14
Organic Phosphonates

THIS chapter reviews the physical and chemical properties, toxicokinetics, toxicological, epidemiological, and exposure data on dimethyl hydrogen phosphite (DMHP),1 an organic phosphonate. The subcommittee used that information to characterize the health risk from exposure to DMHP. The subcommittee also identified data gaps and recommended research relevant for determining the health risk from exposure to DMHP.

PHYSICAL AND CHEMICAL PROPERTIES

As a pure substance, DMHP is a mobile, colorless liquid with a mild odor (Hawley 1981, as cited in IARC 1990; HSDB 1999). The physical and chemical properties of DMHP are summarized in Table 14–1.

OCCURRENCE AND USE

According to IPCS (1997), both halogenated and non-halogenated phosphonate esters are the predominant phosphorous-based flame retardants in use.

1  

In this chapter, the toxicity data were discussed for DMHP because most of the relevant data for organic phosphates were available for this compound.



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Toxicological Risks of Selected Flame-Retardant Chemicals 14 Organic Phosphonates THIS chapter reviews the physical and chemical properties, toxicokinetics, toxicological, epidemiological, and exposure data on dimethyl hydrogen phosphite (DMHP),1 an organic phosphonate. The subcommittee used that information to characterize the health risk from exposure to DMHP. The subcommittee also identified data gaps and recommended research relevant for determining the health risk from exposure to DMHP. PHYSICAL AND CHEMICAL PROPERTIES As a pure substance, DMHP is a mobile, colorless liquid with a mild odor (Hawley 1981, as cited in IARC 1990; HSDB 1999). The physical and chemical properties of DMHP are summarized in Table 14–1. OCCURRENCE AND USE According to IPCS (1997), both halogenated and non-halogenated phosphonate esters are the predominant phosphorous-based flame retardants in use. 1   In this chapter, the toxicity data were discussed for DMHP because most of the relevant data for organic phosphates were available for this compound.

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Toxicological Risks of Selected Flame-Retardant Chemicals TABLE 14–1 Physical and Chemical Properties of Dimethyl Hydrogen Phosphite Property Value Reference Chemical formula C2H7O3P Howard and Meylan 1997 Structure   NTP 1985 CAS Registry # 868–85–9 Howard and Meylan 1997 Synonyms DMHP, dimethyl phosphonate (Chem. Abstr. Name; IUPAC Systematic Name), Bis(hydroxymethyl) phosphine oxide; dimethoxyphosphine oxide; dimethylhydrogenphosphite; dimethyl phosphite; dimethyl acid phosphite; O, O'-dimethyl phosphonate; dimethyl phosphorous acid; DMHP; hydrogen dimethyl phosphite; methyl phosphonate; NCI-C54773; phosphonic acid dimethyl ester; phosphorous acid dimethyl ester; TL 585 IARC 1990; NTP 1985; HSDB 1999 Molecular weight 110.05 Howard and Meylan 1997 Physical state Mobile liquid Hawley 1981; as cited in IARC 1990 Solubility Solubility in water=1×106 mg/L; miscible in most organic solvents; soluble in pyrimidine Howard and Meylan 1997; CRC Press 1992 Color Colorless Hawley 1981; as cited in IARC 1990 Vapor pressure 4.52 mm Hg at 25°C Howard and Meylan 1997 log Kow −1.13 Howard and Meylan 1997 pH Not available — Melting point Not available — Boiling point 170.5 °C Howard and Meylan 1997 Flash point 96 °C Hawley 1981, as cited in IARC 1990

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Toxicological Risks of Selected Flame-Retardant Chemicals Decomposition When heated to decomposition, can emit highly toxic fumes of phosphorous oxides Sax 1984 Reactivity Hydrolyzes in water with half-life of approximately 10 d at 25° C and 19 d at 20° C; basic conditions accelerate hydrolysis Bel'skii et al. 1969; Vilceanu and Schulz 1972; all as cited in HSDB 1999 Density (water=1) 1.195 NTP 1985 DMHP is commercially produced by the reaction of phosphorous trichloride and methanol or sodium methoxide (HSDB 1999; EPA 1985 as cited in IARC 1990). In 1982, U.S. production was estimated to be about 3 million pounds/yr (W.Smithey, Jr., pers. commun. to J.Dunnick 1982, as cited in NTP 1985). DMHP is used in the manufacture of adhesives, pesticides, and is used to impart flame resistance to textiles (Hatlelid 1999; IARC 1990; HSDB 1999; Siemer 1980; Lewis 1975 as cited in NTP 1985; and Lewis 1993). TOXICOKINETICS Dermal Exposure There are no studies that have investigated the absorption, distribution, metabolism, or excretion of DMHP in humans or animals following dermal exposure. Dermal LD50 studies suggest that DMHP is systemically available following dermal application. Inhalation Exposure No data describing toxicokinetics of DMHP from the inhalation route were identified during the course of this review. Oral Exposure Nomeir and Matthews (1997) examined the metabolism and disposition of 14C-labeled DMHP in F-344/N rats and B6C3F1 mice. After gavage administration (10–200 mg/kg), the radio-labeled compound was almost completely absorbed from the gastrointestinal tract in both rats and mice and was primarily

