13
Phosphonic Acid, (3-{[Hydroxymethyl]amino}-3-Oxopropyl)-Dimethyl Ester

THIS chapter reviews the physical and chemical properties, toxicokinetics, toxicological, epidemiological, and exposure data on phosphonic acid, (3-{[hydroxymethyl]amino}-3-oxopropyl)-dimethyl ester, or PA. The subcommittee used that information to characterize the health risk from exposure to PA. The subcommittee also identified data gaps and recommended research relevant for determining the health risk from exposure to PA.

PHYSICAL AND CHEMICAL PROPERTIES

The physical and chemical properties of PA (CAS No. 20120–33–6) are presented in Table 13–1.

OCCURRENCE AND USE

PA flame retardants have been used in various applications in more than 30 countries for almost 40 yr (Ciba 1998a). Ciba-Geigy (formally American



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Toxicological Risks of Selected Flame-Retardant Chemicals 13 Phosphonic Acid, (3-{[Hydroxymethyl]amino}-3-Oxopropyl)-Dimethyl Ester THIS chapter reviews the physical and chemical properties, toxicokinetics, toxicological, epidemiological, and exposure data on phosphonic acid, (3-{[hydroxymethyl]amino}-3-oxopropyl)-dimethyl ester, or PA. The subcommittee used that information to characterize the health risk from exposure to PA. The subcommittee also identified data gaps and recommended research relevant for determining the health risk from exposure to PA. PHYSICAL AND CHEMICAL PROPERTIES The physical and chemical properties of PA (CAS No. 20120–33–6) are presented in Table 13–1. OCCURRENCE AND USE PA flame retardants have been used in various applications in more than 30 countries for almost 40 yr (Ciba 1998a). Ciba-Geigy (formally American

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Toxicological Risks of Selected Flame-Retardant Chemicals TABLE 13–1 Physical and Chemical Properties of Phosphonic Acid, (3-{[Hydroxymethyl]amino}-3-oxopropyl)-Dimethyl Ester Property Value Reference Chemical formula C6H14NO5P ChemID 1999 Structure     CAS Registry # 20120–33–6 ChemID 1999 Synonyms Dimethylphosphono-N-hydroxymethyl-3-propionamide; dimethyl (3-{[hydroxymethyl)]-amino}-3-oxopropyl)phosphonate; phosphonic acid, (2-{[hydroxymethyl)carbamamoyl}ethyl) dimethyl ester; N-methylol dimethylphosphonopropionamide ChemID 1999 Trade names Pyrovatex 3805®; Pyrovatex CP Neu/Special®; Pyrovatex 7620®; Amgard TFR1®; Spolapret OS® ChemID 1999 Molecular weight 211.15 ChemID 1999 Physical state White powder Ciba 1998a Solubility Miscible Ciba 1998a Partition coefficient −1.68 (pH 6.9; 25°C) Ciba 1998a Density 1.27–1.29 g/cm3 Ciba 1998a Cyanamide) is the leading manufacturer of PA-based flame retardants in the United States. PA flame retardants are produced by Ciba-Geigy include Pyrovatex CP Neu (or New)/Special® and Pyrovatex® 7620. Thor Chemical (South Africa) and Albright & Wilson (United States) have produced PA-based flame retardants similar to Pyrovatex CP®. Pax Enterprise Pvt. Ltd., of India, advertises a flame retardant for cellulose-rich fabrics that has chemical characteris-

