15
Tris Monochloropropyl Phosphates

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

PHYSICAL AND CHEMICAL PROPERTIES

Tris monochloropropyl phosphates (TMCPPs) are four isomers having the molecular formula C9H18Cl3O4P (MW 327.55) and belonging to the class of chlorinated alkyl phosphate esters. The most abundant isomer in commercial products is the completely branched isomer, tris (1-chloro-2-isopropyl) phosphate and the least abundant form is the completely linear isomer, tris (2-chloropropyl) phosphate. The chemical and physical properties of TMCPPs are summarized in Table 15–1. Variations in manufacturing methods result in commercial formulations that contain different proportions of the four TMCPPs listed in Table 15–1. Mixtures in which the linear forms are above trace levels tend to be pale yellow; other mixtures are colorless (Albright and Wilson 1980a; Courtaulds Chemicals 1988).

Although tris(1-chloro-2-isopropyl) phosphate (TCIP, CASRN 13674–84–5) is the most abundant isomer, companies have tended to refer to their product



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Toxicological Risks of Selected Flame-Retardant Chemicals 15 Tris Monochloropropyl Phosphates THIS chapter reviews the physical and chemical properties, toxicokinetics, toxicological, epidemiological, and exposure data on tris monochloropropyl phosphates (TMCPPs). The subcommittee used that information to characterize the health risk from exposure to TMCPPs. The subcommittee also identified data gaps and recommended research relevant for determining the health risk from exposure to TMCPPs. PHYSICAL AND CHEMICAL PROPERTIES Tris monochloropropyl phosphates (TMCPPs) are four isomers having the molecular formula C9H18Cl3O4P (MW 327.55) and belonging to the class of chlorinated alkyl phosphate esters. The most abundant isomer in commercial products is the completely branched isomer, tris (1-chloro-2-isopropyl) phosphate and the least abundant form is the completely linear isomer, tris (2-chloropropyl) phosphate. The chemical and physical properties of TMCPPs are summarized in Table 15–1. Variations in manufacturing methods result in commercial formulations that contain different proportions of the four TMCPPs listed in Table 15–1. Mixtures in which the linear forms are above trace levels tend to be pale yellow; other mixtures are colorless (Albright and Wilson 1980a; Courtaulds Chemicals 1988). Although tris(1-chloro-2-isopropyl) phosphate (TCIP, CASRN 13674–84–5) is the most abundant isomer, companies have tended to refer to their product

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Toxicological Risks of Selected Flame-Retardant Chemicals TABLE 15–1 Physical and Chemical Properties of Tris Monochloropropyl Phosphates Property Value Reference Chemical formula C9H18Cl3O4P RTECS 1999 Structures 13674–84–5     6145–73–9   CAS Registry #’s 13674–84–5 [tris(1-chloro-2-isopropyl phosphate] 76025–080–6 [bis(1-chloro-2-isopropyl) (2-chloropropyl) phosphate] 76649–15–5 [bis(2-chloropropyl) (l-chloro-2-isopropyl) phosphate] 6145–73–9 [tris(2-chloropropyl) phosphate] RTECS 1999 Synonyms 13674–84–5: tris(2-chloroisopropyl) phosphate; 2-propanol, 1-chlorophosphate (3:1); 1-chlor-2-propyl phosphate (3:1); tris(beta-chloropropyl) phosphate; phosphoric acid, tris(2-chloro-l-methylethyl) ester; Fyrol PCF; Amgard TMCP; Antiblaze 80; TCPP; TMCP; TCIP TSCA Interagency 1988; IPCS 1998; RTECS 1999   76025–08–6: bis(1-chloro-2-isopropyl) (2-chloropropyl) phosphate; bis(2-chloro-l-methylethyl) 2-chloropropyl phosphate     76649–15–5: bis (2-chloropropyl) (1-chloro-2-isopropyl) phosphate; bis (2-chloropropyl) (1-chloro-2-propyl) phosphate; 2-chloro-l-methylethyl; bis (2-chloropropyl) phosphate  

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Toxicological Risks of Selected Flame-Retardant Chemicals   6145–73–9: tris (2-chloropropyl) phosphate; 1-propanol, 2-chloro-phosphate (3:1); tris (beta-chloropropyl) phosphate, TCPP   Molecular weight 327.59 RTECS 1999 Physical State Liquid; sold commercially as mixture of isomers Albright and Wilson 1980a; Bayer 1993, 1996 Solubility In water, 1.1–1.2 g/L at 25°C Albright and Wilson 1980a; Courtaulds   In DMSO, 95% ethanol, acetone, ≥100 g/L Chemicals 1988; NTP 1999 Melting point 380°C   Vapor Pressure <2 mm Hg at 25°C Courtaulds chemicals 1988 Specific Gravity 1.29 at 25°C Akzo Nobel 1999 Boiling Point: 235–248°C Courtaulds chemicals 1988; IPCS 1998 Flash Point: 218–220°C Courtaulds chemicals 1988; IPCS 1998 Conversion Factor: mg/m3=13.39 ppm IPCS 1998 Thermal Decomposition Begins at ~70°C for the yellow product; at ~190°C for the colorless product Albright and Wilson 1980a; Courtaulds chemicals 1988 Reactivity Hydrolyzes slowly under alkaline or acidic conditions Courtaulds chemicals 1988 by the name tris(2-chloropropyl) phosphate (TCPP), even though that name refers to CAS RN 6415–73–9 (e.g., Albright and Wilson 1999). This has led to a considerable degree of uncertainty in the literature and toxicity databases as to the identity of the substance that has undergone toxicity testing (see Ferrante 1999; Saltzman and Babich 1999). All TMCPP toxicity testing has been carried out on commercial mixtures containing variable amounts of TMCPP isomers, which in addition to those previously mentioned, include bis(1-chloro-2-isopropyl) (2-chloropropyl) phosphate (CAS RN 76025–08–6) and bis(2-chloropropyl) (1 -chloro-2-isopropyl) phosphate (CAS RN 76649–15–5). Therefore, the designation TMCPPs in this document refers to the commercial mixtures containing variable amounts of TMCPP isomers. OCCURRENCE AND USE TCMPPs are not known to occur naturally but are manufactured from propylene oxide and phosphorus oxychloride (IPCS 1998). Although TMCPPs

