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Toxicological Risks of Selected Flame-Retardant Chemicals (2000)

Chapter: 17 Aromatic Phosphate Plasticizers

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Suggested Citation:"17 Aromatic Phosphate Plasticizers ." National Research Council. 2000. Toxicological Risks of Selected Flame-Retardant Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/9841.
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AROMATIC PHOSPHATE PLASTICIZERS 387 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.

AROMATIC PHOSPHATE PLASTICIZERS 388 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; ChemID 1999; RTECS 1999 phosphoric acid, tritolyl ester; phosphoric acid, tris(methylphenyl) ester; tris(tolyloxy)phosphine oxide Trade Names Celluflex 179C, Disflamoll TKP, Durad, Fyrquel IPCS 1990; ChemID 1999; RTECS 1999 150, Flexol Plasticizer TCP, IMOL S 140, Lindol, Koflex 5050, Kronitex-TCP, Phosflex 179, Pliabrac 521, PX.917, Santicizer 140 Molecular Weight 368.36 Budavari et al. 1989 Physical State Colorless liquid HSDB 1999 Solubility 0.36 mg/L in H2O at 25 °C HSDB 1999 Miscible with all the common organic solvents HSDB 1999 and thinners, and also with vegetable oils 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

AROMATIC PHOSPHATE PLASTICIZERS 389 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.

AROMATIC PHOSPHATE PLASTICIZERS 390 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

AROMATIC PHOSPHATE PLASTICIZERS 391 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

AROMATIC PHOSPHATE PLASTICIZERS 392 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.

AROMATIC PHOSPHATE PLASTICIZERS 393 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. 1In 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).

AROMATIC PHOSPHATE PLASTICIZERS 394 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

AROMATIC PHOSPHATE PLASTICIZERS 395 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

AROMATIC PHOSPHATE PLASTICIZERS 396 TABLE 17–2 Summary of Oral Toxicity Dose-Response Data for Tricresyl Phosphate Species, Strain, Dose (mg/kg- Duration, route Effects NOAEL/LOAEL (mg/ Reference Sex, Number d) kg-d) Rat, F-344/N, 0, 360, 730, 13–14 d, gavage Death; diarrhea; LOAEL: 360 NTP 1994 M/F, 10/sex/ 1,450, 2,900, decreased body weight; (increased liver weight) dose or 5,800 decreased neurobehavioral performance; increased liver weight; decreased thymus weight; testicular aspermatogenesis; necrosis in thymus, spleen, salivary gland and lymph node Mouse, 0, 360, 730, 13–14 d, gavage Death; decreased LOAEL: 360 NTP 1994 B6C3F1, M/F, 1,450, 2,900, neurobehavioral (decreased 10/sex/dose or 5,800 performance; increased neurobehavioral liver weight; decreased performance, increased thymus weight; necrosis liver weight) in thymus, spleen and lymph node Rat, F-344/N, 0, 50, 100, 13 wk, gavage Decreased body weight; LOAEL: 50 (lesions in NTP 1994 M/F, 10/sex/ 200, 400, or decreased serum ovary and adrenals, dose 800 cholinesterase; decreased decreased serum neurobehavioral cholinesterase) performance; increased liver weight; decreased thymus weight; atrophy of seminiferous tubules in testes; hypertrophy of ovarian interstitial cells; cytoplasmic vacuolization of the adrenal cortex Mouse, 0, 50, 100, 13 wk, gavage Decreased body weight; LOAEL: 50 (lesions in NTP 1994 B6C3F1, M/F, 200, 400, or hind limb weakness and ovary and adrenals, 10/sex/dose 800 tremors; decreased decreased serum neurobehavioral cholinesterase) 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 Rat, F-344/N, M: 0, 55, 13 wk, diet Decreased food LOAEL: 55/65 (lesions NTP 1994 M/F, 10/sex/ 120, 220, consumption; decreased in ovary and adrenals, dose 430, or 750 body weight; emaciation; decreased serum F: 0, 65, 120, decreased cholinesterase) 230, 430, or neurobehavioral 770 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

