animals were fed a low-calcium diet. 

ZINC BORATE 177 Boric Acid The weight of evidence indicates that boron compounds are not genotoxic (Table 8–4). TABLE 8–4 Genotoxicity of Boron Compounds Test System Boron Compound Genotoxicity End Point Result Reference Escherichia coli Blr/Scl-4 Boric acid Gene mutations Positive Demerec et al. 1951 Salmonella typhimuirum Boric acid, borax Gene mutations Negative NTP 1987 Salmonella typhimuirum Boric acid Gene mutations Negative Stewart 1991 Human fibroblasts Borax Gene mutations Negative Landolph 1985 V79 Chinese hamster Borax Gene mutations Weakly positive Landolph 1985 ovary cells C3H/10T1/2 Borax Gene mutations Negative Landolph 1985 Chinese hamster ovary Boric acid, borax Sister-chromatid exchange Negative NTP 1987 cells and chromosomal aberrations Mouse lymphoma cells Boric acid Gene mutations Negative Rudd 1991, as cited in Moore 1997 Mouse lymphoma cells Boric acid, borax Gene mutations Negative NTP 1987 F-344 rat Boric acid Hepatocyte unscheduled Negative Bakke 1991, as cited in DNA synthesis Moore 1997 Swiss-Webster mice Boric acid Micronucleus test Negative O'Loughlin 1991, as cited in Moore 1997 

ZINC BORATE 178 QUANTITATIVE TOXICITY ASSESSMENT Noncancer Dermal Assessment There are inadequate dermal toxicity data on zinc borate, zinc oxide, or boric acid to derive a risk value for dermal exposure. Inhalation RfC There are inadequate inhalation toxicity data on zinc borate, zinc oxide, or boric acid to derive an inhalation RfC. Oral RfD There are inadequate oral toxicity data on zinc borate to derive an oral RfD. However, zinc borate readily breaks down in the stomach to zinc oxide and boric acid. The subcommittee used the available dose-response data for both compounds to derive their RfDs and selected the more conservative RfD of the two values to characterize the health risk of zinc borate. Zinc Oxide The EPA has established an oral RfD of 0.3 mg/kg-d for zinc (EPA 1999). That RfD is based on a LOAEL of 1.0 mg zinc/kg-d which was identified by Yadrick et al. (1989) who reported a decrease in erythrocyte superoxide dismutase activity in adult women following 10 wk of exposure to zinc supplements. The change in the enzyme activity reflects an alteration in copper levels. That RfD is supported by data from several other clinical studies demonstrating the effect of zinc on copper balance (Fischer et al. 1984; Prasad et al. 1978). The LOAEL was divided by an uncertainty factor of 3 (less than the default factor of 10 because the effects are not severe and zinc is an essential micronutrient) to yield an RfD of 0.3 mg zinc/kg-d. Boric Acid Developmental toxicity appears to be the most sensitive endpoint for boric acid. Price et al. (1996a) identified the lowest LOAEL and the highest NOAEL 

ZINC BORATE 179 (see Hazard Identification section). A LOAEL of 13.3 mg boron/kg-d, based on decreased fetal body weight and skeletal malformations in Sprague-Dawley rats, and a NOAEL of 9.6 mg boron/kg-d were identified. Heindel et al. (1992) identified a LOAEL of 13.6 boron/kg-d based on developmental effects. Allen et al. (1996) calculated a benchmark dose for the developmental toxicity data associated with boric acid exposure in rats and determined that fetal weight, averaged within litters, is the most sensitive, relevant end points to use. Combining the data from Price et al. (1996a) and Heindel et al. (1992), a benchmark dose (BMD5) of 59 mg boric acid/kg-d (10.3 mg boron/kg-d) was calculated for a 5% decrease in fetal weight. An expert scientific panel (consisting of 28 individuals from academia, industry, and government) concluded that the benchmark dose estimated by Allen et al. (1996) was appropriate (Moore 1997). The subcommittee agrees that a benchmark dose (BMD5) of 10.3 mg boron/kg-d is appropriate for use in this risk assessment. The default uncertainty factor for the derivation of the RfD for boric acid would be 100, composed of a factor of 10 for interspecies extrapolation and 10 for intraspecies variability (further broken down to a factor of 4 for toxicokinetic considerations and 2.5 for toxicodynamic considerations). It has been suggested that, in the case of boron compounds, the database is sufficient to warrant adjusting down the UF based on similar absorption, distribution, and elimination of boron in rats and humans, and lack of metabolism in either rats or humans. The International Programme on Chemical Safety (IPCS) (1998) used a total uncertainty factor of 25 when calculating their tolerable intake level for boron. An ad hoc panel, which included representatives from the EPA and Health Canada, that reviewed the data on the elimination of boron has suggested that a total UF of 60 be used (Dourson et al. 1998). The subcommittee, however, decided that an uncertainty factor of 30 should be used. Division of the BMD5 of 10.3 mg boron/kg-d by the UF of 30 yields an RfD of 0.3 mg boron/kg-d for boric acid. The derivation of the oral RfD for boric acid is summarized in Table 8–5. Confidence in the critical studies for boric acid (Heindel et al. 1992; Price et al. 1996a) is high because they are well-conducted studies. There is a large body of literature indicating developmental and reproductive effects within the same order of magnitude, therefore, the confidence in the overall database is high. Therefore, the subcommittee has high confidence in the oral RfD for boric acid high. Zinc Borate In order to derive an oral RfD for zinc borate from the RfDs for zinc compounds and boric acid, the relative contributions of zinc and boron to zinc borate were determined. Boron comprises approximately 11.3% (w/w) of zinc 

