# CPSC 

# Staff Preliminary Risk Assessment of

? 

# Flame Retardant (FR)Chemicals in Upholstered Furniture Foam*

December 21,2006

MichaelA. Babich, Ph.D. Directoratefor Health Sciences U.S. Consumer Product Safety Commission Bethesda,MD 20814

* A draft version of this report appearedin the~lanuary 2006 BriefingPackage on Upholstered Furniture. This report was prepared by the CPSC staff; it has not been reviewed or approvedby, and may not necessarily reflect the views of, the Commission.. . Contents



### ... Summary



### ....................... 

### .:
.................................................................................................. ill Abbreviations



### ........................................................................................... ............................v I

. Introduction



### .......... .......................................................................................... 1



### ........... A



### . Upholstered Furniture Cover Fabrics



### ............................................. 1 

### B

. Upholstered Furniture Foam



### ............................... ; 

### .....................................2 C



### . Risk Assessment and the Federal Hazardous SubstancesAct



### ....................3



### ..................................... 

### ...................................................................... 

### . I1 Hazard i... 

### 5

/ A



### . Tris(l,3.Dichloro. 2.Propyl) Phosphate (TDCP)



### ........................................ 5 

### B



### . Aromatic Phosphate Plasticizers (APP)



### .................................................... 12 C

. Triphenyl Phosphate (TPP)



### ...................................................................... -16 D

. Phenol Isopropylated Phosphate (PIP)



### ..................................................... 21 E



### . Octyl Tetrabromobenzoate (OTB)



### ............................................................ 24 F

. Melamine



### ..................................................... 

### .'.

............................................ 24 111



### . Dose Response



### ............................................................................................... -27 A

. Tris(l,3.Dichloro. 2.Propyl) Phosphate (TDCP)



### ......................................27 B



### . Triphenyl Phosphate 

### (TPP) and Phenol Isopropylated Phosphate (PIP)



### ..29 C

. Octyl Tetrabromobenzoate (OTB)



### ............................................................ 29 D

. Melamine



### ............. 

### ...

### .................................................................................. 29 

### IV


### . Exposure and Bioavailability



### .................................... 

### :
..................................... 30 A

. Laboratory Studies



### ....................................................................................30 

### B



### . Calculations



### ............................................................................................ 1 C



### . Input Parameters



### ....................................................................................... 35



### ......... V



### . Risk



### ........................ : 

### ............................................................................ : 46 A

. Triscl,3.Dichloro. 2.Propyl) Phosphate (TDCP)



### ......................................46 B



### . Triphenyl Phosphate (TPP)



### .......................................................................46 C



### . Phenol Isopropylated Phosphate (PIP)



### ...................................................... 48 D

. Octyl ~etrabromobenzoate (OTB)



### .......................... ; 

### .................................48 E



### . Sensitivity Analysis



### ....................... ; 

### ........................................................... 48VI



### . Discussion



### ......................................... 

### ............................................................... 52



### .................................................................................. 

### .............. . A Toxicity i 52 B

. Exposure



### ................................................................................................ 55 C



### . Variabilityanduncertainty



### ................................. 

### ................................. 59



### . D Conclusions



### ........................................................................................... 60



### ........................................................................................................ VII

.. References -62

Tables

Figures 

### .......................................... Classification

.of Chronic Hazards under the FHSA 4



### ....................... Chronic Health Effects of selected Flame Retardant Chemicals 6 Incidence of Selected Histopathological Effects in Sprague-Dawley Rats



### ........................................................ Exposed to TDCP in Feed : 

### .........................9

........... Tumor Incidence in Sprague-DawleyRats Exposed to TDCP in Feed 10



### ................................................................................ General Input Parameters -36 Input Parameters for Estimating Dermal Exposure



### ......................................... 37



### ................................................................ Chemical-Specific Input Parameters 38 Fraction of Test Substance Transferred from Textile to Skin



### ..........................39 Input Parameters for Estimating Oral Exposure



### .............................................. 40 Input Parameters for Estimating Inhalation Exposure



### ..................................... 42 Physico-Chemical Properties



### ........................................................................... 43



### ........................................................................................... Exposure and Risk 47 Route-Specific Sensitivity Analysis



### ................................................................49 Sensitivity of Cancer Risk to Selected Parameters



### ..........................................50 Sensitivity Analysis of Oral Exposure to Children



### .......................................... 51 Effect of Vapor Pressure on TDCP Hazard Index and Cancer Risk



### ................58



### ................................................................................ . 1 Structures ofFR chemicals 3

. 

### ........................................ 2 Metabolism of tris(l,3.dichloro. 2.propyl)phosphate 7



### ............................................................... .. 3 Metabolism of o-tricresyl phosphate 13

................. 

### .................................................... . 4 Mock-up for exposure studies 

### : 1Summary The U.S. Consumer Product Safety Commission (CPSC) staff developed a draft performance

. standard to address the hazards associated with fires involving residential upholstered furniture. Manufacturers are likely to treat some products with flame retardant (FR) chemicals if the draft standard is adopted. The CPSC staff previously assessed the potential health risks associated with the use of FR chemicals inupholstered furniture cover fabrics. 

### In this report, the CPSC staffpresents a preliminary assessment of the potential health risks associated with the use of selected 

### FR chemicals in upholstered furniture foam. FR-treated foam samples that were available to the CPSC staff for testing included those with three different FR chemicals or mixtures that could be used to meet the draft standard: melamine (108-78-1); 

### tris(l,3-dichloro-2-propy1)phosphate(TDCP) (13674-87-8); and FiremasterTM 550 (FM-550TM). FM-550TM is a mixture containing triphenyl phosphate (TPP) (1145-86-6), phenol isopropylated phosphate (PIP) (68937-41-7), and octyl tetrabromobenzoate (OTB). Samples with the highest available TDCP or FM-550TM levels were included in the study. Numerous other FR treatments that couldbe used in foam have been discussed by the U.S. Environmental Protection Agency's (EPA' s) Design for the Environment Program.

Q The toxicity of FR chemicals was assessed according to the Federal Hazardous Substances Act (FHSA), the supplemental definition of "toxic," and the CPSC chronic hazard guidelines. Although melamine has been studied in chronic bioassays, it does not satisfy the FHSA definition of toxic. Thus, exposure studies with melamine-treated foam were not necessary. Based on the available data, melamine-treated foam would not present a hazard to consumers. TDCPis considered a probable human carcinogen, based on sufficient evidence in animal studies. TDCP also induces non-cancer chronic health effects in animals. Little toxicity information on FM-550TM and its components is available. However, the CPSC staff has previously reviewed the toxicity of two FM-550TMcomponents, TPP and PIP, as well as closely related compounds. No toxicity data were available for OTB. Mock-ups made with the foam samples were tested by the staff to assess the liquid-mediated migration of 

### FR chemicals. These data were used to estimate dermal and oral exposures. The mock-ups were also subjected to an accelerated wear procedure to measure the release of airborne particles containing FR chemical. Two foam samples containing TDCP and one containing FM-550TM were tested. Measurements of migration and particle release from FM-550TM-treated foam were based on the OTB component. The other components were not measured. Exposure to vapor phase chemicals that may be emitted from the foam was assessed using a mathematical model. Based on the CPSC staff's analysis, it appears that inhalation of vapor phase FR chemical contributes the greatest portion of the total exposure. However, a mathematical model was used to estimate inhalation exposure due to the lack of empirical data. Thus, the estimated inhalation exposure is highly uncertain. Toxicity studies by the inhalation route are also lacking. Therefore, the following conclusions are based on limited exposure and/or toxicity data, and should be regarded as preliminary.Most of the predicted exposureto TDCPis from the inhalation of TDCP, which was estimated from a mathematical model. Regarding non-cancer health effects, estimated TDCP exposures were above the acceptable daily intake (ADI). Thehazard index (HI) values were 2 for adults and 5 for children. When the estimated exposure exceeds that AD1 a substance may be considered "hazardous," as defined in the CPSC chronic hazard guidelines and FHSA regulations. 16CFR 1500.135 and 16CFR 1500.3 (c)(2). The estimated cancer risk for a lifetime of exposure to TDCP-treated upholstered furniture was 300 per million. In children, the estimated cancer risk from exposure during the first two years of life alone was 20 per million. Both of these risks exceed one-in-a-million. A substancemay be considered hazardous if the lifetime individual cancer risk exceeds one-in-a-million 

### (ibid.).However, empirical measurements of TDCPemissions, which were not available for this study, are needed to assess more definitively whether TDCP may present a hazard to consumers. Limited toxicity data are available for TPP and PIP. Thus, the range of AD1values for other aromatic phosphates or blends previously reviewed by the CPSC staff was used as a surrogate. Using these surrogate toxicity data,HI values for TPPwere estimated to be between 0.002 and 0.2 in adults and between 0.005 and 0.5 in children. TheHI'SforPIP were about 10-fold lower. 

### IfTPP and PIP are

### not more toxic than the other aromatic phosphates, then TPP and PIP arenot expected to pose any appreciable health risk to consumers. The staff will review any additional toxicity data on TPP and PIP that may become available. Additional toxicity data and measurements of TPP and PIP emissions are needed to assess more definitively whether these compounds may present a hazard to consumers. Measurements of the TPP and PIP components of FM-550TM are needed to reduce the uncertainty in estimating exposure. The CPSC staff has requested the National Toxicology Program to perform additional toxicity tests on aromatic phosphates. Insufficient toxicity data on OTB, another component of FM-550TM, or related compounds were available to assess whether OTB could present a hazard to consumers. Basic toxicity data, physico-chemical data, and additional exposure data are needed to assess whether OTB may be hazardous to consumers. In summary, the staff concludes that: Based on the available data, melamine-treated foam is not expected to present a hazard to consumers. Inhalation studies are lacking for TDCP, TPP, PIP, and OTB. This is significant because inhalation appears to contribute the greatest portion of the total exposure. Empirical data on vapor phase emissions or indoor concentrations are needed to assess whether TDCP, TPP, PIP, or OTB may present a hazard to consumers. Chemical-specific migration and release data are needed to assess more accurately whether TPP and PIP may present a hazard to consumers. <Additional toxicity data are needed to derive AD1 values for TPP and PIP. Basic toxicity and physico-chemical data for OTB are needed to derive an acceptable daily intake value and to estimate exposure.Abbreviations ADD Average daily dose AD1 Acceptable daily intake AFSC American Fire Safety Council APP Aromatic phosphate plasticizer AT Antimony trioxide BMD Benchmark dose CAR Constitutively active receptor CPSC U.S. Consumer Product Safety Commission DBDPO Decabromodiphenyl oxide DfE Design for the Environment (U.S. EPA) ED50 Median effective dose EHDP 2-Ethylhexyl diphenyl phosphate EPA Environmental Protection Agency (U.S.) FHSA Federal Hazardous Substances Act FM-550TM FiremasterTM 550 FR Flame retardant FRCA Fire Retardant Chemicals Association (currentlyAFSC) GD Gestational day HBCD Hexabromocyclododecane HI Hazard index Ic50 Concentration at 50% inhibition IDDP Isodecyl diphenyl phosphate PDP Isopropylphenyl diphenyl phosphate Kow Octanol-water partition coefficient LADD Lifetime average daily dose LD5o Median lethal dose LOAEL Lowest-observed-adverse-effect level MSDS Material safety data sheet NOAEL No-observed-adverse-effect level NRC National Research Council NTE Neurotoxic esterase NTP National Toxicology Program OPlDN Organophosphate induced delayed neurotoxicity OTB Octyl tetrabromobenzoate

. PA Phosphonic acid, (3-{ [hydroxymethyl]amino)-3-oxopropy1)-, dimethyl ester Penta-BDE Pentabromodiphenylether PIP Phenol isopropylated phosphate PUF Polyurethane foam PXR Pregnane X receptor 

### RfD Reference dose SCE Sister chromatid exchange SD Sprague-Dawley SNUR Significant new use ruleTCP TDCP THPC TPP TRIS UDS 

### UF VCCEP Abbreviations (continued) 

### ' Tricresyl phosphate 

### Tris(l,3-dichloro-2-propy1)phosphate 

### Tetrakis(hydroxymethy1)phosphonium chloride Triphenyl phosphate 

### Tris(2,3-dibromopropy1)phosphate Unscheduled 

### DNA synthesis Uncertainty factor Voluntary Children's Chemical Evaluation Program

### I. INTRODUCTION Upholstered furniture fires account for more fire deaths than any other category of products under thejurisdiction of the U.S. Consumer Product Safety Commission (CPSC). The staff estimates that an annual average of 4,800 fires, 360 deaths, 740 injuries, and $133million in property damage would be addressed if the draft standard is enacted (Levenson 2005). These fires are most commonly ignited by either smoldering sources, such as cigarettes, or open flame sources, such as cigarette lighters and candles. CPSC initiated a regulatory proceeding to address the hazard of small open flame ignitions of upholstered furniture (CPSC 2003). The CPSC staff has developed a draftperformance standard to address the hazards associated with both small open flame and cigarette ignitions. I While furniture manufacturers would be free to choosethe means of complyingwith the draft standard, it is likely that some products would be treated with flame retardant (FR) chemicalsif the draft standard were adopted. In addressingthe hazard associated with the flammabilityof upholstered furniture, the CPSC staff is working to develop a performance standard to reduce furniture fires without creating other hazards to consumers. Thus, the CPSC staff has been assessing the potential for health risks associated with the use of selectedFR chemicals in upholstered furniture. Thepurpose of this report is to assess the potential health risks associated with the use of selectedFR chemicals in upholstered furniture foam. A. 

### UpholsteredFurniture Cover Fabrics The first version of the draft flammability standard developedby the CPSC staff involved exposing the upholstered furniture cover fabric to a gas flame that was roughly equivalent to that of a cigarette lighter (CPSC 1997). As part of the risk assessment process for FR chemicals, the Commission held a public hearing in May 1998. In its testimony, the Fire Retardant Chemicals Association (FRCA) (currently the American Fire Safety Council,AFSC) reported that in many cases the furniture cover fabric would be treated with FR chemicalsif the draft standard were adopted (Parkes 1998). The FRCA alsoprovided a list of 16chemicals or chemical classesthat its members would market for use in upholstered furniture. The 16FR chemicals and classes included over 50 individual compounds. The CPSC staff reviewed all the available toxicity data on these chemicals and derived acceptable daily intake (ADI)levels where sufficient data were available (Babich et al. 2004; Babich and Saltzman 1999;Bittner 1999a-d;Bittner 2001; Bittner et al., 2001; Bittner and Ferrante, 1999;Ferrante 1999a-f;Hatlelid 1999a-h). Overall, a considerable number of toxicological studies were available for review. While some FR chemicals have been well studied, only limited data were available for others. The CPSC staff performed quantitative risk assessmentsfor five FR chemicals: antimony trioxide (AT) (CAS no. 1309-64-4);decabromodiphenyl oxide (DBDPO) (1163-19-5); hexabromocyclododecane(HBCD) (3194-55-6); phosphonic acid, (3-{[hydroxymethyl] amino)- 3-oxopropy1)-,dimethyl ester (PA) (20120-33-6); and tetrakis (hydroxymethyl) phosphonium chloride (THPC) (124-64-1) (Babich and Thomas 2001). TheseFR's were selected for study because they are used to complywith the U.K. upholstered furniture flammability standard(except THPC) and fabric samples were available for testing. The staff concludedthat DBDPO, HBCD, and PA would not present a hazard to consumers, and that additional data would be needed to assess AT and THPC. Prior to the completionof the CPSC staffrisk assessment,the National Research Council (NRC) performed a risk assessmentof 16FR chemicals that might be used in upholstered furniture cover fabrics (NRC 2000). The NRC subcommittee, which had minimal exposure data available to them, selected the most toxic chemical to represent each of the same 16 chemicals or classes describedby the FRCA. The NRC concluded that eight of these chemicals could be used withoutpresenting ahazard to consumers, including DBDPO, HBCD, PA, and THPC. They also concluded that additional exposureor toxicity data were needed for the remaining chemicals, including AT, 

### tris(l,3-dichloro-2-propyl) phosphate (TDCP), and aromaticphosphate plasticizers. Following the completionof the NRC report, the CPSC staff found that unidentified compounds were released from THPC-treated fabrics. Thus, the staff concluded that additional information on the identity and toxicity of the THPCby-products was needed. The CPSC staff is participatingin severalregulatory and voluntary programs of the U.S. Environmental Protection Agency (EPA) that involve the potentialhealth and environmental effects of 

### FR chemicals. EPA is developing a significantnew use rule (SNUR) for 

### FR chemicals that may be used in upholstered furniture. A SNUR requires manufacturers to notify EPA before engaging in activities subject to the SNUR. The SNUR process can be used to obtain additional toxicity or exposuredata if needed. TheEPA Design for the Environment (DfE)program is a cooperative effort with industry that is evaluating the potentialhealth risks of FR chemicalsthat may be used in polyurethane foam (PUF). The EPA Voluntary Children's Chemical Evaluation Program (VCCEP)is investigating children's exposure to penta- and octa-bromodiphenyl ether and DBDPO. 

### B. Upholstered Furniture Foam 

### In 2003, the Commission amended the rulemaking activity for upholstered furnitureto include smolderingignition sources, such as cigarettes,and the staff revised the draftperformance standard (CPSC 2003). Due to the changes in the draft flammability standard, fewer upholstery cover fabrics are likelyto be treated with 

### FR chemicalsif the standard is adopted. Rather,in many cases the flexiblePUF or other fillingmaterials may require FR treatment to meet the draft standard. I Until recently, mixtures containingpentabromodiphenyl ether (penta-BDE) and aromatic phosphate esters were the principal 

### FR chemicals for flexible PUF. However, the sole U.S. manufacturer of penta-BDE voluntarily ceased production in December 2004 due to concerns about environmental persistence and bioaccumulation. A number of alternativetreatments are available,including severalnew proprietary formulations (reviewed in EPA 2005a). FR treatments that may be used in upholstered furniturefoam include 

### tris(l,3-dichloro-2-propyl) phosphate (TDCP) (13674-87-8),melamine (108-78-I), and a proprietary formulationmarketed as FiremasterTM 550 (FM-550TM) (Figure 1). FM-550TM is a mixture containingtriphenyl phosphate (TPP) (1145-86-6),phenol isopropylated phosphate (PIP) (68937-41-7), and octyltetrabromobenzoate (mixture of isomers) (OTB) (CAS no. not available) (EPA 2005a).* ' Accordingto its material safety data sheet (MSDS) (Great Lakes 2005),FM-550TM contains
, 6-24% TPP, 24-51% PIP, and 40-60% OTB. Melaminemay be blended with otherFR7s, including TDCP. severalother alternative

### FR chemicals for use in PUF are mixtures that include various aromaticphosphates. This report will assess the potential chronichealth risks associated with the use of TDCP, FM-550TM, and melaminein upholstered furniture foam.

CI-H2C\ CH2-CI 

### c

/ I CI-H2C, 

# ? CH2-C I 

### c-,P-,< CI-H~C/ 0 II CH2-C I 

# me!-+

0
TDCP TPP 

# QXIy I**[-* 0 

# 1

2

PIP 

# Br4w,-o-c,H,,

NH2 OTB Melamine Figure 1. Structures of FR Chemicals



### C. Risk Assessment and the Federal Hazardous SubstancesAct CPSC addresses chemical hazards under the Federal Hazardous Substances Act (FHSA). The FHSA is risk-based. To be considered a "hazardous substance" under the FHSA, a substance or product must satisfy a two-part definition. 15USC 1261 (f)(l)(A). First, it must be "toxic" as defined underthe FHSA, or present one of the other hazards enumerated in the statute. Second, it must have the potential to cause "substantial illness or injury" during or as a result of

* Some of the abbreviationsused in the January 2006 draft of this report were changed to reflect new information that more specifically identifies certain chemicals. BAE (brominated aryl ester) was changed to OTB (octyl tetrabromobenzoate)and ITP (isopropylatedtriphenyl phosphate)was changed to PIP (phenol isopropylated phosphate)."reasonably foreseeable handling or use." Therefore, exposure and risk must be considered in addition to toxicity when assessing potential hazards under the FHSA (CPSC, 1992). .Thefirst step in the risk assessmentprocess is hazard identification, that is, to review the available toxicity data for each chemical under consideration and determine whether the chemical is "toxic" under the FHSA. Acute toxicity is defined by 

### LDS0 (median lethal dose) values in regulations issued under the FHSA. 16 CFR 1500.3 (c) (2) (i). However, reliable human experience data take precedence over animal data. 16CFR 1500.4. 

### In 1992,the Commission issued guidelines for assessing chronic hazards under the FHSA, including carcinogenicity, neurotoxicity, reproductive and developmental toxicity, exposure, bioavailability, risk assessment, and acceptable risk (CPSC, 1992; summarized at 16CFR 1500.135). A substance is considered "toxic" under the FHSA dueto chronic toxicity if it is either known to be, or probably, toxic in humans. 16 CFR 1500.3 (c)(2)(ii). Under the FHSA, a substance or mixture is classified as "knownto be toxic" in humans only if there is sufficient evidence in humans (Table 1). It is considered "probably toxic" if there is either limited evidencein humans or sufficient evidence in animals. Table 1. Classificationof Chronic Hazards under the FHSA

Satisfies the regulatory definition of "toxic."
If a substanceis "toxic" under the FHSA due to chronic toxicity, then a quantitative assessment of exposure and risk is performed to determine whether the chemical may be a "hazardous substance" under the FHSA. The quantitative risk assessment includes a consideration of dose response, bioavailability, and exposure. The acceptable daily intake (ADI) and/or cancer unit risk are derived from appropriate doseresponse information, and the exposure is estimated. If the estimated exposure exceeds the AD1 or if the estimated cancer risk is greaterthan one-in-a-million then the substance may be considered a "hazardous substance" (CPSC 1992). 16CFR 1500.3(c)(2)(ii).11. 

### HAZARD A. 

### Tris(l,3-Dichloro-2-Propy1)Phosphate (TDCP) The toxicity of 

### tris(l,3-dichloro-2-propy1)phosphate(TDCP) has been reviewed by the CPSC staff (Bittner et al. 2001; Ferrante 1999b;Ulsamer et al. 1980) and others (Brandwene 2001; EPA 2005a; IPCS 1998; NRC 2000). The toxicity of TDCP is summarized below (see Table 2). TDCPis a viscous liquid with molecular weight 430.9, log 

### KO, 3.8, vapor pressure 0.01 ton, and low water solubility (reviewed in IPCS 1998). Oral LDsovalues ranged from 2.36 to 3.16 g/kg in rats and from 2.25 to 4.99 mL/kg in mice (reviewed in Ferrante 1999b). The symptoms associatedwith acute exposureincluded ataxia, irritability, hyperactivity, tetanus, and convulsions, suggesting neurological effects. TDCP was not a sensitizer in guinea pigs. It was either a non-imtant or mild irritant in the skin and eyes of rabbits (Stauffer 198 1). 1. Genotoxicity TDCP was either inactive or weakly mutagenic in Salmonella strain TAlOO (Brusick et al. 1980; Gold et al. 1978; Nakamura et al. 1979;Prival et al. 1977; Soderlund et al. 1985; Stauffer 1981) and inactive in yeast (Stauffer 1981). Negative results that were reported in some studies (Brusick et al. 1980; Prival et al. 1977; Soderlund et al. 1985; Stauffer 1981) may be due to the method of metabolic activation (Brusick et al. 1980; Gold et al. 1978; Nakamura et al. 1979; Soderlund et al. 1985). The major urinary metabolite of TDCP, 

### bis(l,3-dichloro-2-propyl) phosphate, was not mutagenic (Gold et al. 1978). However, another metabolite, 1,3-dichloro-2- propanol, was reported to be weakly mutagenic. In addition, the putative metabolite 1,3- dichloro-2-propanone was a strong direct-acting mutagen. TDCP was less mutagenic than the structural analog tris(2,3-dibromopropyl) phosphate (TRIS) (Brusick et al. 1980;Nakamura et al. 1979). TDCP generally gave weak or negative results in mammalian systems. TDCP transformed Syrian hamster embryo cells (Soderlund et al. 1985),but not Balb 3T3 cells (Brusick et al. 1980; ~tauffer 1981), in vitro. TDCP was weakly active in several in vitro assays, including the induction of forward mutations (thymidine kinase), sister chromatid exchanges, and chromosomal aberrations. TDCP did not induce 6-thioguanine resistance in V79 cells, nor did it induce unscheduled DNA synthesis in rat hepatocytes, although TRIS was active at similar doses (Soderlund et al. 1985). TDCP failed to induce chromosomal aberrationsin mouse bone marrow cells in vivo (Brusick et al. 1980; Stauffer 1981). TDCP failed to induce unscheduled DNA synthesis in rat hepatocytes, following oral exposure at doses up to 2,000 mglkg (Cifone 2005), and did not induce micronuclei inmice (Thomas and Collier 1985). TDCP was reported tobind to DNA and proteins in mice exposed in vivo (Morales and Matthews 1980).Table 2. Chronic Health Effects of Selected Flame Retardant Chemicals a

a Adapted from Bittner et al. 2001. Chronic toxicity as defined by the FHSA and the CPSC chronic hazard guidelines: A, known to be toxic in humans; B, probably toxic in humans; C, possibly toxic in humans; I, insufficient data. . Chronic endpoint(s): C, cancer; D, developmental; N, neurotoxic; R, reproductive; 0,other (e.g., liver or other organ toxicity). 

## * ADI, acceptable daily intake; LOAEL, lowest-observed-adverse-effect level; NOAEL, no-observed-adverse-effect level; UF, uncertainty factor. L, LOAEL; ND, not determined; X, data available. Chronic Health Effects i 1 n j .! 

## ' a j b ! id !



## . j 0 j.w,; 

## .; 1 

# - a? i h c 

### .s ioenI a 1-7

,

en ! 

# 1.2% Y 

# / n% OiD 

## .- en! !<en c ! c 

## 125i iwi I E 

## e i w
J- 

### I 

## i.4 i ' "i .; 

# I i I i ! I

........ j

. .. i ! Chemical

Aromatic phosphate plasticizers (APP's):

.. .. . . Availability of Toxicity Data

. 2 , 

### I 

### I j i

I V) ) ! i i ! i i i I

.j i i ! i j I .- .............................. i > + ....-i...... +......-. " r"-".."-.."" .i...i............i.............i.....i...i.....i........-............
....................... Phenol isopropylated

. .-...................... phosphate

. .- (PIP) 

### xeIxj-j-IxI-!x -.... i L 1

.2 C : NO

.. j 

### I ND~ ! -. 4 ! -" Triphenyl phosphate (TPP) 

### x/x~-/x/xIx/x c 

## / 0,j i

s....... .. .-"

.... ......".........................".............-...........-......-~....~...I.-III"I."-~ . -.---,! .-.. +,."
... -.,,.; ,-...- .....-..... ..... ,,,"-" ........- ",-" .... *........-.... .... "!..... ............................. j..... -.............- .............. 1".-... ND 

### :xI-!-;xixix I 'I t-Butylphenyl diphenyl phosphate (BPDP) - i i

.............. .. . . ....... . ......... ........... ............ .... ................. .... ...... ....... i ND - - ._. .! ".i "i .-. ",,!,,," 1 

### 4 L" 2-Ethylhexyl diphenyl phosphate (EHDP) 

### x~xlxIxix~x/- B 

### I 0 1100 1100 i 1.0 - . .- .............. .......... . ................-... *.-.+ "..."! 4 "-",.",-,--,j ",-,",,."! .*-......-........ ..,,; .........-....-...- -..-......-...... "-,,+-"" .....-... .......--...- &
............. ..............-.- +..--.....- ...---.. ..... . .................... lsodecyl diphenyl phosphate (IDDP)

......... .................... .....-- ..... - " ......... Santicizer 141 (>go% EHDP)

. . .. 

### XIXI-:i - /XIXI- clo, j ! ND

. ..j.................. " ... i.".-jj.jjjjj-.-jjji." J . ,,.,,, ............. ","& ...........; 

### x' x'I-j x

# r-'x 1 i< I-

............... ............. ....... ........ .... ....... .............................. -.....-.. -- "- " .+ ! g !--" &. "-,,: Santicizer 148 (> 90% IDDP) 

### x x

## 1 -j 

### x

### 1 x1.x ] -

.. . i........... -.-......-.--.--I-. - 2.. .-.l".&." -i., i ..i......ii -.i iii.. .? Santicizer 154 (TPP 

### + BPDP) 

### xxf-;xjxIx!- i

........... -.--. .... .. . "- -"

. .. i ":jjjjjjj-jjjj-jjjj ~jjjj~i.iiiiii.~iiiiiiiiii~ii./................/~.......~.iiiiiiiii~.... ,v-,,,," .................... B 

### I 0 100
, 100 11.0.

................... ........ ......*.-..... 4..-.......-........ ",-"",,"; .....-.. "*" .......*.......... !..........-....-...............-.?-..-...... " B;oi i 1 0.01

. "2 iiii~iiiiii! j C ' N,O 

### I
..-. $" . .. "L . . ND o-Tricresyl phosphate (0-TCP) X,X~-IX!X;-,X

...... 

### AIN/

.. ..... ........ ....... .................. . ..................................... ..................... ............ 

### I I ND - - - 4- 4". iiiiiii... ..LL.L...LL..LLL.L.LLLLLLL.LL~iiii.i~iiii.iiiiii...iiii_j_j "-,i "4 Tricresyl ,phosphate (TCP) (isoiners) 

### X,X~X!XIX~X[X i i B R,N,O i 50

. L~ 1,000 

## 1 0.05

................... i ,-,--" ",,-;,".-" i Melamine (1,3,5-triazine-2,4,6-triamine) 

### x~xix~xi- 

## I X i - 

### c 

# , C. 

## I j 

### i"- i ND Octyl tetrabromobenzoate (OTB) Tris(l,3-chloropropyl-2) phosphate (TDCP) 

### x/ji-I-~-~ I 

### 1. -. 

### x,x.ix,xIx~x,- I i 1 

### ) ND ! B 

## I C 1 5 L 

# 1 1,000 

## 1 0.0052. Toxicokinetics Ninety percent of orally administered [l,3-14~]2-propyl-labeled TDCP was absorbed in rats (Matthews and Anderson 1979). The highest levels of TDCP were found in thekidney, liver, and lung (Matthews and Anderson 1979; Nomeir et al. 1981; Ulsamer et al. 1979, 1980). Eighty percent of TDCP was eliminated within 24 hours, primarily in the urine, in both rats and rabbits. From 9-to-15% was converted to C02. 

### Bis(l,3-dichlor-2-propyl) phosphate was the primary metabolitein urine. Other metabolites included 1,3-dichloro-2-propanol and 3-chloro-1,2- propanediol (Figure 2). TDCP is also directly conjugated by glutathione, probably through one of the ester groups. It has been suggested that TDCP may also be metabolized to 1,3-dichloro-2- propanone, by analogy to TRIS (Gold et al. 1978),but this has not been observed. In vitro studies suggest that TDCPis metabolized to the diester by an NADPH-dependent mixed function oxidase, as well as by glutathione conjugation (Nomeir et al. 198 1;Sasaki et al. 1984). A glutathione-conjugated metabolite was also identified.

Figure 2. Metabolismof tris(l,3-dichloro-2-propy1)phosphate. Structures: 1)tris(l,3- dichloro-2-propy1)phosphate (TDCP); 2) bis(l,3-dichlor-2-propyl) phosphate; 3) 1,3-dichloro-2- propanol; 4) glutathione conjugate of TDCP; 5) 3-chloro-l,2-propanediol; 6) putative metabolite 1,3-dichloro-2-propanone. Sources: Lynn et al. 1981; Nomeir et al. 1981; Gold et al. 1978.

TDCP was rapidly absorbed through the skin in both rats and rabbits (Nomeir et al. 1981; Ulsamer et al. 1979, 1980). TDCP was absorbed at double the rate of tris(2,3- dibromopropy1)phosphate (Ulsamer et al. 1979). When was applied to the clipped skin of New Zealand white rabbits, up to 15% of the applied dose was absorbed over 96 hours (Ulsamer et al. 1978a). Thus, TRIS was absorbed at a rate of 0.0016 h-'. Nomeir et al. (1981) showed that TDCPisrapidly absorbed in rats, although the absorption rate was not determined. Percutaneous absorption of 14c-TDcp was also studied in vim with hairless mouse skin (Hugheset al. 2001). After 24 hours, from 39-to-57% of applied TDCP was found in the receptor fluid. From 28-to-35% remained in the skin after the skin surface was washed with ethanol. From 73to 85% of applied TDCP was absorbedin 24 hours. Combiningthe amountsin the receptor fluid and skin, TDCP was absorbed at a rate up to 0.035 h-I (Babich and Thomas 2001). Five days following intravenous administrationof I4c-labeledTDCP in rats, 92% of the radiolabel was excreted (Lynn et al. 1981). Fifty-four percent of radiolabel was found in urine, 16% in feces, and 22% was expired as 14c02.The primary metabolite was bis(l,3-dichlor-2- propyl) phosphate, which accounted for 63% of the radiolabel. Other metabolites included 1,3-chloropropylphosphate and 

### 1,3-dichloro-2-propanol. Less than 0.1% of the radiolabel was recovered as TDCP. 3. Subchronic and chronic Studies Groups of 12male and 12female mice were fed up to 1.33% TDCP for 3 months (Kamata et al. 1989). All animals in the high-dose group died within one month. Liver weights were elevated in males at 0.13% and 0.42% and in females at 0.04%, 0.13%, and 0.42%. The overall study noobserved-adverse-effect level (NOAEL)was 0.01% (15 mgkg-d) in females. TDCP was studied in a 24-month dietary bioassay in Sprague-Dawley (SD) rats (Biodynamics ' 198 1;Freudenthal and Henrich 2000; Henrich 1998).* Animals were exposed to TDCPin feed at doses of 0,5,20,or 80mgkg-d in groups of 60 per dose and sex. Ten animals from each dose-sex group were sacrificed at 12months. Complete histopathologywas performed on all high-dose animals, but only on a small number of animals at the low- and mid-doses. Liver and kidney were examinedin all animals at all doses. Non-cancer effects observed at terminal sacrifice included convoluted tubule hyperplasia in males at all doses and in high-dose females (Table 3) (reviewed in NRC 2000). The incidence of parathyroid hyperplasia was significantly elevated in high-dose males only. Erythroidlmyeloid metaplasia of the spleen was significantly elevated in females at all doses; this is not considered a pre-neoplastic lesion. In addition, there were reproductive system lesions in males, including the seminal vesicles (atrophy and decreased secretory product, all doses), testes (periarteritis nodosa and eosinophilic material in the lumen, mid-and high doses), and epididymes (oligospennia and/or degenerated seminal product, mid- and high dose). Altered liver foci, which suggestthe presence of initiated cells, were elevated only in high-dose females. The NRC subcommittee considered the low dose (5mgkg-d) as a lowest observed adverse effect level (LOAEL) (NRC 2000). TDCP may be considered probably toxic to humans (see CPSC 1992), based on sufficient evidence of chronic toxicity (histopathologicaleffects at multiple organ sites) in animals.

* This studywas first described in an unpublished report (Biodynamics 1981),which is also referred to as the "Stauffer Chemical Co. report." The tumorigenic effects were later published in (Freudenthal and Henrich 2000). Henrich (1998)provided additional discussionof tumor incidences.Table 3. Incidence of Selected Histopathological Effects in Sprague-Dawley Rats Exposed t~ TDCP in Feed a

Sex Dose (mdka-dl 5

. 20 Liver, altered foci M Incidence 22/60 20160 16/60 31/60

F Incidence 16/60 23/60 18/55 36/60
Kidney, convoluted tubule Incidence

. 2/60 1 0160 29/60

. 24/59 hyperplasia P 0.015 4.3~1 

### om9 3.4x10-' F Incidence 0160 1/60 3/57 22/60

. - .................... .--.. ........................ P 0.50 0.1 1 1.4~1 

### o-~ Spleen, erythroidlmyeloid

. Incidence 1 3/60

. - 316 '416 1 7/58

. metaplasia 0.15 0.034 0.23

I. F Incidence 1 3/60 516 314 33/60
Parathyroid, hyperplasia M Incidence 1/29 111 012 12/38
- -...... ..... P 0:067 0.94 3.3~1 

### o-~

. .... -...- .. . .... ..... F Incidence 6/29 hlR 

### " NR 9128

....... . . . P 0.24 ' ~estes, eosinophilic M

........... Incidence --.

...... . .............. 2/57 4/60 12/60

. 11/56

. . material in the lumen P 0.36 5.5~10" 7.1XI 

### c3 Testes, periatteritis nodosa M lncidence 5/57 10160 1 9/60 16/56

M Incidence 1 1/55 9/33 7114 36/55 Ep/didymes,oligospermia P 0.30 0.030 1.2~1 

### u6 Epididymes, degenerated Incidence 8/55 ' 7/33 3114

................. 22/55

.......... seminal product P 0.30 0.39 2.4~1 

### o9 Seminal vesicle, M Incidence 1 I56 11/13 1 7/20 23/52
.- ........... . .. decreased secretory product P 4.2x10-'O 4.0~1 0-j3 2.5~1 0-a

...................... .............. .............. Seminal vesicle, atrophy M Incidence 0156 4113 6/20 10152

. ..................... ............. -, .- -

' P 8.3~1 

### o-~- 1.8~1 0" 4.1XIO"

a Data are from NRC 2000, Table 16-4. Includes only significantly elevated sites.

