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ORGANIC PHOSPHONATES 307 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 14â1. OCCURRENCE AND USE According to IPCS (1997), both halogenated and non-halogenated phosphonate esters are the predominant phosphorous-based flame retardants in use. 1In this chapter, the toxicity data were discussed for DMHP because most of the relevant data for organic phosphates were available for this compound.
ORGANIC PHOSPHONATES 308 TABLE 14â1 Physical and Chemical Properties of Dimethyl Hydrogen Phosphite Property Value Reference Chemical formula C2H7O3P Howard and Meylan 1997 Structure NTP 1985 CAS Registry # 868â85â9 Howard and Meylan 1997 Synonyms DMHP, dimethyl phosphonate (Chem. Abstr. Name; IARC 1990; NTP 1985; HSDB 1999 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 Molecular weight 110.05 Howard and Meylan 1997 Physical state Mobile liquid Hawley 1981; as cited in IARC 1990 Solubility Solubility in water=1Ã106 mg/L; miscible in most organic Howard and Meylan 1997; CRC Press solvents; soluble in pyrimidine 1992 Color Colorless Hawley 1981; as cited in IARC 1990 Vapor pressure 4.52 mm Hg at 25Â°C Howard and Meylan 1997 log Kow â1.13 Howard and Meylan 1997 pH Not available â Melting point Not available â Boiling point 170.5 Â°C Howard and Meylan 1997 Flash point 96 Â°C Hawley 1981, as cited in IARC 1990
ORGANIC PHOSPHONATES 309 Decomposition When heated to decomposition, can emit highly toxic Sax 1984 fumes of phosphorous oxides Reactivity Hydrolyzes in water with half-life of approximately Bel'skii et al. 1969; Vilceanu and Schulz 1972; 10 d at 25Â° C and 19 d at 20Â° C; basic conditions all as cited in HSDB 1999 accelerate hydrolysis 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 (10â200 mg/kg), the radio-labeled compound was almost completely absorbed from the gastrointestinal tract in both rats and mice and was primarily
ORGANIC PHOSPHONATES 310 eliminated as expired CO2 (44â57%) 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 (28â49%) greatly exceeded elimination by the fecal route (1â2%) or as volatile organic compounds (2â 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, 2In 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).
ORGANIC PHOSPHONATES 311 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 14â2. 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 âwall lossesâ and hydrolytic degradation were made by dehumidifying chamber air and increasing chamber temperature to 79 Â°F. Nevertheless, the author considered that âgeneration of [test article] levels in excess of 500 ppm [2250 mg/m3] would be difficultâ (Rusch 1980). After 4 d of exposure, all
ORGANIC PHOSPHONATES 312
ORGANIC PHOSPHONATES 313 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 14â2). 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.
ORGANIC PHOSPHONATES 314 Oral Exposure A summary of the noncancer effects from oral exposure to DMHP is presented in Table 14â3. 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 14â3. 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
ORGANIC PHOSPHONATES 315 TABLE 14â3 Noncancer Effects from Oral Exposures to Dimethyl Hydrogen Phosphite Species, Purity Dose Duration, Route Effects Comments Reference Strain, Sex, Number Rat, As received 10.0, 31.6, Single dose, No deaths at 10.0â LD50: ~3,160 Keller 1961a albino, NS, from Hooker 100, 316, intubation 100 mg/kg; single mg/kg 2/dose Chem. Co. 3,160 mg/ death at 3,160 mg/ (âconsidered to kg in 0.5% kg at 4 hr, be free of (v/v) exhibited impuritiesâ) aqueous prostration, methyl labored cellulose respiration, and solution; tremors. Lung untreated hemorrhage, control not kidney reported congestion, gastrointestinal inflammation Rat, F-344/ ~96â98% 0, 1,470, Single dose, Mortality; LD50: 3,283 NTP 1985b N, M/F, 5/ 2,150, gavage inactivity, mg/kg (M); sex/dose 3,160, weakness, 3,040 mg/kg 4,640, 6,810 shallow breathing (F) mg/kg in on d 1 at â¥3,160 corn oil mg/kg; gas in (dose stomach and volume: intestines at 5.675 mL/ necropsy kg) Rat, F-344/ ~96â98% 0, 250, 500, 15 d Deaths atâ¥500 mg/ No other NTP 1985b N, M/F, 5/ 1,000, 2,000 (consecutive), kg; inactivity clinical signs sex/dose mg/kg-d in gavage after dosing or necropsy corn oil; findings 3,000 mg/ reported kg undiluted (dose volume: 2.5 mL/kg) Rat, F-344/ ~96â98% 0, 25, 50, 13 wk (5 d/wk), Deaths atâ¥200 mg/ 3/5 deaths at NTP 1985b N, M/F, 10/ 100, 200, gavage kg in M and 100 and 200 sex/dose 400 mg/kg- atâ¥100 mg/kg in mg/kg d in corn oil F; body weight perhaps due (dose depression atâ¥400 to accidental volume: mg\kg in M and lung gavage. 