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Toxicological Risks of Selected Flame-Retardant Chemicals eliminated as expired CO2 (44–57%) within 24 hr. Radioactivity was primarily distributed to the liver, kidneys, spleen, lungs, and forestomach. The authors concluded that absorption, metabolism, and disposition of DMHP were linear in both species within the dose range that was examined. The rate of clearance was twice as fast in the mouse than in the rat. The metabolite monomethyl hydrogen phosphite (MMHP) was excreted in the urine in both species and indicates that DMHP is demethylated in vivo. Within the first 24 hr of exposure, elimination via urine (28–49%) greatly exceeded elimination by the fecal route (1–2%) or as volatile organic compounds (2–3%). Repeat administration of labeled compound over a period of 5 consecutive days (once/d) had little effect on metabolism to CO2 or elimination in urine. In vitro tests indicate that DMHP is metabolized to formaldehyde (CH2O) by microsomes prepared from the liver, lungs, kidneys, forestomach, and glandular stomach of rats (Nomeir and Mathews 1997). HAZARD IDENTIFICATION2 Dermal Exposure Irritation No signs of dermal irritation were observed in rabbits receiving dermal applications of DMHP at concentrations of up to 3,160 mg/kg (details discussed below under Systemic Effects) (Keller 1961). Systemic Effects DMHP (undiluted, purity not described) was applied to the occluded skin of albino rabbits at doses of 100, 316, 1,000, and 3,160 mg/kg for 24 hr (Keller 1961). After the occlusion period, the treated site was rinsed and the animals were examined for toxic effects and mortality periodically during the first 24 hr post-exposure and every day thereafter for a total of 7 d. During the first 24 hr, all animals had normal appearance and behavior. Between 24 and 48 hr post-exposure, mortality occurred at doses of 1,000 and 3,160 mg/kg (three of four rabbits at each dose died). By 72 hr post-exposure, the fourth animal receiving 1,000 mg/kg died. It exhibited systemic effects of depression, ptosis, 2   In this section, the subcommittee reviewed toxicity data on organic phosphonates, including the toxicity assessment prepared by the U.S. Consumer Product Safety Commission (Hatlelid 1999).

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Toxicological Risks of Selected Flame-Retardant Chemicals labored respiration, ataxia, and placidity before dying. Necropsy results included hemorrhagic lungs, red-tinged fluid in the pleural cavity, thymus and kidney congestion, and stomach mucosal edema. The remaining rabbit in the 3,160 mg/kg group exhibited slight depression and labored respiration after 48 hr of exposure, but recovered by d 3. Thereafter, it appeared normal and gained weight for the duration of the study. Autopsy results for it were also normal. No mortality occurred at the two lowest doses. The calculated LD50 for this study was 681 mg/kg. Neurological Effects Keller (1961) reported depression, ptosis, labored respiration, ataxia, and placidity in a rabbit that received a dermal dose of DMHP of 1,000 mg/kg. These findings could indicate neurotoxicity, but are not adequate to conclude that DMHP causes neurotoxicity following dermal exposure. Other Systemic Effects No data were found regarding the immunological, reproductive, developmental, or carcinogenic effects of DMHP following dermal exposure. Inhalation Exposure A summary of the inhalation toxicity data of DMHP is presented in Table 14–2. Systemic Effects Rusch (1980) exposed Sprague-Dawley rats (5 males and 5 females/dose) to DMHP at concentrations of 0, 431, 843, and 934 ppm (0, 1940, 3794 and 4203 mg/m3), 6 hr/d for 5 consecutive days. Degradation of the test article to phosphoric acid occurred with deposition on the rats as well as exposure chamber surfaces. Skin, eye, and mucous membrane irritation was observed at all exposure levels, but was more severe at the higher concentrations. Attempts to minimize “wall losses” and hydrolytic degradation were made by dehumidifying chamber air and increasing chamber temperature to 79 °F. Nevertheless, the author considered that “generation of [test article] levels…in excess of 500 ppm [2250 mg/m3] would be difficult” (Rusch 1980). After 4 d of exposure, all

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Toxicological Risks of Selected Flame-Retardant Chemicals TABLE 14–2 Inhalation Exposure Studies on Dimethyl Hydrogen Phosphite Species, Strain, Sex, Number Purity Concentration Duration Effects Comments Reference Rats, Sprague-Dawley, M/F, 5/sex/dose As received from Mobil Chemical Co., Edison, NJ 0, 431, 843, 934 ppm (0, 1940, 3794, 4203 mg/m3) 6 hr/d, 5 consecutive days All HC animals died or killed in extremis after d 3 with red stained CSF under brain meninges, gastrointestinal tract vascular lesions, discoloration of trachea and fluid retention in small intestine; labored breathing and neuromuscular impairment at HC; skin, eye, and mucous membrane irritation at all exposures; significant body weight decrease at HC; significant increase in M lung weight at MC and HC; concentration-related lung discoloration; corneal changes Range-finding study for Bio/dynamics 1980; test material degraded to phosphoric acid; degradation product considered responsible for irritant responses Rusch 1980a Rat, Sprague-Dawley, M/F, 20/sex/dose As received from Mobil Chemical Co., Edison, NJ 0, 12, 35, 119, 198 ppm (0, 54, 158, 536, 891 mg/m3) 6 hr/d, 5 d/wk for up to 4 wk; left untreated for next 4 wk Excessive mortality at HC; significant body weight decrease at≥536 mg/m3 (M/F); significant total WBC count at≥536 mg/m3 (M) and at 891 mg/m3 (F); significant decrease in HCT at ≥536 mg/m3 (M); decreasing trend in HGB>536 mg/m3 (M) and 891 mg/m3 (F); significant decrease in blood GLU ≥536 mg/m3 (M/F); increasing trend in blood SGPT, AP, and BUN at 891 mg/m3 (M/F); lenticular opacities at≥158 mg/m3 (4 wk; M/F); cataracts at≥536 mg/m3 (8 wks; M/F); concentration-related increase in absolute and relative kidney weight at all levels (M/F); at necropsy, red discoloration lung/ turbinates in HC (irritation observed in vivo) LOAEL: 12 ppm (54 mg/m3) based on absolute and relative kidney weight changes in M Bio/dynamics 1980a,b AP, alkaline phosphatase; BUN, blood urea nitrogen; CSF, cerebrospinal fluid; F, female; GLU, glucose; HC, high concentration; HCT, hematocrit; HGB, hemoglobin; LOAEL, lowest-observed-adverse-effect level; M, male; MC, mid-concentration; SGPT, serum glutamic pyruvic transaminase; WBC, white blood cell. aLab report from Bio/Dynamics, Inc., to Mobil Oil Corp. bSubmittal from Mobil Oil Corp. to EPA (1981).