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Toxicological Risks of Selected Flame-Retardant Chemicals tics similar to those of the Pyrovatex CP® (see Appendix B, Table 2 for additional flame-retardant products containing PA). PA-based flame retardants have been used in residential furniture in the United Kingdom to meet flammability standards imposed in 1988. In both the United Kingdom and the United States, PA flame retardants have been used to treat commercial furniture, draperies, and work clothing (FRCA 1998). In addition, Pyrovatex CP® was used as a flame retardant in children’s sleepware until 1998, but was voluntarily withdrawn by Ciba from this market in 1999 because of questions about the durability of its flame-retardent properties after repeated washing. The volume of PA flame retardants used in the United States is not known. Estimated use of PA-based flame retardants in the United Kingdom is about 600 tons/yr, and about 80 tons are used for treating textiles used in the manufacture of residential furniture (A.R.Horrocks, Bolton Institute, pers. commun., August 24, 1999). PA and its derivatives are affixed directly to cellulose fibers in fabrics by the application of high heat in the presence of cross-linking agents such as melamine and glyoxal. Cross-linking imparts resistance to laundering through several washings (Ciba 1998b). Applied PA can undergo slow ambient hydrolysis and release from the fabric over a period of years (see Appendix B, Case 3). The interaction of PA, cellulose, and resin compounds prevents the formation of flammable gases during pyrolysis and severely retards combustion. If flame or high heat comes into contact with the PA-resin finish, the cellulose dehydrates, forms a carbon scaffold with PA and the cross-linking resin, and counteracts the penetration of heat and the spread of fire (Ciba 1998b). Production and marketing guidelines state that the weight of Pyrovatex CP New/Special®/ unit fabric area should not be less than 150 g/m2 (Ciba 1998b). The process of affixing PA-based flame retardants to textiles takes place at the end of the textile-milling process. Textiles are treated with PA flame retardants by dipping the fabric in vats that contain Pyrovatex CP Neu®1 or other PA flame retardant, which typically contains a cross-linking resin, an acid catalyst for the cross-linking reaction (such as phosphoric acid), fabric softeners, and fabric-wetting agents. The fabric is then heated to 160° C for 90 sec to cure the cross-linking resin. The treated fabric is then neutralized in an alkaline solution and excess flame retardant is removed. It has been acknowledged by one manufacturer of PA-based flame retardants that this process increases the handling of fabrics and the time required to bring a milled textile to market. Therefore, treatment of upholstery with PA is less economically appealing as 1   Pyrovatex CP Neu® contains (by weight) 40% PA, 8% glyoxal resin, 2% melamine resin, 4% fabric softener (silicone-polyethylene blend), and 2.5% phosphonic acid. Competing PA-containing flame retardants are expected to contain similar components.

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Toxicological Risks of Selected Flame-Retardant Chemicals compared with use of latex back-coating. In the United Kingdom, back-coated fabrics are generally cheaper than PA-treated fabrics and, as a consequence, dominate the upholstery market. TOXICOKINETICS Absorption Dermal The dermal permeability of PA was evaluated in an in vitro pig-ear skin assay (CCR 1993a), which has been shown to be an adequate model of human dermal absorption. PA was extracted from a 100% cotton textile treated with Pyrovatex CP Neu® using a synthetic perspiration extract (the concentration of PA was not reported). Diffusion chambers were constructed with freshly shaved pig skin taken from the outer ear (2–3 mm thick). The surface area of skin separating the donor and receptor chambers was about 1.13 cm2. No PA was detected in the receptor chamber after 0, 0.5, 1, 2, 4, 6, 8, and 24 hr. However, it is not known whether PA was extracted from the treated textile in sufficient quantities to create a concentration gradient large enough to drive diffusion of PA across the dermal barrier. The subcommittee found no studies that measured the absorption of PA through the lung epithelium or gut wall following inhalation or oral exposure. Distribution, Metabolism, and Excretion The subcommittee found no studies that addressed the metabolism, distribution, or excretion of PA in animals or humans following dermal, oral, or inhalation exposure. HAZARD IDENTIFICATION2 All PA-containing commercial FR preparations contain PA as the main ingredient and also contain melamine or a similar polymeric resin or resins, phosphoric acid, detergents, fabric-wetting agents, and possibly other com- 2   In this section, the subcommittee reviewed data on toxicity of phosphonic acid, (3-{[hydroxymethyl]amino}-3-oxopropyl)-dimethyl ester, including the toxicity assessment prepared by the U.S. Consumer Product Safety Commission (Bittner 1999).