3.33 mL/kg) atâ¥200 mg/kg in NOAEL: 100 F; lens mg/kg (based degeneration at on body- 400 mg/kg in M weight and F; corneal depression in inflammation at F) 400 mg/kg in F; urinary bladder calculi at 400 mg/ kg in M
ORGANIC PHOSPHONATES 316 Species, Purity Dose Duration, Route Effects Comments Reference Strain, Sex, Number Rat, F-344/ ~96â98% 0, 100, 200 103 wk (5 d/wk), Mortality at 200 NOAEL: 50 mg/ NTP 1985b. N, M/F, 50/ mg/kg-d in gavage mg/kg in M; dose- kg-d (based on Dunnick et al. sex/dose corn oil for related decreased hyperplasia of 1986c M; 0, 50, weight gain at all lung tissue and 100 mg/kg doses for M and forestomach in in corn oil high dose F; dose- F) Evidence of for F (dose related alveolar dose-related volume: 4.0 and adenomatous cancers, mL/kg) hyperplasia, especially M rats forestomach hyperplasia and hyperkeratosis, cerebellum mineralization in high-dose M; chemical pneumonia Mouse, ~96â98% 0, 1,470, Single dose, Deaths by d 2 LD50: 2,815 mg/ NTP 1985b B6C3F1, M/ 2,150, gavage atâ¥3,160 mg/kg; kg (M) Survival F, 5/sex// 3,160, inactivity, curve too steep dose 4,640, prostration; for estimating 6,810 mg/ shallow breathing LD50 for F kg in corn on d 2 at>2,150 oil (dose mg/kg; white volume: opaque eyes in M 5.675 mL/ at necropsy kg) Mouse, ~96â98% 0, 250, 500, 15 d Deaths by d 9 NTP 1985b B6C3F1, M/ 1,000, (consecutive), atâ¥2,000 mg/kg; F, 5/sex/ 2,000, gavage inactivity atâ¥1,000 dose 3,000 mg/ mg/kg, thickening kg-d in and nodules in corn oil squamous stomach (dose region at â¥250 mg/ volume: 10 kg at necropsy mL/kg) Mouse, ~96â98% 0, 95, 190, 13 wk (5 d/wk), Deaths, tremors, NOAEL: 190 NTP 1985b B6C3F1, M/ 375, 750, gavage and decreased mg/kg-d (M, F, 10/sex/ 1500 mg/ activity in first 4 testicular dose kg-d in wk atâ¥375 mg/kg; atrophy) corn oil testicular atrophy (dose in M at â¥375 mg/ volume: kg; some lung 3.33 mL/kg) congestion, cardiac mineralization in M; hepatocellular vacuolization in F
ORGANIC PHOSPHONATES 317 Mouse, ~96â98% 0, 100, 200 103 wk (5 d/ Decreased body LOAEL: 100 NTP B6C3F1, mg/kg-d in wk), gavage weight gain and mg/kg-d (M, 1985b; M/F, 50/ corn oil survival at 200 testicular Dunnick et sex/dose (dose mg/kg in M; focal calcification) al. 1986c volume: calcification in 4.0 mL/kg) testes of M at both doses Rat, As received 0, 200 mg/ 4, 5, or 6 wk (5 Increase in Nomeir and F-344/N, from Aldrich kg-d in d/wk), gavage forestomach Uraih 1988c M, 18/ Chem. Co., corn oil, weight for all dose Milwaukee, WI (dose doses; volume: 4 forestomach tissue mL) exhibited hyperplasia, hyperkeratosis, subepithelial inflammation, and edema at 6 wk; significantly increased angiotensin converting enzyme in serum at 4â6 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 Rat, Radiochemical 10, 100, Rats: single Highest activity in Rate of labeled Nomeir and F-344/N, purity of 97% 200 mg/kg dose, gavage at liver, kidneys, DMHP Matthews M, NS/ for labeled [14C] 10, 100, 200 spleen, lungs, clearance in 1997c dose compounds DMHP in mg/kg; 5 d forestomach; mice Mouse, corn oil (consecutive), lowest activity in approximately 2 B6C3F1, (dose gavage at 200 brain, skeletal times greater M, NS/ volume: 4 mg/kg-d Mice: muscle, adipose than in rats dose (âat mL/kg); single dose, tissue. least untreated gavage at 200 Elimination as three control not mg/kg CO2 in expired air animals reported (44-57%) and for urine (28â49%); each time little activity in pointâ) feces (1â2%), volume organic compounds (2â 3%) 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. aLabreport from Hazleton Labs to Hooker Chemical Corporation (1961); TSCA Submittal from Occidental Chemical to EPA (1992). BReport of the National Toxicology Program. CPublished study.
