12
Ammonium Polyphosphates

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

PHYSICAL AND CHEMICAL PROPERTIES

Ammonium polyphosphates (APPs) are a class of ammonium salts of linearly condensed polyphosphoric acids of the general chemical formula (NH4)kH(n+2−k)PnO(3n+1). The physical properties of this class of chemicals vary as a function of the degree of phosphate condensation. Short-chain APPs are water soluble, while longer chain APPs have lower water solubility. Toxicity data were available for three commercial APPs: ANTIBLAZE® LR2 (LR2), ANTIBLAZE® LR4 (LR4), and ANTIBLAZE® MC(M). The physical and chemical properties of these commercial APPs are summarized in Table 12–1.

Based on information provided by the manufacturer (Stewart Miller, Albright and Wilson, pers. commun., Nov. 1, 1999), a typical species distribution of polyphosphates in LR2 is 20% orthophosphate, 40% pyrophosphate,



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Toxicological Risks of Selected Flame-Retardant Chemicals 12 Ammonium Polyphosphates THIS chapter reviews the physical and chemical properties, toxicokinetics, toxicological, epidemiological, and exposure data on ammonium polyphosphates (APPs). The subcommittee used that information to characterize the health risk from exposure to APPs. The subcommittee also identified data gaps and recommended research relevant for determining the health risk from exposure to APPs. PHYSICAL AND CHEMICAL PROPERTIES Ammonium polyphosphates (APPs) are a class of ammonium salts of linearly condensed polyphosphoric acids of the general chemical formula (NH4)kH(n+2−k)PnO(3n+1). The physical properties of this class of chemicals vary as a function of the degree of phosphate condensation. Short-chain APPs are water soluble, while longer chain APPs have lower water solubility. Toxicity data were available for three commercial APPs: ANTIBLAZE® LR2 (LR2), ANTIBLAZE® LR4 (LR4), and ANTIBLAZE® MC(M). The physical and chemical properties of these commercial APPs are summarized in Table 12–1. Based on information provided by the manufacturer (Stewart Miller, Albright and Wilson, pers. commun., Nov. 1, 1999), a typical species distribution of polyphosphates in LR2 is 20% orthophosphate, 40% pyrophosphate,

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Toxicological Risks of Selected Flame-Retardant Chemicals TABLE 12–1 Physical and Chemical Properties of Ammonium Polyphosphates Property Value Reference ANTIBLAZE® LR2 Chemical formulaa (NH4)kH(n+2−k)PnO(3n+1) Albright and Wilson 1998a Components APP (CAS # 68333–79–9), urea, (57–13–6), water Albright and Wilson 1998a Synonyms AMGARD® LR2 Albright and Wilson 1998a Physical State Clear, colorless, odorless liquid Albright and Wilson 1998a Vapor Pressure Not volatile at ambient temperature Albright and Wilson 1998a Solubility Completely miscible in water Albright and Wilson 1998a pH ~7.3 Albright and Wilson 1998a Boiling Point 105° C Albright and Wilson 1998a Flash Point Non-flammable Albright and Wilson 1998a Thermal Decomposition Begins at 80°C Albright and Wilson 1998a Density 1.26g/mL at 20°C Albright and Wilson 1998a ANTIBLAZE® LR4 Chemical formulaa (NH4)k H(n+2−k)PnO(3n+1) Albright and Wilson 1998a Chain length 200 Albright and Wilson 1998a Components APP (CAS # 68333–79–9) Albright and Wilson 1998b Synonyms AMGARD® LR4 Albright and Wilson 1998b Physical State White, odorless powder Albright and Wilson 1998b Solubility 4.0 g/100 g water Maximum solubility 10%a Albright and Wilson 1998b pH 5.0–7.0 S.Miller, Albright and Wilson, pers. commun., Nov. 1, 1999 Flash Point Non-flammable Albright and Wilson 1998b Thermal Decomposition Begins at 300°C Albright and Wilson 1998b Density 1.8 g/cm3 at 20°C Albright and Wilson 1998b ANTIBLAZE® MC(M) Chemical formulaa (NH4)k H(n+2−k)PnO(3n+1) Albright and Wilson 1998a Chain length 300 S.Miller, Albright and Wilson, pers. commun., Nov. 1, 1999 Components APP (CAS # 68333–79–9) S.Miller, Albright and Wilson, pers. commun., Nov. 1, 1999 Molecular weight 30,000   Physical state Solid S.Miller, Albright and Wilson, pers. commun., Nov. 1, 1999 aIn this formula, “k” represents the degree of replacement of hydrogen ions with ammonium ions. The value of “k” was not available; however, based on the reported molecular weight of ANTIBLAZE® MC(M), it appears that the value of “k” is approximately equal to n, the degree of polymerization.