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Toxicological Risks of Selected Flame-Retardant Chemicals may be used for textile (non-apparel) finishes, they are also used as flame retardants in rigid and flexible polyurethane foams (Akzo Nobel 1999; Albright and Wilson 1999). According to the IPCS (1998), the annual worldwide demand for TMCPPs exceeded 40,000 metric tons in 1997. TMCPP mixtures are sold under various trade names, including Antiblaze® 80, Amgard® TMCP, Fyrol® PCF, and Hostaflam® OP 820. TOXICOKINETICS Absorption Minegishi et al. (1988) administered radiolabeled 14C-tris (1-chloro-2-propyl) phosphate (14C-TMCPP, presumably CASRN 13674–84–5, 99% pure by gas chromatography), in a single oral dose of 16.4 mg/kg (0.05 mmol/kg; 0.213 mCi/mmol) in olive oil, to groups of three to five male Wistar rats. Absorption was calculated from the radioisotopic measurements of cumulative urinary excretion and cumulative exhalation (performed for 3 or 4 d post-administration), and the amount in blood and tissues of rats sacrificed at 3, 6, 12, 24, 72, and 168 hr following administration. Absorption of radiolabeled TMCPP was rapid; radiolabel was detected throughout the body as early as 3 hr post-administration. At 168 hr, 75.6% of the administered oral dose had been excreted in the urine and expired air, or remained in the carcass. Another 22% was excreted in the feces; however, TMCPP undergoes enterohepatic circulation (see Excretion section), and it is not clear if this proportion includes unabsorbed TMCPP, TMCPP excreted in the bile, or both. Therefore, at least 75.6% is absorbed following oral administration to rats. Distribution Three hr after oral administration of a 16.4 mg/kg dose of 14C-TMCPP in rats, the concentration of radiolabel per gram of tissue was highest in the liver (28.6 nmol/g) and kidney (27.3 nmol/g), and to a lesser extent, in the lung (9.4 nmol/g), but did not accumulate at high levels in other tissues (Minegishi et al. 1988). The concentrations of the radiolabel in blood, heart, spleen, brain, testis, adipose tissue, and muscle were all <4 nmol/g tissue. The radiolabel concentration remained highest in the liver during subsequent timepoints up to d 7. Radiolabel reached its maximum concentration in various tissues 3–6 hr after administration.

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Toxicological Risks of Selected Flame-Retardant Chemicals Metabolism The metabolic transformation of TMCPPs has not been investigated. Excretion Approximately 97% of radiolabeled TMCPP (67% in urine, 22% in feces, and 7.7% in expired air) was excreted within 7 d of administration in rats, as reported by Minegeshi et al. (1988). Only 0.7% of the administered dose was recovered in the carcass after 168 hr, and approximately 2.5% was not recovered. Removal of TMCPP from the tissues followed a biphasic pattern. Excretion was fairly rapid from all compartments (t1/2=5.2–13.5) for the first 24 hr. During the subsequent 6 d, tissue half-lives ranged from 45 hr in the liver to 103.4 hr in adipose tissue. Minegishi et al. (1988) also measured biliary excretion of 14C-TMCPP in cannulated rats for 48 hr following a single oral dose (as above). Biliary radioactivity peaked within 2 hr of administration, and after 48 hr, biliary excretion represented approximately 45% of the administered dose. The ratio of biliary excretion to fecal excretion was calculated to be 2.23, suggesting to the authors that TMCPP is subject to enterohepatic circulation. HAZARD IDENTIFICATION1 No studies were found that investigated the toxicity of TMCPPs in humans. Animal studies were either acute or subacute in duration. Studies were not done according to GLP guidelines unless noted in the text. Dermal Exposure Irritation A product safety data sheet published by Couraulds specifically warns that skin irritation may result from prolonged contact with liquid TMCPP (Courtaulds Chemicals 1988). A data sheet for Fyrol PCF recommends that it should not be used for fabrics intended for apparel uses (Akzo Nobel 1999). 1   In this section, the subcommittee reviewed toxicity data on tris monochloropropyl phosphates, including the toxicity assessments prepared by the U.S. Consumer Product Safety Commission (Bittner 1999; Ferrante 1999; Soltzman and Babich 1999).