ORGANIC PHOSPHONATES 318 among males and appeared to be dose-related. This was considered a chemical pneumonia, evidenced by the fact that all assays were negative for infection (NTP 1985, Appendix L, p. 170). All 24 male rats at the high dose also had lung neoplasms, and pneumonia was widespread in this group (43/50). The authors did not observe an association between pneumonia and these lesions (NTP 1985). The NOAEL for this study was considered to be 50 mg/kg-d based on hyperplasia of lung and forestomach tissue in females. The LOAEL was determined to be 100 mg/kg-d based on testicular calcification in males. Immunological Effects No data were found regarding immunological effects after oral exposure to DMHP. Neurological Effects Oral administration of DMHP at doses of 200 mg/kg to male F-344/N rats for 103 wk resulted in an increase in the incidence of focal mineralization in the granular layer of the cerebellum (observed in 12 of 49 rats) (NTP 1985). Multiple basophilic concretions up to 1-mm diameter were observed in clusters but were not associated with cell damage or the presence of blood vessels. This effect was not observed in any other treatment group of male or female rats and was not noted in the B6C3F1 mice. Reproductive and Developmental Effects No data on reproductive and developmental toxicity of DMHP were located. However, there are some studies on a closely related chemicalâdimethyl methyl phosphonate (DMMP), which is discussed here. DMMP has been shown to be a reproductive toxicant in 13-wk gavage studies of male F-344 rats and male B6C3F1 mice (Dunnick et al. 1984a, 1984b) and in 12-wk gavage studies with male F-344 rats (Chapin et al. 1984). Dunnick et al. (1984a, 1984b) reported dose-related decreases in rat sperm count, motility, and male fertility at all dose levels tested (250, 500, 1,000, and 2,000 mg/kg). Although reproductive function was altered, histological changes were noted only in tissues from rats in the 2,000 mg/kg dose group, characterized by a lack of spermatogenesis and necrosis of cells in the spermatogenic tubules (Dunnick et al. 1984a). Gavage treatment with 1,750 mg/kg DMMP in tap water for periods of 5â12 wk
ORGANIC PHOSPHONATES 319 (5 d/wk) produced morphological alterations in Sertoli cells and elongated spermatids, as well as functional defects in spermatozoa (Chapin et al. 1984). Eighty percent of the rats had normal seminiferous tubules at the end of a 14 wk recovery period. However, all recovered tubules displayed a loss of normal epithelial organization (Chapin et al. 1984). Administration of DMMP to gestating Tif/RAI rats and CD-1 mice in their drinking water or by oral gavage (Hardin et al. 1987; Fritz 1978) did not result in reproductive or developmental toxicity (doses for rats were 2 g/ kg-d on gestation d 6â15; doses for mice were 4.2 g/kg-d on gestation d 6â13). However, the high dose rats in the Fritz (1978) study exhibited maternal toxicity. Cancer DMHP administered by gavage to male F-344/N rats at a dose of 200 mg/kg, 5 d/wk for 103 wk induced alveolar/bronchiolar adenomas or carcinomas in 48% (24 of 50) of the animals. At a dose of 100 mg/kg, alveolar/ bronchiolar carcinomas occurred in one of 50 animals while none occurred among 50 vehicle controls. There was also a dose-related increase in the incidence of squamous cell carcinomas in the lungs of the male rats (0 of 50 in vehicle control, 0 of 50 at 100 mg/kg, 5 of 50 at 200 mg/kg; p=0.020, life table test) (NTP 1985). Further, the combined incidences of squamous cell papillomas and carcinomas of the forestomach were significantly increased in male rats when compared to the vehicle controls (0 of 50 in control, 1 of 50 at 100 mg/kg, 6 of 50 at 200 mg/kg; p=0.006 life table test). The low-dose (100 mg/kg) male rats exhibited a significantly increased incidence of mononuclear cell leukemia when compared to the vehicle control (NTP 1985). Time-to-first tumor for males occurred at wk 92 (NTP 1985, Appendix A, p. 68). The 15% decrease in average body weight of the high-dose males indicates that the maximum tolerated dose for DMHP was reached in this study. The authors note that DMHP caused the highest incidence of lung tumors in the male rat of all chemicals studied by the National Toxicology Program (Dunnick et al. 1986). Historical incidence data for lung squamous cell carcinomas in male rats is 0 of 50 for tests with diallyphthalate, tris (2-ethyl hexyl) phosphate, and toluene diisocyanate; while the historical incidence of alveolar/bronchiolar carcinomas was 1 of 50 for each of the above 3 compounds (NTP 1985, Appendix F, p. 128). For alveolar/bronchiolar adenomas, the historical incidence was 2 of 50, 1 of 50, and 2 of 50 for the above 3 compounds, respectively (NTP 1985, Appendix F, p. 128). Female F-344/N rats were tested under the same protocol but using a different dosing regimen (50 and 100 mg/kg-d DMHP) (NTP 1985; Dunnick et al.