ZINC BORATE 180 borate (3ZnO:2B2O3) (Lide 1991–1992). The RfD for zinc borate, based on the RfD for boron (0.34 mg boron/ kg-d), would be approximately 3.0 mg zinc borate/kg-d. Zinc comprises approximately 51.2% (w/w) of zinc borate (3ZnO:2B2O3). The RfD for zinc borate, based on the RfD for zinc (0.3 mg zinc/kg-d), would be approximately 0.6 mg zinc borate/kg-d. TABLE 8–5 Oral Reference Dose for Boric Acid Critical effect Species Effect level Uncertainty factors RfD References (mg boron/kg- d) Fetal weight Sprague-Dawley BMD5:10.3 UFA: 3 0.3 mg boron/ Heindel et al. 1992; averaged within rats UFH: 10 kg-d Price et al. 1996aa litters Total: 30 BMD5, benchmark dose for a 5% effect; RfD, reference dose; UFA, extrapolation from animals to humans; UFH, intraspecies variability. aThe BMD5 was calculated using the data from both of these studies (Allen et al. 1996). The oral RfD for zinc borate based on zinc is more conservative than the RfD for zinc borate based on boron. Therefore, the overall oral RfD for zinc borate is 0.6 mg zinc borate/kg-d, based on the RfD for zinc. The subcommittee also considered the possibility of additive or synergistic effects between zinc and boron when assessing the risks associated with exposure to zinc borate. The main effects of boron are reproductive and developmental effects. Zinc has been shown to have reproductive effects in animals, but only at extremely high doses (≥200 mg Zn/kg-d). Effects other than reproductive and developmental have only been seen following exposure to boric acid at very high doses (≥1,000 ppm-d). The subcommittee concluded that additive or synergistic effects are not expected because of the lack of target overlap. The subcommittee's confidence in the zinc RfD is medium. The lack of data on the parent compound makes the overall confidence in the oral RfD (0.6 mg zinc borate/kg-d) low. Cancer The potential carcinogenicity of zinc borate, zinc oxide, and boric acid cannot be determined because of inadequate carcinogenicity data from any route of exposure. 

ZINC BORATE 181 EXPOSURE ASSESSMENT AND RISK CHARACTERIZATION Noncancer Dermal Exposure The assessment of noncancer risk by the dermal route of exposure is based on the scenario described in Chapter 3. This exposure scenario assumes that an adult spends 1/4th of his or her time sitting on furniture upholstery treated with zinc borate, that 1/4th of the upper torso is in contact with the upholstery, and that clothing presents no barrier. Zinc borate is considered to be ionic, and is essentially not absorbed through the skin. However, to be conservative, the subcommittee assumed that ionized zinc borate 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 zinc borate (2 mg/cm2), 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 zinc borate (0.6 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 1.0×10−2. Thus it was concluded that zinc borate used as a flame retardant in upholstery fabric is not likely to pose a noncancer risk by the dermal route. Inhalation Exposure Particulates The assessment of the noncancer risk by the inhalation route of exposure is based on the scenario described Chapter 3. This scenario corresponds to a person spending 1/4th of his or her life in a room with low air-change rate (0.25/hr) and with a relatively large amount of fabric upholstery treated with zinc borate (30 m2 in a 30-m3 room), with this treatment gradually being worn away over 25% of its surface to 50% of its initial quantity over the 15-yr lifetime of the fabric. A small fraction, 1%, of the worn-off zinc borate is released into the indoor air as inhalable particles and may be breathed by the occupant. Equations 4 through 6 in Chapter 3 were used to estimate the average concentration of zinc borate present in the air. The highest expected application rate for zinc borate is about 2 mg/cm2. The estimated release rate for zinc borate is 

