17
Aromatic Phosphate Plasticizers

THIS chapter reviews the physical and chemical properties, toxicokinetics, toxicological, epidemiological, and exposure data on tricresyl phosphate (TCP), an aromatic phosphate ester. TCP is one of several aromatic phosphate esters used commercially as flame retardants and plasticizers. TCP was chosen as the representative aromatic phosphate ester flame retardant for risk assessment because it has the most complete toxicity database. The subcommittee used that information to characterize the health risk from exposure to TCP. The subcommittee also identified data gaps and recommended research relevant for determining the health risk from exposure to TCP.

PHYSICAL AND CHEMICAL PROPERTIES

Tricresyl phosphate (TCP) is one of several aromatic phosphate esters used commercially as a flame retardant. The physical and chemical properties of TCP are summarized in Table 17–1.

Commercial TCP is a complex mixture containing the meta TCP (TMCP) and para TCP (TPCP) isomers and mixed tricresyl and dicresyl phosphate esters. The ortho TCP isomer (TOCP) occurs only as a contaminant in commercial mixtures and usually at very low concentrations (<0.1 %). This risk assessment focuses primarily on the toxicity of commercial TCP and the meta and para isomers of TCP. Data for TOCP are extensive and only those studies that are relevant for this risk assessment are included in this chapter.



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Toxicological Risks of Selected Flame-Retardant Chemicals 17 Aromatic Phosphate Plasticizers THIS chapter reviews the physical and chemical properties, toxicokinetics, toxicological, epidemiological, and exposure data on tricresyl phosphate (TCP), an aromatic phosphate ester. TCP is one of several aromatic phosphate esters used commercially as flame retardants and plasticizers. TCP was chosen as the representative aromatic phosphate ester flame retardant for risk assessment because it has the most complete toxicity database. The subcommittee used that information to characterize the health risk from exposure to TCP. The subcommittee also identified data gaps and recommended research relevant for determining the health risk from exposure to TCP. PHYSICAL AND CHEMICAL PROPERTIES Tricresyl phosphate (TCP) is one of several aromatic phosphate esters used commercially as a flame retardant. The physical and chemical properties of TCP are summarized in Table 17–1. Commercial TCP is a complex mixture containing the meta TCP (TMCP) and para TCP (TPCP) isomers and mixed tricresyl and dicresyl phosphate esters. The ortho TCP isomer (TOCP) occurs only as a contaminant in commercial mixtures and usually at very low concentrations (<0.1 %). This risk assessment focuses primarily on the toxicity of commercial TCP and the meta and para isomers of TCP. Data for TOCP are extensive and only those studies that are relevant for this risk assessment are included in this chapter.

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Toxicological Risks of Selected Flame-Retardant Chemicals TABLE 17–1 Physical and Chemical Properties for Tricresyl Phosphate (TCP), Mixed Isomers Properties Value Reference Chemical Formula C21H21O4P HSDB 1999 Structure IPCS 1990 CAS Registry # 1330–78–5 ChemID 1999 Synonyms Tritolyl phosphate; trimethylphenyl phosphate; phosphoric acid, tritolyl ester; phosphoric acid, tris(methylphenyl) ester; tris(tolyloxy)phosphine oxide ChemID 1999; RTECS 1999 Trade Names Celluflex 179C, Disflamoll TKP, Durad, Fyrquel 150, Flexol Plasticizer TCP, IMOL S 140, Lindol, Koflex 5050, Kronitex-TCP, Phosflex 179, Pliabrac 521, PX.917, Santicizer 140 IPCS 1990; ChemID 1999; RTECS 1999 Molecular Weight 368.36 Budavari et al. 1989 Physical State Colorless liquid HSDB 1999 Solubility 0.36 mg/L in H2O at 25 °C Miscible with all the common organic solvents and thinners, and also with vegetable oils HSDB 1999 HSDB 1999 Vapor Pressure 1×10−4 mmHg at 20 °C IPCS 1990 Partition Coefficients Log Kow 5.11 HSDB 1999 Melting Point −33 °C IPCS 1990 Boiling Point 241–255 °C at 4 mm Hg IPCS 1990 Flashpoint 257 °C IPCS 1990 Henry’s Law Constant 1.1–2.8×10−6 atm-m3/mol IPCS 1990 Refraction Index 1.556 at 25 °C HSDB 1999 Viscosity 60 cSt at 25°C, 4 cSt at 100 °C IPCS 1990 Density 1.16 at 25 °C HSDB 1999 Conversion Factor 1 ppm=15.07mg/m3 IPCS 1990