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Toxicological Risks of Selected Flame-Retardant Chemicals Albright and Wilson (1980a) carried out dermal irritation studies on two different production batches of their TMCPP flame retardant Antiblaze® 80. In both tests, 0.5 mL of TMCPP liquid was applied neat to two test sites (abraded and intact) on the back skin of six New Zealand white rabbits (three male and three female). For product A, the exposure sites were wiped after 24 hr and were evaluated after 24 and 72 hr (Albright and Wilson 1980a). Erythema was observed at low levels after 24 hr, was not increased by abrasion of the epidermis, and was reduced after 72 hr. For product B, the test sites were wiped after 24 hr, and scored after 0.5 and 72 hr (Albright and Wilson 1980a). The results of this study were available only in a preliminary report. The test material was assigned in a low irritancy score for intact skin (0.8/8.0) and it was only slightly higher for abraded skin (1.1/8.0); signs of irritation were reduced after 72 hr. The reports concluded that neither compound was a primary skin irritant. Eye irritation tests were conducted on two production batches of the TMCPP flame retardant Antiblaze® 80 (Albright and Wilson 1980a). In both tests, six New Zealand white rabbits (three male and three female) received 0.1 mL of Antiblaze® 80, neat, in one eye and were evaluated for irritation at 1, 24, 48, and 72 h. Treatment with product A (Albright and Wilson 1980a) resulted in minor, transient irritation and the Draize test score (3/110) was considered to be negative. Similarly, treatment with product B resulted in low average irritation scores (Albright and Wilson 1980a, available only as a summary). The report concluded that product B was not a primary eye irritant. Systemic Effects Acute dermal toxicity studies were conducted on two different production batches of the TMCPP flame retardant Antiblaze® 80 (Albright and Wilson 1980a). In both studies, 0.5 mL of neat commercial TMCPP was administered dermally to six New Zealand white rabbits (240 cm2 average exposure area). Two males and one female received TMCPP on abraded skin, and two females and one male received TMCPP on intact skin. The test areas were wiped after 24 h, and the animals were observed for 14 d. After treatment with product A (Albright and Wilson 1980a, Study 462–80), no mortality or other consistent clinical signs resulting from treatment were observed, other than anorexia in five of six animals on d 1. The exposure site in all animals exhibited some erythema and edema formation at 24 hr, but not in the following 2 wk, after which animals were sacrificed. Scaling of the test site was observed at necropsy in two animals. In all three female rabbits (two intact and one abraded) and one male rabbit (abraded), the lungs exhibited diffuse redness and/or white edges. In the females, the liver appeared to be pale, but no other gross pathological lesions were observed. Treatment with product B yielded similar results

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Toxicological Risks of Selected Flame-Retardant Chemicals (Albright and Wilson 1980a, Study 2426–80). The dermal median lethal doses for both product batches of Antiblaze® 80 were above 2 g/kg. Other Systemic Effects No studies were located that investigated the sensitization, immunological, neurological, reproductive, developmental, or carcinogenic effects of TMCPPs following dermal exposure. Inhalation Exposure Systemic Effects In an acute inhalation study, five male and five female Sprague-Dawley rats were exposed (whole-body) to an aerosol of TMCPPs (Antiblaze® 80, product A) at a nominal concentration of 17,800 mg/m3 (Albright and Wilson 1980a, Study 465–80) for 1 hr, and then observed for 14 d. The average integrated aerosol concentration was not stated. No animals died during the study period. Treatment effects included: decreased activity, partially closed eyes, swollen eyelids, lacrimation, soft stool, excessive salivation, yellow or orange discoloration of the fur in the ano-genital area, and oily and/or matted fur, a condition that persisted in all rats for 7 d and in 9/10 rats for 10 d. Most rats exhibited dry rales, wet or dry material around the facial area and excessive salivation. In a few animals, dry rales persisted throughout the observation period. Body weight decreased in four out of five rats of both sexes on the first day of treatment; the condition was transient in males, but three out of five females had lost weight by d 14, compared to their initial body weight. In an acute inhalation study, five male and five female Sprague Dawley rats were exposed to an aerosol of TMCPPs (Antiblaze® 80, product B) at an average integrated aerosol concentration of 5,000 mg/m3 for 4 hr and observed for 14 d (Albright and Wilson 1980a, Study 2425–80). The nominal concentration of 26,300 mg/m3, comparable to that used in the product A study, is a less accurate measure of exposure. The mass median diameter of the particles was 4.1 µm, and>87% of the particles had a cumulative mass aerodynamically equivalent diameter of≤10 µm. The animals were observed prior to exposure, at 15-min intervals during exposure and during the subsequent 0.5-hr recovery period, upon removal from the chamber, and hourly for 4 hr. Body weights were recorded on d 0, 1, 2, 4, 7, and 14, prior to sacrifice. Because of the design of the test chamber, no more than five to seven rats could be observed simultaneously during exposure. Treatment effects are listed in Table 15–2. In the subsequent 14-d period, no males, but two of four females died. Necropsy

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Toxicological Risks of Selected Flame-Retardant Chemicals TABLE 15–2 Inhalation Toxicity Studies on Tris Monochloropropyl Phosphates Chemical, Purity Species, Strain, Sex, Number Concentration (mg/m3) Duration Effects Comments References Nominally IV-tris (2-chloropropyl) phosphate, 100% Probable mixture: I>II>III>IV; likely that I is lower than 75% Rat, Sprague-Dawley, M/F, 5/sex/dose 17,800, nominal 1 hr (14-d observation) No deaths; inactivity; swollen eyelids; increased lacrimation, salivation, dry rales; decreased body weight   Albright and Wilson 1980aa Nominally IV-tris (2-chloropropyl) phosphate, lot 0608 15000; Mixture of I-75%, II-16%, III-1%, IV-<0.1% Rat, Sprague-Dawley, M/F, 5/sex/dose 5,000 average, integrated 4 hr (14-d observation) Mortality; inactivity, weakness, salivation; one F exhibited prostration, convulsions, dyspnea before death 0.5 hr after end of exposure; lacrimation, lethargy, alopecia, decreased body weight LC50(F): ~5,000 mg/m3 LC50(M): >5,000 mg/m3 Albright and Wilson 1980ab I: tris (1-chloro-2-isopropyl phosphate), CAS Registry # 13674–84–5. II: bis (1-chloro-2-isopropyl) (2-chloropropyl) phosphate, CAS Registry # 76025–08–6. III: bis (2-chloropropyl) (1-chloro-2-isopropyl) phosphate, CAS Registry # 76649–15–5. IV: tris (2-chloropropyl) phosphate, CAS Registry # 6145–73–9. aLaboratory report from Bio/dynamics to Mobil Oil Corporation (1980); TSCA Submittal from Albright & Wilson to EPA (1989). bLaboratory report from Gulf South Research Institute to Mobil Environmental Health Sciences Laboratory (1981); TSCA Submittal from Albright and Wilson to EPA (1989).