ORGANIC PHOSPHONATES 320 1986). Alveolar/bronchiolar carcinomas were observed in 6% of the animals in the 100 mg/kg dose group (3 of 50) while none occurred in the vehicle controls (0 of 50) and one occurred in the 50 mg/kg dose group (1 of 49). Female rats displayed a significant (p < 0.05) positive trend for alveolar-bronchiolar carcinoma, but the high- dose effect was not found to be statistically significant when compared to controls. There was no evidence of DMHP carcinogenicity in male or female B6C3F1 mice administered doses of 100 or 200 mg/kg, 5 d/wk for 2 yr (Dunnick et al. 1986). NTP concluded that there was âclear evidence of carcinogenicityâ in male F-344/N rats, âequivocal evidence of carcinogenicityâ in female F-344/N rats, and âno evidence of carcinogenicityâ in male or female B6C3F1 mice (NTP 1985, Dunnick, et al. 1986). IARC (1990) concluded that there was limited evidence for the carcinogenicity of DMHP in experimental animals and that DMHP is not classifiable as to its carcinogenicity to humans (i.e., it is a Group 3 carcinogen). Genotoxicity In vivo genotoxicity studies of DMHP include tests of sex-linked lethal mutagenicity (Woodruff et al. 1985; NTP 1985), the bithorax test of Lewis, Y-chromosome loss test, dominant lethality test, and somatic reversion test of white-ivory in male Canton-S Drosophila melanogaster (Bowman 1980). Exposure routes included injection, ingestion, and inhalation (see Table 14â4 for summaries). Male Canton-S Drosophila melanogaster fruit flies were tested for the presence of sex-linked recessive mutations after feeding (600 or 650 ppm) or injection (1,500 ppm) of DMHP (Woodruff 1985; NTP 1985). The results were negative for this effect. In the Woodruff (1985) study, 30% mortality occurred within 72 hr after feeding or 24 hr after injection. Exposure of Canton-S males to DMHP aerosol (0.07 mL/25 mL air for 5 min) gave positive results for the sex-linked lethal and dominant lethal tests but negative results for the bithorax, Y-chromosome loss, and somatic reversion tests (Bowman 1980). In 13-wk oral (gavage) studies of dimethyl methylphosphonate, a compound structurally similar to DMHP, there was evidence of dominant lethal mutagenicity (Dunnick et al. 1984a, 1984b). There were increased resorptions in dams mated to male F-344 rats administered DMHP at doses of 250, 500, 1,000, and 2,000 mg/kg (Dunnick et al. 1984a). In B6C3F1 mice, Dunnick et al. (1984b) reported dominant lethal effects at doses of 1,000 mg/kg and greater (dose regimen mirrored that of the Dunnick et al. 1984a rat study); after a 15-wk recovery period, resorptions associated with those doses declined to the control group rate (Dunnick et al. 1984b).