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Toxicological Risks of Selected Flame-Retardant Chemicals animals in the high-dose group were dead or were killed. These animals exhibited neuromuscular impairment (slowed righting reflex, loss of toe-pinch reflex, prostration, lack of response to sound stimuli, muscular contractions and splayed stance) and significant body weight depression. Significant body weight depression (males and females) was also noted at concentrations of 3,794 mg/m3. At the 1,940- and 3,794-mg/m3 concentration levels, statistically significant increases in lung weight were noted in males. No necropsy results were reported for animals dead or dying at the highest concentration tested. Based on the results of Rusch (1980), Bio/dynamics (1980) exposed groups of male and female Sprague-Dawley rats (20 males and 20 females/dose) to DMHP at concentrations of 0, 12, 35, 119, and 198 ppm (0, 54, 158, 536, and 891 mg/m3) 6 hr/d, 5 d/wk for 4 wk. The duration-adjusted concentrations were 0, 10, 28, 96, and 159 mg/m3. After the 4-wk period of exposure was completed, Bio/dynamics (1980) maintained the treated and control populations for an additional 4 wk with no further exposure. The most significant effects observed where dose-related increases in absolute and relative kidney weight (that persisted during the 4-wk recovery period), and lenticular opacities that progressed to cataracts during the recovery period (see Table 14–2). According to Bio/dynamics (1980), reduced body weights at the higher exposure levels somewhat obscured the increase in absolute and relative kidney weights. The differences were significant at all exposure concentrations greater than 158 mg/m3 for males and greater than 891 mg/m3 for females. The findings of cataracts in male rats receiving DMHP by gavage supports this finding as a treatment-related effect (NTP 1985). Neurological Effects Neuromuscular impairment (in the form of slowed righting reflex, loss of toe-pinch reflex, prostration, etc.) was observed in rats at the highest concentration level tested by Rusch (1980). Bio/dynamics (1980) observed neurological impairment in all rats of the highest exposure group and in some rats exposed to 536 mg/m3. These effects were usually reversed after cessation of exposure. No studies have been specifically carried out to determine the the neurotoxicity of DMHP following inhalation exposure. Other Systemic Effects No data were found on the immunological, reproductive, developmental, or carcinogenic, effects of inhaled DMHP.

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Toxicological Risks of Selected Flame-Retardant Chemicals Oral Exposure A summary of the noncancer effects from oral exposure to DMHP is presented in Table 14–3. Systemic Effects Groups of two albino rats were given single oral doses of DMHP (in a 0.5% aqueous methyl cellulose solution) ranging from 10 to 3,160 mg/kg. The animals were observed for 48 hr. No explanation regarding the basis for selecting methyl cellulose as a vehicle was provided. A single death occurred at the highest dose tested of 3,160 mg/kg; this animal also exhibited signs of toxicity (prostration, labored breathing, tremors) 4 hr after exposure and shortly before death. Pathological results on this rat revealed lung hemorrhage, congested kidneys, and gastrointestinal tract inflammation. Analyses of these data resulted in an estimated LD50 of 3,160 mg/kg. The NTP (1985) administered DMHP by gavage to F-344/N rats and B6C3F1 mice for 1 d, 15 consecutive days, 13 wk (5 d/wk), and 103 wk (5 d/wk). DMHP was administered in corn oil for all doses except the 15-d 3,000 mg/kg dose, which was administered as undiluted DMHP. Doses, number of rats, dose volume, and toxic response are summarized in Table 14–3. The estimated LD50s were 3,283 mg/kg for males and 3,040 mg/kg for females. In general, females were less sensitive than males, and mice were less sensitive than rats. Dose-related testicular atrophy was observed in B6C3F1 mice given doses of 375 mg/kg-d or greater for 13 wk (NTP 1985). All male mice given doses of 750 mg/kg-d or greater died by wk 4. The NOAEL for this study was 190 mg/kg-d based on testicular atrophy. In the 13-wk study in rats, the NOAEL for DMHP was determined to be 100 mg/kg-d based on body weight depression in female rats. In the 103-wk study, dose-related histopathological changes were observed in tissues of the lung, forestomach, eye, cerebellum, and hematopoietic system. Malignancies of the lung and forestomach occurred in high-dose males (200 mg/kg-d), who also exhibited increased incidences of mononuclear cell leukemia and cataracts. Body weight depression was noted in the high-dose groups, with the greatest difference observed in the high-dose male rats. Survival of the high-dose males was also significantly shorter when compared to the vehicle controls (p=0.008 by life table pairwise comparison). Survival rates for males were 78% (vehicle control), 58% (100 mg/kg), and 46% (200 mg/kg). For females, survival was 80% (vehicle control), 66% (50 mg/kg), and 64% (100 mg/kg). An increased incidence of chronic interstitial pneumonia occurred