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Toxicological Risks of Selected Flame-Retardant Chemicals OCCURRENCE AND USE Currently, TCP is commercially manufactured by reacting phosphorous oxychloride with synthetically prepared cresols (IPCS 1990) to limit the formation of isomers and unwanted contaminants. Early manufacturing practices used petroleum- or coal tar-derived cresols. Few data are available regarding the amount of TCP produced annually. Japanese production of TCP in 1984 was 33,000 tons, and that U.S. production in 1977 was 10,400 tons (IPCS 1990). TCP is applied as a backcoating to upholstery fabrics when used as a flame retardant in upholstered furniture (Piccirillo 1999). It may be applied as backcoating on nylon, polyester, olefin, cotton, non-cotton cellulose, polyvinyl chloride (PVC) and blends of cotton/polyester, wool/nylon, wool/polyester, polyester/nylon, andnylon/olefin (R.Kidder, Fire Retardant Chemicals Association, pers. commun., 1998). TOXICOKINETICS Absorption Dermal No studies were identified that investigated the dermal absorption of TCP in humans. It has been suggested that similarities with regard to structure and physical properties among the isomeric TCPs make it likely that the other isomeric TCPs would also be readily absorbed through the skin (NTP 1994). In the cat, 73% of the radioactivity from a 50-mg/kg dose of 14C-TOCP was no longer present at the application site (intrascapular region)after 12 hr. Maximum concentrations of radioactivity were reached in the examined tissues within 24 hr. By d 10, at least 48% of the dose was absorbed as indicated by urinary and fecal excretion data (Nomeir and Abou-Donia 1986, as reviewed by NTP 1994). Hodge and Sterner (1943), described by IPCS (1990), found that 32P-TOCP (200 mg/kg) was poorly absorbed through dog abdominal skin. The absorption of 2 to 4 mg/kg TOCP by human palm skin was approximately 100 times faster than through the dog abdominal skin based on urinary excretion and surface-area data. Additional details were not provided. Inhalation No studies were identified that have investigated the absorption of TCP in humans or laboratory animals following inhalation exposure.

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Toxicological Risks of Selected Flame-Retardant Chemicals Oral At least 41% of a single gavage dose of 7.8 mg/kg 14C-labeled TPCP in rats was excreted in the urine over 7 d following administration (Kurebayashi et al. 1985). About 12% of a single gavage dose of 89.6 mg/kg in rats was excreted in the urine. Most of the urinary excretion occurred within the 24 hr after administration. All three isomers of TCP (TMCP, TPCP, and TOCP) were administered by gavage to rats at doses of 2, 20, and 200 mg/kg in corn oil, were reported to be well absorbed by NTP (1994). The basis for this conclusion was not stated, but may have been based on comparisons of the area under the blood concentration versus time curves for intravenous (20 mg/kg) versus oral administration. Distribution Dermal Distribution of radioactivity in the dog following a single 200-mg/kg application of 32P-TOCP to the abdominal skin was highest in the liver followed by the blood, kidney, lung, muscle and spinal cord, brain and sciatic nerve at 24 hr post-exposure (Hodge and Sterner 1943, as reviewed by IPCS 1990). In cats, the highest levels of radioactivity occurred in the bile, gall bladder, urinary bladder, kidney, and liver at 1–10 d after application of 50 mg/kg of 14C-TOCP (Nomeir and Abou-Donia 1986, as reviewed by IPCS 1990). In addition, low levels of radioactivity were found in the spinal cord and brain. Analysis showed that the parent compound was found primarily in the brain, spinal cord, and sciatic nerve, while metabolites were primarily found in the liver, kidney, and lung. It is not known if the patterns of distribution for TOCP and metabolites can be generalized to other TCP isomers. Inhalation No studies were identified that investigated the distribution of TCP in humans or laboratory animals following inhalation exposure. Oral Twenty-four hr after 89.6 mg/kg of 14C-TPCP was administered by gavage