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Toxicological Risks of Selected Flame-Retardant Chemicals 40% tripolyphosphate, and 20% tetrapolyphosphate plus higher-level polyphosphates (Stewart Miller, Albright and Wilson, pers. commun., Nov. 1, 1999). OCCURRENCE AND USE APP-based flame retardants have been sold in the U.S., Europe, and Asia for several years. In the U.S., they are used in the treatment of commercial furniture upholstery, automotive interior fabrics, draperies, and in other applications (Albright and Wilson 1998c). Outside the U.S., APPs are also used as flame retardants in commercial furniture upholstery. Water-soluble forms of APPs are approved for use in food as a sequestrant and emulsifier (JECFA 1982). Both LR2 and LR4 are used for semi-durable, flame-retardant (FR) applications (Albright and Wilson 1999). Water-soluble LR2 is applied to cellulose-rich upholstery fabrics. Less-soluble LR4 is applied to fabrics as a latex back-coating. Information on the uses of ANTIBLAZE® MC(M) was not available. Phosphorus is essential in human physiology. Phosphate is a structural component of bones and teeth and is essential in many enzymatic processes. TOXICOKINETICS Absorption JECFA (1974) reported that gastrointestinal absorption of higher polyphosphates is probably low. Polyphosphates are most likely hydrolyzed by stomach acids to phosphate and ammonium ions, which could then be absorbed. Ebel (1958, as cited by JECFA 1974) reported that the rates of hydrolysis and absorption of polyphosphates decrease with increasing size. There are some limited data on the uptake of phosphate from highly polymeric polyphosphates. Approximately 10–30% of an orally administered dose of sodium hexametaphosphate (a cyclic polyphosphate) or Kurrol’s salt1 was absorbed as monophosphate (Lang et al. 1955, as reported by JECFA 1974; Lang 1958, as reported by JECFA 1974). Overall, these data suggest that about 1   Kurrol’s salt is a high-molecular-weight polymer with the chemical formula (KPO3)n•H2O, with n=400–5000. Kurrol’s salt is nearly insoluble in water but, as noted below, the mixture of Kurrol’s salt and diphosphate could be dissolved, and a 1% solution had a pH of 7.6. It is unclear how these authors administered Kurrol’s salt without the addition of diphosphate.

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Toxicological Risks of Selected Flame-Retardant Chemicals one-half of the ingested dose of LR2 or LR4 would be absorbed as monophosphate. No data were located on the absorption of APPs following dermal or inhalation exposure. Metabolism No data were located on the metabolism of APPs following exposure by the dermal, inhalation, or oral routes of exposure. It is known that APPs are hydrolyzed by stomach acids and dissociate to the ammonium and phosphate ions following ingestion. Bacteria located in the intestinal tract may also contribute to the hydrolysis of polyphosphates following ingestion (Schreier and Noller 1955, as reported by JECFA 1974). Distribution Normal adult serum phosphorus levels are about 0.87–1.41 mmol/L (2.5–97.5 percentiles) (IOM 1997). Phosphorous intake estimated to result in the upper boundary of normal adult serum phosphorus is 3.5 g/d. Serum phosphorus levels during infancy range from 1.88 to 2.2 mmol/L. The adult intake of phosphorus that would result in the serum phosphorus levels observed in infants would be 10.2 g/d. No data were located on the distribution of APPs following dermal or inhalation exposure. Excretion Grosselin et al. (1952) found that various polyphosphates were excreted in trace amounts in urine of rodents following oral exposure to hexametaphosphate. Particularly, orthophosphate was found in trace amounts representing a small fraction of the dose. About 40% of an oral dose of sodium trimetaphosphate was excreted in urine (38% as orthophosphate) within 24 hr. About 22% of a dose of sodium tetrametaphosphate was excreted in urine (18% as orthophosphate). These data suggest that large polymers of polyphosphate are excreted less efficiently than smaller polymers. About one-half of the radiolabeled Kurrol’s salt (primarily as polyphosphate) was found in the feces of rats following gavage, while a small percentage of monophosphate was excreted in the urine as monophosphate.

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Toxicological Risks of Selected Flame-Retardant Chemicals No data were located on the excretion of APPs following dermal or inhalation exposure. HAZARD IDENTIFICATION2 Dermal Exposure Irritation LR2 (5% or 10% dissolved in distilled water, (Inveresk 1996) was found to be non-irritating in 36 human volunteers (26 female, 10 male) in a dermal patch test. Volunteers (age: 18–65 yr) were treated with approximately 20 µL of 0%, 5%, and 10% w/w LR2 in petrolatum, which was placed in Finn chambers and applied to their backs3. Forty-eight hr after application, the patches were removed and the application sites were rinsed. Application sites were evaluated 2 hr, 1 d, 2 d, and 5 d after patch removal. Two subjects showed what were reported as doubtful skin reactions to 10% LR2 at the 2-hr evaluation time point. No skin reactions to 5% or 10% LR2 were observed in the volunteers at later time points. LR2 and LR4 were also non-irritating when applied to rabbits (Inveresk 1989, Safepharm 1993a). A single application of 0.5 mL (650 g) of LR2 in neat form (Inveresk 1989) or of 0.5 g of LR4 in 0.5 mL distilled water (Safepharm 1993 a) was applied to the dorsum of three male New Zealand White rabbits and covered for 4 hr. The patch was removed and the skin was evaluated for reactions after 1, 24, 48, and 72 hr. No erythema or edema was observed from LR2 exposure. Very slight erythema was observed from LR4 exposure in 2 of the 3 animals 1 hr after patch removal. There were no skin reactions to treatment with LR4 when the animals were evaluated after 24 and 72 hr. No irritation was observed in one male and two female New Zealand White rabbits exposed topically to fabric treated with LR2 (Inveresk 1990a). The rabbits were exposed to fabric (approximately 2.5 cm×2.5 cm) “impregnated” with LR2 five times for 23 hr each. The amount of LR2 applied to or present 2   In this section, the subcommittee reviewed the toxicity data on ammonium polyphosphates, including the toxicity assessment prepared by the U.S. Consumer Product Safety Commission (Ferrante 1999). 3   Each individual was treated with seven patches: two concentrations of LR2, two concentrations of each of two other flame retardants, and the control using a randomized sequence.