AROMATIC PHOSPHATE PLASTICIZERS 397 Mouse, M: 0, 45, 13 wk, diet Decreased food LOAEL: 45/65 NTP 1994 B6C3F1, M/F, 110, 180, consumption; (adrenal lesions 10/sex/dose 380, or 900; decreased body weight; decreased serum F: 0, 65, tremors; decreased cholinesterase) 130, 230, neurobehavioral 530, or 1,050 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 Rat, F-344/N, M: 0, 3, 6, or 104 wk, diet Decreased Excluding decreased NTP 1994 M/F, 95/sex/ 13; F: 0, 4, neurobehavioral serum cholinesterase dose 7, or 15 performance; (see text): NOAEL: 7 decreased serum LOAEL: 15 (lesions cholinesterase; in ovary and adrenals) hypertrophy of ovarian interstitial cells; cytoplasmic vacuolization of the adrenal cortex Mouse, M: 0, 7, 13, 104 wk, diet Decreased Excluding decreased NTP 1994 B6C3F1, M/F, or 27; F: 0, neurobehavioral serum cholinesterase 95/sex/dose 8, 18, or 37 performance; (see text): NOAEL: decreased serum 7/8 LOAEL: 13/18 cholinesterase; (lesions in liver and increased adrenal adrenals) weight; lesions in the adrenal cortex and liver Rat, Long- M: 0, 100, or M: 56 d before Decreased fertility; LOAEL: 100/200 Carlton et al. Evans, M/F, 200; F: 0, breeding and 10 decreased litter size; (reproductive effects) 1987 12 M/dose, 24 200, or 400 d during decreased sperm F/dose breeding, concentration, motility gavage F: 14 d and velocity; increased before breeding abnormal sperm; through decreased epididymis lactation, gavage weight; necrosis and degeneration of seminiferous tubules; hypospermia in epididymis; vacuolar cytoplasmic alteration of ovarian interstitial cells

AROMATIC PHOSPHATE PLASTICIZERS 398 Species, Strain, Dose (mg/ Duration, route Effects NOAEL/LOAEL Reference Sex, Number kg-d) (mg/kg-d) Mouse, Swiss 0, 62.5, 124 7 d before Decreased body LOAEL: 62.5 NTP 1984; CD- 1, M/F, 20/ or 250 mating through weight; hind limb (reproductive Chapin et al. 1988 sex/dose 14 wk of weakness; decreased effects, decreased breeding, diet litters per pair; body weight) decreased live pups per litter; decreased proportion of pups born alive; decreased pup body weight; decreased kidney and adrenal weight, testis weight and epididymis weight; decreased sperm concentration and motility; increased abnormal sperm; atrophy of seminiferous tubules; hypertrophy and degeneration of adrenals Rat, Wistar, M, 0, 2.4, 6 or 12 6 wk, diet Decreased humoral NOAEL: 2.4 Banerjee et al. 10/dose and cell-mediated LOAEL: 6 1992 immune response (decreased immune response) F, female; LOAEL, lowest-observed-adverse-effect level; M, male; NOAEL, no-observed-adverse-effect level.

AROMATIC PHOSPHATE PLASTICIZERS 399 by gavage to rats or mice caused increases in deaths, decreases in body weight, various neurological effects, and necrosis of various tissues. Diffuse aspermatogenesis was observed in high-dose male rats. Liver weights were significantly increased in mice of both sexes at dose levels≥360 mg/kg-d. Chapin et al. (1988) found that all mice treated with TCP at≥2,280 mg/kg-d died before the end of the 14-d exposure period. Decreases in body weight were observed at doses of 570 and 1,140 mg/kg-d. Subchronic Studies The results of 90-d oral toxicity studies for TCP are summarized in Table 17–2. In a subchronic study conducted by NTP (1994), mortality was not increased in rats or mice treated by gavage with TCP. Terminal body weights were significantly reduced in male rats and mice at ≥200 mg/kg-d, and female mice at ≥400 mg/kg- d. Decreased hindlimb grip strength was noted in female rats at ≥400 mg/kg-d and various neurological parameters were considered abnormal at ≥ 200 mg/kg-d in both male and female mice. Liver and thymus weights were increased in male rats, mice and female rats at doses ≥400 mg/kg-d and ≥200 mg/kg-d in mice. Atrophy of the seminiferous tubules occurred ≥400 mg/kg-d in male rats. Hypertrophy of ovarian interstitial cells occurred in female mice and rats at ≥50 mg/kg-d. The adrenal cortex was also affected in both species (see Table 17–2). NTP (1994) also conducted subchronic toxicity studies for TCP in which rats and mice (10 animals/sex/ dose) were given TCP in their feed for 90 d (see Table 17–2). All animals survived to the end of the study. In rats, final body weight was significantly reduced in males in the 6,600 ppm group and in females in the 3,300 ppm and 6,600 ppm groups without large changes in food intake. In mice, final body weight was reduced in males at 4,200 ppm and in females at 2,100 ppm and 4,200 ppm. The reduction in body weight was accompanied by a reduction in feed consumption in the females. Hindlimb grip strength was reduced in male rats fed TCP at 13,000 ppm and in male and female mice at≥2,100 ppm. Various pathological changes and increases in the weights of various organs were seen in both species for both sexes. Chronic Studies Groups of 95 male and female F-344/N rats were fed diets containing 0, 75, 150, or 300 ppm of TCP for 104 wk (estimated doses of 0, 3, 6, or 13 mg/kg-d in males and 0, 4, 7, or 15 mg/kg-d in females) (NTP 1994). A second group of