ORGANIC PHOSPHONATES 321 TABLE 14â4 Genotoxicity Studies of Dimethyl Hydrogen Phosphite Species, Sex Purity Dose Duration Effects Comments Reference Canton-S NA 150 ppm Single Sex-linked M mated Woodruff et Drosophila injection; injection; lethality: individually to al. 1985a melanogaster, M; 600 ppm feeding-NA negative. 30% 3 harems of Base virain F feeding mortality at 24 Base F hr post- injection or 72 hr post-feeding Canton-S D. ~96â98% 0, 1500 ppm Single Sex-linked M mated with NTP 1985b melanogaster, M; injection injection recessive lethal 3 harems of Base virgin, F (dose vol.= with 24 hr mutations: Base F 0.03 ÂµL); 0, recovery negative. 650 ppm in before feed mating; 3 d in feed Canton-S D. As 0, 0.07 mL 5 min Sex-linked Bowman melanogaster, M received undiluted lethal-positive; 1980c from aerosol in 25 bithorax- sponsor mL air negative; Y chromosome loss-negative; dominant lethal- positive; somatic reversion of white ivory: negative Salmonella As 0.001, 0.01, 48 hr Reversion Positive Brusick typhimurium received 0.10, 1.0, incubation mutation w/o controls 1977d strains TA1535, from 5.0 ÂµL/plate, activation- 1537, 1538, 98, sponsor with and negative; 100; without S9 reversion Saccharomyces activation mutation w/ cerevisiae strain activation: D4 negative S. typhimurium ~96â98% 0, 100, 333, 20 min Mutagenicity NTP 1985b strains TA1535, 1000, 3333, with and 1537, 98, 100 10,000 Âµg/ without plate; with activation: and without negative S9 activation
ORGANIC PHOSPHONATES 322 Species, Sex Purity Dose Duration Effects Comments Reference S. typhimurium As received 0.1, 5.0, 10.0, 20 min Salmonella/ Positive Haworth strains from sponsor 15.0 ÂµL/plate; mammalian controls 1979bc TA1535, 1537, with and without microsome pre- 1538, 98, 100 S9 activation incubation mutagenicity assay: negative for all strains, with and without S9 activation Mouse As received 0.13, 0.18, 0.24, 4 hr Mouse lymphoma Significant Kirby 1979c lymphoma from sponsor 0.32, 0.42, 0.56, mutagenesis assay dose- L5178Y TK+/ 0.75, 1.0, 1.3, 1.8 without dependent â cells ÂµL/plate; with activation: effects with and without S9 negative; with S9 activation activation activation: positive Mouse From NTP Without 4 hr Mouse lymphoma LOED: 2100 McGregor et lymphoma repository; activation: 125, mutagenesis assay Âµg/mL with al. 1988a L5178Y TK+/ same purity 250, 500, 1000, without S9 activation â cells as used in 2000 Âµg/plate; activation: NTP 1985 with activation: negative; with study 1700, 1900, activation: 2100, 2300, 2500 positive atâ¥2100 Âµg/plate Âµg Chinese Where NA; with and NA Chromosomal Tennant et Hamster possible, without activation aberrations at al. 1987a Ovaries same 1,600 Âµg/mL and chemical lot sister chromatid as NTP study exchange at 250 Âµg/mL both with and without activation B6C3F1 From NTP Intraperitoneal 3d Mouse bone Data judged Shelby et al. mouse, M repository; injection of 0, marrow by authors to 1993a same purity 250, 500 mg/kg micronucleus be adequate as used in in corn oil (dose assay-increasing evidence of NTP 1985 vol.=0.4 mL); 1 trend; no effect; study injection/d significant additional increase in tests needed micronucleated percentage of polychromated erythrocytes
ORGANIC PHOSPHONATES 323 S. typhimurium As received 0.3, 3.0, 30.0, 90 min DNA damage/ No clear dose Haworth strains TA1978 from sponsor 50 ÂµL/plate; repair response. 1979cc and 1538; E. coli with and suspension test Strains with strains WP2 and without S9 for E. coli strain positive 100 activation WP100: positive reaction are at 30 Âµg with repair-deficient activation and positive at 50 ÂµgL/plate without activation; same test for Salmonella strain TA1538: negative with activation and positive at 30 ÂµgL/plate without activation F, female; LOED, Lowest Effective Dose; M, male; NA, not applicable. aPublished study. bStudy of the National Toxicology Program. cLab report from EG&G Mason Research Institute, Rockville, MD, to sponsor, Mobil Chemical Company of Princeton, NJ. dLab report from Litton Bionetics, Inc., Kensington, MD, to Mobil Chemical Company (1977); TSCA submittal by Mobil Research and Development Corporation of NY, to EPA Office of Toxic Substances (1981).