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Toxicological Risks of Selected Flame-Retardant Chemicals to rats, the highest concentrations of radioactivity were found in the intestine (including contents), followed by the stomach, adipose tissue, liver, and kidneys (4–13-fold higher than blood concentrations). The lowest concentrations were found in heart, muscle, and brain (lower than blood concentrations) (Kurebayashi et al. 1985). In rats, 14C-TMCP, TPCP, and TOCP were rapidly distributed to muscle and liver following intravenous administration (NTP 1994). This was followed by a redistribution of radioactivity to adipose tissue and skin. The parent compounds were rapidly cleared rapidly from the tissues and did not bioaccumulate. Details of the study were not reported. Metabolism In rats, metabolism of TCP following oral gavage of 7.8 or 89.6 mg/kg was found to involve successive oxidations and hydrolysis resulting in the production of p-hydroxybenzoic acid (Kurebayashi et al. 1985). The major urinary metabolites identified were p-hydroxybenzoic acid, di-p-cresyl phosphate, and p-cresyl p-carboxyphenyl phosphate. The main biliary metabolites were di-p-cresyl phosphate, p-cresyl p-carboxyphenyl phosphate, and the oxidized triesters, di-p-cresyl p-carboxyphenyl phosphate, and p-cresyl p-carboxyphenyl phosphate. Fecal metabolites were similar to the biliary metabolites. 14CO2 was found in expired air following administration and appeared to be formed probably through decarboxylation of p-hydroxybenzoic acid by intestinal microbes. Many studies on the metabolism of TOCP are available. However, they might not be applicable to TMCP or TPCP. TOCP is metabolized to highly neurotoxic derivatives such as salingenin cyclic o-tolyl phosphate. However, there are no data to suggest that TMCP or TPCP is metabolized to neurotoxic metabolites. Exposure to TCP mixtures containing isomers with one or two ortho-cresol groups could result in the formation of neurotoxic metabolites (Johnson 1975; NTP 1994). Excretion Dermal About 48% of a single dermal application of a 50 mg/kg dose was excreted by d 10 post-exposure with 28% of the dose excreted in the urine while 20% of the dose was excreted in the feces (Nomeir and Abou-Donia 1986, as reviewed

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Toxicological Risks of Selected Flame-Retardant Chemicals by NTP 1994). Since the metabolism and excretion of orally administered TOCP appears to be different from TMCP and TPCP, the relevance of dermal excretion data for TOCP to other isomers is uncertain. No excretion data are available for other TCPs following dermal exposure. Approximately 40–60% of an intravenous injection of 2 or 20 mg/kg of radiolabelled TMCP, TPCP, or TOCP underwent biliary excretion within 6 hr of administration (NTP 1994). For TPCP, biliary excretion increased with increasing dose from 2–20 mg/kg resulting in a doubling of biliary excretion. For all three TCPs, the percentage of administered radioactivity excreted in the feces was less than the percentage excreted in bile suggesting that the isomers underwent enterohepatic recirculation. Inhalation No studies were identified that investigated the excretion of TCP in humans or laboratory animals following inhalation exposure. Oral Excretion of radioactivity following oral administration of 14C-TMCP, 14C-TPCP, or 14C-TOCP in rats at doses of 0.5 (14C-TMCP and 14C-TPCP only) 2, 20, and 200 mg/kg was investigated by NTP (1994). Radioactivity from TMCP was excreted primarily in the feces at all dose levels. Radioactivity from TPCP was excreted primarily in the urine at 0.5 and 2 mg/kg and primarily in the feces at 20 and 200 mg/kg. Radioactivity from TOCP was excreted primarily (70%) in the urine at all doses tested. Rats that received 14C-TPCP as a single gavage dose of 7.8 mg/kg excreted 41% of the dose of radioactivity in the urine, 44% in the feces, and 18% in the expired air within 7 d (Kurebayashi et al. 1985). A majority of the excretion occurred within 24 hr. Rats with cannulated bile ducts excreted 28% of the administered radioactivity in the bile during the first 24 hr. Rats treated in a similar manner with 89.6 mg/kg of 14C-TPCP excreted 12% of the administered radioactivity in the urine, 77% in the feces, and 6% in the expired air. The radiolabeled material excreted in urine and bile was identified as metabolites of TPCP in high dose rats (see Metabolism section for details). Parent compound was the dominant isomer excreted in the feces with some lesser amounts of metabolites present.

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Toxicological Risks of Selected Flame-Retardant Chemicals HAZARD IDENTIFICATION1 Dermal Exposure Irritation Broadhurst et al. (1951) reported mild irritation following initial contact with TCP formulations in patch tests on volunteers. Rabbits studied by Broadhurst et al. (1951) did not develop any irritation to TCP. The skin of rabbits exposed for 24 hr to commercial TCP mixtures at both lethal and sublethal doses showed mild inflammation, and in a few instances, focal acanthosis and slight hyperkeratosis (Treon et al. 1955). Repeated dermal exposure produced local skin inflammation. Inflammation was more severe in animals that died from treatment than among survivors (Treon et al. 1955). Eastman Kodak Company (1978) reported moderate skin irritation for TOCP and TPCP, slight irritation for TMCP, and no irritation for a TCP mixture in guinea pigs. No study details were reported. Sensitization Sensitization by TCP has been reported, it is not common. Tarvainen (1995) found no positive responses among 839 patients at a dermatology clinic given patch tests with TCP. Broadhurst et al. (1951) also reported negative results for Sensitization in patch testing of volunteers. Pegum (1966) described the case of a housewife who became sensitized to PVC plasticized with TCP. Patch tests with TCP produced a similar sensitization reaction. However, there is evidence that triphenyl phosphate, which is present in TCP mixtures, is a sensitizing agent (Carlsen et al. 1986) and may account for some or all of the sensitizing potential of TCP mixtures. Eastman Kodak Company (1978) reported moderate skin sensitizing activity for TMCP in guinea pigs. Study details were not available. Systemic Effects No studies were identified that investigated the systemic effects of TCP from dermal exposures in humans. 1   In this section, the subcommittee reviewed toxicity data on aromatic phosphate plasticizers, including the toxicity assessment prepared by the U.S. Consumer Product Safety Commission (Ferrante 1999).