AROMATIC PHOSPHATE PLASTICIZERS 400 rats was fed diets containing 600 ppm TCP for 22 wk and control feed thereafter. Fifteen rats of each sex from each dose group (including 600 ppm) were killed for interim evaluations after 3, 9, and 15 mo. Most of the 600 ppm group (those not included in the interim evaluation groups) were killed and discarded after the 3-mo interim evaluation. The results of this study are summarized in Table 17–2. No treatment-related deaths occurred and no clinical signs of toxicity were reported. Food intakes and body weights of treated and controls were not significantly different. Hindlimb grip strength was significantly reduced in males at ≥300 ppm and females at 600 ppm in the 3-mo interim evaluation, but not in the subsequent 9- and 15-mo evaluations. A treatment-related reduction in serum cholinesterase was observed in both males and females at 3-, 9-, and 15-mo interim evaluations. Treatment-related adrenal cytoplasmic vacuolization occurred in males at 600 ppm at 3 mo, but not at later time periods when this group received control feed. In females, adrenal cytoplasmic vacuolization was significantly increased at 300 ppm at all time periods and at 600 ppm at the 3-mo evaluation. Absolute and relative adrenal weights were significantly increased at≥300 ppm at the 3-mo interim evaluation. The incidence of minimal-to-mild interstitial cell hyperplasia of the ovary was significantly increased at ≥150 ppm in the 3-mo interim evaluation, but only at 300 ppm in subsequent evaluations. In the mouse study, groups of 95 male and female B6C3F1 mice were fed diets containing 0, 60, 125, or 250 ppm of TCP (estimated mg/kg-d dose for males: 7, 13, 27; for females: 8, 18, or 37) for 105 wk (NTP 1994). There were no effects on survival, feed consumption, body weight, or clinical findings. Hindlimb grip strength was significantly reduced in female mice in the 250 ppm group in the 3-mo evaluation, but not in the subsequent evaluations. Serum cholinesterase was significantly reduced in a dose-related manner in both males and females at ≥60 ppm at all time points. Non-neoplastic pathology findings were limited to the adrenal gland and liver. Absolute and relative weights of both the right and left adrenal glands were significantly increased in female mice at 250 ppm in the 15-mo interim evaluation. Microscopic examination revealed a dose-related increase in the severity of ceroid pigmentation, distension of epithelial cells, and macrophages of the adrenal cortex in female mice starting at the 9-mo interim evaluation and continuing through the end of the study. Male mice at the end of the study had significant increases in the incidences of liver lesions at≥125 ppm and higher-dose groups, including clear cell foci (foci of enlarged cells with clear spaces in cytoplasm), fatty change (small vacuoles in hepatocytes throughout the liver), and ceroid pigmentation (cells, sometimes enlarged and clustered, with pigmented granules in cytoplasm).

AROMATIC PHOSPHATE PLASTICIZERS 401 Other Studies Absolute and relative liver weights were significantly increased in male JCL-Wistar rats fed diets containing 0% (n=18) or 0.5% (n=8) TCP (estimated dose=450 mg/kg-d) for 9 wk (Oishi et al. 1982). TCP was a mixture of unspecified composition. TCP had no effect on body and other organ weights as compared to controls. Serum cholesterol, bile acids, total protein, urea nitrogen, and alanine aminotransferase levels were significantly elevated. Mild histopathological changes were found in the liver characterized by cytoplasmic vacuolation, increased number of binucleated cells, and enlarged cell size. Histopathological examination of unspecified tissues found no treatment-related effects in rats exposed for 3 mo to TCP (60–65% TMCP and 35–40% TPCP) suspended in water with 5% gum arabic at doses of 30, 100, 300, or 1,000 mg/kg-d (Saito et al. 1974 as reviewed by IPCS 1990). No further details of this study were reported. Immunological Effects No data were located regarding immunological effects of TCP in humans. Banerjee et al. (1992) reported that dietary exposure to TCP caused a suppression of humoral and cell- mediated immune response in rats. Groups of 10 male Wistar rats were fed diets containing 0, 20, 50, or 100 ppm of TCP (90% ortho, meta, and para isomers) for 6 wk. Doses in the 0-, 20-, 50-, and 100-ppm groups were estimated to be 0, 2.4, 6, and 12 mg/kg-d of TCP, respectively. After 25 d of exposure, rats were immunized with tetanus toxoid. No clinical signs of toxicity were observed, and food and water intake, body weight and relative organ weights in treated rats were similar to controls. Serum antibody titres to tetanus toxoid were significantly reduced at 50 and 100 ppm TCP. Serum immunoglobulins (IgM and IgG) were significantly reduced at 100 ppm TCP while leucocyte and macrophage migration was inhibited at 50 and 100 ppm TCP. Although the results of this study suggest that the immune system may be a sensitive target for TCP, the study included only limited assessment of immune function and the test material was not well characterized. Brinkerhoff et al. (1981) found little evidence of immunotoxicity in mice treated by oral gavage with TOCP at 0, 5, 50, or 500 mg/kg or 50 mg/kg of TMCP, once/wk, for 1–13 wk. Assays were conducted for splenic plaque formation, serum immunoglobulin levels (IgA, IgG, IgM), delayed hypersensitivity in response to sheep erythrocytes, and lymphocyte transformation in response to various mitogens in splenic cultures. No treatment- related changes in body