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Toxicological Risks of Selected Flame-Retardant Chemicals revealed no gross abnormalities, except for opacity of both corneas in one female that died during testing. The 4-hr LC50 was>5,000 mg/m3 for males and approximately 5,000 mg/m3 for females. Other Systemic Effects No studies were located that investigated the immunological, neurological, reproductive, developmental, or carcinogenic effects of TMCPPs following inhalation exposure. Oral Exposure Systemic Effects Bayer (1996) administered a single dose of TMCPPs in corn oil by gavage to male and female Wistar rats (200, or 500 mg/kg for males; only 2,000 mg/kg in females) and found that at or below 500 mg/kg, animals exhibited no clinical signs of toxicity over the subsequent 2-wk observation period. No gross pathological signs of toxicity were observed in treated animals during necropsy. In females given 2,000 mg/kg, all developed clinical signs of toxicity with increasing intensity over time and died within 3–6 hr (see Table 15–3). Necropsy revealed red, mottled lungs. The “approximate median lethal dose” for females was calculated by the authors to be 632 mg/kg (the geometric mean of the 0% and 100% response concentrations); the LD50 for males was above 500 mg/kg. In a range-finding study, groups of five male Wistar rats received TMCPPs at doses of 0, 1, 10, 100, or 1,000 mg/kg-d by gavage in peanut oil for 7 d (Bayer 1993). Treatment had no effect on mortality, clinical signs, body weight, or food intake, but water intake was significantly higher (>30%) in the 1,000 mg/kg-d group than in controls. Absolute testicular weight was significantly reduced in one rat in the 100 mg/kg-d group. In a preliminary trial, groups of male and female CD rats (two/sex) were administered 2,000 or 4,000 mg/kg of neat TMCPPs (neat) by gavage (Gardner 1987) and observed for 5 d. All animals died within 24 hr at the high dose, and both males died at the lower dose. One of two females died at the lower dose. In a second trial, groups of male and female rats (two/sex) were gavaged with 400, 800, 2,000, or 4,000 mg/kg of TMCPP dissolved in corn oil. In the 5-d observation period, there was no mortality at or below the 2,000-mg/kg dose, but 2/2 males and 1/2 females died at the 4,000-mg/kg dose within the first d. In another study (Gardner 1987), groups of five male and five female CD rats received a single dose of TMCPPs (2,500, 3,200, 4,000, or 5,000 mg/kg) by gavage, diluted with corn oil. Clinical signs are described in Table 15–3. Mor-

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Toxicological Risks of Selected Flame-Retardant Chemicals TABLE 15–3 Oral Toxicity Studies on Tris Monochloropropyl Phosphates Chemical, Purity Species, Strain, Sex, Number Dose (mg/kg or mg/kg-d) Duration, Route Effects Comments Reference Tris (chloropropyl) phosphate, TCPP: I; 2 other components, possibly II and II, but different names stated in text; (IV at trace levels) Rat, Wistar, F 5/dose 945, 1,137, 1,349, 1,633, 2,000, 2,400 (dose vol. = 10 mL/kg) Single dose (96-hr observation), gavage Mortality: no deaths at 945 mg/kg; 100% deaths at 2,400 mg/kg within 2–5 hr); clinical signs: tremors, wheezing, oronasal bleeding, clonic convulsions LD50: 1,017 mg/kg Kawasaki et al. 1982a Trichloropropyl phosphate (later document identifies as TCIP, mixture 90–95% isopropyl, 5–10% n-propyl phosphates) Rat, CD, M/F, 2/sex/dose 2,000, 4,000 Single dose (5-d observation), gavage Mortality: 4 of 4 died at 4,000 mg/kg; 2 of 2 M and 1 of 2 F died at 2,000 mg/kg   Courtaulds Chemicals 1988b Trichloropropyl phosphate (later document identifies as TCIP, mixture 90–95% isopropyl, 5–10% n-propyl phosphates) Rat, CD, M/F, 4/sex/dose 400, 800, 2,000, 4,000 (dose vol. = 10 mL/kg) Single dose (5-d observation), gavage Mortality: no deaths at 400–2,000 mg/kg; 2 of 2 M and 1 of 2 F died at 4,000 mg/kg     Trichloropropyl phosphate (later document identifies as TCIP, mixture 90–95% isopropyl, 5–10% n-propyl phosphates) Rat, CD, M/F, 5/sex/dose 2,500, 3,200, 4,000, 5,000 (dose vol. = 10 mL/kg) Single dose (14-d observation), gavage Mortality: deaths in M at≥3,200 mg/kg, in F at≥4,000 mg/kg; clinical signs: piloerection, hunched posture, abnormal gait, increased salivation; followed by lethargy, pallor, ptosis, decreased respiratory rate; clonic convulsions at≥4,000 mg/kg; diarrhea at ≤3,200 mg/kg; decreased body weight gain in wk 1 LD50:3,600 mg/kg (3,800 mg/kg in M; 3,400 mg/kg in F)  