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Toxicological Risks of Selected Flame-Retardant Chemicals pounds including known impurities (Kapura 1994). All studies discussed below are on PA, unless otherwise indicated. Dermal Exposure There are no peer-reviewed, published studies on the dermal effects of PA flame retardants in humans or animals. Several unpublished dermal-toxicity studies of PA were conducted for Ciba-Geigy by the contract laboratory Research & Consulting Company AG. These are described below. Irritation and Sensitization PA was found to be nonirritating to the skin of male and female rabbits (RCC 1992a). PA (0.5 mL/animal) was applied to the shaved skin of New Zealand rabbits (one male and two females) and covered with a dressing. The site was uncovered after 4 hr and evaluated for dermal toxicity after 1, 24, 72 hr, and 7 d. Very slight (nearly imperceptible) erythema was observed in 2 of the 3 rabbits after 1 hr and in 1 of the 3 rabbits after 24 hr. Erythema was not observed in any of the animals 48, 72 hr, or 7 d after application. Local edema was not observed in any of the animals. Fifty volunteers were exposed to PA or a commercial preparation (Muster 2, containing PA at 380 g/L) in combination with other fabric-finishing chemicals (Tronnier 1989a, b). PA or Muster 2 was spotted onto a bandage and applied to the arms of the volunteers, and the test site was assessed for irritation and sensitization. Some volunteers in each study had irritation 48 hr after application, but these reactions subsided within 72 hr. No sensitization reactions were observed in an 11 -person subset known to have allergies. No other details are provided. PA produced moderate skin sensitization when tested in guinea pigs using the maximization test (RCC 1992b). Initially, three groups of 20 female guinea pigs were given three, 0.1 mL intradermal injections of (a) a 50:50 mixture of Freund’s complete adjuvant and physiological saline, (b) PA diluted to 5% with physiological saline, and (c) PA diluted to 5% in a 50:50 emulsion of Freund’s complete adjuvant and physiological saline. Control animals were given similar injections but without PA. The skin was treated with 10% sodium lauryl sulfate in petrolatum oil on d 7 to enhance skin sensitization. On d 8, PA was applied to the test sites and covered. Controls were similarly treated with physiological saline. The application sites were then uncovered and assessed for erythema and edema 1 and 2 d after the removal of the dressing. At 2 wk, test and control animals were challenged with undiluted PA on the left and right flanks and covered. The sites were then uncovered 1 d after challenge and assessed for

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Toxicological Risks of Selected Flame-Retardant Chemicals erythema and edema reactions. Ten of 19 animals had skin reactions the next day after treatment. Six of 19 animals had skin reactions 2 d after challenge. PA was of moderate allergenic potency in female albino guinea pigs according to the criteria developed by Magnusson and Kligman (1969). PA did not induce sensitization in the albino guinea pig maximization test when administered as a 25% solution dissolved in distilled water using identical protocols (RCC 1993). Systemic Effects No systemic effects were observed in Wistar rats treated topically with a single application of PA at a concentration of 2,000 mg/kg (RCC 1992c). Rats (5 male, 5 female) were topically treated with 2 mL of PA and the sites were covered for 24 hr. The dressing was removed and the sites were assessed for skin reactions four times during d1 and once on d 2–15 using methods developed by Noakes and Sanderson (1969). Animals were also evaluated for clinical signs of toxicity. All animals were killed and necropsied on d 15. Over the 15-d observation period, no deaths occurred, and no signs of systemic toxicity were observed. Skin changes were observed at the application site (scaling, yellowing) that disappeared 11–14 d post exposure. Neurological Effects No changes in general behavior or motor susceptibility (such as spasms, clonic muscle spasms, tremor, and muscle twitching) were observed among male and female Wistar rats 15 d after a single, 2 mL dermal application of PA at 2,000 mg/kg (RCC 1992c). Other Systemic Effects No studies were found on the immunological, reproductive, developmental, or carcinogenic effects of PA flame retardants following dermal exposure of humans and animals. Inhalation Exposure Systemic Effects There are no published studies on the toxic effects of PA in humans or ani-

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Toxicological Risks of Selected Flame-Retardant Chemicals mals following inhalation exposure. There is one unpublished acute inhalation study of PA (RCC 1992d). No deaths occurred and there were no clinical signs of toxicity among Wistar rats (5 male and 5 female) exposed (nose-only) to PA at a target concentration of 4.82 mg/L for 4 hr. Animals were monitored for 15 d after exposure. Inhalation exposure was conducted using the methods of Cannon et al. (1983). The nominal concentration of PA used was 4.83 mg/L, and the gravimetric concentration was 2.71±1.44 mg/L (mean±standard deviation). Ninety-four percent of the PA particles were smaller than 3 µm. No significant changes in body weight occurred in treated animals. Isolated dark red foci were observed in the caudal lung lobes of 2 males and 2 females exposed to PA. However, the authors did not comment on the significance of this finding. Other Systemic Effects No studies were found on the immunological, neurological, reproductive, developmental, or the carcinogenic effects of PA following inhalation of PA by humans or animals. Oral Exposure The subcommittee found no studies on toxic effects of PA following oral exposure in humans. Suzuki et al. (1983) reported that the oral LD50 of PA administered to rats as a 50% solution in water was 13,000 mg/kg (95% confidence interface [C.I.], 11,400–14,800 mg/kg) in males and 13,200 mg/kg (95% C.I., 12,300–14,200 mg/kg) in females. Five rats of each sex were given a single dose of PA by oral gavage of 9,100, 10,400, 12,000, 13,600, 15,900, or 18,300 mg/kg and observed for 7 d. Death occurred within 1 hr to 3 d. Toxic signs included depression of spontaneous movement, piloreaction, diarrhea, hypothermia, and bloody lacrimation. Eldefrawi et al. (1977) reported that the LD50 of PA in rats was greater than 10,000 mg/kg, but provided no reference for this statement finding. Ishizu (1975) reported that no deaths were observed in mice 72 hr after they received a dose of 10,000 ppm PA. The subcommittee found a number of unpublished oral-toxicity studies of PA3 conducted for Ciba-Giegy (CCR 1992a; RCC 1992e, f). No deaths, clinical signs of toxicity, or structural organ changes were observed among male and 3   PA is referred to as FAT 80'001/I in these studies.

