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.

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.

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

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).

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.

No data describing toxicokinetics of DMHP from the inhalation route were identified during the course of this review.

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

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).

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).

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,

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.

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.

No data were found regarding the immunological, reproductive, developmental, or carcinogenic effects of DMHP following dermal exposure.

A summary of the inhalation toxicity data of DMHP is presented in Table 14–2.

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

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).

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.

No data were found on the immunological, reproductive, developmental, or carcinogenic, effects of inhaled DMHP.

A summary of the noncancer effects from oral exposure to DMHP is presented in Table 14–3.

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

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.

No data were found regarding immunological effects after oral exposure to DMHP.

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.

No data on reproductive and developmental toxicity of DMHP were located. However, there are some studies on a closely related chemical—dimethyl 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 5–12 wk

(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 6–15; doses for mice were 4.2 g/kg-d on gestation d 6–13). However, the high dose rats in the Fritz (1978) study exhibited maternal toxicity.

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.

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 “clear evidence of carcinogenicity” 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).

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).

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 14–4 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).

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 14–4).

DMHP was tested in Ames Salmonella tester strains TA98, TA100, TA1535, TA1537, and TA1538 at concentrations ranging from 0.001–15.0 µL/plate (Brusick 1977; Haworth 1979b) or 100–10,000 µg/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 µg/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 µg/mL caused chromosomal aberrations and, at 250 µg/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).

There are insufficient dermal toxicity data from which to develop an estimate of a dermal reference dose (RfD) for DMHP.

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.

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 14–5). 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).

No data were found regarding the carcinogenicity of the dermal application of DMHP.

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 1.54×10⁻⁶/µg/m³ was estimated using Equation 16 in Chapter 3 and the oral cancer potency factor for DMHP (see proceeding Oral section).

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

were adjusted for discontinuous exposure and scaled to bw^3/4 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

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.

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 (S_a) for DMHP of 7.5 mg/cm². The extraction rate (µ_w) 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.

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.

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 K_p. However, the dermal penetration constant for DMHP has not been measured experimentally. However, K_p can be estimated from a correlation between the octanol-water partition coefficient (K_ow) and molecular weight (mass/unit amount of substance) using Equation 2 in Chapter 3 yielding an alternate K_p 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 K_p, 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 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.

Particle exposure was estimated using Equations 4 and 5 in Chapter 3. The subcommittee estimated an upholstery application rate (S_a) for DMHP of 7.5 mg/cm². The release rate (µ_r) 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 (C_p) 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.

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 (C_v) of 26,800 mg/m³

was estimated for DMHP. The application density (S_a) 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.

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 (S_a) for DMHP of 7.5 mg/cm². Oral exposure was calculated using Equation 15 in Chapter 3. The extraction rate (µ_w) 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.

Human cancer risk from dermal exposure to DMHP was calculated by multiplying the oral cancer potency factor for DMHP by the most conservative

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.

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.

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.

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.

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.

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

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.

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