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Toxicological Risks of Selected Flame-Retardant Chemicals Chemical, Purity Species, Strain, Sex, Number Dose (mg/kg or mg/kg-d) Duration, Route Effects Comments Reference Antiblaze ®80: product A; lot PP-2B Rat, Sprague-Dawley, M/F, 1–10/dose M: 320, 630, 1,000, 1,250, 1,300, 1,700, 2,300, 2,500, 3,000, 5,000 F: 320, 500, 630, 700, 1,000, 1,400, 2,000, 2,500, 5,000 Single dose (14-d observation), gavage Mortality: no deaths in F at≤700 mg/kg or in M at≤1,250 mg/kg; clinical signs: altered activity, discharge from orifices, hunching, rough coat, anorexia, diarrhea, dehydration, decreased body temperature, alopecia, aggression, teeth chattering, emaciation, clonic convulsions, ataxia, sensitivity to touch LD50(M): 1,546 mg/kg (95%CI: 1,066–2,241 mg/kg) LD50(F):017 mg/kg (95% CI: 727–1,423 mg/kg) Albright and Wilson 1980bc Antiblaze ®80: product B; sample 11 108005; tris (2-chloro-propyl) phosphate Rat, NS, M/F, 4–5 M/dose, 10–12 F/dose M: 1,000, 1,208, 1,450, 2,085, 3,000, 5,000 F: 700, 840, 1,000, 1,450, 2,085, 5,000 Single dose (14-d observation), NS Mortality: 20% for lowest dose in M and F; clinical signs: hunched posture, inactivity, oral discharge; convulsions at 5,000; body weight loss in one F at 5,000. LD50(M): 2,085–3,000 mg/kg LD50(F): 840–1,000 mg/kg Albright and Wilson 1980ac Fyrol ®PCF: “Tri (2-chloropropyl phosphate)”: probable mixture Hen, white leghorn, 17 (10 control) 13,200 mg/kg (dose vol= 10 mL/kg) 2 doses 3 wk apart (3-wk observation after last dose), gavage No deaths; no egg production, decreased food intake and body weight; loss of feathers; no effect on walking or central nervous histology   Sprague et al. 1981a Tris-chloroisopropyl phosphate: I-63.2%; II-27.2%; III-4.4%; IV-0.5%; other 4. 8% Rat, Wistar, M/F, 5/sex/dose M: 200, 500 F: 200, 500, 2,000 (dose vol. = 10 mL/kg) Single dose (14-d observation), gavage Mortality: no deaths in dose range 200–500 mg/kg; 100% mortality at 2,000 mg/kg; clinical signs: apathy, palmospasms, crusted blood on snout; reddened and mottled lungs LD50 (M): >500 mg/kg LD50 (F): 632 mg/kg Bayer 1996d

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Toxicological Risks of Selected Flame-Retardant Chemicals Tris-chloroisopropyl phosphate: 97.85%= (I plus unspecified isomers) Rat, Wistar, M/F, 5/sex/dose 0, 1, 10, 100, 1,000 (dose vol. = 2 mL/kg) 7 consecutive days, gavage No effect on mortality, clinical signs, body weight, or food intake; water intake increased at 1,000 mg/kg-d; no effect on gross pathology, weight of testes (but decreased size and weight of testes in one animal at 100 mg/kg-d)   Bayer 1993e Tris (chloropropyl) phosphate, TCPP: I; 2 other components, possibly II and III, but different names stated in text; (IV at trace level) Rat, Wistar, F, 5/dose 0, 8, 40, 200, 1,000 7 consecutive days (14-d observation) Mortality: one rat died at 1,000 mg/kg-d; no clinical signs; no effect on body weight; relative liver weight increased at 1,000 mg/kg-d; relative kidney weight increased at≥40 mg/kg-d   Kawasaki et al. 1982a Tris (chloropropyl) phosphate, TCPP: I; 2 other components, possibly II and III, but different names stated in text; (IV at trace level) Rat, Wistar, F (pregnant), 11–14/dose 0, 6, 70, 625 (0, 0.01, 0.1, 1% in feed) Gestation d 0–20 (30-d postnatal observation) In dams: no effect on body weight; no clinical signs; no effect on implantation or resorption. In fetus: no effect on mortality, body weight, or sex ratio; no significant increase in external, visceral, or skeletal malformations; at weaning, no effect on survival, body weight Dose-related increase in cervical ribs and missing 13th rib (not statistically significant); no necropsy reported for dams Kawasaki et al. 1982a F, females; M, males. I: tris (1-chloro-2-isopropyl phosphate), CAS Registry # 13674–84–5. II: bis (1-chloro-2-isopropyl) (2-chloropropyl) phosphate, CAS Registry # 76025–08–6. III: bis (2-chloropropyl) (1-chloro-2-isopropyl) phosphate, CAS Registry # 76649–15–5. IV: tris (2-chloropropyl) phosphate, CAS Registry #6145–73–9. aPublished study, bLaboratory report from Huntingdon Research Centre to Courtaulds Chemical Co. (1987); TSCA submittal from Aceto Chem. Co. to EPA. cIncomplete laboratory report by Mobil Environmental Health Sciences Laboratory (1980); TSCA submittal from Albright and Wilson to EPA. dGood Laboratory Practice laboratory report of the Institute of Industrial Toxicology Bayer, A.G. (1996); TSCA submittal from Miles, Inc. to EPA. eGood Laboratory Practice laboratory report of the Institute of Industrial Toxicology Bayer, A.G. (1993); TSCA submittal from Bayer, A.G. to EPA.