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Toxicological Risks of Selected Flame-Retardant Chemicals female Wistar rats over a 15-d period after treatment with a single dose of PA4 of 2,000 mg/kg by oral gavage (RCC 1992e). In a 5-d range-finding study, no deaths occurred among male or female adult Wistar rats given PA by gavage doses of 0, 50, 200, or 1,000 mg/kg (RCC 1992f). The acute toxicity of PA was assessed in NMRI mice in a range-finding study (CCR 1992a). Mice (2/sex/dose) given PA by gavage doses of 2,000, 3,000, 4,000, or 5,000 mg/kg exhibited apathy, a reduction in spontaneous activity, and eyelid closure 1 to 72 hr after dosing. PA was found to be a low potency toxicant when administered to Wistar rats over 28 d (RCC 1992g). Male and female Wistar rats (five/sex-dose group) were given PA by gavage once a d for 28 d at 0, 50, 200, or 1,000 mg/kg body weight. A second group of rats (five/sex) was given PA by gavage once a d for 28 d at 1,000 mg/kg and was sacrificed 15 d after dosing was ended. All animals were necropsied and assessed for pathological changes. There were no treatment-related deaths or effects on clinical signs, blood or clinical biochemistry, urinary excretion, eye chemistry or pathology, gross pathology, or histopathology (adrenals, heart, kidneys, liver, spleen, and stomach) in any of the treatment groups. However, heart weights and heart-body weight ratios were significantly higher among female rats in the 50-mg/kg dose group than in female controls. However, there was no dose-response associated with these increases, therefore the subcommittee concluded that these findings were not treatment-related. Females in the 200-mg/kg dose group had a slightly but statistically significantly higher pituitary:body weight ratio than female controls. High-dose (1,000 mg/kg) males had significantly higher body weight and food consumption over d 22–28 than male controls, but these changes were considered to be coincidental. High-dose males from the recovery group had slightly but significantly increased (p≤0.05) spleen:brain and decreased thyroid:body weight ratios (p≤0.001). These changes were minor, and no pathological findings accompanied these weight changes. Pathological examination of other organs and tissues did not reveal the number or types of lesions encountered to be in excess of those expected in animals of this strain and age. Immunological Effects Saliva leachates of PA-treated textiles were tested in the female mouse lymphocyte-blastogenesis assay and were not effective in inducing immunotoxicity (CCR 1994a). The amount of PA in the extracts was not reported. Splenocytes were exposed to the extracts for 1 hr at subcytotoxic doses and 4   Dissolved in deionized water unless noted otherwise.

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Toxicological Risks of Selected Flame-Retardant Chemicals then they were exposed to mitogens Con A and LPS for 72 hr. Exposure to saliva extracts at concentrations of 80–84% reduced splenocyte viability. Lower concentrations did not induce a mitogenic response (proliferation). Concommitant assays with positive control substances produced the expected dose-dependent suppression of T-lymphocyte blastogenesis. Neurological Effects No changes in general behavior or motor function (spasms, clonic muscle spasms, tremor, muscle twitching) were observed in male and female Wistar rats 15 d after a single dose of PA by oral gavage of 2,000 mg/kg (RCC 1992e). Apathy, a reduction in spontaneous activity, and increased incidence of eyelid closure was observed in mice 72 hr after being given a single dose of PA by oral gavage of 2,000, 3,000, 4,000, or 5,000 mg/kg (CCR 1992a). These findings could be attributed to either a direct or indirect high-dose effect on the nervous system. Other Systemic Effects No studies were found on the reproductive, developmental, or carcinogenic effects of PA following oral exposure of humans and experimental animals. Genotoxicity PA was mutagenic in the Ames test (Salmonella typhimurium TA98, TA100, and TA1537); however, the authors did not report the concentration of PA tested or whether the testing was conducted in the presence of exogenous metabolic activation (Ishidate and Yoshikawa 1980). PA (at a concentration of 1 mg/L) induced chromosomal aberrations in Chinese hamster lung fibroblast cells (CHL) in the presence of exogenous metabolic activation (Ishidate and Yoshikawa 1980). PA (450 mg/L) caused a statistically significant increase in chromosomal breaks (excluding gaps) in Chinese hamster cells (Don-6) and human fibroblast cells (HE 2144) (Sasaki et al. 1980). An unpublished study found PA to be nonmutagenic when tested at concentrations of 10, 33, 100, 333, 1,000, or 5,000 µg/plate in the Ames test (S. typhimurium TA98, TA100, TA1535, TA1537, and TA1538) with or without metabolic activation (from Wistar rat S9 microsomal fraction) (CCR 1992b). PA was toxic to S. typhimurium at 5,000 µg/plate without metabolic activation. Repeat assays confirmed these findings. The subcommittee concluded that this