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Toxicological Risks of Selected Flame-Retardant Chemicals in the fabric was not reported. The application sites were observed for skin reactions 1 hr after each application. No erythema or edema was observed following any of the exposures to the fabric. Sensitization LR2 was found to be a poor skin-sensitizing agent in the Magnusson and Kligman maximization test (Safepharm 1993b). Initially, 20 female Dunkin-Hartley guinea pigs were treated with three 0.1-mL injections containing (1) Freund’s complete adjuvant plus water in a 1:1 ratio; (2) a 1% w/v dilution of test material in distilled water; and (3) a 1% w/v dilution of test material in Freund’s complete adjuvant plus distilled water, respectively. Topical induction was attempted on d 7 with undiluted LR2 (0.2–0.3 mL) applied to filter paper placed over the injection sites and covered for 48 hr. Scattered mild redness was observed at the injection sites in 20/20 animals treated with LR2 1 hr after removal of the filter paper and in 2/20 animals after 24 hr of removal of the filter paper. The animals were then challenged on d 21 for 24 hr with filter paper patches containing 0.1–0.2 mL of 50% or 75% (v/v) solutions of LR2. None of the 20 animals developed a tissue reaction to 50% or 75% LR2 24 or 48 hr after challenge. LR4 was also found to be a poor skin-sensitizing agent in the Magnusson and Kligman maximization test (Safepharm 1993c). Twenty female guinea pigs were initially injected intradermally with a 25% (w/v) solution of LR4. Topical induction was then attempted on d 7 with filter paper patches containing 75% (w/w) LR4 in distilled water. Only 1 of 20 animals had skin changes (scattered mild redness) at the application site 1 hr after removal of the patches. No animals had any visible skin reactions 24 hr after patch removal. None of the animals showed any tissue reaction either 24 or 48 hr after topical challenge with filter paper patches containing 50% or 75% solutions of LR4. Systemic Effects Acute dermal toxicity studies in Sprague-Dawley rats estimated the LD50s for LR2 and LR4 to be>2,000 mg/kg (Safepharm 1994, 1993d). Animals were treated with 2,000 mg/kg of neat LR2 or LR4 (1.59 mL/kg) to a skin area of approximately 10% of the rat total body surface area and covered for 24 hr. The bandage was then removed and the test sites were observed for skin reactions for 14 d. There were no deaths, signs of systemic toxicity, or skin irritation, and

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Toxicological Risks of Selected Flame-Retardant Chemicals weight gain was not affected in animals from either test group. No abnormalities were observed at necropsy. Other Systemic Effects No studies were identified that examined the effect of dermal exposure to APPs, ammonium ions, or polyphosphates on immunological, neurological, reproductive, or developmental parameters in humans or experimental animals. Additionally, no studies were identified that investigated the carcinogenicity of these compounds in humans or animals following dermal exposure. Inhalation Exposure Systemic Effects Only one inhalation toxicity study was located for APPs. Five male and five female Sprague-Dawley rats were exposed to Amgard MC(M) at 5,090 mg/m3 (nose-only exposure) for 4 hr and monitored for 14 d (Safepharm 1993e). The mass median aerodynamic diameter (MMAD) of the APP particles was 5.8 µm, and their geometric standard deviation was 0.35 µm. No deaths occurred among the exposed animals and weight gain was normal over the 14-d observation period. Exposed animals developed a hunched posture, decreased respiratory rate, lethargy, and tiptoe gait 4 hr after exposure, but these symptoms were not evident after 3 d of exposure. The 4-hr-inhalation LC50 for Amgard MC(M) was estimated to be >5,090 mg/m3 (>5.09 mg/L) for male and female rats. Material Safety Data Sheets (MSDSs) report that exposure to LR2 or LR4 may cause nose and upper respiratory tract inflammation (Albright and Wilson 1998a, 1998b, 1998d, 1998e). The MSDSs for both LR2 and LR4 (Albright and Wilson 1998d, 1998e) report a 1-hr-inhalation LC50 >20 mg/L (species and sex not reported). It is not known whether this is an experimentally determined or an estimated value. No data on the inhalation toxicity of ammonium ions or of other polyphosphates were identified. Other Systemic Effects No studies were identified that examined the toxic effects of inhalation exposure to APPs, ammonium, or polyphosphates on immunological, neurolog-