AROMATIC PHOSPHATE PLASTICIZERS 402 or organ weights were detected in treated versus control animals. Lymphocyte proliferation to PWM (but not PHA or LPS) was reduced in all TOCP and TMCP dose groups at 13 wk. However, the decreases were small and there was no evidence of a dose-response relationship. No other evidence for immune effects of TOCP and TMCP were detected in other assays. The researchers concluded that this study found no significant alterations of immune function. Neurological Effects TCP, and especially TOCP, have been implicated in outbreaks of polyneuropathy that have affected tens of thousands of people around the world since the late 1890s (Morgan 1982; IPCS 1990). Most of these outbreaks were traced to contamination of food or cooking oil with lubricating oil, mineral oil, hydraulic fluid, or some similar material containing TCP. The first symptom of delayed neuropathy in affected persons, occurring 3–28 d after exposure, is sharp, cramp-like pain in the calves (IPCS 1990). This is followed within a few days by weakness of the leg muscles and unsteadiness. Symptoms progress over a period of days or weeks to partial or complete paralysis that may include the upper, as well as lower, extremities. These effects are associated with axonopathy of both motor and sensory distal axons characterized by transection of the axon and degeneration of the axon and myelin sheath distal to the transection (IPCS 1990; NTP 1994). The axonopathy is most prominent in long, large-diameter myelinated axons of peripheral nerves and long spinal tracts. Although the effects may regress over time in mild cases, many of the individuals affected in various outbreaks still showed severe effects many years after exposure. Studies in laboratory animals have showed that TOCP produces delayed neuropathy to varying degrees in many species (IPCS 1990). Ability to inhibit brain neurotoxic esterase in animals is used as a marker of delayed neuropathy (referred to as organophosphorous-induced delayed neuropathy [OPIDN]). These studies have shown that TOCP is a much more potent inducer of OPIDN than TCP mixtures. Metabolism of the ortho-cresol residue of TOCP produces a cyclic phosphate that is thought to be the proximate toxicant for TOCP-induced OPIDN (NTP 1994). No evidence has been found that TMCP or TPCP can produce OPIDN (e.g., Aldridge and Barnes 1966; Johannsen et al. 1977; Sprague and Castles 1985). However, it is possible that cyclic phosphate could be formed from the metabolism of mixed, ortho-cresol-containing TCP isomers and produce neurotoxic effects if these isomers are present.

AROMATIC PHOSPHATE PLASTICIZERS 403 Reproductive and Developmental Effects No studies were identified that evaluated the reproductive and developmental effects of TCP in humans. There are a number studies that have investigated the effects of TCP on reproductive and developmental parameters; they are summarized in Table 17–2. TCP, containing <9% TOCP, administered to breeding male and female rats was found to have an effect on various reproductive and developmental toxicity parameters (Carlton et al. 1987). Male rats (12/dose) were administered 0, 100, or 200 mg/kg-d of TCP in corn oil by daily gavage for 56 d prior to breeding and throughout a 10-d breeding period. Females rats (24/dose) were gavaged daily with 0, 200, or 400 mg/kg-d TCP for 14 d prior to breeding and throughout breeding, gestation, and d 21 of lactation. No clinical signs of toxicity or effects on body weight were observed in breeding males or females. Fertility and mean litter size were significantly reduced in a dose-dependent manner in breeding females. All high-dose pups died on lactation d 5. Pup weight, days of eye opening, and vaginal patency were not affected. In breeding adult males, a dose-related increase in the percentage of abnormal sperm was observed in males. Sperm parameters (concentration, motility, and velocity) and epididymis weight were markedly reduced or decreased in the high-dose group. High-dose males also had various reproductive tract lesions including necrosis and degeneration of seminiferous tubules (minimal to mild in severity), hypospermia in the epididymides, degenerated and immature spermatids in the seminiferous tubules and epididymides, and early sperm granulomas in the seminiferous tubules. A dose-related increase in the incidence of diffuse vacuolar cytoplasmic alteration of ovarian interstitial cells was observed in females. Chapin et al. (1988) found that chronic administration of TCP in the diet resulted in decreased fertility among the F0 generation of a continuous breeding study. Male and female mice were fed diets containing 0%, 0.05%, 0.1%, or 0.2% TCP (79% tricresyl phosphate esters, including 21% TMCP, 4% TPCP, and <0.1% TOCP, and 18% dicresyl phosphate esters) starting 7 d before mating and continuing for 14 wk. Doses were estimated by the researchers to be 0, 62.5, 124, and 250 mg/kg-d for the 0%, 0.05%, 0.1%, and 0.2% groups, respectively. After the 14-wk breeding period, the males and females were separated, but continued on treatment. Data were collected on all litters born before the end of 14 wk and then discarded. Litters delivered after the 14- wk period were weaned, treated until breeding age, and then mated to nonsiblings from the same treatment group to produce F2 litters. F2 mice from the high-dose group were then mated with controls in a cross-over study.