One-tailed Fisher's exact test performed by CPSC staff. Probabilities<0.05 are in bold. IVR, not reported; P, probability.1 Table 4. Tumor lncidence in S~raaue-Dawlev Rats Ex~osed to TDCP in Feeda Dose (mqlkq-dl Tumor
., Sex 0 5 20 80 Renal cortex tumor M Incidence 1/60 3/60 9/60 32/59

. ..--.- pb 0.309 8.3~10~1.1~10'" F Incidence 0160 1/60 8/57 29/60

. -
.....- .. . P 0.500

. 2.4~10" 2.0x10-" Testicular interstitial cell M Incidence 7/57

. .- . 8/60

. 26/60.-.-.-. 39/56

. adenoma P. 0.540 1.6~1 

### om4 2.5~10'~~ Hepatocelullar adenoma M Incidence' 2/60 7/60 1/60 16/60 -"

. . P 0.081 OA78 2.7~1 

### o4 F Incidence 1160 1/60 4/55 9/60

. .. . .- . -. . ......... ........... . P 0.752 0.156 8.3~1 

### om3 Hepatocellular carcinoma M Incidence 1/60 2/60 3/60 7/60

. . ..... . ...... . P 0.500 0.309 0.031

. . . ...................... F Incidence 0160 2/60 2/55 4/60

. . . . 

### -

. ...... P 0.248 0.227 0.059 M Incidence 3/60 9/60 4/60 23/60 Hepatocellular acknoma

............. .. . .- .. . . - .. ..................... .orcarcinoma P 0.220 0.500 5.7~1 

### o'~ F Incidence 1160 3/60 6/55 1 3/60

. . .. .... P 0.309 0.044 4.9~1 

### o4 Adrenal cortex adenoma M Incidence 5/59 3114. 5116 5/57

.......................... ..

.- P 0.421 0.031 0.607

. ........................ . ! F 5/27 2/33

. 20159

. . - P 0.740 0.040 0.109

aTumor data are from NRC 2000, Table 16-5.

one-tailed Fisher's exact test performed by CPSC staff. Probabilities (P) ~0.05 are in bold. Several neoplastic lesions were also reported (Biodynamics 1981; Freudenthal and Henrich 2000; Henrich 1998 and reviewed in EPA 2005a; Ferrante 1999b;NRC 2000). The incidence of renal cortical tumors was significantly elevated relative to the controls in mid- and high-dose males and females (Table4). Benign testicular interstitial cell tumors were also significantly elevated in mid- and high-dose males. Hepatocellular adenomas were significantly elevated at the high dose in both sexes, while hepatocellular carcinomas were significantly elevated in highdose males only. The incidence of hepatocellular adenoma %carcinoma was significantly elevated at the high dose in males and the mid- and high doses in females. Adenomas of theadrenal cortex were significantly elevated in mid-dose males (not at the high dose) and significantly reduced in mid-dose females. 4. Reproductive and Developmental Toxicity Groups of 10 male rabbits were given 0,2,20,or 200 mgkg-d TDCP by gavage for,12weeks *(Wilczynski et a1 1983; see also Brandwene 2001). No changes in mating behavior, fertility, or sperm quantity or quality were observed.. ~abbits' atthe high dose had elevated kidney and liver weights. No histopathological effects were observedin thepituitary, testes, epididymes, liver, or kidneys. Other tissue'swere not examined. Groups of 20 female rats were given 0,25, 100,or 400 mglkg-d TDCPby gavage on gestational

. days (GD's) 

### 6 through 15 (Stauffer 1981). At GD 19, high-dose fetuses exhibited reduced viability, weight, and length. The incidences of resorption and incomplete ossification were also increased at the high dose. No malformations were reported. Signs of maternal toxicity included increased mortality at the high dose and decreased body weight and food consumption at the mid- and high doses. 

### In another developmental screen, Kawashima et al. (1983) gavaged female rats at doses of 0,25, 50,200, or 400 mgkg-d on gestational days 

### 7 through 15. Fetal deaths were observed at the high dose, but no malformations occurred. There were signs of maternal toxicity at 200 and 400 mgkg-d, including decreased.bodyweight and food consumption. No malformations were observed in two developmental screening assays in rats (Kawashima 1983; Stauffer 1981; reviewed inFerrante 1999a;NRC 2000). Fetal effects such as reduced viability and body weight, along with signs of maternal toxicity, were observed at the doses of 200 mgkg-d or greaterin both studies. The highest NOAEL in the developmental studies was 100mgkg-d. No effects on male fertility were observedin rabbits exposed to doses up to 200 mgkg-d for 12weeks (Wilczynski et a1 1983). This is somewhat in contrast to the observation of histopathological effects in the testes at 

### 5 mgtkg-d in the two-year bioassay in rats (Biodynamics 1981). However, the lesions in the chronic study did not appear until after the 12- month interim sacrifice. 5. Neurotoxici ty The neurotoxicity of TDCP was studied in hens. No signs of neurotoxicity or paralysis were reported at 420 mgkg-d (by gavage) for 5 days (Stauffer 1981). TDCP was a weak inhibitor of brain neurotoxic esterase in hens given 10,000mglkg-d. Oral TDCP at 4,800 mgkg was fatal in chickens, although lower doses (unspecified) resulted in leg and wing weakness (Celanese 1960). It does not appear that TDCP is capable of inducing organophosphate-induced delayed neurotoxicity (OPIDN) inhens (see below). Exposure of rats to TDCP at high doses lead to clinical signs suggestive of neurotoxicity, such as hyperactivity and convulsions (see above).6. Toxicity under the FHSA TDCPis acutely toxic, as defined in FHSA regulations, although it is not considered "highly" toxic.* That is, the rat LD50is less than or equal to 5,000 mgkg, but greater than 50 mgkg. TDCP exposure led to histopathological effects in rats exposed forup totwo years (Biodynamics 1981). Organ sites affected include the liver, kidney, spleen, parathyroid, and male reproductive organs. Thus, TDCP may be considered probably toxic in humans, based on sufficient evidence of chronic toxicity in animals. TDCP exposure also induced tumors at multiple doses inthe kidneys and liver of both male and female rats. Therefore, TDCP may be considered a probable human carcinogen based on sufficient evidence in animals (Ferrante 1999b;Bittner et al. 2001). This conclusion is further supportedby structural similarity to another animal carcinogen, TRIS. TDCP and its metabolites were genotoxic in some assays, although the majority of tests were negative. Based on the available data, the CPSC staff concludes that there is inadequate evidence of reproductive toxicity and or developmental toxicity in animals (CPSC 1992). In addition, there is inadequate evidence of neurotoxicity in animals. 

### B. Aromatic Phosphate Plasticizers (APP's) The toxicity of various aromatic phosphate plasticizers (APP's) has been reviewed by the CPSC staff (Bittner 2001; Bittner et al. 2001; Ferrante 1999a)and others (EPA 2005a; IPCS 1990, 1991; NRC 2000). The toxicity of the APP's varies among individual compounds and commercial mixtures. Much of the available toxicity data are for commercial mixtures containing two or more APP's. The toxicity data for the APP's are summarized below. In general, the acutetoxicity of APP's is low, with oral LD50values in rats ranging from 3,000 mgkgto >20,000 mgkg (Ferrante 1999a). Tricresyl phosphate (TCP) (mixture of isomers) (1330-78-5) and o-tricresyl phosphate (0-TCP) (78-30-8) are the most toxic with regard to acute toxicity. APP's are weakly irritating or non-irritating in the skin and eyes of rats orrabbits. The APP's were generally non-genotoxic in Salmonella and in mammalian systems. 1. Toxicokinetics TCP (mixed isomers) (NTP 1994) and o-TCP (Somkuti and Abou-Donia 1990) were readily absorbed following oral exposure in rats. The highest levels of radiolabel were found in adipose tissue, muscle, erythrocytes, and liver in rats given [14c]-o-~c~ (Sornkuti and Abou-Donia 1990). However, the highest level of the neurotoxic metabolite, saligenin cyclic o-tolyl phosphate, was found in the testes. Percutaneous absorption of o-TCP in cats was biphasic. Initially, 73% of o-TCP applied to skin was absorbedin 12hours, while the remainder was absorbed at a constant rate of 0.34 d-' (Nomeir and Abou-Donia, 1984). Initially, unmetabolized o-TCPwas found primarily in thebrain, spinal cord, and sciatic nerve in cats. Metabolites were found primarily in the liver, lung, and kidney. In contrast to TCP, 2-ethyhexyldiphenyl

* 16CFR 1500.3 [c)(l).phosphate (EHDP) was reported to be poorly absorbed from the intestinal tract in humans and Wistar rats (reviewed in Ferrante 1999a;IPCS 1990). o-TCPis metabolized by three pathways (Abou-Donia et al. 1990;Casida et al. 1961;Eto et a1 1962;PCS 1990; Nomeir and Abou-Donia 1984, 1986; Somkuti and Abou-Donia 1990). First, one or more methyl groups are hydroxylatedby 'mixed function oxidase. The resulting hydroxylated compound then undergoes a cyclization reaction to form saligenin cyclic o-tolyl phosphate, and releasing o-cresol (Figure 3). Second, o-TCPis hydrolyzed to the diester, monoester, and inorganic phosphate, which also releases o-cresol. Third, hydroxymethyl groups may be further oxidized to the aldehyde and carboxylic acid. The meta and para isomers of TCP are also hydroxylated (Kurebayashi et al. 1985; Johnson 1975). 

### In rats, o-TCPmetabolites are excreted mainly in urine, while the meta isomer metabolites are mainly excreted in feces, and the para isomer divided between urine and feces (Kurebayashiet al. 1985; NTP 1994). TPP was hydrolyzedto the diester by mixed function oxidase and aryl esterase in rat liver microsomes (Sasaki et al. 1984).

PII 0

# &13 - 0

# {-b), 2 + H-5 

### 3 

# '\ 

# d%{&)

2 7 

## -C; 

# (&) \ 

### / 4b O 

# I 2 

### 4a 

# 1 / \ 

# &:r{-b)2 5 0 

# %:&

0 

### \ 

### / 

## + H&



### 6 

### 3 HO,

2
Figure 3. Metabolism of etricresyl phosphate. Structures: 1) tricresyl phosphate (TCP); 2) dicresyl phosphate; 3) cresol; 4a,b) hydroxymethyl intermediate; 5) aldehyde; 6) saligenin cyclic o-tolyl phosphate; 7) carboxylic acid. Adapted from Somkuti and Abou-Donia (1990).2. Subchronic and Chronic Studies TCP was tested in two-year gavage bioassays in B6C3F1mice and F-344 rats (NTP 1994). There was "no evidence of carcinogenic activity" in mice or rats. Non-neoplastic effects were found in female rats at 300 ppm (15 mgkg-d), including cytoplasmic vacuolization of the adrenal cortex and ovarian interstitial cells hyperplasia. The NOAEL was 150ppm (7 mgkg-d) in female rats. The incidences of clear cell foci, fatty change, and ceroid pigmentation of the liver were significantly increased in male mice at 125or 250 ppm (13 or 27 mgkg-d). 

### In addition, increased incidence and severity of ceroid pigmentation of the adrenal cortex occurred in female mice at 250 ppm (37 mgkg-d). The NOAEL was 60ppm (7 mgkg-d) in male mice. SDrats exposed to EHDP in feed for 90 days had enlarged livers and adrenal glands (Solutia 1998). astopathological effects were observedin.the adrenal cortex in both sexes and ovarian hyperplasiain females. The overall LOAEL was 0.2% (about 164mgkg-d). A NOAEL was not established. EHDP was also tested in a two-year bioassay in Carworth albino rats (Treon et al. 1953). Rats were given 0,0.0625,0.125, or 1.O% EHDP in feed. There was no evidence of carcinogenicity, but there was a decreased growth rate at 1%in feed. No significant increases in gross or microscopic histopathological effects were found. No effects in the adrenal cortex or ovaries were reported. However, the histopathological methods and the organs examined were not described in detail. The NOAEL was 0.125% or approximately 100mglkg-d (Ferrante 1999a).. 3. Reproductive and Developmental Toxicity Oral TCPexposure led to infertility and reduced fertilityin mice (Chapin et al. 1988;NTP 1985) and rats (Carlton et al. 1987). The fertility of both male and female mice was affected (NTP 1994). Reduced sperm concentration and motility, as well as increased incidence of abnormal morphology, was reported in rats (Carlton et al. 1987)and mice (Chapin et al. 1988; NTP 1985). Histopathological effects in the testes, epididymes,and ovaries were also observed (Carlton et al. 1987). The LOAEL for reproductive effects was 62.5 mglkg-d (the lowest dose tested) in a continuous breeding study in male CD-1 mice (Chapin et al. 1988; NTP 1985). Oral exposureto o-TCP lead to effects on sperm motility and morphology, as well as testicular effects, in F-344 rats (Somkuti et al. 1987a,b, 1991). The authors considered 25 mglkg-d as the NOAEL and 10mglkg-d as the NOAEL. The teratogenicity of o-TCP was tested in Long Evans rats at doses of 0, 87.5, 175, and 350 mgkg-d (Tocco et al. 1987). Dams were treated on GD's 6 through 18. The high dose was lethal to the dams. Malformations and variations at the low- and mid-doseswere not significantly different from the controls. Mele and Jensh (1977) gave doses of 0,500,or 750 mgkg-d o-TCP to pregnant Wistar rats on GD's 18and 19. The authors reported that there were no malformations or skeletal variations. No other details are available. A mixture of two commercial products containing EHDP was tested in a.one-generation studyin SDrats (Monsanto 1993; Robinson et al. 1986). Groups of 16male and 32 female rats were fed 0,0.2%, 0.4%, or 0.8% DEHP. Males received EHDP continuously from 70 days prior to mating through the end of the study, while females received EHDP from 21 days prior to mating through the end of the study. Initially, treatment-related reductions in food and water

105consumption were observed in mid- and high-dose males and high dosefemales.. This was attributed to the unpalatability of EHDP. Reduced 'food and water consumption persisted in high-dose females throughout the study.' There were no adverse effects on fertility in either sex. Liver weights were increased in a dosedependent manner in parental (Fo)males and females. Relative increases in adrenal, caecal, and kidney weights were observed in high-dose males and females. In addition, spleen weights were reduced in mid- and high-dose females, while hypertrophy and luteinization of ovarian stromal cells occurred at thehigh dose. Centrilobular and periportal hypertrophy was found in the liver in high-dose males and females. Body weight gain was significantly reduced in mid- and high-dose pups (F1). Pup survival was reduced at thehigh dose. The authors attributed these effects to thenutritional status of the dams. In mid- and high-dose pups, liver and adrenal weights were significantly increased, while spleen weights were reduced. The reproductive NOAEL considered to be 0.2% EHDP, or roughly 144mgkg-d. In a teratology screening study, female CDrats were given 0, 300, 1000,or 3000 mgkg-d SanticizerTM 141(>go% EHDP) orally on GD's 6 through 15(Robinson et al. 1986; Solutia 1998). Maternal effects included increased hair loss and yellow staining or matting in the midand high-dose groups. Maternal weight was reduced at thehigh dose, and some animals had inguinal fissures. The incidences of skeletal variations were increased at all doses. Malformations-such as eye anomalies, scoliosis, and dwarfism-were found at the mid- and high doses. The authors considered theincidences of variations and malformations to benot treatment-related, because they were within the range of historical controls. In developmental assays in rats, reported fetal effects included increased frequency soft tissue variations with TPP (seebelow) (Welsch et al. 1987). 4. Neurotoxicity TheAPP's are known primarily for their neurotoxicity. An estimated 50,000 cases of accidental ingestion of o-TCP occurred in the 1930's inthe southern U.S. when "Ginger Jake," an alcoholic extract of Jamaican ginger popular during prohibition, was adulterated with o-TCP(reviewed in Ferrante 1999a;PCS 1990;Weiner and Jortner 1999). Ingestion of mixtures containing o-TCP have resulted in neuropathy, paralysis, axonal degeneration, andlor death. Most patients recovered over a period of up to two years, although someremained permanently paralyzed. Other ingestions have occurred in an occupational setting. Sensitivity among humans is quite variable. Paralysis may occur with doses as low as 2 mgkg, and 1,000mgkgmay be fatal (Ferrante 1999a). APP's induce a delayed neurotoxicity in animals and humans characterized by ataxia, flaccid paralysis, axonal degeneration, and demyelination, referred to as organophosphate-induced delayed neurotoxicity (OPIDN) (reviewed in Weiner and Jortner 1999). The syndrome associated with the APP's is distinct from the effects associated with anticholinergic nerve agents. Humans and other primates, canines, felines, ruminants, and hens are sensitivetoOPIDN, while laboratory rodents are less sensitive. Hens are considered thebest animal model for OPIDN in humans, and have been used extensively in laboratory studies (e.g.,Johannsen et al. 1977;Johnson 1975; Weiner and Jortner 1999). The domestichen is susceptible, exhibits clearly detectable clinical signs, and the time course for developing neuropathy is similarto that in humans (Weiner and Jortner 1999). o-TCP is the most neurotoxic APP in animals and is a known neurotoxicant in humans (Ferrante 1999a;NRC 2000). APP's inhibit a variety of esterases, including plasma pseudocholinesterase, erythrocyte cholinesterase, non-specific carboxylesterase, acetylcholinesterase, and neurotoxic esterase (NTE). The severity of OPIDN symptoms generally correlate with the inhibition of NTE, which is a smooth endoplasmic reticulum-bound carboxylesterase found especiallyin nervous tissue (e.g., Dollahite and Pierce 1969;Johnson 1974; NTP 1994; Weiner and Jortner 1999). Neurotoxicity appears to require irreversible inhibition of NTE, through the formation of a stable, covalently-bound intermediate (Johnson 1974, 1975). Non-toxic APP's are reversible NTE inhibitors, and may protect against neurotoxicAPP' s. Extensive studies of structure activity relationshipshave been performed (Johannsen et al. 1977; Johnson 1975). APP's having one or more alkyl groups at the ortho position are neurotoxic, provided that there is at least onehydrogen at the a-alkyl position to allow formation of the cyclic metabolite. Thus, the t-butyl group is inactive. Neurotoxicity is greater in isomers having only one ortho substituent. Increasing chain size andbranching of the ortho substituent tends to reduce neurotoxicity. Para-substituted APP's are neurotoxic provided that there are .atleast two a-hydrogens. Meta-substituted and unsubstituted APP's (i.e., TPP) arenot neurotoxic. Thus, the relative toxicity of the APP's is as follows: TPP 

### <butylphenyl phosphate <isopropylphenyl phosphate 

### <trixylenyl phosphate 

### <TCP 

### < o-TCP (Weiner and Jortner 1999). Using a multiple dose regimen,the dose causing a 50% incidence of neurotoxicityin hens (EDs0)was estimatedto be 420 mgkgfor o-TCP and 10,000mgkg for isopropylphenyl diphenyl phosphate (IPDP) (Johannsenet al. 1977). 5. Toxicity under the FHSA Previously,the CPSC staff concluded that o-TCPis known to be neurotoxic in humans (Bittner 2001; Ferrante 1999a). The staff also concludedthat TCP (mixed isomers) is probably toxic, based on sufficient evidence of neurotoxicity, chronic organ toxicity, and reproductive toxicity in animals;.2-ethylhexyldiphenylphosphate (EHDP)is probably toxic, based on sufficient evidence of chronic organ toxicity in animals; and isodecyl diphenylphosphate (IDDP) is possibly toxic, based on limited evidence of chronic organ toxicity in animals (Table 2). TPP and PIP are discussed below. C. Triphenyl Phosphate (TPP) The toxicity data for TPP have been reviewed by the CPSC staff (Bittner et al. 2001; Ferrante 1999b) and others (EPA 2005a; PCS 1991). The range of studies on TPP was limited. Oral LDS0 values were reported to range from 1,320mglkg to >5,000 in mice; 3,000 mgkg in rabbits; and from 3,000 mgkgto >20,000 mglkg in rats (reviewedin Ferrante 1999a;PCS 1991). A 70% solution of TPPin alcohol was not irritating to mouse skin (Sutton et al. 1960). No otherdata on skin or eye irritation were reported, although other APP's were either non-irritating or weakly irritating to rabbit skin and eyes. Several cases of contact dermatitis from products contajning TPP or related compounds have been reported (Camarasa and Serra-Baldrich 1992;Carlsen et al. 1986;Hjorth 1964;Holden et al. 2006). TPPis used as a plasticizer inplastics and cellulose acetate. Theproducts involved included eyeglass frames, an oxygen mask, an adhesive, and cellulose acetate. Patients reacted to TPP in patch testing, at levels from 0.05% to 0.5% in petrolatum. Thus, TPP is capable of eliciting an allergic response in humans by dermal exposure. Cross-reactivitywith other triaryl phosphates and triaryl phosphites is likely to occur. 1. Genotoxicity TPP was not mutagenic in Salmonella (TA 1535,TA 1537,TA 1-538, TA 98, and TA loo), Saccharomyces cerevisiae (D4 strain), orL5178Y mouse lymphoma cells (thyrnidine kinase locus) (reviewed in Ferrante 1999a;PCS 1991). Studies were doneboth with and without metabolic activation. 2. Toxicokinetics No data are available on the metabolism of TPPin animals or humans. TPP was reportedtobe hydrolyzed to the diester by rat liver rnicrosomes (Sasaki et al. 1984). Because TPP lacks alkyl substituents,it cannot be oxidized to the neurotoxic metabolite, as occurs with other APP7s (Johannsen et al. 1977; Johnson 1975). Thepercutaneous absorption of formulations containing TPP through human epidermis was reported (Scott and Thompson 1985). Neat ReofosTM 50or ReolubeTM 46 were applied as an "infinite dose" to the epidermal side of cadaver epidermis placed on a static diffusion cell. The receptor fluid was 70% ethanol. The authors calculated a diffusion constant of 1.6x10-~ crdh for TPP. However, the experimental design was unusual in that the other components of the formulation were not identified and the receptor fluid was essentially non-aqueous. Theuse of a static cell could lead to an underestimate of absorption. Therefore, the usefulness of this study for estimating human risk was considered questionable (EPA 1985). 3. Subchronic and Chronic Studies TPPhas been subjected to several repeated-dose oral studies in animals. However, no subchronic or chronic studies with full pathology have been reported. 

### In one study, groups of 5 male Holtzman rats were exposed to 0,0.01%, or 0.5% TPP in feed for 35 days (Sutton et al. 1960). Relative liver weights were significantly elevated at 0.5% TPP; absoluteorgan weights were not reported. Body weights of exposed animals were slightly reduced, but this effects was reversible during the two-week recovery period. Hematology tests were normal and no gross abnormalities observed. Detailed histopathology results were not provided. 

### In a study ofneuromotor function, groups of 10male SD rats were given 0,0.25%, 0.5%, 0.75%, or 1%TPP in feed for 4 months (Sobotka et a1 1986). The resulting dose levels were 0, 161,345, 517, and 711mgkg-d. Behavioral tests were performed monthly. No significant effects on behavior were observed. There was a significant, dose-dependent reduction in weight gain. The NOAEL forreduced weight gain was 0.25% (161mgkg-d). 

### In an immunotoxicity study from the samelaboratory, groups of 10male and 10female SDrats were given TPP at 0, 0.25%, 0.5%, 0.75%, or 1%in feed for 4 months (Hinton et al. 1987). At 60 days, 3 rats from each sexldose group were sacrificed. Beginning at 60 days, 5 rats from each doselsex group were immunized with sheepred blood cells. Immunized and non-immunized TPP-exposed males generally gained weight at a reduced rate, but the differences were statistically significant only for some combinations of dose and time. TPP-exposed animals generally consumed slightly more food than controls. Body weights and food consumption were generally similarin immunized and non-immunized animals. Relativeweights of the thymus and spleen were generally unaffected by 

### TIT exposure or immunization. No significant effects on thymus and spleen histopathology or antibody titers were observed. There was a small, nonsignificant increase in total serum protein in TPP-exposed animals. 

### TPP gave negative results in the strain A mouse assay for pulmonary carcinogens (Theiss et al. 1977). Groups of 20 male strain A mice were given upto 18intraperitoneal injections of 0, 20, 40, or 80 mgkgTPP. All mice were sacrificed at 24 weeks following the first injection. TPP did not significantly increase the incidence of pulmonary adenoma in treated mice. Workers exposed to a weighted average concentration of 3.5 mg/m3

### TPP (range 1.8 to 12mg/m3 for different operations) showed no neurological symptoms, dermatitis or other unusual symptom.^ (Sutton et al. 1960). Erythrocyte esterase activity was significantly reduced (8% lower than controls), but plasma esterase activity was not affected. The duration of exposure was not reported. Potential dermal and oral exposures were not assessed.

. , 4. Reproductive and Developmental Toxicity

, . One study of the potential reproductive and developmental effects of TPPhas been reported. Groups of 40 male and 40female SDrats were fed TPP at levels of 0, 0.25%, 0.5%, 0.75%, or 1% for 9 1 days prior to breeding (Welsh et al. 1987). Theresulting dose levels were 0, 166, 341, 5 16, and 690 mgkg-d. The dams were sacrificed on GD20. Dams exposed to TPP consumed more feed than controls. There was a dose-dependent decrease in dam body weights, although it was statistically significant only at thehigh dose. No effects on reproduction were observed. TPP-exposed male pups weighed significantly more than controls at 0.5% and 1 %. The incidences of hydroureter and enlarged ureters (both moderate to severe) were significantly increased in all TPP-exposed groups, although there was no clear'dose-response. Thenumber of fetuses with two or more soft tissue variations was significantly elevated in all TPP-exposed groups, exceptthehigh dose, which was non-significantly elevated. Thenumber of litters with fetuses having at least two soft tissue variations was significantly elevated at 0.5% and 1%. A clear doseresponse was not observed for any of the reported effects. The numbers of fetuses or litters with one or more soft tissue variations were not significantly elevated. The authors concluded that there was evidence of maternal toxicity at the high dose (decreased weight gain), and that the observed increases in soft tissue variations were not dose-dependent. The CPSCstaff concludes that it is uncertain whether the increased in soft tissue variations is biologically significant. 5. Neurotoxicity 

### In an early study, TPP was reported to cause delayed paralysis with demyelination in cats and monkeys, but not chickens or rabbits (Smith et al. 1932). Subsequently, practical grade TPP was reported to cause a delayed paralysis suggestiveof OPIDN in cats at 200 to 400 mgkg (Sutton et al. 1960). No effects were found in rats, mice, or guinea pigs. However, in studies with purified, syntheticTPP, no evidence of neurotoxicity or neuropathology was observed in cats given from 400 mgkgto 1,000mglkg 

### TPP subcutaneously (Wills et al. 1979). Other toxic effectsanorexia, weight loss, and generalized vascular damage, perivascular edema, and fatty changesin the liver-were observed at all doses, except controls. The authors suggested that the earlier study (Smith et 

### al. 1932) used TPP derived from coal tar, and probably contained neurotoxic impurities. TPP caused a dose-dependent inhibition of whole blood cholinesterase in mice exposed either orally or intraperitoneally at doses from 10to 500 mglkg-d (Sutton et al. 1960). No evidence of neurotoxicitywas observed. 

### In mice exposedby inhalation (757 mg/m3 TPP for up to 4 hours or 363 mg/m3for 6 hours), there was a small, non-significant decrease in whole blood cholinesterase activity. TPP inhibited human plasma and erythrocyte cholinesterase activity in vitro, TPP did not induce delayed neurotoxicity (OPIDN) in numerous studies in hens (reviewed in Johannsen et al. 1977; Johnson 1975;Weiner and Jortner ,1999).

# cannot be metabolized to 

### a neurotoxic intermediate due to the absenceof alkyl substituents. No neuromotor effects were observed in SDrats fed TPP for 4 months at doses up to 711 mgkg-d (Sobotka et al. 1986) (see above). Measures of neuromotor function included motility, exploratory behavior, balance, coordinated motor activity, and grip strength. TPP inhibited the development of neurite-like outgrowths in mouse neuroblastoma and rat glioma cells in vitro (Henschler et al. 1992). .WithTPP, 50% inhibition was observed at concentrations (IC50'S)from 1.5x10-~ to 7.7x10-~ M. TPP was roughly as effective as o-TCP, which had ICsovalues from 3.1~10'~ to 3.8x10-~ M. The authors concluded that TPP may have "very slight" neurotoxic potential. No neurological symptoms were observedin workers exposed to a weighted average concentrationof 3.5 mg/m3 TPP (range 1.8to 12mg/m3 for different operations) (Sutton et al. 1960) (see above). Erythrocyte esterase activity was significantly reduced (8% lower than controls),but plasma esterase activity was not affected. Several cases of accidental ingestions or occupational exposures to TPP have been reported (reviewed in Ferrante 1999a;IPCS 1991). However, all of these were mixtures containing other neurotoxic compounds. Therefore, the significanceof these reports is unknown.6. Other Studies Micromolar levels of TPP and some isopropylated triphosphates activated (or derepressed) human constitutively active receptor (CAR) and pregnane X receptor (PXR) in vitro (Honkakoskiet al. 2004). Variable results were obtained with mouse receptors. CAR and PXR are ligand activated transcription factors that are part of the superfamilyof nuclear receptors. CAR and PXR induce genes that are involved in steroid metabolism, as well as numerous other unidentified genes. 7. Toxicity under the FHSA The database for TPP toxicity is limited. No chronic studies of any kind and no subchronic studies with complete histopathology have been reported. The range of reported 

### LDsovalues is broad. Reported 

### LDsovalues in rats ranged from 3,000 mgkg to >20,000 mgkd (reviewed in Ferrante 1999a;IPCS 1991). While some 

### LDS0 values were below 5,000 mglkg, the majority were greater than 5,000mgkg. The lower (more toxic) values could be due to the presence of impurities in some preparations. Considering all of the data,the CPSC staff concludes that there is limited evidence of acute toxicity in animals. Therefore,TPP is not considered acutely toxic, as definedby the FHSA.* In addition, the staff concludes that there is limited evidence of chronic toxicity in animals,based on decreased body weight gain in a 90-day neurotoxicity study in male rats (Sobotka et al. 1986). Additional data are needed to assess the chronic toxicity of TPP. The staff further concludes that there is inadequate evidence of developmental toxicity in animals,based on increased incidence of soft tissue variations in one study (Welsh et al. 1987). In the same study, there was inadequate evidence of reproductive effects. Finally, the staff concludes that there is, at most, limited evidence of neurotoxicity in animals. TPP was neurotoxic in some studies in cats, although it was not neurotoxic in hens or mice (reviewedin Johannsen et al. 1977; Johnson 1975; Weiner and Jortner 1999). The positive studies may have been due to the presence of impurities. Alternatively, TPP may simply be a very weak neurotoxicant. Thus, there is inadequate evidence of neurotoxicity in animals. Overall,T~P may be considered "possibly toxic in humans" based on limited evidence of toxicity in animals, that is, reduced weight gain in a 90-day feeding study (Sobotka et al. 1986; reviewed in Bittner et al. 2001; Ferrante 1999a). The finding that TPP is "possibly" toxic is not sufficientto satisfy the regulatory definition of "toxic" (CPSC 1992). However, this conclusion is based on limited data. It does not mean that TPP is not toxic. Rather, it means that additional information is needed to assess its toxicity and derive an ADI.

* 16 CFR 1500.3 (c)(l).

### D. Phenol Isopropylated Phosphate (PIP) The toxicity of PIPhas been reviewed by the CPSC staff (Bittner et al. 2001; Ferrante 1999a) and others @PA 2005a; Henrich 2001). Briefly, PIP is typically a complex mixture of PIP isomers and TPP, and may be blended with other aromatic phosphates. PIP i's generally prepared by alkylation of phenol prior to reaction with phosphorus oxychloride (POC13). Commercial products differ in their degree of alkylation, which determines the viscosity of the mixture. PIP is sold under a variety of trade names, including KronitexTM, and DuradTM, 0s-70TM, and ReofosTM. Various commercial products and isomers have been assigned different Chemical Abstracts Service numbers.' The toxicity of PIP, including various commercialproducts and specific isomers, is summarized below. 1. Acute Toxicity PIP and formulations containing PIP are not acutely toxic (reviewedin EPA 2005a; Ferrante 1999a;Henrich 2001). The oral LDSo in various strains of rat is greater than 5,000 mgkg (FMC 1969; FMC 1979; Freeman 1990; Stauffer 1979). The minimum lethal oral dose of 0s-70TM was from 3.2-to-4.7 mLkgin rats (Ferrante 1999a). Observations included respiratory distress and CNS effecrts. Rabbits dying after oral or dermal exposure to 0s-70TM had degenerative liver and kidney changes, and acute hyperemia in the viscera (Ferrante 1999a). The dermal LDSo was >2,000 mgkg in SD rats (Freeman 1990;Henrich 2001). The minimum lethal dose of Durad-1 10TM was from 1.6-to-2.5mLkg by the dermal route (Ferrante 1998a). The 1-hour inhalation LCSo was 

### >200 mg/L in SDrats (Ferrante 1999a;Freeman 1990;Henrich 2001). The oral LDSoYs of KronitexTM K-50, K-100, K-200, K-200B, and K-300 in albino Wistar rats were all >20,000 mgkg (FMC 1979). Clinical signs of toxicity generally included visceral hemorrhage and hematuria. These products are PIP formulations with increasing degrees of isopropylation. No mortalities occurred in rats administeredup to 40,000 mgkg of K-300. However, clinical signs of toxicity included alternating hypoactivity and hyperactivity, increased salivation, piloerection, diarrhea, excessive urination, and wet, oily coat. The dermal LDSo values of these compounds in rabbits were all >10,000 mgkg. Their inhalation LC50'sin rats were all less than 200 mg/L. 2. Dermal and Ocular Effects PIP was non-irritating to moderately irritating to rabbit skin and either non-irritating or slightly irritatingin the rabbit eye (FMC 1979; Ferrante 1999a;Freeman 1990;Henrich 2001; Stauffer 1979). KronitexTM K-100 was mildly irritating to skin and non-irritatingto eye in rabbits (FMC 1976). K-50, K-200, and K-300 were non-irritatingtoboth the skin and eyeinrabbits.

* 68937-41-7,28108-99-8,64532-94-1,93925-53-2,28109-00-4,69500-29-4,96300-97-9,74315-11-0,

26967-76-0,64532-95-2,695 15-46-4,and 68155-51-1.3. Genotoxicity PIP was not mutagenic in Salmonella tester strains TA98, TA100, TA1535, TA1537, and TA1538, either with or without metabolic activation (reviewed in EPA, 2005, Ferrante 1999a; FMC 1979;Henrich 2001; Stauffer 1979). KronitexTM 110was mutagenic without metabolic activation in TA1535 and TA1537,but not in strainsTA98, TA100, or TA1538 (Microbiological Associates 1978). Interestingly, KronitexTM 110was not mutagenic metabolic activation in either TA98, TA100, TA1535, TA1537, or TA 1538. However, in another study, KronitexTM K-110, K-100B, and K-200 were not mutagenicin the same strains, with or without activation. o-IPDP was reported to be non-mutagenic in Salmonella (Stauffer 1979). PIP failedto induce unscheduled DNA synthesis (UDS)in rat hepatocytes in vitro. It was unable to induce phenotypic transformation of Balblc 3T3 cells in vitro (EPA 2005a; FMC 1981). However, o-isopropylphenyl diphenyl phosphate was able to transform Balblc cells, and was weakly mutagenic with metabolic activation in mouse lymphoma cells (Stauffer 1979). In addition,PIP induced sister chromatid exchangein the bone marrow cells of Chinese hamsters following two oral doses, but not following a single dose. 4. Toxicokinetics No data were available on the metabolism of PIP. However, other aromatic phosphates are hydrolyzed to the diester (see above). In addition, alkyl substitutedAPP7s are oxidized at the 2-alkyl position. The resulting hydroxylated compound may then form a cyclic intermediate that is neurotoxic. The percutaneous absorption of formulations containing IPDP through human epidermiswas reported (Scott and Thompson 1985). Neat ReofosTM 50 or ReolubeTM46 were applied as an "infinite dose" to the epidermal side of cadaver epidermisplaced on a static diffusion cell. The receptor fluid was 70% ethanol. The authors calculated a diffusion constant of 2.2xl0-~ cm/h for IPDP. However, the experimental design was unusual in that the other components of the formulation were not identified and the receptor fluid was essentially non-aqueous. Theuse of a static cell could lead to an underestimate of absorption. Therefore, the usefulness of this study for estimating human risk was considered questionable (EPA 1985). 5. Subchronic and Chronic Studies Limited data are available on the subchronic toxicity of PIPin mammals. No chronic studies have been reported. Groups of 10male and 10female SDrats were given 0, 0.1, 0.5 or 1%PIP (KronitexTM 100) in the diet for 28 days (FMC 1977). These doses correspond to 0, 350, 1600, and 3000mglkg-d in males and 0,380, 1500, and 3400 mglkg-d in females. There were 4 deaths each at the low- and mid-dose, and 3 deaths at the high dose, as comparedto 1 death in the controls. The incidence of deaths is not significantly different from the controls by a Fisher's exact test. Relative liver weights were increased at all doses. There were clinical chemistry effects at the mid and high dose, and hematological effects at the high dose. There were no gross lesions and no abnormal histopathologyin the liver or kidney. Other organs were not examined microscopically. No other details were provided.Increased white blood cell and lymphocyte counts were observed in workers exposed to K-SOTM (Kolodner et al. 1987). Erythrocyte cholinesterasewas not affected, and no neurological symptoms were reported. White blood cell and lymphocyte counts were elevated at all doses. There was no reduction in erythrocyte cholinesteraseand there were no neurological effects. No other details were reported. 