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Toxicological Risks of Selected Flame-Retardant Chemicals study adequately characterized the lack of genotoxicity of PA in the Ames assay. Saliva leachates of textile samples treated with PA were judged to be nonmutagenic in S. typhimurium strains TA98 and TA100 with or without the incorporation of rat S9 microsomal fraction (CCR 1994b). The amount of PA in these extracts was not reported. Two unnpublished in vivo studies did not find evidence of the genotoxicity of PA (CCR 1992a, 1993b). PA did not induce DNA damage in hepatocytes of male Wistar rats treated orally with PA either at doses of 200 or 2,000 mg/kg for 16 hr or 2,000 mg/kg for 2 hr (CCR 1993b). The subcommittee notes that there was no evidence that the maximum tolerated dose of PA was used in this experiment. Treatment with positive control compounds produced genotoxicity. The number of polychromatic erythrocyte micronuclei were not increased at doses of 24, 48, or 72 hr in male or female NMRI mice treated with a single dose of PA (at 5,000 mg/kg) compared with controls (CCR 1992a). Clinical signs of toxicity were observed in all treated animals and treatment of the mice with positive-control chemicals produced genotoxicity. QUANTITATIVE TOXICITY ASSESSMENT The current toxicity database for PA and the subcommittee’s corresponding risk assessments do not take into consideration the presence of polymer resins, PA-polymer resin conglomerates, formaldehyde, or other unidentified compounds that might be present in upholstery treated with PA. Noncancer Dermal Assessment The available data on PA are inadequate to derive a dermal reference dose (RfD). Only one unpublished study for PA is available and involves only acute exposure (see RCC 1992c). Human data suggest that PA is not a potent skin irritant. Inhalation RfC The toxicity data on PA are inadequate for deriving an inhalation reference concentration (RfC). Only one inhalation toxicity study is available for PA, but involves only acute exposure in rats. No human toxicity data are available for PA.

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Toxicological Risks of Selected Flame-Retardant Chemicals Oral RfD There are no adequate toxicity data for deriving an oral RfD for PA. No human toxicity data are available on PA, and no subchronic or chronic toxicity studies have been done in laboratory animals. Cancer There are no studies available on the carcinogenicity of PA. The available data are not sufficient for making conclusive judgments on the genotoxic potential of PA. The subcommittee found one in vitro mutagenicity study of PA in the peer-reviewed literature, and its results were inconclusive. A well-conducted but unpublished Ames assay found PA to be nonmutagenic when tested in the presence or absence of exogenous metabolic activation (CCR 1992b). The in vivo data for the clastogenicity of PA are equivocal (Ishidate and Yoshikawa 1980; Sasaki et al. 1980). EXPOSURE ASSESSMENT AND RISK CHARACTERIZATION The following exposure and risk assessment assumes that PA is not chemically altered during the application and curing processes and that leachates from treated upholstery are unreacted PA. The subcommittee notes that this assumption may be inaccurate, but currently there are no data on the chemical forms and amounts of cured PA that is present in PA-treated upholstery following the curing process. Some unreacted PA is left on the upholstery surface after curing, but in reality much of the free PA present on treated upholstery evaporates from the fabric or is washed away in the alkaline wash after curing. Therefore, there is very little free PA present on newly treated upholstery that is available for uptake by end-users. It is known that some PA can be released from the treated fabric by ambient hydrolysis over a period of years (see Appendix B, Case 3). Noncancer Dermal Exposure Dermal exposure to PA was estimated using the dermal exposure scenario described in Chapter 3. This exposure scenario assumes that an adult spends 1/4th of his or her time sitting on furniture upholstery backcoated with PA and