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Toxicological Risks of Selected Flame-Retardant Chemicals tality occurred at and above 3,200 mg/kg, during the first 2 d. The authors estimated the acute LD50 of TMCPPs to be 3,600 mg/kg for rats (3,400 mg/kg for females and 3,800 mg/kg for males). According to a preliminary report (Albright and Wilson 1980b), groups of Sprague Dawley rats (from one to five of each sex/dose) were given TMCPPs (Antiblaze® 80, product A) by mouth and observed for up to 14 d. Females received 320, 500, 630, 700, 1,000, 1,250, 1,400, 2,000, 2,500, or 5,000 mg/kg and males received 320, 630, 1,000, 1,250, 1,300, 1,700, 2,300, 2,500, 3,000, or 5,000 mg/kg. The authors did not indicate whether the material was delivered neat or in a vehicle. Clinical signs observed are noted in Table 15–3. Most deaths occurred on d 1; the LD50 for females was calculated to be 1,017 mg/kg (727–1,423 mg/kg), and for males, it was 1,546 mg/kg (1,066–2,241 mg/kg). In another preliminary report (Albright and Wilson 1980a), groups of rats (strain unspecified) were given a single dose of TMCPPs (Antiblaze® 80, product B) by mouth, and observed for up to 14 d. Groups of five to seven female rats received 700, 840, 1,000, 1,450, 2,085, or 5,000 mg/kg, and groups of four to five male rats received 1,000, 1,208, 1,450, 2,085, 3,000, or 5,000 mg/kg. Treatment related effects are listed in Table 15–3. Mortality was 20% at the lowest dose and 100% at the highest dose for both males and females. The median lethal dose was between 2,085 and 3,000 mg/kg for males, and between 840 and 1,000 mg/kg for females. Kawasaki et al. (1982) gave groups of five female Wistar rats a single dose of 945, 1,137, 1,349, 1,633, 2,000, or 2,400 mg/kg of TMCPPs by gavage in olive oil. Treatment-related effects are listed in Table 15–3. No mortality occurred at the lowest dose, but was 100% at the highest dose and occurred within 2–5 hr after administration. The estimated 96-hr LD50 for this study is 1,017 mg/kg. Kawasaki et al. (1982) gave groups of five female Wistar rats 0, 8, 40, 200, or 1,000-mg/kg of TMCPPs by gavage in olive oil for 7 d. No abnormalities or mortality was observed except for one rat that died in the 1000 mg/kg group. The only treatment-related effects were significant increases in the relative weights of the liver (at 1,000 mg/kg) and of the kidneys (≥40 mg/kg). Neurological Effects Sprague et al. (1981) administered a single neat dose of 13.2 g/kg of TMCPPs (Fyrol® PCF) by gavage to 18 adult White Leghorn hens; 10 hens in the control group received a 10-mL/kg dose of corn oil. No significant effects on the activities of brain neurotoxic esterase or plasma cholinesterase were observed. In a delayed neurotoxicity study, a group of 17 hens received a neat dose of 13.2 g/kg of TMCPPs and 10 hens received 10 mL corn oil; hens re-

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Toxicological Risks of Selected Flame-Retardant Chemicals ceived a second dose 3 wk later, and were observed for another 3 wk. Body weight and food consumption were measured every 3–4 d, and walking behavior was observed weekly. Surviving hens were sacrificed, and the brains and spinal cord were examined histologically. Effects of TMCPP treatment included cessation of egg production, feather loss, and a significant reduction in food consumption and body weight. However, TMCPPs had no significant effect on walking behavior or histology of the central nervous system. Reproductive and Developmental Effects Kawasaki et al. (1982) fed groups of 11–14 pregnant female Wistar rats a diet containing 0%, 0.01%, 0.1%, or 1% TMCPPs during gestation d 0–20. The daily intake of TMCPPs was estimated at 0, 6, 70, or 625 mg/kg-d2. Some dams were sacrificed on gestation d 20, and the fetuses were examined for skeletal or visceral abnormalities. Litters born naturally from groups of five to seven dams were culled to eight neonates each and monitored for 4 wk. TMCPPs had no effect on food consumption or body weight gain in dams. TMCPPs did not affect the number of implants, the number of resorptions, or the number or weight of live fetuses. No fetuses died or had obvious external malformations. The incidence of skeletal or visceral malformations in fetuses from treated litters was not statistically different from controls. However, dose-related increases in the incidence of missing 13th ribs and cervical ribs were observed in treated fetuses; delayed ossification of sternebra was observed in all groups. Dilatation of the renal pelvis was observed in one fetus in the 68 mg/kg-d group. Treatment in utero had no effect on growth or survival of weanlings up to postnatal d 28. Other Systemic Effects No studies were located that investigated immunological effects to TMCPPs following oral exposure. 2   Doses calculated from the following values reported by the authors: total 21-d intake, total body weight gain, and the initial average body weight of the females used for toxicity tests, described in Section 4.1.1; (21-d mg “TMCPPs”)/21 d=mg “TMCPPs”/d divided by the time-weighted average body weight in kg). For example, the 21-d intake of TMCPPs for the 0.1 % dose group was 380 mg; it was divided by 21 to yield 18 mg TMCPP/d. The average body weight gain for that group was 0.117 kg; using 0.20 kg as an initial body weight (from the acute study in the same paper), the average body weight was (initial+final)/2=(0.20 kg+0.317 kg)/2=0.259 kg. Therefore, rats in the 0.1 % dose group received 18 mg TMCPP/ 0.259 kg=70 mg/kg-d.

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Toxicological Risks of Selected Flame-Retardant Chemicals Genotoxicity No studies were located regarding the in vivo genotoxicity of TMCPPs. All of the in vitro tests of genotoxicity yielded negative results. TMCPPs (TCIP, CASRN 13674–84–5), at concentrations ranging from 0 to 1,000 µg/plate, yielded negative results in mutagenicity tests using Salmonella typhimurium strains TA97, TA98, TA100, TA1535, and TA1537, with or without metabolic activation (Zeiger et al. 1992). TMCPPs, at concentrations of 0, 0.1, 1, 10, 100, 500, or 2,000 µg/plate were not mutagenic to S. typhimurium strains TA98, TA100, TA1535, TA1537, or TA1538, with or without metabolic activation (BIBRA 1977). TMCPPs, at concentrations of 0, 98, 328, 980, or 3,300 µg/plate were not mutagenic in tests using S. typhimurium strains TA100 or TA1535, with or without metabolic activation (Nakamura et al. 1979). TMCPPs (Antiblaze®80, product A), in concentrations ranging from 38 to 425 µg/plate yielded negative results in mutagenicity tests using S. typhimurium strains TA98, TA100, TA1535, TA1537, and TA1538, with or without metabolic activation (Albright and Wilson 1980a). QUANTITATIVE TOXICITY ASSESSMENT Noncancer Dermal RfD The database on dermal toxicity of TMCPPs is inadequate for developing a dermal RfD. The duration of all available dermal studies was only 24 hr. Inhalation RfC and Oral RfD No chronic or subchronic studies in humans or animals were located that could provide the basis for developing an inhalation RfC or oral RfD for TMCPPs. Cancer No long-term studies in humans or animals were located that could be used to assess the carcinogenic potency of TMCPPs by any route of exposure.