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Toxicological Risks of Selected Flame-Retardant Chemicals Treon et al. (1955) studied the effects in rabbits of 24-hr dermal exposure to seven commercial TCP mixtures. The minimum lethal dose varied between 0.4–0.6 mL/kg and 1.6–3.2 mL/kg for the different compounds. Lethal doses resulted in diffuse degenerative changes in the brain, liver, and kidney, and edema in the other viscera. Pathological changes were not observed in survivors. Treon et al. (1955) also conducted repeated dermal exposure studies in which groups of three to four female rabbits were exposed to 0.25, 0.5, 1, 2, or 5 mL of one of seven commercial TCP mixtures 2 hr/d, 5 d/wk, for several weeks. Death, which was produced by doses as low as 0.25 mL, was preceded by ataxia and tremors. Degenerative changes were seen in the brain, liver, and kidneys of rabbits that died. Mild changes were also seen in the liver and kidneys of survivors treated with one of the TCP formulations. Broadhurst et al. (1951) reported death and clinical signs of delayed neuropathy (head drop, paralysis) in rabbits treated dermally with TCP. However, no changes in histopathology were reported. Neurological Effects Several cases have been reported of workers who developed polyneuropathy following occupational dermal exposure to TCP, and specifically TOCP (IPCS 1990). Percutaneous absorption was considered to be the most likely route of exposure in each of these cases, although some material may have been inhaled or ingested. The effects in these workers were similar to those observed in people who accidentally ingested TOCP. No data were located regarding neurological effects in animals following dermal exposure to TCP. Other Effects No studies were identified that investigated the immunological, or reproductive, developmental, or carcinogenic effects of TCP following dermal exposure. Inhalation Exposure Systemic and Neurological Effects Only one study was located that investigated the toxicity of TCP in humans following inhalation exposure. Bisesi (1994) reported that Tabershaw and

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Toxicological Risks of Selected Flame-Retardant Chemicals Kleinfeld (1957) found some inhibition of plasma cholinesterase, but no neuromuscular effects, in TOCP-manufacturing plant workers exposed to TOCP air concentrations ranging from 0.27 to 3.40 mg/m3. Animal inhalation toxicity data for TCP were also limited. Mortality was very high in rabbits exposed to TCP aerosols at concentrations of 5,900 mg/m3 to 42,200 mg/m3 for periods of 3 hr to 18 d (Broadhurst et al. 1951). Rabbits were observed to have considerably increased nasal and oral discharge during and immediately following exposure, and respiratory difficulties were noted. Diarrhea was also seen. Delayed neuropathy was also evident, progressing from hyperexciteability to tremors, gait impairment, and in several animals, paralysis of the hind legs. Serum cholinesterase was depressed. Histopathological evaluation of the respiratory tract revealed respiratory irritation, including bronchitis, inflammation of the larynx, and pulmonary edema. Treon et al. (1955) reported only small, transitory changes in body weight, no deaths, no clinical signs of toxicity, and no treatment-related lesions (examined tissues not reported) in 3 rats, 5 mice, 2 rabbits, 2 guinea pigs, and 1 cat exposed 7 hr/d for 8 d to air containing 62 mg/m3 of TCP vapor (unspecified mixture). Other Effects No studies were identified that investigated the immunological, reproductive, developmental, or carcinogenic effects of TCP in humans or animals following inhalation exposure. Oral Exposure Systemic Effects NTP (1994) conducted 16-d gavage studies, 13-wk gavage and feed studies, and 2-yr feed studies of a commercial TCP mixture in rats and mice. A battery of chemical analyses revealed the test material to be a complex mixture containing 79% tricresyl phosphate esters and 18% dicresyl phosphate esters. The results of these and other studies are summarized in Table 17–2 and discussed below. Acute Studies The acute toxicity of TCP has been investigated in rodents by NTP (1994) and Chapin et al. (1988). NTP (1994) found that acute administration of TCP