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Toxicological Risks of Selected Flame-Retardant Chemicals also assumes 1/4th of the upper torso is in contact with the upholstery and clothing presents no barrier. Exposure to other chemicals present in the backcoating was not included in this assessment. As a first estimate of exposure, it was assumed that skin, clothing, and the upholstery did not impede dermal exposure to PA. It was also assumed that there would be sufficient water present from sweat to facilitate dissolution of PA from the material and absorption through the skin. In this scenario, only the dissolution rate of PA from the material is assumed to be the limiting factor in absorption by the body. It is assumed that all of the PA that dissolves is immediately absorbed into the body by the sitting person. Dermal exposure was estimated using Equation 1 in Chapter 3. For this calculation, the subcommittee estimated an upholstery application rate (Sa) for PA of 3.6 mg/cm2. The extraction rate (µw) for PA was estimated to be 0.001 based on laundering data (Horrocks et al. 1992). Using these assumptions, an estimated absorbed daily dose of 0.028 mg/kg was calculated for PA. No adequate data are available to calculate dermal RfD for PA. In addition, PA is likely to polymerize after application to the upholstery fabric; therefore, exposure to PA is not likely to occur and it should not pose a toxic risk by the dermal route of exposure when used as a FR in furniture upholstery. Inhalation Exposure Particles Inhalation exposure estimates for PA 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 30 m2 of PA-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 PA present in 25% of the surface area of the treated fabric is released over 15 yr and 1 % of released particles are of the size that can be inhaled. Particle exposure was estimated using Equations 4 and 5 in Chapter 3. The subcommittee estimated an upholstery application rate (Sa) for PA of 3.6 mg/cm2. The release rate (µr) for PA from upholstery fabric was estimated to be 2.3×10−7/d (using Equation 5 in Chapter 3) yielding a room airborne particle concentration (Cp) of 1.4 µg/m3 and a short time-averaged exposure concentration of 0.35 µg/m3. The time-averaged exposure concentration for particles was calculated using Equation 6 in Chapter 3. No inhalation RfC is available for calculating a hazard index. Therefore, no conclusions can be drawn about

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Toxicological Risks of Selected Flame-Retardant Chemicals the noncancer toxicological risks posed by the inhalation of PA-containing particles. Vapors In addition to the possibility of release of PA in particles from worn upholstery fabric, the subcommittee considered the possibility of the release of PA by evaporation. This approach is described in Chapter 3, and uses an exposure scenario similar to that described above for exposure to PA particles. The rate of flow of PA vapor from the room is calculated using Equations 8–11 in Chapter 3. A saturated vapor concentration (Cv) of 200,000 mg/m3 was estimated for PA. The application density (Sa) for PA in the treated upholstery was estimated as 3.6 mg/cm2. Using the parameters described, the equilibrium room-air concentration of PA was estimated to be 170,000 mg/m3. The short-term time-average exposure concentration for PA was estimated as 42,500 mg/m3 using Equation 12 in Chapter 3 and the equilibrium room-air concentration for PA. It was estimated that this concentration could be maintained for approximately 39 minutes. These results suggest that the vapor inhalation scenario is unrealistic for PA-treated furniture in a residential setting. This conclusion refers to the worst case scenario of a fully hydrolyzed treatment which is a worst-case assumption. In practice, and with an acceptable fabric cleaning regime (see Appendix B, Case 3), the flame retardant will most likely be in a fully polymerized form and so have zero vapor pressure. No inhalation RfC is available for calculating a hazard index, therefore no conclusions can be made about the noncancer toxicological risks posed by the inhalation of PA vapors. Oral Exposure The assessment of noncancer toxicological risk for oral exposure to PA is based on the oral exposure scenario described in Chapter 3. This scenario assumes a child is exposed to PA by sucking on 50 cm2 of fabric treated with PA, 1 hr/d for two yr. The subcommittee estimated an upholstery application rate (Sa) for PA of 3.6 mg/cm2. Oral exposure was calculated using Equation 15 in Chapter 3. The extraction rate (µw) for PA was estimated to be 0.001 based on laundering data (Horrocks et al. 1992-see Appendix B, Case 2). The worst-case average oral daily dose for PA was estimated as 0.00075 mg/kg-d. Therefore, the level of exposure to PA by the oral route is anticipated