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Toxicological Risks of Selected Flame-Retardant Chemicals ical, reproductive, or developmental parameters in humans or laboratory animals. Additionally, no studies were identified that investigated the carcinogenic effects of these compounds following inhalation exposure. Oral Exposure Systemic Effects No oral toxicity data for APPs were located for humans. Typical human dietary phosphorous levels are not harmful, especially in the presence of adequate calcium and vitamin D intake. The mean daily phosphorus dietary intake for adult males and females is estimated to be 1,500 mg/d and 1,000 mg/d, respectively. However, if the intake of phosphorus from processed foods was included in these values, the estimated dietary intake of phosphorous would be up to 20% higher. It is known that high doses of ammonium ions can cause metabolic acidosis; persons with compromised liver function are at highest risk. Exposure to oral doses of 3.2 or 4.8 g ammonium/d as ammonium chloride for 5 d caused metabolic acidosis in two humans with compromised liver function (Sartorius et al. 1949). Effects secondary to acidosis include renal enlargement and demineralization of bone (ATSDR 1990). The oral LD50 for LR2 in rats was estimated to be >5,000 mg/kg (Inveresk 1990b). No deaths or clinical signs of toxicity were observed among five male and five female Sprague-Dawley rats given a single gavage dose of 5,000 mg/kg LR2 in distilled water and observed for 14 d. Weight-gain was normal in females during the second wk of the 2-wk observation period, but weight-gain in exposed males was reduced during the second wk. Gross post-mortem analysis of all dosed animals revealed no abnormalities. No deaths or toxicity symptoms were observed among five male and five female Sprague-Dawley rats treated with a single gavage dose of 2,000 mg/kg LR4 in distilled water (Safepharm 1993f). Body weight gain was normal for all animals during both wk of the observation period and no gross abnormalities were detected at necropsy. Therefore, it was concluded that the LD50 for LR4 in rats is >2,000 mg/kg. JECFA (1974) summarized a number of toxicity studies on phosphates and polyphosphates (see Table 12–2). The primary effect identified in these studies is kidney calcification (nephrocalcinosis), resulting from the precipitation of calcium phosphate due to an upset in phosphate homeostasis. JECFA (1974) noted that it is difficult to identify an effect level for nephrocalcinosis in toxic-

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Toxicological Risks of Selected Flame-Retardant Chemicals TABLE 12–2 Summary of Oral Toxicity Studies on Polyphosphates Species, Strain, Sex, Number Dietary Concentrations Tested (%) Duration Test Material Effect and Lowest Level in Dieta Reference Rat, NS, M, 5/dose 0, 0.2, 2, 10 1 mo Sodium hexametaphosphate Kidney inflammation at 2%; no kidney effects at 0.2% Hodge 1964cb Rat, NS, M, 5/dose 0, 0.2, 2, 10 1 mo Sodium tripolyphosphate Kidney inflammation at 2%; no kidney effects at 0.2% Hodge 1964cb Rat, NS, M/F, 36/sex/dose 0, 3, 5 24 wk Sodium tripolyphosphate Nephrocalcinosis at 3% Hahn and Seifen 1959c, as cited in JECFA 1974; Hahn et al. 1958c, as cited in JECFA 1974 Rat, NS, M/F, 36/sex/dose 0, 1.8, 3, 5 24 wk Graham’s salt Nephrocalcinosis at 3%; slight or absent nephrocalcinosis at 1.8% Hahn and Seifen 1959c, as cited in JECFA 1974; Hahn et al. 1958c, as cited in JECFA 1974 Rat, NS, M/F, 10/sex/dose 0, 0.5, 1, 2.5, 5 12 wk 1/3 Kurrol’s salt and 2/3 disodium/ tetrasodium diphosphate mixture Nephrocalcinosis at 2.5%; data on kidney at 1% not available van Esch et al. 1957c, as cited in JEFCA 1974; van Genderen 1958c, as cited in JECFA 1974 Rat, NS, M, 12/dose 0, 0.9, 3.5 (Mineral levels equalized) 150 d Sodium hexametaphosphate No kidney histopathology up to 3.5% Dymsza et al. 1959c Rat, NS, 30M/dose, 10F/dose 0, 0.5, 1, 2.5, 5 (Control diet contained 0.47% phosphorus) Life span, two generations of offspring 1/3 Kurrol’s salt and 2/3 disodium/ tetrasodium diphosphate mixture Renal calcification at 1% van Esch et al. 1957c, as cited in JECFA 1974

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Toxicological Risks of Selected Flame-Retardant Chemicals Species, Strain, Sex, Number Dietary Concentrations Tested (%) Duration Test Material Effect and Lowest Level in Dieta Reference Rat, NS, M/F, 50/sex/dose 0, 0.05, 0.5, 5 2 yr Sodium tripolyphosphate Increased kidney weight, intertubular calcification and fibrosis at 5%; no apparent effects at 0.5% Hodge 1964ab Rat, NS, M/F, 50/sex/dose 0, 0.05, 0.5, 5 2 yr Sodium hexametaphosphate Increased kidney weight and calcification at 5%; no apparent effects at 0.5% Hodge 1964bb F, female; M, male; NS, not specified. aNOAELs not identified because of the difficulty in determining (based on the available data) whether the next lower dose is really a NOAEL. bUnpublished study. cPublished study.