AROMATIC PHOSPHATE PLASTICIZERS 404 Hind limb weakness and decreased postpartum body weights were observed in F0 females from the 0.2% dose group starting with delivery of a second litter. The number of pairs producing more than one litter was markedly reduced in the 0.2% group. A reduction in the number of live pups per litter and increase in number of dead pups per litter occurred in the 0.1% and 0.2% dose groups. The mean number of litters per pair, number of live pups per litter, proportion of pups born alive, and body weight of live pups were all significantly decreased in the 0.2% group. Pup body weight was also significantly reduced in the 0.1 % group. At necropsy, body, and kidney and adrenal gland weights were decreased in F0 females, while body, testis, and epididymis weights were decreased in males from the 0.2% dose groups. Sperm concentration and motility were significantly reduced, and the percentage of abnormal sperm was significantly increased in F0 males from the 0.2% dose group. Examination of these animals showed atrophy of the seminiferous tubules in males and hypertrophy and degeneration in the adrenals in both males and females. A dose-related decrease in fertility was observed in F1 animals in the 0.05% and 0.1% dose groups. No F1 matings were performed for the 0.2% group because of insufficient numbers of F1 offspring produced in the 0.2% group. There was also a statistically significant, dose-related trend for decreased number of live pups per litter. Necropsy of F1 mice showed an increased incidence and/or severity of adrenal lesions (hypertrophy, degeneration) in both sexes in both dose groups. Decreased body weights were observed in females from both dose groups and decreased testis and epididymis weight in males of the 0.1% group. Decreased sperm motility and increased abnormal sperm was observed in males in both dose groups. Bolon et al. (1997) examined the ovarian sections from both F0 and F1 females and found no effect on differential follicle count related to treatment with TCP. The cross-over mating studies showed impaired reproductive performance whether treated males or females were mated with controls. However, the effect of TCP on reproductive performance was greater when treated females were used. Morrissey et al. (1988) summarizes the effects of TCP on reproductive organ weight and sperm morphology from animals in the NTP (1994) study. Sperm motility and concentration were decreased, and the percentage of abnormal sperm was increased in male rats and mice treated with TCP for 90 d or 104 wk. These effects were generally accompanied by decreased absolute and/or relative weights of the cauda, epididymis, and/or testis. The dose levels at which these effects occurred within each study were not reported. Latendresse et al. (1993, 1994a, b, 1995) used TCP as a positive control in a number of studies of reproductive toxicity in F-344 rats. In these studies, TCP was administered at a high-dose level (400 mg/kg-d) by daily gavage in sesame