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Toxicological Risks of Selected Flame-Retardant Chemicals TABLE 14–3 Noncancer Effects from Oral Exposures to Dimethyl Hydrogen Phosphite Species, Strain, Sex, Number Purity Dose Duration, Route Effects Comments Reference Rat, albino, NS, 2/dose As received from Hooker Chem. Co. (“considered to be free of impurities”) 10.0, 31.6, 100, 316, 3,160 mg/kg in 0.5% (v/v) aqueous methyl cellulose solution; untreated control not reported Single dose, intubation No deaths at 10.0–100 mg/kg; single death at 3,160 mg/kg at 4 hr, exhibited prostration, labored respiration, and tremors. Lung hemorrhage, kidney congestion, gastrointestinal inflammation LD50: ~3,160 mg/kg Keller 1961a Rat, F-344/N, M/F, 5/sex/dose ~96–98% 0, 1,470, 2,150, 3,160, 4,640, 6,810 mg/kg in corn oil (dose volume: 5.675 mL/kg) Single dose, gavage Mortality; inactivity, weakness, shallow breathing on d 1 at ≥3,160 mg/kg; gas in stomach and intestines at necropsy LD50: 3,283 mg/kg (M); 3,040 mg/kg (F) NTP 1985b Rat, F-344/N, M/F, 5/sex/dose ~96–98% 0, 250, 500, 1,000, 2,000 mg/kg-d in corn oil; 3,000 mg/kg undiluted (dose volume: 2.5 mL/kg) 15 d (consecutive), gavage Deaths at≥500 mg/kg; inactivity after dosing No other clinical signs or necropsy findings reported NTP 1985b Rat, F-344/N, M/F, 10/sex/dose ~96–98% 0, 25, 50, 100, 200, 400 mg/kg-d in corn oil (dose volume: 3.33 mL/kg) 13 wk (5 d/wk), gavage Deaths at≥200 mg/kg in M and at≥100 mg/kg in F; body weight depression at≥400 mg\kg in M and at≥200 mg/kg in F; lens degeneration at 400 mg/kg in M and F; corneal inflammation at 400 mg/kg in F; urinary bladder calculi at 400 mg/kg in M 3/5 deaths at 100 and 200 mg/kg perhaps due to accidental lung gavage. NOAEL: 100 mg/kg (based on body-weight depression in F) NTP 1985b

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Toxicological Risks of Selected Flame-Retardant Chemicals Species, Strain, Sex, Number Purity Dose Duration, Route Effects Comments Reference Rat, F-344/N, M/F, 50/sex/dose ~96–98% 0, 100, 200 mg/kg-d in corn oil for M; 0, 50, 100 mg/kg in corn oil for F (dose volume: 4.0 mL/kg) 103 wk (5 d/wk), gavage Mortality at 200 mg/kg in M; dose-related decreased weight gain at all doses for M and high dose F; dose-related alveolar and adenomatous hyperplasia, forestomach hyperplasia and hyperkeratosis, cerebellum mineralization in high-dose M; chemical pneumonia NOAEL: 50 mg/kg-d (based on hyperplasia of lung tissue and forestomach in F) Evidence of dose-related cancers, especially M rats NTP 1985b. Dunnick et al. 1986c Mouse, B6C3F1, M/F, 5/sex//dose ~96–98% 0, 1,470, 2,150, 3,160, 4,640, 6,810 mg/kg in corn oil (dose volume: 5.675 mL/kg) Single dose, gavage Deaths by d 2 at≥3,160 mg/kg; inactivity, prostration; shallow breathing on d 2 at>2,150 mg/kg; white opaque eyes in M at necropsy LD50: 2,815 mg/kg (M) Survival curve too steep for estimating LD50 for F NTP 1985b Mouse, B6C3F1, M/F, 5/sex/dose ~96–98% 0, 250, 500, 1,000, 2,000, 3,000 mg/kg-d in corn oil (dose volume: 10 mL/kg) 15 d (consecutive), gavage Deaths by d 9 at≥2,000 mg/kg; inactivity at≥1,000 mg/kg, thickening and nodules in squamous stomach region at ≥250 mg/kg at necropsy   NTP 1985b Mouse, B6C3F1, M/F, 10/sex/dose ~96–98% 0, 95, 190, 375, 750, 1500 mg/kg-d in corn oil (dose volume: 3.33 mL/kg) 13 wk (5 d/wk), gavage Deaths, tremors, and decreased activity in first 4 wk at≥375 mg/kg; testicular atrophy in M at ≥375 mg/kg; some lung congestion, cardiac mineralization in M; hepatocellular vacuolization in F NOAEL: 190 mg/kg-d (M, testicular atrophy) NTP 1985b