ORGANIC PHOSPHONATES 324 DMHP was studied in several in vitro genotoxicity assays, which include Ames tests, with and without S9 activation, in various tester strains of Salmonella typhimurium and Saccharomyces cerevisiae (Brusick 1977; Haworth 1979b; NTP 1985); mouse lymphoma assays (Kirby 1979; McGregor et al. 1988); a mouse bone marrow micronucleus assay (Shelby et al. 1993); Chinese hamster ovary (CHO) assay for chromosomal aberrations and sister chromatid exchange (Tennant et al. 1987); and DNA damage/repair tests of various Escherichia coli and S. typhimurium tester strains (Haworth 1979c) (See Table 14â4). DMHP was tested in Ames Salmonella tester strains TA98, TA100, TA1535, TA1537, and TA1538 at concentrations ranging from 0.001â15.0 ÂµL/plate (Brusick 1977; Haworth 1979b) or 100â10,000 Âµg/plate (NTP 1985) and the results were negative, with and without S9 activation. Mouse lymphoma assay results were positive at high concentrations (lowest observed effective dose [LOED]=2,100 Âµg/plate) with S9 activation (McGregor et al. 1988) but negative without activation (Kirby 1979). The Kirby (1979) test results indicate dose dependency. In the CHO cell line, DMHP at 1,600 Âµg/mL caused chromosomal aberrations and, at 250 Âµg/mL, caused sister chromatid exchanges (both with and without S9 activation) (Tennant et al. 1987). Mouse bone marrow micronucleus tests revealed a positive, but not significant, increasing trend in percentage of micronucleated, polychromated erythrocytes (Shelby et al. 1993). The authors concluded that there was adequate evidence of clastogenic effect, but that additional tests are needed. DNA damage and repair have been tested in E. coli strains WP2 and WP100 with and without activation (Haworth et al. 1979b). QUANTITATIVE TOXICITY ASSESSMENT Noncancer Dermal Assessment There are insufficient dermal toxicity data from which to develop an estimate of a dermal reference dose (RfD) for DMHP. Inhalation RfC There are inadequate toxicity data for deriving an RfC for DMHP. No chronic inhalation toxicity studies area available for DMHP. There is one subchronic inhalation study for DMHP in rats by Bio/dynamics (1980), however, the subcommittee concluded that this study was not adequate for use in deriving an RfC for DMHP.
ORGANIC PHOSPHONATES 325 Oral RfD The 2-yr chronic gavage exposure study performed by NTP (1985) in F-344/N female rats was selected by the subcommittee as the critical study for the development of a chronic oral RfD for DMHP based on treatment- related hyperplasia of the lung and forestomach. Similar results were observed in mice, but these lesions occurred at greater incidence in rats. EPA does not usually establish RfDs on the basis of hyperplasia where cancer is also seen. However, it is not clear that all forms of observed hyperplastic response is associated only with carcinogenesis. Adenomatous hyperplasia in the female rats is not known to be clearly linked to malignant tumor formation. The NOAEL for hyperplasia of the lung (alveolar epithelium hyperplasia and adenomatous hyperplasia) and forestomach in female F-344/N rats was identified as 50 mg/kg-d. The NOAEL was adjusted for discontinuous exposure by multiplying by the ratio of (5/7) to accommodate the 5-d dosing regimen employed (NTP 1985; Dunnick et al. 1986) yielding an adjusted NOAEL of 35.7 mg/kg-d. A composite uncertainty factor of 300 was applied to the NOAEL giving an oral RfD of 0.12 mg/kg-d (see Table 14â5). A factor of 10 was applied for intraspecies variation, a factor of 10 for extrapolating from animals to humans and a factor of 3 for the adequacy of the toxicity database of DMHP (availability of chronic toxicity results in 2 species). No mammalian multigenerational reproductive toxicity studies and no mammalian developmental toxicology studies on DMHP were found and their absence leaves a critical gap in the toxicological characterization of this compound (Cicmanec et al. 1996). Cancer Dermal No data were found regarding the carcinogenicity of the dermal application of DMHP. TABLE 14â5 Oral Reference Dose for Dimethyl Hydrogen Phosphite RfD (mg/kg-d) Critical effect Species Effect level (mg/kg-d) Uncertainty factors Reference 0.12 Increases in hyperplasia in the Female rats NOAEL: 35.7 UFA=10 NTP 1985 lung (alveolar epithelium UFH=10 hyperplasia, adenomatous UFD=3 hyperplasia) Total=300 NOAEL, no-observed-adverse-effect level; RfD, reference dose; UFA, extrapolation from animals to humans; UFH, intraspecies variability; UFD, inadequate or deficient toxicity database.