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Toxicological Risks of Selected Flame-Retardant Chemicals ity studies because renal calcification occurs naturally to some extent in control rats which is determined by dietary intake of calcium and vitamin D. Studies by van Esch et al. (1957, as cited in JECFA 1974) and Hodge (1964a, 1964b) suggest that chronic exposure to 0.5% polyphosphates in the diet may cause increased kidney weight but no kidney histopathology, while higher concentrations may cause kidney calcification when mineral levels are not equalized. Reproductive and Developmental Effects No information was found regarding the reproductive or developmental effects of APPs following oral exposure. Information on reproductive and developmental effects of ammonium ions was also not located. A study conducted by van Esch et al. (1957, as cited in JECFA 1974) found decreased fertility in rats that were treated with a mixture of one-third Kurrol’s salt and two-thirds diphosphate at a dietary concentration of 5%. No reproductive effects were reported at lower concentrations. Lang (1959, as cited in JECFA 1974), found no effects on reproduction in three generations of rats, each fed diets containing 0.4% or 0.75% phosphoric acid for 90 wk. No effects on fertility, litter size, neonate growth, or neonate survival was observed in a three-generation reproduction study in groups of rats administered 0.5% sodium tripolyphosphate or 0.5% sodium hexametaphosphate (Hodge 1964a, 1964b, and BIBRA 1964). There was also no apparent effect on the histopathology of major organs of the third generation. Other Systemic Effects No studies were identified that examined the immunological, neurological, or carcinogenic effects of oral exposure to APPs, ammonium ions, or polyphosphates. Ammonium ions and polyphosphates are unlikely to be carcinogenic, in light of the physiological roles of ammonium ions and phosphate in the body. Genotoxicity LR2 was not found to be mutagenic in 5 strains of Salmonella typhimurium (TA1535, TA1537, TA1538, TA98, TA100) exposed at concentrations of 25,

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Toxicological Risks of Selected Flame-Retardant Chemicals 75, 250, 750, 2,500, or 5,000 µg LR2/plate in the presence or absence of exogenous metabolic activation (rat liver S9) (Safepharm 1995). No other genotoxicity data were located for APPs or for other polyphosphates. QUANTITATIVE TOXICITY ASSESSMENT Noncancer Dermal Assessment There are no appropriate APP toxicity data available for deriving a dermal RfD. Inhalation RfC Only acute LC50 data are available for APPs; these data are insufficient for the derivation of an RfC. Oral RfD There are no subchronic or chronic toxicity data for LR2 and LR4, therefore it is not possible to derive an oral RfD for these compounds. IOM (1997) has developed a recommended dietary allowance (RDA) for phosphorous of 460 mg for children 1–3 yr old, 500 mg for children 4–8 yr old, 1,250 mg for ages 9–18 yr old, and 700 mg for ages 18 and older. The importance of the calcium:phosphate ratio was also noted; a ratio of less than 1:2 can cause resorption and loss of bone in animals. The Joint Expert Committee on Food Additives (JECFA) of the Food and Agriculture Organization of the World Health Organization (FAO/WHO) has established a maximum tolerable daily intake for phosphates, including APP, of 70 mg phosphorus/kg (JECFA 1974). This value includes all phosphates including those in food and applies to diets that are sufficient in calcium. The JECFA value of 70 mg/kg was derived from the lowest dietary concentration that produced nephrocalcinosis in the rat (1 % phosphorous) as described by van Esch et al. (1957, as cited in JECFA 1974). Extrapolation to the lowest phosphorous level that might conceivably cause nephrocalcinosis in humans was based on a daily food intake of 2,800 calories and a dietary phosphate level of 6,600 mg/d (JECFA 1974). Further details on the calculation were not provided.