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Toxicological Risks of Selected Flame-Retardant Chemicals Mouse, B6C3F1, M/F, 50/sex/dose ~96–98% 0, 100, 200 mg/kg-d in corn oil (dose volume: 4.0 mL/kg) 103 wk (5 d/wk), gavage Decreased body weight gain and survival at 200 mg/kg in M; focal calcification in testes of M at both doses LOAEL: 100 mg/kg-d (M, testicular calcification) NTP 1985b; Dunnick et al. 1986c Rat, F-344/N, M, 18/dose As received from Aldrich Chem. Co., Milwaukee, WI 0, 200 mg/kg-d in corn oil, (dose volume: 4 mL) 4, 5, or 6 wk (5 d/wk), gavage Increase in forestomach weight for all doses; forestomach tissue exhibited hyperplasia, hyperkeratosis, subepithelial inflammation, and edema at 6 wk; significantly increased angiotensin converting enzyme in serum at 4–6 wk but returned to near control levels after 1 wk recovery; Increased level nonprotein soluble sulfhydryls in forestomach at 6 wk; decreased active soluble carboxylesterase in lungs and forestomach at 6 wk   Nomeir and Uraih 1988c Rat, F-344/N, M, NS/dose Mouse, B6C3F1, M, NS/dose (“at least three animals …for each time point”) Radiochemical purity of 97% for labeled compounds 10, 100, 200 mg/kg [14C]DMHP in corn oil (dose volume: 4 mL/kg); untreated control not reported Rats: single dose, gavage at 10, 100, 200 mg/kg; 5 d (consecutive), gavage at 200 mg/kg-d Mice: single dose, gavage at 200 mg/kg Highest activity in liver, kidneys, spleen, lungs, forestomach; lowest activity in brain, skeletal muscle, adipose tissue. Elimination as CO2 in expired air (44-57%) and urine (28–49%); little activity in feces (1–2%), volume organic compounds (2–3%) Rate of labeled DMHP clearance in mice approximately 2 times greater than in rats Nomeir and Matthews 1997c F, female; LD50, lethal dose to 50% of test animals; LOAEL, lowest-observed-adverse-effect level; M, male; NOAEL, no-observed-adverse-effect level; NS, not specified. aLab report from Hazleton Labs to Hooker Chemical Corporation (1961); TSCA Submittal from Occidental Chemical to EPA (1992). BReport of the National Toxicology Program. CPublished study.

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Toxicological Risks of Selected Flame-Retardant Chemicals were adjusted for discontinuous exposure and scaled to bw3/4 to estimate human equivalent doses. The estimated oral SFs for lung and forestomach tumors is summarized in Table 14–6. The subcommittee believes that the use of cancer SF for male lung tumors is appropriate because of the high incidence of these tumors and because the NTP classification for DMHP (clear evidence of carcinogenicity in male rats) was based on these data. Therefore, the subcommittee used the oral cancer SF of 5.4×10−3/mg/kg-d for calculating cancer risk estimates for DMHP EXPOSURE ASSESSMENT AND RISK CHARACTERIZATION Noncancer Dermal Exposure Dermal exposure to DMHP 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 DMHP and also assumes 1/4th of the upper torso are 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 DMHP present in the back-coating. It was also assumed that there would be sufficient water present from sweat to facilitate dissolution of DMHP from the backcoating and absorption through the skin. In this scenario, only the dissolution rate of DMHP from the backcoating is assumed to be the limiting factor in absorption by the body. It is assumed that all of the DMHP 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 DMHP of 7.5 mg/cm2. The extraction rate (µw) for DMHP 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 TABLE 14–6 Cancer Risk Values for Dimethyl Hydrogen Phosphite Determined from Different Curve-fitting Models (Data from NTP 1985) Modela MLE or BMD (mg/kg-d) LED10b (mg/kg-d) Slope Factors (0.1/LED10) (per mg/kg-d) Comment DATA SET: F-344/N male rats, alveolar/bronchiolar adenoma/carcinoma; body weight3/4 utilized for calculation of the human equivalent dose Global 86 (linearized multistage) 21.51 18.51 5.4×10−3 (2.5×10−3)c The p-values for the Monte Carlo test were≥0.05 EPA’s BMD: Gamma 25.27 22.68 4.4×10−3 p-value for χ2 test was 1.00; graphical representation showed a good fit for the data EPA’s BMD: Logistic 27.58 22.73 4.4×10−3 p-value for χ2 test was 0.88; graphical representation showed a good fit for the data EPA’s BMD: Probit 26.33 21.75 4.6×10−3 p-value for χ2 test was 0.97; graphical representation showed a good fit for the data EPA’s BMD: Weibull 26.41 21.27 4.7×10−3 p-value for χ2 test was 0.98; graphical representation showed a good fit for the data DATA SET: F-344/N female rats, alveolar/bronchiolar adenoma/carcinoma; body weight3/4 utilized for calculation of the human equivalent dose; tumor incidence showed a statistically significant dose-related trend, but not a statistically significant pair-wise comparison of incidence at the high-dose with that of control. GLOBAL 86 (linearized multistage) 25.54 16.92 5.9×10−3 (5.7×10−3)c p-value for the Monte Carlo test was 1.00 EPA’s BMD: Gamma 26.18 16.87 5.9×10−3 p-value for χ2 test was 1.00; graphical representation showed a good fit for the data EPA’s BMD: Log-logistic 26.11 16.97 5.9×10−3 p-value for χ2 test was 1.00; graphical representation showed a good fit for the data; logistic model run as log-logistic with slope parameter restricted to≥1