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Toxicological Risks of Selected Flame-Retardant Chemicals TABLE 17–2 Summary of Oral Toxicity Dose-Response Data for Tricresyl Phosphate Species, Strain, Sex, Number Dose (mg/kg-d) Duration, route Effects NOAEL/LOAEL (mg/kg-d) Reference Rat, F-344/N, M/F, 10/sex/dose 0, 360, 730, 1,450, 2,900, or 5,800 13–14 d, gavage Death; diarrhea; decreased body weight; decreased neurobehavioral performance; increased liver weight; decreased thymus weight; testicular aspermatogenesis; necrosis in thymus, spleen, salivary gland and lymph node LOAEL: 360 (increased liver weight) NTP 1994 Mouse, B6C3F1, M/F, 10/sex/dose 0, 360, 730, 1,450, 2,900, or 5,800 13–14 d, gavage Death; decreased neurobehavioral performance; increased liver weight; decreased thymus weight; necrosis in thymus, spleen and lymph node LOAEL: 360 (decreased neurobehavioral performance, increased liver weight) NTP 1994 Rat, F-344/N, M/F, 10/sex/dose 0, 50, 100, 200, 400, or 800 13 wk, gavage Decreased body weight; decreased serum cholinesterase; decreased neurobehavioral performance; increased liver weight; decreased thymus weight; atrophy of seminiferous tubules in testes; hypertrophy of ovarian interstitial cells; cytoplasmic vacuolization of the adrenal cortex LOAEL: 50 (lesions in ovary and adrenals, decreased serum cholinesterase) NTP 1994 Mouse, B6C3F1, M/F, 10/sex/dose 0, 50, 100, 200, 400, or 800 13 wk, gavage Decreased body weight; hind limb weakness and tremors; decreased neurobehavioral performance; decreased serum cholinesterase; increased liver weight; hypertrophy of ovarian interstitial cells; cytoplasmic vacuolization of the adrenal cortex; axonal degeneration in the spinal cord and sciatic nerve LOAEL: 50 (lesions in ovary and adrenals, decreased serum cholinesterase) NTP 1994 Rat, F-344/N, M/F, 10/sex/dose M: 0, 55, 120, 220, 430, or 750 F: 0, 65, 120, 230, 430, or 770 13 wk, diet Decreased food consumption; decreased body weight; emaciation; decreased neurobehavioral performance; decreased serum cholinesterase; increased liver weight; decreased testis weight; atrophy of seminiferous tubules in testes; hypertrophy of ovarian interstitial cells; cytoplasmic vacuolization of the adrenal cortex; edema and necrosis of the renal papilla; hypertrophy of pituitary basophils LOAEL: 55/65 (lesions in ovary and adrenals, decreased serum cholinesterase) NTP 1994

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Toxicological Risks of Selected Flame-Retardant Chemicals Mouse, B6C3F1, M/F, 10/sex/dose M: 0, 45, 110, 180, 380, or 900; F: 0, 65, 130, 230, 530, or 1,050 13 wk, diet Decreased food consumption; decreased body weight; tremors; decreased neurobehavioral performance; decreased serum cholinesterase; hypertrophy of ovarian interstitial cells; cytoplasmic vacuolization of the adrenal cortex; axonal degeneration in the spinal cord and sciatic nerve; hyperplasia in gallbladder; renal tubule regeneration LOAEL: 45/65 (adrenal lesions decreased serum cholinesterase) NTP 1994 Rat, F-344/N, M/F, 95/sex/dose M: 0, 3, 6, or 13; F: 0, 4, 7, or 15 104 wk, diet Decreased neurobehavioral performance; decreased serum cholinesterase; hypertrophy of ovarian interstitial cells; cytoplasmic vacuolization of the adrenal cortex Excluding decreased serum cholinesterase (see text): NOAEL: 7 LOAEL: 15 (lesions in ovary and adrenals) NTP 1994 Mouse, B6C3F1, M/F, 95/sex/dose M: 0, 7, 13, or 27; F: 0, 8, 18, or 37 104 wk, diet Decreased neurobehavioral performance; decreased serum cholinesterase; increased adrenal weight; lesions in the adrenal cortex and liver Excluding decreased serum cholinesterase (see text): NOAEL: 7/8 LOAEL: 13/18 (lesions in liver and adrenals) NTP 1994 Rat, Long-Evans, M/F, 12 M/dose, 24 F/dose M: 0, 100, or 200; F: 0, 200, or 400 M: 56 d before breeding and 10 d during breeding, gavage F: 14 d before breeding through lactation, gavage Decreased fertility; decreased litter size; decreased sperm concentration, motility and velocity; increased abnormal sperm; decreased epididymis weight; necrosis and degeneration of seminiferous tubules; hypospermia in epididymis; vacuolar cytoplasmic alteration of ovarian interstitial cells LOAEL: 100/200 (reproductive effects) Carlton et al. 1987