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Toxicological Risks of Selected Flame-Retardant Chemicals EXPOSURE ASSESSMENT AND RISK CHARACTERIZATION Noncancer Dermal Exposure Dermal exposure to TMCPP was estimated using the dermal exposure scenario described in Chapter 3. This exposure scenario assumes that an adult spends 1/4th of his or her time sitting on furniture upholstery treated with TMCPP and also assumes 1/4th of the upper torso is in contact with the upholstery and clothing presents no barrier. As a first estimate of exposure, it was assumed that skin, clothing, and the upholstery did not impede dermal exposure to TMCPP. It was also assumed that there would be sufficient water present from sweat to facilitate dissolution of TMCPP from the upholstery and absorption through the skin. In this scenario, only the dissolution rate of TMCPP from upholstery is assumed to be the limiting factor in absorption by the body. It is assumed that all of the TMCPP 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 TMCPP of 5 mg/cm2. The extraction rate (µw) for TMCPP 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. Using these assumptions, an estimated absorbed daily dose of 1.5 mg/kg was calculated for TMCPP. Insufficient data are available for deriving a dermal or oral RfD for TMCPP. Therefore, no conclusions can be drawn concerning the noncancer health risks associated with dermal exposure to TMCPP in furniture upholstery. Since there was no appropriate data for estimating TMCPP dermal penetration, a second dermal exposure iteration was not performed for this compound. Inhalation Exposure Particles Inhalation exposure estimates for TMCPP were calculated using the exposure scenario described in Chapter 3. This scenario assumes that a person spends 1/4th of his or her lifetime in a 30 m3 room containing 30 m2 of

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Toxicological Risks of Selected Flame-Retardant Chemicals TMCPP-treated fabric and the room is assumed to have a air-change rate of 0.25/hr. It is also assumed that 50% of the TMCPP present in 25% of the surface area of the treated fabric is released over 15 yr and 1% of released particles are a 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 TMCPP of 5 mg/cm2. The release rate (µr) for TMCPP from upholstery fabric was estimated to be 2.3×10−7/d (see Chapter 3, Equation 5) yielding a room airborne particle concentration (Cp) of 1.9 µg/m3 and a short time-averaged exposure concentration of 0.48 µg/m3. The time-averaged exposure concentration for particles was calculated using Equation 6 in Chapter 3. No inhalation RfC has been derived for TMCPP. Therefore, no conclusions can be drawn concerning the noncancer health risks associated with inhalation of particles from furniture upholstery containing TMCPP. Vapors In addition to the possibility of release of TMCPP in particles from worn upholstery fabric, the subcommittee considered the possibility of the release of TMCPP by evaporation. This approach is described in Chapter 3, and uses an exposure scenario similar to that described above for exposure to TMCPP particles. The rate of flow of TMCPP vapor from the room is calculated using Equations 8–11 in Chapter 3. A saturated vapor concentration (Cν) of 35,300 mg/m3 was estimated for TMCPP. The application density (Sa) for TMCPP in the treated upholstery was estimated as 5 mg/cm2. Using the parameters described, the equilibrium room-air concentration of TMCPP was estimated to be 30,000 mg/m3. The short-term time-average exposure concentration for TMCPP was estimated as 7,500 mg/m3 using Equation 12 in Chapter 3 and the equilibrium room-air concentration for TMCPP. It was estimated that concentration could be maintained for approximately 5 hr. These results suggest that the vapor inhalation scenario is unrealistic for TMCPP-treated furniture in a residential setting. Nevertheless, no inhalation RfC is available for calculating a margin of exposure for TMCPP. Therefore, no conclusions can be drawn about the noncancer health risks posed by the inhalation of TMCPP vapors. Oral Exposure The assessment of noncancer toxicological risk for oral exposure to TMCPP is based on the oral exposure scenario described in Chapter 3. This scenario

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Toxicological Risks of Selected Flame-Retardant Chemicals assumes a child is exposed to TMCPP by sucking on 50 cm2 of fabric treated with TMCPP, 1 hr/d for 2 yr. The subcommittee estimated an upholstery application rate (Sa) for TMCPP of 5 mg/cm2. Oral exposure was calculated using Equation 15 in Chapter 3. The extraction rate (µw) or TMCPP 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 TMCPP was estimated to be 0.04 mg/kg-d. However, a margin of exposure could not be calculated for the oral route because there were insufficient data to derive an oral RfD for this compound. Cancer There are insufficient data for assessing the cancer risk from exposure to TMCPP by any route of exposure. RECOMMENDATIONS FROM OTHER ORGANIZATIONS The subcommittee is not aware of acceptable exposure levels recommended by any regulatory agency or other organizations. DATA GAPS AND RESEARCH NEEDS There are no data on the subchronic or chronic toxicity of TMCPPs for the dermal, inhalation, or oral routes of exposure. No studies have been conducted on the effects of TMCPP exposure on reproduction. Data on the effects of TMCPP exposure on reproduction are also not available. Data on the dermal absorption of TMCPPs as well as information on human exposure to TMCPPs from treated upholstery are also not available. The subcommittee recommends that the potential for release of TMCPP vapor into air and TMCPP released into saline from treated fabric be investigated. REFERENCES Akzo Nobel. 1999. Fyrol® PCF: product information sheet. [Online]. Available: http://www.akzo-nobel.com/phosphorus/TDS/fyrol/fyrolpcf.PDF (Retrieved September 8, 1999).