### 6. Reproductive and Developmental Toxicity In a reproductive and developmental screen, male and femalerats were administered PIP by gavage for 40 days at doses of 0, 25, 100,or 400 mgkg-d (reviewed in EPA 2005a). The liver and adrenal glands were affected in adult males and females; females were more sensitive. The LOAEL for organ toxicity was 25 mgkg-d. There was reduced fertility at the mid- and high dose, and reduced pup survival at the high dose. In addition, ovarian weights were affected at all doses, and epididymalweights at the mid and high dose. No other details were reported. See above (Subchronicand Chronic Studies). 7. Neurotoxicity Numerous studies on the neurotoxicityof PIP in hens havebeen reported (reviewed in EPA 2005a; Ferrante 1999a;FMC 1977, 1979;Henrich 2001; Johannsen et al. 1977). PIP and related isomers are capable of causing OPIDN in hens at relatively high doses. PhosphoflexTM 41P was neurotoxic in hens at 4,000 mgkg (FMC 1977). TheEDsofor KronitexTM 200 was reported to be greater than 20,000 mgkg (Cascieri and Poinsett 1977;Ross et al. 1979). The EDsofor oIPDP was 10,000mgkg, as compared to 420 mgkg for o-TCP (Johannsen et al. 1977). In a series of studies, the acute EDsoin hens was estimated as: >4,000 mgkg for KronitexTM K-50; -8,000 mg/kg for K-100; >20,000 mgkg for K-200; and >16,000mag for K-300 (FMC 1977). In these studies, 400 mgkg o-TCP caused paralysis in at least 90% of hens. 8. Other effects KronitexTM 50 was reported to inhibit monocyte phagocytosis and IgG synthesis in human cells in vitro, while stimulatingthe release of leukotrienes and prostaglandins (Newcombe and Warr 1985). A tris(isopropy1ated)phenyl phosphate was reported to reduce Fc receptor activity and chemotaxis in vitro, with guinea pig alveolar macrophages (BIBRA 1987). These studies suggestpossible effects of PIP on the immune system and inflammation. 9. Toxicity under the FHSA The CPSC staff concludes that there is limited evidenceof neurotoxicity in animals. Although PIP is neurotoxic in hens at high doses, it is very weak in comparison to other APP7s.There are no reports of neurotoxicity 'in humans or other mammals. Thereis also limited evidence of chronic organ effectsin animals, including two poorly documented studies in rats, and inadequate evidenceof reproductive/developmentaleffects in animals. Therefore,the CPSCstaff concludes that PIP is possibly toxic in humans, based on limited evidence of toxicity in animals (neurotoxicity and chronic organ toxicity). 

### E. Octyl Tetrabromobenzoate (OTB) Limited toxicity data for octyl tetrabromobenzoate (OTB) are available (reviewed in EPA 2005a). SDrats were given single oral doses of either OTB isomer. There were no deaths, although exposed animals exhibited effects including piloerection and hunched posture. Thus, both isomers have oral LDsovalues >2000 mgtkg in rats. No other animal or human toxicity data or empirical physico-chemical properties are available. Thereis insufficient information to determine whether OTB is "toxic" under the FHSA. The only conclusion that may be made is that OTB is not "highly toxic" with regard to acute toxicity. 

### In addition, no toxicity data on structural analogues were identified in National Library of Medicine databases. F. Melamine The toxicity of melamine 

### (1,3,5-triazine-2,4,6-triamine) was reviewed by the CPSC staff (Thomas and Brundage 2004) and IARC (IARC 1986, 1999). Briefly, the oral LDsowas between 3,200 and 3,800 mgkg in F344 rats (NTP 1983). Symptoms included lacrimation, dyspnea, intermittent tremors, paralysis, and coma. A single dose of 2,400 mgkg melamine in rats lead to crystalluria (dimelamine monophosphate) and diuresis (Lefaux 1968). A 1 % aqueous solution caused little or no irritation and did not induce sensitization on occluded guinea pig skin (Trochimowicz et al. 1994). Melamine was not irritating to rabbit skin at doses up to 1,000mgkg for 18 hours. A 10% aqueous solution was not irritating to the eyes of rabbits, although the dry solid caused mild, reversible irritation. 1. Genotoxicity Melamine was not mutagenic in Salmonella with or without metabolic activation (Haworth et al. 1983;NTP 1983). It did not induce sister chromatid exchange (SCE) in Chinesehamster ovary cells in vitro or micronuclei in mouse bone marrow in vivo (Mast et al. 1982a,b). Melamine failed to initiatepapilloma formation in an initiation-promotion assay inmouse skin (Perrella and Boutwell, 1983). 2. Toxicokinetics

. 

### In rats given a single oral dose of 14~-melamine, radiolabel was found primarily in the kidney and bladder (Mast et al. 1983). Ninety percent was excretedin the urine, as unmetabolized melamine, within 24 hours. Negligible amounts of radiolabel were found in exhaled air or feces.3. Suchronic and Chronic Studies 

### 1 F344 rats and B6C3F1 mice were given melamine in the diet at levels up to 1.8% for 13weeks (Melnicket al. 1984). These doses were equivalent to 1700mgkg-d in male rats; 1600mag-d in femalerats; 4700 mgkg-d in male mice; and 5900 mgkg-d in female mice. Uroliths (bladder stones) were found in treated animals, especiallymales. Ulceration of the bladder epithelium was observed in treated male and female mice, but this was statistically independent of urolith formation. Increased incidence of epithelialhyperplasia was found in treated male rats. 

### In a two-year dietary study, male F344 rats and B6C3F1 mice were given 0,0.225, or 0.45% melamine, and females were given 0,0.45, or 0.9% melamine (Melnick et al. 1984;

### NTP, 1983). This resulted in doses of 0, 125, and 270 mgkg-d in males rats and 0,252, and 566 mag-din femalerats. The doses in mice were 0,327, and 688 mag-din males and 0,367, and 964 mgkg-d in females. The incidence of transitional-cell carcinomas of the urinary bladder was significantly elevated in high-dose male rats. In addition, there was a statistically significant associationbetween the presence of bladder carcinoma and uroliths. 

### In female rats, the incidenceof chronic kidney inflammationwas elevated at both the low and high dose. The incidenceof chronic inflammation and epithelialhyperplasia of the urinary bladder and increased incidenceof uroliths were elevated in dosed male mice. No tumors were found in male or female mice. In another study, male F344IDuCrjrats were fed melamine at 0,430, or 1200mgkg-day for 36 weeks. Treated animals hadurinary calculi and bladder tumors (Ogasawaraet al. 1995). Cotreatment with 5% or 10% NaCl decreased the formation of both the calculi and bladder tumors. The increase in water intake caused by the NaCl, which increased urinary volume diluting the urinary melamine, was thought to beresponsible for reduction in the precipitation of urinary melamine. Thus, decreased calculi formationwas consideredto be directlyrelated to the reduction in bladder tumors. 4. Reproductive and Developmental Effects Pregnant rats were given intraperitoneal injections of 70 mglkg on GD's 5 and 6, 8 and 9, or 12 and 13(Thiersch 1957). The author reporteddhatthere were no toxic effects or gross malformations in the fetuses. 5. Neurotoxicity No neurotoxicity data were available. 6. Toxicity underthe FHSA Melamine may be considered acutely toxic under the FHSA, althoughit is not highly toxic. The oral LDsoin F344 rats was between 3,200 and 3,800 mgkg (NTP 1983). Aqueous solutions of melamine were non-irritating to the skin and eyes of animals. The dry solid was mildly irritating to the eyes of rabbits. Thus, pure melamine is possibly a mild eye irritant. Based on limited data, there is no evidence of teratogenicityin animals. Reproductive toxicity and neurotoxicity were not studied.Dietary melamine caused the formation 6f papillomas and transitional cell carcinomas in the bladder epithelium of high-dose male F344 rats in a two-year bioassay. The incidence of tumors was not increased in low-dose males rats, female rats, or in mice. There was a significant statistical associationbetween the presence of tumors and calculi. The tumors are considered to result from chronic irritation from the bladder calculi, followed by epithelial hyperplasia (Burin et al. 1995; Meek et al. 2003; Rodent Bladder CarcinogenesisWorking Group 1995). Although the formation of bladder calculi is possible in humans, calculi are typicallynot present in the human urinary tract for a sufficient length of time to cause epithelial hyperplasia (Burin et al. 1995; Meek et al. 2003; Rodent Bladder CarcinogenesisWorking Group 1995). Calculi in humans are typically quickly voided as a result of the anatomy of the urinary tract and the upright, bipedal nature of humans. Therefore,the mode of action by which melamine induces bladder tumors in male rats is consideredto be not relevant to humans. Because melamine caused tumors only at high doses in one sex and species, and the mode of action is probably not relevant to humans, melamine may be considered a possible human carcinogen, based on limited evidence in animals. The finding that melamine is possibly carcinogenicto humans does not satisfy the regulatory definition of "toxic."111. 

### DOSE RESPONSE A. 

### Tris(l,3-Dichloro-2-Propyl) Phosphate (TDCP) The LOAEL for non-cancer effects in the two-year rat studywas 5 mglkg-d (Biodynamics 1981; EPA 2005a; NRC 2000). Histopathological effects were observedin several organs, including the liver, kidney, spleen, parathyroid, testes, epididyrnes,and seminal vesicle. Histopathological effects that were significantly elevated at the LOAEL included seminal vesicle atrophy and decreased seminal vesicle secretory product in males, and erythroidlmyeloid metaplasia of the spleen in females (Table 3). A benchmark dose was not calculatedin this case, due to an incomplete database. With the exception of liver and kidney, only a subset of animals from each doselsex group were subjectedto complete histopathology (see also NRC 2000). None of the available dose-response models was able to adequately fit the available data. Therefore, an uncertainty factor approachwas used. An overall uncertainty factor of 1,000was applied to the LOAEL, including 10-foldfor animal to human extrapolation, 10-fold for inter-individual variability, and 10-fold because a no-observed-adverse-effect level (NOAEL) was not established. This results in an AD1level of 0.005 mglkg-d. TheNRC subcommittee derived a reference dose (R~D)* of 0.005 mglkg-d (NRC 2000). However, the NRC subcommittee applied uncertainty factors of 10-fold for animal to human extrapolation, 3-fold for inter-individual variability, 10-foldbecause a NOAEL was not established, and 3-foldfor an incomplete database. The CPSC chronic hazard guidelines do not provide for an additional uncertainty factor for an incomplete database (CPSC 1992). The default factor for inter-individual variabilityused by CPSC and others is 10-fold. The NRC subcommittee applied a 3-fold factor for 

### inter-individ~al~variability in this case, because there was no evidence of increased sensitivity ofjuvenile animals from developmental toxicity stules (NRC 2000). They did not indicatewhat studies were lacking from the database. The CPSC staff derived a cancer unit risk (potency) estimate for TDCP, based on the incidence of hepatocellulartumors (carcinoma and adenoma) and tumors of the renal cortex. Benign tumors of the testes and adrenal cortex were not included, because no malignancies were present in the organ sites. Thus, it does not appear that these particular tumors would progress to malignancy. 

### In addition, testicular interstitial cell adenomas have a high background rate in rats, and their relevance to human cancer risk is uncertain (CPSC 1992, p. 46636). Hepatocellular carcinomas and adenomaswere combined,+ because hepatocellular adenomas are known to progress to carcinomas (CPSC 1992,p. 46636). Tumor incidence data for males and females were combined, because their unit risks differed by less than a factor of two when computed separately (CPSC 1992,p. 46654). Animal bioassay data were fitted to the multistage model using Global83 (Howe and Crump 1983;Crump 1984),as described in the chronic hazard guidelines (CPSC 1992, p. 46654). The

* Both the acceptabledaily intake (ADI) and reference dose (RfD) are estimates of the amount of a chemical a

person can be exposed to on a daily basis over an extendedperiod of time (upto a lifetime) with a negligible risk of suffering deleterious effects. That is, the incidence is the number of animalswith adenoma carcinoma.unit risk was based on the maximum likelihood estimate of extra risk, that is, the linear term (ql) in the model:

where: P(D), lifetime cancer risk at dose D; qi, model parameters to be fitted. The parameters qi must be non-negative, and i is an integer with a value from 1 to 9. Unit risks for liver and renal tumors were calculated separately and then added, as described in the CPSC chronic hazard guidelines (CPSC 1992,p. 46654). The unit risks in animals for liver and renal tumors, res ectively, were 6.4x10-~ and 2.5x10-~ (mg/kg-d)-'. The overall unit risk in 

# 2 animals was 8.9~ 10- (mg/kg-d)-'. Animal-to-human extrapolation was by the surface area correction, that is, the unit risk is proportional to body weight to the three-quarters power (CPSC 1992,p. 46654; EPA 1992). Mean terminal body weights in untreated controls were 612 g in males and 386 g in females (Freudenthal and Henrich 2000). The average of males and females was 499 g. Thus, humans are estimated to be 3.5-fold more sensitive than the rats:

where: F, interspecies conversion factor, unitless; BWaimal,-average animal body weight (0.499 kg); and BWhumm, average human body weight (75kg). By this methodology, the unit risk forkidney and liver tumors combined is estimated to be 0.031 (mg/kg-d)-l: 

### Q =

### F -q, =3.5x8.9~10" =3.1~10" (mglkg-d)-'
where: Q, unit risk in humans, (mg/kg-d)-'; F, interspecies conversion factor, unitless; and ql,unit risk in animals, (mg/kg-d)-'. The NRC subcommittee derived a unit risk of 0.06 (mg/kg-d)-' (NRC 2000). This was based on the incidence of testicular interstitial cell tumors in the same bioassay cited here (Biodynamics 1981; Freudenthal and Henrich 2000). According to the NRC report, the testicular tumors were used because they were the most sensitive tumor site (NRC 2000). The subcommittee calculated the LEDlo,that is, the 95a lower confidence limit of the dose at which the cancer risk is 0.1, using the multistage model. Linear extrapolation was then used to calculate the unit risk.B. Triphenyl Phosphate (TPP) and Phenol Isopropylated Phosphate (PIP) Previously, the CPSC staff concluded that there were sufficient data to derive AD1values for three of the 10 aromaticphosphates or mixtures that the staffreviewed: Santicizer 148 (roughly 90% isodecyl diphenyl phosphate), 0.01 mgkg-d; TCP isomers, 0.05 mgkg-d; and 2-ethylhexyl diphenylphosphate, 1.0 mglkg-d (Bittner et al. 2001; Ferrante 1999b) (see Table 2). The NRC subcommittee derived an 

### RfD of 

### 0.07 mgkg-d for TCP isomers. The CPSC staff also concludedthat there was insufficient informationto derive AD1levels for PIP or TPP (Ferrante 1999a;Bittner et al. 2001). There are no subchronic or chronic studies with full histopathology for either compound. For thepurpose of the present preliminary risk assessment, estimated exposuresto these compounds will be compared to the AD1values for other aromaticphosphates, which range from 0.01 to 1.0mgkg-d (Bittner 2001; Bittner et al. 2001; Ferrante 1999a)(see Table 2). 

### C. Octyl Tetrabromobenzoate (OTB) There is insufficientinformation to derive an AD1 value for OTB. No structurallyrelated compounds were identified that had sufficient data to derive an ADI. 

### D. Melamine Melamine did not satisfy the FHSA definition of "toxic." Therefore, an AD1 cannot be calculated. A quantitative risk assessment is not needed to determinewhether products containing melamine may be hazardous (CPSC 1992).

### IV. EXPOSUREAND BIOAVAILABILITY As in previous risk assessments involving FR chemicals, exposure was estimatedby analyzing various exposure scenarios (Babich and Thomas 2001; Thomas and Brundage 2006). This was accomplished through a combination of laboratory studies and mathematical models. Dermal, inhalation, and oral exposure routes were included. Inhalation exposure considered both vapor phase and particles. Separate exposure estimates were made for adults and small children. 

### A. Laboratory Studies The CPSC staff conducted laboratory studies to estimate the possible migration of 

### FR chemicals from upholstery foam (Cobb and Bhooshan 2005). Experiments utilized a mock-up consisting of a 9x9~s-inch (23x23~ 1.25 cm) sheet of plywood supporting a 3-inch thick slab of the FR-treated upholstery foam to be tested (Figure 4). The foam was covered by a standard non-FR fabric (50-50 cotton-polyester blend). No interliner orbatting was present in the mock-up, because someupholstered furniture does not have these components. Thepresence of an interliner or batting might be expected to reduce migration. The mock-up and experimental methods were adapted from the staff exposure and risk assessment for mattresses (Cobb 2005; Thomas and Brundage 2005). Three foam samples that could be used to meet the draft flammability standard were tested. Foam "S" contained 6.6% TDCP, foam "Y" contained 3.5% TDCP and 11% melamine, and foam "Zcontained 6% FM-550TMand 2.8% melamine (Cobb and Chen 2005). Foams S and Z contained the highest TDCP and FM-550TMconcentrations among the samples available for testing. To study the potential for dermal and oral exposure, the mock-up was wetted with 25 mL of isotonic saline solution (0.9% NaCl). Two 55 mm diameterpieces of#2 filter paper were placed on the wetted portion and covered with weights. The weights were 2 inches in diameter (5.1 cm) and weighed 3.14 pounds (1.4 kg), resulting in one pound per square-inch (psi) ofpressure (6.9 . kPa). After 6 hours, the filter paper was removed and analyzed for FR content. The test was repeated with the same foam sample for up to eight consecutive days. FR chemical in the filter paper is assumed to be availablefor transfer to the shn or mouthing by children (Thomas and Brundage 2006). FR chemicals on the skin can be absorbed percutaneously or transferred to the mouth by hand-to-mouth activity. Foams S and Y were each tested once. Two specimens of foam Z were tested, one for4 days and the second for 8 days. The average migration from each iteration was used to estimate exposure. Experiments were also conducted to estimate the release of particles containing FR chemicals into air (Cobb and Bhooshan 2005). Mock-ups were subjectedto repetitive impaction with an air-driven piston attached to a 4-inch diameter semi-sphericalform.. Mock-ups were impacted 100,000 times at a rate of 1per second and 3 pounds per square inch pressure. Tests were done inside a closed, inflatable glovebag supported by a metal frame, with a volume of 216 L. Recirculated air was continuously sampled at arate of 2 L per minute to collect inhalable particles. The total amount of particulate phase FR chemical collected was assumed to be released during the lifetime of the furniture. Duplicate samples of foam S and Z were tested. Foam 

### Y was not subjected to this test. Three filter cassettes were used in each test.

### COVER FABRIC FOAM

Figure4. Mock-up for exposur= studies



### B. Calculations To estimate dermal exposure, it is assumed that an external liquid phase facilitates the transfer of 

### FR chemical from the foam to the surface of the cover fabric and then to the skin (compare NRC 2000). During normal use, that is, whlle sitting on furniture, perspiration is assumed to be the liquid phase. The amount of FR chemical migrating to the fabric surface was measured in the laboratory as described above (Cobb and Bhooshan 2005). The AD1and unit risk values for the chemicals of interest are derived from oral studies. The bioavailability, that is, the fraction of the applied dose that is absorbed, generally varies for different exposure routes. Therefore, in calculating exposure and risk from dermal and inhalation exposure, it is appropriate to make a route-to-route adjustment to account for differences in bioavailability (Babich and Thomas 2001). The average daily dose (ADD) from dermal exposurewas calculated by: ADD, =

### Ma F.S.K,.T W.B where: ADDD,average daily dose from dermal exposure, mglkg-d; 

### M, amount of FR chemical that migrates to the fabric surface, mg/cm2;F, fraction of liquid phase transferred to the skin, unitless; S, skin surface area exposed, cm2;

### KT,percutaneous absorption rate, h-l;T, exposure duration, hld; W, body weight, kg; and B is the oral bioavailability, unitless. Oral exposure may occur either by direct mouthing of furniture cover fabric or by hand-to-mouth activity. As with dermal exposure, migration of FR chemical from foam is assumed to be mediated by an external liquid phase, in this case saliva. The amount of FR chemical migrating to the surface of the cover fabric was estimated in laboratory studies as described above (Cobband Bhooshan 2005). The average daily dose from indirect mouthing, that is, hand-to-mouth activity was calculated by: M-F .SH-FH ADD,, = 

### W where: ADDoH,average daily dose from hand-to-mouth activity, mglkg-d; M, amount of FR chemical that migrates to the fabric surface, mg/cm2;F, fraction transferred from the fabric to the hand; SH,surface area of the hand that is mouthed, cm2;FH,hand to mouth transfer factor, d-l;and W, body weight, kg. The average daily dose from direct mouthing activity was calculated by: M-S, .FM ADD,, = W where: ADDoM,average daily dose from direct mouthing activity, mgkg-d; M, amount of FR chemical that migrates to the fabric surface, mg/cm2;SM, surface area of fabric that is mouthed, cm2;FM,fabric to mouth transfer factor, d-l; and W,body weight, kg. Thetotal oral exposure is given by: M(F.SH.FH +SM -F,) ADD, = W where: ADDo, average daily dose from oral exposure, mgkg-d; M, amount of 

### FR chemical that migrates to the fabric surface, mg/cm2;F, fraction transferred from the fabric to the hand; SHY surface area of the hand that is mouthed, cm2;FH, hand to mouth transfer factor, d-l;SM, surface area of fabric that is mouthed, cm2;FM, fabricto mouth transfer, d-l;and W, body weight, kg. Inhalation exposure may occur from the release of semi-volatile

### FR chemicals into the vapor phase or from the release of FR-containing particles during normal wear or aging. Therelease of FR-containing particles was measured in the laboratory as described above (Cobb and Bhooshan 2005). The total amount of particle-bound 

### FR chemical released during the accelerated wear test was assumed to be released over the lifetime of the furniture (compare Thomas and Brundage 2005). Inhalation exposures were estimated using a two-zone mass balance model, where zone 1 is the breathing zone (Thompson and Thompson 1990) and zone 2 is the room containingthe upholstered furniture. The source of 

### FR emissions is located in the breathing zone. The average daily dose from inhalation exposure to vapor phase FR chemical was calculated by:where: ADDIv, average daily dose from inhalation exposure of vapor phase chemical, mglkg-d; Cvl,CV2, concentrations of .vaporphase FR chemical in zones 1 and 2,


### - respectively, mg/m3; TI,T2, exposure duration in zones 1 and 2, h; FR chemical in zone 2, the living or family room, mg/m3;exposure duration in zone 2, h; 

### I, average inhalation rate, m3/h;W, body weight, kg; and B, oralbioavailability, unitless. The concentration of vapor phase chemical was calculated from a two-zone mass-balance model (NRC, 1981). This model assumes that the outdoor concentration of FR chemical is zero, and that the breathing zone (zone 1)does not exchange directly with the outdoor air. Thus, the concentrations of vapor phase 

### I3 chemical in zones 1 and 2 are given by:

where: Cvl; CV2, concentrations of vapor phase FR chemical in zones 1 and 2, respectively, mg/m3;K, air infiltration rate, h-l;V1,volume of zone 1 (breathing zone); A, inter-zone air exchange rate, m3/h;Ev, source strength for vapor phase chemical, in zone 1,mgth; V1,V2, volumes of zones 1 and 2, m3; Kv, decay rate for vapor phase chemical; and T, time, h. This system of two differential equationswas solvedby Euler's method. The concentrations at 12hours were used to calculate exposure, as steady-state is generally reached before this time. The source strength forvapor phase FR, Ev, was estimated by means of a mathematical model (Babich and Thomas 2001) that is essentially similar t6 the model describedby the NRC subcommittee (NRC 2000). The difference is that the CPSC staff separatedthe source strength and mass-balance expressions. This allowed us to change from a l-zoneto a 2-zone model, for example. The source strength is given by:



### Ev1= 1 Csat H for 

### TMm 2 

### P years



### TMU 

## .41 42= 

### p for 

### TMU 

### <P years where: [10.000~~~~]~[,+1x10~S~D~~~ 

### TMm = Csat 

### -DAir 

### - 8,766 A-V.H (8)

and where: 

### T,, maximum time that vapor phase 

### FR canbereleased at the estimatedrate, y; 1x10-~, to convert from cm2to m2; 10,000,to convert from mg/cm2to mg/m2;FRL, 

### FR chemical loading rate, mg/cm2;H,boundary layer height, m; CSa,saturation concentrationin air,mg/m3;D&, diffusivity in 

### air, m2/h; 8766, number of hours per year; Sp, surface area of foam in a suite of furniture, cm2;K, air infiltration rate, h-'; V, room volume, m3;P, product lifetime, y;,and-Ev,source strength, mgh. Csatwas estimated aspreviously (Babich and Thomas 2001):


# - MM 

### .vP-~x~o~ Csal = 

### R

. Temp
where: 

### NIM, molecular mass, grams/mole; VP, vapor pressure, ton; 1x106, to convert from gramsper liter to mg/m3;R, gas constant, 62.4 ton-Llmole-degree Kelvin; Temp, temperature (298°K). 

### Dh was estimated as described by Schwope et al. (1989):

where: DAir,m2/h,

### MM, molecular mass, gramslmole; and 3600/10,000 is to convert from cm2/sectom2/hour. The average daily dose from inhalation of particle-bound FR chemical is given by:

where: ADDp, average daily dose from inhalation exposure of particle-bound chemical, mglkg-d; Cpl,CP2, concentrations of particle-bound FR chemical in zones 1 and 2, mg/m3; TI,T2,exposure duration in zones 1 and 2, hld; 

### I, average inhalation rate, m3/h;W body weight, kg; and B, oral bioavailability, unitless. Theconcentrations ineach zone (Cpl, Cp2) were calculated from thetwo-zone mass balance model:
- -

where: CPl, CP2, concentrations of particle-bound FR chemical in zones 1and 2, respectively, mg/m3; A, inter-zone air exchange rate, m3/h;Ep, source strength for particlebound 

### FR chemical, mg/h; K, air infiltration rate, h-'; K;, particle decay (deposition) rate, h-'; and V1, V2,volumes of zones 1 and 2.As with equation (6) above, this system of two differential equations was solvedby Euler's method. Theconcentrations at 12hours, were used to calculate exposure, as steady-state is

. generally reached before this time. Th? source strength (Ep)was estimated by: s

where: Ep, source strength,mgh;Mp,mass of FR chemical released in the impaction experiment, mg; Fp, scaling factor, unitless; 24, hours per day; 365, days per year; and 

### P, average product lifetime, years. Fpis theratio of thetotal surface area of foam in the product to the area of the mock-up. The overall ADD value was obtained by summing the ADD values for each route of exposure: ADD =ADD, 

## +ADD, +ADD, (14) where: ADD, total average daily dose from all routes, mgkg-d; ADDo, ADDD,and ADDI, average daily doses from oral, dermal, and inhalation exposure, respectively, mgkg-d. The lifetime average daily dose (LADD) was calculated from the ADD as follows:

LADD = ADD 

### -Y

where: LADD, lifetime average daily dose; ADD, average daily dose, mgkg-d; Y, number of years the consumer is exposed, y; 

### L, average life expectancy, y. 

### C. Input Parameters 1. General parameters General input parameters are summarized in Table 

### 5. The average lifetime of a suite of upholstered furniture (P), 15years, was estimated by industry representatives (Babich and Thomas 2001; NRC 2000). For the purpose of uncertainty analysis,'5 and 25 years were assumed to be reasonable lower and upper bounds, respectively. The average number of years of exposureto upholstered furniture (Y) is not necessarily the same as the averageproduct life. A consumer may be exposed to several different types of furniture, which may be treated with different FR chemicals ornone at all. For calculating cancer risk, it was assumed that adults are exposed to the sameFR treatments for a lifetime, which is the most conservative approach. This assumption is onlyrelevant to cancer risk. The average furniture lifetime (15 years) may be considered a reasonable lower bound for exposure duration.For children, an exposure duration (Y) of two years, the first two years of life, was assumed. Children are most likely to place objects in their mouths between 3 months and 12months of age; mouthing activity declines significantlyby 24 months of age (Greene 1998). Mouthing activity is one of the principal quantifiable differences between children and adults that may affect exposure to FR chemicals. The body weight, surface area, and respiration rate are also different in children. The averagelife expectancy 

### (L) and average body weight (W) for adults are from the EPA "Exposure Factors Handbook" (EPA 1997). Body weights for males and females 45-54 years old were averaged (EPA 1997Tables 7-4,7-5). The 5", 50", and 95" percentile values were used as the lower bound, best estimate, and upper bound, respectively. Children's body weights and lengths were for one-year-olds (CDC, 2000). The 5", 50", and 95" percentile values for boys and girls were averaged, and used as the lower bound, best estimate, and upper bound, respectively. The foam surface area, Sp,was estimated as 2.8m2 (28,000 cm2)for a suite of furniture including a sofa, love seat, and chair (Babich and Thomas 2001). The seating area and seat back were assumedto be constructed with polyurethane foam. The average foam mass,Wp,for a similar suiteoffurniture was estimated by the Directorate for Economic ~nal~sis* tobe 15kg. Table 5. General Input Parameters Parameter Best Lower Upper Reference Estimate Bound Bound Bodyweight, W, kg 72 50 101 EPA 1997, Tables 7-4, 7-5 Children 10 8.3 12

. "" CDC 2000 Life expectancy, L,y 75 ND N Years of exposure,Y, y 75 15 75 Assumptions; see text Children 2 2 2 Product lifetime, P, y 15 5 2 5 Product (foam) surface area, Sp, cm2 28,000 1 TO00 56,000 Estimates; see text Product (foam) mass,Wp, kg 25 ND ND ND, not determined.

2. Dermal Exposure For estimating dermal exposure, it was assumed that the consumer is lying on a sofa and wearing a short-sleeved shirt and short pants (Babich and Thomas 2001; Smith 2000). Due to the 3-dimensional shape of the limbs, it was assumed that roughly one-third of the exposed surface area was in contact with the furniture surface at a given time. Thus, the surface areas for the lower leg and arms were combined, then divided by three. For adults, median values for males and females were averaged (EPA 1997,Table 6-2, 6-3). The lower bound for adults was

* Personal communication from Charles Smith, Directorate for Economic Analysis.assumed to be one-third the combined surface areas for the hands and feet. The upper bound was assumed to be one-third the total surface area. Parameters relating to dermal exposure are summarized in Table 6. For children, surface areasforbody parts were available as the percentage of the total surface area. Mean values for the age groups <1 year and 1to <2 years old were averaged (EPA 1997, Table 6-8). Data forthe lower leg were not provided; thus, the lower leg was assumed tobe 40% of the area of the entire leg, which is the case for adults. For children <2 years old, the total surface area was not available (EPA 1997, Tables 6-6 and 6-7). Thus, the average total surface area was calculated as follows (EPA 1997, Equation 6A-8 and Table 6A-1):

where: STotal, total body surface area, m2;L, length, cm; and W,body weight (kg). Absolute surface areas were computed from percent areas and the total surface area. Upper and lower bounds were analogousto the adult values. An average exposure of 4 hours per day (T) for adults was estimated (Babich and Thomas 2001; Smith, 2000) from compiled activity data. This is the amount of time that adults and older children spend in "indoor/leisure" activities (EPA 1997, Table 15-8to 15-10). Exposure durations of 0.5 hours and 16 hours were assumed as reasonable lower and upper bounds. Children up to 2 years old spend approximately3 hours per day in "passive leisure" activities (EPA 1997 Table 15-12). An average exposure duration of 3 hours per day, with lower and upper bounds of 0.5 and 12hours per day, was assumed. The total daily exposure duration may, in fact, be divided among several events. However, dividing the total exposure among several events does not affect the exposure calculation.

Table 6. Input Parametersfor Estimating Dermal Exposure ' . Parameter Best Lower Upper Reference Estimate Bound Bound Fabric to skin transfer F 0.13 0.024 0.84 See Table 8

. . Children 35

v EPA 1-997;Smith 2000; see Exposure duration, T, h/d 4 Children 3 0.5 12 ND, not determined. Chemical-specificinput parameters are summarizedin Table 7. Liquid-mediated migration to the fabric surface (M) was measured as described above. 

### FR chemical migrating to the filter paper was assumed to be deposited on the surface of the cover fabric and, therefore, availablefor transfer to the skin. The components of FM-550TM could not be quantified individually (Cobband Bhooshan 2005). Migration measurements for FM-550TMarebased on the OTB component. Thus, OTB is a surrogate for TPP and PIP. The average migration from each iteration (that is, from each daily measurement) was used to estimate exposure. Results from the two TDCPcontaining samples (n=16) were averaged. Results fromtwo FM-550TM-treatedspecimens were also averaged (n=12).

Table 7. Chemical-Specific Input Parameters Parameter Symbol Units TDCP TPP PIP OTB FR mass percent in' FRW mass foam 5.1 a'b 6.8 6.8 a'C 6.8 a 

### ;

. 

### ~e~ce-nt.

..t.ttt.t.tt.t.t.tt.....t.t..t...t.ttttttttttt... ........ ..t...........t.t.tt.... .... FR loading rate FRL mg/cm2 46 36 36 36 Total FR in product FRT mg 1.3~1 

### o6 1x10~~ 1x10~~ 1 XI 

### o6 Migrationto liquid M mg/cm2 1.5x10-~~'~ 4.5~10~~~~ 4.510-~~*~. 4.5~10-~~

................ ......... ....... ......

eha5e" - - ..... - -- Mass released from impaction

. '

. . MP mg 0.0015 <0.0004 <0.0004 <0.0004

........... ............... . . .... . ..... ............................ -*-- -

Oral bioavailability B unitless 0.9 1.0 1.0~ 1.0~ Dermal absorption rate KT h-' 0.08 

### ' 0.1' 0.1

# ' 0.01 Acceptable daily intake AD1

. mg/kg-d 0.005' 0.01-1.0~ 0.01-l.Om ND

.... .. . .- . .- ..... . .- ................................... Cancer unit risk Q (mg/kg-d)" 0.031

# ' N A IVA IVA

a Measured by CPSC staff (Cobb and Bhooshan 2005; Cobb and Chen-2005). b Average from two samples, foam S and foam Y. Value isfor the OTB component of FM-550TM.Individual components were not quantified. d Estimatedfrom the mass percent. 

### " Average migration from up to 8 repeated tests on consecutive days with the same sample (Cobb and Bhooshan2005). In calculating the average, non-detectswere regarded as one-half the detection limit. Converted from mgto mg/cm2 by dividing by the area of the filter paper, 24 cm2. f Five of 6 TDCP replicates (foam S) and 5 of 5 FM-55OTWreplicates (foam Z) were below the method detection limit. Non-detects were regarded as one-half the detection limit. Matthews and Anderson 1979. h Default assumption. i Estimatedfrom invitro data (Hughes et al. 2001). j Estimatedfrom invivo data for o-tricresyl phosphate (Nomeir and Abou-Donia 1984). k Assumed (see text). I Estimated from two-year study in rats (Biodynamics 1981; Brandwene 2001; Freudenthal and Heinrich 2000). Range of values for aromatic phosphates (Bittner et al. 2001; Ferrante 1999a). 

### " NA, not applicable; IVD, not determined.FR chemical migration from the foam to the filter paper depends, in part, on the volume of liquid phase (25 mL) and the pressure (1psi) applied to the filter paper. The 1 psi was based on the average peak pressure of an adult lying on a mattress (reviewedin Midgett 2005). Upholstered furniture is generally less firm than mattresses, and the consumeris typically seated. Sitting would increase the pressure, relative to lying down. However, some of the weight may be supported by the side and back of the furniture, and the feet. The relatively soft furniture would probably distribute the weight more evenly. The amount of liquid phase was based on the amount of perspiration excreted from the body during an 8-hour period, about 0.05 mL per square centimeter of skin area (reviewed in Thomas and Brundage 2005). However, the average exposure duration of adults to upholstered furniture is estimated as 4 hours. Therefore,the amount of saline solutionmay tend to overestimate exposure. Several authors have studiedthe transfer of various chemicals from treated textiles to human or animal skin. These studies were used to estimate the fraction of FR chemical transferred from the fabric surface (representedby the filter paper) to the skin, that is, the fabric-to-skin transfer efficiency (Table 8). Substances included dust particles (Rodes et al. 200I), glyphosate and malathion (Wester et al. 1996),permethrin (Snodgrass 1992),riboflavin (Cohen-Hubal et al. 2005), and TRIS (Ulsamer et al. 1978b). For the present risk assessment,the overall mean transfer efficiency 0.13 was assumed to be the best estimate for the transfer efficiency, with the minimum (0.024) and maximum (0.84) as the lower and upper bounds. Thepercutaneous absorption rate (KT)is describedbelow (Bioavailability).

Table 8. Fraction of Test Substance Transferred from Textileto Skin Substance Fraction Transferred Textile Skin Method Reference Dry Moist Dust 0.061 0.050 Carpet Human In vivo Rodes et at. 2001

. ....... . . Glyphosate 0.056 0.254 Cloth Human In vitro Wester et al. 1996

.- .............................. . . . . Malathion 0.068 0.837 Cloth Human In vitro Wester et al. 1996 Permethrin 0.031 0.037 Cloth

. Rabbit In vivo Snodgrass 1992

. .. . Riboflavin

.- 0.024 0.050 Carpet Human In vivo ~~hen-~ubal et al. 2004

.... . ....... - ... . - -TRIS 0.046 0.060 Cloth Rabbit In vivo ~lsamer et al. 1978b Mean

. 0.048 0.22

. .................. .......... . ...... --...... -...