ORGANIC PHOSPHONATES 326 Inhalation No data were found regarding the carcinogenicity of DMHP following inhalation exposure. For the calculating a hazard index for this route, an inhalation unit risk of 1.54Ã10â6/Âµg/m3 was estimated using Equation 16 in Chapter 3 and the oral cancer potency factor for DMHP (see proceeding Oral section). Oral The subcommittee believes that there are adequate oral carcinogenicity data for deriving a cancer potency estimate for DMHP. As previously discussed, DMHP induced alveolar/bronchiolar adenomas or carcinomas when administered by gavage to male F-344/N rats at doses of 200 mg/kg, 5 d/wk for 103 wk. There was also a dose-related and increased incidence of squamous cell carcinomas of the lung and squamous cell papillomas and carcinomas of the forestomach combined in male rats exposed to DMHP, 5 d/wk for 103 wk (NTP 1985). There was also a significantly increased incidence of mononuclear cell leukemia in male rats exposed to DMHP at a dose of 100 mg/kg-d, 5 d/wk, for 103 wk as compared to the vehicle controls (NTP 1985). An increased incidence of alveolar/bronchiolar carcinomas occurred in female F-344/N rats exposed to DMHP at dose levels of 50 or 100 mg/kg-d for 5 d/wk, for 103 wk, as compared with vehicle controls (NTP 1985; Dunnick et al. 1986). The female rats displayed a significant (p<0.05) positive trend for alveolar-bronchiolar carcinomas, but the high-dose effect was not found to be statistically significant when compared to controls (Dunnick et al. 1986). No evidence was observed for the carcinogenicity of DMHP in B6C3F1 mice (NTP 1985, Dunnick, et al. 1986). NTP concluded that these studies provide clear evidence of carcinogenicity for DMHP in male F-344/N rats, equivocal evidence of carcinogenicity in female F-344/N rats, and no evidence of carcinogenicity in male or female B6C3F1 mice (NTP 1985, Dunnick, et al. 1986). In its evaluation of the carcinogenicity of DMHP, IARC (1990) concluded that there is limited evidence for the carcinogenicity of DMHP in experimental animals and DMHP is not classifiable as to its carcinogenicity to humans and assigned DMHP a Group 3 rating. The subcommittee concluded that available data suggests that DMHP might be carcinogenic. Cancer slope factors (SF) were derived for DMHP using lung and forestomach tumor data for male and female F-344/N rats. SF calculations were performed using a computerized program of the Global 86 linearized multistage model and several other benchmark dose models. These programs provided LED10 values for derivation of cancer SFs. Dose levels used in the calculations
ORGANIC PHOSPHONATES 327 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 14â6. 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 5.4Ã10â3/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 (Âµw) 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 28Â°C calculated using the equation 2d/2 ÏR (d=film thickness, R=fiber radius) with a correction from fiber to film of a factor of 0.63.
ORGANIC PHOSPHONATES 328 TABLE 14â6 Cancer Risk Values for Dimethyl Hydrogen Phosphite Determined from Different Curve-fitting Models (Data from NTP 1985) Modela MLE or BMD LED10b (mg/kg-d) Slope Factors (0.1/ Comment (mg/kg-d) LED10) (per mg/kg-d) 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 21.51 18.51 5.4Ã10â3 The p-values for the Monte multistage) (2.5Ã10â3)c Carlo test wereâ¥0.05 EPA's BMD: Gamma 25.27 22.68 4.4Ã10â3 p-value for Ï2 test was 1.00; graphical representation showed a good fit for the data EPA's BMD: Logistic 27.58 22.73 4.4Ã10â3 p-value for Ï2 test was 0.88; graphical representation showed a good fit for the data EPA's BMD: Probit 26.33 21.75 4.6Ã10â3 p-value for Ï2 test was 0.97; graphical representation showed a good fit for the data EPA's BMD: Weibull 26.41 21.27 4.7Ã10â3 p-value for Ï2 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 25.54 16.92 5.9Ã10â3 p-value for the Monte (linearized multistage) (5.7Ã10â3)c Carlo test was 1.00 EPA's BMD: Gamma 26.18 16.87 5.9Ã10â3 p-value for Ï2 test was 1.00; graphical representation showed a good fit for the data EPA's BMD: Log- 26.11 16.97 5.9Ã10â3 p-value for Ï2 test was logistic 1.00; graphical representation showed a good fit for the data; logistic model run as log- logistic with slope parameter restricted toâ¥1