AROMATIC PHOSPHATE PLASTICIZERS 405 oil. The TCP used in these studies was analyzed by gas chromatography/mass spectrophotometry and was found to be a mixture of mostly the TPCP and TMCP isomers (62%) containing substantial amounts of cresyl-xylyl (18%) and cresyl-ethylphenyl (18%) phosphates and no detectable TOCP or other TCP species containing the ortho-isomer. It is possible that the ortho-cresol moiety was present in ethylphenyl and xylyl-substituted species. The initial study (Latendresse et al. 1994a) included light microscopic, morphometric, histochemical, and ultrastructural examination of reproductive tissues of male and female rats treated with TCP for 20, 40, or 60 d (3/sex/duration). Findings included cholesteryl lipidosis and hypertrophy of adrenocortical cells in rats of both sexes and ovarian interstitial cells in females, and degeneration of the seminiferous tubules in males. These lesions all occurred within 20 d of exposure and progressed as exposure continued. Testicular weight was significantly reduced in males after 60 d of exposure. Accumulation of cholesteryl ester in cytoplasmic lipid droplets in the adrenals and ovaries was associated with almost complete inhibition of neutral cholesteryl ester hydrolase, which converts cholesteryl ester to cholesterol, in both tissues (Latendresse et al. 1993). Cholesteryl lipidosis apparently did not result from inhibition of steroidogenesis, since serum concentrations of corticosterone and androstenedione were not decreased in treated rats, and serum concentrations of estradiol were significantly increased (Latendresse et al. 1995). TCP had no effect on the estrous cycle of treated rats (Latendresse et al. 1995). In a continuous breeding study, TCP at 400 mg/kg-d slightly reduced body weight in F-344 rat dams, significantly reduced fertility (number producing at least one litter/number mated), eliminated the occurrence of second and third litters by breeding pairs, and significantly decreased the number of live pups per litter (Latendresse et al. 1994b). Cross-over mating trials showed that these reproductive findings were due to effects on the males and not the females. The only teratogenicity study located for TCP and isomers was a study of TOCP in rats. Groups of 10–16 pregnant female Long-Evans Hooded rats were treated with 0, 87.5, 175, or 350 mg/kg-d of TOCP in corn oil on d 6–18 of gestation by gavage (Tocco et al. 1987). Deaths occurred among high-dose dams (28%). There were no treatment-related effects on preimplantation loss, resorptions, sex ratio, fetal body weight, or the incidence of external, visceral, or skeletal malformations or variations. The study did not include investigation of potential functional developmental deficits. Cancer No data were located regarding the carcinogenicity of TCP in humans. Ex

AROMATIC PHOSPHATE PLASTICIZERS 406 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.

AROMATIC PHOSPHATE PLASTICIZERS 407 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.

AROMATIC PHOSPHATE PLASTICIZERS 408 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.

AROMATIC PHOSPHATE PLASTICIZERS 409 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 7×10−2 UFH: 10 Total: 100 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.

AROMATIC PHOSPHATE PLASTICIZERS 410 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

AROMATIC PHOSPHATE PLASTICIZERS 411 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

AROMATIC PHOSPHATE PLASTICIZERS 412 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.

AROMATIC PHOSPHATE PLASTICIZERS 413 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.

AROMATIC PHOSPHATE PLASTICIZERS 414 Banerjee, B.D., S.Saha, K.K.Ghosh, and P.Nandy. 1992. Effect of tricresyl phosphate on humoral and cell-mediated immune responses in albino rats. Bull. Environ. Contam. Toxicol. 49(2):312–317. Bisesi, M.S. 1994. Esters. Pp. 2967–3118 in Patty's Industrial Hygiene and Toxicology, Fourth Ed., Vol. II, Part D, Toxicology. G.D.Clayton, and F.E.Clayton, eds. New York: John Wiley & Sons. Bolon, B., T.J.Bucci, A.R.Warbritton, J.J.Chen, D.R.Mattison, and J.J.Heindel. 1997. Differential follicle counts as a screen for chemically induced ovarian toxicity in mice: results from continuous breeding bioassays. Fundam. Appl. Toxicol. 39(1): 1–10. Brinkerhoff, C.R., R.P.Sharma, and D.R.Bourcier. 1981. The effects of tri-o-tolyl phosphate (TOTP) on the immune system of mice. Ecotoxicol. Environ. Saf. 5(3):368–376. Broadhurst, C.A., A.F.Grady, N.Jarvik, et al. 1951. A Toxicological Study of Tricresyl Phosphate. Institute of Industrial Medicine, New York University-Bellevue Medical Center. Budavari, S., M.J.O'Neil, A.Smith, and P.E.Heckehnan. 1989. The Merck Index, Eleventh Edition. S.Budavari, M.J.O'Neil, A.Smith, and P.E.Heckehnan, eds. Rahway, NJ: Merck & Co., Inc. Carlsen, L., K.E.Andersen, and H.Egsgaard. 1986. Triphenyl phosphate allergy from spectacle frames. Contact Dermatitis 15(5):274–277. Carlton, B.D., A.H.Basaran, L.E.Mezza, and M.K.Smith. 1987. Examination of the reproductive effects of tricresyl phosphate administered to Long-Evans rats. Toxicology 46(3):321–328. Chapin, R.E., J.D.George, and J.C.Lamb, 4th. 1988. Reproductive toxicity of tricresyl phosphate in a continuous breeding protocol in Swiss (CD-1) mice. Fundam. Appl. Toxicol 10(2):344–354. ChemID. 1999. On-Line Database. [Online]. Available: http://igm.nlm.nih.gov/cgi-bin/ doler?account=++&password=++&datafile=chemid National Library of Medicine, Bethesda, MD. Rev: May 10, 1999 Eastman Kodak Company. 1978. Toxicity and Health Hazard Summaries for Aryl Phosphates. OTS0206526. Ferrante, J. 1999. Toxicity Review for Aromatic Phosphate Plasticizers. Memorandum updated from Jacqueline Ferrante, Pharmacologist, Division of Health Sciences, to Ronald L.Medford, Assistant Executive Director for Hazard Identification and Reduction. U.S. Consumer Product Safety Commission, Washington, DC. Haworth, S., T.Lawlor, K.Mortelmans, W.Speck, and E.Zeiger. 1983. Salmonella mutagenicity test results for 250 chemicals. Environ. Mutagen. 5(Suppl. 1):3–142. Hodge, H.C., and J.H.Sterner. 1943. The skin absorption of triorthocresyl phosphate as shown by radioactive phosphorus. J. Pharmacol. Exp. Ther. 79:225–234. HSDB (Hazardous Substances Data Bank). 1999. [Online]. Available: http://sis.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB National Library of Medicine, Bethesda, MD. IPCS (International Programme on Chemical Safety). 1990. Environmental Health Criteria 110: Tricresyl Phosphate. World Health Organization, Geneva. Johannsen, F.R., P.L.Wright, D.E.Gordon, G.J.Levinskas, R.W.Radue, and P.R.