Overall Mean Minimum 0.024

..-.. . Maximum 0.843. Oral Exposure Oral exposure to 

### FR chemical may occur either indirectly by transfer of FR chemical from the fabric surface to thehand or directly by mouthing of upholstered furniture. FR chemical on the hand may be ingested by hand-to-mouth contact orby transfer of FR chemical from the hands to food or other objects. Indirect transfer is assumed to occur in both children and adults, while direct mouthing is assumed to occur primarily in children. Therelevant surface area for hand-tomouth activity (SH)was assumed to be the ventral surface (palm) of the hands orroughly onehalf the surface area of the hands. Parameters are summarized in Table 9. One-tenth of the best estimate, roughly equivalent to the fingertips, was assumed as a reasonable lower bound. The entire surface area of both hands, the theoretical maximum, was used as an upper bound. Table 9. Input Parameters for Estimating Oral Exposure Parameter Best Lower Upper Reference Estimate Bound Bound Mouthed surface area, hand, SH,cm2 450 45 900 EPA 1997; see text Children 130 13 260 Hand to mouth transfer, FH,d" 0.4 0.03 Hatlelid 2003 Mouthed surface area, fabric, SM, cm2 0 0 50 Assumption; see text Children 10 0 50 CPSC 1983; NRC 2000 Fabric to mouth transfer, FM,d-' 0.4 0.03 7 Hatlelid 2003 ND, not determined.

For adults, the median surface area of thehands is 0.099 m2in men and 0.0817 m2 in women (EPA 1997, Tables 6-2 and 6-3). Averaging the two values and dividing by two gives 0.045 m2 or 450 cm2. For children aged c1and 1 to Q years old, the hands represent 5.3 and 5.7 % of the total body surface area, respectively (EPA 1997,Table 6-8). Thetotal surface area was calculated as 0.48 m2(equation (16)). Multiplying the total surface area by 5.5 % (the average of 5.3 and 5.7) and dividing by two gives roughly 0.013 m2 or 130 cm2. For direct mouthing, a surface area (SM) of 10 cm2was assumed for children. The CPSC staff has previously used values of 10or 11cm2for direct mouthing (Babich et al. 2004; Babich and Thomas 2001; CPSC 1983). Upper and lower bounds of 0 and 50 cm2were assumed. Theupper bound is the value used by theNRC subcommittee (NRC 2000). For adults, zero cm2was assumed as both thebest estimate and lower bound, while 50cm2was assumed for the upper bound. Few data on the transfer of chemicals from thehand to themouth (FH)or fabric to the mouth (FM) are available. For playground equipment made from pressure-treated lumber, the CPSC staff used an average value of 0.43 for hand-to-mouth transfer, with a range of 0.03 to 7 (Hatlelid 2003). This was derived from the ratio of soilloading on thehands and soil ingestion (Hatlelid 2003; Lee 1990a,b). This value was for a 24-hour period, independent of thenumber& individual mouthing events. Theupper bound is greater than one, because thehand can be"re-loaded" during the course of a day. For the present risk assessment, an average value of 0.4, with lower and upper bounds of 0.03 and 7, was assumed for both hand-to-mouth and fabric-tomouth transfer. 4. Inhalation Exposure I Long term average inhalation rates (I)--0.55 m3/hfor adults and 0.24 m3/hfor children (EPA 1997,Table 5-23)-were used, as the exposure duration includes sleep and other indoor activities (Table 10). The adult value is the average for men and women. The lower and upper bounds for adults are for rest and light activities, respectively. For children, the upper and lower bounds were assumed to be proportional tothe adult values. Consumers spend an average of 16hours in their residence each day (EPA 1997,p.15-17). Thus, it was assumed that thetotal exposure duration for inhalation exposure is 16h/d. Thetime in the breathing zone was assumed to bethe time spent sitting onupholstered furniture, that is, the exposure duration for dermal exposure (see above, Table 6). Thus, the exposure duration in the breathing zone (TI)was 4 h/d for adults and 3 h/d for children. Thetime spent outside the breathing zone (Tz)was assumed to be the difference between thetotal exposure duration (16hours) and TI,or 12hours for adults and 13hours for children. Thelower and upper bounds for TI are also the same as for dermal exposure. Thelower and upper bounds for thetotal time indoors were assumed to be 

### 8 and 24h/d, respectively. The total of T1and T2 in any given instancecannot exceed 24 hours. Thus, the lower and upper bounds for Tzwere assumed tobe 

### 8h/d and 23.5 h/d. A breathing zone of 1 m3is typically used for estimating the exposure of a consumer to volatile compounds, such as arts and crafts materials (Thompson and Thompson 1990). For the present case, the breathing zone was assumed to include a 1meter-high rectangle over the horizontal seating area of a suite of furniture. Thehorizontal surface area was estimated as 1.7 m2(see above). Thus V1was 1.7 m3. One-half this value was assumed as the lowerbound, and twice this value as theupper bound. Thebest estimateof the room volume (V2)was assumed as the upper bound. Theroom volume (V2)was estimated as 120m3. Thisrepresents the volume of an open living room, dining room, and kitchen in a typical 1,500ft2ranch home (CPSC 1990). One-half the value (60 m3) was assumed tobethe lowerbound. Theupper bound was assumed to be the median total volume for U.S. residences (EPA 1997,Table 17-1). The average (whole-house) air infiltration rate (K) is themedian value for all seasons and all regions of the U.S. (Koontz and Rector 1993, Table 2). The 5'h and 95'h percentiles were used as lower and upper bounds. The air exchange rate between thebreathing zone and the room (A) was estimated as 17m3/h. Thebreathing zone is an abstract volume of space, bounded only by the seating area and seat back of the furniture. Thus, the air exchangerate was assumed to be greaterthan the exchange between rooms orbetween indoors and outdoors. Thevalue for A is equivalentto 10air changes per hour (10 h-I). That is, the air in thebreathing zone is replaced 10times per hour or once every 6 minutes. This is, in turn, equivalent to a linear air flow ("cross-breeze") of 17m/h or 0.01 miles per hour. For comparison, whole house air infiltration rates are typically on the orderof 2 h-' with the windows open (Koontz and Rector 1993). Outdoors, the air exchange rate may range from 10to over 100h-'. A one mile per hour breeze is equivalent to 160h-l. The lower and upper bounds were assumed to be equivalent to 1and 20 air changes per hour. Table 10. Input Parameters for Estimating Inhalation Exposure Parameter Best Lower Upper Reference Estimate Bound Bound Average inhalation rate, I, m3/h 0.55 0.4 1 .O EPA 1997; Table 5-23 Children 0.24 0.17 0.4

. .........- .. .. 

### - -. Exposure duration, in the breathing zone, TI, h/d 4 0.5 16 Children 3 0.5 12 EPA 1997, Table 5-23;

......... . ........................................ see text Exposureduration, outside the breathing zone, T2, h/d a 12 8 23.5 Children 13 8 23.5 Volume, breathing zone, V,, m3 1.7 0.85 ' 3.4 Assumption;,see text

... 

### -. Volume, room, V, m3 120 60 EPA 1997, Table 17-1; see 320 text

. -
. -
... ......... .......... Air infiltration rate, K, h-' 0.4 0.1 5. 1.7 Koontz & Rector 1993 Inter-zone air exchange rate, A, m3/h 17 I .7. 34 Assumption; see text

. .. - . .

Particle decay rate, KD,h-' 2.0 0.5

, 4.0 EPA 1997; Table 17-1 3 Vapor phase decay rate, Kv, h-' 0 0 1 Assumption; NRC 2000

.. - . . ... . - . ... . - . Scaling factor, FP 60 30 120 calculated from SP Boundary layer height, H, m 0.01 0.001 0.1 NRC 2000;see .text

-. .. - . . a The total of TI and T2 in any given case may not exceed 24 hours.
Exposure to particles deposited in the nasopharyngeal (-5-30 pm), tracheobronchial (- 1-5pm), and alveolar (-1 pm) regions of the respiratory tract are all relevant, because the chemicals of interest are systemic toxicants. Deposition rates for particles roughly corresponding to these size ranges include: 0.5 h-' (1 -5 pm), 1.4h-' (5-10 pm), and 2.4 h-' (10-25 pm) (EPA 1997,Table 17- 13). Particles released from the wear and aging of upholstered furniture components are likely to include a broad range of particle sizes (Stevens et al. 2003). A decay rate of 2 h-', representing particles from 1to 25 pm in diameter, was considered as the best estimate. The lower and upper bound values were for particles in the sizeranges 1-to-5 pm and >25 pm, respectively. The mass of FR chemical released from impaction 

### (Mp)was measured as described above. Nondetects were assumed to equal one-halfthe detection limit (Table 7). All of the FM-550TM samples and most of the TDCP samples were non-detects. The components of FM-550TM could not be quantified individually (Cobb and Bhooshan 2005). Therefore, the total migration of FM-550TM was used to calculate exposureto each component (TPP, PIP, or Om). The total amount of FR chemical retained by the filters was assumed to be released over the lifetime of the product (15 years).The seating area and seatback are assumed to be constructed with polyurethane foam. This area was estimated as 2.8 m2 (28,000 cm2)for a suite of furnitureincluding a sofa, love seat, and chair (Babich and Thomas 2001). The mock-up has a surface area of 530 cm2or 0.053 m2(9x9 inch). Thus,the scaling factor was calculated by dividing 2.8 m2by 0.053m3,which is approximately 60-fold. Thelower bound assumed a suite of furniture in which only the horizontal seating area included foam. Theupper bound assumed two suites of furniture in the home, such as in a living room and family room. The source strength (Ep)was calculated using equation (13). Physico-chemical properties are summarized in Table 1

### 1. The saturation concentration (CSat) was calculated from the vapor pressure using equation (9). The diffusivity was estimated with equation (10). Theboundary layer height was the value used by theNRC subcommittee (NRC 2000). Values of 0.1-fold and 10-fold were assumed as lower and upper bounds. The decay rate for vapor phase 

### FR was assumed to equal zero (Babich and Thomas 2001; NRC 2000). A value of one was assumed as an upper bound. Table 11. Physico-Chemical Properties Parameter Symbol Units 'TDCP TPP PIPa OTB Molecular mass MM dm01 430.91 326.29 368.37 549.93
" " " " " " -....-...u-......--..--" vapor pressure VP torr 2.7~1 

### o-' 6.3~1 0-6 Csd 3.5x10-' dse <1xl0-~~ Saturation concentration in air Csat ' mg/m 0.63 0.24 0.0069 0.015

" " *...- Diffusivity in air Dair m2/h 0.012 0.013 0.013 0.010

" " Octanol-water partition coefficient.' Log Kow unitless 3.65 4.59 5.31 8.75, 12.0'

a Data are for c-IPDP, a component of PIP b Extrapolated from data for TDCP-treated foam in Cobb and Bhooshan 2005. Extrapolated from empirical data [EPA 2005a, SRC 2006). d Syracuse Research Corp. physical properties database, accessed through the National Library of Medicine ChemlD database. June 2006.

. Model estimate.

f Upper bound model estimate (EPA 2005a). One-half this value (5x10-') was used to estimate Csat. Calculated from the vapor pressure and molecular mass. Estimated as described in Schwope et al. 1989. 

### ' The log Kow is not required for the risk assessment. It is included for discussion purposes. Model estimates for the two component isomers (EPA 2005a).

Thephysical properties of o-PDP(28108-99-8) wereused for PP. PDPis a component of PIP, which is a complex substance. Themolecular mass of OTB was calculated from themolecular formula (Cobb and Bhooshan 2005). Thevapor pressure of OTB is an upper bound estimate I from a mathematical model (EPA 2005a). Because it is an upper-bound, one-half theupper bound estimatewas used to estimate exposure. The vapor pressure of PDPis 

### an estimated value (SRC 2006). The log Kow values for thetwo OTB isomers aremodel estimates. The log KowYs of TDCP, TPP, and IPDP are empirical (SRC 2006). Log Kow is not required for therisk 134assessment calculations, but is useful in comparing the other physico-chemical and biological properties of environmental contaminants. The effective saturation concentration of TDCP was extrapolated from data in Cobb and Bhooshan (2005). TDCP-treated foam was placed in a sealed flask. The TDCP concentrationin

. the air inside the flask was measured at 65°C and 120°C. The concentration at 25°C was estimated from a plot of the logarithm of the concentration against the reciprocal of the absolute temperature, by analogy to the Clausius-Clapeyron equation: I

where: m, slope; and C1,C2,concentrations (mg/m3)at temperatures T1and T2(OK). The concentration at 25°C (273°K) was then calculated from:

5. Bioavailability In general, little information on the bioavailability of the chemicals of interest was available. The AD1 values are based on oral studies. The oralbioavailability of TDCP was reported to be about 90% (Matthews and Anderson 1979). In the absence of appropriate data, the bioavailabilities of the other chemicals are assumed to be 100% (CPSC 1992). Inhalation may also contribute tototal FR chemical exposure. In the absence of appropriate data, 100% of inhaled FR chemical, whether in the vapor phase or bound to particles, is assumed to be absorbed. Dermal exposureislikely to be a significant exposure route for FR chemicals in upholstered furniture. Thepercutaneous absorptionrate for o-TCP, estimated from animal studies,.wasused for the aromatic phosphates TPP and PIP. A dose of 50mg radiolabeled o-TCP dissolved in acetone was applied to the clipped necks of cats (Nomeir and Abou-Donia 1984). The acetone was evaporated under a stream of air. The application site was approximately 10cm2. Thus, the specific dose was approximately 5 mg/cm2. After 12hours, 73% of the applied dose was absorbed. Assuming lSt-order kinetics, the absorption rate was about 0.1h-l:

where: FA, fraction of applied dose absorbed, unitless; KT,percutaneous absorption rate (or transfer rate), h-l; and T, time, h.Solving for KT: -ln(l- 

### FA) 

### KT = T Thepercutaneous absorption rate (KT)for TDCP was derived from invitro studiesusing hairless mouse skin (Hughes et al. 2001). It is the samevalue used previously by the CPSC staff (Babich and Thomas 2001). 14c-~abeled TDCP was applied to the skinby solvent deposition. At 24 hours, from 39 to 57% of the applied dosewas found in the receptor fluid. From 28 to 34% was found in the skin, after unabsorbed TDCP was removed by thorough washing. The percentage absorption at 24 hours, including TDCP in both the receptor fluid and skin, was used to estimate the percutaneous absorption rate. Total absorption of TDCP ranged from 73percent to 85 percent of the applied dose, depending on the applied dose (0.014 to 0.14 pg/cm2). Based on 85 percent absorption at 24 hours, and assuming lSt-order kinetics,the percutaneous absorption rate for TDCPwas estimated as 0.08 h-l. No data relating to percutaneous absorption of OTB were available. The OTB isomers are expected to be extremely hydrophobic, with predicted log 

### &, values of 8.75 and 12(EPA 2005a). The molecularmass (549.93) is relatively high. Percutaneous absorption generally increases with increasing 

### &, and decreases with increasingmolecular mass (Potts and Guy 1992). Other brominated FR chemicalsreviewed by the CPSC staff include DBDPO and HBCD. HBCD was absorbed at a rate of approximately0.003h-' (Babich and Thomas 2001), based on invitro studies (Hughes 2000). 

### In the same study,DBDPO was absorbed at arate of 0.001h-I to 0.01 h-I (Babich and Thomas 2001), depending on the applied dose (Hughes 2000; Hughes et al. 2001). 

### In the absence of appropriate data, a value of 0.01 h-' was assumed for OTB.

### V. RISK Thepotential risk from non-cancer endpoints is evaluatedby calculatingthe hazard index 

### (HI), which is the ratio of the ADD to the acceptable daily intake (ADI), that is: ADD HI =- ADI where: HI, hazard index,unitless; ADD, overall average daily dose,mgkg-d; and ADI, acceptable daily intake, mglkg-d. When the HI is greater than one, the product or exposure scenariounder considerationis considered to present ahazard to consumers. The lifetime individual excess cancer risk was calculatedby:

where: R, lifetime individual excess cancer risk; Q, unit cancerrisk or cancer potency, (mag-d)-'; and LADD, lifetime average daily dose, mag-d. Theresults of the exposure and risk assessment are summarized in Table 12. A. 

### Tris(l,3-Dichloro-2-Propyl) Phosphate (TDCP) The estimated HI for non-cancer effects is 2 in adults and 5 in children. Thus, the estimated exposure exceeds the ADI. The estimated lifetimeindividual cancerrisk in adults is 300 per million,based on a lifetime of exposure to'furniture with similar levels of TDCP. The estimated cancerrisk in children from two-years of exposure to TDCP-containing furniture is 20 per million. Cancer risks greater than one-in-a-millionare considered relevant for regulatory consideration under the CPSC chronichazard guidelines (CPSC 1992). In both adults and children, inhalation of vapor phase TDCP contributed the largest fraction, over 95%, of the total exposure. TDCP exposure from the dermal and oral routes, is based on migration measurements using a mock-up (Cobb and Bhooshan 2005). TDCP exposure from inhalation of airborne particles is alsobased on studies with the mock-up. The exposure estimate for vapor phase TDCP is based on a mathematical model. Empirical data on inhalation exposureto vapor phase TDCP areneeded to assess whetherTDCP may present ahazard to consumers.Table 12. Exposure and Risk Result TDCP 

## - TPP a 

## - PIP a OTB 

## - Adults Children Adults Children Adults Children Adults Children ADD (mglkg-d) 9.5~10" 2.6x10-* 1.8~1 4.8~10" 1.8~1 

### c4 4.0~1 

### o-~ 2.0~1 0"' 5.5~1 

### o-~

. ---."

. . . .......... . Percent of total: 0

.. . -,.. .. .- ..........-.. ... .... - . . . .............. ..... .................... Dermal 1.7 0.7 3.6 1.4 35.3 17.4 2.9

. 1.1

. . .. . ... ..-. . Oral, indirect 0.5 0.4 0.9 0.6 8.5 7.8 7.7 5.7

. ... . - ...... ...... .- Oral, direct 0.0 0.2 0.0 0.4 0.0 ' . 4.6 0.0 3.4 Inhalation, vapor 97.7 98.7 95.6 97.5 56.2 70.1 89.4,. 89.8

... . 

### ... . .- ..... . . . . . ",,-" ........ .- .. . ... .,,-,,* --..- ..... .- Inhalation, particles 0.0 0.0 0.0 0.0 0.0 0.0 0.0' 0.0 AD1 (mglkg-d) 0.005

........... ........ - ........ ....... . -... - .. 

### - ....... -" . ........ ......... ....... . .- . ... LADD (mglkg-d) 9.5~10" 7.4~1 

### o-~ 1.8~1 

### o-~ 1.3~1 1.8~1 

### c4 1.1x10-~ 2.0~10.~ 1.5~1 

### o-' Cancer risk per million 300
ADD, average daily dose; HI, hazard index; LADD, lifetime average daily dose; ND, not determined.

a Deimal, oral, and airborne particle exposures are based on measurements of the OTB component of FM-550TM (Cobb and Bhooshan 2005). b Inhalation exposure to vapor phase FR chemical is based on a mathematical model (see text).

Insufficient data were available to derive ADl's for TPP and PIP. The Hl's a're based on the range of AD1 values for other aromatic phosphate plasticizers (Ferrante 1999a). d Insufficient data were available to derive an AD1 for OTB or related compounds.B. Triphenyl Phosphate (TPP) There was insufficient informationto derive an AD1for TPP. Therefore, the ADI's for other aromatic phosphates (0.01 to 1 mgkg-d) were used to calculate a range of hazard indices. The estimated HI, based on non-cancer effects,ranges from 0.002 to 0.2 in adults and 0.005to 0.5 in children. As with TDCP, inhalation of vapor phase TPP contributed the largest fraction of the total estimated exposure, over 95%. TPP exposure from the dermal and oral routes is based on migration measurements for the OTB component of FM-550TM (Cobb and Bhooshan 2005). TPP exposure from inhalation of airborne particles is based on measurements of OTB release. Exposure to vapor phase TPP was estimated by a mathematical model. Empirical data are needed to estimate TPP exposure more accurately. 

### C. Phenol Isopropylated Phosphate (PIP) There was insufficient informationto derive an AD1for PIP. Therefore,the ADI's for other aromatic phosphates (0.01 to 1 mgkg-d) were used to calculate a range of hazard indices. The estimated HI, based on non-cancer effects,ranges from 0.0002 to 0.02 in adults and 0.0004 to 0.04 in children. Znhalation of vapor phase PIP contributed about 56% of the total estimated exposurein adults and 70% in children. Dermal exposurecontributed about 19% in adults and 9% in children. PIP exposure from the dermal and oral routes is based on migration measurements for the OTB componentof FM-550TM (Cobb and Bhooshan 2005). PIP exposure from inhalation of airborne particles is based on measurements of OTB release. Exposure to vaporphase PIP was estimated by a mathematical model. Empirical data are needed to estimate PIP exposure more accurately. 

### D. Octyl Tetrabromobenzoate (OTB) There was insufficientinformation to derive an AD1for OTB orrelated compounds. The average daily dose was estimated to be 2.0x10-~ mgkg-d in adults and 5.5x10-~ in children. Over 89% of the total estimated exposure in adults and children was from inhalation of vapor phase OTB. Exposure to vapor phase OTB was estimatedby a mathematical model.


# . E. Sensitivity Analysis A sensitivity analysis of the exposure model was conducted to assess variability and uncertainty. This was done by individually adjusting input parameters to the lower or upper bound, and then determiningthe relative effect (ratio) on the estimated average daily dose (ADD). This was done in aroute-specific manner. That is, the effect of varyingparameters that apply to multipleroutes was based on the total ADD. The effects of varyingparameters that apply only to dermal, oral, or inhalation exposure,were based on ADDD,ADDo, and ADDI, respectively. TDCP exposure was the basis for the sensitivity analysis (Table 13).Table 13. Route-SpecificSensitivity Analysis I Best 

### I

. . Parameter

. 

### / Estimate 

# 1 Lower Bound 

## I Upper Bound

. iiiiiiiii iiii ..... L.- ... -..... I i j 

# I value Ratio 

### I

. Value Ratio f All Routes i 

### I i i Bodyweight, W, kg

. 

### 1 72 i 50 1.4 

## 1 105 0.7 Years of exposure, Y, y 15 1.0 

### 1 75 1 .O Product Product ; lifetime, >P,y i : 15 1 5 -1.0 

## I i 25 I .O

......... i.i.-.i-. .~.....i..i..i.i.i..i.i~i...

.......ii ...i...i.......i..+... -..... .. ..... surface area, Sp, cm2. 

### / 28,000 

### 1 17,000 0.6 , 56,000

. 1.9 i Dermal 

## I i I i i I i Fabric to skintransfer, F 1 0.13 1 0.024 0.2 

## 1 0.84 6.5 Surface area of exposed skin, S, cm2 

## ( 1,700 

# 1 700 0.4 

### 1

. 6,000 3.5 i Exposure duration, T, h/d 

# " / 4 I 0.5 0.1 I 16 4.0 I I j Oral

. , i i Mouthed surface area, hand, SH,cm2 

# 1 450 ( 45 0.1 1 900 2.0 I Handto mouthtransfer, FH,d-' 

# 1 0.4 

## ( 0.03 0.1 1 7 17.5 i ~~uthed surface area, fabric, S, cm2 

# I 0 

# I 0 

### -- ! 50

. "- .. ............. I .................................. . i ...i...i~..ii..i~i..ii.i.ii..i..ii.i..iiii.iiiiiii.iiiiii.iii..ii.ii.. .-.L . 

### - . . . . 1.8 Fabric to mouth transfer, FM,d-' 1 i 0.4 1 i 0.03 1.0 

## 1 .7 1 .O
; .......... 4 2 . . - Fabric to skin transfer, F 

# / 0.13 0.024 0.2 

### 1 0.84 6.5 i ! Inhalation i i Average inhalation rate, I, m3/h i 0.55 

# 1' 0.4 0.7 1 .O 1.8

. - .. i . i . . .- *- .. .... i Exposure duration, breathing zone, j 

## ! 0.5 TI, h/d 0.5 

### j 24 2.7

.- . . .- . i 4 ; 1 Exposure duration, outside breathing i I. 12 

### 1

2, 8 0.8 23.5 zone, TP,h/d 0.9a , ...... . ................................................................................................................................................................................ -. .....I....... +." +

Scaling factor, FP 30 1.0 I - 120

,I -0 i Breathing zone volume, V1,' m3 1 1.7 1
- 0.85 1.0 

### I 3.4 1 .O

.. ................. . ....... . .... iii.ii~iiiii..iiii.iiii.iiiiiiii.i.iiiii.~

........................................ ......- .. 2- . ........-..... ......... -....... -........ ....... i Room volume;V2, m3 

### / 120 

### / 60 1.5 

## f 320 0.9

.. L

. ..-r

................... 

### . 4

.... - -.....................

Air infiltration rate, A, hi' 

## I -0.4 

### 1 0.15 1.6 

### 1 1.7 0.6 Inter-zone exchange rate, m3/h i Particle decay rate, KD,h-' 

### 1, 2.0 ] 0.5 1.0 

### I 4.0 1 .O

...... ......... ....... :. . ............ :. 

### i Vapor phase decay rate, Kv, h-' 10 0 -- i 

### i 0.6

. ....... .. .. 4 . .. ................... Boundary layer height, H, m 

### 1 0.01 

### / 0.001 2.9 

### / 0.1 0.1 This sensitivity analysis is based onthe estimatedTDCP exposure to adults. The ratio is the relative effect on the ADD when parameters are varied individually from the best estimate to the lower or upper bound. Ratios for parameters affecting all routes are based on the total ADD. Ratios for the dermal, oral, and inhalation parameters are based on ADD(D), ADD(O), and ADD(I), respectively.

a TI was set to the lower bound so that T1

### +T2I24 h.Varying theparameters that affect all routes-body weight, years exposed, product lifetime, and product surface area-had very small effects on the overall average daily dose. Varying these parameters generally had a small effect on cancer risk, except that thecancer risk is directly related to years of exposure (Table 14).

, Table 14. Sensitivity of Cancer 

### Risk to Selected Parameters 

# I Best 

## / Lower Bound Parameter i Estimate l Upper Bound i

........ : . . - L. 4
. . :
. : . i 

### ! Value Ratio Value Ratio Body weight, W, kg 

## , 72 1 I 50 1.4 

### / 105 0.7

....... .- . iiiiiiiii ..... .............. .......... ............. ... 4 Years of exposure, Y, y
, 1 75 

# 1 15 0.2 

### 1 

### -- --

.-

. .. .- L.

...LLL.......L..... .L,...LL~ jii .......... -.i.i..i.i

....... ............... .-..1 . I Product lifetime, P, y i 15 5 1.0 ( 25 1.O

. ....................................................................................................................................................... j .

Product surface area, Sp, cm2 

# / 28,000 

## , 17,000 0.6 ] 56,000 1.9 This sensitivity analysis is based on the estimated cancer risk in adults exposed to TDCP in upholstery foam. The ratio is the relative effect on risk when parameters are varied individually from the best estimate to the lower or upper bound. By varying the dermal exposureparameters, the estimated dermal exposure ranged from roughly one-tenth to 

### 7 times thebest estimate (Table 13). Thehand-to-mouth transfer factor had a substantial effect on oral exposure; the estimated oral exposureranged from one-tenth to almost 20-fold, relative tothebest estimate. Most of the inhalation parameters had less than a 3-fold effect on exposure. Changingthe inter-zone air exchange rate to the lowerbound resulted in a 5-fold increase in exposure. Increasing theboundary layer height to theupper bound reduced exposure to one-tenth. Reducing theboundary layer height to the lowerbound increased exposure by 3-fold. A sensitivity analysis was also performed using inputparameters for children (Table 15). For children, the fabric-to-mouth transfer factorhad a significant effect, dueto the direct mouthing scenario. Raising this factor to the upper bound resulted in a 12-foldincreasein oral exposure. Thefabric-to-skin transfer factor also had a substantial effect on oral exposure, due to indirect mouthing. All other results (not shown) were essentially similar to those for adults. Generally, the chemical-specific input parameters (Table 7) were based on limited data. For example, the amount of chemical migrating to the liquid phase (M) and the amount released from impaction were (Mp) measured with a limited number of samples and limited number of replicates. Thus, theuncertainty in these values cannot be assessed. Theequations for dermal (1) and oral (4) exposure are linear and,therefore, thevariance in migration (M)would lead to a proportional effect in dermal and oral exposure. Although the equations for inhalation exposure arenonlinear, the concentrations in thebreathing zone (C1) and the room are (Cz)are proportional to the source strength (not shown). The source strength (Ep) for particle-phase 

### F'R chemical isproportional to the amount released by impaction 

### (Mp),as in equation (13). Thus,the variance in the amount released from impaction 

### (Mp)would lead to a proportional effect in the inhalation exposure to particles. Information on the uncertainties of the physico-chemical properties (Table 11) is generallynot available. The precisions of empirical measurements arenot usually reported. Several of the values used here are model estimates or extrapolated values, including the vapor pressures for TPP, PIP, and OTB. The saturation concentrationin air (CSat) and diffusivity 

### (D~) were estimated.

Table 15. Sensitivity Analysis of Oral Exposureto Children

Parameter . j Best 

### I Lower Bouna

, : Upper Bound i 

## I Estimate 

# I value Ratio

. , Value Ratio

. . Mouthedsurface area, hand, SH,cm2 

# 1 130 

# 1 13 0.4 , 260 1.7 I Hand to mouth transfer, FH,d-' 

### 1 0.4 1 0.03 0.4 

### 1 7 12 0 ! Mouthed surface area, fabric, SM,cm2 

## 1 10 

## 1 0.6 1 50 2.5 Fabric to mouthtransfer, FM,d-' 

## 1 0.4 

## 1 0.03 0.7 

## 1 7 7.3 : Fabric-to skin transfer, F 

## 1 0.13 

# 1 0.024 0.5 

## 1 0.84 4.5 1 This sensitivity analysis is based on the estimated oralTDCP exposure to children. The ratio is the relative effect on the oral average daily dose when parameters are varied individually from the best estimate to the lower or upper bound.VI. DISCUSSION This risk assessment should be considered preliminary due to data gaps in several areas. Insufficient toxicity data were availableto derive ADI's for TPP, PIP, and OTB. Only three foam samples were subjectedto exposure testing, and the components of FM-550TM (TPP, PIP, and OTB) could not be individually quantified. No empirical data on emissions of vapor phase chemicals were available. Thus, a mathematical model was used to estimate exposure. However, the lack of vapor pressure data for TPP, PIP, and OTB severely limits the usefulness of the vapor phase model. Data on vapor phase emissions are critical, because inhalation of vapor phase 

### FR chemical appears to contribute the greatest portion of the total exposure. A. Toxicity There was a general lack of inhalation toxicity studies, which is significantbecause inhalation appearsto be the most impoftant route of exposure. There are no data relating topossible interactions among aromatic phosphates and OTB. There are no data to evaluate the relative sensitivityof children or juvenile animals to any of the 

### FR chemicals under consideration. Exposureto carcinogens early in life or in utero may lead to 

### an increased cancer risk (reviewed in EPA 2005b). No adjustments were applied to account for the possible increased sensitivityof children (CSPC 1992). Thus, the risk assessment for children is based only on differences in exposure. The HI'Scalculated for children are conservative in that they are based on a two-year exposure period, while the ADI's used to calculated the HI'S are generallybased on a lifetime of exposure. The cancerrisk in children represents the contribution to the lifetime risk from exposure during the first two years of life. Because only children are exposedby direct mouthing, the risk from this route ofexposure may be added to the risk in adults to obtainthe true lifetime risk. 'However, the estimated cancer risk from mouthing is negligible in comparison to the lifetime cancer risk in adults

Limited toxicological and bioavailability data are available for the components of F'M-550TM. No toxicological data on the mixture is available. There was insufficient informationto derive AD1values for TPP, PIP, or OTB. TPP and PIP are members of a broader class of compounds, the aromatic phosphate plasticizers, that has been reviewed by the CPSC staff. AD1values for other aromatic phosphates, including mixtures, were used as surrogates for TPP and PIP. These other AD1values ranged from 0.01 to 1.0mglkg-d (Ferrante 1999a;Bittner et al. 200 1). Although several aromatic phosphates have been studied in subchronic studies, only two have been tested in chronic studies. The CPSC staff has nominated the aromatic phosphates, as a class, for additional testing by the National Toxicology Program (NTP). There was insufficient information to assess the acute toxicity of OTB, and no information on chronic toxicity. Furthermore, no toxicity data for structurally-related chemicals were identified. Thus, 

### an AD1 and HI could not be estimated.2. Melamine Melaminehas been well studied in comparison to TPP, PIP, and OTB, including two-year studiesin mice and rats. The CPSC staff concludes that melamine does not satisfythe regulatory definition of "toxic." However,we note that the databaseincludes no neurotoxicity or reproductive studies, and only one limited developmental screen. 3. 

### Tris(l,3-Dichloro-2-Propyl) Phosphate (TDCP) TDCPhas alsobeen well studied, including a two-year study in rats. This study was sufficientto derive a chronicAD1level and cancerpotency estimate. However, inhalation appears to be the primary route of exposure, whereas the bioassay was by the oral route. Differences in absorption (i.e., bioavailability), distribution, and metabolismbetween exposureroutes could significantly affect toxicity and carcinogenicity. No information on the inhalation bioavailability of TDCP was available. 

### heref fore, we made the default assumption that 100% of inhaled TDCP was absorbed. To the extent that the bioavailabilityis less than loo%, the inhalation exposure and resulting risk will be overestimated. Any chemical absorbed through the lungs will enter the systemiccirculationprior to being metabolized in the liver. Thus, systemic exposure to the parent compound may be increased. The effect of increased systemic exposure depends on whether the parent compound or a metaboliteis the proximate toxic species. If the parent compoundis responsible for either carcinogenicity or non-cancer effects, then the effective dose and its resultingrisk may be underestimated. TDCP is metabolized to the diester plus 1,3-dichloro-2-propanol (Nomeir et al. 1981;Sasaki et al. 1984). The alcoholis further metabolized to 

### 3-chloro-l,2-propanediol. TDCP is also directly conjugated by glutathione. The species responsible for toxicity and carcinogenicity are unknown, and need not be the same. TDCP is aphosphotriester and 

### ,thus, could be an alkylating agent. TDCP formed adducts with protein and DNA in mice (Morales and Matthews 1980). Thus, direct alkylation by TDCP might contributeto either organ toxicity or carcinogenicity. TDCP is, at best, weakly mutagenic. The diester was not mutagenic in Salmonella, while the diol metabolite was weakly mutagenic (Gold et al. 1978). However, the putative metabolite 

### 1,3-dichloro-2-propanone was a strong direct-acting mutagen. This suggests that a metabolitemay be responsiblefor carcinogenicityandlor toxicity. Overall, TDCP was weakly genotoxicin bacteria and in some mammalian systems. It was generally less mutagenic than the structural analog TRIS. Although TDCP is only weakly genotoxic, the metabolite 1,3-dichloro-2-propanol was mutagenic in Salmonella TA-100 without metabolic activation. Furthermore, TDCP was shown to bind to DNA in vivo. Therefore, the possibility of a genotoxic mode of action for carcinogenicity cannotbe dismissed. On the other hand, the absence of the putative metabolite 

### 1,3-dichloro-2-propanone could explain why TDCP is less mutagenic than TRIS.In any case, genotoxicity is not a prerequisite for applying a linear dose-response model to estimate cancer risk. Linearity at low doses is the default assumption in the absence of convincing evidence to the contrary (CPSC 1992). An understanding of the mode of action or other information relating to the dose responsewould be needed to support a different dose response model. Obtaining sufficient data is generally very difficult and may require years of research (Meek et al. 2003). 

### If the default assumption of low-dose linearity is not applied, then the cancer risk couldbe assessed by a variety of methods, including a non-linear risk model, such as the probit or logit, or by an uncertainty factor approach, applying uncertainty factors to either the NOAEL or a benchmark dose (BMD). For example,using the benchmark dose approach, the dose at which the extra risk is 5% (BMDo5)was estimatedto be 

### 7.7 mgkg-d, using the multistage model (equation (I)) and data for renal tumors. Applying the default uncertainty factors for interspecies differencesin sensitivity and to protect sensitive individuals, the AD1for cancer would be 0.08 mgkg-d. Comparing this to the ADD (Table 12),the HIfor cancer would be 0.1 in adults and 0.3 in children. Thus, by this approach TDCPprobably would not present a cancerhazard to consumers. Thepercutaneous absorption rate of TDCP was estimated from an in vitro study using hairless mouse skin (Hughes et al. 2001). When human skin is not available, skin from the hairless mouse is preferred for in vitro studies (Bronaugh et al. 2005). The studies were performed by U.S. EPA staff at the request of CPSC (Hughes et al. 2001). TDCP was applied to the skin in an acetone solution. The acetone was evaporatedunder a stream of air. Acetone is not likely to damage the skin due to the limited contacttime. The cumulative amount of TDCP in the receptor fluid at 24 hours was added to the amount remaining in the skin after thoroughlyremoving TDCP from the surface of the skin. This is to estimate systemic exposure, since hydrophobic compounds do not partition well into the aqueous receptor fluid (Bronaugh et al. 2005). It is assumedthat TDCP in the skin would 

### be absorbed in vivo. 

### In this case, more than half of the TDCP was in the receptor fluid (Hughes et al. 2001). Thus, including only TDCP in the receptor fluid would reduce the estimated dermal doseby less than 2-fold. In vivo, the amount of chemical remaining within the skin may be considered as a reservoirthat may be absorbed over time. If absorption from this reservoir is sufficiently slow, the reservoir may be lost due to normal exfoliation. Thus, net systemic absorption is the result of two competing events-absorption and exfoliation. As discussed above, over half of TDCP was found in the receptor fluid. Thus, even if the entire reservoir is lost due to exfoliation, which occurs over a period of about 14 days, then the effect on systemic absorption would be less than two-fold. Percutaneous absorption rates may be greaterwith animal than human skin (Bronaugh 2005). Thepercutaneous absorption of a related 

### FRY tris(chloropropyl)phosphate (TCPP),was tested in vitro using human skin and an aqueous vehicle (Maas 2005a). TCPP was absorbed at roughly the same rate as TDCP. This suggests that the hairless mouse model is a reasonable surrogate forhuman skin, and that the acetonein the Hughes et al. (2001) studyprobably did not adversely affect skin permeability. While 

### in vitro studies are generally predictive of 

### in vivo percutaneous absorption rates, 

### invivo studies are preferred. 

### In vitro studiesmay under-predict absorption of hydrophobic compounds, because hydrophobic compounds do not partition well into the aqueousreceptor fluid (Bronaugh 2005). TDCP was reported to be readily absorbed through the skin of rats 

### in vivo, although the study was not designed to measure the absorption rate (Nomeir et al. 1981). Ulsamer et al. (1979, 1980) reported that TDCP was absorbed at twice the rate of TRIS in rabbits. No other detail's were reported. 