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Toxicological Risks of Selected Flame-Retardant Chemicals The subcommittee chose to use the JECFA (1974) acceptable daily intake for phosphorous of 70 mg phosphorus/kg-d for deriving an oral RfD for APPs. The oral RfD was calculated by multiplying the approximate amount of phosphorous present, by weight, in LR2 and LR4. The solids portion of LR2 contains approximately 26% phosphorus, therefore, the oral RfD for LR2 is estimated to be 270 mg/kg-d (≈300 mg/kg-d). LR4 contains a minimum of 27% phosphorus by weight (Stewart Miller, Albright and Wilson, pers. commun., Nov. 1, 1999), corresponding to a minimal oral RfD of 260 mg/kg-d (≈300 mg/kg-d). The U.S. EPA has developed an RfD for ammonium sulfamate (EPA 1999), but the subcommittee did not use this RfD for APPs because the primary toxic moiety of ammonium sulfamate may be the sulfamate ion, rather than the ammonium ion. Cancer No data are available on the carcinogenic effects of APPs by any route of exposure. Because of the absence of carcinogenicity data, the subcommittee concluded that the carcinogenic potential of APPs cannot be determined. Carcinogenicity data on ammonium ion or polyphosphates were not located. However, based on the physiological roles of these compounds they would not be expected to be carcinogenic. 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 upholstered with APPs, that 1/4th of the upper torso is in contact with the upholstery, and that clothing presents no barrier. APPs are considered to be ionic and are essentially not absorbed through the skin. However, to be conservative, the subcommittee assumed that ionized APPs permeate 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 APPs of 7.5 mg/cm2, and Equation 1 in Chapter 3, the subcommittee calculated a dermal exposure level of 2.2 mg/kg-d. The oral RfD for APPs (300 mg/kg-d; see Oral RfD in Quantitative Toxicity

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Toxicological Risks of Selected Flame-Retardant Chemicals section) was used as the best estimate of the internal dose from dermal exposure. Dividing the exposure level by the oral RfD yields a hazard index of 7.3 ×10−3. Thus it was concluded that APPs used as FRs in upholstery fabric are not likely to pose a noncancer risk from dermal exposure. Inhalation Exposure Particles Inhalation exposure estimates for APPs were calculated using the exposure scenario described in Chapter 3. This scenario assumes that a person spends 1/4th of his or her life in a 30-m3 room containing 30m2 of APP-treated fabric and the room is assumed to have an air-change rate of 0.25/hr. It is also assumed that 50% of the APP present in 25% of the surface area of the treated fabric is released over 15 yr and that 1% of released particles are small enough to be inhaled. Particle exposure was estimated using Equations 4 and 5 in Chapter 3. The subcommittee estimated an upholstery application rate (Sa) for APPs of 7.5 mg/cm2. The release rate (µr) for APPs from upholstery fabric was estimated to be 2.3×10−7/d (by using Equation 5 in Chapter 3) yielding a room airborne particle concentration (Cp) of 2.9 µg/m3 and a short time-averaged exposure concentration of 0.71 µg/m3. The time-averaged exposure concentration for particles was calculated using Equation 6 in Chapter 3. In the absence of relevant inhalation exposure data, the subcommittee chose to estimate inhalation RfCs from oral RfDs. The subcommittee, however, recognizes that it is not an ideal approach and also recognizes that the estimated RfC levels might be considerably different than actual levels (if inhalation data were available). Extrapolating from one route of exposure (oral) to another (inhalation) requires specific knowledge about the uptake kinetics into the body by each exposure route, including potential binding to cellular sites. The subcommittee believes that its extrapolation of oral RfDs to inhalation RfCs is highly conservative; it assumes that all of the inhaled compound is deposited in the respiratory tract and completely absorbed into the blood. The NRC committee on Toxicology (NRC 1985) has used this approach when inhalation exposure data were insufficient to derive inhalation exposure levels. The subcommittee believes that such an approach is justified for conservatively estimating the toxicological risk from exposure to APPs. This RfC should be used as an interim or provisional level until relevant data become available for the derivation of an inhalation RfC for the calculation of a hazard index.

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Toxicological Risks of Selected Flame-Retardant Chemicals In order to calculate a hazard index for the inhalation route, a provisional inhalation RfC of 1,050 mg/m3 was derived using the oral RfD for ANTIBLAZE® LR2 and ANTIBLAZE® LR4 of 300 mg/kg-d, respectively and Equation 7 in Chapter 3. Division of the time-average exposure concentration of 0.71 µg/m3 by the provisional RfC for APPs of 1,050 mg/m3 yields a hazard index of 6.8×10−7. These findings suggest that under this worst-case exposure scenario, inhalation of APP particles from furniture upholstery is not likely to pose a noncancer risk to humans. Vapors APPs are ionic with negligible vapor pressure at ambient temperatures. Therefore, inhalation of APP vapor is not likely to pose a noncancer risk when incorporated into furniture upholstery. Oral Exposure The assessment of noncancer toxicological risk for oral exposure to APPs is based on the oral exposure scenario described in Chapter 3. This scenario assumes a child is exposed to APPs by sucking on 50 cm2 of fabric backcoated with APPs, 1 hr/d for 2 yr. The subcommittee estimated an upholstery application rate (Sa) for APPs of 7.5 mg/cm2. Oral exposure was calculated using Equation 15 in Chapter 3. The extraction rate (µw) for APPs was estimated to be 0.038 based on extraction data for organic phosphates in polyester fiber (McIntyre et al. 1995). The release rate from the fiber for estimating extraction was 0.06/d at 28°C calculated using the equation 2d/2 πR (d=film thickness, R=fiber radius) with a correction from fiber to film of a factor of 0.63. The worst-case average oral daily dose for APPs was estimated to be 0.059 mg/kg-d. Division of the oral dose estimate by the oral RfD for APPs of 300 mg/kg-d yields a hazard index of 2.0×10−4. These results indicate that under the given worst-case exposure scenario, oral exposure to APPs is not likely to pose a health risk to humans. Cancer There are no adequate data available to assess the carcinogenicity of APPs by the dermal, inhalation, or oral routes.