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Toxicological Risks of Selected Flame-Retardant Chemicals EPA’s BMD: Log-probit 23.86 16.63 6.0×10−3 p-value for χ2 test was 0.95; graphical representation showed a good fit for the data; probit model run as log-probit with slope parameter restricted to≥1 EPA’s BMD: Quantal quadratic 24.26 16.90 5.9×10−3 p-value for χ2 test was 0.99; graphical representation showed a good fit for the data DATA SET: F-344/N male rats, forestomach squamous cell papilloma/carcinoma; body weight3/4 utilized for calculation of the human equivalent dose GLOBAL 86 (linearized multistage) 35.46 27.02 3.7×10−3 (3.8×10−3)c p-value for the Monte Carlo test was 1.00 EPA’s BMD: Gamma 35.17 27.97 3.6×10−3 p-value for χ2 test was 0.00; graphical representation showed a good fit for the data EPA’s BMD: Log-logistic 35.26 17.93 3.6×10−3 p-value for χ2 test was 1.00; graphical representation showed a good fit for the data; the logistic model run was as log-logistic with slope parameter restricted to≥1 EPA’s BMD: Log-probit 34.94 26.51 3.8×10–3 p-value for χ2 test was 1.00; graphical representation showed a good fit for the data; probit model run as log-probit with slope parameter restricted to≥1 EPA’s BMD: Quantal quadratic 35.91 27.09 3.7×10−3 p-value for χ2 test was 0.95; graphical representation showed a good fit for the data EPA’s BMD: Weibull 35.34 26.74 3.7×10−3 p-value for χ2 test was 1.00 graphical representation showed a good fit for the data BMD, benchmark dose; LED10, lower 95% bound on the effective dose corresponding to a 10% tumor response in test animals; MLE, maximum likelihood estimate aAll other models were rejected because p-values for χ2 tests were <0.05, graphical representation did not show a good fit for the data, and/or the benchmark dose computation failed. bLED10 is the same as the BMDL (lower confidence limit on the BMD) in EPA’s BMD software program. cThe number in parenthesis is the q1* derived from GLOBAL 86.

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Toxicological Risks of Selected Flame-Retardant Chemicals Using these assumptions, an estimated absorbed daily dose of 2.2 mg/kg was calculated for DMHP. A hazard index of 18.3 was calculated for this first iteration by dividing the estimated daily dermal dose of 2.2 mg/kg-d by the oral RfD for DMHP of 0.12 mg/kg-d. At this time, the oral RfD is used as the best estimate of the internal dose associated with dermal exposure to DMHP. These results suggest that DMHP could pose a toxic risk from dermal exposure. Alternative Iteration The estimated dermal daily dose for DMHP is also calculated using an estimate of the dermal penetration rate for DMHP (Chapter 3: Equations 2 and 3). Instead of assuming that all dissolved DMHP immediately penetrates the skin and enters systemic circulation, it is assumed that the skin slows the absorption of DMHP to a specific amount of chemical absorbed/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 DMHP 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 1.46×10−3 cm/d. In the absence of a dermal RfD, the subcommittee believes it is appropriate to use the oral RfD for DMHP of 0.12 mg/kg-d as the best estimate of the internal dose from dermal exposure Using Equation 3 in Chapter 3 and the alternate Kp, the dermal daily dose rate for DMHP was estimated to be 11.4 mg/kg-d. A hazard index of 95 was calculated by dividing the estimated daily dermal dose of 11.4 mg/kg-d by the oral RfD for DMHP of 0.12 mg/kg-d. These results suggest that under the given exposure conditions, dermal exposure to DMHP could pose a noncancer toxic risk to humans and should be investigated further. Inhalation Exposure Particles Inhalation exposure estimates for DMHP were calculated using the exposure scenario described in Chapter 3. This scenario assumes that a person spends 1/4th of his or her life in a 30 m3 room containing 30 m2 of DMHP-treated fabric and the room is assumed to have a air-change rate of 0.25/hr. It is also assumed that 50% of the DMHP present in 25% of the surface area of the treated fabric is released over 15 yr and 1%, of released particles are of size that can be inhaled.