### In another study, however, 15% of the applied dose of TRIS was absorbed through the skin of rabbits in 96 hours (Ulsamer et al. 1978a). Thus, TRIS was apparently absorbed at a much lower rate 

### in vivo in rabbits (0.0016 h-l)than TDCPwas absorbed 

### in vitro (0.035h-') using mouse skin. 

### B. Exposure The exposure assessment is limited in that only a small number of foam samples were tested, as well as the limited number of tests on each sample. Therefore, it is uncertain whether these results may be applicable to other foam samples treated with the same chemicals, and how precisely the results can be replicated. However, with the two TDCP samples,migration was roughly proportional to the TDCP content. Foam S (TDCP) and Foam Z (FM-550TM) were selectedbecause they contained the highest FR concentrations available. Furniture treated with theFR chemicals was not availablefor testing. The aromatic phosphate components of FM-550TM generally were not quantified in the exposure studies. Themigration dataused to estimatedermal and oral exposure, as well as data on the ' release of airborne particles, arebased on the OTB component of FM-550TM (Cobb and Bhooshan 2005). Therefore,the exposures for theseroutes areuncertain. Except for mass-balance models in general, the laboratory or mathematicalmodels used to estimate exposure have not been validated by comparison with reliable exposure data, such as from field studies. Appropriatedata do not exist. The mathematicalmodels generally assume conditions of chemical equilibrium and steady-state. These assumptions are commonlyused, in part, because dynamic models are much more complicated. However, the assumption of equilibrium or steady-state conditionsmay over-estimate exposureif steady-stateis not reached during exposure. 

### If exposure depends on a series of intermittentevents that begin each time one sits on an upholstered chair, then it is possible that steady-stateis not achieved. This might be the case for dermal exposure, for example. On the other hand, if exposure is a continuous process, then steady-stateis more likely to be achieved. This might apply to the inhalation of vapor phase FR chemicals, which does not require direct contact with the product. The indoor concentration of vapor phase FR would vary to a degree, depending on ventilation and other factors, but it might be relatively stable over time.1. Dermal Exposure The method for estimating thepotential for dermal exposure was adapted from exposure studies for mattress filling materials (Thomas and Brundage 2006). The method was intended to provide a realistic exposure estimate. However, the appropriate pressure and amount of liquid phase are difficult to estimate, and the values used for mattresses might not be optimal for upholstered furniture. No interliner or batting was present in the mock-up, because some upholstered furniture does not have these components. The presence of an interliner or batting might be expected toreduce migration. As with mattresses, these migration data were also used to estimate oral exposure. Recently, the migration of TCPP from polyurethane foam was studied using artificial sweat as a solvent (Maas 2005b). TCPP is structurally related to TDCP. A stack of 15filters was placed directly on the foam. Total TCPP released was 5.6pg/cm2withno pressure applied and 9.2 pg/dm2 with pressure applied (Maas 2005b,Appendix 1). 

### Jn comparison, themigration of TDCP ' , was 0.15 pg/cm2, as measured by the CPSC staff (Cobb and Bhooshan 2005). The different results may be due, in part, to differences in methodology and the type of foam. 

### Jn addition, TCPP is about 10-fold more water-soluble than TDCP (IPCS 1998). 2. Inhalation Exposure The potential for release of particles containing FR chemicals was also assessed using a method developed for mattresses. For the most part, FR chemicals were not detectable in airborne particles released when the mock-up was subjected to impaction. Therefore, it does not appear that inhalation of particles would contribute significantly to consumer exposure. This is not unexpected, since the foam is resilient and is an internal component. However, aged or inservice foams were not tested. The source strength of vapor phase FR chemical was estimated using a mathematical model that is essentially similar to the model described by the NRC Subcommittee on Flame Retardant Chemicals (NRC 2000; see also Babich and Thomas 2001). The model includes several conservative assumptions, including the lack of affinity of the FR for the foam and barriers to vaporization of FR chemical. In practice, theFR chemicals may have an affinity forthe foam matrix due to covalent or non-covalent binding. The foam, interliner, and cover fabric may all impede the release of FR chemical into air. Also in accordance with theNRC study, we assumed that there are no sinks or decayprocesses to attenuate the indoor concentration dueto the lack of data to estimate the rates of these processes. Semi-volatilechemicals areknown to be absorbed by other household furnishings or materials, including carpets, draperies, and wallboard. This tends to reduce the indoor air levels of these chemicals. Vapor phase FR chemicals may also be adsorbed to airborne particles or break down to other substances. Therefore, the model is expected to overestimate exposureto vapor phase FR chemical. Furthermore, in the absence of bioavailability data, 100% absorption and retention of vapor phase chemicals was assumed.Although.the vapor phase model includes a number of conservative assumptions, the source strength calculation isbased on diffusion in a static environment. This maybe most applicable to a scenario in which upholstered furniture sits in an unoccupied room. However, typical use of the furniture such as sitting, fidgeting, or active child play will apply mechanical actions that might increase therelease of vapor phase 

### FR chemical, as well as particles. Thereliance on a purely theoretical model to estimate vapor phase exposure is of concern, because inhalation was the major route of exposure for all of the compounds under consideration, accounting forbetween 75% and 99% of the total estimated exposure (Table 12). Furthermore, there is considerable uncertainty in the vapor pressures of several of the FR chemicals, which are primary input values to the model. Empirical vapor pressures are not available for PIP and OTB. The vapor pressures for PIP (SRC 2006) and 

### OTB (EPA 2005a) were estimated from mathematical models. Thevapor pressure of TPP was extrapolated from empirical data (EPA 2005a; SRC 2006). Several different vapor pressures havebeen reported for TDCP. The empirical vapor pressure was reported to be 0.01 torr at 30°C (IPCS 1998) and 0.024 ton at 20°C (Supresta 2006). Another report gives the empirical vapor pressure at temperatures ranging from 50to 500°F (Akzo 1998), from which we interpolated the vapor pressure tobe 0.15 torr at 20°C and 0.2torr at 25°C. Other authoritative sourcescite estimated vapor pressures of 1x10-~ torr (EPA 2005a) and 7.4x10-~ torr at 25°C (SRC 2006). The CPSC staff measured the concentration of TDCP vapor at 65°C and 120°C in a sealed flask containing either liquid TDCP or TDCP-treated foam (Bhooshan and Cobb 2005). From these data we extrapolated the vapor pressure at 25°C as 0.0014 tom. 

### In addition, the effective vapor pressure with TDCP treated foam was estimated as 2.7x10-~ torr at 25°C. Because TDCP was not detected at 65"C, we used one-half the detection limit for extrapolation. The vapor pressure estimated from TDCP-treated foam was used in the present risk assessment, because it is based on empirical data and it was obtained with TDCPtreated foam. Thus, it replaces two conservative assumptions of the mathematical model, that the 

### FR chemical does not have 

### an affinity for the foam and that the foam does not impede evaporation. The average daily dose (ADD) for TDCP was estimated to be 0.023 mglkg-d, with over 99% from inhalation of vapor phase TDCP (Table 12). Because most of the exposure was from inhalation of vapor phase TDCP,the vapor pressure has a significant impact on risk. However, changingthe vapor pressure to the highest reported value increases the estimated hazard index and cancer risk only slightly (Table 16). This isbecause in the standard case, the source strength is near the maximum value allowed by the model. The maximum emission rate is therate that would deplete all of the 

### FR chemical during the lifetime of the product, defined by equation (7). Changingthe vapor pressure to the lowest reported value decreases the hazard index for noncancer effects to well below a value of one. However, the cancer risk is still greater than one per million, largely due tothe contribution of the other exposure routes. Even if the vapor pressure were zero, the estimated risk would be 7 per million (not shown).Table 16. Effect of Vapor Pressureon 'TDCP Hazard Index and Cancer Riska VP, Torr HI VP Source Note Cancer Risk per Million 7.4~10" 0.05 7 SRC 2006 Estimate <I .ox10-6 0.08 20 EPA 2005a Estimate

" 2.7~1 

### o-~ 2 300 Bhooshan and ' Empirical, with Cobb 2005 treatedfoam
" - 1.4~1 6 900 Bhooshan and Cobb 2006 Empirical

... " " "...,,, " . 1.ox10-'

. . 6 900 IPCS 1998 Empirical

" " -

. . 2.0~10-' 6 900 Akzo 1998 Empirical

a In adults. VP, vapor pressure; HI, hazard index. b Calculated as one-half the detection limit, or 5x10-'.

. Value used in the risk assessment. Theuncertainty in estimating inhalation exposure can bereduced by obtaining empirical data in a setting that at least approximates typical use. A simple approach would beto measure vapor levels in the impaction studies that were used for particle release. Another approach would beto make measurements in a test house with FR-treated furniture. In estimating inhalation exposures, the indoor environment was modeled as a two-zone model, including a breathing zone (Thompson and Thompson 1990) and theroom in which the upholstered furniture is located. This approach was used because concentrations of airborne pollutants are generally higher near the source. A consumer sitting on a couch is not only close to the source, but the consumer's movements may contributeto it. This breathing zone approach requires assumptions regarding the size of thebreathing zone, the air exchange ratebetween the breathing zone and room air, and the exposure duration in each zone. An alternative to the two-zone model is a single-zone model in which the zone is the size of an entirehome. Any emissions of vapor or particles are assumed to beevenly distributed throughout the home. In reality, the concentrations of airbornepollutants are greater near the source (breathing zone) and in the room where the source is located. However, when interior doors are open or when forced air heating and air conditioning are operating, the differences in concentration arerelatively small. Treating the entire home as a single zone essentially averages the various microenvironments (rooms and proximity to the source). Using a one-zone model with a volume equivalent to the room volume (V2)(120 m3) would reduce the ADD of 

### TDCP from 9.5~10'~ mglkg-d to 5.7x10-~, or less than Zfold (not shown). Therefore, in this case the choice of model has a small,perhaps Zfold, effect on the estimated HI and cancer risk.

1 Other than the impaction experiments,thepotential effects of accelerated aging or wear on dermal or oral exposure were not evaluated. Small-scalemock-ups were used in lieu of furniture samples, which were not available.. . 

### C. Variability and Uncertainty The variability and uncertainty associated with general input parameters were assessed by a sensitivity analysis. That is, the input variables were varied individually from the lower to upper bound. The effects on the estimated exposure were generally modest. 

### In most cases, the estimated exposure varied by less than 5-fold from thebest estimate (Tables 13-15). The oral exposure was most sensitiveto the hand-to-mouth transfer factor. Changing this parameter to the lower or upper bound changed the oral exposure to either one-tenth or 18-times thebest estimate. Dermal exposure was most sensitiveto thefabric-to-slun transfer factor, with a range of from one-fifth to 7-fold. Inhalation exposure was most sensitive to the inter-zone air exchangerate. At the lower bound, the estimated exposure increased by almost 5-fold. The effect was minor at theupper bound however. Furthermore, the sensitivity analysis does not capture all sources of uncertainty. Some parameters arebased on data with surrogate chemicals, including the fabric-to-skin and hand-tomouth transfer factors (Tables 5-1 1). Hand-to-mouth transfer was used as a surrogate for the fabric-to-mouth transfer factor. Some input parameters, such as the surface area of exposed skin and exposure durations, arebased on a combination of empirical data and assumptions. Others, such as the inter-zone air exchange rate and boundary value height, are assumptions. The variability of chemical-specific input parameters, such as migration and particle release, were not considered due to the limited number of samples tested. Thus, variability between diffeient products cannot be assessed. Theprimary contributor to the estimated exposure is inhalation of vapor phase FR chemical. However, there are no empirical data to estimate inhalation exposure. Rather, a purely mathematical model was used. Furthermore, this model is highly dependent on the vapor pressure of the chemical. Empirical vapor pressure values arenot available for several of the FR chemicals of interest. Their vapor pressures were estimated by mathematical models, in part because the vapor pressures are low and difficult to measure. Nonetheless, we used a mathematical model using input data from another model, compounding the uncertainty. TDCP has measured vapor pressures between 0.01 to 0.24 ton. In contrast, model estimates range from 1x10-~ torr and 7.4x10-*torr at 25OC. The discrepancy between the empirical and estimated vapor pressures suggests that the estimated vapor pressures for PIP and OTB may be highly uncertain. Probabilistic methods were not used in this case to assess variability and uncertainty, dueto the lack of adequate information on the distributions of most of the variables. Somepotentially significant sources of uncertainty are difficult or impossible to quantify. Most of the models and methods used to estimate exposure have not been validated. Thus, it is impossibletoknow whether these methods reasonably approximate true exposures. The effect of additional toxicity data on AD1values cannot be predicted. The cancer unit risk estimate for TDCP is highly dependent on the choice of doseresponse model. At present, it is impossibleto know which model is more likely to be correct. The default model used by the CPSC staff generally results in a higher cancer risk estimate. The use of alternative models (e-g.,non-linear dose response models) would most likely reduce the estimated cancer risk. Using an uncertainty factor approach could result in a negligible cancer risk. However, based on the CPSC chronic hazard guidelines, the default assumption of low-dose linearity is applied unless there is convincing evidence tojustify an alternative approach. while there are many sources of uncertainty,most of them can be addressedby additional studies on toxicity and exposure. 

### D. Conclusions The following conclusions are based on limited exposure and/or toxicity data, and should be regarded as preliminary. Based on a mathematical model derived by the National Research Council (NRC 2000), inhalation of vapor phase 

### FR chemical appears to be the primary route of exposure for TDCP and the components ofFM-550TM. The model contains several assumptionsthat may tend to overestimate inhalation exposure. However, the model and certain input parameters are also highly uncertain and, therefore, may either overestimate or underestimate exposure. '~m~irical data on vapor phase emissions or indoor concentrations are needed to assess whether these chemicalsmay present a hazard to consumers. Based on the limited available exposure data, upholstered furniture manufactured with TDCPtreated foam in upholstered furniture might present a hazard to consumers,based on both cancer and non-cancer hazards. As discussed above, empirical data relating to TDCP emissions are needed to assess whether TDCP may be hazardous to consumers. Based on the limited available toxicity and exposure data, it does not appearthat TPP or PIP would present a hazard to consumers. However, there were insufficient toxicity datato derive ADI's forTPP and PIP. This conclusion is based on the assumption that TPP and PIP are not more toxic than other aromatic phosphates. Additional toxicity and exposure data are needed to assess whether TPP or PIP may be hazardous to consumers. The National Toxicology Program (NTP) is considering a request from the CPSC staff to perform additional toxicity studies on aromatic phosphates. The staff will review any additional toxicity data that become available. As discussed above, empirical data relating to emissions of these compounds are also needed to assess whether they may be hazardous to consumers. Exposure data specific for TPP and PIP are alsoneeded toreduce the uncertainty in exposure. No chronic toxicity data on OTB or related compounds are available. The toxicity andipotential risks of OTB cannot be assessed. Basic toxicity data and an empirical vapor pressure (or upper bound) are needed to conduct a preliminary risk assessmentfor OTB. Continued development and validation of the exposure methods in general would also serveto reduce the uncertainty in estimating exposure to FR chemicals. Melaminehas been studied in chronicbioassays (reviewed in Thomas and Brundage 2004). Melamine does

### not satisfy the regulatory definition of toxic. Thus, exposure studies withmelamine-treated foam were notpecessary. Based on the available data, melamine-treatedfoam is not expectedto present a hazard to consumers. A number of otherFR treatments that couldbe used in foam havebeen discussed by the U.S. EPA's Design for the EnvironmentProgram @PA 2005a). In summary, the staff concludes that: Based on the available data, melamine-treated foam is not expected to present a hazard to consumers. Inhalation studies are lacking for TDCP, TPP, PIP, and OTl3. This is significantbecause inhalation appears to contribute the greatest portion of the total exposure. Empirical data on vapor phase emissions or indoor concentrations are needed to assess whether TDCP, TPP, PIP, or OTB maypresent ahazard to consumers. Chemical-specific data on liquid-mediationmigration and airborne particle release are needed to assess more accuratelywhether TPP and PIP may present a hazard to consumers. Additional toxicity data are needed to derive acceptable daily intake values for TPP and PIP. Basic toxicity and physico-chemicaldata for OTl3 areneeded to derive an acceptable daily intake value and to estimate exposure.VII. 

### REFERENCES'

. Abou-DoniaMB,Momeir AA, Bower JH, Makkawy HA (1990) Absorption, distribution, excretion and metabolism of a single oral dose of [14C]tri-o-cresylphosphate (TOCP) in the male rat. Toxicology 65: 61-74. Akzo Nobel (1998) Technical Data Sheet for Fyrol FR-2. Akzo Nobel Functional Chemicals LLC, Dobbs Ferry, NY. November 1,1998. Accessed July 25,2006. http://phosphorus.akzonobelusa.com/business/phosphorus/TDS/TDS Fyrol.htm1 Babich MA, Hatlelid K, Osterhout C (2004) Update on the toxicity of selected flame retardant chemicals. U.S. Consumer Product Safety Commission, Directorate for Health Sciences, Bethesda, 

### MD 20814. July 20,2004. Babich MA, Saltzman LE (1999)Tris(chloropropy1) phosphate (TCPP). U.S. ConsumerProduct Safety Commission,Directorate for Health Sciences, Bethesda,

### MD 20814. August 4, 1999. Babich MA, Thomas TA (2001) CPSC staff exposure and risk assessmentof flame retardant chemicals in residential upholstered furniture. U.S. Consumer Product Safety Commission, Bethesda, 

### MD 20814. April 2001. BIBRA (1987) The effects of DVP412 on cultures of guinea-pigalveolar macrophages. British Industrial Research Association ;Surrey,UK. Prepared for Ciba-Geigy, CheshireUK. October 1987. EPA document no. 86-880000110. Biodynamics (1981) A two-year oral toxicity/carcinogenicitystudy on Fyrol FR-2 in rats (final report). EPA no. OTS204911. Bittner PM (1999a) Toxicity review for decabromodiphenyl oxide. U.S. ConsumerProduct

. Safety Commission, Directorate for Health Sciences, Bethesda,

### MD 20814. March 3, 1999. 

### , Bittner PM (1 999b) Toxicity review forphosphonic acid, (3-{ [hydroxymethyl]a~hino) -3- oxopropyl-, dimethyl ester. U.S. ConsumerProduct Safety Commission, Directorate for Health Sciences, Bethesda,MD 20814. March 3, 1999. Bittner PM (1999~) Toxicity review for tetrakis(hydroxymethy1) phosphonium salts precondensate with urea. U.S. Consumer Product Safety Commission, Directorate for Health Sciences, Bethesda, MD 20814. March 6,1999. Bittner PM (1999d)Toxicity review for tris(2~chloropropyl) phosphate. U.S. Consumer Product Safety Commission, Directorate for Health Sciences, Bethesda,

### MD 20814. March 3, 1999. Bittner PM (2001) Update on the flame retardant (FR) chemicals toxicity reviews. U.S. ConsumerProduct Safety Commission, Directorate for Health Sciences, Bethesda, MD 20814. April 4,2001.Bittner PM, Ferrante J (1999) Comparison of British Department of Trade and Industry toxicity assessments on selected flame retardant (FR) chemicalsto the CPSC toxicity reviews of identical or similarFR chemicalsor chemical classes. U.S. ConsumerProduct Safety Commission, Directorate for Health Sciences, Bethesda,MD 20814. August 6, 1999. Bittner PM, Ferrante J, Hatlelid 

### KM, Saltzman LE, Babich MA (2001) An evaluation of the toxicity data for selected flame retardant chemicals. The Toxicologist 60: 2014A.



### - Brandwene D (2001)High ProductionVolume (HPV) Challenge Program test plan and robust summary for 

### tris(l,3-dichloro-2-propy1)phosphate. Akzo Nobel Functional ChemicalsLLC, Dobbs Ferry, 

### NY. March 2001. Bronaugh RL, KraelingMEK, Yourick JJ (2005) Determination of percutaneous absorptionby in vitro techniques. In, "Percutaneous Absorption," 4" Edition, Bronaugh 

### RL, Maibach HI, editrs. Taylor and Francis Group,New York. Chapter 18. Pages 265-269. Brusick D,Matheson D., Janannath DR, Goode S, Lebowitz H, Reed M, Roy G, Benson S (1980). A comparis,onof the genotoxicproperties of tris(2,3-dibromopropy1)pohosphateand 

### tris(l,3,-dichloro-2-propy1)phosphate in a battery of short-termbioassays. Journal of Environmental Pathology and Toxicology 3: 207-226. Burin GJ, Gibb HJ, Hill 

### RN (1995)Human bladder cancer: evidence for a potential irritationinduced mechanism.Food and Chemical Toxicology 33: 785-795. As cited in Thomas and Brundage 2004. CamarasaJG, Serra-Baldrich E (1992) Allergic contact dermatitis from triphenyl phosphate. Contact Dermatitis 26: 264-5. Carlsen L, Andersen 

### KE,Egsgaard H (1986) Triphenylphosphate allergy from spectacle frames. ContactDermatitis, 15:274-277. Carlton BD, Basaran AH, Mezza LE, Smith MK. (1987) Examination of thereproductive effects of tricresyl phosphate administered to Long-Evansrats. Toxicology 46: 321-8. Cascieri T, PoinsettWW (1977) KronitexTM200 triaryl phosphate neurotoxicity screening study in hens. FMC Corporation, Princeton,NJ. EPA document no. 40-7742029. September 1977. Casida JE, Eto M, Baron RL (1961) Biological activityof a tri-o-cresyl phosphate metabolite. Nature 191: 1396-1397. Celanese Corporation (1960) Mellon InstituteReport, Cellulube FR-2. Celanese Corporation of America. February 1960. As cited in Ulsamer et al., 1980. Centers for Disease Control (CDC) (2000) CDC Growth Charts: United States. National Center for Health Statistics,Centers for Disease Control and Prevention, Hyattsville, MD. December 4, 2000.Chapin RE, George JD, Lamb JC 4th. (1988) Reproductivetoxicity of tricresyl phosphate in a continuous breeding protocol in Swiss (CD-1) mice. Fundamental and Applied Toxicology 1988 10:344-54. CifoneMA (2005)In vivo/invitro unscheduled DNA synthesis in rat primary hepatocyte cultures at two timepoints with a dose range finding assay. Covance Laboratories, Vienna,VA. Prepared for Albemarle Corporation, Baton Rouge, LA and Supresta,Ardsley, 

### NY. Study number 7674- 102. November 4,2005. Cobb D (2005) Migration of Flame Retardant Chemicals in Mattress Barriers. U.S. Consumer Product Safety Commission, Bethesda,

### MD 20814. December 2005. Cobb D, Bhooshan B (2005) Migration of flame retardant chemicals in upholstered furniture foam. U.S. Consumer Product Safety Commission,Bethesda,MD 20814. December 10,2005. Cobb D, Chen S-B (2005) Analysis of 

### FR chemicals added to foams, fabric, batting, loose fill, and barriers. U.S. ConsumerProduct Safety Commission, Bethesda,MD 20814. May 10,2005. Cohen Hubal EA, Suggs JC, Nishioka MG, Ivancic WA (2005) Characterizing residue transfer efficiencies using a fluorescent imaging technique. Journal of Exposure Analysis and Environmental Epidemiology 15: 26 1-270. ConsumerProduct Safety Commission (CPSC) (1983) Risk Assessment on Di (2-ethylhexyl) Phthalate in Children's Products. U.S. CPSC, Washington, DC 20207. August 1983. ConsumerProduct Safety Commission (CPSC) (1 990) CPSC HAZARD-IFire Assessment Model. User Manual and Tutorial. U.S. Consumer Product Safety Commission, Bethesda,MD 20814. September29,1990. Page 3. Consumer Product Safety Commission (CPSC) (1992) Labelingrequirements for 

### art materials presenting chronic hazards; guidelines for determining chronic toxicity of products subjectto the FHSA; supplementary definition of "toxic"under the Federal Hazardous Substances Act; final rules. Federal Register 57:46626-46674. ConsumerProduct Safety Commission (CPSC) (1997)BriefingPackage on Upholstered Furniture Flammability: Regulatory Options for Small Open Flame and SmokingMaterial Ignited Fires. U.S. Consumer Product Safety Commission,Bethesda, 

### MD 20814. October 1997. Consumer Product Safety Commission (CPSC) (2003) Ignition of Upholstered Furniture by Small Open Flames andlor Smoldering Cigarettes;Advance Notice of Proposed Rulemaking; Request for Comments and Information. Federal Register 68: 60629-60632. Thursday, October 23,2003. Crump KS (1984) An improved method for low-dose carcinogenicrisk assessment from animal data. Journal of EnvironmentalPathology and Toxicology,5: 675-684.Dollahite

### JW, Pierce 

### KR (1969) Neurologic disturbances due to triaryl phosphate toxicity. American Journal of Veterinary Research 30: 1461-1464. Environmental Protection Agency (EPA) (1985) Review of in vivo absorptionthrough human epidermis of Reofos 50. Internalmemorandum from Letty Tahan to John Helm. Environmental Protection Agency, Office of Toxic Substances, Washington, DC 20460. October 1985. EPA document no. 40-85421350. Environmental Protection Agency (EPA) (1992) A cross-species scaling factor for carcinogen risk assessment based on equivalenceof mg/kg3'4/day. Federal Register 57: 24152-24173. Environmental Protection Agency (EPA) (1997) Exposure Factors Handbook. Office of Research and Development, U.S. Environmental Protection Agency, Office of Toxic Substances, Washington, DC 20460. August 1997. EPA 600P-951002F. Environmental ~rotiction Agency (EPA) (2005a) "Furniture Flame RetardancyPartnership: Environmental Profiles of ChemicalFlame-Retardant Alternativesfor Low-Density PolyurethaneFoam." Design for the Environment Program,U.S. EnvironmentalProtection Agency,Washington, DC. September2005. Environmental Protection Agency (EPA) (2005b) Supplemental Guidance for AssessingCancer Susceptibility from Early-Life Exposure to Carcinogens. U.S. EnvironmentalProtection Agency, Risk AssessmentForum, Washington DC 20460. March 2005. EPAl630lR-031003F. Eto M, Casida J, Eto T (1962) Hydroxylation and cyclizationreactions involved in the metabolism of tri-o-cresylphosphate. Biochemical Pharmacology 11: 337-352. Ferrante J (1999a) Toxicityreview of aromaticphosphate plasticizers. U.S. Consumer Product Safety Commission, Bethesda,

### MD 20814. June 7, 1999. Ferrante J (1999b) Toxicity review of tris (1,3-dichloropropyl-2) phosphate (Fyrol FR-2 or TDCP). U.S. Consumer Product Safety Commission, Bethesda,

### MD 20814. Undated. Ferrante J (1999~) Toxicityreview for 

### tris(1-chloro-2-propy1)phosphate and bis(2-chloropropyl) 1-(chloro-2-propyl)phosphate. U.S. Consumer Product Safety Commission, Directorate for Health Sciences, Bethesda, MD 20814. July 9, 1999. Ferrante J (1999d) Toxicityreview for alumina tihydrate. U.S. Consumer Product Safety Commission, Directorate for Health Sciences, Bethesda,

### MD 208 14. Undated. Ferrante J (1999e) Toxicity,reviewfor magnesium hydroxide. U.S. ConsumerProduct Safety Commission,Directorate for ~ealth' Sciences, Bethesda,

### MD 208 14. Undated. Ferrante J (1999f) Toxicityreview for ammoniumpolyphosphates. U.S. Consumer Product Safety Commission, Directorate for Health Sciences, Bethesda,

### MD 20814. Undated.

156FMc Corporation (FMC) (1969) Acute toxicity study in rats administered 10materials. FMC, Corporation, ~altimore, MD. EPA document number 40-6942188. June 1969. FMC Corporation (FMC) (1977) A neurotoxicity studyin hens administered commercially available phosphate ester products. FMC, Corporation, Princeton, NJ. EPA documentnumber 40-7642197. April 1977. FMC Corporation (FMC) (1979) Health effect studies on various aryl phosphates. FMC, Corporation, Philadelphia, PA. EPA'documentnumber40-7442485. November 1979. FMC Corporation (FMC) (1981) Evaluation of the test article Kronitex 50 for mutagenic potential employing the L5178Y TK +I-mutagenesis assay. FMC, Corporation, Philadelphia, PA. EPA document number 40-8 142497. August 1981. Freeman C (1990) Nandefinitive acute toxicity studies--dermal, oral, primary kin and eye irritation with triaryl phosphate esters-Durad TM 110, 300 and 20B. FMC Corporation, Philadelphia, PA. EPA document number 86-910000033. Freudenthal 

### RI, Henrich RT (2000) Chronic toxicity and carcinogenic potential of tris-(1,3- dichloro-2-propyl) phosphate in Sprague-Dawley rat. International Journal of Toxicology 19: 119-125. Gold NID, Blum A, Ames BN (1978) Another flame retardant,tris-(l,3-dichloro-2-propy1)- phosphate, and its expected metabolites are mutagens. Science 200: 785-787. Great Lakes Chemical Company (2005) Material Safety Data Sheet for FiremasterTM 550. Great Lakes Chemical Company, West Lafayette, IN. March 10,2005. MSDS no. 00896. Greene, M.A. (1998) Statistical methods for prediction of DINP intake by young children. U.S. Consumer Product Safety ~omdssion, Bethesda, MD 20814. December 1998. Hatlelid K (1999a) Toxicity review for antimony trioxide. U.S. Consumer Product Safety

, Commission, Bethesda,

### MD 20814. March 2, 1999. Hatlelid'K (1999b)Toxicity review for hexabromocyclododecane. U.S. Consumer Product Safety Commission, Bethesda, MD 20814. March 2, 1999. Hatlelid K (1999~) Toxicity review for cyclic phosphonate esters. U.S. Consumer Product Safety Commission, Bethesda,

### MD 20814. February 8, 1999. Hatlelid K (1999d)Toxicity review for organic phosphonates. U.S. Consumer Product Safety Commission, Bethesda,MD 20814. February 8, 1999. Hatlelid K (1999e) Toxicity review for chlorinatedparaffins. U.S. Consumer Product Safety Commission, Bethesda, MD 208 14. March 25, 1999.Hatlelid K (1999f) Toxicity review for calcium molybdate and zinc molybdate. U.S. Consumer Product Safety Commission, Bethesda,

### MD 20814. March 2, 1999. Hatlelid K (19998) Toxicity review for antimony pentoxide and sodium antimonate. U.S. Consumer Product Safety Commission, Bethesda,

### MD 20814. March 2, 1999. Hatlelid K (199911) Toxicity review for zinc borate. U.S. Consumerproduct Safety Commission, Bethesda, 

### MD 20814. March 2, 1999. Hatlelid K (2003) Cancer risk assessment for arsenic exposure from CCA-treated playground structures. U.S. Consumer Product Safety Commission, Bethesda,

### MD 20814. January 23, 2003. Haworth S,Lawlor T, Mortelmans K, SpeckW, ZeigerE (1983) Salmonella mutagenicity test results for 250 chemicals. Environmental Mutagenesis 5 (Suppl. 1):l-142. Henrich RT (1998) Letter from RT Henrich, Akzo-Nobel Chemicals, Dobbs Ferry, NY, to Dale Ray andMichael Babich, U.S. Consumer Product Safety Commission, Bethesda, MD. June 2, 1998. Henrich R (2001) Test and robust summaries for isopropylated diphenyl phosphate. Great Lakes Chemical Corporation, west Lafayette,

### IN. November 29,2001. Henschler D, Schmuck G, van Aerssen M, Schiffmann D (1992) The inhibitory effect of neuropathic organophosphate esters on neurite outgroyth in cell cultures: a basis for screening for delayed neurotoxicity. Toxicology in Vitro 6: 327-335. Hinton DM, Jessop JJ, Arnold A, Albert 

### RH, Hines FA (1987) Evaluation of immunotoxicity in a subchronic feeding study of triphenyl phosphate. Toxicology and Industrial Health 3: 71-89. Hjorth N (1964) Contact dermatitis from cellulose acetate film. Cross-sensitizationbetween tricresyl phosphate (TCP) and triphenyl phosphate (TPP). Contact Dermatitis 12: 86-100. As cited in lPCS 1991. Holden CR, Shum KW, Gawkrodger DJ (2006) Contact allergy to triphenyl phosphate: probable cross-reactivityto triphenyl phosphite present in an EN46001 System 22 clear oxygen facemask. Contact Dermatitis 54: 299-300. HonkakoskiP, Palvimo JJ, Penttila L, VepsalainenJ, Auriola S (2004) Effects of triaryl phosphates on mouse and human nuclear receptors. Biochemical Pharmacology 67: 97-106. Howe 

### RB, Crump KS (1983) Globa183. Science Research Systems, Inc., 1201Gaines Street, Ruston,LA 71270. September 1983.Hughes 

### MF (2000)In vitro dermal absorptionrate testing of flameretardant chemicals. National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711. July 25,2000. Hughes MF, Edwards BC, Mitchell CT,Bhooshan B (2001) In vitro dermal absorption of flame retardant chemicals. Food and Chemical Toxicology 39: 1263: 1270. International Agency for Research on Cancer (IARC) (1986) Melamine. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans 39: 333-346. International Agency for Research on Cancer (IARC) (1999) Melamine. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans 73: 329-338. International Programme on Chemical Safety (IPCS) (1990) Tricresyl Phosphate.

, Environmental Health Criteria No. 110. World Health Organization, Geneva.