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Toxicological Risks of Selected Flame-Retardant Chemicals RECOMMENDATIONS FROM OTHER ORGANIZATIONS The Joint FAO/WHO Expert Committee on Food Additives (JECFA) established a maximum tolerable daily intake for phosphates, including APPs, of 70 mg phosphorus/kg-d (JECFA 1974). The Food and Nutrition Board of the Institute of Medicine (IOM 1997) derived a tolerable upper intake level (UL) for phosphorous of 4 g/d for adults 19–70 yr of age. The UL for persons over 70 yr is 3 g/d and accounts for the higher prevalence of impaired renal function among older persons. DATA GAPS AND RESEARCH NEEDS Key information, such as data on the leaching of APPs from furniture upholstery and data on dermal penetration of APPs, is not available. There are no data on subchronic or chronic toxicity, developmental or reproductive effects, and little information on the genotoxicity of APPs. However, acute studies indicate that these compounds are probably not very potent toxicants and current use of these compounds as food additives further supports this opinion. Hazard indices calculated using the given exposure scenarios were less than one for the dermal, inhalation, and oral routes of exposure, indicating that these chemicals are not likely to pose health risks. Therefore, the subcommittee concludes that no further research is needed for assessing health risks from exposure to ammonium polyphosphates. REFERENCES Albright and Wilson (Albright & Wilson UK Limited). 1998a. Safety Data Sheet (To requirements of Directive 91/155/EEC) ANTIBLAZE® LR2. Ref. FR/LR2/010, Revision 1. West Midlands, UK. Albright and Wilson (Albright & Wilson UK Limited). 1998b. Safety Data Sheet (To requirements of Directive 91/155/EEC) ANTIBLAZE® LR4. Ref. FR/LR4/012, Revision 1. West Midlands, UK. Albright and Wilson. 1998c. Product Summary for ANTIBLAZE® LR2, LR3, and LR4, Ammonium Polyphosphates. Glen Allen, VA. Albright and Wilson (Albright & Wilson Americas, Inc.). 1998d. Material Safety Data Sheet. ANTIBLAZE® LR2. Ref. PSMSD-30B, Revision 4. Glen Allen, VA. Albright and Wilson (Albright & Wilson Americas, Inc.). 1998e. Material Safety Data Sheet. ANTIBLAZE® LR4. Ref. PSMSD-30C, Revision 3. Glen Allen, VA. Albright and Wilson. 1999. Product Summary. [Online]. Available: http://www.albright-wilson.com/feb99/products/pda/flame/flame.htm ATSDR (Agency for Toxic Substances and Disease Registry). 1990. Toxicological

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Toxicological Risks of Selected Flame-Retardant Chemicals Profile for Ammonia. TP-90–03. Agency for Toxic Substances and Disease Registry, U.S. Public Health Service. BIBRA (British Industrial Biological Research Association). 1964. Summaries of toxicological data: Toxicity studies on phosphates. Food Cosmet. Toxicol. 2:147–154. Dymsza, H.A, G.Reussner, Jr., and R.Thiessen, Jr. 1959. Effect of normal and high intakes of orthophosphate and metaphosphate in rats. J. Nutr. 69:419–428. Ebel, J.P. 1958. Generalites sur la structure des phosphates condensés. Annales de la Nutrition et de L Alimentaion 12:57–97. EPA (U.S. Environmental Protection Agency). 1992. Dermal Exposure Assessment: Principles and Applications. EPA/600/8–91–011B. Office of Health and Environmental Assessment, U.S. Environmental Protection Agency, Washington, DC. EPA (U.S. Environmental Protection Agency). 1999. Integrated Risk Information System (IRIS). National Center for Environmental Assessment. [Online]. Available: http://www.epa.gov/iris U.S. Environmental Protection Agency, Washington, DC. Downloaded August, 1999. Ferrante, J. 1999. Toxicity review for ammonium polyphosphates. Memorandum, from Jacqueline Ferrante, Pharmacologist, Division of Health Sciences, to Ronald Medford, Assistant Executive Director for Hazard Identification and Reduction. U.S. Consumer Product Safety Commission. Washington, DC. Gosselin, R.E., A.Rothstein, G.J.Miller, and H.L.Berke. 1952. The hydrolysis and excretion of polymeric phosphate. J. Pharmacol. Exp. Ther. 106:180–191. Hahn, F., and E.Seifen. 1959. Further studies on the effect of chronic feeding of phosphates. Arzneimittel-Forschung 9:501–503. Hahn, F., H.Jacobi, and E.Seifen. 1958. Do ortho- and polyphosphates show variable compatibilities on chronic feeding? Arzneimittel-Forschung 8:286–289. Hodge, H.C. 1964a. Chronic oral toxicity studies of sodium tripolyphosphate in rats. [Summary]. Food Cosmet. Toxicol. 2:147–154. Hodge, H.C. 1964b. Chronic oral toxicity studies of sodium hexametaphosphate in rats. [Summary]. Food Cosmet. Toxicol. 2:147–154. Hodge, H.C. 1964c. Short-term oral toxicity tests of condensed phosphates in rats and dogs. [Summary]. Food Cosmet. Toxicol. 2:147–154. Inveresk (Inveresk Research International). 1989. AMGARD LR2: Acute Dermal Irritation Test in Rabbits. Project 243137. Report No. 5915. Musselburgh, Scotland. Inveresk (Inveresk Research International). 1990a. Fabric Treated with AMGARD LR1 and LR2: Dermal Irritancy Study in Rabbits—5 Day Repeat Application. Project 243137. Report No. 5920. Musselburgh, Scotland. Inveresk (Inveresk Research International). 1990b. AMGARD LR2: Acute Oral Toxicity (LD50) Test in Rats. Project 243137. Report 5910. Musselburgh, Scotland. Inveresk (Inveresk Research International). 1996. Three Flame-Retardant Formulations a Human Skin Patch Test (46 h Exposure). Project 591521. Report No. 14158. Tranent, Scotland. IOM (Institute of Medicine). 1997. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Food and Nutrition Board, Institute of Medicine. Washington, DC.: National Academy Press.