ZINC BORATE 182 2.3×10−7/d. Using those values, the estimated time-averaged exposure concentration for zinc borate is 0.19 µg/m3. Although lack of sufficient data precludes deriving an inhalation RfC for zinc borate, the oral RfD (0.6 mg zinc borate/kg-d; see Oral RfD in Quantitative Toxicity section), which represents a conservative estimate, was used to estimate an RfC of 2.1 mg/m3 (see Chapter 4 for the rationale). Division of the exposure concentration (0.19 µg/m3) by the estimated RfC (2.1 mg/m3) results in a hazard index of 9.1×10−5. Therefore, the subcommittee concluded that, under the worst-case exposure scenario, exposure to zinc borate particles from its use as an upholstery fabric flame retardant is not likely to pose a noncancer risk. Vapor In addition to the possibility of release of zinc borate in particles worn from upholstery fabric, the subcommittee considered the possibility of its release by evaporation. However, because of zinc borate's negligible vapor pressure at ambient temperatures, the subcommittee concluded that exposure to zinc borate vapors from its use as an upholstery fabric flame retardant is not likely to pose a noncancer risk. Oral Exposure The assessment of the noncancer risk by the oral exposure route is based on the scenario described in Chapter 3. The exposure assumes a child is exposed to zinc borate through sucking on 50 cm2 of fabric, backcoated with zinc borate, daily for two yr, one hr/d. The highest application rate for zinc borate is 2 mg/m2. A fractional rate (per unit time) of zinc borate extraction by saliva is estimated as 0.001/d, based on leaching of antimony from polyvinyl chloride cot mattresses (Jenkins et al. 1998). Using those assumptions in Equation 15 in Chapter 3, the average oral dose rate was estimated to be 0.00017 mg/kg-d. Division of that exposure estimate (0.00017 mg/kg-d) by the oral RfD (0.6 mg/kg-d; see Oral RfD in Quantitative Toxicity Assessment Section) results in a hazard index of 2.8×10−4. Therefore, under the worst-case exposure assumptions, zinc borate, used as a flame retardant in furniture-upholstery fabric, is not likely to pose a noncancer risk by the oral route of exposure. 

ZINC BORATE 183 Cancer There are inadequate data to characterize the carcinogenic risk from exposure to zinc borate, zinc oxide, or boric acid from any route of exposure. RECOMMENDATIONS FROM OTHER ORGANIZATIONS The U.S. Environmental Protection Agency (EPA), as detailed in the Integrated Risk Information System (IRIS), has established an oral RfD for boron of 0.09 mg/kg-d (EPA 1999). The risk assessment for boron has not been updated since 1989. However, that RfD is currently under review and a revised RfD is expected in the yr 2000 (Fed. Regist. 63 (December 10, 1998):68353–68364). The International Programme on Chemical Safety (IPCS) has an Environmental Health Criteria document (IPCS 1998) on boron in which a tolerable intake for boron is set at 0.4 mg boron/kg-d based on recent reproductive and developmental data. The Agency for Toxic Substances and Disease Registry (ATSDR) has published toxicological profiles for zinc and boron. An oral minimal risk level (MRL) of 0.3 mg Zn/kg-d for zinc was based on hematological effects (ATSDR 1994). ATSDR lists an oral MRL for boron of 0.01 mg boron/kg-d based on developmental effects (ATSDR 1992). The National Research Council (NRC) has established a recommended dietary allowance (RDA) for zinc of 12–15 mg/d (0.17–0.21 mg/kg-d of zinc for a 70-kg person (NRC 1980). The Occupational Safety and Health Administration (OSHA) and the American Conference of Government Industrial Hygienists (ACGIH) considered the toxicity from zinc borate and its components in the workplace to be due to “Particulate Not Otherwise Classified” or “Nuisance Dust.” Therefore, the OSHA permissible exposure level is 15 mg/m3 for total dust and 5 mg/m3 for respirable dust, and the ACGIH Threshold Limit Value for zinc oxide dust is 10 mg/m3 (ACGIH 1999). DATA GAPS AND RESEARCH NEEDS There are little toxicity data available for zinc borate. Once in the body, zinc borate readily breaks down to zinc oxide and boric acid. There are no chronic studies investigating the carcinogenicity of zinc oxide and boric acid. There are 

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