International Programme on Chemical Safety (IPCS) (1991) Triphenyl Phosphate. Environmental Health Criteria No. 1 11. World Health Organization, Geneva. International Programme on Chemical Safety (IPCS) (1998)Flame Retardants: Tris(chloropropy1) Phosphate and Tris(2-chloroethyl) Phosphate. Environmental Health Criteria No. 209. World Health Organization, Geneva. Johannsen FR,Wright PL, Gordon DE,Levinskas GK, Radue RW,

# am PR (1977) Evaluation of delayed neurotoxicity and dose-response relationships of phosphate esters in the adult hen. Toxicology and Applied Pharmacology 4 1:291-304. Johnson MK (1974) The primary biochemical lesion leading to the delayed neurotoxic effects of some organophosphorus esters. Journal of Neurochemistry 23: 785-789. Johnson MK (1975) Organophosphorus esters causing delayed neurotoxic effects. Archives of Toxicology 34: 259-288. Kamata E,Naito K,Nakaji Y, Ogawa Y, Suzuki S, Kaneko T, Takada K, Kurokawa Y, Tobe M (1989)

## cute and subacute toxicity studies of 

### tris(l,3-dichloro-2-propyl) phosphate on mice. Eisel ShikenjoHokoku 107: 36-43. English abstract. As cited in Ferrante 1999b. Kawashima K, Tanaka S,Nakaura D, Nagao S,Endo T, Onoda K, Takanaka A, Omori 

### Y (1983) Effect of phosphoric acid tri-esters on the prenatal and postnatal developments of rats. Journal of Toxicological Sciences 8: 339. (Abstract only). Kolodner K, Cameron L, Gittlesohn A, Emmett EA (1987) Morbidity study of workers in a resin-production processing plant. Johns Hopkins University, Baltimore, MD. December 1987. Prepared for General Electric Company, Pittsfield, MA. EPA document no. 86-900000030.Koontz 

### MD, Rector 

### HE (1993) Estimationof distributions for residential air exchange rates. GEOMETTechnologies, Inc., Germantown,NID 20874. October 29, 1993. GEOMETReport Number IE-2603. Table 2. Kurebayashi 

### H, Tanaka A, Yarnaha T (1985)Metabolism and disposition of the flameretardant plasticizer, tri-p-cresyl phosphate, in the rat. Toxicologyand Applied Pharmacology 77: 395- 404. Lee BC (1990a) Dislodgeable arsenic on playground equipment wood and the estimated risk of skin cancer. U.S. Consumer Product Safety Commission, Bethesda,

### MD. August 1990. Lee BC (1990b)Estimation of hand-to-mouth activity by children based on soil ingestion for dislodgeable arsenic exposure assessment. U.S. Consumer Product Safety Commission, Bethesda,

### MD. August 1990. Lefaux,R. (1968) Practical Toxicologyof Plastics. CRC Press, Inc.Cleveland, OH. As cited in Thomas and Brundage 2004. LevensonM (2005) Upholstered Furniture AddressableFire Loss Estimates for 1999 -2002. U.S. Consumer Product Safety Commission, Bethesda, NID. November 2005. Lynn RK, Wong K, GarvieGould C, Kennish JM (1981)Disposition of the flame retardant, tris (1,3-dichloro-2-propyl)phosphate, in the rat. Drug Metababolism and Disposition 9 (5): 434. Maas WJM (2005a)In vitro percutaneous absorption of [14c] tris(2-chloro- 1-methylethyl) phosphate (TCPP) through human skin membranes using flow-through diffusion cells. Netherlands Organization for Applied Scientific Research, the Netherlands. December 8,2005. Report no. V6578102. Prepared for, Chlorinated Phosphates 4' Priority Consortium, Brussels, Belgium. Maas WJM (2005b) Releasetest for 

### tris(2-chloro-1-methylethy1)-phosphate (TCPP) from a. flexiblefoam. Netherlands Organization for Applied Scientific Research,the Netherlands. December 9,2005. Report no. V6578101. Prepared for, Chlorinated phosphates 4" Priority Consortium, Brussels, Belgium. Mast RW, Friedman MA,Finch R A (1982a) Mutagenicity testing of melamine. Toxicologist2: 172. As cited in Thomas and Brundage 2004. Mast RW, Naisrnith RW,Friedman MA (1982b) Mouse micronucleus assay of melamine. Environmental and MolecularMutagenesis 4: 340-341. As cited in Thomas and Brundage 2004. Mast RW, Jeffcoat AR, Sadler BM, Kraska RC, Friedman MA (1983) Metabolism,disposition and excretion of [14C]melaminein male Fischer 344 rats. Food and Chemical Toxicology 21: 807-810. As cited in Thomas and Brundage 2004.Matthews HB, Anderson 

### MW (1979) Disposition of 

### tris-(l,3-dichloro-2-propy1)-phosphate in the rat. Toxicology and Applied Pharmacology 48: A184. Meek 

### ME, Bucher JR, Cohen SM, DellarcoV, Hill 

### RN, Lehman-McKeemanLD, Longfellow DG, Pastoor T, Seed J, Patton DE (2003) A framework for human relevance analysis of information on carcinogenic modes of action. Critical Reviews in Toxicology 33: 591-653. Mele JM,'Jensh 

### RP (1977) Teratogenic effects of orally administered tri-o-cresyl phosphate on Wistar albino rats.' Teratology 15: 32A. Melnick 

### RL, Boorman GA, Haseman JK., Montali RJ, Huff J (1984) Urolithiasis and bladder carcinogenicity of melamine in rodents. Toxicology and Applied Pharmacology 72: 292-303. As cited in Thomas and Brundage 2004. Microbiological Associates (1978) Activity of KronitexTMin the Salmonella/microsomal assay for bacterial mutagenicity. Microbiological Associates, Bethesda,

### MD. Prepared for FMC Corporation, Princeton, NJ. August 1978. EPA documentno. 87-8210440. Midgett JD (2005). Human factors affecting sampling on mattress surfaces. U.S. Consumer Product Safety Commission, Bethesda, 

### MD. October 2005. Monsanto (1993) A single generation reproduction study with 2-ethylhexyl diphenyl phosphate (EHDP) in rats. Monsanto Company, St.Louis, MO. EPA document no. 88-930000142. As cited in Ferrante 1999a. Morales 

### NM, Matthews 

### HI3 (1980) In vivo binding of the flame retardants tris(2,3- dibromopropyl) phosphate and 

### tris(l,3-dichloro-2-propyl)phosphate to macromolecules of mouse liver, kidney and muscle. Bulletin of Environmental Contamination and Toxicology 25: 34-8. Nakamura A, Aateno N, Kojima S,Kaniwa M-A, Kawamura T (1979) The mutagenicity of halogenated alkanols and their phosphoric acid esters for Salmonella typhimurium. Mutation Research 66: 373-380. National Research Council (NRC) (1981) Monitoring and modeling of indoor air pollution. In, Indoor Pollutants. Committee on Indoor Pollutants, National Research Council, National Academy of Sciences. National Academy Press, Washington, DC. Chapter VI, pages VI-24 - VI-27. National Research Council (NRC) (2000) Toxicological Risks of Selected Flame-Retardant Chemicals. Subcommittee on Flame Retardant Chemicals, National Research Council, National Academy of Sciences. National Academy Press, Washington, DC. National Toxicology Program (NTP) (1983) Carcinogenesis Bioassay of Melamine (CAS No. 108-78-1)in F344/N Rats and B6C3F1 Mice (Feed Study). Report No. 245.National Toxicology Program (NTP) (1985) Tricresyl Phosphate (CAS #1330-78-5) Reproduction and Fertility Assessment in CD-1 Mice When Administered In Feed. Report No. RACB84114. National Toxicology Program (NTP) (1994) Toxicology and Carcinogenesis Studies of Tricresyl
, Phosphate in F334/N Rats and B6C3F1Mice (Gavage and Feed Studies). Report No. 433. NewcombeDS, Warr GA (1985) Effects of organophosphates on monocyte nonspecific esterase activity and peripheral blood monocyte functions. Johns Hopkins University, Baltimore,MD. December 1985. Prepared for General Electric Corporation, Pittsfield, MA. EPA document no. 87-8216228. Nomeir AA, Abou-Donia MB (1984) Disposition of [14C]tri-o-cresyl phosphate and its metabolites in various tissues of the male cat following a single dermal application.. Drug Metabolism and Disposition 12: 705-7 11. Nomeir AA, Abou-Donia MB (1986) Studies on the metabolism of the neurotoxic tri-o-cresyl phosphate. Distribution, excretion, and metabolism in male cats after a single, dermal application. Toxicology 38: 15-33. Nomeir AA, Kato S,Matthews 

### HB (1981) The metabolism and disposition of tris (1,3-dichloro2-propyl) phosphate (Fyrol FR-2) in the rat. Toxicology and Applied Pharmacology 57: 401-413. OgasawaraH, Imaida K, IshiwataH, Toyoda K, KawanishiT,Uneyania C,Hayashi S, Takahashi M, Hayashi 

### Y (1995) Urinary bladder carcinogenesis induced by melaminein F344 male rats: correlation between carcinogenicity and urolith formation. Carcinogenesis 16:2773- 2777. As cited in Thomas and Brundage 2004. Parkes D (1998) Testimony presented to the U.S. Consumer Product Safety Commission, for the FireRetardant Chemicals Association (currentlythe American Fire Safety Council), Lancaster, PA. May 5,1998. Perrella FW, Boutwell RK (1983) Triethylenemelamine:an initiator of two-stage carcinogenesis in mouse skin which lacks the potential of a complete carcinogen. Cancer Letters 21: 37-41. As citedin Thomas and Brundage 2004. Potts RO, Guy 

### RH (1992) Predicting skin permeability. Pharmaceutical Research 9: 663-669. Prival MJ, McCoy EC, Gutter B, RosenkranzHS (1977) Tris (2,3-dibromopropyl)phosphate: mutagenicity of a widely used flameretardant. Science 195:76-78. RobinsonEC, Hammond BG, Johannsen

### FR, Levinskas GJ, Rodwell DE (1986) Teratogenicity studies of alkylaryl phosphate ester plasticizers in rats. Fundamental and Applied Toxicology 7:138-143.Rodent Bladder CarcinogenesisWorking Group (RBCWG) (1995) Urinary bladder carcinogenesis: Implications forrisk assessment. Food and Chemical Toxicology 33: 797-802. Rodes CE,NewsomeJR,Vanderpool RW, Antley JT, Lewis RG (2001) ~x~erimental. methodologies and preliminary transfer factor data for estimation of dermal exposures to particles. Journal of ~x~osure Analysis and Environmental Epidemiology 11: 123-39. Ross DB, Robers 

### NL, Phillips CNK, Prentice DE, Majeed SK (1979) The neurotoxic effects of KronitexTM 200 on the domestic hen. ~udtin~don Research Centre, Cambridgeshire, UK. Prepared for FMC Corporation, Princeton, NJ. May 1979. EPA documentno. 40-7942040. Sasaki K, SuzukiT,Takeda M, Uchiyama M (1984) Metabolism of phosphoric acid triestersby rat liver homogenate. Bulletin of Environmental Contamination and Toxicology 33: 281-288. SchwopeAD, Lyman WJ, Reid RC (1989) Methods for Assessing Exposure to Chemical Substances. Volume 11. Methodology for Estimating the Migration of Additives and Impurities from Polymeric Materials. Prepared for, Office of Pesticides and Toxic Substances, U.S. Environmental Protection Agency, Washington, DC 20460. August 1989. EPA 56015-85-015. Scott RC, Thompson MA (1985) In vitro absorption through human epidermis of "Reofos 50" and "Reolube Hyd 46." Imperial Chemical Industries, Cheshire,UK. October 1985. EPA document no. 40-8542167. Smith TP (2000) Estimates of input parameters for upholstered furniture risk assessment. U.S. Consumer Product Safety Commission, Bethesda, MD 20814. August 4, 2000. Smith MI, Engel EW, Stohlman FF (1932) Further studies on the pharmacology of certain phenol esters with special reference to the relation of chemical constitution and physiologic action. National Institutes of Health Bulletin 160: 1-53. Washington, DC. As cited in Sobotka et al. 1986. Snodgrass HL (1992) ~Lrmethrin transfer from treated cloth to the skin surface: potential for exposurein humans. Journal of Toxicology and Environmental Health 35: 9 1 -105. SobotkaTJ, Brodie RE, Arnold A, West GL, OYDonnell 

### MW (1986) Neuromotor function in rats during subchronic dietary exposure to triphenyl phosphate. Neurobehavioral Toxicology and Teratology 8: 7-10. Soderlund EJ, Dybing E, Holme JA, Hongslo JK, Rivedal E, Sanner T,Nelson SD (1985)Acta Pharmacologicaet Toxicologica 56: 20-29. Solutia, Inc. (1998) Toxicology reports for Santicizer 141. Submitted toCPSC July 10, 1998. Sornkuti SG, Abou-DoniaMB (1990) Disposition, elimination, and metabolism of tri-o-cresyl . phosphate following daily oral administration in Fischer 344 male rats. Archives of Toxicology 64: 572-579.Somkuti SG,Lapadula DM, Chapin RE, Lamb JC4th, Abou-Donia MB (1987a) Reproductive tract lesions resulting from subchronic administration (63 days) of tri-o-crebyl phosphate in male rats. 'Toxicology and Applied Pharmacology 89: 49-63. Somkuti SG, LapadulaDM, Chapin RE, Lamb JC4th, Abou-DoniaNIB (1987b) Time course of the tri-o-cresyl phosphate-induced testicular lesion in F-344 rats: enzymatic, hormonal, and sperm parameter studies. Toxicology and Applied Pharmacology 89: 64-72. SomkutiSG,LapadulaDM, Chapin RE, Abou-Donia MB (1991) Light and electron microscopic evidence of tri-o-cresylphosphate (T0CP)-mediated testicular toxicity in Fischer 344 rats. Toxicology and Applied Pharmacology 107: 35-46. Stauffer Chemical Company (1979) Test protocols and data summaries for t-butyl phenyl diphenyl phosphate, tricresyl phosphate, trixylenyl phosphate, mixed triaryl phosphate and isopropyl phenyl diphenyl. Stauffer Chemical 'Company, Westport, CT. December 1979. EPA document no. 40-7942072. Stauffer Chemical Company (1981)Toxicological tests on Fyrol FR-2, Volumes 

### I and 

### IT. February 3, 1981. EPA doc. no. 8EHQ-028 1-040 1;microficheno. OTS020491. Stevens GC, Ghanem R, Thomas JL, Horrocks AR, Kandola

### N (2003) Understanding flame retardant release to the environment. Polymer Research Centre, University of Surrey, UK. Supresta (2006) Material Data Safety Sheet for Fyrol FR-2. Supresta, Ardsley, 

### NY. July 20, 2006. Accessed July 26, 2006. http://www.supresta.com/safetv data sheets.php Sutton WL, Terhaar CJ, Miller FA, ScherbergerRF, Riley EC, Roudabush RL, Fassett DW (1960) Studies on the industrial hygiene and toxicology of triphenyl phosphate. Archives of Environmental Health 1: 45-58. Syracuse Research Corporation (SRC) (2006) Physical Properties Database, Syracuse Research Corp., Syracuse,NY. Accessed through..the National Library of Medicine ChemlD database. June 2006. >. Theiss JC, Stoner GD, Shimkin

### MB, Weisburger EK (1977) Test for carcinogenicity of organic contaminants of United States drinking waters by pulmonary tumor response in strain A mice. Cancer Research 37: 2717-20. Thiersch JB (1957) Effect of 2,4,6-triamino-'S1-triazine(TR),2,4,6-~eimino)-'S"- triazine (TEM) and 

### N,N1,N"-triethylenephosphoamide (TEPA) on rat litter in utero. Proceedings of the Society of Experimental Biology and Medicine 94: 36-40. As cited in Thomas and Brundage 2004.Thomas TA, Brundage P (2004) Qualitative assessmentof potentialhealth effects from the use of flame retardant chemicals in mattresses. U.S. Consumer Product Safety Commission, Bethesda, 

### MD 20814. September 2004. In CPSC 2004. Thomas TA, Brundage P (2006) Quantitativeassessment of potential health effects from the use of flame retardant (FR) chemicals in mattresses. U.S. ConsumerProduct Safety Commission, Bethesda, 

### MD 208 14. January 2006. Thomas MB, Collier, TA (1985) Tolgard T.D.C.P.LV: OECD 474 micronucleus studyin the mouse. SafephannLaboratories Limited, Derby, UK. Prepared for Albright and Wilson Limited, Bristol, UK, Experimentno. 16418507. September 8, 1985. Thompson FM, Thompson PG (1990) Arts and Crafts. In,Health and Safety Beyond the Workplace. Cralley LV, Cralley 

### LJ, CooperWC, editors. John Wiley and Sons, Inc., New York, NY. Chapter 2, pp. 9-32. ToccoDRY Randall JL, York RG, SmithMK (1987) Evaluation of the teratogenic effects of triortho-cresyl phosphate in the Long-Evans hooded rat. Fundamental and Applied Toxicology 8: 29 1-297. Treon JE, Dutra FM, Cleveland

### FP (1953) Toxicity of 2-ethylhexyldiphenyl phosphate, I. Immediate toxicity and effects of long-term feeding experiments. AMA Archives of Industrial Hygiene and Occupational Medicine 8: 268-280. TrochimowiczHJ, Kennedy GL, Krivanek ND (1994) Heterocyclic and MiscellaneousNitrogen Compounds. In Patty's Industrial Hygiene and Toxicology. Wiley Interscience,New York. Pp. 3402-3405. Ulsamer AG, Osterberg RE, McLaughlin J (1980)Flame-retardantchemicals in textiles. Clinical Toxicology 17: 101 - 131. Ulsamer AG, Porter WK, Osterberg RE (1978a)The oral and dermal uptake of radiolabeled TRIS (2,3-dibromopropyl)phosphate by rats and rabbits. Toxicology and Applied Pharmacology 45: 251. As cited in Ulsamer et al. 1980. Ulsamer AG, Porter WK, Osterberg RE (1978b) Percutaneous absorption of radiolabeled TRIS from flame-retarded fabric. Journal of Experimental Pathology and Toxicology 1: 543-549. Ulsamer AG, Wright PL, Collins R (1979)The oral and dermaluptake of radiolabeled Fyrol. 18thAnnual Meeting of the Societyof Toxicology, 1979. Weiner ML, Jortner BS (1999) Organophosphate-induced delayed neurotoxicity of triaryl phosphates. Neurotoxicology 20: 653-674.Welsh JJ, Collins TFX, Whitby KE, Black TN, Arnold A (1987) Teratogenic potential of triphenyl phosphate in Sprague-Dawley (Spartan) rats. Toxicology and Industrial Health 3: 357- 369: Wester RC, Quan D, Maibach HI (1996) 

### In vitro percutaneous absorption of model compounds glyphosphate and malathion from cotton fabric into and through human skin. Food and Chemical Toxicology 34: 731-735. Wilczynski SL, Killinger JM. Zwicker GM, Freudenthal RI (1983)Fyrol FR-2 fertility studyin male rabbits. The Toxicologist 3: 22. (Abstract only). Wills JH, Barron K, Groblewski GE, Benitz 

### KF, Johnson MK (1979) Does triphenyl phosphate produce delayed neurotoxic effects? ToxicologyLetters 4: 221-24.Memorandum

Date: December 21, 2006 TO : Dale Ray, Project Manager for Upholstered Furniture, Directorate for Analysis THROUGH : ary 

### Ann Danello, Ph.D., Associate ExecutiveDirector for Health Sciences ~ri 

### E. Saltman,M.S., Director, DivisionofHealth Sciences FROM 6ichael A. Babich,Ph.D., Chemist, DivisionofHealth Sciences SUBJECT : Response to Peer Review Comments on the CPSC Staff PreliminaryRisk Assessment of Flame Retardant (FR) Chemicals in Upholstered Furniture ~oarn*

The CPSC staff completed a draft risk assessment on the use of flame retardant (FR) chemicals in upholstered furniture foam in January 2006 (Babich et al. 2006). This documentwas peerreviewed by two independent experts in toxicology and risk assessment. The staffhas made appropriaterevisions to the risk assessment (Babich 2006), based on comments from peer reviewers and public comments. Below are the staff responsesto the peer reviewers7 comments. t Thepeer reviewers' comments included the methods and models used to estimate exposure. In particular,the reviewers suggested the use of a "breathing zone" model to estimate inhalation exposure. This resulted in a slight increase in the estimated inhalation exposure. The peer reviewers also requested additional details and discussion. As a result ofthe changes made in response to the peer review and public comments, the relative contribution ofinhalationto total exposureincreased. However, the overall conclusions ofthe risk assessment did not change.

- * These comments arethose ofthe CPSC staff, have not been reviewed or approved by, and may not necessarily

reflect the views of, the Commission. Thepeer reviewers' responses are reported verbatim.

167

, CPSC Hotline: 1-800-638-CPSC (2772) CPSC'sWeb Site:http://www.cpsc.govI. COMMENTS ON EXPOSURE ASSESSMENT Comment: "The experimental work presented in the provided documents is excellent and provides some much-needed data. As mentioned in a previous review for FR in mattresses and bedding, these data have been lacking from evaluations of flame-retardant materials conductedto date, and these experimental results are precious in that they represent a significant contributionto the field. Once again we have noted that CPSC staff needs to conduct a painstaking reconstruction and check of all of the algorithm details and calculations that went into the risk assessment. This detailed evaluation of the specific calculationswas considered beyond the scope ofthis peer review, aside from the comments below on a key computational error discovered in all the spreadsheets." Response: The CPSC staff has reviewed and verified the calculations.
comment: "The most significant issue found in this review was a computational error in the spreadsheets. The calculationofthe density of the FR substances measured in the extraction tests drives the estimation of exposure and risk for both the dermal and oral portions of the evaluation. This calculation takes the average amount of FR detected on the 5.5 cm diameter filterpaper and calculates a surface densityby dividing this amountby the surface area ofthe filter @i*(dia/2)2)). This calculationis done in cell E24 of the spreadsheets. The content of cell E24 of all the spreadsheet is: =El9/(PI()*(5.5/2A2)) Microsoft Excel does power or exponentiationcalculation before it does division or multiplication+thin parenthetical expressions. Thus instead of dividing 5.512 to calculatethe radius and then squaringthe result, the 2 in the denominator was squared first and then divided. This resulted in an OVERESTIMATION of all dermal and oral exposures and risk (HI determinations) of 5.5 fold. Thus, all the predicted Hazard Indices will be lower. Those analyses that were driven predominantly by dermal and oral exposure (TDCP and BAE) * with HISof about 

### 5 or less within this analysis should now correctlyhave HISless than 1. The HI for TPP (FM-550)was reduced less (about 2 fold) with the correctionsofthis error because of the greater contribution of estimated inhalation exposure to overall risk from this FR substance. Sincethe dermal and oral routes made up the vast majority of the exposure and risk for TDCP and BAE, correcting this error does not materially change the relative estimated contributions of

Some ofthe abbreviations were changed to reflect new information that more specifically identifies certain chemicals. BAE (brominated aryl ester) was changed to OTB (octyl tetrabromobenzoate) and ITP (isopropylated triphenylphosphate) was changed to PIP (phenol isopropylated phosphate).these routes. It does materially change the distribution of estimated contributions for TPP (FM550) taking the inhalation portion of HI from 50% to 85%." Response:

2 The expression was inadvertently entered as

# ($1 instead of 

# [y )

. This error was corrected in the revised risk assessment. However, some other changes were made inresponse to comments from the peer reviewers and public comments. Changes were made to some of the input parameters for estimating dermal exposure,the vapor pressure of TDCP, and the model for estimating inhalation exposure. These changes are discussed in detail below: As a net result of these changes, HI for TDCP is still roughly 

### 1. However, the relative importance of inhalation has increased for TDCP, TPP, and PIP (ITP). Comment:.

, "Since the estimated dermal exposure accountsfor a majority ofthe estimated risk for TDCP and BAE, any error or omissions in this analysiswill have a significant effect onthe overall predictions. Theprimary manner of estimating systemic absorption in this document was the use of a percutaneous absorption rate combined with other parameters. This assumes that a steadystate has been established between material going onto the skin and then into the circulating elements of the body. This is clearly an overestimating assumption which deserves some discussion inthe text especially related to the characteristics ofthe 

### FR compounds under study." Response:

. . The staff agrees that the assumption of steady-state conditions may lead to an overestimation of exposure. We have added this point to our discussion. However, we also note that this approach is protective of public health and istypically used for risk assessment purposes. Comment: "Perhaps the largest factor absent from consideration in this analysis is the integration of the effects of standard skin shedding (desquamation) into the estimation of the ultimate absorption of compounds with high values of MW or 

### &,. Skin is continuously replaced through epidermal turnover, the process by which new cells are generated at the base of the epidermis while the outermost surface flakes off (i.e.,desquamates) atthe same rate. Of course, any chemical in desquamated skincannot be absorbed systemically. The typical time required to replace allof the skin cells (birth-to-shedding) in the stratum cornium (sc) is approximately 14days, but varies with physiological location and age and can be as long as 60 days or shorter than 14days for diseased skin. In short, substances that take a relatively long time to penetrate skin will not be absorbedby the body if this up-welling of skin layers occur at a significantly faster rate than the penetration of the toxicant through the scto the viable dermis. The substance would be shed with the skin cells! and thus eliminated from the body. It would be analogous to a weak or slow salmon that never made it upstream to the "target"pool to spawn but was instead washed back out to sea. Dr. Wil tenBerge has actually put together a kinetic model of dermal penetration which accounts forthe rate of dermal penetration that occurs versus the nominal amount that might be lost via desquamation. This model is availablefor download at the bottom ofthe following web page which provides the details of the model: http://home.planet.nl/-wtberge/skinperm.html Last year, Dr. Annette Bunge shared a preprint entitled:Does Desquamation Reduce Permeation? (Micaela B. Reddyand Annette L. Bunge) which I believe confirmsthe reality and im ortance ofthis mechanism for chemicalswith high MW (>350 g/mole or high Kow (Kow > log,. Excerpted text from this paper: Except for highly IipopHilicor large lblW chemicals, nearly all of the chemical in the epidermis at the end of an exposure will systemically absorb (i.e., Fraction Absorbed or FA

# - I), regardless of the length of time the skin was exposed to the chemical. Only for chemicals with large values of MW (> about 350 Da) or IogKolw (> approximately 4 for most chemicals) will epidermal turnover reduce FA significantly. Clearly, TDCP and BAE fall into this category ofMW >350 or logKow >4. While the SKINPERMmodel could be used to predict the magnitude ofthis effect, there is arguably not enough data available at this point to specifically quantify this effect on systemic absorption. However,it would be appropriate for the evaluation to include a discussion as explanatory text of the issue of desquamation and itspotentially striking implication on dermal exposure and risk.:' Response: Percutaneousabsorption of TDCP was measured in vitro (Hughes et al. 2001), under an interagency agreement between CPSC and the EPA Human Effects Research Laboratory (HERL). During the planning stagesofthis work, we sought the advice of Dr. Robert Bronaugh, FDA, who is an expert inpercutaneous absorption and has contributed to the development of in vitro methods. Because TDCP is hydrophobic, transfer from skin to the receptor medium is expected to be slow, relative to in vivo studies. Therefore, we assumed as a reasonable default that any TDCP that reaches the upper, papillary dermis would be absorbed in vivo. We agree that this assumption merits additional discussion. We have expanded the discussion on this point in the revised risk assessment. Comment: "Oral exposureoccurring from hand-to-mouth activity appears to be adequately describedby takingthe amount of chemical that migrated to the fabric surfacefrom the somewhat superficial wetting/pressureprotocol and applying the predicting factorsused in the report. The amount of material extracted by direct mouthing or sucking, however, may not be reasonably simulatedby using the amount of chemical that migrates to the fabric surfacein this test.Two factors could combine to exacerbate the oral exposurefrom sucking. First, the volume of salivainjected into and potentially sucked out ofthe foamby a child couldbe anticipatedto be much greater than the amount used in the migration protocol. Second, this added volume of warm "extractant" would be expected to penetrate more deeply into the foam and thus potentially be ableto pull out more FR substance from it per active sucking event and unit area. A simpleprotocol to gauge this exposurepotential would be to saturate a small (ca. 3 cm x 3 cm x 1cm thick) section of foam with approximately 10cm3of saline initially at 36-38°C in a small watch glass or dish. After wetting, knead the wetted foam for 10minutes, s ueeze to expressthe 

# 9 water from the foam, analyzethe extractantand estimate the amount per cm extracted. One could then use this value for M in equation 3. Please note: that M for hand-to-mouthtransfer would continueto use the current migration data and these experimental values would alsobe used in equations 1 and 2. If a different protocol results in a different values of M for direct mouthing -it shouldhave a different notationto differentiate it from transfer,perhaps M, for direct mouthing transfer and Mtfor hand-to-mouth transfer. This would also mean that equation 

### 4 would need to be reconstructed to accountfor these two types of

### M values. The aboveprotocol is only one suggestedapproach. The point is that the amount ofFR obtained from the current migration procedure is most likely not representativeofthat obtainable during the direct mouthing/suckingscenario and that a more rigorous extractiontest is needed to simulate this potentially critical exposureroute." Response: In prior work, the CPSC staff has used several methods to estimate oral exposure due to migration of chemicals from various substrates. We have considered the commentspresented here. However, the staff concludes that the CPSC staffmethod of measuring leaching,which involves a significant volume of liquid and a weight, is sufficiently stringentto estimateoral exposure in children. Furthermore, in observational studies conducted by the CPSC staff,direct mouthing of furnitureby children was an infrequent event (Kiss 2002; Smith and Kiss 1998). Comment: "Inhalation exposure represents a relatively small portion of the overall predicted exposure for TDCP and 

### BAE but represents a significantportion ofthe exposure predicted for TPP (FM-550). There are a number of issues related to this estimatein the report that are worthy ofmention. While these comments and suggested actionswould most likely not provide results that would changethe conclusionsofthe report for TDCP and BAE, they could change the results ofthe estimated exposure to TPP (FM-550). The only experimental measurementrelated to inhalation exposure in the report occurred for the determination of particulate emission during normal use. The protocol used is quite ingenious. and does indeed show that the level of exposure from airborneparticulate is extremely low relative to any reasonable exposure limit 

### (i. e.,truly de minimus).Unfortunately, there is no experimental determination of Csat, only its estimation from VP (cited for TPP and model-estimated for TDCP and BAE). Csat in turn drives the estimation of source strength, which is used to calculate breathing zone concentrations. This approach introduces a considerable amount of uncertainty which could be reduced by the direct measurement of Csat. Thevalue for VP for TDCP and BAE is estimated in the report at % the estimated upper bound figure or 

### 5 x 10'~ ton. This vapor pressure would render a Csat of:

Csat TDCP = 0.012 mg/m3 Csat TPPIITP = 0.110 mg/m3 (based on VP = 6.3 x Csat BAE = 0.01

### 5 mg/m3 Note: The following relationship was used to convert ppm v/v to mg/m3.

?\ It is suggestedthat a relative simple laboratory protocol could be used to significantly refine these estimates. This would be done by first taking 6 square pieces of 1m2 foamjoined to form a 1m3cubic box and then allowing the interior volume ofthis closed foam box to equilibrate at room temperature. Given enough time, the offgassing 

### FR substance will equilibrate at Csat in the box without the effect of absorptive losses to any non-ventilatory surface sinks. Consider a volume with an initial fixed level of airborne concentration (Co= 100)and no new material entering the room air with the incoming ventilation. Given good mixing, this situation is described as:

C= concentration in the room at any time Co=concentration in the room at time = 0 ventilation rate =volume/time When the product of (ventilationrate) and (time) equals the chamber volume, a single mixing air ' changehas occurred and C = Coe-' or C/ Co= .368. In this situation C would be reduced from 100 to 36.8 after a single air change and approximately 63% of the original molecules (air and contaminant) were removed. - Thus, it can be shown with first principle kinetic modeling that any volume of contaminated air that is replaced with good mixing with an equal volume of incoming pure air (i.e., 1 m3of air into a lm3box) will lose 63% ofthe original air (and contaminant) molecules and retain 37% of the original air and contaminant. Thus, a 1 m3 air sample taken from the interior volume of thisbox should capture at least 63% ofthe FR molecules originally in the box air with approximately 33% remaining in the box due to the influx and mixing ofmake up air that would occur during air sampling. Assuming all of the above estimated vapor pressures are correct, this would mean the collection of an analytical sample amount of 8 micrograms of TDCP and 9 micrograms of BAE. Doing the same analysis with TPPIITP should yield a sample of about 69micrograms. Thus the determination of Csat for each FR substance out of the foam box would simplybe the sampled concentration divided by 0.63. Note that this analysis also assumes that there are no new emissions to the air volume during the relatively short sampling period.

. Indeed, given the excellent laboratory capabilities demonstrated by the CPSC, analytical detection limits in the fraction of a microgram range could dramatically drive down the determined Csat for any and all of the compounds out ofreal foam. For example, assume that BAE was a "non-detect" at a limit of detection (LOD) <0.5 ug. Since the estimated Csat predicts 9 ug ofBAE, a "non-detect" at LOD <0.5 ug would lower the determined Csat (and subsequently the estimated exposure) by approximately 18fold versus the current estimate. Csat is a critical value for the estimation of inhalation potential; however, the length oftime it takes to reach a significant portion of this saturated concentration could also be an important factor especially as it relates to bolus injection ofvapors into room air from foam contraction which will be discussed below. Once the time-to-equilibrium is established at room temperature, conducting the tests at45', 35" and 25" C would dramatically enhance the amount of available analytical sample and improve our understanding of just how much FR is potentially coming off as a vapor into real rooms." Response: Thereviewer provided a helpful discussion on the importance of Csat in estimating inhalation exposure to vapor phase FR chemicals. For a pure compound, Csat should.equa1the theoretical value estimated from the vapor pressure, provided that the temperature and atmospheric pressure are the same. For FR-treated foam, an empirically determined Csat may be lower due to interactions between the FR and the foam. Using an empirical or "effective" CSat measured with treated foam would be slightly more accurate. However, even with an empirical CSat here would still be considerable uncertainty in estimating inhalation exposure,because the source strength was estimated by means of a theoretical model, rather than measuring it in a chamber or test house. In revisingthe risk assessment, we estimated the "effective" vapor pressure of TDCP using TDCP-treated foam (Cobb and Bhooshan 2005). We used this value (2.7~10'~ torr) to estimate inhalation exposure inthe revised risk assessment. In addition, we more thoroughly investigated the available data on the vapor pressure of pure TDCP (Babich 2006). We found empirical and estimated values from authoritative sources (EPA, National Library ofMedicine, International Programme on Chemical Safety, and industry reports) that ranged over seven orders of magnitude (7.4x10-' to 0.2 torr). The "effective" vapor pressure from TDCP-treated foam was much greater than the value we used inthe draft risk assessment (5x10-~ tom), although it is less than empirical values for pure TDCP (0.0014 to 0.2torr).In response to comments fiom peer reviewers and others, the staff made a number of changes in the input parameters and models used to estimate exposure. As a result of these changes,the estimated dermal exposures were generally lower, while the estimated inhalation exposures generallyincreased. Therefore, the relative contribution of vapor phase inhalationhas greatly increased. Comment: "Other areas of the analysis that could be improved include the determination of the affected volume for emissions from foam furniture and the determinationofthe diffusivity (Dair -or 

### D& of FR compounds in air. Finally the topic of bolus injection of vapors into room air from rapid foamcontraction (sitting) will be discussed separately below. The current methodology estimates the source term for release of particles from a small-volume (glovebox) experiment and then scalesthat source term into a much larger well-mixed single box (320 m3)roornhouse model. As mentioned in our previous review,the exposure scenario suggestedby these particle emissionscan be reasonably describedusing the following characteristics: Relatively small emission area in a relatively largeroom and house volume, impaction source proximate to the breathing zone of the subject (i.e., the subject is causingthe emission and persona cloud, and the potential for relatively large and quickly settling particles All ofthe above suggests that the well-mixed room or house volume model will dramatically under-estimatethe breathing zone concentration ofparticles resulting from this essentially "nearfield" or proximate source. It would be more appropriate to take the airborne concentration in the smallervolume of the glove bag as areasonable approximation of the "near-field" concentration around the breathing zone ofthe person in bed. Going from 320 m3for the whole house volume to 1m3as a personal cloud volume represents two to three order of magnitude increase in exposure. Values for potential inhalation exposure from particulate are so small, however, as to still be de minimus, evenwith this increase." Response: As discussed in the risk assessment,we consideredtwo approaches. One approach isto consider exposure in the room wherethe furniture is located, which requires assumptions for consumer activity patterns, that is, the amount oftime spent in each room. We chose a simpler approach, which was essentially to "average" the exposure overthe entire home for 16h, the average time that a consumer spends at home. Thus, the increased concentrationin the room where the source is located, in the first approach,would be off-set by the shorter exposure duration in the second approach. Nonetheless, we agree that our approachcould significantly underestimate exposure to particulate and vapor emissions. As suggestedby the reviewer, we used a third approachtoestimateinhalation exposure in the revised risk assessment. In this approach, a consumer sitting on the furniture is considered to be in a "breathing zone," that is, a location that is intimately associated with the source of emiksion. The breathing zone exchanges air rapidly with the remainder ofthe room. This change increased the estimated inhalation exposure by less than 2-fold. Comment: "There is also a strong likelihood that exposure fiom FR vapors is relatively low and this is particularlytrue for emissions from TDCP and BAE. 