AROMATIC PHOSPHATE PLASTICIZERS 415 Graham. 1977. Evaluation of delayed neurotoxicity and dose-response relationships of phosphate esters in the adult hen. Toxicol. Appl. Pharmacol. 41(2):291–304. Johnson, M.K. 1975. Organophosphorus esters causing delayed neurotoxic effects: Mechanism of action and structure activity studies. Arch. Toxicol. 34(4):259–288. Kurebayashi, H., A.Tanaka, and T.Yamaha. 1985. Metabolism and disposition of the flame retardant plasticizer, tri-p-cresyl phosphate, in the rat. Toxicol. Appl. Pharmacol. 77(3):395–404. Latendresse, J.R., S.Azhar, C.L.Brooks, and C.C.Capen. 1993. Pathogenesis of cholesteryl lipidosis of adrenocortical and ovarian interstitial cells in F344 rats caused by tricresyl phosphate and butylated triphenyl phosphate. Toxicol. Appl. Pharmacol. 122(2):281–289. Latendresse, J.R., C.L.Brooks, and C.C.Capen. 1994a. Pathologic effects of butylated triphenyl phosphate-based hydraulic fluid and tricresyl phosphate on the adrenal gland, ovary, and testis in the Fischer-344 rat. Toxicol. Pathol. 22(4):341–352. Latendresse, J.R., C.L.Brooks, C.D.Flemming, and C.C.Capen. 1994b. Reproductive toxicity of butylated triphenyl phosphate and tricresyl phosphate fluids in F344 rats. Fundam. Appl. Toxicol. 22(3):392–399. Latendresse, J.R., C.L.Brooks, and C.C.Capen. 1995. Toxic effects of butylated triphenyl phosphate-based hydraulic fluid and tricresyl phosphate in female F344 rats. Vet. Pathol. 324:394–402. 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. Mirsalis, J., K.Tyson, J.Beck, E.Loh, K.Steinmetz, C.Contreras, L.Austere, S.Martin, and J.Spalding. 1983. Induction of unscheduled DNA synthesis (UDS) in hepatocytes following in vitro and in vivo treatment. [Abstract]. Environ. Mutagen. 5:482. Morgan, J.P. 1982. The Jamaica ginger paralysis. JAMA 248(15): 1864–1867. Morrissey, R.E., B.A.Schwetz, J.C.Lamb, 4th, M.D.Ross, J.L.Teague, and R.W. Morris. 1988. Evaluation of rodent sperm, vaginal cytology, and reproductive organ weight data from National Toxicology Program 13-week studies. Fundam. Appl. Toxicol. 11(2):343–358. NIOSH (National Institute for Occupational Safety and Health). 1996. NIOSH Chemical Listing and Documentation of Revised IDLM Values. [Online]. Available: http://www.cdc.gov/niosh/idlh/intridl4.html (Retrieved March 8, 2000). Nomeir, A.A., and M.B.Abou-Donia. 1986. Studies on the metabolism of the neurotoxic tri-o-cresyl phosphate. Distribution, excretion, and metabolism in male cats after a single, dermal application. Toxicology 38(1): 15–33. (Cited in IPCS 1990 and NTP 1994) NRC (National Research Council). 1985. Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Volume 5. Committee on Toxicology. Board on Toxicology and Environmental Health Hazards, National Research Council. Washington, DC: National Academy Press. NTP (National Toxicology Program). 1994. Toxicology and Carcinogenesis Studies of Tricresyl Phosphate (CAS No. 1330–78–5) in F344/N Rats and B6C3F1 Mice (Gavage and Feed Studies). NTP Technical Report 433. NIH Publication No. 94–3164.