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Toxicological Risks of Selected Flame-Retardant Chemicals Albright and Wilson (Albright & Wilson Americas, Inc.). 1980a. Eighteen health and safety studies on Antiblaze® 80. TSCATS 311056. EPA/OTS Doc. # 86–890000114. OTS# 0517715. Albright and Wilson (Albright & Wilson Americas, Inc.). 1980b. Oral LD50 of Tris (2-Chloropropyl) Phosphate, Lot PP-28, in Sprague-Dawley Rats After a Single Administration. TSCATS 311058. EPA/OTS Doc. # 86–0000115. OTS 0517716. Albright and Wilson (Albright & Wilson Americas, Inc.). 1988. Memorandum from B.E.Johnson to H.H.King, Re: Composition of Antiblaze 80 and Equivalents, dated December 21, 1988. Albright and Wilson. 1999. Flame Retardants. [Online]. Available: http://www.albright-wilson.com/feb99/products/pda/flame/flame.htm (Retrieved Septembers, 1999). Bayer (Bayer AG). 1993. Tris-chlorisopropylphosphat, Vorversuch zur Dosisfindung fur eine subakute toxikologische Studie an mannlichen Wistar-Ratten (Verabreichung mit der Magensonde uber 7 Tage). [Article in German]. TSCATS 442098. EPA/OTS Doc. # 86–94–0000032. OTS # 0556628. Bayer (Bayer AG). 1996. Tris(2-chlorisopropyl)phosphat (13674–84–5): Acute Oral Toxicity Study in Male and Female Wistar Rats. Study No. T0060914. Bayer AG, Institute of Toxicology, Wuppertal, Germany. TSCATS 444651. EPA/OTS Doc. #86–960000566. OTS# 0558767. BIBRA (British Industrial biological Research Association). 1977. Microbial Mutagenicity Test With Trichloroethyl Phosphate and Trichloropropyl Phosphate. Report No. 214/1/77. Surrey, UK. Bittner, P. 1999. Toxicity Review for Tris(2-chloropropyl) Phosphate. Memorandum, dated March 3, 1999, from Patricia Bittner, Toxicologist, Division of Health Sciences, to Ronald Medford, Assistant Executive Director for Hazard Identification and Reduction, U.S. Consumer Product Safety Commission, Washington, DC. Courtaulds Chemicals. 1988. Hazard Data Sheet, Tris-(2-Chloroisopropyl) Phosphate (TCPP). Derby, UK. Ferrante, J. 1999. Memorandum from Jacqueline Ferrante, Pharmacologist, Division of Health Sciences to Ronald L.Medford, Assistant Executive Director for Hazard Identification and Reduction, Subject: Toxicity Review for Tris (1-chloro-2-propyl) phosphate and bis (2-chloropropyl) 1-(chloro-2-propyl) phosphate. U.S. Consumer Product Safety Commission, Washington, DC. Gardner, J.R. 1987. Acute Oral Toxicity to Rats of Trichloropropyl Phosphate. HRC Report No. 871285D/CLD 23/AC. Huntingdon Research Centre, Ltd., Cambridgeshire, UK. IPCS (International Programme on Chemical Safety). 1998. Environmental Heath Criteria 209: Flame Retardants: Tris(chloropropyl) Phosphate and Tris(2-chloroethyl) Phosphate. Geneva: World Health Organization. Kawasaki, H. et al. 1982. Studies on the Toxicity of Insecticides and Food Additives in Pregnant Rats- (5) Foetal Toxicity of Tris-(Chloropropyl) Phosphate. Oyo Yakuri 24(5):697–702. TSCATS 442991. EPA/OTS Doc. # 86–950000008. OTS# 0557521. 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. Minegishi, K.-I., H.Kurebayashi, S.Nambaru, K.Morimoto, T.Takashi, and T.

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Toxicological Risks of Selected Flame-Retardant Chemicals Yamaha. 1988. Comparative studies on absorption, distribution, and excretion of flame retardants halogenated alkyl phosphate in rats. Eisei Kagaku 34(2): 102–114. Nakamura, A., N.Tateno, S.Kojima, M.A.Kaniwa, and T.Kawamura. 1979. The mutagenicity of halogenated alkanols and their phosphoric acid esters for Salmonella typhimurium. Mutat. Res. 66(4):373–380. NTP (National Toxicology Program). 1999. [Online]. Available: http://ntp-server.mehs.nih.gov/. Last updated 08/13/99 RTECS (Registry of Toxic Effects of Chemical Substances). 1999. Micromedex, Inc. Sprague, G.L., L.L.Sandvik, M.J.Brookins-Hendricks, and A.A.Bickford. 1981. Neurotoxicity of two organophosphorus ester flame retardants in hens. J. Toxicol. Environ. Health 8(3):507–518. Saltzman, L., and M.Babich. 1999. Tris(chloropropyl) phosphate. Memorandum, dated August 4, 1999, from Lori Saltzman, Director, Division of Health Sciences, and Michael Babich, Chemist, Divison of Health Sciences, to Ronald Medford, Assistant Executive Director for Hazard Identification and Reduction, U.S. Consumer Product Safety Commission, Washington, DC. TSCA Interagency (Toxic Substances Control Act Interagency Testing Committee). 1988. Information Review: Tris (Chloropropyl) Phosphates. IR-509. Toxic Substances Control Act Interagency Testing Committee. Prepared by Dynamac Corporation. December 9, 1988. Williams, G.M., H.Mori, and C.A.McQueen. 1989. Structure-activity relationships in the rat hepatocyte DNA-repair test for 300 chemicals. Mutat. Res. 221(3):263–286. Zeiger, E., B.Anderson, S.Haworth, T.Lawlor, and K.Mortelmans. 1992. Salmonella mutagenicity tests: V. Results from the testing of 311 chemicals. Environ. Mol. Mutagen. 19(Suppl. 21):2–141.