### In light of the above mentioned imprecisionin the likely overestimationof Csat vapor concentrations and vapor emission source rates we believe that an uncertainty analysis with the primary diffusion of vapors into smaller affected volumes would be appropriate. This analysis could help to inform a decision on whether to do actually testing of Csat especially for TPP (FM-550)." Response: As discussed above,the staff made a number of changes inthe input parameters and models used to estimateexposure in response to comments from peer reviewers and others. As a result of these changes,the estimated dermal exposureswere generally lower, while the estimated inhalation exposures generally increased. Therefore, the relative contribution of vapor phase inhalation has greatly increased. Comment: "The molecular diffusivity in air (Dair) calculated for the FR substances used a referenced relationship from Schwopeet 

### a1 1989. A more refined algorithm to estimate Dair has actually been developed and published more recently by the EPA. Specifically, this includes the evaporative source term algorithms from a subsequent publication of the US Environmental Protection Agency (EPA 199 1 EngineeringManual [EPA (1

### 99 1). Preparation ofEngineering ~ssessments, Volume I: CEB Manual, Chemical Engineering Branch, Economics and Technology Division, Office ofToxic Substances, Washington, D.C. February 28, 1991. pp. 4- 23 to 4-33] were used. The key equations in this document for emission from vaporizingpools are presented below along with their designationswithin this reference:



### Equation 4-22

where: G = Generation rate, lblhr M = Molecular weight, lb/lbmole 

### P- = Vapor Pressure, inches ofHg A = Area, 

### fi2Dab = Diffusion coefficient, ft2/sec of coinpound a through b (in this case b is air) -the same as Dair. VZ = Air velocity, ftlmin T = Temperature, OK Az = Pool length along flow direction, ft Gas diffusivities of volatile compounds in air are available for several existing chemicals. However, the diffusion coefficient often will not be known. An equation to estimate diffusion coefficientis expressed as:

where: Dab

. = Diffusion coefficient, cm2/sec 

### (NB : the units of Dabare different in Equations 4-22 and 4-23) T = Temperature, OK M = Molecular weight, lb/lb mole pt = Pressure, atm Equation 4-23 is arguably more refined than equation 10inthe evaluation. ConvertingDab in Equation 4.23 to units of ft2/sec and substituting:


### (J= 0.5 0.5 TO.~~AZ 

# 4 Equation 4-24
where: G - - 

### M = P' - -
vz - - A - 

### T - Az = Pt = Generation rate, lbh Molecular weight, lb/lb mole Vapor Pressure, in. Hg Air velocity, Wmin Area, 

## ft2 Temperature, OK Pool length along flow direction, ft Overall pressure, atm One could use any Csat determined experimentally as suggested above to directly calculate the effectivevapor pressure, P', using a rearrangement of equation 

### (9) of the CPSC report. Given a value for Pethe above equation could be used to estimate or gain some insight into the time required to achieve equilibrium in any enclosed volume."Response: The CPSCstaff could consider using a different algorithm for estimatingDu, or the source strength. However, the exposure from vapor phase inhalation is based on a theoretical model. A different algorithm would not address the many other uncertaintiesinthe exposure estimate. Due to its relative importance to overall exposure, it is more importantto obtain empirical datato estimate inhalation exposure. Comment: "Bolus Injection of Vapors Into Room Air from Foam Contraction [While working on anotherproject, one ofour colleagues]suggested the following inhalation exposure scenario for FR treated foam: "Given enough time, the FR compoundwill vaporize into the void volume ofthe foam ultimately to a concentration of CSat for that compoundcoming out ofthat polymeric matrix. When the foam is contracted (from someone sitting on it) the amount ofFR substance potentially injected into the surrounding air would be equal to (Csat) x (Compressed Volume). This direct injection mechanism could conceivable result in relatively high localized breathing zone concentrations of the FR substance aroundthe contracted area. The appropriate gauging of this effect would require the estimation ofboth Csat and the compressed volume. One would also need to understandthe kinetics of vaporization to determinethe time course and capacity of this effect. Ifthe vaporization rate is relatively slow, then this effect would not contribute significantly to the indoor concentrations or the exposure potential. Given a more accurate estimation of Csat and the emissionrate of FR vaporization to air from foam, our opinion is that it is highly unlikely that the bolus injection from foam contraction would provide a significant level of exposure forthe current FR substances of interest. However, our opinionis not a risk assessment. Conformation of that opinion means first conducting a reasonable worst-case uncertainty analysis ofthis factor with the currentuncertain (but likely over-estimated) estimates of Csat


## . ~kasonable worst case estimates of compressed volumes, rates of sitting, and an assumptionof quick "recharge" ofthe FR concentration in the void volume could also dramatically overestimatethe exposure and risk from this mechanism. If this analysis indicated an 

### HI significantlygreaterthan 1,then refined estimates for Csat and FR vaporizationrate might be necessary." - Response: As discussed by the reviewer, the importanceofthis pathway depends on the rate at which vapor phase FR chemical in the cells of the foam is replenished. Given the surface to volumeratio, this might occur rapidly. One way to assess this would be to measure vapor phase FR during the impaction tests. We added a discussion ofthis modelto the revised risk, assessment.We performed some simulations to gaugethe relative contribution of an "injection" model to inhalation exposure. Such a model requires several assumptions, such as how frequently and to what depth the foam is compressed. The depth of foam compression would depend onthe foam properties, weight of the consumer, and velocity ofmotion. These assumptions, which are difficult to verify or measure, make the model highly uncertain. We estimated that the vapor phase inhalation exposure from the injection model is about 

### 40% ofthat from the NRC model. Comment: "UncertaintvAnalysis We commend CPSC for conducting a sensitivity analysis for the exposureparameters. While it can be more informative to vary multiple parameters simultaneously, the approach used by CPSC gives reasonable estimates of the impact ofuncertainty inthe input parameters and the magnitude of a reasonable upper bound estimate of exposure. CPSC also provided practical and level-headed interpretations ofthe results ofthe sensitivity analysis. Aside from the additional analyses suggested above, we have no comments onthe sensitivity analysis or discussion of uncertainty." Response: We chose to perform a sensitivity analysis for exposure parameters, rather than a probabilistic analysis, because only limited information was available on the distributions ofthe input parameters. We consider that a probabilistic analysis with such limited data couldprovide the reader with a false sense that the uncertainty and variability in this risk assessment are wellcharacterized.11. COMMENTS ON TOXICITY AND DOSE-RESPONSE ASSESSMENT Comment: "While it is recognized that CPSC is an independentagency, CPSC may wish to consider further harmonizationwith the methods of other organizations*. This includes the use ofbenchmark dose methods, inhalation dosimetry for effects on the respiratory tract, consideration of the implicationof extrapolation from subchronicto lifetime exposures, and the use of chemicalspecific adjustment factors instead ofuncertainty factors. Other agencies and organizations, includingthe Agency for Toxic Substancesand Disease Registry (ATSDR), Health Canada, and the International Programme on Chemical Safety (IPCS) include some or all ofthese considerations. For example, Health Canada includes an uncertainty factor of 1-1 00 for inadequacies ofthe database, includinglack of adequatedata on developmental, chronic or reproductivetoxicity, use of a LOAEL, and inadequacies ofthe critical study (Meek et al., 1994). While these specific adjustmentsmay not always have a significantimpact on the overall assessment, use of these values, where possible and feasiblewithin resource limitations,tends to improvethe scientific basis for the assessment. In this spirit ofharmonization, Table 1 presents risk values for the FR chemicalsdevelopedby other organizationsand the bases for these values. The data are from the NAS review offlame retardants (NRC, 2000), and IRIS data from EPA (http://www.epa.gov/iris/), and supplemented by data fiom ATSDR. Key differencesfrom other organizations are bolded. The ITER database (available at http://www.tera.org/iter/and http://toxnet.nlm.nih.gov/)provideskey information about risk values developedby U.S. and international agencies, as well as independentlydeveloped and peer-reviewed values, and can be a resource for such information." Response: Therisk assessment, including the use ofuncertainty factors,was conducted according to the CPSC Chronic Hazard Guidelines, which were issued in 1992. The guidelines do not provide for additionaluncertainty factors to account for inadequacies ofthe data base or for the potential sensitivityof children relative to adults. However, the guidelines allow the use of chemicalspecific adjustment factors on a case-by-case basis, provided there are sufficient data to deviate firomthe default factors. In the present case, the CPSC staff did not considerthat there were adequate datatojustify the use of chemical-specificuncertainty factors. The differences

* "Note that harmonization is not standardization. Harmonizationinvolves (1) understanding the methods and
0 practices used by various organizations; (2) developing confidence in, and acceptanceof, assessmentsusing different approaches; and (3) willingnessto work toward a convergenceofmethodologies as a long-termgoal (Sonich-Mullin, 1997)." Table 1,provided by the peer reviewers, appears on page 14 ofthis document.Table 1. Comparison of Toxicity Values ofFR Chemicals Developed by Various organizationse Chemical Tris (1,3-Dichloro-2- Propyl) Phosphate (TDCP)

Triphenyl Phosphate (TPP) lsopropylated Triaryl Phosphate (ITP) Brominated Aryl Esters (BAE'S) Tris (1,3-Dichloro-2- Propyl) Phosphate (TDCP) CPSC AD1 = 0.005 mglkg-day LOAEL = 5 mglkg-day (Biodynamics 1981) UF = 1000 (1OA, 1 OH, 10L) Oral cancer unit risk = 0.031lmglkgday (based on qlfrom BMD modeling for kidney and liver tumors combined) Date: 2006

Possibly toxic in humans. lnsufficient informationto derive an AD1 directly. NOAEL= 160 mglkg-day (Sobotka et al., 1986) Possibly toxic in humans. lnsufficient information to derive an AD1 lnsufficient information to determine whether the BAE1s'are "toxic" in humans or to derive an ADI. NAS RfD = 0.005 mglkg-day LOAEL = 5 mglkg-day (Biodynamics 1981) UF = 1000~(10A, 3H, IOL, 3D) RfC = 0.018 mg/m3(based on route-toroute extrapolation from RfD) Oral unit risk = 0.06 lmglkg-day (based on BMDL extrapolation to zero for testiculartumors) Inhalation unit risk = 1.71 x 10"/ug/m3 (based on route-to-route extrapolation from oral unit risk) Date: 2000 No assessment

No assessment No assessment EPA No RfDIRfC

No RfDIRfC

No RfDlRfC

UF ='lo00 (IOA, IOH, 10L) Oral cancer unit risk = 0.03llmglkgday (based on qlfrom BMD modeling for kidney and liver tumors combined) Date: 2006 AD1 = 0.005 mglkg-day - LOAEL = 5 mglkg-day (Biodynamics 1981 1

* Table provided by the peer reviewers. UF ='I 000 (IOA, 3H, 1 OL; 3D) RfC = 0.018 mglm3(based on route-toroute extrapolation from RfD) RfD = 0.005 mglkg-day LOAEL = 5 mglkg-day (Biodynamics 1981

Oral unit risk = 0.06 lmglkg-day (based on BMDL extrapolation to zero for testicular tumors) Inhalation unit risk = 1.71 x 10-~1u~lm~ (based on route-to-route extrapolation No RfDIRfC ATSDR No assessment

No assessment

No assessment

No assessmentOC nI

### a



# d W

O V) n 0



# - Q o 

## .- E 8 c o Q U) .- L



# : 30 -0 

# ga "$@: 9,az + C a, 

## 5 U) 

### 3 U) m 0 z 

### 9 

### !z 

### 62 

### nr 0 Z

u C a, 

## 6 U) 

### 2 U) m o Z

a, c 

### .- C= 

## E .c a, .2 

### =Euxo 0Ba mmc&l& Ea,gm, ,'.Zmm.r Ew&0.gBEmo 

## sgeg; (oq a, E~I: (o 

### ~jg E 5.2'

I-~F~ 

### uka"' a,uuw a,< %m%m .G ';; 9.;; CI C a,. 

# 6 U) a, U) U) m 0 z 

### 9 !z L3u

### nr 0 Z

+ C 

## E U) U)

w 

# - cga, a,=m .-
," 

# ; g 

# 5es =ZSz $2 mm? Em2

. 

### .- E
.- 0 C 7j m-103~ .- EWC0.- 

## 3g8'-& n.~z~n.~=

a, u m I: a U) 0 I: n - > C a,^ rn 

### .gn 

### I-L CI C

U) 

## E U) 

### 3 U) m 0 z
s2 

### !z 62 

### nr 0 Z

u C a, 

## E U) 

### 3 U) m o Z -E a, .G 

## g U) 

### "ja ,,-,

a, .Em 

### xgll~>~a,~",

- 2 .- m L

u



## (us - 

## gc 8s namwbetween CPSC's risk assessment practices and those of other U.S. agencies are minor and have been discussed elsewhere in detail (Babich 1998;Rhomberg 1997). Comment: "It would be usefil for the documentationin the quantitative assessmentto provide sufficient rationale for the readers to understand the reasons for the key decision points, particularly where CPSC decisions differed from those of other organizations. While the reader can be referred to the qualitative assessment for additionaldetails (where such details are provided in that assessment), it can be usefil to have all ofthe key exposureand toxicity decisions documented in one place. It would be desirable for each chemical summaryto include an overallpicture of available database, even in light ofthebrief summary in the risk assessment document. For example, although the two-year chronic study for TDCP was judged to be the critical study,the findings from this study are supportedby other studies, such as acMe and subchronic studies, developmental and reproductive studies, and neurotoxicity studies. The current version ofthe summarydocument (risk assessment document) does not mentionthe existing developmental and reproductive studies, probably due to the lack of positive findings from these studies. Without such supporting information,the confidence for the derived ADIs would be significantly compromised. The differences in the methods used by different regulatory agencies in risk assessment highlight the importanceof clear documentation ofthe key decision points in derivingrisk values." {seeTable 1 ) Response: The staff agrees with the reviewer, and has substantially expanded the suinmaries in the hazard identification and dose response sections in the revised riskassessment. Comment: "The summary document does not mention any information about potential skin and eye irritation effect. In addition, there was no mention of any information about inhalationtoxicity. Since such data may be available, it would be helpfil to briefly mention the results even though they showed negative responses." Response: This information has been added to the hazard identification section ofthe risk assessment. Comments on Specific Chemical Assessments "These comments are based on review of the qualitativeand quantitative assessments for the chemicals of interest provided by CPSC, supplementedby other documentationprovided by authoritative reviews by other organizations or agencies. Since TDCP is the only one among the four chemicals summarizedin'the CPSC review document that has enough data for deriving an ADI, a more detailed discussion is provided for TDCP."Comment: 

### Tris(l,3-Dichloro-2-Pro~7/1) Phosphate (TDCP)

. "We recognize that the purpose of the primary document being reviewed (the risk assessment document) is to focus onthe overall risk assessment,rather than the details of the studies. However, as mentioned in the general comments, it is much easier for the reader, and improves the overall credibility of the assessment, if the key toxicity information is presented. While it is appropriateto reference the supporting documents for the study details, it is recommended that CPSC include a list (either text or tabular) of other relevant studies (including the neurotoxicity, developmental, and reproductive toxicity studies). It would be useful for this list to identifjthe effects observed and NOAELsILOAELs. For example, neurological effects were mentioned in the summary of acute studies, but the risk assessment document did not address the follow-up neurotoxicity studies conducted inhens treated with repeated doses of TDCP (Stauffer Chemical Co., 1981; Celanese Corp., 1960). Description ofthe findings from these latter studies would present a complete picture ofthe potential neurotoxicityof TDCP. In additionto data on toxicity from oral exposure,the summary should also include information on available toxicity information from dermal and inhalation exposure. At the least, it wouldbe useful to note that few data are available for these routes. In addition, as noted below, it would be useful for CPSC to do some rough analyses to evaluate the importance (or lack thereof) of these data gaps." Response: Additional informationhas been added to the hazard identification, dose response, and discussion sections. Comment: "As an important component ofhazard characterization, information regarding reproductive and development toxicity should always be mentioned. Even though the detailed information is presented in the earlier supporting documents, summarizingthe results ofthe reproductive and developmental toxicity studies in the risk assessment document would address a potential data gap in the reader's mind, even ifthese studies show negative results (e.g., for TDCP, developmental toxicity only in the presence of maternal toxicity or no reproductive effects in rabbits). Three developmental and reproductive studies have been conducted in two different animal species, rabbit and rat (Wilczynski et al., 1983; Stauffer Chemical Co., 1977-1978; Kawashima et al., 1983;Akzo Nobel Functional Chemicals LLC, 2001). Results ofthese studies are ofparticular relevance for TDCP, since the critical effect for the noncancer assessmentis a male reproductive endpoint. It would be useful to address consistency between the negative results in these studies and the use of a male reproductive effect as the critical effect. We agree that this inconsistency is not necessarily problematic, sincethe two-year bioassay was in rats and the male reproductive toxicity study was inrabbits, and different endpoints were evaluated,but these differences should be noted. Overall, further consideration of endpoints evaluated and relative sensitivity of the species would be useful, since the rabbit NOAEL of200 mgkg-day for male reproductive function was 40x the rat 

### LOAEL of 

### 5 mglkg-day."Response:

. . Additional explanation has been provided. Comment: "It would be useful to state more explicitly in the risk assessment document what the experimentalprotocol was for the chronictwo-year study in rats (e.g. "animals were exposed..


## . in diet for 2 years). Because this document only mentions the interim sacrifice,but does not mention the terminal sacrifice, the reader may wonder whether the dosing inthis study continued for two years or just one year followed by a 12-month recovery. The text could also be clarified if the terminal sacrifice and number were noted after the mention of the interim sacrifice. More significantly,it is not clear fiom the text whether the reported effects were observed at the interim or terminal sacrifice, and whether there was any progression with additional exposure. In addition, the identification of doses tested should include the dose of 0 mgkg-day, to make it clear that the study did include the appropriatecontrol. Although the summary identifies the lowest treatment dose of 5 mgkg-day as a free-standing LOAEL, it does not identify the effects on which thisjudgment was based. It would be useful to remind the reader that the LOAEL is based on seminal vesicle lesions, and to more specifically identify the observed lesion(s)." Response: Additionalinformation has been included in the revised risk assessment. Comment: "While it appears that the focus of the genotoxicity summary is strictly in support of the carcinogenicity assessment, it would be useful to provide some additional information. In particular, more information and/or further analyses would be useful regarding the "mixed results" in mammalian systems. Were consistent results observed within a study type (e.g.,DNA damage, gene mutation, chromosome aberration)? The more detailed evaluation by CPSC in Ferrante (1999b), describes "weak or variable" results in mammalian systems. It would have been useful to provide more information in that document regarding the "variable" results, and interpretationofthose studies. In particular, it was not clear whether Ferrante (1999b) considered all ofthe relevant studies evaluated by NRC (2000). Ferrante (1999b) alsopresented a nice review of studies investigating different microsome activation systems. However, it would have been useful for CPSC to conduct a more critical evaluation ofthe overall conclusion regarding the impact ofthe S9 systems, such considerationsmay provide information regarding the enzymes that metabolize TDCP to a genotoxic form. Regardless of the conclusionsof this analysisofthe impact of S9, a brief statement should be included in the final risk assessment, noting the variety of S9 systemstested and the results and implications of such testing.

, Most ofthe tumor response data showed a dose-response trend. Nevertheless, adenomas ofthe

adrenal cortex were significantly elevated only in mid-dose males and were reduced in mid-dosefemales, with no significant changes in the high dose groups. These observationsraise an issue about whether the increase in this tumor observed in mid-dose animals was chemical treatrnentrelated, and if so, whether it was biologically significant. Adding an analysis ofthese considerations would facilitate the reader's understanding ofthe significance of these observations." Response: Additional informationwas included in the hazard identificationand discussion sectionsofthe revised risk assessment. ~ose-respons'e assessment Comment: "As stated in the general comments, it would be useful for the documentationin the quantitative assessmentto provide sufficient rationale for the readers to understand the reasons for the key decision points, particularly where CPSC decisions differed from those of other organizations. For example, in noncancer assessment, a composite uncertainty factor of 1000was used to account for interspecies and intraspeciesdifferences, and for LOAEL to NOAEL extrapolation. However,NRC used an uncertainty factor of 1000 to account for interspecies and intraspecies differences, LOAEL to NOAEL extrapolation,and database deficiency. Thus, althoughboth organizations calculated the same final value, the approachused (and presumable the rationale used), differed. It would be useful for CPSC to present the rationale for the uncertainty factors in a bit more detail, explaining how and why its values differ fiom those ofNRC." Response: Additional explanationwas included in the dose response section of the revised risk assessment. The CPSC staff applied an overall uncertainty factor of 1,000to the LOAEL, including 10-fold for animal to human extrapolation, 10-foldfor inter-individual variability, and 10-foldbecause a no-observed-adverse-effect level (NOAEL) was not established. This results in an AD1 level of 0.005mglkg-d. These are the defaultuncertainty factors described in the CPSC chronichazard guidelines (CPSC 1992). TheNRC subcommittee derived a reference dose 

### (RfD)*of 0.005 mglkg-d (NRC 2000). However, the NRC subcommittee applied uncertainty factors of 10-fold for animal to human extrapolation, 3-fold for inter-individualvariability, 10-foldbecause a NOAEL was not established,and 3-fold for an incompletedatabase. The CPSC chronic hazard guidelines do not provide for an additional uncertainty factor for an incomplete database (CPSC 1992). The default factor for inter-individualvariability used by the CPSC staffand others is 10-fold. The NRC subcommittee applied a 3-fold factor for inter-individualvariability in this case, because

* Both the acceptable daily intake (ADI) and reference dose (RfD) are estimates of the amount of a chemical a

person can be exposed to on a daily basis over an extendedperiod oftime (up to a lifetime) with a negligible risk of suffering deleterious effects.

, 185 

### ithere was no evidence of increased sensitivity of juvenile animals from developmental toxicity studies (NRC 2000). They did not indicate what studies were lacking fiomthe database. Comment: "The summary document states that benign tumors ofthe testes and adrenal cortex were not included in the calculation of cancer unit risk, but the summary provides no rationale why these endpoints were not used. The rationale for this decision should be presented." Response: Additional explanation was included inthe dose response section ofthe revised risk assessment. P Benign tumors ofthe testes and adrenal cortex were not included, because no malignancies were present in the organ sites. Thus, it does not appear that these particular tumors would progress to malignancy. In addition, testicular interstitial cell adenomas have a high background rate in rats, and their relevance to human cancer risk is uncertain (CPSC 1992,p. 46636). Comment: "The CPSC approach of combining incidence data for males and females when the separatelycomputed unit risks differ by less than a factor oftwo is a reasonable approach in general, although it is not identical to the approach of other international regulatory agencies. However, the approach of calculating the human equivalent dose (HED) when data are combined should be 'considered further. Because the body weight to the % conversion is designed to adjust for differences in tissue dose between species, it seems that a preferred approach for combining risk would be to calculatethe risk for each sex separately, calculate the HED, and then combine risk, rather thanincidence. This accounts (at least roughly -considering scaling but not sex-specific differences in enzyme expression) for sex-specific differences in tissue dose for a given mg/kgday (which could affect the resulting tumor incidence), as well as accounting for differences in background response." Response: In this particular case, both the background tumor levels and dose-dependent tumor incidences were roughly similar. The alternative approach of calculating sex-specific unit risks separately and then averaging them would have a negligible effect. Comment: "Using the maximum likelihood estimate of extra risk (ql) as the basis for the unit risk is a reasonable choice that is consistent with the approach used by some organizations,but different from that used by others. However, CPSC should explicitly note this decision inthe section on risk calculations (comparison to exposure), in addition to the current identification ofthis choice in the dose-response assessment. Consideration of bounds could also provide useful input to the nice uncertainty discussion in the document. While the software used by CPSC does notcalculate the lower confidence limit for the estimated ql (i.e., the ql*), other software can do so. Alternatively, CPSC could use the approachused by the USEPA, calculating the BNIDL10, and then using linear extrapolation to zero. While comparing these results with that using the ql would not capture all ofthe uncertainties relating to cancer risk, the comparison would capture at least some ofthe uncertainties related to model choice and experimental variability." Response: The staff has added a discussion of the effect ofmodel choice to the discussion section ofthe revisedrisk assessment. The risk assessment was conducted in accordance with the CPSC chronic hazard guidelines. The softwareused by the CPSC staffdoes, in fact, calculate ql*. We use ql* when ql is zero to ensure a linear dose response. The uncertainty in the estimate of ql (generally within 3-fold) is small in comparisonto the uncertainty associated with the choice of mathematical model. The current EPA approach-benchmark dose combined with linear extrapolation-would give a unit risk that is very similar to that calculatedby the CPSC staff. Theprimary difference is that the CPSC staffprefers to use the best estimate ofrisk, rather than the upper confidence limit. The use of a non-linear model, however, would result in a much lower estimate of risk. Comment: "It would be helpful if the mathematical equation for calculation of the unit risk for humans from the rat data (based on the unit risk isproportional to body weight to the three-quarters power) were presented. While this calculation is fairly standard, presentation of the equation enhances transparency, especially since some aspects of the conversion can lead to confusion." Response: The equation was added to the dose-response section. Comment: "Another method used in the dose-response analysis that is different from that used by other agencies is the addition ofunit risks for different endpoints (liver and renal tumors). Again, while cogent arguments can be made for this approach, it would be useful to provide additional informationregarding its rationale." Response: The risk assessment was performed in accordance with the CPSC chronic hazard guidelines. The differences between CPSC staffsrisk assessment practices and those of other U.S. agencies areminor and have been discussed elsewhere in detail (Babich 1998; Rhomberg 1997).The cancer risks for different tumor sites are calculated separately, because they are considered to arise independently. Thispractice could result in a slightly greater unit risk, relativeto using total tumor incidence, ifthere are individual animals in the bioassay with, tumors at both sites. Comment: "Although there are only very limited data from inhalation studies, a robust database from oral exposure studies could provide valuable information for deriving inhalation ADI. Since TDCP is not water soluble, and not a reactive compound, it is expected to produce similar systemic toxicity as by oral route exposure. This means that the approach used by CPSC in the calculation ofrisk (using only the systemic dose rather than consideringportal of entry effects from inhalation exposure) is appropriate as 

### an initial calculation. However, it should be noted that chemicals absorbed from the gastrointestinaltract have to go through first-pass metabolism before they reach the systemic circulation,while parent compound absorbed from the respiratory tract can be directly distributed throughout the body before it is metabolized. Therefore,routeto-route extrapolation from oral datato inhalation exposure needs to present any available informationregardingthe potential impact offirst-pass metabolism on effects or on internal dose. In particular, it would be useful for CPSC to further consider whether the noncancer toxicity ofTDCP is due to the parent compound or to a metabolite. First-pass metabolism would decreasethe tissue dose (for the reproductive tract, but not necessarily for the liver) ofthe parent compoundfrom the oral route, comparedto the tissue dose of the parent from inhalation exposure to the same amount. This means that a given "dose" from inhalation exposuremay have greatertoxicological consequencesthan the same dose from oral exposure. Conversely, inhalation exposuremay result in lower tissue doses to a metabolite than the "equivalent" oral exposure, again depending on the target and mode of action. Further consideration ofthis issue by CPSC would be important. In addition, the discussion of uncertainty should capture this issue, since it could result in inhalation exposure contributing a different, and possibly higher, percentage of total dosethan is apparent from Table

### 4." Response: A discussion of the reviewer's points has been included in the discussion section of the revised risk assessment. Comment: "Analternative approach to the route-to-routeextrapolation would be to estimate an inhalation AD1 fromthe oral ADI, and then combine the hazard quotients and cancer risk." Response: While this alternativeapproach is valid, the staffdid notf apply it because it is not clear how this approach would reduce the uncertainty.Comment: "The CPSC assessmentincluded a nice sensitivity analysis in the exposure assessment, as well as a nice discussionof'the exposureuncertainties in the discussion. In contrast, the consideration of toxicological uncertainties for TDCP in the discussion addresses only the sufficiency of data to calculatethe AD1 and cancer slope factor. A more complete consideration oftoxicological uncertainty (qualitative, and, to the degreepossible, quantitative),would be useful. This discussion could include uncertainties in the cancer calculation and in the route-to-route extrapolation fiom oral to inhalation data, as described above. In addition, consideration of the uncertainties addressed by the uncertaintyfactors and the implications ofthe overalluncertainty factor would be informative." Response: The staff agrees that these are significant sources ofuncertainty that merit fbrther discussion, but many are also difficultto quantify. For example, it is not possible to estimate the probability that a given dose response model is correct. However, the discussion section of the revised risk assessment has been expanded to include a more thorough discussion ofthese sources of uncertainty. Comment: "Finally, overall confidence in the derived AD1 value can be presented. Such discussion would facilitatereaders' understanding of the overall confidence in the estimated AD1 and calculated cancer risk. In addition, deeper consideration ofuncertaintiesis consistent with the OMB proposed Risk Assessment Bulletin, although the approaches suggested here are less detailed than many ofthe approachesrecommended in the OMB proposed Bulletin." Response: In deriving AD1 values, the CPSC staffreviews all of the available data and considerswhether the studies were well designed and well executed, as described in the CPSC chronichazard

, guidelines (CPSC 1992). Studies are classified as providing inadequate, limited, or sufficient evidence oftoxicity. The CPSC staff also discusses sources ofuncertainty, such as the completeness ofthe database. Triphenyl Phosphate (TPP) Comment: "Based on EPA's review ofTPP (EPA 2005), the available data on delayed neurotoxicity, adult neurotoxicity, developmental toxicity, and immunotoxicity werejudged as negative responses.

, However, this information is not presented in the current summary document, and much was not

presented in the more detailed evaluation'by Ferrante (1999a), eventhough the studies were published prior to that evaluation. While the risk assessment summary document does not necessarily need to include a critical evaluation of all of these studies, it is critical that thesummary document present a clear overview of the entire database, so that the endpoints of interest and data gaps are clear." Response: The hazard identification section has been expanded, and includes all the available data. Comment: "It is indicated in the summary document that the lowest NOAEL reported for TPP was 160 mgfkg-d for effects on body weight gain in male SD rats fed TPP for 90 days in a neurotoxicity screening study (Sobotka et al., 1986). In their publication, Sobotka et al. 

### (1986) statedthat their study was a part of a larger subchronic feeding study designedto assess the general toxicity, teratologic effects and immunotoxicity of TPP. In addition, the published part of irnmunotoxicity report by Hinton et al. 

### (1987) also suggested that the only effects noted were a decreased rate of growth rate and increases in the levels of alpha- and beta-globulins suggestive of increased hepatic activity. All these reports indicated that there might be sufficient doseresponse information from the original large subchronic study, and decreased body weight gain is a potential critical effect. Since a well-conducted subchronic study can constitute a minimum database for deriving a safe dose, and decreased'bodyweight is routinely considered as a

. benchmark in evaluation ofwhether administrated doses used in a long term experiment reach a maximum tolerable dose, it is recommended that CPSC review the original subchronic study for general toxicity. Ifpossible, CPSC couId also contact the authors ofthat study for relevant unpublished data. The final conclusion and dose response assessment should be based on this additionalreview and consideration of any additional data." Response:

. . The CPSC staff contacted one ofthe authors ofthe FDA studies. ~nfortun&ely, the "larger study" was never completed and there are no additional'data. Comment: Isopropylated Triaryl Phosphate (ITP) "The CPSC approach to the toxicity evaluation ofITP, and conclusions of that evaluation appear tobe reasonable." Brominated Arvl Esters (BAE's) "The CPSC approachto the toxicity evaluation ofBAE's, and conclusions ofthat evaluation appearto be reasonable." Response: No response required.Risk Calculations and Other Considerations Comment: "Since there was insufficient information to derive AD1 values for TPP and ITP, AD1values for other aromatic phosphates, including mixtures, were used as surrogates for TPP and ITP. While the structural analogy among these chemicals suggests that the other aromatic phosphates were appropriate surrogates, it would be useful to present any additional supporting evidence. In particular, a comparison of the available (albeit limited) toxicity data for TPP and ITP compared to other aromaticphosphates would be useful. The Ferrante (1999a) document does a nicejob of presenting the data, but it would be useful to present tables directly comparing the toxicity results for the different aromatic phosphates, to aid in the extrapolation. For example, a quantitative comparison between effective doses, (e.g., ED10 or NOAEL), for causing the same toxic effect, (e.g., decrease in body weight), by TPP and other aromatic phosphates in repeated dosing studies would provide strong support for using other data as the surrogate for TPP and other similar compoundsin risk assessment." Response: The staff expanded the hazard identification to include a brief review of all of the aromatic phosphates. Comment: "While the calculation ofthe LADD for children is correct; it would be useful to explain the calculation a bit more, noting that the child LADD is the exposure as a child, averaged over a lifetime. Conversely, calculation of the 

### HI for the child is conservative (assuming that the exposure and toxicity benchmarks are appropriate and appropriately consider the potential for child sensitivity), since the AD1 assumes lifetime exposure, rather than exposure for 2 years." Response: Additional explanation was added to the revised risk assessment. MinorLEditorial Comments Comment: "Page 3, the 3rd line from the bottom: A statistical P value of 0.05 is usually used as the criterion injudging whether a observed response is significantly different from the control. The P value for the hepatocellular carcinoma at high dose is less than 0.03 (less than 0.05) as shown in the Table 1 in the summary document. 

### It is not clear why it is still considered: 

### '.



### .

## .non-significantly elevated..


## .' 

### "Response: This was a typographical error. The text should have said that the response in females, not males, was non-significantly elevated. Theresponse inthe males was indeed statistically significant. Thetext has been revised.

. .

Comment:

. ' "Page 3, the last line: should 

### '



### . . . significantly elevated at the high dose in males and the midand high dose in females' be 

### '.



## . . significantly elevated atthe high dose in males and the midand high doses in females?' 

### " Response: The change has been made. Comment: "P. 1

### 1 (line just before equation lo): Schwopeet al. (1999) should be Schwopeet al. (1989). P. 11 (2nd linejust after equation 13): It appears that the units for 

### Mp should be mg, not ug. This both keeps the units consistent for equation 13, and appearsto be the units used in the spreadsheets." Response: The changes were made. Comment: "The EPA cancer guidelines are now final (as of 2005). The correct citation is: U.S. EPA (Environmental Protection Agency). (2005) Guidelines for carcinogen risk assessment. Risk Assessment Forum, Washington, DC; EPA1630P-03/001B. Available from: <http://www.epa.gov/iris/backgr-d. htm>. U.S. EPA (Environmental Protection Agency). (2005) Supplemental guidance for assessing susceptibility from early-life exposureto carcinogens.Risk Assessment Forum, Washington, DC; EPAl63OiR-031003F.Available from: 

### <http://www.epa.gov/iris/backgr-d.htm>." Response: The referencehas.beenupdated.Reference Listed by the Reviewers Nobel Functional Chemicals LLC, 200 1. High Production Volume (HPV) Challenge Program. Test plan for FYROL FR-2 

### (Tris[l,3-dichloro-2-propyl] Phosphate. References Cited by the CPSC Staff Babich MA (1998) Risk assessment of low-level chemical exposures fiom consumerproducts under the U.S. Consumer Product Safety Commission chronic hazard guidelines. Environmental Health Perspectives, 106, Supplement 1:387-390. Babich MA (2006) CPSC StaffPreliminary Risk Assessment of Flame Retardant (FR) Chemicalsin Upholstered Furniture Foam. U.S. ConsumerProduct Safety Commission, Bethesda, MD 20814. September2006. Revised draft. Babich MA, Thomas TA, Ha-tlelid

### K (2006) CPSC Staff Preliminary Risk Assessment ofFlame Retardant (FR) Chemicals in Upholstered Furniture Foam. U.S. Consumer Product Safety Commission, Bethesda, MD 20814. January 2006. Peer review draft. Cobb D, Bhooshan B (2005) Migration offlame retardant chemicals in upholstered furniture foam. U.S. ConsumerProduct Safety Commission, Bethesda, MD 208 14. December 10,2005. Consumer Product Safety Commission (CPSC) (1992) Labeling requirements for art materials presenting chronic hazards; guidelines for determining chronic toxicity ofproducts subject to the FHSA; supplementary definition of "toxic"under the Federal Hazardous SubstancesAct; final rules. Federal Register 57:46626-46674. Hughes MF, Edwards BC, Mitchell CT, Bhooshan

### B (2001) In vitro dermal absorption of flame retardant chemicals. Food and Chemical Toxicology 39: 1263: 1270. Kiss C (2002) A Mouthing Observation Study of Children Under 6 Years. U.S. Consumer Product Safety Commission, Bethesda,MD 20814. June 2002. National Research Council (NRC) (2000)ToxicologicalRisks of SelectedFlame-Retardant Chemicals. Subcommittee on Flame Retardant Chemicals, National Research Council,National Academy of Sciences. National Academy Press, Washington,DC. Rhomberg LR (1997) A survey of methods for chemical health risk assessment among federal regulatory agencies. Presidential/CongressionalCommission on Risk Assessment and Risk Management. Washington, DC. Smith 

### TP, Kiss CT (1998) Empirical observations of children's mouthing behaviors: Frequencies and durations. U.S. Consumer Product Safety Commission, Bethesda,MD 20814. Submittedfor publication.Memorandum

Date: December 21,2006 TO : Dale Ray, Project Managerfor Upholstered Furniture, Directoratefor Economic Analysis 

# vr THROUGH: ary Ann Danello, Ph.D., Associate Executive Directorfor Health Sciences eri E. Saltzman. M.S.. Director. Divisionof Health Sciences 

## Lr/ FROM 

# ld' ichael A. Babich, Ph.D., Chemist, Division ofHealth Sciences 

# :v SUBJECT : Response to Public Comments on the CPSC Staff PreliminaryRisk Assessment of Flame Retardant (FR) Chemicalsin upholstered Furniture ~oam*

. . The CPSC staffcompleted a draftrisk assessment on the use of flame retardant (FR) chemicals in upholstered furniture foam in January 2006 (Babich et al. 2006). The risk assessment was part ofthe January 2006 Briefing Package on Upholstered Furniture. SuprestaLLC, a manufacturer ofFR chemicals, submitted technical comments on the risk assessment. No other public comments were received. The staffhas made appropriate revisionsto the risk assessment (Babich 2006),based on commentsfrompeer reviewers and Supresta LLC. Below are the staffsresponses to the public comments submittedby Supresta LLC. Many of the comments submittedby SuprestaLLC involved the factors used to estimate exposure, such as the surface area exposed and the fabricto skin transfer factor. The CPSC staff made several of the suggested changes,which reduced the estimated dermal exposure somewhat. Supresta also commented on the staffsmethods for assessing the dose response of TDCP, and suggested changes that would significantly reduce TDCP's cancerpotency. The staffdisagreed with these comments and did not make the suggested changes. As a result of the changes made in response to the public and peer review comments, the relative contribution of inhalationto total exposure increased. However, the overall conclusionsof the risk assessment did not change.

* These comments arethose ofthe CPSC staff, have not been reviewed or approved by, and may not necessarily

reflect the views of, the Commission. Comments, including tables, references, and appendices, are reported verbatim.

CPSC Hotline: 1-800-638-CPSC (2772) CPSC'sWeb Site:http:llwww.cpsc.govComment: "The draft CPSC report compares the health risks associated with two commercial flame retardant products, tris(l,3-dichloro-2-propyl)phosphate (TDCP) and FiremasterTM 550 (FM-550) which consists of a mixture oftriphenyl phosphate (TPP), isopropylatedtriaryl phosphate (ITP), and a proprietarybrominated aryl phosphate ester (BAEs)." * Response: The CPSC staff risk assessment consideredflame retardant (FR) chemicals present in foam samplesthat were availableto the staff. This work was not performed solely as a comparison of two products. Comment: "On page 3 of the draft report, the first paragraph under Hazard Identification states "TDCP is acutelytoxic by oral administration." This implies that TDCP's oral LD50 is significantly differentfrom that of ITP, melamine, and other flameretardants. The oral LD50 for almost all of the phosphate ester flame retardants is above 2000 mgkg, indicating low acute oral toxicity. In a 1999CPSC review of TDCP, Ferrante listed rat acute oral LD50 values of 2.83 gkg(Celanese study), 3.6 gkg(Stauffer study) and 2.36 gkg (CPSC study) (1). An acute oral LD50 test conducted in 1985in full GLP complianceprovides a TDCP oral LD50 of 2.36 g/kg (2). I thus suggest CPSC change the "acutely toxic" language for TDCP." Response: As statedby the comrnenter, TDCP has an oral LDso less than 5,000 mgkg. Therefore, it is "toxic," as defined by Federal Hazardous Substances Act (FHSA) regulations. 