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Toxicological Risks of Selected Flame-Retardant Chemicals Particle exposure was estimated using Equations 4 and 5 in Chapter 3. The subcommittee estimated an upholstery application rate (Sa) for DMHP of 7.5 mg/cm2. The release rate (µr) for DMHP 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 2.9 µg/m3 and a short time-averaged exposure concentration of 0.725 µg/m3. The time-averaged exposure concentration for particles was calculated using Equation 6 in Chapter 3. In the absence of relevant inhalation exposure data, the subcommittee chose to estimate inhalation RfCs from oral RfDs. The subcommittee, however, recognizes that it is not an ideal approach and also recognizes that the estimated RfC levels might be considerably different than actual levels (if inhalation data were available). Extrapolating from one route of exposure (oral) to another (inhalation) requires specific knowledge about the uptake kinetics into the body by each exposure route, including potential binding to cellular sites. The subcommittee believes that its extrapolation of oral RfDs to inhalation RfCs is highly conservative; it assumes that all of the inhaled compound is deposited in the respiratory tract and completely absorbed into the blood. The NRC committee on Toxicology (NRC, 1985) has used this approach when inhalation exposure data were insufficient to derive inhalation exposure levels. The subcommittee believes that such an approach is justified for conservatively estimating the toxicological risk from exposure to DMHP. That RfC should be used as interim or provisional level until relevant data becomes available for the derivation of inhalation RfC. In order to calculate a hazard index for the inhalation route, a provisional inhalation RfC of 0.42 mg/m3 was derived using the oral RfD for DMHP and Equation 7 in Chapter 3. Division of the time-average exposure concentration of 0.725 µg/m3 by the provisional RfC for DMHP of 0.42 mg/m3 yields a hazard index of 1.73×10−3 indicating that inhalation of DMHP-containing particulate from treated upholstery is not likely to pose a noncancer toxic risk to humans based on worst-case estimates in the given exposure scenario. Vapors In addition to the possibility of release of DMHP in particles from worn upholstery fabric, the subcommittee considered the possibility of the release of DMHP by evaporation. This approach is described in Chapter 3, and uses an exposure scenario similar to that just described for exposure to DMHP particles. The rate of flow of DMHP vapor from the room is calculated using Equations 8–11 in Chapter 3. A saturated vapor concentration (Cv) of 26,800 mg/m3

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Toxicological Risks of Selected Flame-Retardant Chemicals was estimated for DMHP. The application density (Sa) for DMHP in the treated upholstery was estimated as 7.5 mg/cm2. Using the parameters described, the equilibrium room-air concentration of DMHP was estimated to be 22,600 mg/m3. The short-term time-average exposure concentration for DMHP was estimated as 5,650 mg/m3 using Equation 12 in Chapter 3 and the equilibrium room-air concentration for DMHP. It was estimated that concentration could be maintained for approximately 10 hr. These results clearly show that the model for this scenario is substantially incorrect for DMHP if it is a useful FR, since any such material would have to be sufficiently well bound to the fabric to stay in place for years. However, the subcommittee has no further information on plausible rates of evaporation of DMHP from treated fabrics, and these calculations suggest that further information is required. Oral Exposure The assessment of noncancer toxicological risk for oral exposure to DMHP is based on the oral exposure scenario described in Chapter 3. This scenario assumes a child is exposed to DMHP by sucking on 50 cm2 of fabric back-coated with DMHP, 1 hr/d for two yr. The subcommittee estimated an upholstery application rate (Sa) for DMHP of 7.5 mg/cm2. Oral exposure was calculated using Equation 15 in Chapter 3. The extraction rate (µw) for DMHP 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 DMHP was estimated as 0.059 mg/kg-d. Division of the dose estimate by the oral RfD for DMHP of 0.12 mg/kg-d gives a hazard index of 0.49. This suggests that under the subcommittee’s worst-case exposure assumptions, DMHP is not anticipated to be a non-cancer toxic risk to children when incorporated into furniture upholstery at the given concentration level. Cancer Dermal Human cancer risk from dermal exposure to DMHP was calculated by multiplying the oral cancer potency factor for DMHP by the most conservative

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Toxicological Risks of Selected Flame-Retardant Chemicals lifetime average dermal dose rate of 11.4 mg/kg-d. The subcommittee believes that the use of the oral cancer potency factor for DMHP was acceptable for the calculation of cancer risk for dermal exposure since the oral cancer potency factor is based on carcinogenic effects following near-complete systemic absorption and the appearance of tumors not at the site of DMHP application. Using the dose rate obtained in the alternate iteration, a lifetime average daily dose of 11.4 mg/kg-d was estimated for DMHP. Multiplication of 11.4 mg/kg-d times the cancer potency estimate of 5.4×10−3/mg/kg-d, the lifetime risk estimate is 6.1×10−2. This estimate suggests that the dermal route of exposure may pose a carcinogenic hazard for persons exposed to DMHP incorporated into residential furniture upholstery at the indicated concentration levels and under the given worst-case exposure scenario. Further evaluation of the cancer risk associated with dermal exposure to DMHP should be conducted. Inhalation Particles The average room-air concentration and average exposure concentration to DMHP particles estimated in the previous sections were used for the cancer assessment. An inhalation cancer potency value was not available for DMHP, therefore a provisional inhalation cancer potency value of 1.54×10−6/µg/m3 was derived from oral cancer potency data for DMHP. Multiplication of the exposure estimates of 0.725 µg/m3 for particulate times the provisional cancer potency value yields an estimated lifetime cancer risk of 1.1×10−6 and suggests that the cancer risk associated with the inhalation of DMHP particulates is negligible at the given upholstery concentrations and the exposure parameters in the worst-case exposure scenario. However, the subcommittee concluded that exposure to DMHP by this route needs further evaluation. Vapors For DMHP vapors, the equilibrium concentration of vapor-phase DMHP in room air was estimated as described in the Noncancer Inhalation Exposure section. The long-term time-average vapor exposure concentration for DMHP was estimated using Equation 14 in Chapter 3. Using the estimated inhalation unit risk for DMHP of 1.54×10−6/µg/m3, the upper bound on lifetime cancer risk for inhalation exposure to DMHP in the vapor phase is 6.6×10−4. This risk estimate indicates that further investigation of cancer risks associated with DMHP vapors should be considered.