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Toxicological Risks of Selected Flame-Retardant Chemicals JECFA (Joint FAO/WHO Expert Committee onFood Additives). 1974. Toxicological Evaluation of Some Food Additives Including Anticaking Agents, Antimicrobials, Antioxidants, Emulsifiers and Thickening Agents. WHO Food Additives Series No. 5. Seventeenth report of the Joint FAO/WHO Expert Committee on Food Additives, Technical Report Series 539; FAO Nutrition Meetings Report Series, No. 53. JECFA (Joint FAO/WHO Expert Committee on Food Additives). 1982. Evaluation of Certain Food Additives and Contaminants. Twenty-sixth report of the Joint FAO/WHO Expert Committee on Food Additives. WHO Technical Report Series, No. 683. Lang, K. 1958. Kondensierte Phosphate in Lebensmitteln, Berlin: Springer. Lang, K. 1959. Z.Lebensmitt-Untersuch. 110:450. Lang, K. et al. 1955. Der stoffwechsel von polyphosphaten. Biochemische Zeitschrift. 327(8): 118–125. McIntyre, J.E., I.Holme, and O.K.Sunmonu. 1995. The desorption of model compounds from poly(ethylene terephthalate) fibre. Colourage 41(13)77–81. NRC (National Research Council). 1985. Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Volume 5. Committee on Toxicology. Board on Toxicology and Environmental Health Hazards, National Research Council. Washington, DC.: National Academy Press. Safepharm (Safepharm Laboratories, Limited). 1993a. AMGARD LR4: Acute Dermal Irritation Test in the Rabbit. Project 71/163. Derby, UK. Safepharm (Safepharm Laboratories, Limited). 1993b. AMGARD LR2: Magnusson & Kligman Maximisation Study in the Guinea Pig. Project 71/154. Derby, UK. Safepharm (Safepharm Laboratories, Limited). 1993c. AMGARD LR4: Magnusson & Kligman Maximisation Study in the Guinea Pig. Project 71/162. Derby, UK. Safepharm (Safepharm Laboratories, Limited). 1993d. AMGARD LR4: Acute Dermal Toxicity (Limit Test) in the Rat. Project 71/161. Derby, UK. Safepharm (Safepharm Laboratories, Limited). 1993e. AMGARD MC(M): Acute inhalation toxicity study. Four-hour exposure (nose-only) in the rat. Project 71/167. Safepharm (Safepharm Laboratories, Limited). 1993f. AMGARD LR4: Acute Oral Toxicity (Limit Test) in the Rat. Project 071/160. Derby, UK. Safepharm (Safepharm Laboratories, Limited). 1994. AMGARD LR2: Acute Dermal Toxicity (Limit Test) in the Rat. Project 71/320. Derby, UK. Safepharm (Safepharm Laboratories, Limited). 1995. AMGARD LR2: Reverse Mutation Assay “Ames Test” Using Salmonella Typhimurium. Project 071/385. Derby, UK. Sartorius, O.W., J.C.Roemmelt, and R.F.Pitts. 1949. The renal regulation of acid-base balance in man. IV. The nature of the renal compensation in ammonium chloride acidosis. J. Clin. Invest. 28:423–439. Schreier, K., and H.G.Nöller. 1955. Naunyn-Schmiedeberg’s Arch. Exp. Pathol. Pharmakol. 227:199. van Esch, G.J., H.H.Vink, S.J.Vit, and H.van Genderen. 1957. The physiologic action of polyphosphates. Arzneimittel Forsch. 7:172–175. van Genderen, H. 1958. Kondensierte Phosphate in Lebensmitteln. Berlin: Springer.