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Toxicological Risks of Selected Flame-Retardant Chemicals tensive human experience with TCP, including poisonings of tens of thousands of people over the past 100 yr, has produced no evidence that oral exposure to TCP can cause cancer in humans. NTP (1994) conducted a 2-yr cancer bioassay in rats and mice using a commercial TCP mixture. A battery of chemical analyses revealed the test material to be a complex mixture containing 79% tricresyl phosphate esters and 18% dicresyl phosphate esters. F-344/N rats (50/sex/dose) were fed diets containing 0, 75, 150, or 300 ppm of TCP for 104 wk (0, 3, 6, or 13 mg/kg-d in males; 0, 4, 7, or 15 mg/kg-d in females). B6C3F1 mice (50/sex/dose) were fed diets containing 0, 60, 125, or 250 ppm of TCP for 105 wk (0, 7, 13, or 27 mg/kg-d in males and 0, 8, 18, or 37 mg/kg-d in females). There were no effects on survival, feed consumption or body weight in either species. Treatment-related systemic effects were identified and the MTD (maximum tolerated dose) was achieved in both species (see Systemic Effects section). In female rats, there was an increased incidence of mononuclear cell leukemia. However, this effect was not considered to be treatment-related because of the unusually low tumor incidence in controls and low-dose groups, In mice, there was a nontreatment-related increase in the incidence of Harderian gland adenoma in males. NTP concluded that this study provided no evidence of carcinogenic activity for TCP in male or female rats or mice. Genotoxicity Few data were located regarding the genotoxicity of TCP. Results were negative for commercial TCP (<0.1% TOCP) and TMCP in the Ames assay (Salmonella typhimurium strains TA100, TA1535, TA1537, and TA98) with and without metabolic activation (Haworth et al. 1983; NTP 1994). The same TCP mixture was also negative in tests for sister chromatid exchange and chromosomal aberrations in Chinese hamster ovary cells with and without metabolic activation (NTP 1994). The TCP mixture used in these studies was the same as that used in the NTP toxicity and carcinogenicity studies. Mirsalis et al. (1983), in an abstract, reported negative results for TCP in an assay for unscheduled DNA synthesis in hepatocytes from Fischer-344 rats treated with TCP. Additional details regarding this study were unavailable. QUANTITATIVE TOXICITY ASSESSMENT Quantitative toxicity assessments of aromatic phosphate esters was estimated using toxicity data for TCP. Therefore, these assessments will be overly conservative for the toxicity of other aromatic phosphate esters.

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Toxicological Risks of Selected Flame-Retardant Chemicals Noncancer Dermal Assessment No studies were identified that could be used to derive a dermal RfD for TCP. In the absence of a dermal RfD, the subcommittee believes it is appropriate to use the oral RfD for TCP of 7×10−2 mg/kg-d as the best estimate of the internal dose from dermal exposure (derivation of the oral RfD for TCP is presented below). Inhalation RfC The available inhalation toxicity data are inadequate for the derivation of an RfC for TCP. Oral RfD The oral toxicity database for TCP contains several studies that are potentially useful for the derivation of an oral RfD, including chronic dietary studies in rats and mice (NTP 1994), subchronic feeding and gavage studies in rats and mice (NTP 1994), reproduction studies in rats and mice (Carlton et al. 1987; Chapin et al. 1988), and a study of immune function in rats (Banerjee et al. 1992). The subcommittee chose to use the results from the chronic feeding studies reported by NTP (1994) for deriving an oral RfD for TCP. These studies were chosen because they evaluated a broad range of toxicity end points in two species following lifetime exposure to an appropriate range of doses of TCP in the diet. The most sensitive end point for toxicity in these studies was identified as changes in serum cholinesterase. However, the subcommittee concluded that this end point is not appropriate for setting an oral RfD for TCP because there is some question as to whether inhibition of serum cholinesterase by TCP in these studies constitutes an adverse effect. The subcommittee concluded that the neurobehavioral effects and neuropathology findings in the NTP (1994) studies are consistent with TCP-induced delayed neuropathy and not cholinesterase inhibition. The subcommittee identified the adrenal gland and ovarian lesions in female rats and adrenal and liver lesions in female mice that occurred at 7 mg/kg-d to be the key critical effect for deriving an oral RfD for TCP. Application of a composite uncertainty factor (UF) of 100 (10 for interspecies variability and 10 for intraspecies variability) as summarized in Table 17–3, yields an oral RfD of 7×10−2 mg/kg-d.