ORGANIC PHOSPHONATES 329 EPA's BMD: Log-probit 23.86 16.63 6.0Ã10â3 p-value for Ï2 test was 0.95; graphical representation showed a good fit for the data; probit model run as log-probit with slope parameter restricted toâ¥1 EPA's BMD: Quantal quadratic 24.26 16.90 5.9Ã10â3 p-value for Ï2 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 3.7Ã10â3 p-value for the Monte Carlo test was 1.00 (3.8Ã10â3)c EPA's BMD: Gamma 35.17 27.97 3.6Ã10 â3 p-value for Ï2 test was 0.00; graphical representation showed a good fit for the data EPA's BMD: Log-logistic 35.26 17.93 3.6Ã10â3 p-value for Ï2 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 toâ¥1 EPA's BMD: Log-probit 34.94 26.51 3.8Ã10â3 p-value for Ï2 test was 1.00; graphical representation showed a good fit for the data; probit model run as log-probit with slope parameter restricted toâ¥1 EPA's BMD: Quantal quadratic 35.91 27.09 3.7Ã10 â3 p-value for Ï2 test was 0.95; graphical representation showed a good fit for the data EPA's BMD: Weibull 35.34 26.74 3.7Ã10â3 p-value for Ï2 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 Ï2 tests were <0.05, graphical representation did not show a good fit for the data, and/or the benchmark dose computation failed. bLED is the same as the BMDL (lower confidence limit on the BMD) in EPA's BMD software program. 10 cThe number in parenthesis is the q * derived from GLOBAL 86. 1
ORGANIC PHOSPHONATES 330 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 1.46Ã10â3 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.
ORGANIC PHOSPHONATES 331 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 (Âµr) for DMHP from upholstery fabric was estimated to be 2.3Ã10â7/d (see Chapter 3, Equation 5) yielding a room airborne particle concentration (Cp) of 2.9 Âµg/m3 and a short time-averaged exposure concentration of 0.725 Âµg/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 Âµg/m3 by the provisional RfC for DMHP of 0.42 mg/m3 yields a hazard index of 1.73Ã10â3 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 8â11 in Chapter 3. A saturated vapor concentration (Cv) of 26,800 mg/m3
ORGANIC PHOSPHONATES 332 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 (Âµw) 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 28Â°C calculated using the equation 2d/2 ÏR (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
ORGANIC PHOSPHONATES 333 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 5.4Ã10â3/mg/kg-d, the lifetime risk estimate is 6.1Ã10â2. 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 1.54Ã10â6/Âµg/m3 was derived from oral cancer potency data for DMHP. Multiplication of the exposure estimates of 0.725 Âµg/m3 for particulate times the provisional cancer potency value yields an estimated lifetime cancer risk of 1.1Ã10â6 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 1.54Ã10â6/Âµg/m3, the upper bound on lifetime cancer risk for inhalation exposure to DMHP in the vapor phase is 6.6Ã10â4. This risk estimate indicates that further investigation of cancer risks associated with DMHP vapors should be considered.
ORGANIC PHOSPHONATES 334 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 1.7Ã10â3 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 Ã10â3/mg/kg-d yielding a cancer risk estimate of 9.1Ã10â6. 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 1Ã10â6 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
ORGANIC PHOSPHONATES 335 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. 6:1297â1300. Bio/dynamics (Bio/dynamics, Inc.). 1980. A Four Week Inhalation Toxicity Study of MCTR-242â79 in the Rat. Bio/Dynamics Inc., East Millstone, NJ. EPA OTS Doc. #8EHQ-0182â0366. Bowman, J.T. 1980. Drosophila Mutagenicity Assays of Mobil Chemical Company Compound MCTR-111â79. MRI Report No. 344. EG&G Mason Research Institute, Rockville, MD. EPA OTS Doc #88â8100187. Brusick, D.J. 1977. Mutagenicity Evaluation of MCTR-214â77, Final Report. LBI Project No. 2683. Litton Bionetics, Kensington, MD. EPA/ OTS Doc. #88â8100187. 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. 41:126â140. Cicmanec, J.L., M.L.Dourson, and R.C.Hertzberg. 1995. Noncancer risk assessment: Present and emerging issues. Pp. 293â310 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):379â387. 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(2â3):213â218. 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):264â270. 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):33992â34003.
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