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Toxicological Risks of Selected Flame-Retardant Chemicals to be small, given the worst-case parameters and conditions used in the exposure calculation. No oral RfD is available for calculating a hazard index; therefore, no conclusions can be drawn concerning noncancer toxicological risks associated with oral exposure to PA in upholstered fabric. Cancer No data are available on the carcinogenicity of PA by the dermal, oral, or inhalation routes of exposure. RECOMMENDATIONS FROM OTHER ORGANIZATIONS The subcommittee is not aware of any exposure limits that have been recommended by any regulatory agency or other organizations. DATA GAPS AND RESEARCH NEEDS Key information on the types and amounts (and ratios) of PA derivatives present in treated upholstery are not available. Information on exposure levels to PA from the dermal, inhalation, and oral routes are also not available. Data on the dermal penetration of PA, as well as the amounts of PA leached from treated fabric by simulated body fluids, are also not available. Subchronic or chronic toxicity data are not available for the dermal, inhalation, or oral routes of exposure. There are no data on the effects of PA on reproduction or development. It is important to note that PA polymerizes within the fiber and fabric structure and may also react with other FR formulation components present; therefore, it will likely undergo other chemical changes that could alter its chemical properties and toxicity. It is also likely that oxidized forms of this FR will be present in or on the aged FR-treated fabric. The subcommittee recommends that research be conducted to determine whether new chemical species are formed and, if so, to identify them. REFERENCES Bittner, P. 1999. Toxicity review for phosphonic acid, (3-{[hydroxymethyl]amino}-3-oxopropyl)-dimethyl ester. Memorandum, dated March 3, 1999, from Patricia Bittner, Toxicologist, Division of Health Sciences, to Ronald

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Toxicological Risks of Selected Flame-Retardant Chemicals Medford, Assistant Executive Director for Hazard Identification and Reduction, U.S. Consumer Product Safety Commission, Washington, DC. Cannon, W.C., E.F.Blanton, and K.E.McDonald. 1983. The flow-past chamber: An improved nose-only exposure system for rodents. Am. Ind. Hyg. Assoc. J. 44(12):923–928. CCR (Cytotest Cell Research GmbH & Co. KG). 1992a. Micronucleus Assay in Bone Marrow Cells of the Mouse with FAT 80'001/I. CCR Project 269537. Study conducted by Cytotest Cell Research GmbH & Co. KG for Ciba-Geigy AG. CCR (Cytotest Cell Research GmbH & Co. KG). 1992b. Salmonella Typhimurium Reverse Mutation Assay with FAT 80'001/I. CCR Project 269515. Study conducted by Cytotest Cell Research GmbH & Co. KG for Ciba-Geigy AG. CCR (Cytotest Cell Research GmbH & Co. KG). 1993a. Skin permeability in vitro absorption through pig ear skin with Pyrovatex® CP neu. CCR Project 310228. Study conducted by Cytotest Cell Research GmbH & Co. KG for Ciba Speciality Chemicals Corp. CCR (Cytotest Cell Research GmbH & Co. KG). 1993b. In vivo/in vitro Unscheduled DNA Synthesis in Rat Hepatocytes withFAT 80'001/I. CCR Project 404818. Study conducted by Cytotest Cell Research GmbH & Co. KG for Ciba-Geigy AG. CCR (Cytotest Cell Research GmbH & Co. KG). 1994a. Lymphocyte Blastogenesis Assay on Spleenocytes of Mice In Vitro with Pyrovatex CP New (Saliva Extract of the Textile Sample). CCR. Projects 477104, 477204, 477304. Study conducted by Cytotest Cell Research GmbH & Co. KG for Pfersee Chemie GmbH. CCR (Cytotest Cell Research GmbH & Co. KG). 1994b. Salmonella Typhimurium Reverse Mutation Assay with Pyrovatex CP New (Saliva Extract of the Textile Sample). CCR. Projects 477101, 477201, 477301. Study conducted by Cytotest Cell Research GmbH & Co. KG for Pfersee Chemie GmbH. ChemID. 1999. Chemical ID Data Base. National Library of Medicine, National Toxicology Information Program, Bethesda, MD. Ciba (Ciba Specialty Chemicals Corporation). 1998a. Pyrovatex® Flame Retardants for Use in Upholstered Furniture. Presentation to the United States Consumer Product Safety Commission, May 5–6, 1998 by Carl D’Ruiz and D.Parkes. Ciba Specialty Chemicals, Consumer Care Division. High Point, NC. Ciba (Ciba-Geigy Corporation). 1998b. Fabric Processing and Finishing: Cotton-Pyrovatex®. Production and Marketing Guidelines. Ciba-Geigy Consumer Care. Eldefrawi, A.T., N.A.Mansour, L.B.Brattsten, V.D.Ahrens, and D.J.Lisk. 1977. Further toxicologic studies with commercial and candidate flame-retardant chemicals. Part II. Bull. Environ. Contain. Toxicol. 17(6):720–726. FRCA (Fire Retardants Chemicals Association). 1998. Textile Flame-Retardant Applications by Product Classes for 1997 Within and Outside of the United States. Submitted to the U.S. Consumer Product Safety Commission, prepared by Fire Retardants Chemicals Association. Lancaster, PA. Horrocks, A.R., J.Allen, S.Ojinnaka, and D.Price. 1992. Influence of laundering on durable flame-retarded cotton fabrics-Part 1. Effect of oxidant concentration and detergent type. J. Fire Sci. 10:335–351. Ishizu, S. 1975. Toxicity of organophosphorus retardants. Kobunshi 24:788–92. Ishidate, M., Jr., and K.Yoshikawa. 1980. Chromosome aberration tests with Chinese