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Toxicological Risks of Selected Flame-Retardant Chemicals Confidence in the oral toxicity database for TCP is medium. Supporting data were available from subchronic, reproductive, and developmental toxicity studies, but studies of reproductive function did not identify a NOAEL for TCP and only one developmental toxicity study was located. There was one report on immune-system effects associated with TCP exposure, but the available database was insufficient to evaluate this claim. Confidence in the key studies is high. These studies included an appropriately identified range of doses, a large number of animals, lifetime exposure by a relevant route (diet), and evaluation of a broad array of systemic toxicity end points. Cancer Dermal No studies were located that investigated the carcinogenicity of TCP in humans or animals following dermal exposure to TCP. The absence of route-specific data is a source of uncertainty with regard to a potential portal-of-entry effect, but there are no data to suggest that such an effect would be expected for TCP. Therefore, the weight-of-evidence classification from the oral data is expected to apply for dermal exposure as well. Inhalation No studies were located that investigated the carcinogenicity of TCP in humans or animals following inhalation exposure. The absence of route-specific data is a source of uncertainty with regard to a potential portal-of-entry effect, but there are no data to suggest that such an effect would be expected for TCP. Therefore, the weight-of-evidence classification from the oral data is expected to apply for inhalation exposure as well. Oral Extensive human experience with TCP, including poisonings of tens of thousands of people over the past 100 yr, has produced no evidence that oral exposure to TCP can cause cancer in humans. No evidence for the carcinogenicity of TCP was found in rats or mice chronically exposed to this compound for two yr in their diet (NTP 1994). Available genotoxicity studies, including assays for mutagenicity, cytogenetic effects, and DNA damage, found no evidence that TCP produces genotoxic effects. Therefore, TCP is considered not likely to be carcinogenic.

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Toxicological Risks of Selected Flame-Retardant Chemicals TABLE 17–3 Oral Reference Dose for Tricresyl Phosphate Critical effect Species Effect level (mg/kg-d) Uncertainty factors RfD (mg/kg-d) Adrenal and liver lesions Female rats, male mice NOAEL: 7.0 UFA: 10 UFH: 10 Total: 100 7×10−2 NOAEL, no-observed-adverse-effect level; RfD, reference dose; UFA, uncertainty factor for interspecies variability to humans; UFH, uncertainty factor for intraspecies variability. EXPOSURE ASSESSMENT AND RISK CHARACTERIZATION Noncancer Dermal Dermal exposure to TCP 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 TCP and 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. First Iteration As a first estimate of exposure, it was assumed that skin, clothing, and the upholstery did not impede dermal exposure to TCP present in the backcoating. It was also assumed that there would be sufficient water present from sweat to facilitate dissolution of TCP from the backcoating and absorption through the skin. In this scenario, only the dissolution rate of TCP from the backcoating is assumed to be the limiting factor in absorption by the body. It is assumed that all of the TCP 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 TCP of 5 mg/cm2. The extraction rate (µw) for TCP 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.

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Toxicological Risks of Selected Flame-Retardant Chemicals Using these assumptions, an estimated absorbed daily dose of 1.5 mg/kg was calculated for TCP. In the absence of a dermal RfD, the subcommittee believes it is appropriate to use the oral RfD for TCP of 7×10−2 mg/kg-d as the best estimate of the internal dose from dermal exposure. A hazard index of 21.3 was calculated for this first iteration by dividing the estimated daily dermal dose of 1.5 mg/kg-d by the oral RfD for TCP of 0.07 mg/kg-d. These results suggest that TCP could be a toxic hazard if all applied TCP is absorbed into the body simultaneously. This is an impossible event. Alternative Iteration The estimated dermal daily dose for TCP can be calculated using an estimate of the dermal penetration rate for TCP (Chapter 3: Equations 2 and 3). Instead of assuming that all dissolved TCP immediately penetrates the skin and enters systemic circulation, it is assumed that the skin slows the absorption of TCP to a specific amount of chemical absorbed per unit of time. This estimate can be measured experimentally and is referred to as the skin permeability coefficient Kp. However, the dermal penetration constant for TCP has not been measured experimentally. However, Kp can be estimated from a correlation between the octanol-water partition coefficient (Kow) and molecular weight (mass/unit amount of substance) using Equation 2 in Chapter 3 yielding an alternate Kp of 1.04 cm/d. Using Equation 3 in Chapter 3 and the alternate Kp, the dermal daily dose rate for TCP was estimated to be 3.0×10−3 mg/kg-d. In the absence of a dermal RfD, the subcommittee believes it is appropriate to use the oral RfD for TCP of 7×10−2 mg/kg-d as the best estimate of the internal dose from dermal exposure. A hazard index of 4.3×10−2 was calculated by dividing the estimated daily dermal dose of 3.0×10−3 mg/kg-d by the oral RfD for TCP of 0.07 mg/kg-d. These results suggest that TCP is not anticipated to be a toxic risk by the dermal route at the stated application concentrations and under the worst-case exposure scenario. Inhalation Exposure Particles Inhalation exposure estimates for TCP 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 TCP-treated