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Toxicological Risks of Selected Flame-Retardant Chemicals Oral As discussed previously, DMHP is judged by the subcommittee to be a rodent carcinogen. Therefore, the conservative approach for risk assessment purposes is to assume that DMHP represents a carcinogenic risk to humans. Using Equation 16 in Chapter 3, the lifetime average dose rate for DMHP by the oral exposure route was calculated to be 1.7×10−3 mg/kg-d. Lifetime cancer risk for this exposure scenario was then estimated by multiplying the oral lifetime daily dose rate times the oral cancer potency factor for DMHP of 5.4 ×10−3/mg/kg-d yielding a cancer risk estimate of 9.1×10−6. This suggests that under the subcommittee’s worst-case exposure assumptions, DMHP could be a carcinogenic hazard by the oral route of exposure. RECOMMENDATIONS FROM OTHER ORGANIZATIONS There is a single report documenting a workplace maximum air concentration for DMHP of 0.5 mg/m3, established by the Ukrainian Ministry of Health (Kuz'minov et al. 1992). In 1990, IARC reported that no regulatory standards or guidelines had been established for this compound. Further, DMHP is not listed on IRIS or HEAST, in the online version of the NIOSH Pocket Guide to Chemical Hazards, or in the online version of listings available from the American Conference of Governmental Industrial Hygienists. It has not been addressed in publications of the CRAVE Work Group or the EPA Office of Pesticide Programs. DATA GAPS AND RESEARCH NEEDS There are no data on the subchronic or chronic toxicity of DMHP by the dermal or inhalation routes of exposure. No information is available on human exposure to DMHP from treated furniture upholstery. No studies have been conducted on the leaching of DMHP from treated materials. The hazard indices of greater than one were calculated for DMHP for the dermal route of exposure. Cancer risk estimates were greater than 1×10−6 for the dermal, inhalation, and oral routes of exposure. Therefore, the subcommittee concluded that future research for TDCPP should focus on determining the actual amounts of DMHP leached from treated furniture and the dermal penetration of these compounds through human skin. An oral RfD for DMHP (the representative compound of the organic phosphonate and cyclic phosphonate ester flame retardants) is available based on a

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Toxicological Risks of Selected Flame-Retardant Chemicals 2-yr chronic gavage study. An inhalation RfC was calculated by the subcommittee based on a 4-wk study. Cancer potency slope factors were available for oral and inhalation. Because DMHP is soluble in water, there is concern about noncancer effects after dermal absorption and concern about cancer risk by all three routes of exposure. The subcommittee recommends that the potential for release of vapor and particles into air and DMHP release into saline from treated fabric be investigated. Because of a dermal hazard index of greater than 1, the subcommittee also recommends that the dermal absorption of DMHP from treated fabric be investigated. REFERENCES Bel'skii, V.E., et al. 1969. Izv. Akad. Nauk. SSSR Ser. Khim. 6:1297–1300. Bio/dynamics (Bio/dynamics, Inc.). 1980. A Four Week Inhalation Toxicity Study of MCTR-242–79 in the Rat. Bio/Dynamics Inc., East Millstone, NJ. EPA OTS Doc. #8EHQ-0182–0366. Bowman, J.T. 1980. Drosophila Mutagenicity Assays of Mobil Chemical Company Compound MCTR-111–79. MRI Report No. 344. EG&G Mason Research Institute, Rockville, MD. EPA OTS Doc #88–8100187. Brusick, D.J. 1977. Mutagenicity Evaluation of MCTR-214–77, Final Report. LBI Project No. 2683. Litton Bionetics, Kensington, MD. EPA/OTS Doc. #88–8100187. Chapin, R.E., S.L.Dutton, M.D.Ross, B.M.Sumrell, and J.C.Lamb, IV. 1984. Development of reproductive tract lesions in male F344 rats after treatment with dimethyl methylphosphonate. Exper. Molec. Pathol. 41:126–140. Cicmanec, J.L., M.L.Dourson, and R.C.Hertzberg. 1995. Noncancer risk assessment: Present and emerging issues. Pp. 293–310 in Toxicology and Risk Assessment: Principles, Methods and Applications. A.M.Fan, and L.E.Chang, eds. New York: Marcel Dekker. Dunnick, J.K., B.N.Gupta, M.W.Harris, and J.C.Lamb, IV. 1984a. Reproductive toxicity of dimethyl methyl phosphonate (DMMP) in the male Fischer 344 rat. Toxicol. Appl. Pharmacol. 72(3):379–387. Dunnick, J.K., H.A.Solleveld, M.W.Harris, R.Chapin, and J.C.Lamb, IV. 1984b. Dimethyl methyl phosphonate induction of dominant lethal mutations in male mice. Mutat. Res. 138(2–3):213–218. Dunnick, J.K., G.A.Boorman, J.K.Haseman, J.Langloss, R.H.Cardy, and A.G. Manus. 1986. Lung neoplasms in rodents after chronic administration of dimethyl hydrogen phosphite. Cancer Res. 46(1):264–270. EPA (U.S. Environmental Protection Agency). 1985. Chemical Hazard Information Profile: Dimethyl Hydrogen Phosphite. TSCA Interagency Testing Committee, Washington, DC. EPA (U.S. Environmental Protection Agency). 1986. Guidelines for Carcinogen Risk Assessment. Fed. Regist. 51(185):33992–34003.

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