### 16CFR 1500.3 (c)(l). Comment: "Also in that paragraph, fatty degenerationwas described as the only histological lesion in an acute study. Diagnostic pathology is not usually performed in acute tests. I suggest this statement be removed, asthe study described by Ferrante is not an acute toxicity test, but rather a repeated dose toxicity test, a copy ofwhich is unattainable for confirmation of the findings." Response: The wording has been changed in the revised risk assessment.

* Some ofthe abbreviations were changed to reflect new information that identifies certain chemicalsmore specifically. BAE (brominated aryl ester) was changed to OTB (octyl tetrabromobenzoate) and ITP (isopropylated triphenylphosphate) was changedto PIP (phenol isopropylated phosphate).Comment: "On page 3, TDCP is alleged to have reproductive toxicity and is "considered probably toxic to humans" based solely on changes observed in the testes of aging rats in a chronic cancer bioassay. I believe the available data do not support classificationas a possible reproductive toxin. In a GLP-compliant fertility study, male rabbitsreceived daily doses ofup to 200 mglkglday for 12weeks prior to mating (3,4)." Response: TheAD1 was based on histopathological effects in the testes, not reproductive function. This is better described as general organtoxicity, rather than reproductive toxicity. This is the same endpointused by theNRC subcommittee(NRC 2000). The testicular effects were seen in a chronic study in rats, while the reproductive study was of short duration and in a different species. The revised risk assessmentexplainsthis point more clearly. Comment: "It is known that various changes inthetestes of aging rats occur spontaneouslyand this is confirmed by the 12month pathologyresults from the chronicrat bioassay. Rather,TDCP exacerbated the various changesGthatnormally occur in the testes of aging male rats during their second year. Since significanttreatment-related changes did not occur in the testes during the first full year of treatment, TDCP should not be considered a reproductive toxin. Rather, I suggestthe CPSC utilize the carefullyconductedrabbit reproduction study and the pathology report for the 12 month sacrifice in the chronic study as a basis for concludingthat TDCP is not a reproductive toxin." Response: While these effects did not appear until late in the chronic study,they are still a chronic, degenerative lesion. While these may occur spontaneously, the increased incidence was treatment-related and statistically significant. Therefore,we regarded this as evidence of chronic organ toxicity. Comment: "Further, it is clear that the CPSC applied the uncertainty factorspublished in the NRC 2000 report without due consideration ofthe science. Since the changes that occurredin the seminal vesicles in the aging male rats do not represent treatment-related testicular toxicity,because they occurred with similar incidence in the control animals, the 5 mglkglday dose is, in fact, an NOAEL. Thus, the uncertainty factor of 10 for extrapolatingfrom an LOAEL to anNOAEL shouldbe deleted, as should the factor of 3 for a limited database. This would result in a significantly lower human health risk. Thehazard index (HI) would be 0.05 mglkg-d (uncertaintyfactorsUFA=10 for extrapolation from rats to humans; 

### UFH=3 intraspecies variability; 

### UFD=3 for adequacy oftoxicity database)."Response: The staffdid not apply the same safety factors as the NRC subcommittee. While we regard the NRC report as authoritative and representingthe best available science, we evaluated the data and derived the AD1 in accordance with the CPSC chronic hazard guidelines (CPSC 1992). This point is discussed in the revised risk assessment. We disagree with the reviewer's conclusion that the increase in incidence was not statistically significant. Our own statisticaltests (onetailed Fisher's exact test) show that these effects are statistically significant (Babich 2006, Table 3). Comment: 

### TDCP 

### -Genotoxicity/Carcinogenicity "In the cancer bioassay, TDCP appears to exacerbate the incidence of benign tumors that normally occur in older rats. There was no significant increase in malignant tumors in any organ in the two-year cancer bioassay. The presence of a non-DNA-reactive, epigeneticmechanism for the induction ofthe benign tumors is supportedby the results of the many genotoxicitytests which, on a weight of evidence basis, confirm that TDCP does not express genotoxicity. While certain Ames Tests showed positive responses,the majority of the microbial mutagenicity tests were negative. TDCP was without genotoxicactivity in almost all of the in vitro tests using mammalian cells as test systems. More important, TDCP was consistently without genotoxic activity in the several in vivo mutagenicitytests conducted. Ferrante lists the earlier negative in vivo tests. More recently, a GLP-compliantMouse Micronucleus Test, conducted twice per OECD Guideline, was negative (5), as was a recently completed in vivo UDS Test, also conducted twice per OECD Guideline, which showed no evidence of UDS 

### (6). While in vitro tests provide a quick, predictive evaluation of mutagenicpotential,the more comprehensivein vivo testsprovide conclusive indication as to.whether a substance has genotoxic activity in the living animal. TDCP was negative in all ofthe in vivo tests in which it was evaluated. 

### I therefore suggest that the first paragraph on page 4 be revised to reflect the results ofthe recently conducted mutagenicity tests, and thus indicate that the weight of evidence strongly indicates that TDCP does not have genotoxic activity in the living animal. In that same paragraph, the statementthat TDCP is a probable human carcinogen shouldbe deleted, based on a lack of genotoxicity in vivo and a lack of a significantincidence ofmalignant tumors in any tissue. The exacerbation in the incidenceof normally occurring benign tumors late in life should not be interpreted as carcinogenic activity. There is insufficient evidence to conclude that TDCP is a probable human carcinogen. " Response: The staff agrees that TDCP is only weakly genotoxic. However, this does not alter our conclusionthat TDCP is a probable human carcinogen, as defined in the CPSC chronic hazard guidelines (CPSC 1992). Increased incidence or decreased time to occurrence of spontaneously occurring tumors is generallyregarded as evidence of a carcinogenic effect (CPSC 1992).Comment: "Under Section 2, Dose Response Assessment,the LOAEL for non-cancer effects should be changed to NOAEL per the previous discussion on changes seen in the control animals at the twelve month interim sacrifice. This would eliminatethe uncertainty factor of 10 applied for the extrapolation from an LOAEL to anNOAEL. The 

### RfD would changeto 0.05 mgtkglday." Response: The CPSC staff disagrees with this comment. The lack of changes at 12months is not relevant to the LOAEL or NOAEL in a chronic study. Comment: "Examining further the risk calculations,we find that the CPSC calculated the cancer unit risks for adults and children using the linearized multistage model, which assumes a non-threshold genotoxicmechanism. This is consistent with theNRC 2000 report. However, now that new in vivo genotoxicity tests are available which show a lack of genotoxic activity, the determination ofthe 

### RfD for non-genotoxic cancer effects should use the same calculationsused for systemic toxicity. The cancerrisk assessmentdevelopedby the CPSC without the benefit ofthe new genotoxicitytests should be deleted from the CPSC report. Based on theNOAEL of 5 mglkg for carcinogenicity,the RfD would be 0.05 mgikglday." Response: The lack of genotoxicty does not change the method for estimating cancer risk. Cancer risk is assumed to be linear at low dose unless there is convincing evidenceto the contrary (CPSC 1992),such.asan understanding of the mode of action (MOA). "Non-genotoxic" is not an MOA. It only means that the MOA does not involve directmutations. Furthermore,TDCP is weakly genotoxic. It is not completely lacking in genotoxic effects. Therefore, as discussed in the revised risk assessment, a possible role for genotoxicity in tumorigenesis cannot be ruled out. Comment: TDCP -Dermal Exposure 

### "I believe the CPSC basis for determiningdermal exposure is overly conservative and uses unrealistic assumptions that result in highly exaggerated exposure and absorption determinations. For example, when estimating dermal exposureof consumersto TDCP from upholstered foam, the CPSC assumedthat the consumeris lying on a sofa and wearing a short-sleeved shirt and short pants. The exposed body surfacewas calculatedby adding the surface areas for the lower leg and arms, then dividingby two. This assumesthat half ofthe uncovered body parts is in contact with the sofa. This is anunrealistic overestimation. For essentially circular structures (arms and legs), a more realistic and reasonable estimatewould be 20-25% ofthe total surface are is in contact with the sofa. Even 25% is an exaggeration in that people do not lie stiff, withelbows and knees locked to provide the proposed contact area. Utilizingthe worst case value of 25% ofthe surface area would result in a 50%reduction in the estimated dermal absorption." Response:


## . The assumptionsregardingthe manner in which consumers interact with upholstered furniture were developedby staff from the CPSC Division ofHuman Factors. They are intended to be reasonably protective of public health. We agree that the assumption that 50% of the exposed skin contacts the furniture surface isprobably an overestimate, due to the 3-dimensional nature (roughly cylindrical) ofthe legs and arms. However, it is difficult to characterize the contact surface more precisely, especially for a malleable surface such as upholstered furniture. In addition,the softness of upholstered furnitureis variable. We chose 50% as a reasonable upper bound. The best estimate is probablybetween 25% and 50%. In the revised risk assessment, we assumed 33% as a best estimate. Comment: "The CPSC discusses exposure by children separately on page 14, using an estimationmethod developed by EPA many years ago. The body surface areas for children under the age of 2 years were estimatedfrom the median surfacearea-to-body weight ratio (age 0-2 years: 0.062 [EPA 1997,Table 6-91). As is apparent from the table, this ratio is highly dependent on age. For example, for children aged 2.1 years the median ratio is 0.042. It is therefore assumed that for children withthe selected body weight of 11kg, using a ratio of 0.062 leads to overestimation of skin surface. 

### In orderto refine the estimatedbody surface area for the selectedbody weight, it has been suggested that the more refined formula for surface area in relation to length and weight be used (Gehan and George 1970 [in:EPA 1997,ExposureFactors Handbook, Appendix 6A]) instead. This highly regarded formula, SA = 0.02350 x Ho 42246 Wo 51456 (SA in m2, H in cms, W in kg), provides a more accurate estimation ofdermal exposure, and is applicable for adults and for children under the age of 5 years (n=229). The estimated body surface for children of the aselected weight category (1 1 kg, equivalentto an age of approximately 12 months and length of 78 cm) is 0.5 m2. Using this more accurateformula would lead to a reduction ofthe estimated dermal exposure of children by about 25%." Response: The staff generally selected the methods and data recommended in the EPA ExposureFactors Handbook (EPA 1997). However, we agree that the approach suggestedby the comrnenterhas merit. Therefore, we adopted the approach suggestedby the cornmenter with minor changes. We substitutedparameters that were specific for the age range of interest (0-2 years). We also used the most recent available body weight and length data for infants from the CDC (CDC 2000). Thus, we assumed an average body weight of 10kg (rather than 11kg) and a length of 75 cm (ratherthan 78 cm). Using this method, the total surface area of 1 -year-oldswas estimatedto be 0.48 m2.Comment: "In the CPSC surface migration experiments,Cobb and Bhooshan used miniature furniture mock-ups, 9" x 9" consisting of plywood and foam with a cotton overlay. They applied 25 mL of saline solution directlyto the mockup to simulate 8 hours of sweat. The CPSC states that using this wet mock-up and 8 hours of sweat will lead to an overestimationof exposure (page 19, because they really believe daily contacttime to be 4 hours. While this, alone, is problematic, there are additional deficienciesin the experimental design. The surfacearea ofthe circular filter paper in contact with the mockup measured 23.76 cm2(diameter 5.5 cm). This means the moistened mockup (surface area: 523 cm2) is only partially covered, in contrast to the situation that the test aims to mimic, a person lying on a sofa. Further, there appears to be a calculation error in the draft report. The results from the surface migration experiments(Table 2 

### in Cobb and Bhooshan 2005) are expressed as pg of flame retardant chemical. Apparentlythe 8- day average from foams S and 

### Y (3.63 pg) was transferred to the CPSC risk assessmentreport as mg/cm2 (Table 3). 

### I believe the 0.0036 mg extracted shouldbe converted to mg/cm2. This results in a migration to liquid phase 

### (M) value of 0.00015 mg/cm2instead of the 0.0036 shown in Table 3 for TDCP. This would result in a substantially lower ADD and an HI of below 1.0." Response: The migration data were'theonly data available. Both the estimate of the amount of liquid and 'thecontacttime are average values with considerable variability. We agree that the saline solution was not evenly distributed across the surface of the mock-up. Rather, it was applied to a point onthe surfaceofthe mock-up and allowed to distributeby capillary action and hydrostatics. We do not agree, however, that this is inconsistentwith consumer exposure. A consumer sitting on a sofa is not exposedto the entire surface. What appearsto be a calculation error is actually a typographic error in the table. This has been correctedinthe revised risk assessment. Comment: "Furthermore, for estimating the transfer from fabric to skin,the CPSC selectively uses the availableinformation from Wester et al. 1996 and ignoresthe data for a second substance, glyphosate, for which transfer factors from fabricto skin were determined.Unlike malathion which was dissolved in 50% ethanol, glyphosate was dissolved in water, which more closely resembles sweat. The percutaneous absorptionfor glyphosate was 1.42%,for immediate exposure to treated fabric 0.74%, declining to 0.08% after one or two days of drying. Remoistening with water resulted in a percutaneous absorption of 0.36%. These figuresleadto transfer efficienciesof 0.52 for direct exposure to treated fabric and 0.25 forremoistened fabric. In view ofthe more relevant solvent, this part ofthe Wester et a1 study is more applicable for transfer fromupholstered furniture to skin. Even the 0.25 transfer efficiency ratio for glyphosate from the Wester et a1 study shouldbe considered an exaggeration, as confirmedby a studyby Snodgrass (7). He showed that the transfer efficiency ofpermethrin from impregnated clothing to skin was only 0.005 and was independentof the presence of sweat or the type ofclothing. I therefore believe that a worst case transfer efficiency of 0.25 be used by the CPSC which would result in a 37.5% reduction of the estimated dermal exposure." Response: As explainedinthe draft risk assessment,we selected malathion as a surrogate for FR chemicals because it is more hydrophobic than glyphosate, which is water soluble. The FR chemicals under consideration are hydrophobic. In consideringthis comment, we were prompted to search for additional studies on this subject. In addition to the data by Snodgrass,we identified otherpotential sources of data on the transfer ofchemicals from textiles to skin. The data include hydrophobic and water-soluble chemicals and particles. These properties appear to have no effect on surface-to-skintransfer. Considering all ofthe data, we derived a new estimate ofthe transfer factor, as well as its upper and lower bounds (Babich 2006, Table 7). This change resulted in a 3-fold lower estimate of surface-toskin transfer. Comment: "The bioavailabilityof TDCP as a result of dermal absorption is calculated by the CPSC based on the in vitro studies conducted with hairless mouse skin (Hughes 2000; Hughes et al. 2001). The skin of hairless mice is very different fromhuman skin and Hughes et a1 used acetone as a vehicle for the study. Acetone is known to substantially enhance the transfer of substances throughthe skin. Thus the use of the Hughes studies for determining bioavailability is inappropriate. Rather, the CPSC should use the results from an industry sponsoredin vitro dermal absorption study using human skin and the structurally similar substanceTCPP, dissolved in artificial sweat (8,9). We recognize that the results ofthis very recent study were not availableto the CPSC when the draft report was written. This study was conducted in accordancewith the 2004 OECD guidance document for conducting skin absorption studies (10). Accuratemeasurements were made using "c-TCPP. The 24-hour absorption after 8 hours contact time was 40 percent, a level that was relatively independent ofthe concentration. This is equivalentto a dermal absorption rate of 0.05 h-'. The study final report will be made available to the CPSC for consideration of extrapolationto TDCP. This would provide real data using human skin for a substance that has a very similar chemical structure. Using the more accurate dermal absorption rate of 0.05 h" will result in a 37.5percent reduction of the internal exposure estimate." Response: Dr. Robert Bronaugh, Food and Drug Administration, is a recognized expert in the measurement ofpercutaneous absorption using in 

### vitro methods. Dr. Bronaugh advised us in designing the in 

### vitro studiesperformed by Hughes et al. (2001). The skin from hairless mice was chosen for the in 

### vitropercutaneous absorption experiments because it is considered a reasonable surrogatefor human skin (Bronaugh et al. 2005). Acetone was used to dissolveTDCP for skin application; then it was allowed to evaporateprior to conductingthe experiment. This is a standard methodfor the study of extremely hydrophobic compounds. Acetone did not remain on the skin and, therefore, is not likely to affect the permeability ofthe skin. The study submitted by the cornrnenter was on the percutaneous absorption of an analog of TDCP, tris(chloropropy1)phosphate (TCPP),using human skin in vitro. The comrnenter cited the results from experiments in which TCPP was present in limiting concentrations. Thus, the absorption rate declined over time, probably following first-orderkinetics, as the TCPP on the skin surface was depleted (Bronaugh et al. 2005). The comrnenters erroneouslyconcluded that TCPP was absorbed at a lower rate throughhuman skinthan TDCP was absorbedthrough mouse skin. Other experimentsin the same report applied a largertotal volume of TCPP to the skin. In these experiments, the TCPP was not depleted and the absorption rate remained constant throughout the course of the experiment. In these experiments, TCPP was absorbed at roughly the same rate as TDCP. Comment: TDCP -New Input Parameters. New Exposure Values and Risk Assessments "The attachedAppendices 1,2, and 3 contain the CPSC Tables 2,3, and 

### 4 with corrected fabric to skintransfer, surface area of exposed skin,migration to liquid phase, measured vapor pressure 

### (1I), dermal absorption, and acceptable daily intake (ADI) values which have been used to calculatenew, more accurate acceptable daily dose (ADD)values and a new hazard Index (HI). Using the new values in Tables 

### 2 and 3, the HI is determined to be 0.01 for adults and 0.02 for children. Certainly the documentationprovided in this letter and the articles referenced in the table footnotes support the accuracy of these new values." Response: The staffconsidered each parameter and made changes in the revised risk assessment as appropriate. We reevaluated the fabric-to-skintransfer factor, total skin surface area of children, fraction of skin surface in contact with furniture, and TDCP vapor pressure. These changes are discussed above in more detail. The net effect ofthese changes reduced the estimated dermal and oral exposure, but increased inhalationexposure. However, the conclusionthat TDCP might present a hazard to consumers isunchanged. Comment: Melamine - Some Reasons for Concern "I believe melamine does meet the FHSA definition oftoxic, and thus shouldbe reviewed along with TDCP and FM-550. In 

### national Toxicology Program chronic cancer bioassay, melamine ' caused transitional cell carcinomasin the urinary bladders of male rats (12). Although bladder stoneswere found in most of the male rats that expressed bladder cancer, suggesting a correspondencebetween the presence of stones and bladder tumors, bladder stones were also observed in female rats and in both male and femalemice, which did not expressbladder tumors. TheNTP concludedthat melamine is carcinogenic in male rats. The InternationalAgency for

202Research on Cancer confirmed that melamine exposure resulted in bladder and urethral carcinomas in male rats and urinary bladder hyperplasia in male mice (13). They indicate that whilethe tumors "appear to be producedby a non-DNA-reactive mechanism involving epithelial hyperplasia," there was insufficient genotoxicity data availableto reach a firm conclusion."

, , Response: The bladder tumors induced by melamine are consideredto be induced by a mechanismthat is not relevant in humans. Therefore, the CPSC staff considers melamine as a possible carcinogen, due to limited evidence in animal studies. This does not satisfy the FHSA definition of "toxic." The discussiononthis point has been expanded in the revised risk assessment. Comment: "Teratogenic effects of melamine have been reported in toads, where it caused anomalies in the



## . mouth, gills, gonads, and renal tubules (14). In a non-guideline rodent developmental toxicity

study, melamine was injected intraperitoneally on two gestation days, with no gross malformations observed. During combustion, melamine decomposes with evolution of poisonous hydrogen cyanide (15). Will this not pose a potential health risk to humans? With the causation of cancer in a rodent bioassay, no reproductive toxicity tests available, and no in vivo mammalian mutagenicity tests, I believe melamine could be considered "toxic" and included in the CPSC review." Response: The developmental effects in toads are ofuncertain relevance to humans. Smoke toxicity is beyond the scope of this risk assessment.

. Comment:

. . FM-550 -New Toxicity Data "The report states that because there has been very little testing of two of the three components, ITP and the BAEs, the CPSC used surrogatedata to calculate a hazard index, "assuming that TPP and ITP are no more toxic than the other aromaticphosphates." I believe this is an erroneous asshptionfor ITP, based on toxicology test results recently made public. In a May 5, 2004 TSCA 8(e) substantial risk notificationto the U.S. EPA, the manufacturer of FM-550 reported that their commercial ITP caused significant reproductive toxicity inrats. Decreased fertility was observed at all doses, so anNOAEL was not identified. Further, it is not known whether the effect is in the males, females', or in both sexes. Reversibility of the effect was not shown. Litter size and pup survival were also affected. Since FM-550 consists of 24-5 1%ITP, there could be a significant human reproductive risk associated with exposureto foam containing this flame retardant. In a June 9,2004 TSCA 8(e) notification, the manufacturer reported significant adverse effects observed in an ITP developmental toxicity study, further justifying concern that both the human fetus and adult may be at risk. I urge the CPSC to carefullyconsiderthe results of these recently conducted studies and not rely on data from surrogate chemicals." Response:

. . The May 5,2004 notice (8e-HQ-0504-15566)provides minimal details. The actual report is not yet available. The same information was describedin arecent EPA report (EPA 2005) that we cited in the draft risk assessment. The June 9,2004 notice (8e-HQ-0604-15587)is for tricresyl phosphate, not ITP (PIP). These reports provide no new information and no changesin the risk assessment are needed. Comment: "Page 6 states that there is insufficient information to derive an AD1 for isopropylatedtriaryl phosphate. I believethe lowest dose fiom the recently conducted reproductive toxicity study, 25 mgkgtday, can be used as it caused significantreproductive toxicity in that GLP-compliant study. Now there is sufficient informationavailable for the CPSC to conclude that ITP is possibly toxic to humans. The statement onpage 7, that there is insufficient data for ITPto derive AD1 values, is also no longer accurate." Response:

, As the commenter states, the study is not currently available. We will review the new data when they become available. However, depending on the study design, a reproductive study alone is not necessarily sufficientto derive an ADI. Generally, a 90-day subchronic study with full pathology is needed to provide minimal information for an ADI. 

### . comment: "Page 7, Section C implies that since there is insufficienttoxicology information to determine whetherthe BAEs are toxic, they will be treated as non-toxic until shown to be toxic. How does this afford protection for workers and consumers who may be exposed to the BAEs? Shouldn't the OECD Base Set of tests be required of a substanceto which infants, children, and adults may have daily contact?" Response: i Under the FHSA, data showing a toxic effect, i.e., "causing substantial illness or injury," are needed to conclude that a substance is "toxic." 15 USC 1261 (f)(l)(A). In the absenceof data, CPSC cannot promulgate a mandatory regulation. The OECD set of tests are not required under the FHSA or the Toxic Substances Control Act (TSCA), which is administeredby EPA. Comment: "1 believe there are severalpublications that show brominated flame retardants express significant toxicity. For example,recent studies have shown that the polybrominated diphenylether flame retardants adversely affect the central nervous system. They disrupt behavior and impair learning and memory, especially after neonatal exposure (16, 17). The brominated phosphate esters cause genetic recombination in mammalian cells, which can result in various forms ofmutation (18). A recent publication by EPA scientists expresses concern over the use ofbrominated flame retardants after finding significant levels in human tissues and in the environment 

### (19). Recognizing that several brominated flame retardants have neurotoxic and mutagenic activity, how can the CPSC conclude they do not fit the definition oftoxic? If FM-550 is to be considered one of the major flameretardants approved for furniture, a responsible course of action would be to require the manufacturer to provide base settoxicity data on the BAEs, either via a SNUR or a consent agreement." Response: Brominated FR chemicals (BFR's) are a broad class of compounds with varying toxicological effects. The chemical structure ofthe BAEYs is not closely related to other BFR's for which data are available. FM-550TM was reviewed by EPA under its new chemicals program (EPA 2005). Thus, it has already gonethrough the same process that would be imposed by a significant new use rule (SNUR). Under the FHSA, CPSC does not have the authority to require additional toxicity tests. However, CPSC canrequest studies through the EPA Interagency Testing Committee (ITC) or the National Toxicology Program (NTP). The CPSC staff recently requested additional testing of selected FR chemicals, including triaryl phosphates, by NTP. Comment: "The statement onpage 20 "assuming that TPP and ITP are no more toxic than other aromatic phosphates.. 

## ." is no longer valid, due to the significant reproductive toxicity reported for ITP. Sincethere is no NOAEL in the ITP reproduction study, an additional factor should be included in the calculation of risk. The Discussion section begins by exclaiming that there is no toxicity data on FM-550, and insufficient information for ITP, TPP, and BAEs to calculate an AD1value. Yet the toxicity ofthe three components may be additive or synergistic. It therefore seems reasonableto include an additional 10-foldor 100-fold safety factor in the calculation ofrisk, rather than making the dangerous and unsupported assumption that the components of FM-550 are no more toxic than other aromatic phosphates."

We assumed that TPP and ITP were no more toxic than the other members of the class. This is only an assumption and must be supported by data. We have requested additional testing by NTP. We correctly reported that'there are limited data for OTB (BAE). Comment: "On page 26, the CPSC points out that the estimated upper bound for TPPIITP exposures would exceed the AD1value for the most toxic aromatic phosphate, then goes on to exonerate FM-550 by stating that doesn't matter because ofthe inclusion of "several assumptions that tend to overestimate exposure." Doesn't the exposure scenario used for TDCP also include manyconservative assumptions that overestimateexposure? Why is the lack of toxicity data for FM550 and its components and an inability to measure TPP and ITP not cause for concern?" Response: The lack of data in this risk assessment is a significantlimitation of the risk assessment, as discussed inthe report. The staff did not intend to imply that FM-550TM shouldbe "exonerated." Rather, we pointed out the limitations of the risk assessment. Comment: "I believe that a reexamination ofthe availablegenotoxicity data,the reproductivetoxicity study conductedin rabbits, the 12month chronicbioassay pathology results, the more accurate dermal absorption values, and the corrected CPSC calculations will result in a conclusion that furniturecontaining TDCP-treated foam will not present an appreciable health risk to consumers. For FM-550, the results ofthe reproductivetoxicity test should negate the conclusion at the top ofpage 27 that states "there is no evidencethat upholstered furniture containing foam treated with FM-550 would pose an appreciablehealth risk to consumers." Having no toxicity data should not make a product safer in a health risk assessment than one with considerable data, even if certain ofthe data indicate a degree oftoxicity associated with the product." Response: The CPSC staff evaluated these comments in detail and made appropriate changes to the revised risk assessment, as discussed in detail above. Briefly, we re-evaluated several exposureparameters including the fabric-to-skintransfer coefficient,the estimated total surface area of children, and the fraction of skin surface in contact with upholstered furniture. These revised parameters are close to the values recommendedby the cornrnenter, though not identical. These changes reduced the estimated dermal exposure

-. from TDCP.

, . We consideredthe in vitro percutaneous absorption study with a related FR chemical, tris(chloropropy1)phosphate (TCPP) submittedby the cornmenter. We disagree with the commenter's interpretation of this study, as well asthe commenter's interpretationofthe TDCP studythat we used (Hughes et al. 2001). We concludethat both studies were of high quality. The data suggestto us that the time course of absorption of TCPP is approximately the same as that ofTDCP. There is nojustification for using percutaneous absorption data for a surrogate chemical (TCPP)when data from a well-conducted study with the compound ofinterest (TDCP) are available. If we were to use the TCPP data, the results would not be affected significantly. The new genotoxicity data submittedby the commenter provide additional evidence that TDCP isprobably not genotoxic in animals. However, as explained above, this is not sufficient to changethe dose response model that we used to estimate cancer risk.We also reconsidered the availableinformation on the vapor pressure of TDCP. We chose to use an empirical value obtained in the CPSC Chemistry Laboratory using TDCP-treated foam. We consider that this is more relevant to the current risk assessment than empirical or calculated values for pure TDCP. This change has the effect of increasing the estimated inhalation exposure. However,we recognize that there is considerable uncertaintyin estimatinginhalation exposure and recommend obtaining additional data. We disagree with the conclusion of the commenterthat the 12-month interimpathology results shouldbe used to derive the ADI. We consider that the lifetime exposure study is more appropriate for assessing chronic toxicity. However,we clarifiedthat the non-cancerAD1 is based.onchronic organ toxicity, in which the testes were the most sensitive organ site. We do 

## not conclude that TDCP affects reproductive function. In additionto the public comments discussed here, we also received'comments from independent peer reviewers. As a result of all of the comments, the relative contributionsof oral &d dermal exposure have been reduced, while the relative contribution of inhalation exposure has increased. The conclusion that TDCP might present a hazard to consumers and,therefore, additional data are needed, has not changed. ; The reproductive study with FM-550TM describedby the commenter is not yet availableto us. Therefore, we cannot consider it in our evaluation ofFM-550TM. We must thoroughlyreview the study before we can draw any conclusions and evaluate whether it is appropriate for deriving an ADI. We agree with the commenter that the lack oftoxicity data for FM-550TM is not evidenceof its safety. We considered all ofthe available data on the FR chemicals of interest in assessingtheir potential risks, as described in the chronichazard guidelines (CPSC 1992). We concluded that basic toxicity and physico-chemical data are needed to assess the potential risks associatedwith the use ofFM-550TMin upholstered furniture.ReferencesListed by the Commenter 1. Ferrante,J. Toxicity Review ofTris(l,3-dichloropropyl-2)phosphate (Fyrol FR-2 or TDCP), U.S. CPSC, Bethesda, MD. 1999. 2. Safepharm Laboratories. Acute Oral Toxicity Test in Rats. 1985. 3. Stauffer Chemical Company. Fertility Study of Fyrol FR-2 in Male Rabbits. 1982. 4. Wilczynski, S., Kilinger, J., and Zwicker, G. Fyrol FR-2 Fertility Study in MaleRabbits. Toxicologist 3:22, 1983. 5. SafepharmLaboratories. OECD 474 Micronucleus Study in the Mouse. 1985. 6. Covance Laboratories. OECD 486 In Vivo/In VitroWnscheduled DNA Synthesisin Rat Primary Hepatocyte Cultures at Two TimePoints. 2005 7. Snodgrass, H.L. Permethrin Transfer from Treated Clothto the Skin Surface: Potential for Exposure in Humans. 

### J. Toxicol.Environ. Health 35:91-105, 1992. 8. Maas, W.J.M. Release test for tris(2-chloro-1-methylethy1)-phosphate (TCPP) from a flexible foam 

## - pilot study.TNO Quality of Life report V6578/01, 9 December 2005. 9. Maas, W.J.M. 

### In vitro percutaneous absorption of [14~]tris(2-chloro- 1

-methylethyl)- phosphate (TCPP) through human skin membranes using flow-through diffusion cells.TNO Quality of Life report V6578/02, 8 December 2005. 10.OECD Guidance Document for the Conduct of Skin Absorption Studies. OECD EnvironmentalHealth and SafetyPublications. No. 28, March 5,2004. 11. Tremain S.P. TDCP: determinationof vapour pressure. Safepharm Laboratoriesproject 1613/003,7 March 2002. 12.National Institutes of Health, National Toxicology Program Technical Report No. 245, 1983. 13. IARC Monograph No. 73. The Evaluation ofthe Carcinogenic Risk of Chemicalsto Humans, 1999. 14.Rengel, 

### D. and Pisano, A. TeratogenicEffects and Cannibalism Caused by Melamineon Bufo arenarum Larvae. Jnl Lab. Invest. Embryiologicas 126:4-9, 1994. 15. Morikawa,T. The Evolution ofHydrogen Cyanide During Combustion and Pyrolysis of Melamine. J. Combust. Toxicol. 5:3 15-319, 1978. 16.Viberg, H. et al. Neonatal Exposure to Polybrominated Diphenyl Ether Disrupts SpontaneousBehavior, Impairs Learning and Memory, and Decreases Hippocampal CholinergicReceptors in Adult Mice. Toxicol. Appl. Pharmacol. 192:95-106,2003 17.Branchi, 

### I., Capone, 

### F., Alleva, E. and Costa, L. Polybrominated Diphenyl Ethers: Neurobehavioral Effects FollowingDevelopmental Exposure. Neurotoxicol. 24:449-462, 2003 18. Helleday, T., et al. BrominatedFlame Retardants Induce Intragenic Recombination in Mammalian Cells. Mutat. Res. 439:137- 147, 1999. 19. Birnbaum, L. and Staskal, D. Brominated Flame Retardants: Cause for Concern? Environ. Health Perspect. 112:9-14,2003.References, Cited by the CPSC Staff Babich MA, Thomas TA, Hatlelid K (2006) CPSC Staff Preliminary Risk Assessment ofFlame Retardant (FR) Chemicals in Upholstered Furniture Foam. U.S. Consumer Product Safety Commission, Bethesda, MD 208 14. January 2006. Peer review draft. Babich MA (2006) CPSC Staff PreliminaryRisk Assessment ofFlame Retardant (FR) Chemicalsin Upholstered Furniture Foam. U.S. Consumer Product Safety Commission, Bethesda, MD 20814. September 2006. Revised draft. Bronaugh RL, Kraeling MEK, Yourick JJ (2005)~eterrnination of percutaneous absorption by in vitro techniques. In, "Percutaneous Absorption,"4" Edition, Bronaugh RL, Maibach 

### HI, editors. Taylor and

## ran cis Group, New York. Chapter 18. Pages 265-269. Centers for Disease Control (CDC) CDC Growth Charts: United States. National Center for Health Statistics, Centers for Disease control and Prevention, Hyattsville, 

### MD. December 4, 2000. Consumer Product Safety Commission (CPSC) (1992) Labeling requirements for art materials presenting chronic hazards; guidelines for determining chronic toxicity of products subjectto the FHSA; supplementary definition of "toxic" under the Federal Hazardous SubstancesAct; final rules. Federal Register 57:46626-46674. Environmental Protection Agency (EPA) (1997) Exposure Factors Handbook. Office of Research and Development, U.S. Environmental Protection Agency, Office of Toxic Substances, Washington, D.C 20460. August 1997. EPA 600P-951002F. Environmental Protection Agency (EPA) (2005) "Furniture Flame Retardancy Partnership: Environmental Profiles of Chemical Flame-Retardant Alternatives for Low-Density PolyurethaneFoam." Design for the Environment Program, U.S. Environmental Protection Agency, Washington,D.C. September 2005. National Research Council (NRC) (2000)Toxicological Risks of Selected Flame-Retardant Chemicals. Subcommittee on Flame Retardant Chemicals, National Research Council,National Academy of Sciences. National Academy Press, Washington, D.C.Appendices Attached to the Comments



## Appendix 1':

Table 

### 2. General In~ut Parameters


## I Dermal 

## 1

Parameter

Fabric to skin transfer, F 

# 1 0.25 

# 1 0.005 

# 1 0.52 

# 1 Wester et al. 1996; Snodgrass 1992; see text Best Estimate 

# / Surface area ofexposed skin, S, cm2

### ' 

# I I I I 1,250 

# 1 500 

# 1 4,500 

# 1 EPA 1997; Smith 2000 

## 1 - Children esf

## 1 275 

## 1 150 

## 1 1250 

## 1 EPA 1997; Smith 2000 

## 1 Lower Bound

Wester et al. 1996, transfer based on experimentswith glyphosatein water 25% oftotal surface ofrelevantbody parts is in contactwith upholsteredhiture

. 'using body surfaceof 0.5 m2for children weighing 11kg (aged 12months; length 78 cm)

* The citations in this table refer to the CPSC risk assessment [Note added by the CPSC staff]. Upper Bound ReferenceAppendices Attached to the Comments

Table3. Chemical-SpecificInput Parameters

corrected for contact surface area in Cobb and Bhooshan 2005 study

, hTremain2002 

### 'Calculated from vaporpressure and molecular mass 

## 'Based on in vitro dermal absorption study with TCPP and human skin

NOAEL for systemictoxicity is 5 mglkg-d 

## 'Threshold model because ofnon-genotoxicmechanism oftumor formation (NOAEL is 5 mgtkg-d) Parameter Symbol
Vapor pressure 

# , Saturation concentration in air

Dermal absorption rate Acceptable daily intake Cancer

### RfD Units

VP
Gat 

### KT AD1 RfD TDCP

ton mg/d

hmgfl<g-d mgkg-d TPPATP BAE

4.2 x lo-'

0.001 

### ' 0.05' 0.05 0.05

# ' 6.3 x 0.1 1 0.1 0.01

## - 1.0 <1 x 

### lo-6 0.015 0.01 NDAppendices Attached to the Comments .



## Appendix 3

Table 4. Exposure and Risk



### "AD1 for systemic effectsproposed change f?om 0.005 to 0.05 mglkg-d Parameter

ADD (mgkg-d) Percent of total: Dermal Oral, indirect Oral, direct Inhalation, vapor Inhalation, particles HI 

### " LADD (mglkg-d) 

### BAE TDCP Adults 1.8x10J

8 0 14 0 6 0 ND 1.8~10" TPPATP Adults 2.4x10-~

56 40 0 3 0 0.005 2.4x10-~ Children 3.2~10'~

65 23 3 9 0 ND 8.6x10-~ Adults 2.7~10"

53 9 0 38 0 0.003 

### - 0.3 2.7x10-~ Children 5.0x10-~

29 56 11 5 0 0.010 1.3x10-~ Children 5.8~10~~

3 6 13 2 50 0 0.006 - 0.6

1.6~10'