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Toxicological Risks of Selected Flame-Retardant Chemicals fabric and the room is assumed to have an air-change rate of 0.25/hr. It is also assumed that 50% of the TCP 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 TCP of 5 mg/cm2. The release rate (µr) for TCP 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-average exposure concentration of 0.48 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 this 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 FRs, and the derived RfC value should be used as an interim or provisional level until relevant data become available for the derivation of an inhalation RfC. In order to calculate a hazard index for the inhalation route, a provisional inhalation RfC of 0.245 mg/m3 was derived using the oral RfD for TCP and Equation 7 in Chapter 3. Division of the time-average exposure concentration of 0.48 µg/m3 by the provisional RfC for TCP of 0.245 mg/m3 gives a hazard index of 1.9×10−3. This suggests that under the subcommittee’s worst-case exposure assumptions, TCP would not be considered a toxic hazard by the inhalation route of exposure. Vapors In addition to the possibility of release of TCP in particles from worn upholstery fabric, the subcommittee considered the possibility of the release of TCP

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Toxicological Risks of Selected Flame-Retardant Chemicals by evaporation. This approach is described in Chapter 3, and uses an exposure scenario similar to that described above for exposure to TCP particles. The rate of flow of TCP vapor from the room is calculated using Equations 8–11 in Chapter 3. A saturated vapor concentration (Cν) of 2.0 mg/m3 was estimated for TCP. The application density (Sa) for TCP in the treated upholstery was estimated as 5 mg/cm2. Using the parameters described, the equilibrium room-air concentration of TCP was estimated to be 1.7 mg/m3. The short-term time-average exposure concentration for TCP was estimated as 0.417 mg/m3 using Equation 12 in Chapter 3 and the equilibrium room-air concentration for TCP. It was estimated that concentration could be maintained for approximately 10 yr. Division of the short-term inhalation vapor exposure concentration of 0.417 mg/m3 by the provisional RfC of 0.245 mg/m3 yields a hazard index of 1.7, which indicates that inhalation exposure at the worst-case levels might pose a noncancer risk. Oral Exposure The assessment of noncancer toxicological risk for oral exposure to TCP is based on the oral exposure scenario described in Chapter 3. This scenario assumes a child is exposed to TCP by sucking on 50 cm2 of fabric backcoated with TCP, 1 hr/d for two yr. The subcommittee estimated an upholstery application rate (Sa) for TCP of 5 mg/cm2. Oral exposure was calculated using Equation 15 in Chapter 3. The extraction rate (µw) for TCP 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 TCP was estimated as 0.04 mg/kg-d. Division of the dose estimate by the oral RfD for TCP of 0.07 mg/kg-d gives a hazard index of 0.57. This suggests that under the subcommittee’s worst-case exposure assumptions, TCP is not likely to pose a health risk by the oral route of exposure. Cancer Dermal There are no studies available to evaluate the carcinogenicity of TCP in humans or laboratory animals following dermal exposure.

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Toxicological Risks of Selected Flame-Retardant Chemicals Inhalation There are inadequate data to assess the carcinogenicity of TCP in humans or animals following inhalation exposure. Oral TCP is not likely to be a human carcinogen by the oral route of exposure. Therefore, TCP is not anticipated to cause cancer in humans from oral exposure to treated furniture upholstery. RECOMMENDATIONS FROM OTHER ORGANIZATIONS IPCS (1990) concluded that there is no safe level of ingestion for TCP, and that exposure through inhalation or dermal contact should be minimized. There is an ACGIH Threshold Limit Value (TLV) for TOPCP (CAS RN 78–30–8) of 0.1 mg/m3 for skin (ACGIH 1999). The NIOSH REL (skin) and OSHA PEL for TOCP is also 0.1 mg/m3 (NIOSH 1996). DATA GAPS AND RESEARCH NEEDS There are no chronic toxicity data for TCP for the dermal and inhalation routes of exposure. There is no information on the types and amounts of TCP species that are present in upholstery backcoating. Data on the leaching of these species from upholstery backcoating are also not available. Information on the dermal penetration of TCP and its possible derivatives would be helpful. Based on an inhalation hazard index greater than 1, the subcommittee recommends that the potential for vapor release from treated fabric should be investigated. REFERENCES ACGIH (American Conference of Government Industrial Hygienists). 1999. Threshold Limit Values and Biological Exposure Indices. Cincinnati, OH: American Conference of Government Industrial Hygienists. Aldridge, W.N., and J.MBarnes. 1966. Esterases and neurotoxicity of some organophosphorus compounds. Biochem. Pharmacol. 15(5):549–554.

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