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Toxicological Risks of Selected Flame-Retardant Chemicals hamster cells in vitro with and without metabolic activation—A comparative study on mutagens and carcinogens. Arch. Toxicol. Suppl. 4:41–44. Kapura, A.A. 1994. Chemistry of flame retardants. II. NMR and HPLC analysis of Pyrovatex CP. J. Fire Sci. 12:3–12. Magnusson, B., and A.M.Kligman. 1969. The identification of contact allergens by animal assay. The guinea pig maximization test. J. Invest. Dermatol. 52(3):268–76. Noakes, D.N., and D.M.Sanderson. 1969. A method for determining the dermal toxicity of pesticides. Br. J. Ind. Med. 26(1):59–64. RCC (Research & Consulting Company AG). 1992a. Primary Skin Irritation Study with Fat 80’001/i in Rabbits (4-hour Semi Occlusive Application). RCC Project 316697. Study conducted by RCC Research & Consulting Company AG for Ciba Speciality Chemicals Corp. RCC (Research & Consulting Company AG). 1992b. Contact Hypersensitivity to FAT 80’001/I in Albino Guinea Pigs Maximization-Test. RCC Project 316710. Study conducted by RCC Research & Consulting Company AG for Ciba-Geigy AG. RCC (Research & Consulting Company AG). 1992c. Acute Dermal Toxicity Study With FAT 80’001/I in Rats. RCC Project 316686. Study conducted by RCC, Research & Consulting Company AG for Ciba-Geigy AG. RCC (Research & Consulting Company AG). 1992d. 4-Hour acute inhalation toxicity study (limit test) with FAT 80’001/I in rats. RCC Project 317002. Study conducted by RCC Research & Consulting Company AG for Ciba Speciality Chemicals Corp. RCC (Research & Consulting Company AG). 1992e. Acute Oral Toxicity Study with FAT 80’001/I in Rats. RCC Project 316675. Study conducted by RCC Research & Consulting Company AG for Ciba-Geigy AG. RCC (Research & Consulting Company AG). 1992f. 5-Day Oral Toxicity (Range-Finding) Study With FAT 80’001/I in Rats. RCC Project 316721. Study conducted by RCC Research & Consulting Company, Ltd. for Ciba-Geigy AG. RCC (Research & Consulting Company AG). 1992g. Subacute 28-Day Oral Toxicity (Gavage) Study With FAT 80’001/I in the Rat. RCC Project 316732. Study conducted by RCC Research & Consulting Company, Ltd. for Ciba-Geigy AG. RCC (Research & Consulting Company AG). 1993. Contact Hypersensitivity to Pyrovatex CP Neu in Albino Guinea Pigs Maximization-Test. RCC Project 347692. Study conducted by RCC Research & Consulting Company AG for Pfersee Chemie GmbH. Sasaki, M., K.Sugimura, M.A.Yoshida, and S.Abe. 1980. Cytogenetic effects of 60 chemicals on cultured human and Chinese hamster cells. Kromosomo (Tokyo) 2:574–584. Suzuki, Y., K.Naito, and M.Tobe. 1983. Acute toxicity of chemicals used in the household [English abstract]. Eisei Shikensho Hokoku 101:152–6. Tronnier, H. 1989a. Dermal irritation/sensitization study of parent compound in human volunteers. [Report in German]. Study conducted by Prof. Dr. H.Tronnier, Dortmund, Germany, for Ciba Speciality Chemicals Corp. Tronnier, H. 1989b. Dermal irritation/sensitization study of Muster 2 in human volunteers. [Report in German]. Study conducted by Prof. Dr. H.Tronnier, Dortmund, Germany, for Ciba Speciality Chemicals Corp.