AROMATIC PHOSPHATE PLASTICIZERS 416 Oishi, H., S.Oishi, and K.Hiraga. 1982. Toxicity of several phosphoric acid esters in rats. Toxicol. Lett. 13(1–2):29–34. Pegum, J.S. 1966. Contact dermatitis from plastics containing tri-aryl phosphates. Br. J. Dermatol. 78(12):626–631. Piccirillo, V.J. 1999. Flame-retardant product chemistries, toxicology and hazard evaluations. NPC Inc., Sterling, VA. Saito, C., T.Kato, H.Taniguchi, et al. 1974. [Subacute toxicity of tricresylphosphate (TCP) in rats.] Pharmacometrics. 8:107–118. [Article in Japanese]. Sprague, G.L., and T.R.Castles. 1985. Estimation of the delayed neurotoxic potential and potency for a series of triaryl phosphates using an in vitro test with metabolic activation. Neurotoxicology 6(1):79–86. Tabershaw, I.R., and M.Kleinfeld. 1957. A.M.A. Arch. Ind. Health. 15:541. Tarvainen, K. 1995. Analysis of patients with allergic patch test reactions to a plastics and glue series. Contact Dermatitis 32(6):346–351. Tocco, D.R., J.L.Randall, R.G.York, and M.K.Smith. 1987. Evaluation of the teratogenic effects of tri-ortho-cresyl phosphate in the Long- Evans hooded rat. Fundam. Appl. Toxicol. 8(3):291–297. Treon, J.F., F.P.Cleveland, and J.Cappel. 1955. The toxicity of certain aromatic phosphate esters. University of Cincinnati, Wright Air Development Center. Technical Report 54–345.

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Toxicological Risks of Selected Flame-Retardant Chemicals Get This Book
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Ignition of upholstered furniture by small open flames from matches, cigarette lighters, and candles is one of the leading causes of residential-fire deaths in the United States. These fires accounted for about 16% of civilian fire deaths in 1996. On average, each year since 1990, about 90 deaths (primarily of children), 440 injuries, and property losses amounting to 50 million dollars have resulted from fires caused by the ignition of upholstered furniture by small open flames. Certain commercial seating products (such as aircraft and bus seats) are subject to flammability standards and sometimes incorporate FR-treated upholstery cover materials, but there is no federal-government requirement for residential upholstered furniture, and it is generally not treated with FR chemicals.

It is estimated that less than 0.2% of all U.S. residential upholstery fabric is treated with flame-retardant (FR) chemicals. The Consumer Product Safety Act of 1972 created the U.S. Consumer Product Safety Commission (CPSC) as an independent federal regulatory agency whose mission is to protect the public from unreasonable risks of injury and death associated with consumer products. CPSC also administers the Flammable Fabrics Act, under which it regulates flammability hazards and the Federal Hazardous Substances Act (FHSA), which regulates hazardous substances including chemicals. In 1993, the National Association of State Fire Marshals petitioned CPSC to issue a performance-based flammability standard for upholstered furniture to reduce the risk of residential fires. The Commission granted that portion of the petition relating to small open flame ignition risks.

In response to concerns regarding the safety of FR chemicals, Congress, in the fiscal year 1999 appropriations report for CPSC, requested that the National Research Council conduct an independent study of the health risks to consumers posed by exposure to FR chemicals that are likely to be used in residential upholstered furniture to meet a CPSC standard. The National Research Council assigned the project to the Committee on Toxicology (COT) of the Commission on Life Sciences' Board on Environmental Studies and Toxicology. COT convened the Subcommittee on Flame-Retardant Chemicals, which prepared this report. Subcommittee members were chosen for their recognized expertise in toxicology, pharmacology, epidemiology, chemistry, exposure assessment, risk assessment, and biostatistics.

Toxicological Risks of Selected Flame-Retardant Chemicals is organized into 18 chapters and two appendices. Chapter 2 describes the risk assessment process used by the subcommittee in determining the risk associated with potential exposure to the various FR chemicals. Chapter 3 describes the method the subcommittee used to measure and estimate the intensity, frequency, extent, and duration of human exposure to FR chemicals. Chapters 4-19 provide the subcommittee's review and assessment of health risks posed by exposure to each of the 16 FR chemicals. Data gaps and research needs are provided at the end of these chapters.

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